MCH receptor antagonists

This application is a 371 of PCT/US02/31059 Sep. 30, 2002, which claims priority to United States Provisional Application 60/326463, filed Oct. 1, 2001 and to United States Provisional Application 60/326758, filed Oct. 2, 2001.

The present invention relates to compounds which act as antagonists for MCH receptors and to the use of these compounds in pharmaceutical compositions.

Melanin Concentrating Hormone (MCH), a cyclic peptide, has been identified as the endogenous ligand of the orphan G-protein coupled receptor SLC-1. 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 alter a number of behavioral responses such as feeding habits. For example, injection of MCH into rats has been reported to increase their consumption of food. Reports indicate that genetically engineered mice which lack MCH show lower body weight and increased metabolism. See Saito et al., TEM, vol. 11, 299 (2000). As such, the literature suggests that discovery of MCH antagonists that interact with SCL-1 expressing cells will be useful in developing obesity treatments. See Shimomura et al., Biochem. Biophys. Res. Commun. 261, 622-26 (1999).

G protein-coupled receptors (GPCRs) share a common structural motif. All these receptors have seven sequences of between 22 to 24 hydrophobic amino acids that form seven alpha helices, each of which spans the membrane. The fourth and fifth transmembrane helices are joined on the extracellular side of the membrane by a strand of amino acids that forms a relatively large loop. Another larger loop, composed primarily of hydrophilic amino acids, joins transmembrane helices five and six on the intracellular side of the membrane. The carboxy terminus of the receptor lies intracellularly, and the amino terminus lies in the extracellular space. It is thought that the loop joining helices five and six, as well as the carboxy terminus, 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 link to the intracellular transduction pathway to produce a biological response. Changing the receptor conformation to the active state allows linkage to the transduction pathway and produces a biological response.

A receptor may be stabilized in an active state by an endogenous ligand or an exogenous agonist ligand. Recent discoveries, including but not exclusively limited to, modifications to the amino acid sequence of the receptor, provide alternative mechanisms other than ligands to stabilize the active state conformation. These approaches effectively stabilize the receptor in an active state by simulating the effect of a ligand binding to the receptor. Stabilization by such ligand-independent approaches is termed “constitutive receptor activation.” 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 therefore inhibit the intracellular responses by agonists.

Certain 2-aminoquinazoline derivatives have been reported to be NPY antagonists which are said to be effective in the treatment of disorders and diseases associated with the NPY receptor subtype Y5. See WO 97/20823. Quinazoline derivatives have also been found to be useful by enhancing antitumor activity. See WO 92/07844.

Recently, our current knowledge of human obesity has advanced dramatically. Previously, obesity was viewed as an oppugnant behavior of inappropriate eating in the setting of appealing foods. Studies of animal models of obesity, biochemical alterations in both humans and animals, and the complex interactions of psychosocial and cultural factors that create receptiveness to human obesity indicate that this disease in humans is multifaceted and deeply entrenched in biologic systems. Thus, it is almost certain that obesity has multiple causes and that there are different types of obesity. Not only does MCHR1 antagonist have potent and durable anti-obesity effects in rodents, it has surprising antidepressant and anxiolytic properties as well (Borowsky et al., Nature Medicine, 8, 825-830, 2002). MCHR1 antagonists have been reported to show antidepressant and anxiolytic activities in rodent models such as social interaction, forced swimming test and ultrasonic vocalization. These findings indicate that MCHR1 antagonists could be useful for treatment of obesity patients with multiple causes. Moreover, MCHR1 antagonists could be used to treat subjects not only with obesity, but also those with depression and anxiety. These advantages make it different from NPY receptor antagonists, with which anxiogenic-like activity may be expected, as NPY itself has anxiolytic-like effect.

Obesity is also regarded as a chronic disease and the possibly of long-term treatment is a concept that is receiving more attention. In this context, it is noteworthy that the depletion of MCH leads to hypophagia as well as leanness (Shimada et al., Nature, 396, 670-674, 1998). By contrast, NPY (Erickson et al., Nature, 381, 415-418, 1996), as well as the Y1 (Pedrazzini et al., Nature Medicine, 4, 722-726, 1998) and Y5 receptors (Marsh et al., Nature Medicine, 4, 718-721, 1998), disrupted mice maintained a stable body weight or rather became obese. Considering the above reports, MCHR1 antagonists may be more attractive than Y1 or Y5 receptor antagonists in terms of long-term treatment of obese patients.

An increasing number of children and adolescents are overweight. Although not all overweight children will necessarily become overweight adults, the growing occurrence of obesity in childhood is likely to be reflected in increasing obesity in adult years. 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 measurement of the excess body fat relative to lean body mass and is defined as a body weight more than 20% above the ideal body weight. Recent estimates suggest that 1 in 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. Relat. Metab. Disor. 39 (1998). Both overweight conditions and clinical obesity are a major health concerns worldwide, in particular because clinical obesity is often accompanied by numerous complications, i.e., hypertension and Type II diabetes, which in turn can cause coronary artery disease, stroke, late-stage complications of diabetes and premature death. (See, e.g., Nishina P. M. et al., 43 Metab. 554 (1994)).

Although the etiologic mechanisms underlying obesity require further clarification, the net effect of such mechanisms leads to an imbalance between energy intake and expenditure. Both genetic and environmental factors are likely to be involved in the pathogenesis of obesity. These include excess caloric intake, decreased physical activity, and metabolic and endocrine abnormalities.

Treatment of overweight conditions and clinical obesity via pharmaceutical agents are not only of importance with respect to the conditions themselves, but also with respect to the possibility of preventing other diseases that are associated with, e.g., clinical obesity, as well as enhancement of the positive feeling of “self” that often accompanies those who are overweight or clinically obese and who encounter a significant reduction in body weight. Given the foregoing discussion, it is apparent that compounds which help in the treatment of such disorders would be useful and would provide an advance in both research and clinical medicine. The present invention is directed to these, as well as other, important ends.

The present invention, in one aspect, relates to compounds represented by Formula I:

or a pharmaceutically acceptable salt or prodrug thereof, wherein Q is

R 1 represents

(i) C 1 -C 16 alkyl,

C 1 -C 16 alkyl substituted by substituent(s) independently selected from

halogen,

hydroxy,

oxo,

C 1 -C 3 alkoxy,

C 1 -C 3 alkoxy substituted by substituent(s) independently selected from

carbocyclic aryl, heterocyclyl, heterocyclyl substituted by C 1 -C 3 alkyl,

C 1 -C 3 alkylcarbonyloxy,

carbocyclyloxy,

carbocyclic aryloxy,

carbocyclic aryloxy substituted by substituent(s) independently selected from

halogen, nitro, carbocyclic aryl, carbocyclic aryl substituted by C 1 -C 3 alkoxy, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted by substituent(s) independently selected from

cyano, carbocyclic aryl, heterocyclyl,

mono- or di-carbocyclic arylamino,

mono- or di-carbocyclic arylamino substituted by substituent(s) independently selected from

hydroxy, C 1 -C 3 alkyl,

C 1 -C 3 alkylcalbonylamino,

C 1 -C 3 alkylcalbonylamino substituted by substituent(s) independently selected from

C 1 -C 3 alkylcalbonylamino, carbocyclic arylcalbonylamino, heterocyclyl,

C 1 -C 4 alkoxycalbonylamino,

heterocyclyl calbonylamino,

carbocyclic arylsulfonylamino,

carbocyclic arylsulfonylamino substituted by substituent(s) independently selected from

nitro, C 1 -C 3 alkyl, mono- or di-C 1 -C 3 alkylamino,

C 1 -C 3 alkylthio,

C 1 -C 3 alkylthio substituted by substituent(s) independently selected from

mono- or di-carbocyclic arylaminocarbonyl, halogenated mono- or di-carbocyclic arylaminocarbonyl, mono- or di-carbocyclic arylamino, halogenated mono- or di-carbocyclic arylamino, carbocyclic aryl, carbocyclic aryl substituted by substituent(s) independently selected from

halogen, C 1 -C 3 alkyl,

carbocyclic arylsulfonyl,

halogenated carbocyclic arylsulfonyl,

heterocyclylthio,

heterocyclylthio substituted by substituent(s) independently selected from

nitro, C 1 -C 3 alkyl,

C 3 -C 6 cycloalkyl,

C 3 -C 6 cycloalkyl substituted by C 1 -C 3 alkyl,

C 3 -C 6 cycloalkenyl,

carbocyclyl,

carbocyclyl substituted by substituent(s) independently selected from

halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 2 -C 3 alkenyl, C 2 -C 3 alkenyl substituted by carbocyclic aryl, C 2 -C 3 alkenyl substituted by carbocyclic aryl substituted C 1 -C 3 alkylsulfinyl,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen, hydroxy, nitro, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted by substituent(s) independently selected from

hydroxy, C 1 -C 3 alkyl, C 1 -C 3 alkyl substituted by carbocyclic aryl, C 1 -C 3 alkoxy, C 1 -C 3 alkoxy substituted by carbocyclic aryl, carbocyclic aryl, halogenated carbocyclic aryl,

(ii) C 2 -C 8 alkenyl,

C 2 -C 8 alkenyl substituted by substituent(s) independently selected from

halogen,

oxo,

C 1 -C 3 alkoxy,

C 1 -C 3 alkoxy substituted by carbocyclic aryl,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen, hydroxy, nitro, C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halogenated C 1 -C 3 alkoxy,

heterocyclyl,

heterocyclyl substituted by substituent(s) independently selected from

hydroxy, nitro, C 1 -C 3 alkyl, C 1 -C 3 alkoxy,

(iii) C 2 -C 4 alkynyl,

C 2 -C 4 alkynyl substituted by carbocyclic aryl,

(iv) C 3 -C 6 cycloalkyl,

C 3 -C 6 cycloalkyl substituted by substituent(s) independently selected from

C 1 -C 3 alkyl,

C 1 -C 3 alkyl substituted by substituent(s) independently selected from

hydroxy, oxo, carbocyclic aryl,

mono- or di-C 1 -C 3 alkylamino,

mono- or di-C 1 -C 3 alkylamino substituted by carbocyclic aryl,

carbocyclic arylcarbonylamino,

carbocyclic aryl,

(v) C 3 -C 6 cycloalkeyl,

C 3 -C 6 cycloalkeyl substituted by C 1 -C 3 alkyl,

(vi) carbocyclyl,

carbocyclyl substituted by substituent(s) independently selected from

hydroxy,

nitro,

(vii) carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen,

hydroxy,

cyano,

nitro,

C 1 -C 9 alkyl,

C 1 -C 9 alkyl substituted by substituent(s) independently selected from

halogen, hydroxy, oxo, C 1 -C 3 alkoxy, carbocyclic aryloxy, mono- or di-C 1 -C 3 alkylamino-N-oxy, mono- or di-C 1 -C 3 alkylamino, mono- or di-C 1 -C 3 alkylamino substituted by carbocyclic aryl, mono- or di-carbocyclic arylamino, carbocyclylimino, carbocyclylimino substituted by carbocyclic aryl, mono- or di-carbocyclic arylamino, mono- or di-carbocyclic arylamino substituted by C 1 -C 3 alkoxy, mono- or di-carbocyclic arylaminocarbonyl, mono- or di-carbocyclic arylaminocarbonyl substituted by C 1 -C 3 alkoxy, carbocyclic aryl, carbocyclic aryl substituted by substituent(s) independently selected from

hydroxy, halogen, carboxy, mono- or di-C 1 -C 3 alkylamino, carbocyclic aryl, halogenated carbocyclic aryl, heterocyclyl, heterocyclyl substituted by substituent(s) independently selected from

halogen, nitro, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, C 1 -C 3 alkoxy,

heterocyclyloxy,

heterocyclyloxy substituted by substituent(s) independently selected from

halogen, C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl,

(carbocyclic aryl)S(O) 2 O,

carboxy,

C 1 -C 3 alkoxycarbonyl,

mono- or di-C 1 -C 3 alkylaminocarbonyl,

mono- or di-C 1 -C 3 alkylaminocarbonyl substituted by carbocyclic aryl,

mono- or di-carbocyclic arylaminocarbonyl,

mono- or di-carbocyclic arylaminocarbonyl substituted by C 1 -C 3 alkyl,

amino,

mono- or di-C 1 -C 4 alkylamino,

mono- or di-C 1 -C 4 alkylamino substituted by cyano,

mono- or di-carbocyclic arylamino,

C 1 -C 3 alkynylcarbonylamino,

C 1 -C 3 alkynylcarbonylamino substituted by carbocyclic aryl,

carbocyclic arylsulfonylamino,

carbocyclic arylsulfonylamino substituted by C 1 -C 3 alkyl,

(carbocyclic aryl)NHC(O)NH,

(carbocyclic aryl)NHC(O)NH substituted by C 1 -C 3 alkoxy,

(carbocyclic aryl)NHC(O)NH substituted by haloganated C 1 -C 3 alkoxy,

carbocyclic aryl diazo,

carbocyclic aryl diazo substituted by mono- or di-C 1 -C 3 alkylamino,

C 1 -C 3 alkylthio,

halogenated C 1 -C 3 alkylthio,

carbocyclic arylthio,

carbocyclic arylthio substituted by substituent(s) independently selected from

halogen, cyano, C 1 -C 3 alkyl,

heterocyclylthio,

C 1 -C 3 alkylsulfonyl,

mono- or di-C 1 -C 3 alkylaminosulfonyl,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

C 1 -C 7 alkyl, halogenated C 1 -C 7 alkyl,

heterocyclyl,

heterocyclyl substituted by substituent(s) independently selected from

C 1 -C 3 alkyl, carbocyclic aryl, halogenated carbocyclic aryl,

(viii) heterocyclyl,

or heterocyclyl substituted by substituent(s) independently selected from

halogen,

hydroxy,

cyano,

nitro,

C 1 -C 4 alkyl,

C 1 -C 4 alkyl substituted by substituent(s) independently selected from

halogen, hydroxy, oxo, C 1 -C 3 alkylcarbonyloxy, carbocyclic arylcarbonylamino, halogenated carbocyclic arylcarbonylamino, C 1 -C 3 alkoxycarbonyl, C 1 -C 3 alkylthio, C 1 -C 3 alkylthio substituted by carbocyclic aryl, C 1 -C 3 alkylthio substituted by halogenated carbocyclic aryl, carbocyclic aryl, carbocyclic aryl substituted by substituent(s) independently selected from

halogen, C 1 -C 3 alkyl,

mono- or di-C 1 -C 3 alkylamino,

C 1 -C 4 alkylcarbonylamino,

C 1 -C 3 alkylthio,

C 1 -C 3 alkenylthio,

carbocyclic arylthio,

halogenated carbocyclic arylthio,

carbocyclic arylthio substituted by C 1 -C 3 alkoxycarbonyl,

heterocyclylthio,

heterocyclylthio substituted by C 1 -C 3 alkyl,

C 1 -C 3 alkylsulfonyl,

carbocyclic arylsulfonyl,

halogenated carbocyclic arylsulfonyl,

carbocyclic arylsulfonyl substituted by C 1 -C 4 alkyl,

C 1 -C 3 alkoxycarbonyl,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen, nitro, C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halogenated C 1 -C 3 alkoxy,

heterocyclyl,

heterocyclyl substituted by substituent(s) independently selected from

halogen, C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkoxycarbonyl;

R 2 is —NHNH 2 , —NHNHBoc, —N(R 2a )(R 2b ), morpholino, 4-acetyl-piperazyl, or 4-phenyl-piperazyl;

wherein R 2a is H or C 1 -C 3 alkyl;

R 2b is C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted by substituent(s) independently selected from

hydroxy,

C 1 -C 3 alkoxy,

amino,

—NHBoc,

C 3 -C 6 cycloalkyl,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, —SO 2 NH 2 ,

heterocyclyl,

C 3 -C 6 cycloalkyl, carbocyclic aryl, carbocyclic aryl substituted by substituent(s) independently selected from

halogen,

C 1 -C 3 alkyl,

C 1 -C 3 alkoxy,

or a group of Formula IV;

wherein Boc is carbamic acid tert-butyl ester and R 3 is C 1 -C 3 alkyl or C 1 -C 3 alkyl substituted by substituent(s) independently selected from

carbocyclic aryl, halogenated carbocyclic aryl, carbocyclic aryl substituted by C 1 -C 3 alkoxy;

L is selected from Formula V-XIX;

wherein R 4 is H or C 1 -C 3 alkyl;

R 5 is H, C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted by a substituted carbocyclic aryl;

Y is —S(O) 2 —, —C(O)—, or —(CH 2 ) m ;

m is 0 or 1;

wherein carbocyclic aryl is phenyl, naphthyl, anthranyl, biphenyl, or phenanthryl; 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, 1,2,3,4-tetrahydro-naphthyl, or bicyclo[2.2.1]hepteny;

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, 1H-pyrrolo[2,3-c]pyridyl, 1H-pyrrolyl, 1-oxo-3H-isobenzofuranyl, 2,2′,5′,2″-terthiophenyl, 2,2′-bithiophenyl, 2,3-dihydro-1-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-2H-benzo[b][1,4]dioxepinyl, 4H-benzo[1,3]dioxinyl, 4H-benzopyranyl, 4-oxo-1,5,6,7-tetrahydro-indolyl, 4-oxo-3,4-dihydro-phthalazinyl, 4-oxo-benzopyranyl, 9,10,10-trioxo-thioxanthenyl, 9H-carbazolyl, 9H-xanthenyl, azetidinyl, benzimidazolyl, benzo[1,3]dioxolyl, benzo[2,1,3]oxadiazolyl, benzo[b]thienyl, benzofuryl, benzothiazolyl, cinnolyl, furyl, imidazo[2,1-b]thiazolyl, imidazolyl, isoxazolyl, morpholino, morpholinyl, oxazolyl, oxolanyl, piperazyl, piperidyl, piridyl, pyrazolo[5,1-b]thiazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrrolidyl, quinolyl, quinoxalyl, thiazolidyl, thiazolyl, thienyl, thiolanyl, 2,3-dihydro-benzofuryl, tetrahydro-thienyl, or benzofuranyl;

halogen is fluoro, chloro, bromo, or iodo.

Preferred compounds of this invention are those compounds of Formula I wherein,

Q is Formula II;

R 1 represents

(i) C 1 -C 10 alkyl,

C 1 -C 10 alkyl substituted by substituent(s) independently selected from

halogen,

oxo,

C 1 -C 3 alkoxy,

C 1 -C 3 alkoxy substituted by carbocyclic aryl,

C 1 -C 3 alkylcarbonyloxy,

carbocyclyloxy,

carbocyclic aryloxy,

carbocyclic aryloxy substituted by substituent(s) independently selected from

halogen, nitro, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted by substituent(s) independently selected from

C 1 -C 3 alkylcalbonylamino, carbocyclic arylcalbonylamino, heterocyclyl,

C 1 -C 4 alkoxycalbonylamino,

heterocyclyl calbonylamino,

carbocyclic arylsulfonylamino,

carbocyclic arylsulfonylamino substituted by substituent(s) independently selected from

nitro, C 1 -C 3 alkyl, mono- or di-C 1 -C 3 alkylamino, C 1 -C 3 alkylthio, C 1 -C 3 alkylthio substituted by substituent(s) independently selected from

mono- or di-carbocyclic arylaminocarbonyl, halogenated mono- or di-carbocyclic arylaminocarbonyl, carbocyclic aryl, carbocyclic aryl substituted by substituent(s) independently selected from

halogen, C 1 -C 3 alkoxy,

carbocyclic arylthio, carbocyclic arylthio substituted by substituent(s) independently selected from

halogen, C 1 -C 3 alkyl,

carbocyclic arylsulfonyl, halogenated carbocyclic arylsulfonyl, heterocyclylthio, heterocyclylthio substituted by substituent(s) independently selected from

nitro, C 1 -C 3 alkyl,

C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl substituted by C 1 -C 3 alkyl, C 3 -C 6 cycloalkenyl, carbocyclyl, carbocyclyl substituted by substituent(s) independently selected from

halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 2 -C 3 alkenyl, C 2 -C 3 alkenyl substituted by carbocyclic aryl, C 2 -C 3 alkenyl substituted by carbocyclic aryl substituted C 1 -C 3 alkylsulfinyl,

carbocyclic aryl, carbocyclic aryl substituted by substituent(s) independently selected from

halogen, hydroxy, nitro, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted by substituent(s) independently selected from

oxo, carbocyclic aryl, heterocyclyl,

C 1 -C 4 alkoxy, C 1 -C 4 alkoxy substituted by substituent(s) independently selected from

halogen, carbocyclic aryl,

carbocyclic aryloxy, C 1 -C 3 alkylcarbonyloxy, mono- or di-carbocyclic arylamino, halogenated mono- or di-carbocyclic arylamino, mono- or di-carbocyclic arylaminocarbonyl, mono- or di-carbocyclic arylaminocarbonyl substituted by substituent(s) independently selected from

halogen, nitro, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halogenated C 1 -C 3 alkoxy,

mercapto, C 1 -C 3 alkylthio, halogenated C 1 -C 3 alkylthio, C 1 -C 3 alkylsulfonyl, C 3 -C 6 cycloalkyl, carbocyclic aryl, heterocyclyl,

heterocyclyl, heterocyclyl substituted by substituent(s) independently selected from

hydroxy, C 1 -C 3 alkyl, C 1 -C 3 alkyl substituted by carbocyclic aryl, C 1 -C 3 alkoxy, C 1 -C 3 alkoxy substituted by carbocyclic aryl, carbocyclic aryl, halogenated carbocyclic aryl,

(ii) C 2 -C 6 alkenyl,

C 2 -C 6 alkenyl substituted by substituent(s) independently selected from

oxo, carbocyclic aryl, carbocyclic aryl substituted by substituent(s) independently selected from

halogen, nitro, C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halogenated C 1 -C 3 alkoxy,

heterocyclyl, heterocyclyl substituted by substituent(s) independently selected from

hydroxy, C 1 -C 3 alkyl, C 1 -C 3 alkoxy,

(iii) C 3 -C 6 cycloalkyl,

C 3 -C 6 cycloalkyl substituted by substituent(s) independently selected from

C 1 -C 3 alkyl, C 1 -C 3 alkyl substituted by substituent(s) independently selected from

oxo, carbocyclic aryl,

carbocyclic arylcarbonylamino, carbocyclic aryl,

(iv) carbocyclyl,

carbocyclyl substituted by nitro,

(v) carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen, hydroxy, cyano, nitro, C 1 -C 9 alkyl, C 1 -C 9 alkyl substituted by substituent(s) independently selected from

halogen, oxo, carbocyclic aryloxy, carbocyclylimino, carbocyclylimino substituted by carbocyclic aryl, mono- or di-carbocyclic arylaminocarbonyl, mono- or di-carbocyclic arylaminocarbonyl substituted by C 1 -C 3 alkoxy, carbocyclic aryl, carbocyclic aryl substituted by substituent(s) independently selected from

halogen, C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl,

heterocyclyl, heterocyclyl substituted by C 1 -C 3 alkyl,

C 1 -C 7 alkoxy, C 1 -C 7 alkoxy substituted by substituent(s) independently selected from

halogen, carbocyclic aryl,

C 1 -C 3 alkylcarbonyloxy, carbocyclic aryloxy, carbocyclic aryloxy substituted by C 1 -C 3 alkoxy, C 1 -C 3 alkoxycarbonyl, mono- or di-C 1 -C 3 alkylaminocarbonyl, mono- or di-C 1 -C 3 alkylaminocarbonyl substituted by carbocyclic aryl, mono- or di-carbocyclic arylaminocarbonyl, mono- or di-carbocyclic arylaminocarbonyl substituted by C 1 -C 3 alkyl, amino, mono- or di-C 1 -C 3 alkylamino, C 1 -C 3 alkynylcarbonylamino, C 1 -C 3 alkynylcarbonylamino substituted by carbocyclic aryl, carbocyclic arylsulfonylamino, carbocyclic arylsulfonylamino substituted by C 1 -C 3 alkyl, (carbocyclic aryl)NHC(O)NH, (carbocyclic aryl)NHC(O)NH substituted by C 1 -C 3 alkoxy, (carbocyclic aryl)NHC(O)NH substituted by haloganated C 1 -C 3 alkoxy, C 1 -C 3 alkylthio, halogenated C 1 -C 3 alkylthio, carbocyclic arylthio, carbocyclic arylthio substituted by cyano, C 1 -C 3 alkylsulfonyl, mono- or di-C 1 -C 3 alkylaminosulfonyl, carbocyclic aryl, carbocyclic aryl substituted by substituent(s) independently selected from

C 1 -C 7 alkyl, halogenated C 1 -C 7 alkyl,

heterocyclyl, heterocyclyl substituted by substituent(s) independently selected from

C 1 -C 3 alkyl, carbocyclic aryl, halogenated carbocyclic aryl,

(vi) heterocyclyl,

or heterocyclyl substituted by substituent(s) independently selected from

halogen, nitro, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted by substituent(s) independently selected from

halogen, oxo, C 1 -C 3 alkylthio, C 1 -C 3 alkylthio substituted by carbocyclic aryl, C 1 -C 3 alkylthio substituted by halogenated carbocyclic aryl, carbocyclic aryl, halogenated carbocyclic aryl, heterocyclyl,

C 1 -C 3 alkoxy, carbocyclic aryloxy, carbocyclic aryloxy substituted by substituent(s) independently selected from

halogen, C 1 -C 3 alkyl,

C 1 -C 3 alkylthio, C 1 -C 3 alkenylthio, carbocyclic arylthio, C 1 -C 3 alkylsulfonyl, carbocyclic arylsulfonyl, halogenated carbocyclic arylsulfonyl, carbocyclic arylsulfonyl substituted by C 1 -C 4 alkyl, carbocyclic aryl, carbocyclic aryl substituted by substituent(s) independently selected from

halogen, nitro, C 1 -C 3 alkyl, C 1 -C 3 alkoxy,

heterocyclyl, heterocyclyl substituted by substituent(s) independently selected from

C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl;

R 2 is —NHNH 2 , —NHNHBoc, —N(R 2a )(R 2b ), morpholino, 4-acetyl-piperazyl, or 4-phenyl-piperazyl;

wherein R 2a is H or C 1 -C 3 alkyl;

R 2b is C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted by substituent(s) independently selected from

hydroxy,

C 1 -C 3 alkoxy,

amino,

—NHBoc,

C 3 -C 6 cycloalkyl,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, —SO 2 NH 2 ,

heterocyclyl,

C 3 -C 6 cycloalkyl, carbocyclic aryl, carbocyclic aryl substituted by substituent(s) independently selected from

halogen,

C 1 -C 3 alkyl,

C 1 -C 3 alkoxy,

or a group of Formula IV;

wherein Boc is carbamic acid tert-butyl ester and R 3 is C 1 -C 3 alkyl or C 1 -C 3 alkyl substituted by substituent(s) independently selected from

carbocyclic aryl, halogenated carbocyclic aryl, carbocyclic aryl substituted by C 1 -C 3 alkoxy;

L is selected from Formula V-XIX;

wherein R 4 is H or C 1 -C 3 alkyl;

R 5 is H, C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted by a substituted carbocyclic aryl;

Y is —C(O)—;

wherein carbocyclic aryl is phenyl, naphthyl, anthranyl, or biphenyl;

carbocyclyl is 10,11-dihydro-5-oxo-dibenzo[a,d]cycloheptyl, 1-oxo-indanyl, 9H-fluorenyl, 9-oxo-fluorenyl, acenaphthyl, anthraquinonyl, C-fluoren-9-ylidene, indanyl, indenyl, 1,2,3,4-tetrahydro-naphthyl, or bicyclo[2.2.1]hepteny;

heterocyclyl is 1,2,3-thiadiazolyl, 1,2,3-triazolyl, 1,2-dihydro-3-oxo-pyrazolyl, 1,3-dioxo-isoindolyl, 1H-indolyl, 1H-pyrrolyl, 1-oxo-3H-isobenzofuranyl, 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[b][1,4]dioxepinyl, 4-oxo-1,5,6,7-tetrahydro-indolyl, 4-oxo-3,4-dihydro-phthalazinyl, 4-oxo-benzopyranyl, 9,10,10-trioxo-thioxanthenyl, 9H-xanthenyl, azetidinyl, benzimidazolyl, benzo[1,3]dioxolyl, benzo[2,1,3]oxadiazolyl, benzo[b]thienyl, cinnolyl, furyl, imidazolyl, isoxazolyl, morpholino, morpholinyl, oxazolyl, oxolanyl, piperidyl, piridyl, pyrazolyl, pyridyl, pyrimidyl, pyrrolidyl, quinolyl, quinoxalyl, thiazolidyl, thiazolyl, thienyl, thiolanyl, tetrahydro-thienyl, benzofuranyl, or benzothiazolyl;

halogen is fluoro, chloro, bromo, or iodo.

Other preferred compounds of this invention are those compounds of Formula I wherein,

Q is Formula II;

R 1 represents

(i) C 1 -C 10 alkyl,

C 1 -C 10 alkyl substituted by substituent(s) independently selected from

oxo,

di-propylaminocarbonyl,

methoxy substituted by carbocyclic aryl,

methylcarbonyloxy,

carbocyclic aryloxy,

halogenated carbocyclic aryloxy,

carbocyclic aryloxy substituted by nitro,

heterocyclyloxy substituted by methyl,

substituted heterocyclyl-ethylideneaminooxy,

tert-butoxycarbonylamino,

carbocyclic arylcarbonylamino,

C 1 -C 2 alkylthio,

C 1 -C 2 alkylthio substituted by substituent(s) independently selected from

halogenated carbocyclic aryl, carbocyclic aryl substituted by methoxy,

carbocyclic arylthio,

hetrocyclylthio substituted by nitro,

hetrocyclylthio substituted by methyl,

C 5 -C 6 cycloalkyl,

C 5 -C 6 cycloalkenyl,

carbocyclyl substituted by substituent(s) independently selected from

halogen, methyl, methoxy, ethenyl substituted by carbocyclic aryl substituted methylsulfinyl,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen, hydroxy, nitro, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted by substituent(s) independently selected from

C 1 -C 2 alkyl, C 1 -C 2 substituted by carbocyclic aryl, methoxy, methoxy substituted by carbocyclic aryl, carbocyclic aryl, halogenated carbocyclic aryl,

(ii) C 2 -C 3 alkenyl substituted by substituent(s) independently selected from

carbocyclic aryl,

halogenated carbocyclic aryl,

carbocyclic aryl substituted by nitro,

(iii) C 3 -C 6 cycloalkyl,

C 3 -C 6 cycloalkyl substituted by substituent(s) independently selected from

methyl substituted by oxo,

methyl substituted by carbocyclic aryl,

carbocyclic aryl,

(iv) carbocyclyl,

(v) carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen,

hydroxy,

cyano,

nitro,

C 1 -C 9 alkyl,

C 1 -C 9 alkyl substituted by substituent(s) independently selected from

halogen, oxo, carbocyclic aryl, carbocyclic aryl substituted by methyl, carbocyclic aryloxy,

C 1 -C 7 alkoxy,

halogenated C 1 -C 7 alkoxy,

C 1 -C 7 alkoxy substituted by carbocyclic aryl,

methylcarbonyloxy,

carbocyclic aryloxy,

carbocyclic aryloxy substituted by methoxy,

amino,

di-methylamino,

propargynylcarbonylamino substituted by carbocyclic aryl,

carbocyclic arylsulfonylamino substituted by methyl,

(carbocyclic aryl)NHC(O)NH substituted by halogenated methoxy,

halogenated methylthio,

carbocyclic arylthio substituted by cyano,

di-propylamino sulfonyl,

mono- or di-ethylaminocarbonyl substituted by carbocyclic aryl,

carbocyclic aryl,

heterocyclyl substituted by methyl,

heterocyclyl substituted by halogenated carbocyclic aryl,

(vi) heterocyclyl,

or heterocyclyl substituted by substituent(s) independently selected from

halogen,

nitro,

C 1 -C 4 alkyl,

C 1 -C 4 alkyl substituted by substituent(s) independently selected from

halogen, methylthio substituted by halogenated carbocyclic aryl, carbocyclic aryl, halogenated carbocyclic aryl, heterocyclyl,

methoxy,

carbocyclic aryloxy,

carbocyclic aryloxy substituted by methyl,

C 1 -C 3 alkylthio,

propenylthio,

carbocyclic arylthio,

C 1 -C 3 alkylsulfonyl,

carbocyclic arylsulfonyl substituted by C 1 -C 4 alkyl,

carbocyclic aryl,

halogenated carbocyclic aryl,

carbocyclic aryl substituted by methyl,

carbocyclic aryl substituted by nitro,

heterocyclyl;

R 2 is methylamino or dimethylamino;

L is selected from Formula Va, VIIIa, or IXa;

wherein R 4 and R 5 are independently selected from H or C 1 -C 3 alkyl;

Y is —C(O)—;

wherein carbocyclic aryl is phenyl, naphthyl, anthranyl, or biphenyl;

carbocyclyl is 1-oxo-indanyl, 9-oxo-fluorenyl, indenyl, anthraquinonyl, C-fluoren-9-ylidene, 1,2,3,4-tetrahydro-naphthyl, or bicyclo[2.2.1]hepteny;

heterocyclyl is 1,2,3-thiadiazolyl, 1,2,3-triazolyl, 1,2-dihydro-3-oxo-pyrazolyl, 1,3-dioxo-isoindolyl, 1H-indolyl, 1H-pyrrolyl, 1-oxo-3H-isobenzofuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, 2,4-dihydro-3-oxo-pyrazolyl, 2H-benzopyranyl, 2-oxo-benzopyranyl, 3,4-dihydro-2H-benzo[b][1,4]dioxepinyl, 4-oxo-3,4-dihydro-phthalazinyl, 4-oxo-benzopyranyl, 9,10,10-trioxo-thioxanthenyl, 9H-xanthenyl, azetidinyl, benzimidazolyl, benzo[1,3]dioxolyl, benzo[2,1,3]oxadiazolyl, benzo[b]thienyl, furyl, imidazolyl, isoxazolyl, morpholino, morpholinyl, oxolanyl, piperidyl, piridyl, pyrazolyl, pyridyl, quinolyl, quinoxalyl, thiazolidyl, thiazolyl, thienyl, thiolanyl, 2,3-dihydro-1-oxo-isoindolyl, 2,3-dihydro-benzofuryl, 2-oxo-pyrrolidinyl, 4-oxo-1,5,6,7-tetrahydro-indolyl, cinnolyl, pyrimidyl, pyrrolidyl, tetrahydro-thienyl, benzofuranyl, or benzothiazolyl;

halogen is fluoro, chloro, bromo, or iodo.

Other more preferred compounds of this invention are those compounds of Formula I wherein,

Q is Formula II;

R 1 represents

(i) C 1 -C 10 alkyl substituted by substituent(s) independently selected from

oxo,

di-propylaminocarbonyl,

methoxy substituted by carbocyclic aryl,

methylcarbonyloxy,

carbocyclic aryloxy,

halogenated carbocyclic aryloxy,

carbocyclic aryloxy substituted by nitro,

heterocyclyloxy substituted by methyl,

tert-butoxycarbonylamino,

carbocyclic arylcarbonylamino,

C 1 -C 2 alkylthio,

C 1 -C 2 alkylthio substituted by substituent(s) independently selected from

halogenated carbocyclic aryl, carbocyclic aryl substituted by methoxy,

carbocyclic arylthio,

hetrocyclylthio substituted by nitro,

hetrocyclylthio substituted by methyl,

C 5 -C 6 cycloalkenyl,

carbocyclyl substituted by substituent(s) independently selected from

halogen, methyl, methoxy, ethenyl substituted by carbocyclic aryl substituted methylsulfinyl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen, hydroxy, nitro, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted by substituent(s) independently selected from

oxo, carbocyclic aryl, heterocyclyl,

C 1 -C 4 alkoxy, halogenated C 1 -C 4 alkoxy, C 1 -C 4 alkoxy substituted by carbocyclic aryl, carbocyclic aryloxy, halogenated mono-carbocyclic arylaminocarbonyl, carbocyclic aryl, heterocyclyl,

heterocyclyl substituted by substituent(s) independently selected from

C 1 -C 2 alkyl, C 1 -C 2 substituted by carbocyclic aryl, methoxy, methoxy substituted by carbocyclic aryl, carbocyclic aryl, halogenated carbocyclic aryl,

(ii) C 2 -C 3 alkenyl substituted by substituent(s) independently selected from

carbocyclic aryl,

halogenated carbocyclic aryl,

carbocyclic aryl substituted by nitro,

(iii) C 3 -C 6 cycloalkyl substituted by substituent(s) independently selected from

methyl substituted by oxo,

methyl substituted by carbocyclic aryl,

carbocyclic aryl,

(iv) carbocyclyl,

(v) carbocyclic aryl substituted by substituent(s) independently selected from

halogen,

hydroxy,

cyano,

nitro,

C 1 -C 9 alkyl,

C 1 -C 9 alkyl substituted by substituent(s) independently selected from

halogen, oxo, carbocyclic aryl, carbocyclic aryl substituted by methyl, carbocyclic aryloxy,

C 1 -C 7 alkoxy,

halogenated C 1 -C 7 alkoxy,

C 1 -C 7 alkoxy substituted by carbocyclic aryl,

methylcarbonyloxy,

carbocyclic aryloxy,

carbocyclic aryloxy substituted by methoxy,

amino,

di-methylamino,

propargynylcarbonylamino substituted by carbocyclic aryl,

carbocyclic arylsulfonylamino substituted by methyl,

(carbocyclic aryl)NHC(O)NH substituted by halogenated methoxy,

halogenated methylthio,

carbocyclic arylthio substituted by cyano,

di-propylamino sulfonyl,

mono- or di-ethylaminocarbonyl substituted by carbocyclic aryl,

carbocyclic aryl,

heterocyclyl substituted by methyl,

heterocyclyl substituted by halogenated carbocyclic aryl,

(vi) or heterocyclyl substituted by substituent(s) independently selected from

halogen,

nitro,

C 1 -C 4 alkyl,

C 1 -C 4 alkyl substituted by substituent(s) independently selected from

halogen, methylthio substituted by halogenated carbocyclic aryl, carbocyclic aryl, halogenated carbocyclic aryl, heterocyclyl,

methoxy,

carbocyclic aryloxy,

carbocyclic aryloxy substituted by methyl,

C 1 -C 3 alkylthio,

propenylthio,

carbocyclic arylthio,

C 1 -C 3 alkylsulfonyl,

carbocyclic arylsulfonyl,

carbocyclic arylsulfonyl substituted by C 1 -C 4 alkyl,

carbocyclic aryl,

halogenated carbocyclic aryl,

carbocyclic aryl substituted by methyl,

carbocyclic aryl substituted by nitro,

heterocyclyl;

R 2 is methylamino or dimethylamino;

L is selected from Formula XX-XXII;

Y is —C(O)—;

wherein carbocyclic aryl is phenyl, naphthyl, or biphenyl;

carbocyclyl is 1-oxo-indanyl, 9-oxo-fluorenyl, indenyl, anthraquinonyl, C-fluoren-9-ylidene, 1,2,3,4-tetrahydro-naphthyl, or bicyclo[2.2.1]hepteny;

heterocyclyl is 1,2,3-thiadiazolyl, 1,2,3-triazolyl, 1,2-dihydro-3-oxo-pyrazolyl, 1H-indolyl, 1H-pyrrolyl, 2,4-dihydro-3-oxo-pyrazolyl, 2H-benzopyranyl, 4-oxo-benzopyranyl, azetidinyl, benzo[b]thienyl, furyl, isoxazolyl, morpholinyl, piperidyl, piridyl, pyrazolyl, pyridyl, quinolyl, thiazolidyl, thiazolyl, thienyl, thiolanyl, 2,3-dihydro-1-oxo-isoindolyl, 2,3-dihydro-benzofuryl, 2-oxo-benzopyranyl, 2-oxo-pyrrolidinyl, 4-oxo-1,5,6,7-tetrahydro-indolyl, 9H-xanthenyl, cinnolyl, imidazolyl, morpholino, pyrimidyl, pyrrolidyl, tetrahydro-thienyl, benzofuranyl, or benzothiazolyl;

halogen is fluoro, chloro, bromo, or iodo.

Further other more preferred compounds of this invention are those compounds of Formula I wherein,

Q is Formula II;

R 1 represents

(i) C 1 -C 5 alkyl substituted by substituent(s) independently selected from

oxo,

di-propylaminocarbonyl,

methoxy substituted by carbocyclic aryl,

methylcarbonyloxy,

carbocyclic aryloxy,

halogenated carbocyclic aryloxy,

carbocyclic aryloxy substituted by nitro,

heterocyclyloxy substituted by methyl,

substituted heterocyclyl-ethylideneaminooxy,

tert-butoxycarbonylamino,

carbocyclic arylcarbonylamino,

C 1 -C 2 alkylthio,

C 1 -C 2 alkylthio substituted by substituent(s) independently selected from

halogenated carbocyclic aryl, carbocyclic aryl substituted by methoxy,

carbocyclic arylthio,

hetrocyclylthio substituted by nitro,

hetrocyclylthio substituted by methyl,

cyclohexenyl,

carbocyclyl substituted by substituent(s) independently selected from

halogen, methyl, methoxy, ethenyl substituted by carbocyclic aryl substituted methylsulfinyl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen, hydroxy, nitro, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted by substituent(s) independently selected from

oxo, carbocyclic aryl, heterocyclyl,

C 1 -C 2 alkoxy, halogenated C 1 -C 2 alkoxy, C 1 -C 2 alkoxy substituted by carbocyclic aryl, carbocyclic aryloxy, halogenated mono-carbocyclic arylaminocarbonyl, carbocyclic aryl, heterocyclyl,

heterocyclyl substituted by substituent(s) independently selected from

C 1 -C 2 alkyl, C 1 -C 2 substituted by carbocyclic aryl, methoxy, methoxy substituted by carbocyclic aryl, carbocyclic aryl, halogenated carbocyclic aryl,

(ii) C 2 -C 3 alkenyl substituted by substituent(s) independently selected from

carbocyclic aryl,

halogenated carbocyclic aryl,

carbocyclic aryl substituted by nitro,

(iii) C 3 -C 6 cycloalkyl substituted by substituent(s) independently selected from

methyl substituted by oxo,

methyl substituted by carbocyclic aryl,

carbocyclic aryl,

(iv) carbocyclyl,

(v) carbocyclic aryl substituted by substituent(s) independently selected from

halogen,

hydroxy,

cyano,

nitro,

C 1 -C 4 alkyl,

C 1 -C 2 alkyl substituted by substituent(s) independently selected from

halogen, oxo, carbocyclic aryl, carbocyclic aryl substituted by methyl, carbocyclic aryloxy,

C 1 -C 2 alkoxy,

halogenated C 1 -C 2 alkoxy,

C 1 -C 2 alkoxy substituted by carbocyclic aryl,

methylcarbonyloxy,

carbocyclic aryloxy,

carbocyclic aryloxy substituted by methoxy,

amino,

di-methylamino,

propargynylcarbonylamino substituted by carbocyclic aryl,

carbocyclic arylsulfonylamino substituted by methyl,

(carbocyclic aryl)NHC(O)NH substituted by halogenated methoxy,

halogenated methylthio,

carbocyclic arylthio substituted by cyano,

di-propylamino sulfonyl,

mono- or di-ethylaminocarbonyl substituted by carbocyclic aryl,

carbocyclic aryl,

heterocyclyl substituted by methyl,

heterocyclyl substituted by halogenated carbocyclic aryl,

(vi) or heterocyclyl substituted by substituent(s) independently selected from

halogen,

nitro,

C 1 -C 4 alkyl,

C 1 -C 4 alkyl substituted by substituent(s) independently selected from

halogen, methylthio substituted by halogenated carbocyclic aryl, carbocyclic aryl, halogenated carbocyclic aryl, heterocyclyl,

methoxy,

carbocyclic aryloxy,

carbocyclic aryloxy substituted by methyl,

C 1 -C 3 alkylthio,

propenylthio,

carbocyclic arylthio,

C 1 -C 3 alkylsulfonyl,

carbocyclic arylsulfonyl,

carbocyclic arylsulfonyl substituted by methyl,

carbocyclic aryl,

halogenated carbocyclic aryl,

carbocyclic aryl substituted by methyl,

carbocyclic aryl substituted by nitro,

heterocyclyl;

R 2 is methylamino or dimethylamino;

L is selected from Formula XX-XXII;

Y is —C(O)—;

wherein carbocyclic aryl is phenyl, naphthyl, or biphenyl;

carbocyclyl is 1-oxo-indanyl, indenyl, 9-oxo-fluorenyl, 1,2,3,4-tetrahydro-naphthyl, or bicyclo[2.2.1]hepteny;

heterocyclyl is 1H-indolyl, 2,4-dihydro-3-oxo-pyrazolyl, furyl, pyrazolyl, pyridyl, thienyl, 1,2,3-triazolyl, 1H-pyrrolyl, 2,3-dihydro-1-oxo-isoindolyl, 2,3-dihydro-benzofuryl, 2H-benzopyranyl, 2-oxo-benzopyranyl, 4-oxo-1,5,6,7-tetrahydro-indolyl, imidazolyl, isoxazolyl, morpholino, morpholinyl, pyrazolyl, pyrimidyl, quinolyl, thiazolyl, tetrahydro-thienyl, benzofuranyl, or benzothiazolyl;

halogen is fluoro, chloro, bromo, or iodo.

The following compounds are specially preffered;

Other more preferred compounds of this invention are those compounds of Formula I wherein,

Q is Formula II;

R 1 represents

(i) C 1 -C 10 alkyl,

C 1 -C 10 alkyl substituted by substituent(s) independently selected from

C 5 -C 6 cycloalkyl,

carbocyclic aryl,

heterocyclyl,

(ii) C 3 -C 6 cycloalkyl,

(iii) carbocyclic aryl,

(iv) or heterocyclyl;

R 2 is methylamino or dimethylamino;

L is selected from Formula XX-XXII;

Y is —C(O)—;

wherein carbocyclic aryl is phenyl, naphthyl, anthranyl, or biphenyl;

heterocyclyl is 1,3-dioxo-isoindolyl, 1H-indolyl, 1-oxo-3H-isobenzofuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, 3,4-dihydro-2H-benzo[b][1,4]dioxepinyl, 4-oxo-3,4-dihydro-phthalazinyl, 9,10,10-trioxo-thioxanthenyl, 9H-xanthenyl, benzimidazolyl, benzo[1,3]dioxolyl, benzo[2,1,3]oxadiazolyl, benzo[b]thienyl, furyl, imidazolyl, isoxazolyl, morpholino, oxolanyl, piperidyl, pyridyl, quinoxalyl, thienyl, quinolyl, or benzothiazolyl;

halogen is fluoro, chloro, bromo, or iodo.

Further other more preferred compounds of this invention are those compounds of Formula I wherein,

Q is Formula II;

R 1 represents

(i) C 1 -C 4 alkyl,

C 1 -C 4 alkyl substituted by substituent(s) independently selected from

cyclopentyl,

carbocyclic aryl,

heterocyclyl,

(ii) carbocyclic aryl,

(iii) or heterocyclyl;

R 2 is methylamino or dimethylamino;

L is selected from Formula XX-XXII;

Y is —C(O)—;

wherein carbocyclic aryl is phenyl, naphthyl, anthranyl, or biphenyl;

heterocyclyl is 9H-xanthenyl, benzo[1,3]dioxolyl, benzo[2,1,3]oxadiazolyl, benzo[b]thienyl, thienyl, 1H-indolyl, quinoxalyl, quinolyl, or benzothiazolyl;

halogen is fluoro, chloro, bromo, or iodo.

The following compounds are specially preffered;

Preferred compounds of this invention are those compounds of Formula I wherein,

Q is Formula II;

R 1 represents

(i) C 1 -C 10 alkyl,

C 1 -C 10 alkyl substituted by substituent(s) independently selected from

halogen,

hydroxy,

oxo,

C 1 -C 3 alkoxy,

C 1 -C 3 alkoxy substituted by substituent(s) independently selected from

carbocyclic aryl, heterocyclyl, heterocyclyl substituted by C 1 -C 3 alkyl,

carbocyclic aryloxy,

carbocyclic aryloxy substituted by substituent(s) independently selected from

halogen, halogen, nitro, carbocyclic aryl, carbocyclic aryl substituted by C 1 -C 3 alkoxy, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted by substituent(s) independently selected from

cyano, carbocyclic aryl, heterocyclyl,

mono- or di-carbocyclic arylamino,

mono- or di-carbocyclic arylamino substituted by C 1 -C 3 alkyl,

C 1 -C 3 alkylcalbonylamino,

C 1 -C 4 alkoxycalbonylamino,

carbocyclic arylsulfonylamino,

carbocyclic arylsulfonylamino substituted by substituent(s) independently selected from

nitro, C 1 -C 3 alkyl, mono- or di-C 1 -C 3 alkylamino,

C 1 -C 3 alkylthio,

C 1 -C 3 alkylthio substituted by substituent(s) independently selected from

mono- or di-carbocyclic arylamino, halogenated mono- or di-carbocyclic arylamino, carbocyclic aryl, carbocyclic aryl substituted by substituent(s) independently selected from

halogen, C 1 -C 3 alkyl,

carbocyclic arylsulfonyl,

halogenated carbocyclic arylsulfonyl,

heterocyclylthio,

C 3 -C 6 cycloalkyl,

C 3 -C 6 cycloalkyl substituted by C 1 -C 3 alkyl,

carbocyclyl,

carbocyclyl substituted by substituent(s) independently selected from

halogen, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkenyl substituted by carbocyclic aryl, C 2 -C 3 alkenyl substituted by carbocyclic aryl substituted C 1 -C 3 alkylsulfinyl,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen, hydroxy, nitro, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted by substituent(s) independently selected from

C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkoxy substituted by carbocyclic aryl, carbocyclic aryl, halogenated carbocyclic aryl,

(ii) C 2 -C 9 alkenyl,

C 2 -C 8 alkenyl substituted by substituent(s) independently selected from

halogen,

C 1 -C 3 alkoxy,

C 1 -C 3 alkoxy substituted by carbocyclic aryl,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen, hydroxy, C 1 -C 3 alkoxy, halogenated C 1 -C 3 alkoxy,

heterocyclyl,

heterocyclyl substituted by nitro,

(iii) C 2 -C 4 alkynyl,

C 2 -C 4 alkynyl substituted by carbocyclic alkyl,

(iv) C 3 -C 6 cycloalkyl,

C 3 -C 6 cycloalkyl substituted by substituent(s) independently selected from

C 1 -C 3 alkyl,

C 1 -C 3 alkyl substituted by substituent(s) independently selected from

hydroxy, oxo, carbocyclic aryl,

mono- or di-C 1 -C 3 alkylamino,

mono- or di-C 1 -C 3 alkylamino substituted by carbocyclic aryl,

carbocyclic aryl,

(v) C 3 -C 6 cycloalkeyl,

C 3 -C 6 cycloalkeyl substituted by C 1 -C 3 alkyl,

(vi) carbocyclyl,

carbocyclyl substituted by substituent(s) independently selected from

hydroxy,

nitro,

(vii) carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen,

hydroxy,

cyano,

nitro,

C 1 -C 9 alkyl,

C 1 -C 9 alkyl substituted by substituent(s) independently selected from

halogen, hydroxy, oxo, C 1 -C 3 alkoxy, carbocyclic aryloxy, mono- or di-C 1 -C 3 alkylamino-N-oxy, mono- or di-C 1 -C 3 alkylamino, mono- or di-C 1 -C 3 alkylamino substituted by carbocyclic aryl, mono- or di-carbocyclic arylamino, mono- or di-carbocyclic arylamino substituted by C 1 -C 3 alkoxy, carbocyclic aryl, halogenated carbocyclic aryl, heterocyclyl, heterocyclyl substituted by C 1 -C 3 alkyl,

C 2 -C 3 alkenyl,

C 2 -C 3 alkenyl substituted by carbocyclic aryl,

C 1 -C 9 alkoxy,

C 1 -C 9 alkoxy substituted by substituent(s) independently selected from

hydroxy, halogen, carboxy, mono- or di-C 1 -C 3 alkylamino, carbocyclic aryl, halogenated carbocyclic aryl, heterocyclyl, heterocyclyl substituted by substituent(s) independently selected from

halogen, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, C 1 -C 3 alkoxy,

heterocyclyloxy,

heterocyclyloxy substituted by substituent(s) independently selected from

halogen, C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl,

(carbocyclic aryl)S(O) 2 O,

carboxy,

C 1 -C 3 alkoxycarbonyl,

mono- or di-C 1 -C 3 alkylaminocarbonyl,

mono- or di-C 1 -C 3 alkylaminocarbonyl substituted by carbocyclic aryl,

amino,

mono- or di-C 1 -C 4 alkylamino,

mono- or di-C 1 -C 4 alkylamino substituted by cyano,

mono- or di-carbocyclic arylamino,

C 1 -C 3 alkylcarbonylamino,

carbocyclic arylsulfonylamino,

carbocyclic arylsulfonylamino substituted by C 1 -C 3 alkyl,

(carbocyclic aryl)NHC(O)NH,

(carbocyclic aryl)NHC(O)NH substituted by C 1 -C 3 alkoxy,

(carbocyclic aryl)NHC(O)NH substituted by haloganated C 1 -C 3 alkoxy,

C 1 -C 3 alkylthio,

halogenated C 1 -C 3 alkylthio,

carbocyclic arylthio,

halogenated carbocyclic arylthio,

carbocyclic arylthio substituted by C 1 -C 3 alkyl,

heterocyclylthio,

C 1 -C 3 alkylsulfonyl,

mono- or di-C 1 -C 3 alkylaminosulfonyl,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

C 1 -C 7 alkyl, halogenated C 1 -C 7 alkyl,

heterocyclyl,

heterocyclyl substituted by substituent(s) independently selected from

C 1 -C 3 alkyl, carbocyclic aryl, halogenated carbocyclic aryl,

(viii) heterocyclyl,

or heterocyclyl substituted by substituent(s) independently selected from

halogen,

hydroxy,

cyano,

nitro,

C 1 -C 4 alkyl,

C 1 -C 4 alkyl substituted by substituent(s) independently selected from

halogen, hydroxy, oxo, C 1 -C 3 alkylcarbonyloxy, C 1 -C 3 alkoxycarbonyl, C 1 -C 3 alkylthio substituted by carbocyclic aryl, C 1 -C 3 alkylthio substituted by halogenated carbocyclic aryl, carbocyclic aryl, carbocyclic aryl substituted by substituent(s) independently selected from

halogen, nitro, C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halogenated C 1 -C 3 alkoxy,

heterocyclyl,

heterocyclyl substituted by substituent(s) independently selected from

C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkoxycarbonyl;

R 2 is —NHNH 2 , —NHNHBoc, —N(R 2a )(R 2b ), morpholino, 4-acetyl-piperazyl, or 4-phenyl-piperazyl;

wherein R 2a is H or C 1 -C 3 alkyl;

R 2b is C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted by substituent(s) independently selected from

hydroxy,

C 1 -C 3 alkoxy,

amino,

—NHBoc,

C 3 -C 6 cycloalkyl,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, —SO 2 NH 2 ,

heterocyclyl,

C 3 -C 6 cycloalkyl, carbocyclic aryl, carbocyclic aryl substituted by substituent(s) independently selected from

halogen,

C 1 -C 3 alkyl,

C 1 -C 3 alkoxy,

or a group of Formula IV;

wherein Boc is carbamic acid tert-butyl ester and R 3 is C 1 -C 3 alkyl or C 1 -C 3 alkyl substituted by substituent(s) independently selected from

carbocyclic aryl, halogenated carbocyclic aryl, carbocyclic aryl substituted by C 1 -C 3 alkoxy;

L is selected from Formula V-XIX;

wherein R 4 is H or C 1 -C 3 alkyl;

R 5 is H, C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted by a substituted carbocyclic aryl;

Y is —(CH 2 ) m , m is 0 or 1;

wherein carbocyclic aryl is phenyl, naphthyl, phenanthryl, or biphenyl;

carbocyclyl is 9H-fluorenyl, 9-oxo-fluorenyl, acenaphthyl, anthraquinonyl, indanyl, or indenyl;

heterocyclyl is 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, 1H-pyrrolo[2,3-c]pyridyl, 1H-pyrrolyl, 2,2′,5′,2″-terthiophenyl, 2,2′-bithiophenyl, 2,3-dihydro-1-oxo-isoindolyl, 2,3-dihydro-benzo[1,4]dioxinyl, 2,3-dihydro-benzofuryl, 2,4-dihydro-3-oxo-pyrazolyl, 2H-benzopyranyl, 2-oxo-pyrrolidinyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, 3,4-dihydro-2H-benzo[b][1,4]dioxepinyl, 4H-benzo[1,3]dioxinyl, 4H-benzopyranyl, 4-oxo-1,5,6,7-tetrahydro-indolyl, 4-oxo-benzopyranyl, 9H-carbazolyl, 9H-xanthenyl, azetidinyl, benzimidazolyl, benzo[1,3]dioxolyl, benzo[b]thienyl, benzofuryl, benzothiazolyl, furyl, imidazo[2,1-b]thiazolyl, imidazolyl, isoxazolyl, morpholino, morpholinyl, oxolanyl, piperazyl, piperidyl, pyrazolo[5,1-b]thiazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrrolidyl, quinolyl, quinoxalyl, thiazolidyl, thiazolyl, thienyl, or thiolanyl;

halogen is fluoro, chloro, bromo, or iodo.

Other preferred compounds of this invention are those compounds of Formula I wherein,

Q is Formula II;

R 1 represents

(i) C 1 -C 10 alkyl substituted by substituent(s) independently selected from

methoxy,

methoxy substituted by carbocyclic aryl,

carbocyclic aryloxy,

halogenated carbocyclic aryloxy,

mono-C 1 -C 2 alkylamino substituted by cyano,

mono- or di-C 1 -C 2 alkylamino substituted by carbocyclic aryl,

mono-carbocyclic arylamino,

mono-carbocyclic arylamino substituted by methyl,

carbocyclic arylsulfonylamino substituted by methyl,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen, nitro, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted by carbocyclic aryl, C 1 -C 4 alkyl substituted by hydroxy, C 1 -C 2 alkoxy, halogenated C 1 -C 2 alkoxy,

heterocyclyl substituted by carbocyclic aryl,

(ii) C 2 -C 8 alkenyl substituted by substituent(s) independently selected from

methoxy substituted by carbocyclic aryl,

carbocyclic aryl,

carbocyclic aryl substituted by methoxy,

(iii) C 2 -C 4 alkynyl substituted by carbocyclic aryl,

(iv) cyclohexyl substituted by carbocyclic arylmethyl,

(v) carbocyclyl,

(vi) carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen,

hydroxy,

cyano,

amino,

C 1 -C 9 alkyl,

halogenated C 1 -C 9 alkyl,

C 1 -C 9 alkoxy,

C 1 -C 9 alkoxy substituted by substituent(s) independently selected from

halogen, halogenated carbocyclic aryl,

propenyloxy,

methylamino,

di-C 1 -C 2 alkylamino,

di-C 1 -C 2 alkylamino substituted by cyano,

methylthio,

halogenated methylthio,

(vii) heterocyclyl,

or heterocyclyl substituted by substituent(s) independently selected from

halogen,

C 1 -C 4 alkyl,

C 1 -C 4 alkyl substituted by hydroxy,

C 1 -C 4 alkyl substituted by carbocyclic aryl,

methoxy,

C 1 -C 2 alkoxycarbonyl,

carbocyclic arylthio substituted by methoxycarbonyl,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen, halogenated methyl,

heterocyclyl;

R 2 is methylamino or dimethylamino;

L is selected from Formula Va, VIIIa, or IXa;

wherein R 4 and R 5 are independently selected from H or C 1 -C 3 alkyl;

Y is —(CH 2 ) m , m is 0 or 1;

wherein carbocyclic aryl is phenyl, naphthyl, phenanthryl, or biphenyl;

carbocyclyl is 9H-fluorenyl, acenaphthyl, or anthraquinonyl;

heterocyclyl is 1,2,3-thiadiazolyl, 1,2,3-triazolyl, 1,2-dihydro-3-oxo-pyrazolyl, 1,3-dioxolanyl, 1H-indolyl, 1H-pyrrolyl, 2,2′,5′,2″-terthiophenyl, 2,2′-bithiophenyl, 2,3-dihydro-benzo[1,4]dioxinyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, 4-oxo-benzopyranyl, 9H-carbazolyl, 9H-xanthenyl, benzimidazolyl, benzo[1,3]dioxolyl, benzo[b]thienyl, benzofuryl, benzothiazolyl, furyl, imidazolyl, isoxazolyl, oxolanyl, pyrazolo[5,1-b]thiazolyl, pyrazolyl, pyridyl, pyrimidyl, quinolyl, quinoxalyl, thiazolidyl, thiazolyl, thienyl, 2H-benzopyranyl, 4H-benzo[1,3]dioxinyl, azetidinyl, imidazo[2,1-b]thiazolyl, morpholinyl, or 2,3-dihydro-benzofuryl;

halogen is fluoro, chloro, bromo, or iodo.

Other more preferred compounds of this invention are those compounds of Formula I wherein,

Q is Formula II;

R 1 represents

(i) C 1 -C 7 alkyl substituted by substituent(s) independently selected from

methoxy,

methoxy substituted by carbocyclic aryl,

carbocyclic aryloxy,

halogenated carbocyclic aryloxy,

mono-ethylamino substituted by cyano,

di-methylamino substituted by carbocyclic aryl,

mono-carbocyclic arylamino,

mono-carbocyclic arylamino substituted by methyl,

carbocyclic arylsulfonylamino substituted by methyl,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen, nitro, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted by carbocyclic aryl, C 1 -C 4 alkyl substituted by hydroxy, metoxy, halogenated methoxy,

heterocyclyl substituted by carbocyclic aryl,

(ii) C 2 -C 7 alkenyl substituted by substituent(s) independently selected from

methoxy substituted by carbocyclic aryl,

carbocyclic aryl,

carbocyclic aryl substituted by methoxy,

(iii) butynyl substituted by carbocyclic aryl,

(iv) cyclohexyl substituted by carbocyclic arylmethyl,

(v) carbocyclyl,

(vi) carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen,

hydroxy,

cyano,

amino,

C 1 -C 2 alkyl,

halogenated methyl,

C 1 -C 3 alkoxy,

C 1 -C 3 alkoxy substituted by substituent(s) independently selected from

halogen, halogenated carbocyclic aryl,

propenyloxy,

di-C 1 -C 2 alkylamino,

di-C 1 -C 2 alkylamino substituted by cyano,

methylthio,

halogenated methylthio,

(vii) heterocyclyl,

or heterocyclyl substituted by substituent(s) independently selected from

halogen,

C 1 -C 3 alkyl,

C 1 -C 3 alkyl substituted by hydroxy,

C 1 -C 3 alkyl substituted by carbocyclic aryl,

methoxy,

ethoxycarbonyl,

carbocyclic arylthio substituted by methoxycarbonyl,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen, halogenated methyl,

heterocyclyl;

R 2 is methylamino or dimethylamino;

L is selected from Formula XX-XXII;

Y is —(CH 2 ) m , m is 0 or 1;

wherein carbocyclic aryl is phenyl, naphthyl, or biphenyl;

carbocyclyl is acenaphthyl;

heterocyclyl is 1H-indolyl, 1H-pyrrolyl, 2,3-dihydro-benzo[1,4]dioxinyl, 9H-carbazolyl, benzo[1,3]dioxolyl, furyl, pyrazolyl, thienyl, 4-oxo-benzopyranyl, azetidinyl, imidazo[2,1-b]thiazolyl, pyridyl, imidazolyl, 2,3-dihydro-benzofuryl, or benzo[b]thienyl;

halogen is fluoro, chloro, bromo, or iodo.

The following compounds are specially preffered;

Preferred compounds of this invention are those compounds of Formula I wherein,

Q is Formula II;

R 1 represents

(i) C 1 -C 16 alkyl,

C 1 -C 16 alkyl substituted by substituent(s) independently selected from

halogen,

carbocyclyl,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen, nitro, C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl,

(ii) C 2 -C 3 alkenyl,

C 2 -C 3 alkenyl substituted by carbocyclic aryl,

(iii) carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen, cyano, nitro, C 1 -C 5 alkyl, C 1 -C 5 alkyl substituted by substituent(s) independently selected from

halogen, oxo,

C 2 -C 3 alkenyl, C 1 -C 4 alkoxy, C 1 -C 4 alkoxy substituted by substituent(s) independently selected from

halogen, heterocyclyl, halogenated heterocyclyl,

carbocyclic aryloxy, carbocyclic aryloxy substituted by substituent(s) independently selected from

halogen, nitro,

heterocyclyloxy, heterocyclyloxy substituted by substituent(s) independently selected from

halogen, C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl,

C 1 -C 3 alkoxycarbonyl, mono- or di-C 1 -C 4 alkylamino, C 1 -C 3 alkylcarbonylamino, carbocyclic aryl diazo, carbocyclic aryl diazo substituted by mono- or di-C 1 -C 3 alkylamino, C 1 -C 3 alkylsulfonyl, carbocyclic aryl,

(iv) heterocyclyl,

or heterocyclyl substituted by substituent(s) independently selected from

halogen, C 1 -C 3 alkyl, C 1 -C 3 alkyl substituted by substituent(s) independently selected from

halogen, oxo, carbocyclic arylcarbonylamino, halogenated carbocyclic arylcarbonylamino, heterocyclyl, heterocyclyl substituted by substituent(s) independently selected from

halogen, C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl,

C 1 -C 3 alkoxy, C 1 -C 3 alkylcarbonylamino, carbocyclic arylsulfonyl, C 1 -C 3 alkoxycarbonyl, carbocyclic aryl, halogenated carbocyclic aryl, heterocyclyl, heterocyclyl substituted by substituent(s) independently selected from

halogen, C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl;

R 2 is —NHNH 2 , —NNHBoc, —N(R 2a )(R 2b ), morpholino, 4-acetyl-piperazyl, or 4-phenyl-piperazyl;

wherein R 2a is H or C 1 -C 3 alkyl;

R 2b is C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted by substituent(s) independently selected from

hydroxy,

C 1 -C 3 alkoxy,

amino,

—NHBoc,

C 3 -C 6 cycloalkyl,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, —SO 2 NH 2 ,

heterocyclyl,

C 3 -C 6 cycloalkyl, carbocyclic aryl, carbocyclic aryl substituted by substituent(s) independently selected from

halogen,

C 1 -C 3 alkyl,

C 1 -C 3 alkoxy,

or a group of Formula IV;

wherein Boc is carbamic acid tert-butyl ester and R 3 is C 1 -C 3 alkyl or C 1 -C 3 alkyl substituted by substituent(s) independently selected from

carbocyclic aryl, halogenated carbocyclic aryl, carbocyclic aryl substituted by C 1 -C 3 alkoxy;

L is selected from Formula V-XIX;

wherein R 4 is H or C 1 -C 3 alkyl;

R 5 is H, C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted by a substituted carbocyclic aryl;

Y is —S(O) 2 —;

wherein carbocyclic aryl is phenyl, naphthyl, or biphenyl;

carbocyclyl is 7,7-dimethyl-2-oxo-bicyclo[2.2.1]heptyl;

heterocyclyl is 1,2,3,4-tetrahydro-isoquinolyl, 1,2,3-thiadiazolyl, 1H-pyrrolyl, benzo[2,1,3]oxadiazolyl, benzo[b]thienyl, furyl, imidazolyl, isoxazolyl, pyrazolyl, pyridyl, quinolyl, thiazolyl, or thienyl;

halogen is fluoro, chloro, bromo, or iodo.

The following compounds are specially preffered;

Preferred compounds of this invention are those compounds of Formula I wherein,

Q is Fomura II;

R 1 is selected from H, —CO 2 t Bu, or —CO 2 Bn (Bn is a benzyl group);

R 2 is methylamino or dimethylamino;

L is selected from Formula XX-XXII;

Y is a single bond;

or a salt thereof.

Also provided in accordance with the present invention are methods of modulating G-protein receptor SLC-1 comprising contacting the SLC-1 receptor with a compound of the invention.

The present invention further provides pharmaceutical compositions containing MCH receptor antagonists of the invention.

FIG. 1 provides an illustration of IP 3 production from several non-endogenous, constitutively activated version of MCH receptor as compared with the endogenous version of this receptor.

The present invention relates to MCH receptor antagonist compounds, and methods of modulating MCH receptors by contacting the receptors with one or more compounds of the invention.

The term “antagonist” is intended to mean moieties that competitively bind to the receptor at the same site as agonists (for example, the endogenous ligand), but which do not activate the intracellular response initiated by the active form of the receptor, and can thereby inhibit the intracellular responses by agonists or partial agonists. Antagonists do not diminish the baseline intracellular response in the absence of an agonist or partial agonist. As used herein, the term “agonist” is intended to mean moieties that activate the intracellular response when they bind to the receptor, or enhance GTP binding to membranes. In the context of the present invention, a pharmaceutical composition comprising a MCH receptor antagonist of the invention can be utilized for modulating the activity of the MCH receptor, decreasing body weight and/or affecting metabolism such that the recipient loses weight and/or maintains weight. Such pharmaceutical compositions can be used in the context of disorders and/or diseases where weight gain is a component of the disease and/or disorder such as, for example, obesity.

As used herein, the term “contact” or “contacting” shall mean bringing the indicated moieties together, whether in an in vitro system or an in vivo system. Thus, “contacting” an MCH receptor with a compound of the invention includes the administration of a compound of the invention to an animal having an MCH receptor, as well as, for example, introducing a compound of the invention into a sample containing a cellular or more purified preparation containing an MCH receptor.

Compounds of the invention include those having Formula I, shown below:

wherein Q can be either Foemura II or III:

R 1 represents

(i) C 1 -C 16 alkyl,

C 1 -C 16 alkyl substituted by substituent(s) independently selected from

halogen,

hydroxy,

oxo,

C 1 -C 3 alkoxy,

C 1 -C 3 alkoxy substituted by substituent(s) independently selected from

carbocyclic aryl, heterocyclyl, heterocyclyl substituted by C 1 -C 3 alkyl,

C 1 -C 3 alkylcarbonyloxy,

carbocyclyloxy,

carbocyclic aryloxy,

carbocyclic aryloxy substituted by substituent(s) independently selected from

halogen, nitro, carbocyclic aryl, carbocyclic aryl substituted by C 1 -C 3 alkoxy, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted by substituent(s) independently selected from

cyano, carbocyclic aryl, heterocyclyl,

mono- or di-carbocyclic arylamino,

mono- or di-carbocyclic arylamino substituted by substituent(s) independently selected from

hydroxy, C 1 -C 3 alkyl,

C 1 -C 3 alkylcalbonylamino,

C 1 -C 3 alkylcalbonylamino substituted by substituent(s) independently selected from

C 1 -C 3 alkylcalbonylamino, carbocyclic arylcalbonylamino, heterocyclyl,

C 1 -C 4 alkoxycalbonylamino,

heterocyclyl calbonylamino,

carbocyclic arylsulfonylamino,

carbocyclic arylsulfonylamino substituted by substituent(s) independently selected from

nitro, C 1 -C 3 alkyl, mono- or di-C 1 -C 3 alkylamino,

C 1 -C 3 alkylthio,

C 1 -C 3 alkylthio substituted by substituent(s) independently selected from

mono- or di-carbocyclic arylaminocarbonyl, halogenated mono- or di-carbocyclic arylaminocarbonyl, mono- or di-carbocyclic arylamino, halogenated mono- or di-carbocyclic arylamino, carbocyclic aryl, carbocyclic aryl substituted by substituent(s) independently selected from

halogen, C 1 -C 3 alkyl,

carbocyclic arylsulfonyl,

halogenated carbocyclic arylsulfonyl,

heterocyclylthio,

heterocyclylthio substituted by substituent(s) independently selected from

nitro, C 1 -C 3 alkyl,

C 3 -C 6 cycloalkyl,

C 3 -C 6 cycloalkyl substituted by C 1 -C 3 alkyl,

C 3 -C 6 cycloalkenyl,

carbocyclyl,

carbocyclyl substituted by substituent(s) independently selected from

halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 2 -C 3 alkenyl, C 2 -C 3 alkenyl substituted by carbocyclic aryl, C 2 -C 3 alkenyl substituted by carbocyclic aryl substituted C 1 -C 3 alkylsulfinyl,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen, hydroxy, nitro, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted by substituent(s) independently selected from

hydroxy, C 1 -C 3 alkyl, C 1 -C 3 alkyl substituted by carbocyclic aryl, C 1 -C 3 alkoxy, C 1 -C 3 alkoxy substituted by carbocyclic aryl, carbocyclic aryl, halogenated carbocyclic aryl,

(ii) C 2 -C 8 alkenyl,

C 2 -C 8 alkenyl substituted by substituent(s) independently selected from

halogen,

oxo,

C 1 -C 3 alkoxy,

C 1 -C 3 alkoxy substituted by carbocyclic aryl,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen, hydroxy, nitro, C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halogenated C 1 -C 3 alkoxy,

heterocyclyl,

heterocyclyl substituted by substituent(s) independently selected from

hydroxy, nitro, C 1 -C 3 alkyl, C 1 -C 3 alkoxy,

(iii) C 2 -C 4 alkynyl,

C 2 -C 4 alkynyl substituted by carbocyclic aryl,

(iv) C 3 -C 6 cycloalkyl,

C 3 -C 6 cycloalkyl substituted by substituent(s) independently selected from

C 1 -C 3 alkyl,

C 1 -C 3 alkyl substituted by substituent(s) independently selected from

hydroxy, oxo, carbocyclic aryl,

mono- or di-C 1 -C 3 alkylamino,

mono- or di-C 1 -C 3 alkylamino substituted by carbocyclic aryl,

carbocyclic arylcarbonylamino,

carbocyclic aryl,

(v) C 3 -C 6 cycloalkeyl,

C 3 -C 6 cycloalkeyl substituted by C 1 -C 3 alkyl,

(vi) carbocyclyl,

carbocyclyl substituted by substituent(s) independently selected from

hydroxy,

nitro,

(vii) carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen,

hydroxy,

cyano,

nitro,

C 1 -C 9 alkyl,

C 1 -C 9 alkyl substituted by substituent(s) independently selected from

halogen, hydroxy, oxo, C 1 -C 3 alkoxy, carbocyclic aryloxy, mono- or di-C 1 -C 3 alkylamino-N-oxy, mono- or di-C 1 -C 3 alkylamino, mono- or di-C 1 -C 3 alkylamino substituted by carbocyclic aryl, mono- or di-carbocyclic arylamino, carbocyclylimino, carbocyclylimino substituted by carbocyclic aryl, mono- or di-carbocyclic arylamino, mono- or di-carbocyclic arylamino substituted by C 1 -C 3 alkoxy, mono- or di-carbocyclic arylaminocarbonyl, mono- or di-carbocyclic arylaminocarbonyl substituted by C 1 -C 3 alkoxy, carbocyclic aryl, carbocyclic aryl substituted by substituent(s) independently selected from

hydroxy, halogen, carboxy, mono- or di-C 1 -C 3 alkylamino, carbocyclic aryl, halogenated carbocyclic aryl, heterocyclyl, heterocyclyl substituted by substituent(s) independently selected from

halogen, nitro, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, C 1 -C 3 alkoxy,

heterocyclyloxy,

heterocyclyloxy substituted by substituent(s) independently selected from

halogen, C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl,

(carbocyclic aryl)S(O) 2 O,

carboxy,

C 1 -C 3 alkoxycarbonyl,

mono- or di-C 1 -C 3 alkylaminocarbonyl,

mono- or di-C 1 -C 3 alkylaminocarbonyl substituted by carbocyclic aryl,

mono- or di-carbocyclic arylaminocarbonyl,

mono- or di-carbocyclic arylaminocarbonyl substituted by C 1 -C 3 alkyl,

amino,

mono- or di-C 1 -C 4 alkylamino,

mono- or di-C 1 -C 4 alkylamino substituted by cyano,

mono- or di-carbocyclic arylamino,

C 1 -C 3 alkynylcarbonylamino,

C 1 -C 3 alkynylcarbonylamino substituted by carbocyclic aryl,

carbocyclic arylsulfonylamino,

carbocyclic arylsulfonylamino substituted by C 1 -C 3 alkyl,

(carbocyclic aryl)NHC(O)NH,

(carbocyclic aryl)NHC(O)NH substituted by C 1 -C 3 alkoxy,

(carbocyclic aryl)NHC(O)NH substituted by haloganated C 1 -C 3 alkoxy,

carbocyclic aryl diazo,

carbocyclic aryl diazo substituted by mono- or di-C 1 -C 3 alkylamino,

C 1 -C 3 alkylthio,

halogenated C 1 -C 3 alkylthio,

carbocyclic arylthio,

carbocyclic arylthio substituted by substituent(s) independently selected from

halogen, cyano, C 1 -C 3 alkyl,

heterocyclylthio,

C 1 -C 3 alkylsulfonyl,

mono- or di-C 1 -C 3 alkylaminosulfonyl,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

C 1 -C 7 alkyl, halogenated C 1 -C 7 alkyl,

heterocyclyl,

heterocyclyl substituted by substituent(s) independently selected from

C 1 -C 3 alkyl, carbocyclic aryl, halogenated carbocyclic aryl,

(viii) heterocyclyl,

or heterocyclyl substituted by substituent(s) independently selected from

halogen,

hydroxy,

cyano,

nitro,

C 1 -C 4 alkyl,

C 1 -C 4 alkyl substituted by substituent(s) independently selected from

halogen, hydroxy, oxo, C 1 -C 3 alkylcarbonyloxy, carbocyclic arylcarbonylamino, halogenated carbocyclic arylcarbonylamino, C 1 -C 3 alkoxycarbonyl, C 1 -C 3 alkylthio, C 1 -C 3 alkylthio substituted by carbocyclic aryl, C 1 -C 3 alkylthio substituted by halogenated carbocyclic aryl, carbocyclic aryl, carbocyclic aryl substituted by substituent(s) independently selected from

halogen, C 1 -C 3 alkyl,

mono- or di-C 1 -C 3 alkylamino,

C 1 -C 4 alkylcarbonylamino,

C 1 -C 3 alkylthio,

C 1 -C 3 alkenylthio,

carbocyclic arylthio,

halogenated carbocyclic arylthio,

carbocyclic arylthio substituted by C 1 -C 3 alkoxycarbonyl,

heterocyclylthio,

heterocyclylthio substituted by C 1 -C 3 alkyl,

C 1 -C 3 alkylsulfonyl,

carbocyclic arylsulfonyl,

halogenated carbocyclic arylsulfonyl,

carbocyclic arylsulfonyl substituted by C 1 -C 4 alkyl,

C 1 -C 3 alkoxycarbonyl,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen, nitro, C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halogenated C 1 -C 3 alkoxy,

heterocyclyl,

heterocyclyl substituted by substituent(s) independently selected from

halogen, C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkoxycarbonyl;

R 2 is —NHNH 2 , —NHNHBoc, —N(R 2a )(R 2b ), morpholino, 4-acetyl-piperazyl, or 4-phenyl-piperazyl;

wherein R 2a is H or C 1 -C 3 alkyl;

R 2b is C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted by substituent(s) independently selected from

hydroxy,

C 1 -C 3 alkoxy,

amino,

—NHBoc,

C 3 -C 6 cycloalkyl,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, —SO 2 NH 2 ,

heterocyclyl,

C 3 -C 6 cycloalkyl, carbocyclic aryl, carbocyclic aryl substituted by substituent(s) independently selected from

halogen,

C 1 -C 3 alkyl,

C 1 -C 3 alkoxy,

or a group of Formula IV;

wherein Boc is carbamic acid tert-butyl ester and R 3 is C 1 -C 3 alkyl or C 1 -C 3 alkyl substituted by substituent(s) independently selected from

carbocyclic aryl, halogenated carbocyclic aryl, carbocyclic aryl substituted by C 1 -C 3 alkoxy;

L is selected from Formula V-XIX;

wherein R 4 is H or C 1 -C 3 alkyl;

R 5 is H, C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted by a substituted carbocyclic aryl;

Y is —S(O) 2 —, —C(O)—, or —(CH 2 ) m ;

m is 0 or 1;

wherein carbocyclic aryl is phenyl, naphthyl, anthranyl, biphenyl, or phenanthryl;

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, 1,2,3,4-tetrahydro-naphthyl, or bicyclo[2.2.1]hepteny;

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, 1H-pyrrolo[2,3-c]pyridyl, 1H-pyrrolyl, 1-oxo-3H-isobenzofuranyl, 2,2′,5′,2″-terthiophenyl, 2,2′-bithiophenyl, 2,3-dihydro-1-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-2H-benzo[b][1,4]dioxepinyl, 4H-benzo[1,3]dioxinyl, 4H-benzopyranyl, 4-oxo-1,5,6,7-tetrahydro-indolyl, 4-oxo-3,4-dihydro-phthalazinyl, 4-oxo-benzopyranyl, 9,10,10-trioxo-thioxanthenyl, 9H-carbazolyl, 9H-xanthenyl, azetidinyl, benzimidazolyl, benzo[1,3]dioxolyl, benzo[2,1,3]oxadiazolyl, benzo[b]thienyl, benzofuryl, benzothiazolyl, cinnolyl, furyl, imidazo[2,1-b]thiazolyl, imidazolyl, isoxazolyl, morpholino, morpholinyl, oxazolyl, oxolanyl, piperazyl, piperidyl, piridyl, pyrazolo[5,1-b]thiazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrrolidyl, quinolyl, quinoxalyl, thiazolidyl, thiazolyl, thienyl, thiolanyl, 2,3-dihydro-benzofuryl, tetrahydro-thienyl, or benzofuranyl;

halogen is fluoro, chloro, bromo, or iodo.

Preferred compounds of this invention are those compounds of Formula I wherein,

Q is Formula II;

R 1 represents

(i) C 1 -C 10 alkyl,

C 1 -C 10 alkyl substituted by substituent(s) independently selected from

halogen,

oxo,

C 1 -C 3 alkoxy,

C 1 -C 3 alkoxy substituted by carbocyclic aryl,

C 1 -C 3 alkylcarbonyloxy,

carbocyclyloxy,

carbocyclic aryloxy,

carbocyclic aryloxy substituted by substituent(s) independently selected from

halogen, nitro, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted by substituent(s) independently selected from

C 1 -C 3 alkylcalbonylamino, carbocyclic arylcalbonylamino, heterocyclyl,

C 1 -C 4 alkoxycalbonylamino,

heterocyclyl calbonylamino,

carbocyclic arylsulfonylamino,

carbocyclic arylsulfonylamino substituted by substituent(s) independently selected from

nitro, C 1 -C 3 alkyl, mono- or di-C 1 -C 3 arylamino,

C 1 -C 3 alkylthio,

C 1 -C 3 alkylthio substituted by substituent(s) independently selected from

mono- or di-carbocyclic arylaminocarbonyl, halogenated mono- or di-carbocyclic arylaminocarbonyl, carbocyclic aryl, carbocyclic aryl substituted by substituent(s) independently selected from

halogen, C 1 -C 3 alkyl,

carbocyclic arylsulfonyl,

halogenated carbocyclic arylsulfonyl,

heterocyclylthio,

heterocyclylthio substituted by substituent(s) independently selected from

nitro, C 1 -C 3 alkyl,

C 3 -C 6 cycloalkyl,

C 3 -C 6 cycloalkyl substituted by C 1 -C 3 alkyl,

C 3 -C 6 cycloalkenyl,

carbocyclyl,

carbocyclyl substituted by substituent(s) independently selected from

halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 2 -C 3 alkenyl, C 2 -C 3 alkenyl substituted by carbocyclic aryl, C 2 -C 3 alkenyl substituted by carbocyclic aryl substituted C 1 -C 3 alkylsulfinyl,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen, hydroxy, nitro, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted by substituent(s) independently selected from

hydroxy, C 1 -C 3 alkyl, C 1 -C 3 alkyl substituted by carbocyclic aryl, C 1 -C 3 alkoxy, C 1 -C 3 alkoxy substituted by carbocyclic aryl, carbocyclic aryl, halogenated carbocyclic aryl,

(ii) C 2 -C 6 alkenyl,

C 2 -C 6 alkenyl substituted by substituent(s) independently selected from

oxo,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen, nitro, C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halogenated C 1 -C 3 alkoxy,

heterocyclyl,

heterocyclyl substituted by substituent(s) independently selected from

hydroxy, C 1 -C 3 alkyl, C 1 -C 3 alkoxy,

(iii) C 3 -C 6 cycloalkyl,

C 3 -C 6 cycloalkyl substituted by substituent(s) independently selected from

C 1 -C 3 alkyl,

C 1 -C 3 alkyl substituted by substituent(s) independently selected from

oxo, carbocyclic aryl,

carbocyclic arylcarbonylamino,

carbocyclic aryl,

(iv) carbocyclyl,

carbocyclyl substituted by nitro,

(v) carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen,

hydroxy,

cyano,

nitro,

C 1 -C 9 alkyl,

C 1 -C 9 alkyl substituted by substituent(s) independently selected from

halogen, oxo, carbocyclic aryloxy, carbocyclylimino, carbocyclylimino substituted by carbocyclic aryl, mono- or di-carbocyclic arylaminocarbonyl, mono- or di-carbocyclic arylaminocarbonyl substituted by C 1 -C 3 alkoxy, carbocyclic aryl, carbocyclic aryl substituted by substituent(s) independently selected from

halogen, carbocyclic aryl,

C 1 -C 3 alkylcarbonyloxy,

carbocyclic aryloxy,

carbocyclic aryloxy substituted by C 1 -C 3 alkoxy,

C 1 -C 3 alkoxycarbonyl,

mono- or di-C 1 -C 3 alkylaminocarbonyl,

mono- or di-C 1 -C 3 alkylaminocarbonyl substituted by carbocyclic aryl,

mono- or di-carbocyclic arylaminocarbonyl,

mono- or di-carbocyclic arylaminocarbonyl substituted by C 1 -C 3 alkyl,

amino,

mono- or di-C 1 -C 3 alkylamino,

C 1 -C 3 alkynylcarbonylamino,

C 1 -C 3 alkynylcarbonylamino substituted by carbocyclic aryl,

carbocyclic arylsulfonylamino,

carbocyclic arylsulfonylamino substituted by C 1 -C 3 alkyl,

(carbocyclic aryl)NHC(O)NH,

(carbocyclic aryl)NHC(O)NH substituted by C 1 -C 3 alkoxy,

(carbocyclic aryl)NHC(O)NH substituted by haloganated C 1 -C 3 alkoxy,

C 1 -C 3 alkylthio,

halogenated C 1 -C 3 alkylthio,

carbocyclic arylthio,

carbocyclic arylthio substituted by cyano,

C 1 -C 3 alkylsulfonyl,

mono- or di-C 1 -C 3 alkylaminosulfonyl,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

C 1 -C 7 alkyl, halogenated C 1 -C 7 alkyl,

heterocyclyl,

heterocyclyl substituted by substituent(s) independently selected from

C 1 -C 3 alkyl, carbocyclic aryl, halogenated carbocyclic aryl,

(vi) heterocyclyl,

or heterocyclyl substituted by substituent(s) independently selected from

halogen,

nitro,

C 1 -C 4 alkyl,

C 1 -C 4 alkyl substituted by substituent(s) independently selected from

halogen, oxo, C 1 -C 3 alkylthio, C 1 -C 3 alkylthio substituted by carbocyclic aryl, C 1 -C 3 alkylthio substituted by halogenated carbocyclic aryl, carbocyclic aryl, halogenated carbocyclic aryl, heterocyclyl,

C 1 -C 3 alkoxy,

carbocyclic aryloxy,

carbocyclic aryloxy substituted by substituent(s) independently selected from

halogen, C 1 -C 3 alkyl,

C 1 -C 3 alkylthio,

C 1 -C 3 alkenylthio,

carbocyclic arylthio,

C 1 -C 3 alkylsulfonyl,

carbocyclic arylsulfonyl,

halogenated carbocyclic arylsulfonyl,

carbocyclic arylsulfonyl substituted by C 1 -C 4 alkyl,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen, nitro, C 1 -C 3 alkyl, C 1 -C 3 alkoxy,

heterocyclyl,

heterocyclyl substituted by substituent(s) independently selected from

C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl;

R 2 is —NHNH 2 , —NHNHBoc, —N(R 2a )(R 2b ), morpholino, 4-acetyl-piperazyl, or 4-phenyl-piperazyl;

wherein R 2a is H or C 1 -C 3 alkyl;

R 2b is C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted by substituent(s) independently selected from

hydroxy,

C 1 -C 3 alkoxy,

amino,

—NHBoc,

C 3 -C 6 cycloalkyl,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, —SO 2 NH 2 ,

heterocyclyl,

C 3 -C 6 cycloalkyl, carbocyclic aryl, carbocyclic aryl substituted by substituent(s) independently selected from

halogen,

C 1 -C 3 alkyl,

C 1 -C 3 alkoxy,

or a group of Formula IV;

wherein Boc is carbamic acid tert-butyl ester and R 3 is C 1 -C 3 alkyl or C 1 -C 3 alkyl substituted by substituent(s) independently selected from

carbocyclic aryl,

halogenated carbocyclic aryl,

carbocyclic aryl substituted by C 1 -C 3 alkoxy;

L is selected from Formula V-XIX;

wherein R 4 is H or C 1 -C 3 alkyl;

R 5 is H, C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted by a substituted carbocyclic aryl;

Y is —C(O)—;

wherein carbocyclic aryl is phenyl, naphthyl, anthranyl, or biphenyl;

carbocyclyl is 10,11-dihydro-5-oxo-dibenzo[a,d]cycloheptyl, 1-oxo-indanyl, 9H-fluorenyl, 9-oxo-fluorenyl, acenaphthyl, anthraquinonyl, C-fluoren-9-ylidene, indanyl, indenyl, 1,2,3,4-tetrahydro-naphthyl, or bicyclo[2.2.1]hepteny;

heterocyclyl is 1,2,3-thiadiazolyl, 1,2,3-triazolyl, 1,2-dihydro-3-oxo-pyrazolyl, 1,3-dioxo-isoindolyl, 1H-indolyl, 1H-pyrrolyl, 1-oxo-3H-isobenzofuranyl, 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[b][1,4]dioxepinyl, 4-oxo-1,5,6,7-tetrahydro-indolyl, 4-oxo-3,4-dihydro-phthalazinyl, 4-oxo-benzopyranyl, 9,10,10-trioxo-thioxanthenyl, 9H-xanthenyl, azetidinyl, benzimidazolyl, benzo[1,3]dioxolyl, benzo[2,1,3]oxadiazolyl, benzo[b]thienyl, cinnolyl, furyl, imidazolyl, isoxazolyl, morpholino, morpholinyl, oxazolyl, oxolanyl, piperidyl, piridyl, pyrazolyl, pyridyl, pyrimidyl, pyrrolidyl, quinolyl, quinoxalyl, thiazolidyl, thiazolyl, thienyl, thiolanyl, tetrahydro-thienyl, benzofuranyl, or benzothiazolyl;

halogen is fluoro, chloro, bromo, or iodo.

Other preferred compounds of this invention are those compounds of Formula I wherein,

Q is Formula II;

R 1 represents

(i) C 1 -C 10 alkyl,

C 1 -C 10 alkyl substituted by substituent(s) independently selected from

oxo,

di-propylaminocarbonyl,

methoxy substituted by carbocyclic aryl,

methylcarbonyloxy,

carbocyclic aryloxy,

halogenated carbocyclic aryloxy,

carbocyclic aryloxy substituted by nitro,

heterocyclyloxy substituted by methyl,

substituted heterocyclyl-ethylideneaminooxy,

tert-butoxycarbonylamino,

carbocyclic arylcarbonylamino,

C 1 -C 2 alkylthio,

C 1 -C 2 alkylthio substituted by substituent(s) independently selected from

halogenated carbocyclic aryl, carbocyclic aryl substituted by methoxy,

carbocyclic arylthio,

hetrocyclylthio substituted by nitro,

hetrocyclylthio substituted by methyl,

C 5 -C 6 cycloalkyl,

C 5 -C 6 cycloalkenyl,

carbocyclyl substituted by substituent(s) independently selected from

halogen, methyl, methoxy, ethenyl substituted by carbocyclic aryl substituted methylsulfinyl,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen, hydroxy, nitro, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted by substituent(s) independently selected from

C 1 -C 2 alkyl, C 1 -C 2 substituted by carbocyclic aryl, methoxy, methoxy substituted by carbocyclic aryl, carbocyclic aryl, halogenated carbocyclic aryl,

(ii) C 2 -C 3 alkenyl substituted by substituent(s) independently selected from

carbocyclic aryl,

halogenated carbocyclic aryl,

carbocyclic aryl substituted by nitro,

(iii) C 3 -C 6 cycloalkyl,

C 3 -C 6 cycloalkyl substituted by substituent(s) independently selected from

methyl substituted by oxo,

methyl substituted by carbocyclic aryl,

carbocyclic aryl,

(iv) carbocyclyl,

(v) carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen,

hydroxy,

cyano,

nitro,

C 1 -C 9 alkyl,

C 1 -C 9 alkyl substituted by substituent(s) independently selected from

halogen, oxo, carbocyclic aryl, carbocyclic aryl substituted by methyl, carbocyclic aryloxy,

C 1 -C 7 alkoxy,

halogenated C 1 -C 7 alkoxy,

C 1 -C 7 alkoxy substituted by carbocyclic aryl,

methylcarbonyloxy,

carbocyclic aryloxy,

carbocyclic aryloxy substituted by methoxy,

amino,

di-methylamino,

propargynylcarbonylamino substituted by carbocyclic aryl,

carbocyclic arylsulfonylamino substituted by methyl,

(carbocyclic aryl)NHC(O)NH substituted by halogenated methoxy,

halogenated methylthio,

carbocyclic arylthio substituted by cyano,

di-propylamino sulfonyl,

mono- or di-ethylaminocarbonyl substituted by carbocyclic aryl,

carbocyclic aryl,

heterocyclyl substituted by methyl,

heterocyclyl substituted by halogenated carbocyclic aryl,

(vi) heterocyclyl,

or heterocyclyl substituted by substituent(s) independently selected from

halogen,

nitro,

C 1 -C 4 alkyl,

C 1 -C 4 alkyl substituted by substituent(s) independently selected from

halogen, methylthio substituted by halogenated carbocyclic aryl, carbocyclic aryl, halogenated carbocyclic aryl, heterocyclyl,

methoxy,

carbocyclic aryloxy,

carbocyclic aryloxy substituted by methyl,

C 1 -C 3 alkylthio,

propenylthio,

carbocyclic arylthio,

C 1 -C 3 alkylsulfonyl,

carbocyclic arylsulfonyl substituted by C 1 -C 4 alkyl,

carbocyclic aryl,

halogenated carbocyclic aryl,

carbocyclic aryl substituted by methyl,

carbocyclic aryl substituted by nitro,

heterocyclyl;

R 2 is methylamino or dimethylamino;

L is selected from Formula Va, VIIIa, or IXa;

wherein R 4 and R 5 are independently selected from H or C 1 -C 3 alkyl;

Y is —C(O)—;

wherein carbocyclic aryl is phenyl, naphthyl, anthranyl, or biphenyl;

carbocyclyl is 1-oxo-indanyl, 9-oxo-fluorenyl, indenyl, anthraquinonyl, C-fluoren-9-ylidene, 1,2,3,4-tetrahydro-naphthyl, or bicyclo[2.2.1]hepteny;

heterocyclyl is 1,2,3-thiadiazolyl, 1,2,3-triazolyl, 1,2-dihydro-3-oxo-pyrazolyl, 1,3-dioxo-isoindolyl, 1H-indolyl, 1H-pyrrolyl, 1-oxo-3H-isobenzofuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, 2,4-dihydro-3-oxo-pyrazolyl, 2H-benzopyranyl, 2-oxo-benzopyranyl, 3,4-dihydro-2H-benzo[b] [1,4]dioxepinyl, 4-oxo-3,4-dihydro-phthalazinyl, 4-oxo-benzopyranyl, 9,10,10-trioxo-thioxanthenyl, 9H-xanthenyl, azetidinyl, benzimidazolyl, benzo[1,3]dioxolyl, benzo[2,1,3]oxadiazolyl, benzo[b]thienyl, furyl, imidazolyl, isoxazolyl, morpholino, morpholinyl, oxolanyl, piperidyl, piridyl, pyrazolyl, pyridyl, quinolyl, quinoxalyl, thiazolidyl, thiazolyl, thienyl, thiolanyl, 2,3-dihydro-1-oxo-isoindolyl, 2,3-dihydro-benzofuryl, 2-oxo-pyrrolidinyl, 4-oxo-1,5,6,7-tetrahydro-indolyl, cinnolyl, pyrimidyl, pyrrolidyl, tetrahydro-thienyl, benzofuranyl, or benzothiazolyl;

halogen is fluoro, chloro, bromo, or iodo.

Other more preferred compounds of this invention are those compounds of Formula I wherein,

Q is Formula II;

R 1 represents

(i) C 1 -C 10 alkyl substituted by substituent(s) independently selected from

oxo,

di-propylaminocarbonyl,

methoxy substituted by carbocyclic aryl,

methylcarbonyloxy,

carbocyclic aryloxy,

halogenated carbocyclic aryloxy,

carbocyclic aryloxy substituted by nitro,

heterocyclyloxy substituted by methyl,

substituted heterocyclyl-ethylideneaminooxy,

tert-butoxycarbonylamino,

carbocyclic arylcarbonylamino,

C 1 -C 2 alkylthio,

C 1 -C 2 alkylthio substituted by substituent(s) independently selected from

halogenated carbocyclic aryl, carbocyclic aryl substituted by methoxy,

carbocyclic arylthio,

hetrocyclylthio substituted by nitro,

hetrocyclylthio substituted by methyl,

C 5 -C 6 cycloalkenyl,

carbocyclyl substituted by substituent(s) independently selected from

halogen, methyl, methoxy, ethenyl substituted by carbocyclic aryl substituted methylsulfinyl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen, hydroxy, nitro, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted by substituent(s) independently selected from

oxo, carbocyclic aryl, heterocyclyl,

C 1 -C 4 alkoxy, halogenated C 1 -C 4 alkoxy, C 1 -C 4 alkoxy substituted by carbocyclic aryl, carbocyclic aryloxy, halogenated mono-carbocyclic arylaminocarbonyl, carbocyclic aryl, heterocyclyl,

heterocyclyl substituted by substituent(s) independently selected from

C 1 -C 2 alkyl, C 1 -C 2 substituted by carbocyclic aryl, methoxy, methoxy substituted by carbocyclic aryl, carbocyclic aryl, halogenated carbocyclic aryl,

(ii) C 2 -C 3 alkenyl substituted by substituent(s) independently selected from

carbocyclic aryl,

halogenated carbocyclic aryl,

carbocyclic aryl substituted by nitro,

(iii) C 3 -C 6 cycloalkyl substituted by substituent(s) independently selected from

methyl substituted by oxo,

methyl substituted by carbocyclic aryl,

carbocyclic aryl,

(iv) carbocyclyl,

(v) carbocyclic aryl substituted by substituent(s) independently selected from

halogen,

hydroxy,

cyano,

nitro,

C 1 -C 9 alkyl,

C 1 -C 9 alkyl substituted by substituent(s) independently selected from

halogen, oxo, carbocyclic aryl, carbocyclic aryl substituted by methyl, carbocyclic aryloxy,

C 1 -C 7 alkoxy,

halogenated C 1 -C 7 alkoxy,

C 1 -C 7 alkoxy substituted by carbocyclic aryl,

methylcarbonyloxy,

carbocyclic aryloxy,

carbocyclic aryloxy substituted by methoxy,

amino,

di-methylamino,

propargynylcarbonylamino substituted by carbocyclic aryl,

carbocyclic arylsulfonylamino substituted by methyl,

(carbocyclic aryl)NHC(O)NH substituted by halogenated methoxy,

halogenated methylthio,

carbocyclic arylthio substituted by cyano,

di-propylamino sulfonyl,

mono- or di-ethylaminocarbonyl substituted by carbocyclic aryl,

carbocyclic aryl,

heterocyclyl substituted by methyl,

heterocyclyl substituted by halogenated carbocyclic aryl,

(vi) or heterocyclyl substituted by substituent(s) independently selected from

halogen,

nitro,

C 1 -C 4 alkyl,

C 1 -C 4 alkyl substituted by substituent(s) independently selected from

halogen, methylthio substituted by halogenated carbocyclic aryl, carbocyclic aryl, halogenated carbocyclic aryl, heterocyclyl,

methoxy,

carbocyclic aryloxy,

carbocyclic aryloxy substituted by methyl,

C 1 -C 3 alkylthio,

propenylthio,

carbocyclic arylthio,

C 1 -C 3 alkylsulfonyl,

carbocyclic arylsulfonyl,

carbocyclic arylsulfonyl substituted by C 1 -C 4 alkyl,

carbocyclic aryl,

halogenated carbocyclic aryl,

carbocyclic aryl substituted by methyl,

carbocyclic aryl substituted by nitro,

heterocyclyl;

R 2 is methylamino or dimethylamino;

L is selected from Formula XX-XXII;

Y is —C(O)—;

wherein carbocyclic aryl is phenyl, naphthyl, or biphenyl;

carbocyclyl is 1-oxo-indanyl, 9-oxo-fluorenyl, indenyl, anthraquinonyl, C-fluoren-9-ylidene, 1,2,3,4-tetrahydro-naphthyl, or bicyclo[2.2.1]hepteny;

heterocyclyl is 1,2,3-thiadiazolyl, 1,2,3-triazolyl, 1,2-dihydro-3-oxo-pyrazolyl, 1H-indolyl, 1H-pyrrolyl, 2,4-dihydro-3-oxo-pyrazolyl, 2H-benzopyranyl, 4-oxo-benzopyranyl, azetidinyl, benzo[b]thienyl, furyl, isoxazolyl, morpholinyl, piperidyl, piridyl, pyrazolyl, pyridyl, quinolyl, thiazolidyl, thiazolyl, thienyl, thiolanyl, 2,3-dihydro-1-oxo-isoindolyl, 2,3-dihydro-benzofuryl, 2-oxo-benzopyranyl, 2-oxo-pyrrolidinyl, 4-oxo-1,5,6,7-tetrahydro-indolyl, 9H-xanthenyl, cinnolyl, imidazolyl, morpholino, pyrimidyl, pyrrolidyl, tetrahydro-thienyl, benzofuranyl, or benzothiazolyl;

halogen is fluoro, chloro, bromo, or iodo.

Further other more preferred compounds of this invention are those compounds of Formula I wherein,

Q is Formula II;

R 1 represents

(i) C 1 -C 5 alkyl substituted by substituent(s) independently selected from

oxo,

di-propylaminocarbonyl,

methoxy substituted by carbocyclic aryl,

methylcarbonyloxy,

carbocyclic aryloxy,

halogenated carbocyclic aryloxy,

carbocyclic aryloxy substituted by nitro,

heterocyclyloxy substituted by methyl,

substituted heterocyclyl-ethylideneaminooxy,

tert-butoxycarbonylamino,

carbocyclic arylcarbonylamino,

C 1 -C 2 alkylthio,

C 1 -C 2 alkylthio substituted by substituent(s) independently selected from

halogenated carbocyclic aryl, carbocyclic aryl substituted by methoxy,

carbocyclic arylthio,

hetrocyclylthio substituted by nitro,

hetrocyclylthio substituted by methyl,

cyclohexenyl,

carbocyclyl substituted by substituent(s) independently selected from

halogen, methyl, methoxy, ethenyl substituted by carbocyclic aryl substituted methylsulfinyl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen, hydroxy, nitro, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted by substituent(s) independently selected from

oxo, carbocyclic aryl, heterocyclyl,

C 1 -C 2 alkoxy, halogenated C 1 -C 2 alkoxy, C 1 -C 2 alkoxy substituted by carbocyclic aryl, carbocyclic aryloxy, halogenated mono-carbocyclic arylaminocarbonyl, carbocyclic aryl, heterocyclyl,

heterocyclyl substituted by substituent(s) independently selected from

C 1 -C 2 alkyl, C 1 -C 2 substituted by carbocyclic aryl, methoxy, methoxy substituted by carbocyclic aryl, carbocyclic aryl, halogenated carbocyclic aryl,

(ii) C 2 -C 3 alkenyl substituted by substituent(s) independently selected from

carbocyclic aryl,

halogenated carbocyclic aryl,

carbocyclic aryl substituted by nitro,

(iii) C 3 -C 6 cycloalkyl substituted by substituent(s) independently selected from

methyl substituted by oxo,

methyl substituted by carbocyclic aryl,

carbocyclic aryl,

(iv) carbocyclyl,

(v) carbocyclic aryl substituted by substituent(s) independently selected from

halogen,

hydroxy,

cyano,

nitro,

C 1 -C 4 alkyl,

C 1 -C 2 alkyl substituted by substituent(s) independently selected from

halogen, oxo, carbocyclic aryl, carbocyclic aryl substituted by methyl, carbocyclic aryloxy,

C 1 -C 2 alkoxy,

halogenated C 1 -C 2 alkoxy,

C 1 -C 2 alkoxy substituted by carbocyclic aryl,

methylcarbonyloxy,

carbocyclic aryloxy,

carbocyclic aryloxy substituted by methoxy,

amino,

di-methylamino,

propargynylcarbonylamino substituted by carbocyclic aryl,

carbocyclic arylsulfonylamino substituted by methyl,

(carbocyclic aryl)NHC(O)NH substituted by halogenated methoxy,

halogenated methylthio, carbocyclic arylthio substituted by cyano, di-propylamino sulfonyl, mono- or di-ethylaminocarbonyl substituted by carbocyclic aryl, carbocyclic aryl, heterocyclyl substituted by methyl, heterocyclyl substituted by halogenated carbocyclic aryl,

(vi) or heterocyclyl substituted by substituent(s) independently selected from

halogen, nitro, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted by substituent(s) independently selected from

halogen, methylthio substituted by halogenated carbocyclic aryl, carbocyclic aryl, halogenated carbocyclic aryl, heterocyclyl,

methoxy, carbocyclic aryloxy, carbocyclic aryloxy substituted by methyl, C 1 -C 3 alkylthio, propenylthio, carbocyclic arylthio, C 1 -C 3 alkylsulfonyl, carbocyclic arylsulfonyl, carbocyclic arylsulfonyl substituted by methyl, carbocyclic aryl, halogenated carbocyclic aryl, carbocyclic aryl substituted by methyl, carbocyclic aryl substituted by nitro, heterocyclyl;

R 2 is methylamino or dimethylamino;

L is selected from Formula XX-XXII;

Y is —C(O)—;

wherein carbocyclic aryl is phenyl, naphthyl, or biphenyl;

carbocyclyl is 1-oxo-indanyl, indenyl, 9-oxo-fluorenyl, 1,2,3,4-tetrahydro-naphthyl, or bicyclo[2.2.1]hepteny;

heterocyclyl is 1H-indolyl, 2,4-dihydro-3-oxo-pyrazolyl, furyl, pyrazolyl, pyridyl, thienyl, 1,2,3-triazolyl, 1H-pyrrolyl, 2,3-dihydro-1-oxo-isoindolyl, 2,3-dihydro-benzofuryl, 2H-benzopyranyl, 2-oxo-benzopyranyl, 4-oxo-1,5,6,7-tetrahydro-indolyl, imidazolyl, isoxazolyl, morpholino, morpholinyl, pyrazolyl, pyrimidyl, quinolyl, thiazolyl, tetrahydro-thienyl, benzofuranyl, or benzothiazolyl;

halogen is fluoro, chloro, bromo, or iodo.

The following compounds are specially preffered;

Other more preferred compounds of this invention are those compounds of Formula I wherein,

Q is Formula II;

R 1 represents

(i) C 1 -C 10 alkyl,

C 1 -C 10 alkyl substituted by substituent(s) independently selected from

C 5 -C 6 cycloalkyl,

carbocyclic aryl,

heterocyclyl,

(ii) C 3 -C 6 cycloalkyl,

(iii) carbocyclic aryl,

(iv) or heterocyclyl;

R 2 is methylamino or dimethylamino;

L is selected from Formula XX-XXII;

Y is —C(O)—;

wherein carbocyclic aryl is phenyl, naphthyl, anthranyl, or biphenyl;

heterocyclyl is 1,3-dioxo-isoindolyl, 1H-indolyl, 1-oxo-3H-isobenzofuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, 3,4-dihydro-2H-benzo[b] [1,4]dioxepinyl, 4-oxo-3,4-dihydro-phthalazinyl, 9,10,10-trioxo-thioxanthenyl, 9H-xanthenyl, benzimidazolyl, benzo[1,3]dioxolyl, benzo[2,1,3]oxadiazolyl, benzo[b]thienyl, furyl, imidazolyl, isoxazolyl, morpholino, oxolanyl, piperidyl, pyridyl, quinoxalyl, thienyl, quinolyl, or benzothiazolyl;

halogen is fluoro, chloro, bromo, or iodo.

Further other more preferred compounds of this invention are those compounds of Formula I wherein,

Q is Formula II;

R 1 represents

(i) C 1 -C 4 alkyl,

C 1 -C 4 alkyl substituted by substituent(s) independently selected from

cyclopentyl,

carbocyclic aryl,

heterocyclyl,

(ii) carbocyclic aryl,

(iii) or heterocyclyl;

R 2 is methylamino or dimethylamino;

L is selected from Formula XX-XXII;

Y is —C(O)—;

wherein carbocyclic aryl is phenyl, naphthyl, anthranyl, or biphenyl;

heterocyclyl is 9H-xanthenyl, benzo[1,3]dioxolyl, benzo[2,1,3]oxadiazolyl, benzo[b]thienyl, thienyl, 1H-indolyl, quinoxalyl, quinolyl, or benzothiazolyl;

halogen is fluoro, chloro, bromo, or iodo.

The following compounds are specially preffered;

Preferred compounds of this invention are those compounds of Formula I wherein,

Q is Formula II;

R 1 represents

(i) C 1 -C 10 alkyl,

C 1 -C 10 alkyl substituted by substituent(s) independently selected from

halogen,

hydroxy,

oxo,

C 1 -C 3 alkoxy,

C 1 -C 3 alkoxy substituted by substituent(s) independently selected from

carbocyclic aryl, heterocyclyl, heterocyclyl substituted by C 1 -C 3 alkyl,

carbocyclic aryloxy,

carbocyclic aryloxy substituted by substituent(s) independently selected from

halogen, nitro, carbocyclic aryl, carbocyclic aryl substituted by C 1 -C 3 alkoxy, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted by substituent(s) independently selected from

cyano, carbocyclic aryl, heterocyclyl,

mono- or di-carbocyclic arylamino,

mono- or di-carbocyclic arylamino substituted by C 1 -C 3 alkyl,

C 1 -C 3 alkylcalbonylamino,

C 1 -C 4 alkoxycalbonylamino,

carbocyclic arylsulfonylamino,

carbocyclic arylsulfonylamino substituted by substituent(s) independently selected from

nitro, C 1 -C 3 alkyl, mono- or di-C 1 -C 3 alkylamino,

C 1 -C 3 alkylthio,

C 1 -C 3 alkylthio substituted by substituent(s) independently selected from

mono- or di-carbocyclic arylamino, halogenated mono- or di-carbocyclic arylamino, carbocyclic aryl, carbocyclic aryl substituted by substituent(s) independently selected from

halogen, C 1 -C 3 alkyl,

carbocyclic arylsulfonyl,

halogenated carbocyclic arylsulfonyl,

heterocyclylthio,

C 3 -C 6 cycloalkyl,

C 3 -C 6 cycloalkyl substituted by C 1 -C 3 alkyl,

carbocyclyl,

carbocyclyl substituted by substituent(s) independently selected from

halogen, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkenyl substituted by carbocyclic aryl, C 2 -C 3 alkenyl substituted by carbocyclic aryl substituted C 1 -C 3 alkylsulfinyl,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen, hydroxy, nitro, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted by substituent(s) independently selected from

C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkoxy substituted by carbocyclic aryl, carbocyclic aryl, halogenated carbocyclic aryl,

(ii) C 2 -C 8 alkenyl,

C 2 -C 8 alkenyl substituted by substituent(s) independently selected from

halogen,

C 1 -C 3 alkoxy,

C 1 -C 3 alkoxy substituted by carbocyclic aryl,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from halogen,

hydroxy, C 1 -C 3 alkoxy, halogenated C 1 -C 3 alkoxy,

heterocyclyl,

heterocyclyl substituted by nitro,

(iii) C 2 -C 4 alkynyl,

C 2 -C 4 alkynyl substituted by carbocyclic aryl,

(iv) C 3 -C 6 cycloalkyl,

C 3 -C 6 cycloalkyl substituted by substituent(s) independently selected from

C 1 -C 3 alkyl,

C 1 -C 3 alkyl substituted by substituent(s) independently selected from

hydroxy, oxo, carbocyclic aryl,

mono- or di-C 1 -C 3 akylamino,

mono- or di-C 1 -C 3 alkylamino substituted by carbocyclic aryl,

carbocyclic aryl,

(v) C 3 -C 6 cycloalkeyl,

C 3 -C 6 cycloalkeyl substituted by C 1 -C 3 alkyl,

(vi) carbocyclyl,

carbocyclyl substituted by substituent(s) independently selected from

hydroxy,

nitro,

(vii) carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen,

hydroxy,

cyano,

nitro,

C 1 -C 9 alkyl,

C 1 -C 9 alkyl substituted by substituent(s) independently selected from

halogen, hydroxy, oxo, C 1 -C 3 alkoxy, carbocyclic aryloxy, mono- or di-C 1 -C 3 alkylamino-N-oxy, mono- or di-C 1 -C 3 alkylamino, mono- or di-C 1 -C 3 alkylamino substituted by carbocyclic aryl, mono- or di-carbocyclic arylamino, mono- or di-carbocyclic arylamino substituted by C 1 -C 3 alkoxy, carbocyclic aryl, halogenated carbocyclic aryl, heterocyclyl, heterocyclyl substituted by C 1 -C 3 alkyl,

C 2 -C 3 alkenyl,

C 2 -C 3 alkenyl substituted by carbocyclic aryl,

C 1 -C 9 alkoxy,

C 1 -C 9 alkoxy substituted by substituent(s) independently selected from

hydroxy, halogen, carboxy, mono- or di-C 1 -C 3 alkylamino, carbocyclic aryl, halogenated carbocyclic aryl, heterocyclyl, heterocyclyl substituted by substituent(s) independently selected from

halogen, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, C 1 -C 3 alkoxy,

heterocyclyloxy,

heterocyclyloxy substituted by substituent(s) independently selected from

halogen, C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl,

(carbocyclic aryl)S(O) 2 O,

carboxy,

C 1 -C 3 alkoxycarbonyl,

mono- or di-C 1 -C 3 alkylaminocarbonyl,

mono- or di-C 1 -C 3 alkylaminocarbonyl substituted by carbocyclic aryl,

amino,

mono- or di-C 1 -C 4 alkylamino,

mono- or di-C 1 -C 4 alkylamino substituted by cyano,

mono- or di-carbocyclic arylamino,

C 1 -C 3 alkylcarbonylamino,

carbocyclic arylsulfonylamino,

carbocyclic arylsulfonylamino substituted by C 1 -C 3 alkyl,

(carbocyclic aryl)NHC(O)NH,

(carbocyclic aryl)NHC(O)NH substituted by C 1 -C 3 alkoxy,

(carbocyclic aryl)NHC(O)NH substituted by haloganated C 1 -C 3 alkoxy,

C 1 -C 3 alkylthio,

halogenated C 1 -C 3 alkylthio,

carbocyclic arylthio,

halogenated carbocyclic arylthio,

carbocyclic arylthio substituted by C 1 -C 3 alkyl,

heterocyclylthio,

C 1 -C 3 alkylsulfonyl,

mono- or di-C 1 -C 3 alkylaminosulfonyl,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

C 1 -C 7 alkyl, halogenated C 1 -C 7 alkyl,

heterocyclyl,

heterocyclyl substituted by substituent(s) independently selected from

C 1 -C 3 alkyl, carbocyclic aryl, halogenated carbocyclic aryl,

(viii) heterocyclyl,

or heterocyclyl substituted by substituent(s) independently selected from

halogen,

hydroxy,

cyano,

nitro,

C 1 -C 4 alkyl,

C 1 -C 4 alkyl substituted by substituent(s) independently selected from

halogen, hydroxy, oxo, C 1 -C 3 alkylcarbonyloxy, C 1 -C 3 alkoxycarbonyl, C 1 -C 3 alkylthio, C 1 -C 3 alkylthio substituted by carbocyclic aryl, C 1 -C 3 alkylthio substituted by halogenated carbocyclic aryl, carbocyclic aryl, carbocyclic aryl substituted by substituent(s) independently selected from

halogen, nitro, C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halogenated C 1 -C 3 alkoxy,

heterocyclyl,

heterocyclyl substituted by substituent(s) independently selected from

C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkoxycarbonyl;

R 2 is —NHNH 2 , —NHNHBoc, —N(R 2a )(R 2b ), morpholino, 4-acetyl-piperazyl, or 4-phenyl-piperazyl;

wherein R 2a is H or C 1 -C 3 alkyl;

R 2b is C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted by substituent(s) independently selected from

hydroxy,

C 1 -C 3 alkoxy,

amino,

—NHBoc,

C 3 -C 6 cycloalkyl,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, —SO 2 NH 2 ,

heterocyclyl,

C 3 -C 6 cycloalkyl, carbocyclic aryl, carbocyclic aryl substituted by substituent(s) independently selected from

halogen,

C 1 -C 3 alkyl,

C 1 -C 3 alkoxy,

or a group of Formula IV;

wherein Boc is carbamic acid tert-butyl ester and R 3 is C 1 -C 3 alkyl or C 1 -C 3 alkyl substituted by substituent(s) independently selected from

carbocyclic aryl, halogenated carbocyclic aryl, carbocyclic aryl substituted by C 1 -C 3 alkoxy;

L is selected from Formula V-XIX;

wherein R 4 is H or C 1 -C 3 alkyl;

R 5 is H, C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted by a substituted carbocyclic aryl;

Y is —(CH 2 ) m , m is 0 or 1;

wherein carbocyclic aryl is phenyl, naphthyl, phenanthryl, or biphenyl;

carbocyclyl is 9H-fluorenyl, 9-oxo-fluorenyl, acenaphthyl, anthraquinonyl, indanyl, or indenyl;

heterocyclyl is 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, 1H-pyrrolo[2,3-c]pyridyl, 1H-pyrrolyl, 2,2′,5′,2″-terthiophenyl, 2,2′-bithiophenyl, 2,3-dihydro-1-oxo-isoindolyl, 2,3-dihydro-benzo[1,4]dioxinyl, 2,3-dihydro-benzofuryl, 2,4-dihydro-3-oxo-pyrazolyl, 2H-benzopyranyl, 2-oxo-pyrrolidinyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, 3,4-dihydro-2H-benzo[b][1,4]dioxepinyl, 4H-benzo[1,3]dioxinyl, 4H-benzopyranyl, 4-oxo-1,5,6,7-tetrahydro-indolyl, 4-oxo-benzopyranyl, 9H-carbazolyl, 9H-xanthenyl, azetidinyl, benzimidazolyl, benzo[1,3]dioxolyl, benzo[b]thienyl, benzofuryl, benzothiazolyl, furyl, imidazo[2,1-b]thiazolyl, imidazolyl, isoxazolyl, morpholino, morpholinyl, oxolanyl, piperazyl, piperidyl, pyrazolo[5,1-b]thiazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrrolidyl, quinolyl, quinoxalyl, thiazolidyl, thiazolyl, thienyl, or thiolanyl;

halogen is fluoro, chloro, bromo, or iodo.

Other preferred compounds of this invention are those compounds of Formula I wherein,

Q is Formula II;

R 1 represents

(i) C 1 -C 10 alkyl substituted by substituent(s) independently selected from

methoxy,

methoxy substituted by carbocyclic aryl,

carbocyclic aryloxy,

halogenated carbocyclic aryloxy,

mono-C 1 -C 2 aklylamino substituted by cyano,

mono- or di-C 1 -C 2 alkylamino substituted by carbocyclic aryl,

mono-carbocyclic arylamino,

mono-carbocyclic arylamino substituted by methyl,

carbocyclic arylsulfonylamino substituted by methyl,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen, nitro, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted by carbocyclic aryl, C 1 -C 4 alkyl substituted by hydroxy, C 1 -C 2 alkoxy, halogenated C 1 -C 2 alkoxy,

heterocyclyl substituted by carbocyclic aryl,

(ii) C 2 -C 8 alkenyl substituted by substituent(s) independently selected from

methoxy substituted by carbocyclic aryl,

carbocyclic aryl,

carbocyclic aryl substituted by methoxy,

(iii) C 2 -C 4 alkynyl substituted by carbocyclic aryl,

(iv) cyclohexyl substituted by carbocyclic arylmethyl,

(v) carbocyclyl,

(vi) carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen,

hydroxy,

cyano,

amino,

C 1 -C 9 alkyl,

halogenated C 1 -C 9 alkyl,

C 1 -C 9 alkoxy,

C 1 -C 9 alkoxy substituted by substituent(s) independently selected from

halogen, halogenated carbocyclic aryl,

propenyloxy,

methylamino,

di-C 1 -C 2 alkylamino,

di-C 1 -C 2 alkylamino substituted by cyano,

methylthio,

halogenated methylthio,

(vii) heterocyclyl,

or heterocyclyl substituted by substituent(s) independently selected from

halogen,

C 1 -C 4 alkyl,

C 1 -C 4 alkyl substituted by hydroxy,

C 1 -C 4 alkyl substituted by carbocyclic aryl,

methoxy,

C 1 -C 2 alkoxycarbonyl,

carbocyclic arylthio substituted by methoxycarbonyl,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen, halogenated methyl,

heterocyclyl;

R 2 is methylamino or dimethylamino;

L is selected from Formula Va, VIIIa, or IXa;

wherein R 4 and R 5 are independently selected from H or C 1 -C 3 alkyl;

Y is —(CH 2 ) m , m is 0 or 1;

wherein carbocyclic aryl is phenyl, naphthyl, phenanthryl, or biphenyl;

carbocyclyl is 9H-fluorenyl, acenaphthyl, or anthraquinonyl;

heterocyclyl is 1,2,3-thiadiazolyl, 1,2,3-triazolyl, 1,2-dihydro-3-oxo-pyrazolyl, 1,3-dioxolanyl, 1H-indolyl, 1H-pyrrolyl, 2,2′,5′,2″-terthiophenyl, 2,2′-bithiophenyl, 2,3-dihydro-benzo[1,4]dioxinyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, 4-oxo-benzopyranyl, 9H-carbazolyl, 9H-xanthenyl, benzimidazolyl, benzo[1,3]dioxolyl, benzo[b]thienyl, benzofuryl, benzothiazolyl, furyl, imidazolyl, isoxazolyl, oxolanyl, pyrazolo[5,1-b]thiazolyl, pyrazolyl, pyridyl, pyrimidyl, quinolyl, quinoxalyl, thiazolidyl, thiazolyl, thienyl, 2H-benzopyranyl, 4H-benzo[1,3]dioxinyl, azetidinyl, imidazo[2,1-b]thiazolyl, morpholinyl, or 2,3-dihydro-benzofuryl;

halogen is fluoro, chloro, bromo, or iodo.

Other more preferred compounds of this invention are those compounds of Formula I wherein,

Q is Formula II;

R 1 represents

(i) C 1 -C 7 alkyl substituted by substituent(s) independently selected from

methoxy,

methoxy substituted by carbocyclic aryl,

carbocyclic aryloxy,

halogenated carbocyclic aryloxy,

mono-ethylamino substituted by cyano,

di-methylamino substituted by carbocyclic aryl,

mono-carbocyclic arylamino,

mono-carbocyclic arylamino substituted by methyl,

carbocyclic arylsulfonylamino substituted by methyl,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen, nitro, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted by carbocyclic aryl, C 1 -C 4 alkyl substituted by hydroxy, metoxy, halogenated methoxy,

heterocyclyl substituted by carbocyclic aryl,

(ii) C 2 -C 7 alkenyl substituted by substituent(s) independently selected from

methoxy substituted by carbocyclic aryl,

carbocyclic aryl,

carbocyclic aryl substituted by methoxy,

(iii) butynyl substituted by carbocyclic aryl,

(iv) cyclohexyl substituted by carbocyclic arylmethyl,

(v) carbocyclyl,

(vi) carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen,

hydroxy,

cyano,

amino,

C 1 -C 2 alkyl,

halogenated methyl,

C 1 -C 3 alkoxy,

C 1 -C 3 alkoxy substituted by substituent(s) independently selected from

halogen, halogenated carbocyclic aryl,

propenyloxy,

di-C 1 -C 2 alkylamino,

di-C 1 -C 2 alkylamino substituted by cyano,

methylthio,

halogenated methylthio,

(vii) heterocyclyl,

or heterocyclyl substituted by substituent(s) independently selected from

halogen,

C 1 -C 3 alkyl,

C 1 -C 3 alkyl substituted by hydroxy,

C 1 -C 3 alkyl substituted by carbocyclic aryl,

methoxy,

ethoxycarbonyl,

carbocyclic arylthio substituted by methoxycarbonyl,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen, halogenated methyl,

heterocyclyl;

R 2 is methylamino or dimethylamino;

L is selected from Formula XX-XXII;

Y is —(CH 2 ) m , m is 0 or 1;

wherein carbocyclic aryl is phenyl, naphthyl, or biphenyl;

carbocyclyl is acenaphthyl;

heterocyclyl is 1H-indolyl, 1H-pyrrolyl, 2,3-dihydro-benzo[1,4]dioxinyl, 9H-carbazolyl, benzo[1,3]dioxolyl, furyl, pyrazolyl, thienyl, 4-oxo-benzopyranyl, azetidinyl, imidazo[2,1-b]thiazolyl, pyridyl, imidazolyl, 2,3-dihydro-benzofuryl, or benzo[b]thienyl;

halogen is fluoro, chloro, bromo, or iodo.

The following compounds are specially preffered;

Preferred compounds of this invention are those compounds of Formula I wherein,

Q is Formula II;

R 1 represents

(i) C 1 -C 16 alkyl,

C 1 -C 16 alkyl substituted by substituent(s) independently selected from

halogen,

carbocyclyl,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen, nitro, C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl,

(ii) C 2 -C 3 alkenyl,

C 2 -C 3 alkenyl substituted by carbocyclic aryl,

(iii) carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen,

cyano,

nitro,

C 1 -C 5 alkyl,

C 1 -C 5 alkyl substituted by substituent(s) independently selected from

halogen, oxo,

C 2 -C 3 alkenyl,

C 1 -C 4 alkoxy,

C 1 -C 4 alkoxy substituted by substituent(s) independently selected from

halogen, heterocyclyl, halogenated heterocyclyl,

carbocyclic aryloxy,

carbocyclic aryloxy substituted by substituent(s) independently selected from

halogen, nitro,

heterocyclyloxy,

heterocyclyloxy substituted by substituent(s) independently selected from

halogen, C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl,

C 1 -C 3 alkoxycarbonyl,

mono- or di-C 1 -C 4 alkylamino,

C 1 -C 3 alkylcarbonylamino,

carbocyclic aryl diazo,

carbocyclic aryl diazo substituted by mono- or di-C 1 -C 3 alkylamino,

C 1 -C 3 alkylsulfonyl,

carbocyclic aryl,

(iv) heterocyclyl,

or heterocyclyl substituted by substituent(s) independently selected from

halogen,

C 1 -C 3 alkyl,

C 1 -C 3 alkyl substituted by substituent(s) independently selected from

halogen, oxo, carbocyclic arylcarbonylamino, halogenated carbocyclic arylcarbonylamino, heterocyclyl, heterocyclyl substituted by substituent(s) independently selected from

halogen, C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl;

R 2 is —NHNH 2 , —NHNHBoc, —N(R 2a )(R 2b ); morpholino, 4-acetyl-piperazyl, or 4-phenyl-piperazyl;

wherein R 2a is H or C 1 -C 3 alkyl;

R 2b is C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted by substituent(s) independently selected from

hydroxy,

C 1 -C 3 alkoxy,

amino,

—NHBoc,

C 3 -C 6 cycloalkyl,

carbocyclic aryl,

carbocyclic aryl substituted by substituent(s) independently selected from

halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, —SO 2 NH 2 ,

heterocyclyl,

C 3 -C 6 cycloalkyl, carbocyclic aryl, carbocyclic aryl substituted by substituent(s) independently selected from

halogen,

C 1 -C 3 alkyl,

C 1 -C 3 alkoxy,

or a group of Formula IV;

wherein Boc is carbamic acid tert-butyl ester and R 3 is C 1 -C 3 alkyl or C 1 -C 3 alkyl substituted by substituent(s) independently selected from

carbocyclic aryl, halogenated carbocyclic aryl, carbocyclic aryl substituted by C 1 -C 3 alkoxy;

L is selected from Formula V-XIX;

wherein R 4 is H or C 1 -C 3 alkyl;

R 5 is H, C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted by a substituted carbocyclic aryl;

Y is —S(O) 2 —;

wherein carbocyclic aryl is phenyl, naphthyl, or biphenyl;

carbocyclyl is 7,7-dimethyl-2-oxo-bicyclo[2.2.1]heptyl;

heterocyclyl is 1,2,3,4-tetrahydro-isoquinolyl, 1,2,3-thiadiazolyl, 1H-pyrrolyl, benzo[2,1,3]oxadiazolyl, benzo[b]thienyl, furyl, imidazolyl, isoxazolyl, pyrazolyl, pyridyl, quinolyl, thiazolyl, or thienyl;

halogen is fluoro, chloro, bromo, or iodo.

The following compounds are specially preffered;

Preferred compounds of this invention are those compounds of Formula I wherein,

Q is Fomura II;

R 1 is selected from H, —CO 2 t Bu, or —CO 2 Bn (Bn is a benzyl group);

R 2 is methylamino or dimethylamino;

L is selected from Formula XX-XXII;

Y is a single bond;

or a salt thereof.

One embodiment of the invention includes any compound of the invention which selectively binds an MCH receptor, such selective binding is preferably demonstrated by a Ki for one or more other GPCR(s), preferably NPY, being at least 10-fold greater than the Ki for any particular MCH receptor, preferable MCHR1.

As used herein, the term “alkyl” is intended to denote hydrocarbon compounds including straight chain and branched chain, including for example 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 various places in the present specification substituents of compounds of the invention are disclosed in groups. It is specifically intended that the invention include each and every individual subcombination 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 predicted to have seven membrane-spanning domains and are coupled to their effectors via G-proteins linking receptor activation with intracellular biochemical sequelae such as stimulation of adenylyl cyclase. Melanin Concentrating Hormone (MCH), a cyclic peptide, has been identified as the endogenous ligand of the orphan G-protein coupled receptor SLC-1. 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 alter a number of behavioral responses.

Mammalian MCH (19 amino acids) is highly conserved between rat, mouse, and human, exhibiting 100% amino acid identity, but its physiological roles are less clear. MCH has been reported to participate in a variety of processes including feeding, water balance, energy metabolism, general arousal/attention state, memory and cognitive functions, and psychiatric disorders. For reviews, 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 feeding or body weight regulation is supported by Qu et al., Nature 380:243-247, (1996), demonstrating that MCH is over expressed in the hypothalamus of ob/ob mice compared with ob/+mice, and that fasting further 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). MCH also has been reported to functionally antagonize the behavioral effects of α-MSH; see: Miller et al., Peptides 14:1-10, (1993); Gonzalez et al, Peptides 17:171-177, (1996); and Sanchez et al., Peptides 18:3933-396, (1997). In addition, stress has been shown to increase POMC mRNA levels while decreasing the MCH precursor preproMCH (ppMCH) mRNA levels; Presse et al., Endocrinology 131:1241-1250, (1992). Thus MCH may serve as an integrative neuropeptide involved in the reaction to stress, as well as in the regulation of feeding and sexual activity; Baker, Int. Rev. Cytol. 126:1-47, (1991); Knigge et al., Peptides 17:1063-1073, (1996).

The localization and biological activities of MCH peptide suggest that the modulation of MCH receptor activity may be useful in a number of therapeutic applications. MCH is expressed in the lateral hypothalamus, a brain area implicated 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 very similar localization to MCH in the lateral hypothalamus; Sakurai et al., Cell 92:573-585 (1998). MCH mRNA levels in this brain region are increased in rats after 24 hours of food-deprivation; Herve and Fellmann, Neurpeptides 31:237-242 (1997); after insulin injection, a significant increase in the abundance and staining intensity of MCH immunoreactive perikarya and fibres was observed concurrent with a significant increase in the level of MCH 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 mRNA levels are upregulated in the hypothalami of obese ob/ob mice; Qu et al., Nature 380:243-247, (1996); and decreased in the hypothalami of rats treated with leptin, whose food intake and body weight gains are also decreased; Sahu, Endocrinology 139:795-798, (1998). MCH appears to act as a functional antagonist of the melanocortin system in its effects on food intake and on hormone secretion within the HPA (hypothalamopituitary/adrenal axis); Ludwig et al., Am. J. Physiol. Endocrinol. Metab. 274:E627-E633, (1998). Together these data suggest a role for endogenous MCH in the regulation of energy balance and response to stress, and provide a rationale for the development of specific compounds acting at MCH receptors for use in the treatment of obesity and stress-related disorders.

Accordingly, a MCH receptor antagonist is desirable for the prophylaxis or treatment of obesity or obesity related disorders. An obesity related disorder is a disorder that has been directly or indirectly associated to obesity, such as, type II diabetes, syndrome X, impaired glucose tolerance, dyslipidaemia, hypertension, coronary heart disease and other cardiovascular disorders including atherosclerosis, insulin resistance associated with obesity and psoriasis, for treating diabetic complications and other diseases such as polycystic ovarian syndrome (PCOS), certain renal diseases including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal diseases and microalbuminuria as well as certain eating disorders.

In species studied to date, a major portion of the neurons of the MCH cell group occupies a rather constant location in those areas of the lateral hypothalamus and subthalamus where they lie and may be a part of some of the so-called “extrapyramidal” motor circuits. These involve substantial striato- and pallidofugal pathways involving the thalamus and cerebral cortex, hypothalamic areas, and reciprocal connections to subthalamic nucleus, substantia nigra, and mid-brain centers; Bittencourt et al., J. Comp. Neurol. 319:218-245, (1992). In their location, the MCH cell group may offer a bridge or mechanism for expressing hypothalamic visceral activity with appropriate and coordinated motor activity. Clinically it may be of some value to consider the involvement of this MCH system in movement disorders, such as Parkinson's disease and Huntingdon's Chorea in which extrapyramidal circuits are known to be involved.

Human genetic linkage studies have located authentic hMCH loci on chromosome 12 (12q23-24) and the variant hMCH loci on chromosome 5 (5q12-13) (Pedeutour et al., 1994). Locus 12q23-24 coincides with a locus to which autosomal dominant cerebellar ataxia type II (SCA2) has been mapped; 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 an olivopontocerebellar atrophy. Furthermore, the gene for Darier's disease, has been mapped to locus 12q23-24; Craddock et al., Hum. Mol. Genet. 2:1941-1943, (1993). Dariers' disease is characterized by abnormalities I keratinocyte adhesion and mental illnesses in some families. In view of the functional and neuroanatomical patterns of the MCH neural system in the 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 mapped to this locus. Indeed, the gene responsible for chronic or acute forms of spinal muscular atrophies has been assigned to chromosome 5q12-13 using genetic linkage analysis; Melki et al., Nature (London) 344:767-768, (1990); Westbrook et al., Cytogenet. Cell. Genet. 61:225-231, (1992). Furthermore, independent lines of evidence support the assignment of a major schizophrenia locus to chromosome 5q11.2-13.3; 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). The above studies suggest that MCH may play a role in neurodegenerative diseases and disorders of emotion.

Additional therapeutic applications for MCH-related compounds are suggested by the observed effects of MCH in other biological systems. For example, MCH may regulate reproductive functions in male and female rats. MCH transcripts and MCH peptide were found within germ cells in testes of adult rats, suggesting that MCH may participate in stem cell renewal and/or differentiation of early spermatocytes; Hervieu et al., Biology of Reduction 54:1161-1172, (1996). MCH injected directly into the medial preoptic area (MPOA) or ventromedial nucleus (VMN) stimulated sexual activity in female rats; Gonzalez et al., Peptides 17:171-177, (1996). In ovariectomized rats primed with estradiol, MCH stimulated luteinizing hormone (LH) release while anti-MCH antiserum inhibited LH release; Gonzalez et al., Neuroendocrinology 66:254-262, (1997). The zona incerta, which contains a large population of MCH cell bodies, has previously been identified as a regulatory site for the pre-ovulatory LH surge; MacKenzie et al., Neuroendocrinology 39:289-295, (1984). MCH has been reported to influence release of pituitary hormones including ACTH and oxytocin. MCH analogues may also be useful in treating epilepsy. In the PTZ seizure model, injection of MCH prior to seizure induction prevented seizure activity in both rats and guinea pigs, suggesting that MCH-containing neurons may participate in the neural circuitry underlying PTZ-induced seizure; Knigge and Wagner, Peptides 18:1095-1097, (1997). MCH has also been observed to affect behavioral correlates of cognitive functions. MCH treatment hastened extinction of the passive avoidance response in rats; McBride et al., Peptides 15:757-759, (1994); raising the possibility that MCH receptor antagonists may be beneficial for memory storage and/or retention. A possible role for MCH in the modulation or perception of pain is supported by the dense innervation of the periaqueductal grey (PAG) by MCH-positive fibers. Finally, MCH may participate in the regulation of fluid intake. ICV infusion of MCH in conscious sheep produced diuretic, natriuretic, and kaliuretic changes in response to increased plasma volume; Parkes, J. Neuroendocrinol. 8:57-63, (1996). Together with anatomical data reporting the presence of MCH in fluid regulatory areas of the brain, the results indicate that MCH may be an important peptide involved in the central control of fluid homeostasis in mammals.

In a recent citation MCHR1 antagonists surprisingly demonstrated their use as an anti-depressants and/or anti-anxiety agents. MCHR1 antagonists have been reported to show antidepressant and anxiolytic activities in rodent models, such as, social interaction, forced swimming test and ultrasonic vocalization. Therefore, MCHR1 antagonists could be useful to independently treat subjects with depression and/or anxiety. Also, MCHR1 antagonists could be useful to treat subjects that suffer from depression and/or anxiety and obesity.

This invention provides a method of treating an abnormality in a subject wherein the abnormality is alleviated by decreasing the activity of a mammalian MCH1 receptor which comprises administering to the subject an amount of a compound which is a mammalian MCH1 receptor antagonist 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, genta gastrointestinal disorder, a cardiovascular disorder, an electrolyte balance disorder, hypertension, diabetes, a respiratory disorder, asthma, a reproductive function disorder, an immune disorder, an endocrine disorder, a musculoskeletal disorder, a neuroendocrine disorder, a cognitive disorder, a memory disorder, a sensory modulation and transmission disorder, a motor coordination disorder, a sensory integration disorder, a motor integration disorder, a dopaminergic function disorder, a sensory transmission disorder, an olfaction disorder, a sympathetic innervation disorder, an affective disorder, a stress-related disorder, a fluid-balance disorder, a seizure disorder, pain, psychotic behavior, morphine tolerance, opiate addiction or migraine.

Compositions of the invention may conveniently be administered in unit dosage form and may 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 employed as the sole active agent in a pharmaceutical or can be used in combination with other active ingredients which could facilitate the therapeutic effect of the compound.

Compounds of the present invention or a solvate or physiologically functional derivative thereof can be used as active ingredients in pharmaceutical compositions, specifically as a MCH receptor antagonists. By the term “active ingredient” is defined in the context of a “pharmaceutical composition” and shall mean a component of a pharmaceutical composition that provides the primary pharmaceutical benefit, as opposed to an “inactive ingredient” which would generally be recognized as providing no pharmaceutical benefit. The term “pharmaceutical composition” shall mean a composition comprising at one active ingredient and at least one ingredient that is not an active ingredient (for example and not limitation, a filler, dye, or a mechanism for slow release), whereby the composition is amenable to use for a specified, efficacious outcome in a mammal (for example, and not 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 carrier or excipient (e.g., pharmaceutical carrier or excipient) may be used in the treatment of clinical conditions for which a MCH receptor antagonist is indicated. At least one compound of the present invention may be combined with the carrier in either solid or liquid form in a unit dose formulation. The pharmaceutical carrier must be compatible with the other ingredients in the composition and must be tolerated by the individual recipient. Other physiologically active ingredients may be incorporated into the pharmaceutical composition of the invention if desired, and if such ingredients are compatible with the other ingredients in the composition. Formulations may be prepared by any suitable method, typically by uniformly mixing the active compound(s) with liquids or finely divided solid carriers, or both, in the required proportions, and then, if necessary, forming the resulting mixture into a desired shape.

Conventional excipients, such as binding agents, fillers, acceptable wetting agents, tabletting lubricants, and disintegrants may be used in tablets and capsules for oral administration. Liquid preparations for oral administration may be in the form of solutions, emulsions, aqueous or oily suspensions, and syrups. Alternatively, the oral preparations may be in the form of dry powder that can be reconstituted with water or another suitable liquid vehicle before use. Additional additives such as suspending or emulsifying agents, non-aqueous vehicles (including edible oils), preservatives, and flavorings and colorants may be added to the liquid preparations. Parenteral dosage forms may be prepared by dissolving the compound of the invention in a suitable liquid vehicle and filter sterilizing the solution before filling and sealing an appropriate vial or ampoule. These are just a few examples of the many appropriate methods well known in the art for preparing dosage forms.

It is noted that when the MCH receptor antagonists are utilized as active ingredients in a pharmaceutical composition, these are not intended for use only in humans, but in other non-human mammals as well. Indeed, recent advances in the area of animal health-care mandate that consideration be given for the use of MCH receptor antagonists for the treatment of obesity in domestic animals (e.g., cats and dogs), and MCH receptor antagonists in other domestic animals where no disease or disorder is evident (e.g., food-oriented animals such as cows, chickens, fish, etc.). Those of ordinary skill in the art are readily credited with understanding the utility of such compounds in such settings.

Pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting 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, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, dioxane, or acetonitrile are preferred. For instance, when the compound (I) possesses an acidic functional group, it can form an inorganic salt such as an alkali metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g. 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 (e.g., hydrochloride, sulfate, phosphate, hydrobromate, etc.) or an organic salt (e.g., 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 of them are included as a compound of the invention. For example, when a chemical formula is represented as showing no stereochemical designation(s), such as Formula IX, then all possible stereoisomer, optical isomers and mixtures thereof are considered within the scope of that formula. Accordingly, Formula XXII, specifically designates the cis relationship between the two amino groups on the cyclohexyl ring and therefore this formula is also fully embraced by Formula IX.

The novel substituted quinazolines of the present invention can be readily prepared according to a variety of synthetic manipulations, all of which would be familiar to one skilled in the art. Preferred methods for the preparation of compounds of the present invention include, but are not limited to, those described in Scheme 1-31.

The common intermediate (E) of the novel substituted quinazolines can be prepared as shown in Scheme 1. Commercially available 1H,3H-quinazoline-2,4-dione (A) is converted to 2,4-dihalo-quinazoline (B) by a halogenating agent with or without a base (wherein X is halogen such as chloro, bromo, or iodo). The halogenating agent includes phosphorous oxychloride (POCl 3 ), phosphorous oxybromide (POBr 3 ), or phosphorus pentachloride (PCl 5 ). The base includes a tertiary amine (preferably N,N-diisopropylethylamine, etc.) or an aromatic amine (preferably N,N-dimethylaniline, etc.). Reaction temperature ranges from about 100° C. to 200° C., preferably about 140° C. to 180° C. The halogen of 4-position of 2,4-dihalo-quinazoline (B) is selectively substituted by a primary or secondary amine (HNR 2a R 2b , wherein R 2a and R 2b are as defined above) with or without a base in an inert solvent to provide the corresponding 4-substitued amino adduct (C). 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 lower alkyl alcohol solvents (preferably methanol, ethanol, 2-propanol, or butanol, etc.), ethereal solvents (preferably tetrahydrofuran or dioxane, etc.), or amide solvents (preferably N,N-dimethylformamide or 1-methyl-pyrrolidin-2-one, etc.). Reaction temperature ranges from about 0° C. to 200° C., preferably about 10° C. to 150° C.

In turn, this is substituted by the mono-protected diamine (R 4 HN-A-NR 5 P, wherein R 4 HN-A-NR 5 P is as defined below, R 4 and R 5 are as defined above, and P is a protective group) with or without a base in an inert solvent to provide 2,4-disubstituted amino quinazoline (D). 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 lower alkyl alcohol solvents (preferably methanol, ethanol, 2-propanol, or butanol, etc.) or amide solvents (preferably N,N-dimethylformamide or 1-methyl-pyrrolidin-2-one, etc.). Reaction temperature ranges from about 50° C. to 200° C., preferably about 80° C. to 150° C. Also this reaction can be carried out under microwave conditions. Representative protecting groups suitable for a wide variety of synthetic transformations are disclosed in Greene and Wuts, Protective Groups in Organic Synthesis , second edition, John Wiley & Sons, New York, 1991, the disclosure of which is incorporated herein by reference in its entirety. The deprotection of the protective group leads to the common intermediate (E) of the novel substituted quinazolines.

R 4 HN-A-NR 5 P is;

The conversion of the common intermediate (E) to the novel substituted quinazolines (F-H) of the present invention is outlined in Scheme 2.

The amine (E) is reacted with a sulfonyl chloride (R 1 SO 2 Cl) and a base in an inert solvent to provide the novel sulfonamide (F) of the present invention. The base includes an alkali metal carbonate (preferably sodium carbonate or potassium carbonate, etc.), an alkali metal hydrogencarbonate (preferably sodium hydrogencarbonate or potassium hydrogencarbonate, 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.). Reaction temperature ranges from about −20° C. to 50° C., preferably about 0° C. to 40° C.

The amine (E) is reacted with a carboxylic acid (R 1 CO 2 H) and a dehydrating condensing agent in an inert solvent with or without a base to provide the novel amide (G) of the present invention. The dehydrating condensing agent includes dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl), bromo-tris-pyrrolidino-phosnium hexafluorophosphate (PyBroP), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), or 1-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.). In case of need, 1-hydroxybenzotriazole (HOBT), HOBT-6-carboxaamidomethyl polystyrene, or 1-hydroxy-7-azabenzotriazole (HOAT) can be used as a reactant agent. Reaction temperature ranges from about −20° C. to 50° C., preferably about 0° C. to 40° C.

Alternatively, the novel amide (G) of the present invention can be obtained by amidation reaction using an acid chloride (R 1 COCl) 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 hydrogencarbonate, 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.). Reaction temperature ranges from about −20° C. to 50° C., preferably about 0° C. to 40° C.

The novel amide (G) of the present invention is reacted with a reducing agent in an inert solvent to provide the novel amine (H) 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 lithium tri-tert-butoxyaluminum hydride), dialkylaluminum hydrides (preferably di-isobutylaluminum hydride), borane, dialkylboranes (preferably di-isoamyl borane), alkali metal trialkylboron hydrides (preferably lithium triethylboron hydride). The inert solvent includes ethereal solvents (preferably tetrahydrofuran or dioxane) or aromatic solvents (preferably toluene, etc.). Reaction temperature ranges from about −78° C. to 200° C., preferably about 50° C. to 120° C.

Alternatively, the novel amine (H) of the present invention can be obtained by reductive amination reaction using aldehyde (R 1 CHO) and a reducing agent in an inert solvent with or without an acid. The reducing agent includes sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, or boran-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). Reaction temperature ranges from about −20° C. to 120° C., preferably about 0° C. to 100° C. Also this reaction can be carried out under microwave conditions.

Compounds of Formula (I) can be prepared as shown in Scheme 3. The amine of commercially available trans-4-aminomethyl-cyclohexancarboxylic acid is protected as tert-butyl carbamate. The carboxylic acid is reduced to the alcohol by sodium borohydride via the mixed acid anhydride. Tosylation of the alcohol with tosylchloride followed by azidation give the adide, which is converted to the amine by lithium aluminum hydride reduction. The coupling of the amine with the quinazoline core (C), which is synthesized in Scheme 1, gives 2,4-disubstituted amino quinazoline. The deprotection of Boc-group is achieved by an acid to give compounds of Formula (I).

Compounds of Formula (K) can be prepared as shown in Scheme 4. Known cis-(4-aminomethyl-cyclohexylmethyl)-carbamic acid tert-butyl ester (J), synthesis of which is described in WO 01/2710, can be leaded to compounds of Formula (K) according to the method of scheme 3.

Compounds of Formula (L) can be prepared as shown in Scheme 5. The amine of cis-[4-(2-amino-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester is protected as benzyl carbamate. The deprotection of Boc-group is achieved by an acid to give the amine. The coupling of the amine with quinazoline core (C), which is synthesized as scheme 1, gives 2,4-disubstituted amino quinazoline. The deprotection of Z-group is achieved by hydrogen reduction to give compounds of Formula (L).

Compounds of Formula (N) can be prepared as shown in Scheme 6. The amine of commercially available trans-4-aminomethyl-cyclohexanecarboxylic acid is protected as tert-butyl carbamate. The carboxylic acid is transformed to benzyl carbamate (M) by curtius rearrangement. The deprotection of Z-group is achieved by hydrogen reduction to give the amine. The amine is converted to compounds of Formula (N) according to the method of scheme 3.

Compounds of Formula (O) can be prepared from the compound of Formula (M), which is described in Scheme 6, as shown in Scheme 7. The compound of Formula (M) can be leaded to compounds of Formula (O) according to the method of scheme 5.

Compounds of Formula (Q) can be prepared as shown in Scheme 8. [4-(Benzyloxycarbonylamino-methyl)-cyclohexyl]-carbamic acid tert-butyl ester (P), synthesis of which is described in WO 01/72710, can be leaded to compounds of Formula (Q) according to the method of scheme 5.

Alternatively compounds of Formula (Q) can be prepared as shown in Scheme 9. The amine of commercially available cis-4-amino-cyclohexanecarboxylic acid is protected as tert-butyl carbamate. The carboxylic acid (R) is converted to the amide (S) by aqueous ammonia via the mixed acid anhydride. The deprotection of Boc-group is achieved by an acid to give the amine. The coupling of the amine with quinazoline core (C), which is synthesized as scheme 1, gives 2,4-disubstituted amino quinazoline. The amide is reduced to compounds of Formula (Q).

Compounds of Formula (T) can be prepared from the compound of Formula (P), which is described in Scheme 8, as shown in Scheme 10. The compound of Formula (P) can be leaded to compounds of Formula (T) according to the method of scheme 6.

Alternatively compounds of Formula (T) can be prepared as shown in Scheme 11. The amide (S), which is described in Scheme 9, is reduced to the amine. The amine can be leaded to compounds of Formula (T) according to the method of scheme 3.

Compounds of Formula (V) can be prepared as shown in Scheme 12. The mono-protection of commercially available trans-cyclohexane-1,4-diamine can be achieved by the method described in Synthetic communications, 20, 2559-2564 (1990). The conversion to compounds of Formula (V) can be accomplished according to the method of scheme 3.

Compounds of Formula (X) can be prepared as shown in Scheme 13. The dicarboxylic acid of commercially available cis-cyclohexane-1,4-dicarboxylic acid is transformed to dibenzyl carbamate by curtius rearrangement. The deprotection of Z-group is achieved by hydrogen reduction to give the diamine. The mono-protection of the diamine can be achieved according to the method of scheme 12 to give the compound (W). The conversion to compounds of Formula (X) can be accomplished according to the method of scheme 3.

Alternatively the compound of Formula (W) can be prepared as shown in Scheme 14. The carboxylic acid (R), which is described in Scheme 9, is transformed to benzyl carbamate by curtius rearrangement. The deprotection of Z-group is achieved by hydrogen reduction to give the compound of Formula (W).

Compounds of Formula (Y) can be prepared according to the method described in Scheme 12 by using commercially available 4-aminomethyl-benzylamine as a starting material (Scheme 15).

Compounds of Formula (A′) can be prepared as shown in Scheme 16. The mono-protection of commercially available 4-aminomethyl-phenylamine can be achieved by using an equimolecular amount of (Boc) 2 O to give mono-tert-butyl carbamate (Z). The amine can be leaded to compounds of Formula (A′) according to the method of scheme 3.

Compounds of Formula (B′) can be prepared from the compound of Formula (Z), which is described in Scheme 16, as shown in Scheme 17. The compound of Formula (Z) can be leaded to compounds of Formula (B′) according to the method of scheme 5.

Compounds of Formula (C′) can be prepared according to the method described in Scheme 3 by using commercially available (4-amino-phenyl)-carbamic acid tert-butyl ester as a starting material (Scheme 18).

Compounds of Formula (E′) can be prepared as shown in Scheme 19. The selective protection of the secondary amine in the presence of the primary amine of commercially available 4-(aminomethyl)piperidin is achieved by the method described in Synthetic communications, 22, 2357-2360 (1992) to give the amine (D′). The amine is converted to compounds of Formula (E′) according to the method of scheme 3.

Compounds of Formula (F′) can be prepared from the compound of Formula (D′), which is described in Scheme 19, as shown in Scheme 20. The compound of Formula (D′) can be leaded to compounds of Formula (F′) according to the method of Scheme 5.

Compounds of Formula (G′) can be prepared according to the method described in Scheme 5 by using commercially available 1-benzyl-piperidin-4-ylamine as a starting material (Scheme 21).

Compounds of Formula (H′) can be prepared as shown in Scheme 22. The amine of commercially available 1-benzyl-piperidin-4-ylamine is protected as tert-butyl carbamate. The deprotection of benzyl group is achieved by hydrogen reduction to give the amine. The amine can be leaded to compounds of Formula (H′) according to the method of scheme 3.

Compounds of Formula (I′) can be prepared according to the method described in Scheme 3 by using commercially available pyrrolidin-3-yl-carbamic acid tert-butyl ester as a starting material (Scheme 23).

Alternatively, the novel sulfonamide (F), the novel amide (G), and the novel amine (H) of the present invention are directly synthesized from the quinazoline core (C), which is synthesized in Scheme 1, as shown in Scheme 24. This coupling is performed 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 lower alkyl alcohol solvents (preferably methanol, ethanol, 2-propanol, or butanol, etc.) or amide solvents (preferably N,N-dimethylformamide or 1-methyl-pyrrolidin-2-one, etc.). Reaction temperature ranges from about 50° C. to 200° C., preferably about 80° C. to 180° C. Also this reaction can be carried out under microwave conditions.

Compounds of Formula (K′) can be prepared as shown in Scheme 25. Commercially available trans-4-aminomethyl-cyclohexanecarboxylic acid is reacted with sulfonyl chloride (R 1 SO 2 Cl) to give the sulfonamide. The carboxylic acid is converted to the amide via the mixed acid anhydride. The amide is reduced to the amine (J′) by borane reduction. The coupling of the amine with the quinazoline core (C), which is synthesized in Scheme 1, gives the novel sulfonamide (K′) of the present invention.

Compounds of Formula (L′) can be prepared from the compound of Formula (U), which is described in Scheme 12, as shown in Scheme 26. The amine (U) is reacted with sulfonyl chloride (R 1 SO 2 Cl) to give the sulfonamide. The deprotection of Boc-group is achieved by an acid to give the amine. The coupling of the amine with quinazoline core (C), which is synthesized as scheme 1, gives the novel sulfonamide (L′) of the present invention.

Compounds of Formula (M′) can be prepared according to the method described in Scheme 26 by using the compound of Formula (D′), which is described in Scheme 19, as a starting material (Scheme 27).

Compounds of Formula (N′) can be prepared according to the method described in Scheme 26 by using commercially available pyrrolidin-3-yl-carbamic acid tert-butyl ester as a starting material (Scheme 28).

Compounds of Formula (O) can be prepared from the compound of Formula (Z), which is described in Scheme 16, as shown in Scheme 29. The aniline (Z) is reacted with carboxylic acid (R 1 CO 2 H) to give the amide. The deprotection of Boc-group is achieved by an acid to give the amine. The coupling of the amine with quinazoline core (C), which is synthesized as scheme 1, gives the novel sulfonamide (O′) of the present invention.

Compounds of Formula (P′) can be prepared as shown in Scheme 30. The amine (W), which is synthesized in Scheme 13, is subjected to reductive amination by aldehyde (R 1 CHO). The deprotection of Boc-group is achieved by an acid to give the amine. The coupling of the amine with quinazoline core (C), which is synthesized as scheme 1, gives the novel amine (P′) of the present invention.

Scheme 31 shows the preparation of compounds (Q′) of the invention where Q of Formula I has Formula III. The compound (J′), which is synthesized in Scheme 25, is reacted with (1-tert-butoxycarbonylamino-1 trifluorometlanesulfonylimino-methyl)-carbamic acid tert-butyl ester. The deprotection of Boc-group is achieved by an acid to give the novel guanidine (Q′) of the present invention.

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 without, however, limiting the invention to the particulas of these examples. “Ambient temperature” as referred to in the following example is meant to indicate a temperature falling between 0° C. and 40° C.

Abbreviations used in the instant specification, particularly the Schemes and Examples, are as follows:

1 H NMR: proton nuclear magnetic resonance spectrum

AcOH: acetic acid

APCI: atmospheric pressure chemical ionization

(Boc) 2 O: di-tertiary-butyl dicarbonate

BuLi: butyl lithium

BuOH: butanol

CaCl 2 : calcium chloride

CDCl 3 : deuterated chloroform

CF 3 CO 2 H: trifluoroacetic acid

CH 2 Cl 2 : dichloromethane

CHCl 3 : chloroform

CI: chemical ionization

CuCl: copper (1) chloride

D 2 O: deuterium oxide

DMAP: 4-dimethylaminopyridine

DMF: N,N-dimethylformamide

DMSO: dimethyl sulfoxide

EDC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

ESI: electrospray ionization

Et 2 O: diethyl ether

EtOAc: acetic acid ethyl ester

EtOH: ethanol

FAB: fast atom bombardment

H 2 SO 4 : sulfuric acid

HATU: O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphate

HCHO: formaldehyde

HCl: hydrogen chloride

HOAt: 1-hydroxy-7-azabenzotriazole

HOBt: 1-hydroxybenzotriazole

HPLC: high performance liquid chromatography

K 2 CO 3 : potassium carbonate

KHSO 4 : potassium bisulfate

Me 2 NH: dimethylamine

MeNH 2 : methylamine

MeOH: methanol

MgSO 4 : magnesium sulfate

Na 2 CO 3 : sodium carbonate

Na 2 SO 4 .10H 2 O: sodium sulfate decahydrate

NaBH(OAc) 3 : sodium triacetoxyborohydride

NaBH 3 CN: sodium cyanoborohydride

NaBH 4 : sodium borohydride

NaHCO 3 : sodium hydrogencarbonate

NaN 3 : sodium azide

NaNO 2 : sodium nitrate

Pd(OH) 2 : palladium hydroxide

Pd/C: palladium carbon

POCl 3 : phosphoryl chloride

PVP: poly(4-vinylpyridine)

PyBroP: bromo-tris-pyrrolidino phosphonium hexafluoro phosphate

SOCl 2 : thionyl chloride

t-BuOH: tertiary butanol

TFA: trifluoroacetic acid

THF: tetrahydrofuran

WSC: water solubule carbodiimide

ZCl: benzyloxycarbonyl chloride

s: singlet

d: doublet

t: triplet

q: qualtet

dd: doublet doublet

dt: doublet triplet

ddd: doublet doublet doublet

brs: broad singlet

m: multiplet

J: coupling constant

Hz: Hertz

The analytical condition of high performance liquid chromatography is as follows:

Solvent A: 0.050% TFA in water Solvent B: 0.035% TFA in acetonitrile 5-100% B over 5 min, flow rate 3.5 ml/min

trans-4-Bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2-trifluoromethoxy-benzenesulfonamide

To a suspension of 1H-quinazoline-2,4-dione (150 g, 925 mmol) in POCl 3 (549 mL, 5.89 mol) was added dimethyl-phenyl-amine (123 mL, 962 mmol). The mixture was stirred at reflux for 7 hr and concentrated. The solution was poured into ice water, and the aqueous layer was extracted with CHCl 3 (three times). The combined organic layer was dried over MgSO 4 , filtered, concentrated, and purified by flash chromatography (silica gel, 50% CHCl 3 in hexane to 10% EtOAc in CHCl 3 ) to give 2,4-dichloro-quinazoline (159 g, 86%) as a pale yellow solid.

CI MS m/e 199, M + ; 1 H NMR (300 MHz, CDCl 3 ) δ 8.27 (dt, J=8.3, 1.1 Hz, 1 H), 7.95-8.04 (m, 2 H), 7.71-7.81 (m, 1 H).

A solution of 2,4-dichloro-quinazoline (102 g, 530 mmol) in THF (1.2 L) was cooled to 4° C. and 50% aqueous Me 2 NH (139 mL, 1.33 mol) was added. The mixture was stirred at ambient temperature for 80 min. The solution was alkalized with saturated aqueous NaHCO 3 (pH=9), and the aqueous layer was extracted with CHCl 3 (three times). The combined organic layer was dried over MgSO 4 , filtered, and concentrated. The residue was suspended in 50% Et 2 O in hexane (250 mL) and stirred at ambient temperature for 30 min. The solid was collected by filtration, washed with 50% Et 2 O in hexane, and dried at 80° C. to give (2-chloro-quinazolin-4-yl)-dimethyl-amine (104 g, 94%) as a pale yellow solid.

ESI MS m/e 207, M + ; 1 H NMR (300 MHz, CDCl 3 ) δ 8.00 (d, J=8.4 Hz, 1 H), 7.73-7.78 (m, 2 H), 7.68 (ddd, J=8.4, 6.9, 1.4 Hz, 1 H), 3.41 (s, 6 H).

To a solution of trans-4-aminomethyl-cyclohexanecarboxylic acid (150 g, 954 mmol) in 1.32 M aqueous sodium hydroxide (750 mL) were added t-BuOH (1680 mL) and (Boc) 2 O (215 g, 985 mmol). The reaction mixture was stirred at ambient temperature for 18 hr. To the reaction mixture was added H 2 O (2.8 L), and cooled at 5° C. The aqueous layer was acidified with saturated aqueous KHSO 4 (pH=3), extracted with EtOAc (three times). The combined organic layer was washed with saturated aqueous NaRCO 3 and brine, dried over MgSO 4 , filtered, concentrated and dried under reduced pressure to give trans-4-(tert-butoxycarbonylamino-methyl)-cyclohexanecarboxylic acid (165 g, 67%) as a white solid.

ESI MS m/e 280, M+Na + ; 1 H NMR (300 MHz, CDCl 3 ) δ 4.60 (brs, 1 H), 2.98 (t, J=6.3 Hz, 2 H), 2.19-2.33 (m, 1 H), 1.99-2.11 (m, 2 H), 1.77-1.90 (m, 2 H), 1.44 (s, 9 H), 1.34-1.52 (m, 3 H), 0.86-1.05 (m, 2 H).

A suspension of trans-4-(tert-butoxycarbonylamino-methyl)-cyclohexane-carboxylic acid (155 g, 603 mmol) in CH 2 Cl 2 (1.35 L) was cooled at −65° C. and triethylamine (126 mL, 904 mmol) and a solution of ethyl chloroformate (58 mL, 751 mmol) in CH 2 Cl 2 (200 mL) were added below −60° C. The reaction mixture was stirred at 0° C. for 50 min. The mixture was acidified with saturated aqueous KHSO 4 (pH=3), and the aqueous layer was extracted with CHCl 3 (three times). The combined organic layer was washed with saturated aqueous Na 2 CO 3 and brine, dried over MgSO 4 , filtered, and concentrated to give a colorless oil. A solution of the above oil in THF (1.5 L) was cooled at −65° C. and NaBH 4 (26.6 g, 703 mmol) and MeOH (45 mL) were added. The mixture was stirred at −40° C. for 25 min, and stirred at 4° C. for 3 hr. The mixture was acidified with saturated aqueous KHSO 4 (pH=3), and the aqueous layer was extracted with EtOAc (three times). The combined organic layer was washed with saturated aqueous Na 2 CO 3 and brine, dried over MgSO 4 , filtered, and concentrated, and purified by flash chromatography (silica gel, 17% MeOH in CHCl 3 ) to give trans-(4-hydroxymethyl-cyclohexylmethyl)-carbamic acid tert-butyl ester (123 g, 84%) as a white solid.

ESI MS m/e 266, M+Na + ; 1 H NMR (300 MHz, CDCl 3 ) δ 4.59 (brs, 1 H), 3.46 (d, J=6.4 Hz, 2 H), 2.98 (t, J=6.3 Hz, 2 H), 1.75-1.94 (m, 4 H), 1.45 (s, 9 H), 1.24-1.70 (m, 3 H), 0.81-1.12 (m, 4 H).

A solution of trans-(4-hydroxymethyl-cyclohexylmethyl)-carbamic acid tert-butyl ester (123 g, 505 mmol) in pyridine (1 L) was cooled at 4° C. and a solution of p-toluenesulfonyl chloride (125 g, 657 mmol) in pyridine (200 ml) was added below 10° C. The mixture was stirred at ambient temperature for 15 hr and concentrated. After dissolution with EtOAc and H 2 O, the organic layer was separated. The aqueous layer was extracted with EtOAc (three times), the combined organic layer was washed with H 2 O, dried over MgSO 4 , filtered, and concentrated to give a pale yellow oil. To a solution of the above oil in DMF (1.6 L) was added NaN 3 (98.8 g, 1.52 mol). The reaction mixture was stirred at ambient temperature for 14 hr and concentrated. After dissolution with CHCl 3 and saturated aqueous NaHCO 3 , the organic layer was separated. The aqueous layer was extracted with CHCl 3 (three times), the combined organic layer was dried over MgSO 4 , filtered, concentrated, and purified by flash chromatography (silica gel, 17% EtOAc in hexane) to give trans-(4-azidomethyl-cyclohexylmethyl)-carbamic acid tert-butyl ester (124 g, 91%) as a colorless oil.

ESI MS m/e 291, M+Na + ; 1 H NMR (300 MHz, CDCl 3 ) δ 4.59 (brs, 1 H), 3.13 (d, J=6.5 Hz, 2 H), 2.98 (t, J=6.4 Hz, 2 H), 1.70-1.90 (m, 4 H), 1.44 (s, 9 H), 1.25-1.65 (m, 2 H), 0.87-1.07 (m, 4 H).

A suspension of lithium aluminum hydride (2.76 g, 72.6 mmol) in THF (225 mL) was cooled at 0° C. and a solution of trans-(4-azidomethyl-cyclohexylmethyl)-carbamic acid tert-butyl ester (15.0 g, 55.9 mmol) in THF (75 mL) was added over 1 hr. The reaction mixture was stirred at ambient temperature for 6 hr. The reaction was quenched with Na 2 SO 4 .10H 2 O, filtered through a pad of celite, and concentrated. The residue was purified by flash chromatography (silica gel, 50% MeOH in CHCl 3 ) to give trans-(4-aminomethyl-cyclohexylmethyl)-carbamic acid tert-butyl ester (12.3 g, 91%) as a pale yellow oil.

ESI MS m/e 243, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 4.60 (brs, 1 H), 2.97 (t, J=6.3 Hz, 2 H), 2.53 (d, J=6.4 Hz, 2 H), 1.70-1.92 (m, 4 H), 1.44 (s, 9 H), 1.08-1.54 (m, 4 H), 0.81-1.02 (m, 4 H).

Step G: Synthesis of trans-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-carbamic acid tert-butyl ester

A mixture of (2-chloro-quinazolin-4-yl)-dimethyl-amine (15.2 g, 73.3 mmol) and trans-(4-aminomethyl-cyclohexylmethyl)-carbamic acid tert-butyl ester (14.8 g, 61.0 mmol) in 2-propanol (80 mL) was stirred at reflux for 4 days, poured into saturated aqueous NaHCO 3 , and the aqueous layer was extracted with CHCl 3 (three times). The combined organic layer was dried over MgSO 4 , filtered, concentrated, and purified by flash chromatography (NH-silica gel, 33% EtOAc in hexane) to give trans-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-carbamic acid tert-butyl ester (20.4 g, 81%) as a pale yellow solid.

ESI MS m/e 414, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ7.81 (d, J=8.2 Hz, 1 H), 7.40-7.52 (m, 2 H), 6.98-7.06 (m, 1 H), 4.93 (brs, 1 H), 4.59 (brs, 1 H), 3.35 (t, J=6.2 Hz, 2 H), 3.26 (s, 6 H), 2.97 (t, J=6.2 Hz, 2 H), 1.72-1.95 (m, 4 H), 1.44 (s, 9 H), 1.30-1.62 (m, 2 H), 0.84-1.12 (m, 4 H).

Step H: Synthesis of trans-4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2-trifluoromethoxy-benzenesulfonamide hydrochloride.

To a suspension of trans-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]cyclohexylmethyl}-carbamic acid tert-butyl ester (3.84 g, 9.28 mmol) in EtOAc (50 mL) was added 4 M hydrogen chloride in EtOAc (38 mL). The mixture was stirred at ambient temperature for 40 min and concentrated to give a white solid. To a suspension of the solid in CH 2 Cl 2 (50 mL) was added diisopropylethylamine (6.46 mL, 37.1 mmol). The mixture was cooled at 4° C. and a solution of 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (3.31 g, 9.75 mmol) in CH 2 Cl 2 (10 mL) was added below 5° C. The reaction mixture was stirred at 4° C. for 1.5 hr. The reaction was quenched with saturated aqueous NaHCO 3 The aqueous layer was extracted with CHCl 3 (three times). The combined organic layer was dried over MgSO 4 , filtered, concentrated, and purified by flash chromatography (NH-silica gel, 20% EtOAc in hexane) to give trans-4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2-trifluoromethoxy-benzenesulfonamide (3.45 g, 60%) as a pale yellow solid.

ESI MS m/e 616, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.89 (d, J=8.9 Hz, 1 H), 7.81 (d, J=7.6 Hz, 1 H), 7.35-7.61 (m, 4 H), 7.02 (t, J=6.8 Hz, 1 H), 4.96 (brs, 1 H), 3.35 (t, J=6.1 Hz, 2 H), 3.26 (s, 6 H), 2.79 (d, J=6.7 Hz, 2 H), 1.32-1.98 (m, 6 H), 0.72-1.12 (m, 4 H).

trans-4-Bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2-trifluoromethoxy-benzenesulfonamide hydrochloride

Step A: Synthesis of trans-4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2-trifluoromethoxy-benzenesulfonamide hydrochloride.

A solution of trans-4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2-trifluoromethoxy-benzenesulfonamide obtained step H of example 1 (3.45 g, 5.61 mmol) in EtOAc (100 mL) was cooled on an ice-bath and 4 M hydrogen chloride in EtOAc (1.66 mL) was added. The mixture was stirred at ambient temperature for 1 hr and concentrated to give a white solid. The solid was recrystallized from 16% EtOH in Et 2 O, and dried under reduced pressure to give trans-4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2-trifluoromethoxy-benzenesulfonamide hydrochloride (2.76 g, 75%) as a white solid.

ESI MS m/e 616, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 13.50 (brs, 1H), 8.42 (t, J=6.0 Hz, 1 H), 7.86-7.94 (m, 2 H), 7.51-7.68 (m, 4H), 7.21-7.28 (m, 1 H), 4.83 (d, J=6.4 Hz, 1 H), 3.51 (s, 6 H), 3.35 (t, J=6.0 Hz, 2H), 2.78 (t, J=6.4 Hz, 2H), 1.73-1.95 (m, 4H), 1.35-1.65 (m, 2H), 0.81-1.12 (m, 4H).

trans-4-Bromo-N-9-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexyl}-2-trifluoromethoxy-benzenesulfonamide

Step A: Synthesis of trans-[4-(tert-butoxycarbonylamino-methyl)-cyclohexyl]-carbamic acid benzyl ester.

To a suspension of trans-4-aminomethyl-cyclohexanecarboxylic acid (15.0 g, 95.4 mmol) in CHCl 3 (150 mL) were added 1 M aqueous sodium hydroxide (150 mL) and (Boc) 2 O (21.9 g, 100 mmol) successively. The reaction mixture was stirred at ambient temperature for 15 hr, and partitioned between CHCl 3 and water. The aqueous layer was acidified with saturated aqueous KHSO 4 (pH=3), extracted with CHCl 3 (three times). The combined organic layer was washed with brine, dried over MgSO 4 , filtered, and concentrated to give a white solid. To a suspension of the above solid in benzene (75 mL) were added phosphorazidic acid diphenyl ester (16.2 g, 58.9 mmol) and triethylamine (5.94 g, 58.7 mmol). The reaction mixture was stirred at reflux for 3 hr (Caution! Vigorous exothermic reaction). Benzyl alcohol (6.65 g, 61.5 mmol) was added, the reaction mixture was stirred at reflux for 24 hr, concentrated. After dissolution with EtOAc and H 2 O, the organic layer was separated. The aqueous layer was extracted with EtOAc (twice), the combined organic layer was washed with 1 M aqueous KHSO 4 , saturated aqueous NaHCO 3 and brine, dried over MgSO 4 , filtered, concentrated, and purified by flash chromatography (silica gel, 33% EtOAc in hexane) to give a white solid. A suspension of the above solid in Et 2 O was stirred at ambient temperature for 30 min and filtered. The filtrate was washed with Et 2 O and dried under reduced pressure to give trans-[4-(tert-butoxycarbonylamino-methyl)-cyclohexyl]-carbamic acid benzyl ester (17.4 g, 50%) as a white solid.

ESI MS m/e 385, M+Na + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.22-7.41 (m, 5 H), 5.09 (s, 2 H), 4.20-4.68 (m, 2 H), 3.23-3.60 (m, 1 H), 2.96 (t, 2H, J=6.4 Hz), 1.62-2.18 (m, 4 H), 1.44 (s, 9 H), 1.30-1.60 (m, 1 H), 0.90-1.23 (m, 4 H).

To a suspension of trans-[4-(tert-butoxycarbonylamino-methyl)-cyclohexyl]-carbamic acid benzyl ester (4.00 g, 11.0 mmol) in EtOAc (40 mL) was added 4 M hydrogen chloride in EtOAc (10 mL). To the reaction mixture was added CHCl 3 (10 mL) and the mixture was stirred at ambient temperature for 3 hr. To the reaction mixture was 4 M hydrogen chloride in EtOAc (20 mL) and the mixture was stirred at ambient temperature for 1.5 hr, filtered, washed with EtOAc, and dried under reduced pressure to give trans-(4-aminomethyl-cyclohexyl)-carbamic acid benzyl ester hydrochloride (2.96 g, 90%) as a white solid.

ESI MS m/e 263, M (free)+H + ; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.12 (brs, 3 H), 7.25-7.40 (m, 5 H), 7.21 (d, 1 H, J=7.8 Hz), 5.00 (s, 2 H), 3.17-3.30 (m, 1 H), 2.62 (d, 2 H, J=7.0 Hz), 1.64-1.88 (m, 4 H), 1.42-1.60 (m, 1 H), 0.90-1.21 (m, 4 H).

Step C: Synthesis of trans-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexyl}-carbamic acid benzyl ester.

A mixture of (2-chloro-quinazolin-4-yl)-dimethyl-amine (1.50 g, 7.22 mmol) and trans-(4-aminomethyl-cyclohexyl)-carbamic acid benzyl ester hydrochloride (2.59 g, 8.67 mmol) in 2-propanol (15 mL) was stirred at reflux for 8 days and dissolved in CHCl 3 and MeOH. The mixture was poured into saturated aqueous NaHCO 3 , and the aqueous layer was extracted with CHCl 3 (three times). The combined organic layer was dried over MgSO 4 , filtered, concentrated, and purified by flash chromatography (H-silica gel, 33% EtOAc in hexane) to give trans-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexyl}-carbamic acid benzyl ester (1.20 g, 38%) as a pale yellow solid.

ESI MS m/e 434, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.76-7.82 (m, 1 H), 7.40-7.50 (m, 2 H), 7.25-7.40 (m, 5 H), 6.95-7.04 (m, 1 H), 5.08 (s, 2 H), 4.82-5.05 (m, 1 H), 4.40-4.70 (m, 1 H), 3.40-3.60 (m, 1 H), 3.35 (t, 2H, J=6.3 Hz), 3.26 (s, 6 H), 1.96-2.18 (m, 2 H), 1.80-1.96 (m, 2 H), 1.45-1.61 (m, 1 H), 1.00-1.20 (m, 4 H).

Step D: Synthesis of trans-4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexyl}-2-trifluoromethoxy-benzenesulfonamide.

To a suspension of trans-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexyl}-carbamic acid benzyl ester (500 mg, 1.15 mmol) in MeOH (5 mL) was added 5% Pd/C (50 mg). The mixture was stirred at ambient temperature under hydrogen atmosphere for 2 hr, at 50° C. for 8 hr, and at ambient temperature for 10.5 hr, filtered, and concentrated to give a colorless oil. To a solution of the above oil in CH 2 Cl 2 (5 mL) was added diisopropylethylamine (420 μL, 2.41 mmol). The mixture was cooled to 4° C. and a solution of 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (431 mg, 1.27 mmol) in CH 2 Cl 2 (2 mL) was added below 5° C. The reaction mixture was stirred at 4° C. for 1.5 hr. The reaction was quenched with saturated aqueous NaHCO 3 The aqueous layer was extracted with CHCl 3 (three times). The combined organic layer was dried over MgSO 4 , filtered, concentrated, and purified by flash chromatography (NH-silica gel, 33% to 50% EtOAc in hexane) to give trans-4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexyl}-2-trifluoromethoxy-benzenesulfonamide (560 mg, 81%) as a pale yellow solid.

ESI MS m/e 602, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.90 (d, 1 H, J=8.9 Hz), 7.80 (dd, 1 H, J=8.4, 0.9 Hz), 7.38-7.58 (m, 4 H), 7.01 (ddd, 1 H, J=8.4, 6.7, 1.6 Hz), 4.85-5.04 (m, 1 H), 3.31 (t, 2 H, J=6.3 Hz), 3.24 (s, 6 H), 3.07-3.20 (m, 1 H), 1.70-1.90 (m, 4 H), 1.42-1.58 (m, 1 H), 0.90-1.28 (m, 4 H).

N 2 -[1-(4-Bromo-2-trifluoromethoxy-benzenesulfonyl)-piperidin-4-yl]-N 4 ,N 4 -dimethyl-quinazoline-2,4-diamine

Using the procedure for the step G of example 1, the title compound was obtained.

ESI MS m/e 362, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.80 (d, J=7.6 Hz, 1 H), 7.20-7.52 (m, 7 H), 6.97-7.05 (m, 1 H), 4.74-4.90 (m, 1 H), 3.90-4.05 (m, 1 H), 3.53 (s, 2 H), 3.26 (s, 6 H), 2.78-2.90 (m, 2 H), 2.02-2.24 (m, 4 H), 1.48-1.62 (m, 2 H).

Step B: Synthesis of IV-[1-(4-bromo-2-trifluoromethoxy-benzenesulfonyl)-piperidin-4-yl]-N 4 ,N 4 -dimethyl-quinazoline-2,4-diamine.

To a solution of N 2 -(1-benzyl-piperidin-4-yl)-N 4 ,N 4 -dimethyl-quinazoline-2,4-diamine (500 mg, 1.38 mmol) in MeOH (5 mL) was added 20% Pd(OH) 2 (100 mg). The mixture was stirred at ambient temperature under hydrogen atmosphere for 1.5 hr, at 50° C. for 8 hr, at ambient temperature for 16.5 hr, filtered through a pad of celite, and concentrated. To a solution of the residue in CH 2 Cl 2 (5 mL) was added diisopropylethylamine (510 μL, 2.93 mmol). The mixture was cooled to 4° C. and a solution of 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (493 mg, 1.45 mmol) in CH 2 Cl 2 (2 mL) was added below 5° C. The reaction mixture was stirred at 4° C. for 2 hr. The reaction was quenched with saturated aqueous NaHCO 3 The aqueous layer was extracted with CHCl 3 (three times). The combined organic layer was dried over MgSO 4 , filtered, concentrated, and purified by flash chromatography (NH-silica gel, 33% EtOAc in hexane) to give N 2 -[1-(4-bromo-2-trifluoromethoxy-benzenesulfonyl)-piperidin-4-yl]-N 4 ,N 4 -dimethyl-quinazoline-2,4-diamine (339 mg, 43%) as a pale yellow solid.

ESI MS m/e 596, M+Na + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.87 (d, J=8.2 Hz, 1 H), 7.81 (dd, J=8.3, 1.0 Hz, 1 H), 7.36-7.61 (m, 4 H), 7.04 (ddd, J=8.3, 6.8, 1.4 Hz, 1 H), 4.77 (d, J=7.8 Hz, 1 H), 3.97-4.14 (m, 1 H), 3.68-3.86 (m, 2 H), 3.25 (s, 6 H), 2.87-3.01 (m, 2 H), 2.10-2.23 (m, 2 H), 1.51-1.70 (m, 2 H).

trans-4-Bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-2-trifluoromethoxy-benzenesulfonamide

To a solution of trans-cyclohexane-1,4-diamine (15.0 g, 131 mmol) in 1,4-dioxane (85 mL) was added (Doc) 2 O (3.61 g, 16.5 mmol) dropwise over 4 hr. The mixture was stirred at ambient temperature for 19 hr and concentrated. To the residue was added H 2 O and the insoluble material was removed by filtration. The filtrate was extracted with CHCl 3 (three times). The combined organic layer was dried over MgSO 4 , filtered, concentrated to give trans-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester (3.15 g, 11% based on diamine, 89% based on (Boc) 2 O) as a white solid.

ESI MS m/e 215, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 4.43 (brs, 1 H), 3.36 (brs, 1 H), 2.57-2.70 (m, 1 H), 1.78-2.04 (m, 4 H), 1.44 (s, 9 H), 1.05-1.38 (m, 4 H).

Step B: Synthesis of trans-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester.

Using the procedure for the step G of example 1, the title compound was obtained

ESI MS m/e 408, M+Na + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.80 (d, J=8.2 Hz, 1 H), 7.39-7.52 (m, 2 H), 7.02 (ddd, 1H, J=8.3, 6.3, 1.9 Hz, 1 H), 4.68-4.78 (m, 1 H), 4.43 (brs, 1 H), 3.89 (brs, 1 H), 3.46 (brs, 1 H), 3.25 (s, 6 H), 2.15-2.24 (m, 2 H), 1.97-2.10 (m, 2 H), 1.45 (s, 9 H), 1.21-1.35 (m, 4 H).

Step C: Synthesis of trans-4-bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-2-trifluoromethoxy-benzenesulfonamide.

To a solution of trans-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester (500 mg, 1.30 mmol) in EtOAc (5 mL) was added 4 M hydrogen chloride in EtOAc (5 mL). The mixture was stirred at ambient temperature for 1 hr and concentrated to give a white solid. To a suspension of the above solid in CH 2 Cl 2 (7 mL) was added diisopropylethylamine (905 μL, 5.20 mmol). The mixture was cooled to 4° C. and a solution of 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (462 mg, 1.36 mmol) in CH 2 Cl 2 (2 mL) was added below 5° C. The reaction mixture was stirred at 4° C. for 1.5 hr. To the reaction mixture was added a solution of 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (88 mg, 0.26 mmol) in CH 2 Cl 2 (0.5 mL) and the mixture was stirred at 4° C. for 1 hr. To the reaction mixture was added diisopropylethylamine (230 μL, 1.32 mmol) and the mixture was stirred at 4° C. for 1.5 hr. The reaction was quenched with saturated aqueous NaHCO 3 The aqueous layer was extracted with CHCl 3 (three times). The combined organic layer was dried over MgSO 4 , filtered, concentrated, and purified by flash chromatography (NH-silica gel, 50% EtOAc in hexane) to give trans-4-bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-2-trifluoromethoxy-benzenesulfonamid (339 mg, 44%) as a white solid.

ESI MS m/e 588, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.92 (d, J=8.9 Hz, 1 H), 7.80 (dd, J=8.3, 0.7 Hz, 1 H), 7.37-7.59 (m, 4 H), 6.99-7.06 (m, 1 H), 4.64-4.75 (m, 1 H), 3.78-3.94 (m, 1 H), 3.17-3.30 (m, 7 H), 2.09-2.20 (m, 2 H), 1.85-1.97 (m, 2 H), 1.12-1.47 (m, 4 H).

trans-4-Bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-2-trifluoromethoxy-benzenesulfonamide

To a suspension of trans-[4-(tert-butoxycarbonylamino-methyl)-cyclohexyl]-carbamic acid benzyl ester (4.00 g, 11.0 mmol) in MeOH (40 mL) was added 5% Pd/C (400 mg). The mixture was stirred at ambient temperature under hydrogen atmosphere for 1 hr, filtered through a pad of celite, and concentrated to give a white solid. A suspension of the above solid in hexane (15 mL) was stirred at ambient temperature for 30 min. The solid was collected by filtration, washed with hexane, dried under reduced pressure to give trans-(4-amino-cyclohexylmethyl)-carbamic acid tert-butyl ester (2.52 g, 100%) as a white solid.

ESI MS m/e 229, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 4.56-4.88 (m, 1 H), 3.00 (t, J=6.5 Hz, 2 H), 2.54-2.65 (m, 1 H), 1.70-1.94 (m, 4 H), 1.44 (s, 9 H), 1.18-1.50 (m, 1 H), 0.92-1.15 (m, 4 H).

Step B: Synthesis of trans-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-carbamic acid tert-butyl ester.

Using the procedure for the step G of example 1, the title compound was obtained

ESI MS m/e 422, M+Na + ; 1 H NMR (300 MHz, CDCl 3 ) 7.81 (d, J=7.9 Hz, 1 H), 7.38-7.52 (m, 2 H), 6.96-7.07 (m, 1 H), 4.55-4.84 (m, 2 H), 3.75-3.97 (m, 1 H), 3.26 (s, 6 H), 3.01 (t, J=6.4 Hz, 2 H), 2.15-2.30 (m, 2 H), 1.75-1.88 (m, 2 H), 1.45 (s, 9 H), 1.35-1.54 (m, 1 H), 1.00-1.30 (m, 4 H).

Step C: Synthesis of trans-4-bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-2-trifluoromethoxy-benzenesulfonamide.

To a suspension of trans-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-carbamic acid tert-butyl ester (500 mg, 1.25 mmol) in EtOAc (5 mL) was added 4 M hydrogen chloride in EtOAc (5 mL). The mixture was stirred at ambient temperature for 1 hr and concentrated to give a white solid. To a suspension of the above solid in CH 2 Cl 2 (7 mL) was added diisopropylethylamine (905 μL, 5.20 mmol). The mixture was cooled to 4° C. and a solution of 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (446 mg, 1.31 mmol) in CH 2 Cl 2 (2 mL) was added below 5° C. The reaction mixture was stirred at 4° C. for 1.5 hr. To the reaction mixture was added a solution of 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (85 mg, 0.25 mmol) in CH 2 Cl 2 (0.5 mL) and the mixture was stirred at 4° C. for 1 hr. To the reaction mixture was added diisopropylethylamine (220 μL, 1.26 mmol) and the mixture was stirred at 4° C. for 1 hr. The reaction was quenched with saturated aqueous NaHCO 3 . The aqueous layer was extracted with CHCl 3 (three times). The combined organic layer was dried over MgSO 4 , filtered, concentrated, and purified by flash chromatography (NH-silica gel, 50% EtOAc in hexane) to give trans-4-bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-2-trifluoromethoxy-benzenesulfonamide (624 mg, 83%) as a pale yellow solid.

ESI MS m/e 602, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.89 (d, J=8.9 Hz, 1 H), 7.80 (d, J=8.5 Hz, 1 H), 7.39-7.60 (m, 4 H), 7.04 (ddd, J=8.2, 6.8, 1.6 Hz, 1 H), 3.71-3.92 (m, 1 H), 3.30 (s, 6 H), 2.85 (d, J=6.5 Hz, 2 H), 2.10-2.22 (m, 2 H), 1.70-1.86 (m, 2 H), 1.37-1.53 (m, 1 H), 0.98-1.32 (m, 4 H).

N 2 -[1-(4-Bromo-2-trifluoromethoxybenzenesulfonyl)-piperidin-4-ylmethyl]-N 4 ,N 4 -dimethyl-quinazoline-2,4-diamine

To a solution of C-piperidin-4-yl-methylamine (15.0 g, 131 mmol) in toluene (165 mL) was added benzaldehyde (13.9 g, 131 mmol) and the mixture was stirred at reflux with a Dean-Stark trap under N 2 atmosphere for 3 hr, and cooled on an ice-bath. To the reaction mixture was added (Boc) 2 O (31.5 g, 144 mmol) dropwise over 15 min. The mixture was stirred at ambient temperature for 2.5 days, and concentrated. To the residue was added 1 M aqueous KHSO 4 and the mixture was stirred at ambient temperature for 7 hr, the aqueous layer was washed with EtO (twice), alkalized with sodium hydroxide, and extracted with CHCl 3 (five times). The combined organic layer was dried over MgSO 4 , filtered, concentrated. The precipitate was suspended in hexane (10 mL) and the suspension was stirred at ambient temperature for 10 min. The solid was collected by filtration and dried under reduced pressure to give 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (25.8 g, 92%) as a white solid.

ESI MS m/e 215, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 3.85-4.22 (m, 2 H), 2.90 (d, J=6.8 Hz, 2 H), 2.50-2.80 (m, 2 H), 1.70-2.02 (m, 3 H), 1.45 (s, 9 H), 1.10-1.28 (m, 2 H).

Step B: Synthesis of 4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester.

Using the procedure for the step G of example 1, the title compound was obtained

ESI MS m/e 386, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.81 (d, J=8.4 Hz, 1 H), 7.41-7.53 (m, 2 H), 6.99-7.06 (m, 1 H), 5.16 (brs, 1 H), 4.00-4.20 (m, 2 H), 3.41 (t, J=6.1 Hz, 2 H), 3.26 (s, 6 H), 2.60-2.77 (m, 2 H), 1.67-1.84 (m, 3 H), 1.45 (s, 9 H), 1.11-1.28 (m, 2 H).

Step C: Synthesis of N 2 -[1-(4-bromo-2-trifluoromethoxy-benzenesulfonyl)-piperidin-4-ylmethyl]-N 4 ,N 4 -dimethyl-quinazoline-2,4-diamine.

To a suspension of 4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.30 mmol) in EtOAc (5 mL) was added 4 M hydrogen chloride in EtOAc (5 mL). The mixture was stirred at ambient temperature for 1 hr and concentrated to give a white solid. To a suspension of the above solid in CH 2 Cl 2 (5 mL) was added diisopropylethylamine (480 μL, 2.76 mmol). The mixture was cooled to 4° C. and a solution of 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (462 mg, 1.36 mmol) in CH 2 Cl 2 (2 mL) was added below 5° C. The reaction mixture was stirred at 4° C. for 3 hr. The reaction was quenched with saturated aqueous NaHCO 3 The aqueous layer was extracted with CHCl 3 (three times). The combined organic layer was dried over MgSO 4 , filtered, concentrated, and purified by flash chromatography (NH-silica gel, 14% to 20% EtOAc in hexane) to give N 2 -[1-(4-bromo-2-trifluoromethoxy-benzenesulfonyl)-piperidin-4-ylmethyl]-N 4 ,N 4 -dimethyl-quinazoline-2,4-diamine (420 mg, 55%) as a yellow solid.

ESI MS m/e 588, M+H + , 1 H NMR (300 MHz, CDCl 3 ) δ 7.85 (d, J=8.9 Hz, 1 H), 7.81 (dd, J=8.7, 0.9 Hz, 1 H), 7.40-7.56 (m, 4 H), 7.04 (ddd, J=8.2, 6.7, 1.6 Hz, 1 H), 5.10-5.46 (brs, 1 H), 3.85 (d, J=12.4 Hz, 2 H), 3.40 (t, J=6.4 Hz, 2 H), 3.27 (s, 6 H), 2.56-2.67 (m, 2 H), 1.64-1.91 (m, 3 H), 1.23-1.43 (m, 2 H).

4-Bromo-N-[1-(4-dimethylamino-quinazolin-2-yl)-piperidin-4-ylmethyl]-2-trifluoromethoxy-benzenesulfonamide

To a solution of 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (7.00 g, 32.7 mmol) in CHCl 3 (70 mL) was added triethylamine (3.64 g, 36.0 mmol). The resulting solution was cooled to 4° C. and ZCl (6.13 g, 35.9 mmol) was added below 8° C. over 15 min. The reaction mixture was stirred at ambient temperature for 18 hr, and poured into saturated aqueous NaHCO 3 . The aqueous layer was extracted with CHCl 3 (three times), dried over MgSO 4 , filtered, concentrated, and purified by flash chromatography (silica gel, 33% to 50% EtOAc in hexane) to give 4-(benzyloxycarbonylamino-methyl)-piperidine-1-carboxylic acid tert-butyl ester (10.7 g, 94%) as a colorless oil.

ESI MS m/e 371, M+Na + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.26-7.37 (m, 5 H), 5.09 (s, 2 H), 4.84-5.01 (m, 1 H), 3.95-4.22 (m, 2 H), 2.98-3.16 (m, 2 H), 2.66 (t, J=12.4 Hz, 2 H), 1.58-1.72 (m, 3 H), 1.45 (s, 9 H), 0.98-1.18 (m, 2 H).

A solution of 4-(benzyloxycarbonylamino-methyl)-piperidine-1-carboxylic acid tert-butyl ester (10.2 g, 29.3 mmol) in EtOAc (100 mL) was cooled on an ice-bath and 4 M hydrogen chloride in EtOAc (100 mL) was added. The mixture was stirred at ambient temperature for 1 hr and concentrated. The residue was suspended in hexane (30 mL) and the mixture was stirred at ambient temperature for 30 min. The solid was collected by filtration, washed with hexane, and dried under reduced pressure to give piperidin-4-ylmethyl-carbamic acid benzyl ester hydrochloride (7.24 g, 87%) as a white solid.

ESI MS m/e 271, M (free)+Na + ; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.10 (brs, 2 H), 7.20-7.50 (m, 6 H), 5.02 (s, 2 H), 3.15-3.28 (m, 2 H), 2.68-3.02 (m, 4 H), 1.56-1.82 (m, 3 H), 1.20-1.52 (m, 2 H).

Step C: Synthesis of [1-(4-dimethylamino-quinazolin-2-yl)-piperidin-4-ylmethyl]-carbamic acid benzyl ester.

Using the procedure for the step C of example 3, the title compound was obtained

ESI MS m/e 420, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.78 (d, J=8.2 Hz, 1 H), 7.21-7.49 (m, 7 H), 6.95-7.04 (m, 1 H), 5.06-5.17 (m, 2 H), 4.83-4.98 (m, 3 H), 3.24 (s, 6 H), 3.00-3.16 (m, 2 H), 2.77-2.91 (m, 2 H), 1.58-1.97 (m, 3 H), 1.12-1.33 (m, 2 H).

Step D: Synthesis of 4-bromo-N-[1-(4-dimethylamino-quinazolin-2-yl)-piperidin-4-ylmethyl]-2-trifluoromethoxy-benzenesulfonamide.

Using the procedure for the step D of example 3, the title compound was obtained

ESI MS m/e 588, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.87 (d, J=8.7 Hz, 1 H), 7.78 (d, J=8.2 Hz, 1 H), 7.44-7.59 (m, 4 H), 6.97-7.06 (m, 1 H), 4.94-5.04 (m, 1 H), 4.89 (d, J=13.2 Hz, 2 H), 3.25 (s, 6 H), 2.75-2.88 (m, 4 H), 1.64-1.82 (m, 3 H), 1.05-1.28 (m, 2 H).

cis-4-Bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-2-trifluoromethoxy-benzenesulfonamide

To a suspension of cis-cyclohexane-1,4-dicarboxylic acid (25.0 g, 145 mmol) in benzene (125 mL) were added phosphorazidic acid diphenyl ester (81.9 g, 298 mmol) and triethylamine (30.1 g, 297 mmol). The reaction mixture was stirred at reflux for 2.5 hr (Caution! Vigorous exothermic reaction). Benzyl alcohol (32.2 g, 298 mmol) was added and the mixture was stirred at reflux for 24 hr. The reaction mixture was concentrated and the residue was dissolved in EtOAc and H 2 O. The organic layer was separated and the aqueous layer was extracted with EtOAc (twice). The combined organic layer was washed with 1 M aqueous KHSO 4 , saturated aqueous NaHCO 3 , and brine, dried over MgSO 4 , filtered, concentrated, and purified by flash chromatography (silica gel, 33% EtOAc in hexane) to give cis-(4-benzyloxycarbonylamino-cyclohexyl)-carbamic acid benzyl ester (52.0 g, 94%) as a colorless oil.

ESI MS m/e 405, M+Na + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.15-7.40 (m, 10 H), 5.07 (s, 4 H), 4.70-5.00 (m, 2 H), 3.52-3.80 (m, 2 H), 1.60-1.80 (m, 4 H), 1.45-1.60 (m, 4 H).

To a solution of cis-(4-benzyloxycarbonylamino-cyclohexyl)-carbamic acid benzyl ester (91.7 g, 240 mmol) in MeOH (460 mL) was added 5% Pd/C (9.17 g). The reaction mixture was stirred at ambient temperature under hydrogen atmosphere for 2.5 days, filtered through a pad of celite, and concentrated to give a diamine as a colorless oil. To a solution of the diamine in MeOH (550 mL) was added a solution of (Boc) 2 O (6.59 g, 30.2 mmol) in MeOH (80 mL) dropwise over 4 hr. The reaction mixture was stirred at ambient temperature for 1.5 days and concentrated. After dissolution with H 2 O, the aqueous layer was extracted with CHCl 3 (three times). The combined organic layer was dried over MgSO 4 , filtered, and concentrated to give cis-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester (7.78 g, 15%, crude) as a colorless oil. The aqueous layer was concentrated and the residue was dissolved in MeOH, dried over MgSO 4 , filtered, and concentrated to give a recovered diamine (32.9 g) as a colorless oil. To a solution of the recovered diamine (32.9 g, 288 mmol) in MeOH (660 mL) was added a solution of (Boc) 2 O (6.29 g, 28.8 mmol) in MeOH (80 mL) dropwise over 5 hr. The reaction mixture was stirred at ambient temperature for 10 hr and concentrated. After dissolution with H 2 O, the aqueous layer was extracted with CHCl 3 (three times). The combined organic layer was dried over MgSO 4 , filtered, and concentrated to give cis-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester (8.16 g, 16%, crude) as a colorless oil. The aqueous layer was concentrated and the residue was dissolved in MeOH, dried over MgSO 4 , filtered, and concentrated to give a recovered diamine (23.1 g) as a colorless oil. To a solution of the recovered diamine (23.1 g, 202 mmol) in MeOH (462 mL) was added a solution of (Boc) 2 O (4.42 g, 20.3 mmol) in MeOH (56 mL) dropwise over 4 hr. The reaction mixture was stirred at ambient temperature for 3.5 days and concentrated. After dissolution with H 2 O, the aqueous layer was extracted with CHCl 3 (three times). The combined organic layer was dried over MgSO 4 , filtered, and concentrated to give cis-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester (5.01 g, 10% based on starting material) as a colorless oil. The aqueous layer was concentrated and the residue was dissolved in MeOH, dried over MgSO 4 , filtered, and concentrated to give a recovered diamine (16.0 g) as a colorless oil. To a solution of the recovered diamine (16.0 g, 140 mmol) in MeOH (320 mL) was added a solution of (Boc) 2 O (3.06 g, 14.0 mmol) in MeOH (40 mL) dropwise over 4 hr. The reaction mixture was stirred at ambient temperature for 13 hr and concentrated. After dissolution with H 2 O, the aqueous layer was extracted with CHCl 3 (three times). The combined organic layer was dried over MgSO 4 , filtered, and concentrated to give cis-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester (3.53 g, 7% based on the starting material) as a colorless oil. The aqueous layer was concentrated and the residue was dissolved in MeOH, dried over MgSO 4 , filtered, and concentrated to give a recovered diamine (11.1 g) as a colorless oil.

ESI MS m/e 215, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 4.30-4.82 (m, 1 H), 3.50-3.80 (m, 1 H), 2.78-2.95 (m, 1 H), 1.44 (s, 9 H), 1.20-1.80 (m, 8 H).

A mixture of (2-chloro-quinazolin-4-yl)-dimethyl-amine obtained in step B of example 1 (3.00 g, 14.4 mmol) and cis-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester (3.72 g, 17.4 mmol) in 2-propanol (10 mL) was stirred at reflux for 5.5 days, poured into saturated aqueous NaHCO 3 , and the aqueous layer was extracted with CHCl 3 (three times). The combined organic layer was dried over MgSO 4 , filtered, concentrated, and purified by flash chromatography (NH-silica, 20% EtOAc in hexane) to give cis-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester including solvent (5.44 g) as a colorless oil. To a solution of the above material (5.44 g) in EtOAc (10 mL) was added 4 M hydrogen chloride in EtOAc (50 mL). The reaction mixture was stirred at ambient temperature for 2 hr, and concentrated. The residue was alkalized with saturated aqueous NaHCO 3 , and the precipitate was collected by filtration to give cis-N 2 -(4-amino-cyclohexyl)-N 4 ,N 4 -dimethyl-quinazoline-2,4-diamine (2.26 g, 55%) as a white solid. The aqueous layer was extracted CHCl 3 (three times). The combined organic layer was dried over MgSO 4 , filtered, and concentrated to give cis-N 2 -(4-amino-cyclohexyl)-N 4 ,N 4 -diethyl-quinazoline-2,4-diamine (687 mg, 17%) as a white solid.

ESI MS m/e 285, M; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.86 (d, J=7.5 Hz, 1 H), 7.47 (t, J=8.3 Hz, 1 H), 7.29 (d, J=8.3 Hz, 1 H), 7.01 (t, J=7.6 Hz, 1 H), 6.56 (d, J=7.5 Hz, 1 H), 3.83-4.06 (m, 1 H), 3.38-3.52 (m, 1 H), 3.20 (s, 6 H), 1.22-1.82 (m, 8 H).

Step D: Synthesis of cis-4-bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-2-trifluoromethoxy-benzenesulfonamide.

To a suspension of cis-N 2 -(4-amino-cyclohexyl)-N 4 ,N 4 -dimethyl-quinazoline-2,4-diamine (680 mg, 2.38 mmol) in CH 2 Cl 2 (7 mL) was added diisopropylethylamine (620 μL, 3.56 mmol). The mixture was cooled on an ice-bath and a solution of 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (849 mg, 2.50 mmol) in CH 2 Cl 2 (3 mL) was added dropwise. The reaction mixture was stirred on an ice-bath for 6.5 hr. The reaction was quenched with saturated aqueous NaHCO 3 The aqueous layer was extracted with CHCl 3 (three times). The combined organic layer was dried over MgSO 4 , filtered, concentrated, and purified by flash chromatography (NH-silica gel, 33% EtOAc in hexane) to give cis-4-bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-2-trifluoromethoxy-benzenesulfonamide (782 mg, 56%) as a pale yellow solid.

ESI MS m/e 588, M + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.92 (d, J=8.9 Hz, 1 H), 7.81 (dd, J=8.3, 1.2 Hz, 1 H), 7.41-7.58 (m, 4 H), 7.04 (ddd, J=8.3, 6.6, 1.6 Hz, 1 H), 4.00-4.12 (m, 1 H), 3.36-3.45 (m, 1 H), 3.31 (s, 6 H), 1.54-1.84 (m, 8 H).

A solution of 4-bromo-1-iodo-2-trifluoromethoxy-benzene (1.00 g, 2.72 mmol) in THF (15 mL) was cooled to −78° C., and 2.66 M BuLi in hexane (2.05 mL, 5.44 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 1.5 h, and N-formylmorpholine (0.57 mL, 5.63 mmol) was added. The reaction mixture was stirred at −78° C. for 15 min and at ambient temperature for 80 min. The reaction was quenched with 0.25 M aqueous citric acid (10 mL), and the resulting mixture was extracted with EtOAc (three times). The combined organic layer was dried over MgSO 4 , filtered, concentrated, and purified by flash chromatography (silica gel, 2% to 5% EtOAc in hexane) to give 4-bromo-2-trifluoromethoxy-benzaldehyde (560 mg, 77%) as a pale brown solid.

CI MS m/e 269, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 10.33 (s, 1 H), 7.85 (d, J=8.1 Hz, 1 H), 7.50-7.67 (m, 2 H).

A solution of 4-bromo-2-trifluoromethoxy-benzaldehyde (550 mg, 2.04 mmol) in 1,4-dioxane (27 mL) and H 2 O (9 mL) was cooled at 4° C. To the solution were added amidosulfuric acid (296 mg, 3.05 mmol) and sodium dihydrogen phosphate dihydrate (1.4 g, 8.98 mmol). The mixture was stirred at 4° C. for 15 min. To the reaction mixture was added a solution of sodium chlorite (238 mg, 2.63 mmol) in H 2 O (1.5 mL) and stirred at 4° C. for 15 min. To the reaction mixture was added Na 2 CO 3 (304 mg, 2.41 mmol) and stirred at 4° C. for 15 min. The mixture was acidified with conc-HCl (pH=1), and the aqueous layer was extracted with CHCl 3 (three times). The combined organic layer was dried over MgSO 4 , filtered, concentrated, and purified by flash chromatography (silica gel, 1% MeOH in CHCl 3 ) to give 4-bromo-2-trifluoromethoxy-benzoic acid (471 mg, 81%) as a white solid.

ESI MS m/e 284, M + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.98 (d, J=8.4 Hz, 1 H), 7.53-7.62 (m, 2 H).

Step C: Synthesis of trans-4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2-trifluoromethoxy-benzamide.

To a solution of 4-bromo-2-trifluoromethoxy-benzoic acid (454 mg, 1.59 mmol) in CH 2 Cl 2 (6 mL) were added DMF (1.5 μL, 0.02 mmol) and SOCl 2 (158 μL, 2.17 mmol). The mixture was stirred at reflux for 1 hr and concentrated to give acid chloride as a pale yellow oil. To a suspension of trans-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]cyclohexylmethyl}-carbamic acid tert-butyl ester obtained in step G of example 1 (624 mg, 1.51 mmol) in EtOAc (10 mL) was added 4 M hydrogen chloride in EtOAc (8 mL). The mixture was stirred at ambient temperature for 40 min and concentrated to give a white solid. To a suspension of the solid in CH 2 Cl 2 (6 mL) was added diisopropylethylamine (552 μL, 3.17 mmol). The mixture was cooled at 4° C. and a solution of acid chloride in CH 2 Cl 2 (6 mL) was added below 5° C. The reaction mixture was stirred at 4° C. for 2.5 hr. The reaction was quenched with saturated aqueous NaHCO 3 The aqueous layer was extracted with CHCl 3 (three times). The combined organic layer was dried over MgSO 4 , filtered, concentrated, and purified by flash chromatography (NH-silica gel, 33% EtOAc in hexane) to give trans-4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2-trifluoromethoxy-benzamide (309 mg, 35%) as a pale yellow solid.

ESI MS m/e 580, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.89 (d, J=8.4 Hz, 1 H), 7.81 (d, J=8.2 Hz, 1 H), 7.39-7.67 (m, 4 H), 7.02 (ddd, J=8.2, 6.4, 1.9 Hz, 1 H), 6.53 (brs, 1 H), 4.99 (brs, 1 H), 3.37 (t, J=6.5 Hz, 2 H), 3.32 (t, J=6.3 Hz, 2 H), 3.27 (s, 6 H), 1.76-2.02 (m, 4 H), 1.48-1.67 (m, 2 H), 0.94-1.16 (m, 4 H).

To a solution of cis-[4-(tert-butoxycarbonylamino-methyl)-cyclohexylmethyl]-carbamic acid tert-butyl ester (2.55 g, 7.45 mmol) in CH 2 Cl 2 (40 mL) was added 4 M hydrogen chloride in EtOAc (4 mL). The reaction mixture was stirred at ambient temperature for 5 hr and concentrated. The residue was dissolved in 1,4-dioxane (20 mL) and 10% aqueous sodium hydroxide (40 mL) and the resulting solution was cooled on an ice-bath. (Boc) 2 O (829 mg, 3.80 mmol) was added dropwise and the mixture was stirred at ambient temperature for 3 h. The aqueous layer was extracted with CHCl 3 (three times). The combined organic layer was dried over MgSO 4 , filtered and concentrated, and purified by flash chromatography (silica gel, 9% MeOH in CHCl 3 ) to give cis-(4-aminomethyl-cyclohexylmethyl)-carbamic acid tert-butyl ester (255 mg, 14%) as a pale yellow oil.

ESI MS m/e 243, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 4.58 (brs, 1 H), 3.06 (t, J=6.7 Hz, 2 H), 2.60 (d, J=5.9 Hz, 2 H), 1.28-1.70 (m, 19 H).

Step D: Synthesis of cis-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-carbamic acid tert-butyl ester.

Using the procedure for the step G of example 1, the title compound was obtained.

ESI MS m/e 414, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.81 (d, J=7.8 Hz, 1 H), 7.42-7.52 (m, 2 H), 7.02 (ddd, J=8.3, 6.3, 1.9 Hz, 1 H), 4.52 (brs, 1 H), 3.45 (t, J=6.6 Hz, 2 H), 3.27 (s, 6 H), 3.08 (t, J=6.5 Hz, 2 H), 1.34-1.86 (m, 19 H).

Step E: Synthesis of cis-4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2-trifluoromethoxy-benzenesulfonamide.

Using the procedure for the step H of example 1, the title compound was obtained.

ESI MS m/e 616, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.90 (d, J=8.9 Hz, 1 H), 7.81 (d, J=7.8 Hz, 1 H), 7.41-7.58 (m, 4 H), 7.03 (ddd, J=8.2, 6.6, 1.5 Hz, 1 H), 3.41 (t, J=6.5 Hz, 2-H), 3.50 (s, 6 H), 2.90 (d, J=7.3 Hz, 2 H), 1.32-1.86 (m, 10 H).

cis-4-Bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexyl}-2-trifluoromethoxy-benzenesulfonamide

A suspension of cis-4-amino-cyclohexanecarboxylic acid (244 g, 1.70 mol) in MeOH (2.45 L) was cooled to −8° C. Thionyl chloride (45.0 mL, 617 mmol) was added dropwise. The resulting solution was stirred at ambient temperature for 4.5 hr and concentrated to give a white solid. To a suspension of the above solid in CHCl 3 (3.00 L) were added triethylamine (261 mL, 1.87 mol) and (Boc) 2 O (409 g, 1.87 mol) successively. The reaction mixture was stirred at ambient temperature for 5 hr and poured into water. The aqueous layer was extracted with CHCl 3 (three times). The combined organic layer was dried over MgSO 4 , filtered, concentrated, and purified by flash chromatography (silica gel, CHCl 3 only to 10% MeOH in CHCl 3 ) to give a colorless oil (531 g). To a suspension cooled at −4° C. of lithium aluminum hydride (78.3 g, 2.06 mol) in Et 2 O (7.9 L) was added a solution of above oil (530.9 g) in Et 2 O (5.3 L) below 0° C. The resulting suspension was stirred at ambient temperature for 2 hr. The reaction mixture was cooled on an ice-bath, quenched with cold water, filtered through a pad of celite. The filtrate was dried over MgSO 4 , filtered, and concentrated. The precipitate was suspended in hexane (300 mL), filtered, washed with hexane, and dried under reduced pressure to give cis-(4-hydroxymethyl-cyclohexyl)-carbamic acid tert-butyl ester (301 g, 77%) as a white solid.

ESI MS m/e 252, M+Na + ; 1 H NMR (300 MHz, CDCl 3 ) δ 4.30-4.82 (m, 1 H), 3.75 (brs, 1 H), 3.51 (d, J=6.2 Hz, 1 H), 1.52-1.77 (m, 7 H), 1.45 (s, 9 H), 1.16-1.36 (m, 2 H).

Step B: Synthesis of cis-[4-(benzyloxycarbonylamino-methyl)-cyclohexyl]-carbamic acid tert-butyl ester.

To a solution of cis-(4-hydroxymethyl-cyclohexyl)-carbamic acid tert-butyl ester (17.7 g, 77.2 mmol) in THF (245 mL) were added triphenylphosphine (20.2 g, 77.0 mmol) and phthalimide (11.4 g, 77.5 mmol) successively. The resulting suspension was cooled on an ice-bath and 40% diethyl azodicarboxylate (DEAD) in toluene was added over 1 hr. The reaction mixture was stirred at ambient temperature for 2.5 days, concentrated, and purified by flash chromatography (silica gel, 33% EtOAc in hexane) to give a white solid. To a suspension of above solid (27.5 g) in EtOH (275 mL) was added hydrazine hydrate (5.76 g, 115 mmol). The mixture was stirred at reflux for 2.25 hr, cooled, concentrated. The precipitate was dissolved in 10% aqueous sodium hydroxide (350 mL). The aqueous layer was extracted with CHCl 3 (three times). The combined organic layer was dried over MgSO 4 , filtered and concentrated. To a solution of the above residue in CHCl 3 (275 mL) was added triethylamine (8.54 g, 84.4 mmol). The resulting solution was cooled to 0° C. and ZCl (14.4 g, 84.4 mmol) was added below 5° C. The reaction mixture was stirred at ambient temperature for 16 hr, and poured into saturated aqueous NaHCO 3 . The aqueous layer was extracted with CHCl 3 (three times). The combined organic layer was dried over MgSO 4 , filtered, concentrated, and purified by flash chromatography (silica gel, 2% MeOH in CHCl 3 ) to give cis-[4-(benzyloxycarbonylamino-methyl)-cyclohexyl]-carbamic acid tert-butyl ester (25.3 g, 91%) as a colorless oil.

ESI MS m/e 385, M+Na + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.27-7.38 (m, 5 H), 5.09 (s, 2 H), 4.76-4.92 (m, 1 H), 4.42-4.76 (m, 1 H), 3.72 (brs, 1 H), 3.10 (t, J=6.4 Hz, 2 H), 1.48-1.75 (m, 7 H), 1.44 (s, 9 H), 1.13-1.31 (m, 2 H).

Step C: Synthesis of cis-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexyl}-carbamic acid tert-butyl ester.

A mixture of cis-[4-(benzyloxycarbonylamino-methyl)-cyclohexyl]-carbamic acid tert-butyl ester (4.00 g, 11.0 mmol) and 5% Pd/C (400 mg) in MeOH (40 mL) was stirred under hydrogen atmosphere at ambient temperature for 8.5 hr and at 50° C. for 12 hr, filtered through a pad of celite, and concentrated. The precipitate was suspended in hexane and the suspension was stirred at ambient temperature for 30 min. The solid was collected by filtration, washed with hexane, and dried (3.03 g). A mixture of (2-chloro-quinazolin-4-yl)-dimethyl-amine obtained in step B of example 1 (1.00 g, 4.82 mmol) and the above solid (1.65 g, 7.23 mmol) in 2-propanol (10 mL) was stirred at reflux for 5 days, poured into saturated aqueous NaHCO 3 , and the aqueous layer was extracted with CHCl 3 (three times). The combined organic layer was dried over MgSO 4 , filtered, concentrated, and purified by flash chromatography (NH-silica gel, 20% EtOAc in hexane) to give cis-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexyl}-carbamic acid tert-butyl ester (629 mg, 43%) as a pale yellow solid.

ESI MS m/e 400, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.81 (d, J=8.2 Hz, 1 H), 7.42-7.56 (m, 2 H), 6.98-7.06 (m, 1 H), 4.64-4.75 (m, 1 H), 3.67-3.82 (m, 1 H), 3.29-3.44 (m, 2 H), 3.28 (s, 6 H), 1.50-1.78 (m, 7 H), 1.45 (s, 9 H), 1.21-1.42 (m, 2 H).

Step D: Synthesis of cis-4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexyl}-2-trifluoromethoxy-benzenesulfonamid.

Using the procedure for the step H of example 1, the title compound was obtained.

ESI MS m/e 602, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.91 (d, J=8.9 Hz, 1 H), 7.82 (dd, J=8.0, 1.0 Hz, 1 H), 7.42-7.56 (m, 4 H), 7.04 (ddd, J=8.3, 6.6, 1.6 Hz, 1 H), 3.44-3.50 (m, 1 H), 3.40 (t, J=6.0 Hz, 2 H), 3.28 (s, 6 H), 1.22-1.78 (m, 9 H).

cis-4-Bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-2-trifluoromethoxy-benzenesulfonamide

To a solution of cis-[4-(benzyloxycarbonylamino-methyl)-cyclohexyl]-carbamic acid tert-butyl ester obtained in step C of example 23 (12.9 g, 35.6 mmol) in EtOAc (129 mL) was added 4 M hydrogen chloride in EtOAc (129 mL). The reaction mixture was stirred at ambient temperature for 3 hr, filtered, washed with EtOAc, and dried under reduced pressure. The solid was dissolved in saturated aqueous NaHCO 3 . The aqueous layer was extracted with CHCl 3 (five times), dried over MgSO 4 , filtered and concentrated, and dried under reduced pressure to give cis-(4-amino-cyclohexylmethyl)-carbamic acid benzyl ester (8.88 g, 95%) as a colorless oil.

ESI MS m/e 263, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.36 (s, 5 H), 5.12 (brs, 3 H), 2.96-3.32 (m, 3 H), 1.36-1.98 (m, 9 H).

Step B: Synthesis of cis-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-carbamic acid benzyl ester.

Using the procedure for the step G of example 1, the title compound was obtained.

ESI MS m/e 434, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.81 (d, J=9.0 Hz, 1 H), 7.26-7.52 (m, 7 H), 7.01 (ddd, J=8.2, 6.5, 1.7 Hz, 1 H), 5.10 (s, 2 H), 4.93-5.06 (m, 1 H), 4.82-4.93 (m, 1 H), 4.18-4.28 (m, 1 H), 3.26 (s, 6 H), 3.11 (t, J=6.3 Hz, 2 H), 1.80-1.93 (m, 2 H), 1.52-1.73 (m, 5 H), 1.23-1.40 (m, 2 H).

Step C: Synthesis of cis-4-bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-2-trifluoromethoxy-benzenesulfonamide.

Using the procedure for the step D of example 3, the title compound was obtained.

ESI MS m/e 602, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.90 (d, J=8.9 Hz, 1 H), 7.81 (dd, J=8.3, 1.3 Hz, 1 H), 7.38-7.59 (m, 4 H), 7.02 (ddd, J=8.2, 6.8, 1.2 Hz, 1 H), 4.75-5.24 (m, 1 H), 4.16-4.27 (m, 1 H), 3.27 (s, 6 H), 2.86 (d, J=6.4 Hz, 2 H), 1.78-1.91 (m, 2 H), 1.51-1.70 (m, 5 H), 1.21-1.38 (m, 2 H).

4-Bromo-N-[1-(4-dimethylamino-quinazolin-2-yl)-pyrrolidin-3-yl]-2-trifluoromethoxy-benzenesulfonamide

Step A: Synthesis of [1-(4-dimethylamino-quinazolin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester.

Using the procedure for the step G of example 1, the title compound was obtained.

ESI MS m/e 358, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.81 (d, J=8.2 Hz, 1 H), 7.45-7.54 (m, 2 H), 6.98-7.05 (m, 1 H), 4.67-4.80 (m, 1 H), 4.25-4.40 (m, 1 H), 3.85-3.94 (m, 1 H), 3.68-3.79 (m, 2 H), 3.52-3.62 (m, 1 H), 3.27 (s, 6 H), 2.16-2.28 (m, 1 H), 1.86-2.01 (m, 1 H), 1.45(s, 9 H).

Step B: Synthesis of 4-bromo-N-[1-(4-dimethylamino-quinazolin-2-yl)-pyrrolidin-3-yl]-2-trifluoromethoxy-benzenesulfonamide.

Using the procedure for the step H of example 1, the title compound was obtained.

ESI MS m/e 560, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.94 (d, J=8.4 Hz, 1 H), 7.81 (d, J=8.1 Hz, 1 H), 7.44-7.58 (m, 4 H), 7.03 (ddd, J=8.4, 5.7, 2.6 Hz, 1 H), 4.76-5.04 (m, 1 H), 3.96-4.11 (m, 1 H), 3.70-3.82 (m, 2 H), 3.58-3.68 (m, 1 H), 3.45-3.54 (m, 1 H), 3.25 (s, 6 H), 2.11-2.24 (m, 1 H), 1.86-1.99 (m, 1 H).

4-Bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-benzyl]-2-trifluoromethoxy-benzene sulfonamide

To a solution of 4-aminomethyl-phenylamine (1.00 g, 8.19 mmol) in CHCl 3 (10 mL) was added triethylamine (870 mg, 8.60 mmol). After cooling on an ice-bath, (Boc) 2 O (1.88 g, 8.61 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature for 55 min and poured into saturated aqueous NaHCO 3 . The aqueous layer was extracted with CHCl 3 (three times). The combined organic layer was dried over MgSO 4 , filtered, concentrated, and purified by flash chromatography (silica gel, 9% MeOH in CHCl 3 ) to give (4-amino-benzyl)-carbamic acid tert-butyl ester (1.79 g, 99%) as a yellow solid.

ESI MS m/e 245, M+Na + ; 1 H NMR (200 MHz, CDCl 3 ) δ 7.07 (d, J=8.4 Hz, 2 H), 6.63 (d, J=8.4 Hz, 2 H), 4.76 (brs, 1 H), 4.18 (d, J=5.3 Hz, 2 H), 3.65 (brs, 2 H), 1.45 (s, 9 H).

Step B: Synthesis of 4-bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-benzyl]-2-trifluoromethoxy-benzenesulfonamide.

A mixture of (2-chloro-quinazolin-4-yl)-dimethyl-amine obtained in step B of example 1 (1.00 g, 4.82 mmol) and (4-amino-benzyl)-carbamic acid tert-butyl ester (1.28 g, 5.76 mmol) in 2-propanol (10 mL) was stirred at reflux for 3 hr, cooled, poured into saturated aqueous NaHCO 3 , and the aqueous layer was extracted with CHCl 3 (three times). The combined organic layer was dried over MgSO 4 , filtered, concentrated, and purified by flash chromatography (NH-silica gel, 20% EtOAc in hexane) to give a pale yellow solid (2.32 g). To a solution of the above solid (750 mg, 1.91 mmol) in EtOAc (7 mL) was added 4 M hydrogen chloride in EtOAc (7 mL). The mixture was stirred at ambient temperature for 2 hr, concentrated to give a white solid. To a suspension of the above solid in CH 2 Cl 2 (5 mL) was added diisopropylethylamine (730 μL, 4.19 mmol). The mixture was cooled on an ice-bath and a solution of 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (777 mg, 2.29 mmol) in CH 2 Cl 2 (2 mL) was added dropwise. The reaction mixture was stirred on an ice-bath for 9 hr, poured into saturated aqueous NaHCO 3 . The aqueous layer was extracted with CHCl 3 (three times). The combined organic layer was dried over MgSO 4 , filtered, concentrated, and purified by medium-pressure liquid chromatography (NH-silica gel, 20% EtOAc in hexane) to give 4-bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-benzyl]-2-trifluoromethoxy-benzenesulfonamide (519 mg, 56%) as a pale yellow solid.

ESI MS m/e 618, M+Na + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.88 (t, J=9.0 Hz, 2 H), 7.64 (d, J=8.6 Hz, 2 H), 7.48-7.61 (m, 4 H), 6.98-7.20 (m, 4 H), 4.96 (brs, 1 H), 4.13 (s, 2 H), 3.34 (s, 6 H).

4-Bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-benzyl}-2-trifluoromethoxy-benzenesulfonamide

To a solution of 4-aminomethyl-benzylamine (15.0 g, 110 mmol) in CHCl 3 (85 mL) was added a solution of (Boc) 2 O (3.03 g, 13.9 mmol) in CHCl 3 (45 mL) dropwise over 3.5 hr. The reaction mixture was stirred at ambient temperature for 13 hr, and concentrated. After dissolution with H 2 O, the aqueous layer was extracted with EtOAc (three times). The combined organic layer was washed with H 2 O (three times), dried over MgSO 4 , filtered, and concentrated to give (4-aminomethyl-benzyl)-carbamic acid tert-butyl ester (3.20 g, 12%) as a white solid.

ESI MS m/e 237, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.21-7.30 (m, 4 H), 4.86-5.02 (m, 1 H), 4.29 (d, J=5.8 Hz, 2 H), 3.84 (s, 2 H), 1.46 (s, 9 H).

Step B: Synthesis of {4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-benzyl}-carbamic acid tert-butyl ester.

Using the procedure for the step G of example 1, the title compound was obtained.

ESI MS m/e 408, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.85 (d, J=8.2 Hz, 1 H), 7.47-7.55 (m, 2 H), 7.37 (d, J=8.0 Hz, 2 H), 7.24 (d, J=8.0 Hz, 2 H), 7.05-7.10 (m, 1 H), 5.35-5.45 (m, 1 H), 4.90-5.04 (m, 1 H), 4.72 (d, J=5.8 Hz, 2 H), 4.31 (d, J=5.8 Hz, 2 H), 3.27 (s, 6 H), 1.49 (s, 9 H).

Step C: Synthesis of 4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-benzyl}-2-trifluoromethoxy-benzenesulfonamide.

Using the procedure for the step H of example 1, the title compound was obtained.

ESI MS m/e 610, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.83 (d, J=8.4 Hz, 2 H), 7.44-7.54 (m, 4 H), 7.29 (d, J=7.9 Hz, 2 H), 7.11 (d, J=8.1 Hz, 2 H), 7.06 (ddd, J=8.3, 6.3, 2.0 Hz, 1 H), 4.67 (d, J=5.9 Hz, 2 H), 4.15 (s, 2 H), 3.26 (s, 6 H).

Using the procedure for the step G of example 1, the title compound was obtained.

ESI MS m/e 362, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.80 (d, J=7.6 Hz, 1 H), 7.20-7.52 (m, 7 H), 6.97-7.05 (m, 1 H), 4.74-4.90 (m, 1 H), 3.90-4.05 (m, 1 H), 3.53 (s, 2 H), 3.26 (s, 6 H), 2.78-2.90 (m, 2 H), 2.02-2.24 (m, 4 H), 1.48-1.62 (m, 2 H).

To a solution of N 2 -(1-benzyl-piperidin-4-yl)-N 4 ,N 4 -dimethyl-quinazoline-2,4-diamine (1.80 g, 4.98 mmol) in MeOH (18 mL) was added 20% Pd(OH) 2 (360 mg). The mixture was stiffed at 50° C. under hydrogen atmosphere for 3 days, filtered through a pad of celite, and concentrated to give N 4 ,N 4 -dimethyl-N 2 -piperidin-4-yl-quinazoline-2,4-diamine (1.33 g, 99%) as a pale yellow solid.

ESI MS m/e 272, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.86 (d, J=8.6 Hz, 1 H), 7.43-7.62 (m, 2 H), 7.15 (t, J=8.2 Hz, 1 H), 4.12-4.29 (m, 1 H), 3.29-3.47 (m, 2 H), 3.37 (s, 6 H), 2.96-3.12 (m, 2 H), 2.20-2.34 (m, 2 H), 1.79-1.97 (m, 2 H).

Step C: Synthesis of IV-[1-(4-bromo-2-trifluoromethoxy-benzyl)-piperidin-4-yl-]N 4 ,N 4 -dimethyl-quinazoline-2,4-diamine.

Using the procedure for the step B of example 15, the title compound was obtained.

ESI MS m/e 546, M+Na + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.80 (dd, J=8.7, 0.9 Hz, 1 H), 7.34-7.54 (m, 5 H), 7.01 (ddd, J=8.3, 6.6, 1.6 Hz, 1 H), 4.76-4.95 (m, 1 H), 3.87-4.06 (m, 1 H), 3.52 (s, 2 H), 3.25 (s, 6 H), 2.71-2.86 (m, 2 H), 2.17-2.33 (m, 2 H), 1.97-2.12 (m, 2 H), 1.44-1.61 (m, 2 H).

To a solution of 4-aminomethyl-phenylamine (3.00 g, 24.6 mmol) in CHCl 3 (30 mL) was added triethylamine (2.61 g, 25.8 mmol). After cooling on an ice-bath, (Boc) 2 O (5.63 g, 25.8 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature for 55 min and poured into saturated aqueous NaHCO 3 . The aqueous layer was extracted with CHCl 3 (three times) and the combined organic layer was dried over MgSO 4 , filtered, and concentrated to give a pale yellow oil. To a solution of the above oil in CHCl 3 (30 mL) was added diisopropylethylamine (3.33 g, 25.8 mmol). The resulting solution was cooled to 4° C. and ZCl (4.40 g, 25.8 mmol) was added below 10° C. over 5 min. The reaction mixture was stirred at ambient temperature for 12 hr, and poured into saturated aqueous NaHCO 3 . The aqueous layer was extracted with CHCl 3 (three times). The combined organic layer was dried over MgSO 4 , filtered, concentrated, and purified by flash chromatography (silica gel, 2% MeOH in CHCl 3 ) to give [4-(tert-butoxycarbonylamino-methyl)-phenyl]-carbamic acid benzyl ester (2.64 g, 30%) as a white solid.

ESI MS m/e 379, M+Na + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.11-7.44 (m, 9 H), 6.76 (brs, 1 H), 5.19 (s, 2 H), 4.81 (brs, 1 H), 4.25 (d, J=5.1 Hz, 2 H), 1.45 (s, 9 H).

A solution of [4-(tert-butoxycarbonylamino-methyl)-phenyl]-carbamic acid benzyl ester (1.25 g, 3.51 mmol) in EtOAc (20 mL) was cooled on an ice-bath and 4 M hydrogen chloride in EtOAc (20 mL) was added. The mixture was stirred at ambient temperature for 20 min. The precipitate was collected by filtration, washed with EtOAc, and dried under reduced pressure to give (4-aminomethyl-phenyl)-carbamic acid benzyl ester hydrochloride (957 mg, 93%) as a white solid.

ESI MS m/e 279, M+Na + ; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.90 (s, 1 H), 8.37 (brs, 3H), 7.29-7.55 (m, 9 H), 5.15 (s, 2 H), 3.85-4.01 (m, 2 H).

Step C: Synthesis of {4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-phenyl}-carbamic acid benzyl ester.

Using the procedure for the step C of example 3, the title compound was obtained.

ESI MS m/e 428, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.82 (d, J=7.5 Hz, 1 H), 7.25-7.52 (m, 11 H), 6.98-7.07 (m, 1 H), 6.74 (brs, 1 H), 5.28 (brs, 1 H), 5.19 (s, 2 H), 4.65 (d, J=5.9 Hz, 2 H), 3.25(s, 6 H).

Step D: Synthesis of 4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-phenyl}-2-trifluoromethoxy-benzenesulfonamide.

To a solution of {4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-phenyl}-carbamic acid benzyl ester (318 mg, 0.744 mmol) in MeOH (3 mL) was added 5% Pd/C (30 mg). The mixture was stirred at 50° C. under hydrogen atmosphere for 41.5 hr, filtered through a pad of celite, and concentrated. To a solution of 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (505 mg, 1.49 mmol) in CH 2 Cl 2 (12 mL) was added PVP (6 mL). To the resulting suspension was added a solution of the above residue in CH 2 Cl 2 (10 mL). The mixture was stirred at ambient temperature for 1.5 days, filtered, poured into saturated aqueous NaHCO 3 . The aqueous layer was extracted with CHCl 3 (three times). The combined organic layer was dried over MgSO 4 , filtered, concentrated, and purified by medium-pressure liquid chromatography (NH-silica gel, 33% EtOAc in hexane) to give 4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-phenyl}-2-trifluoromethoxy-benzenesulfonamide (330 mg, 74%) as a pale brown solid.

ESI MS m/e 596, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.83 (d, J=8.4 Hz, 1 H), 7.77 (d, J=8.4 Hz, 1 H), 7.41-7.60 (m, 4 H), 7.22 (d, J=8.6 Hz, 2 H), 7.08-7.18 (m, 1 H), 6.99 (d, J=8.6 Hz, 2 H), 4.56 (d, J=5.6 Hz, 2 H), 3.34 (s, 6 H).

To a suspension of (methoxymethyl) triphenylphosphonium chloride (5.29 g, 14.9 mol) in Et 2 O (50 mL) was added 1.8 M phenyl lithium in 30% Et 2 O in cyclohexane (8.58 mL, 15.5 mmol). The mixture was stirred at ambient temperature for 10 min. To the reaction mixture was added 4-bromo-2-trifluoromethoxy-benzaldehyde (4 g, 14.9 mmol) in Et 2 O (18 mL). The mixture was stirred at ambient temperature for 4 hr, filtrated, and concentrated. To the above residue was added 10% H 2 SO 4 in AcOH (40 mL). The mixture was stirred at ambient temperature for 90 min. The solution was poured into H 2 O, and the aqueous layer was extracted with CHCl 3 (three times). The combined organic layer was washed with saturated aqueous NaHCO 3 , washed with brine, dried over MgSO 4 , filtered, concentrated, and purified by flash chromatography (silica gel, 9% EtOAc in hexane) to give (4-bromo-2-trifluoromethoxy-phenyl)-acetaldehyde (1.25 g, 30%) as a pale brown oil.

ESI MS m/e 284, M+H + ; 1 H NMR (200 MHz, CDCl 3 ) δ 9.74 (t, J=1.5 Hz, 1 H), 7.41-7.51 (m, 2 H), 7.16 (d, J=8.4 Hz, 1 H), 3.75 (d, J=1.5 Hz, 2 H).

Step B: Synthesis of cis-N 2 {4-[2-(4-bromo-2-trifluoromethoxy-phenyl)-ethylamino]-cyclohexyl}-N 4 ,N 4 -dimethyl-quinazoline-2,4-diamine dihydrochloride.

To a suspension of cis-N 2 -(4-amino-cyclohexyl)-N 4 ,N 4 -dimethyl-quinazoline-2,4-diamine obtained in step C of example 9 (300 mg, 1.05 mmol) in CH 2 Cl 2 (3 mL) were added (4-bromo-2-trifluoromethoxy-phenyl)-acetaldehyde (357 mg, 1.26 mmol), AcOH (76 mg, 1.26 mmol), and NaBH(OAc) 3 (334 mg, 1.57 mmol). The reaction mixture was stirred at ambient temperature for 4.5 hr. The reaction was quenched with saturated aqueous NaHCO 3 The aqueous layer was extracted with CHCl 3 (three times). The combined organic layer was dried over MgSO 4 , filtered, concentrated, and purified by flash chromatography (NH-silica gel, 50% EtOAc in hexane) to give a pale yellow solid. To a solution of above solid in EtOAc (0.8 mL) was added 4 M hydrogen chloride in EtOAc (0.25 mL). The mixture was stirred at ambient temperature for 30 min and concentrated. A solution of the residue in Et 2 O (2 mL) was stirred at ambient tempareture for 30 min. The precipitate was collected by filtration, washed with Et 2 O, and dried under reduced pressure to give cis-N 2 -{4-[2-(4-bromo-2-trifluoromethoxy-phenyl)-ethylamino]-cyclohexyl}-N 4 ,N 4 -dimethyl-quinazoline-2,4-diamine dihydrochloride (161 mg, 25%) as a white solid.

ESI MS m/e 552, M (free) + ; 1 H NMR (200 MHz, CDCl 3 ) δ 12.66 (brs, 1 H), 9.91 (brs, 2 H), 8.71 (brs, 1 H), 7.93 (d, J=6.6 Hz, 1 H), 7.19-7.77 (m, 6 H), 4.31 (brs, 1 H), 3.54 (s, 6 H), 3.09-3.78 (m, 5 H), 2.00-2.48 (m, 6 H), 1.62-1.96 (m, 2 H).

A solution of 2,4-dichloro-quinazoline obtained in step A of example 1 (125 g, 628 mmol) in THF (1 L) was cooled to 4° C. and 40% aqueous MeNH 2 (136 mL, 1.57 mol) was added. The mixture was stirred at ambient temperature for 80 min. The solution was alkalized with saturated aqueous NaHCO 3 (pH=9) and concentrated. The precipitate was collected by filtration, washed with H 2 O and hexane, and dried at 80° C. to give (2-chloro-quinazolin-4-yl)-methyl-amine (114 g, 94%) as a white solid.

ESI MS m/e 193, M + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.68-7.78 (m, 3 H), 7.39-7.48 (m, 1 H), 6.34 (brs, 1 H), 3.22 (d, J=4.8 Hz, 3 H).

Step B: Synthesis of cis-[4-(4-methylamino-quinazolin-2-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester.

Using the procedure for the step G of example 1, the title compound was obtained.

ESI MS m/e 372, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.36-7.56 (m, 3 H), 7.06 (ddd, J=8.2, 6.8, 1.3 Hz, 1 H), 5.71 (brs, 1 H), 5.10 (brs, 1 H), 4.45-4.72 (m, 1 H), 4.00-4.26 (m, 1 H), 3.49-3.76 (m, 1 H), 3.12 (d, J=4.8 Hz, 3 H), 1.50-1.93 (m, 8 H), 1.46 (s, 9 H).

Step C: Synthesis of cis-N 2 -[4-(4-bromo-2-trifluoromethoxy-benzylamino)-cyclohexyl]-N 4 -methyl-quinazoline-2,4-diamine dihydrochloride.

To a suspension of cis-[4-(4-methylamino-quinazolin-2-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester (1.75 g, 4.71 mmol) in EtOAc (5 mL) and CHCl 3 (10 mL) was added 4 M hydrogen chloride in EtOAc (15 mL). The reaction mixture was stirred at ambient temperature for 2 hr, and concentrated. The residue was alkalized with saturated aqueous NaHCO 3 and the aqueous layer was extracted with CHCl 3 (three times). The combined organic layer was dried over MgSO 4 , filtered, concentrated (2.15 g). To a suspension of the above residue (300 mg, 1.11 mmol) in CH 2 Cl 2 (3 mL) were added 4-bromo-2-trifluoromethoxy-benzaldehyde obtained in Step A of Example 13 (297 mg, 1.10 mmol), AcOH (66 mg, 1.10 mmol), and NaBH(OAc) 3 (351 mg, 1.66 mmol). The reaction mixture was stirred at ambient temperature with CaCl 2 tube for 4 hr, poured into saturated aqueous NaHCO 3 , and the aqueous layer was extracted with CHCl 3 (three times). The combined organic layer was dried over MgSO 4 , filtered, concentrated, purified by medium-pressure liquid chromatography (NH-silica gel, 50% EtOAc in hexane), and concentrated to give a pale yellow oil (91 mg). To a solution of the residue (71 mg) in EtOAc (1 mL) was added 4 M hydrogen chloride in EtOAc (5 mL). The reaction mixture was stirred at ambient temperature for 30 min, and concentrated. A solution of the residue in Et 2 O (10 mL) was stirred at ambient temperature for 1 hr and the precipitate was collected by filtration to give cis-N 2 -[4-(4-bromo-2-trifluoromethoxy-benzylamino)-cyclohexyl]-N-4-methyl-quinazoline-2,4-diamine dihydrochloride (62 mg, 20%) as a white solid.

ESI MS m/e 524, M (free)+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.34-7.57 (m, 6 H), 7.05 (ddd, J=8.2, 6.8, 1.4 Hz, 1 H), 5.52 (brs, 1 H), 4.09-4.27 (m, 1 H), 3.82 (s, 2 H), 3.12 (d, J=4.8 Hz, 3 H), 2.57-2.72 (m, 1 H), 1.41-1.94 (m, 8 H).

To a solution of (ethoxy-methoxymethyl-phosphinoyl)-acetic acid ethyl ester (3.45 g, 15.4 mmol) in THF (230 mL) was added 60% sodium hydride in oil (370 mg, 15.4 mmol). The mixture was stirred at ambient temperature for 50 min and cooled at 4° C. To the reaction mixture was added 4-bromo-2-trifluoromethoxy-benzaldehyde (3 g, 11.2 mmol) in THF (100 mL). The mixture was stirred at ambient temperature for 15 hr. The solution was poured into H 2 O, and the aqueous layer was extracted with EtOAc (three times). The combined organic layer was dried over MgSO 4 , filtered, concentrated, and purified by flash chromatography (silica gel, 5% EtOAc in hexane) to give (E)-3-(4-Bromo-2-trifluoromethoxy-phenyl)-acrylic acid ethyl ester (2.98 g, 79%) as a colorless oil.

CI MS m/e 339, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.85 (d, J=15.8 Hz, 1 H), 7.42-7.58 (m, 3 H), 6.48 (d, J=15.8 Hz, 1 H), 4.29 (q, J=7.0 Hz, 2 H), 1.35 (t, J=7.0 Hz, 3 H).

A suspension of lithium aluminum hydride (834 mg, 22.0 mmol) in Et 2 O (20 mL) was cooled at 4° C. A solution of (E)-3-(4-bromo-2-trifluoromethoxy-phenyl)-acrylic acid ethyl ester (2.98 g, 8.79 mmol) in Et 2 O (9 mL) was added dropwise, and the mixture was stirred at ambient temperature for 90 min. The reaction was quenched with EtOAc (6 mL) and saturated aqueous NH 4 Cl was added dropwise. The aqueous layer was extracted with EtOAc (three times). The combined organic layer was washed with 1 M aqueous HCl, dried over MgSO 4 , filtered, concentrated, and purified by flash chromatography (silica gel, 25% EtOAc in hexane) to give 3-(4-bromo-2-trifluoromethoxy-phenyl)-propan-1-ol (1.14 g, 43%) as a colorless oil.

ESI MS m/e 298, M + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.10-7.43 (m, 3 H), 3.68 (t, J=6.4 Hz, 2 H), 2.67-2.80 (m, 2 H), 1.75-1.94 (m, 2 H).

A solution of 3-(4-bromo-2-trifluoromethoxy-phenyl)-propan-1-ol (1.03 g, 3.44 mmol) in CH 2 Cl 2 (47 mL) was cooled at 4° C. and added celite (1.4 g) and pyridinium chlorochromate (1.11 g, 5.16 mmol). The reaction mixture was stirred at ambient temperature for 6 hr and filtered through a pad of celite, concentrated, and purified by flash chromatography (silica gel, 16% EtOAc in hexane) to give 3-(4-bromo-2-trifluoromethoxy-phenyl)-propionaldehyde (659 mg, 64%) as a colorless oil.

CI MS m/e 297, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 9.80 (t, J=1.1 Hz, 1 H), 7.32-7.42 (m, 2 H), 7.17 (d, J=8.4, Hz, 1 H), 2.96 (t, J=7.4 Hz, 2 H), 2.72-2.81 (m, 2 H).

Step D: Synthesis of cis-N 2 -{4-[3-(4-bromo-2-trifluoromethoxy-phenyl)-propylamino]-cyclohexyl}-N 4 ,N 4 -dimethyl-quinazoline-2,4-diamine dihydrochloride.

Using the procedure for the step B of example 37, the title compound was obtained.

ESI MS m/e 566, M (free)+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 8.81 (d, J=7.2 Hz, 1 H), 7.91 (d, J=7.9 Hz, 1 H), 7.60-7.70 (m, 1 H), 7.49 (d, J=8.4 Hz, 1 H), 7.12-7.42 (m, 5 H), 4.31 (brs, 1 H), 3.52 (s, 6 H), 3.23 (brs, 1 H), 3.02-3.14 (m, 2 H), 2.78 (t, J=7.8 Hz, 2 H), 1.97-2.36 (m, 8 H), 1.59-1.85 (m, 2 H).

cis-N 2 -{4-[4-(4-Bromo-2-trifluoromethoxy-phenyl)-butylamino]-cyclohexyl}-N 4 ,N 4 -dimethyl-quinazoline-2,4-diamine dihydrochloride

Using the procedure for the step A of example 62, the title compound was obtained.

ESI MS m/e 352, N; 1 H NMR (300 MHz, CDCl 3 ) δ 7.33-7.53 (m, 3 H), 6.64 (d, J=16.2 Hz, 1 H), 6.37 (dt, J=16.0, 7.1 Hz, 1 H), 4.18 (q, J=7.2 Hz, 2 H), 3.28 (dd, J=7.1, 1.5 Hz, 2 H), 1.29 (t, J=7.2 Hz, 3 H).

Using the procedure for the step B of example 62, the title compound was obtained.

ESI MS m/e 312, M + ; 1 H NMR (200 MHz, CDCl 3 ) δ 7.10-7.42 (m, 3 H), 3.68 (t, J=5.1 Hz, 2 H), 2.60-2.82 (m, 2 H), 1.50-1.79 (m, 4 H), 1.10-1.50 (brs, 1 H).

Using the procedure for the step C of example 62, the title compound was obtained.

ESI MS m/e 311, M+H + ; 1 H NMR (200 MHz, CDCl 3 ) δ 9.79 (s, 1 H), 7.02-7.22 (m, 3 H), 2.60-2.84 (m, 2 H), 2.49 (t, J=5.9 Hz, 2 H), 1.80-2.03 (m, 2 H).

Step D: Synthesis of cis-N 2 -{4-[4-(4-bromo-2-trifluoromethoxy-phenyl)-butylamino]-cyclohexyl}-N 4 ,N 4 -dimethyl-quinazoline-2,4-diamine dihydrochloride.

To a suspension of cis-N 2 -(4-amino-cyclohexyl)-N 4 ,N 4 -dimethyl-quinazoline-2,4-diamine obtained in step C of example 9 (240 mg, 0.84 mmol) in MeOH (3 mL) were added 4-(4-bromo-2-trifluoromethoxy-phenyl)-butyraldehyde (262 mg, 0.84 mmol), acetic acid (79 mg, 1.26 mmol), and NaBH 3 CN (79 mg, 1.26 mmol). The reaction mixture was stirred at ambient temperature for 8 hr. The reaction was quenched with saturated aqueous NaHCO 3 The aqueous layer was extracted with CHCl 3 (three times). The combined organic layer was dried over MgSO 4 , filtered, concentrated, and purified by medium-pressure liquid chromatography (NH-silica gel, 50% EtOAc in hexane) to give a pale yellow solid. To a solution of above solid in EtOAc (2 mL) was added 4 M hydrogen chloride in EtOAc (10 mL). The mixture was stirred at ambient temperature for 1 hr and concentrated. A solution of the residue in Et 2 O (20 mL) was stirred at ambient tempareture for 1 hr. The solid was collected by filtration, washed with Et 2 O, and dried under reduced pressure to give cis-N 2 -{4-[4-(4-bromo-2-trifluoromethoxy-phenyl)-butylamino]-cyclohexyl}-N 4 ,N 4 -dimethyl-quinazoline-2,4-diamine dihydrochloride (220 mg, 40%) as a white solid.

ESI MS m/e 580, M (free)+H + ; 1 H NMR (200 MHz, CDCl 3 ) δ 12.73 (brs, 1 H), 9.55 (brs, 2 H), 8.66-8.88 (m, 1 H), 7.92 (d, J=7.9 Hz, 1 H), 7.66 (t, J=7.3 Hz, 1 H), 7.48 (d, J=7.7 Hz, 1 H), 7.12-7.40 (m, 3 H), 4.20-4.42 (m, 1 H), 3.52 (s, 6 H), 2.92-3.42 (m, 3 H), 2.60-2.78 (m, 2 H), 1.58-2.59 (m, 12 H).

cis-N 2 -(4-{[2-(4-Bromo-2-trifluoromethoxy-phenyl)-ethylamino]-methyl}-cyclohexyl)-N 4 ,N 4 -dimethyl-quinazoline-2,4-diamine dihydrochloride

To a solution of cis-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-carbamic acid benzyl ester obtained in step B of example 24 (12.1 g, 27.9 mmol) in MeOH (120 mL) was added 10% Pd/C (1.21 g). The mixture was stirred at 50° C. under hydrogen atmosphere for 19 hr, filtered, concentrated, and purified by flash chromatography (NH-silica gel, 66% EtOAc in hexane to 15% MeOH in chloroform) to give N 2 -(4-aminomethyl-cyclohexyl)-N 4 ,N 4 -dimethyl-quinazoline-2,4-diamine (6.9 g, 83%) as a yellow solid.

CI MS m/e 300, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.81 (d, J=8.4 Hz, 1 H), 7.40-7.51 (m, 2 H), 6.98-7.04 (m, 1 H), 5.04 (d, J=7.3 Hz, 1 H), 4.24-4.30 (m, 1 H), 3.27 (s, 6 H), 2.60 (d, J=6.4 Hz, 2 H), 1.81-1.96 (m, 2 H), 1.57-1.76 (m, 4 H), 0.90-1.51 (m, 5 H).

Step B: Synthesis of cis-N 2 -(4-{[2-(4-bromo-2-trifluoromethoxy-phenyl)-ethylamino]-methyl}-cyclohexyl)-N 4 ,N 4 -dimethyl-quinazoline-2,4-diamine dihydrochloride.

Using the procedure for the step B of example 37, the title compound was obtained.

ESI MS m/e 566, M (free)+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 12.45 (s, 1 H), 9.74 (brs, 2 H), 8.70 (d, J=7.6 Hz, 1 H), 7.90 (d, J=8.4 Hz, 1 H), 7.66 (t, J=7.6 Hz, 1 H), 7.17-7.52 (m, 4 H), 4.30 (brs, 1 H), 3.52 (s, 6 H), 3.32-3.50 (m, 2 H), 3.17 (brs, 2 H), 3.01 (brs, 2 H), 1.56-2.10 (m, 9 H).

Using the procedure for the step B of example 13, the title compound was obtained

ESI MS m/e 298, M + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.39-7.47 (m, 2 H), 7.22 (d, J=8.1 Hz, 1 H), 3.70 (s, 2 H).

Step B: Synthesis of cis-2-(4-bromo-2-trifluoromethoxy-phenyl)-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-acetamide hydrochloride.

Using the procedure for the step A of example 47, the title compound was obtained.

ESI MS m/e 566, M (free)+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 13.15 (s, 1 H), 8.91 (d, J=7.7 Hz, 1 H), 7.89 (d, J=8.4 Hz, 1 H), 7.61-7.70 (m, 1 H), 7.48-7.56 (m, 1 H), 7.39-7.45 (m, 1 H), 7.21-7.33 (m, 2 H), 6.02 (d, J=8.8 Hz, 1 H), 4.19-4.33 (m, 1 H), 3.82-4.03 (m, 1 H), 3.53 (s, 2 H), 3.51 (s, 6 H), 1.64-1.97 (m, 8 H).

cis-2-(4-Bromo-2-trifluoromethoxy-phenyl)-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-acetamide hydrochloride

Step A: Synthesis of cis-2-(4-bromo-2-trifluoromethoxy-phenyl)-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-acetamide hydrochloride.

Using the procedure for the step A of example 47, the title compound was obtained.

ESI MS m/e 580, M (free)+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 12.85 (brs, 1 H), 9.08 (d, J=8.4 Hz, 1 H), 7.90 (d, J=8.8 Hz, 1 H), 7.58-7.72 (m, 1 H), 7.19-7.54 (m, 5 H), 6.81-6.98 (m, 1 H), 4.28-4.51 (m, 1 H), 3.83 (s, 2 H), 3.51 (s, 6 H), 3.29-3.34 (m, 2 H), 1.42-2.03 (m, 9 H).

cis-3-(4-Bromo-2-trifluoromethoxy-phenyl)-N-[4-(4-dimethylamino-quinazolin-2-ylamino)cyclohexyl]-propionamide hydrochloride

To a solution of 3-(4-bromo-2-trifluoromethoxy-phenyl)-propan-1-ol obtained in step B of example 62 (1 g, 3.34 mmol) in acetone (15 mL) was added Jones reagent (4 mL) at 4° C. The mixture was stirred at ambient temperature for 2 hr. The solution was poured into water (50 mL), and the aqueous layer was extracted with Et 2 O (three times). The combined organic layer was dried over MgSO 4 , filtered, concentrated, and purified by flash chromatography (silica gel, 25% EtOAc in hexane) to give 3-(4-Bromo-2-trifluoromethoxy-phenyl)-propionic acid (930 mg, 89%) as a colorless oil.

ESI MS m/e 313, M + ; 1 H NMR (200 MHz, CDCl 3 ) δ 7.31-7.50 (m, 2 H), 7.10-7.29 (m, 1 H), 2.97 (t, J=7.7 Hz, 2 H), 2.65 (t, J=7.7 Hz, 2 H).

Step B: Synthesis of cis-3-(4-bromo-2-trifluoromethoxy-phenyl)-N-[4-(4-dimethylamino-quinazolin-2-ylamino)cyclohexyl]-propionamide hydrochloride.

Using the procedure for the step A of example 47, the title compound was obtained.

ESI MS m/e 580, M (free)+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 13.12 (brs, 1 H), 8.92 (d, J=7.9 Hz, 1 H), 7.90 (d, J=8.3 Hz, 1 H), 7.47-7.73 (m, 2 H), 7.15-7.44 (m, 3 H), 5.92 (d, J=8.4 Hz, 1 H), 4.18-4.38 (m, 1 H), 3.76-4.03 (m, 1 H), 3.51 (s, 6 H), 2.98 (t, J=7.7 Hz, 2 H), 2.44 (t, J=7.7 Hz, 2 H), 1.55-1.96 (m, 9 H).

Using the procedure for the step A of example 64, the title compound was obtained.

ESI MS m/e 286, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.35-7.59 (m, 3 H), 6.97-7.11 (m, 1 H), 5.59 (brs, 1 H), 5.00-5.18 (m, 1 H), 4.21-4.39 (m, 1 H), 3.13 (d, J=4.8 Hz, 3 H), 2.61 (d, J=6.2 Hz, 2 H), 1.57-1.99 (m, 5H), 1.04-1.52 (m, 4 H).

Step B: Synthesis of cis-N 2 -(4-{[3-(4-bromo-2-trifluoromethoxy-phenyl)-propylamino]-methyl}-cyclohexyl)-N 4 -methyl-quinazoline-2,4-diamine dihydrochloride.

Using the procedure for the step D of example 63, the title compound was obtained.

ESI MS m/e 566, M (free)+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 11.63 (s, 1 H), 9.45 (brs, 3 H), 8.41 (d, J=8.5 Hz, 1 H), 8.32 (d, J=7.9 Hz, 1 H), 7.46 (t, J=7.54 Hz, 1 H), 7.24-7.39 (m, 3 H), 6.99-7.17 (m, 2 H), 4.13-4.35 (m, 1 H), 2.85-3.12 (m, 7 H), 2.75 (t, J=7.6 Hz, 2 H), 2.27-2.47 (m, 2 H), 1.97-2.18 (m, 1 H), 1.37-1.91 (m, 8 H).

To a suspension of trans-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-carbamic acid tert-butyl ester obtained in step B of example 6 (400 mg, 1.00 mmol) in EtOAc (10 mL) was added 4 M hydrogen chloride in EtOAc (5 mL). The mixture was stirred at ambient temperature for 80 min. The reaction mixture was alkalized with 2 M aqueous sodium hydroxide, and the aqueous layer was extracted with CHCl 3 (three times). The combined organic layer was dried over MgSO 4 , filtered, concentrated, purified by medium-pressure liquid chromatography (NH-silica gel, 33% EtOAc in hexane to 3% MeOH in CHCl 3 ) to give N 2 -(4-aminomethyl-cyclohexyl)-N 4 ,N 4 -dimethyl-quinazoline-2,4-diamine (250 mg, 83%) as a pale yellow oil.

ESI MS m/e 300, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.80 (d, J=9.3 Hz, 1 H), 7.38-7.53 (m, 2 H), 6.97-7.05 (m, 1 H), 4.77 (d, J=9.3 Hz, 1 H), 3.73-4.02 (m, 1 H), 3.26 (s, 6 H), 2.57 (d, J=6.2 Hz, 2 H), 2.13-2.31 (m, 2 H), 1.75-1.96 (m, 2 H), 0.92-1.45 (m, 7 H).

Step B: Synthesis of trans-N 2 -{4-[(4-bromo-2-trifluoromethoxy-benzylamino)-methyl]-cyclohexyl}-N 4 ,N 4 -dimethyl-quinazoline-2,4-diamine dihydrochloride

Using the procedure for the step B of example 37, the title compound was obtained

ESI MS m/e 552, M (free)+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 12.72 (s, 1 H), 10.19 (brs, 2 H), 8.18 (d, J=8.9 Hz, 1 H), 8.06 (d, J=7.9 Hz, 1 H), 7.91 (d, J=8.3 Hz, 1 H), 7.42-7.65 (m, 3 H), 7.35 (d, J=8.3 Hz, 1 H), 7.23 (t, J=7.5 Hz, 1 H), 4.18-4.29 (m, 2 H), 3.69-3.89 (m, 1 H), 3.52 (s, 6 H), 2.64-2.81 (m, 2 H), 1.90-2.24 (m, 5 H), 1.02-1.56 (m, 4 H).

Using the procedure for the step A of example 81, the title compound was obtained

ESI MS m/e 258, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.80 (d, J=8.2 Hz, 1 H), 7.41-7.57 (m, 2 H), 6.93-7.06 (m, 1 H), 3.61-4.02 (m, 4 H), 3.40 (dd, J=11.0, 4.97 Hz, 1 H), 3.26 (s, 6 H), 2.09-2.30 (m, 1 H), 1.68-1.87 (m, 1 H), 1.22-1.63 (m, 2 H).

Step B: Synthesis of {2-[3-(4-bromo-2-trifluoromethoxy-benzylamino)-pyrrolidin-1-yl]-quinazolin-4-yl}-dimethyl-amine dihydrochloride

Using the procedure for the step B of example 37, the title compound was obtained.

ESI MS m/e 510, M (free)+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 8.05-8.61 (m, 2 H), 7.61-7.96 (m, 2 H), 7.33-7.57 (m, 2 H), 7.17-7.31 (m, 1 H), 4.42-4.64 (m, 2 H), 4.34 (s, 2 H), 3.58-4.24 (m, 3 H), 3.46 (s, 6 H), 2.81 (brs, 1 H), 2.31-2.60 (m, 1 H).

Using the procedure for the step A of example 64, the title compound was obtained.

ESI MS m/e 286, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.79 (d, J=8.3 Hz, 1 H), 7.42-7.52 (m, 1 H), 7.23-7.36 (m, 1 H), 6.94-7.07 (m, 1 H), 4.94 (d, J=12.7 Hz, 2 H), 3.26 (s, 6 H), 2.74-3.01 (m, 2 H), 2.61 (d, J=6.6 Hz, 2 H), 1.46-1.99 (m, 4 H), 1.01-1.39 (m, 3 H).

Step B: Synthesis of (2-{4-[(4-bromo-2-trifluoromethoxy-benzylamino)-methyl]-piperidin-1-yl}-quinazolin-4-yl)-dimethyl-amine dihydrochloride

Using the procedure for the step B of example 37, the title compound was obtained.

ESI MS m/e 538, M (free)+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 12.66 (s, 1 H), 8.50 (d, J=8.1 Hz, 1 H), 8.23 (d, J=8.6 Hz, 1 H), 7.88 (d, J=8.4 Hz, 1 H), 7.66 (t, J=7.9 Hz, 1 H), 7.50 (dd, J=8.4, 1.9 Hz, 1 H), 7.36-7.41 (m, 1 H), 7.24-7.34 (m, 1 H), 5.01 (brs, 2 H), 4.27 (s, 2 H), 3.49 (s, 6 H), 3.05-3.37 (m, 2 H), 2.44-2.92 (m, 3 H), 1.82-2.37 (m, 2 H), 1.14-1.62 (m, 2 H).

Using the procedure for the step A of example 81, the title compound was obtained.

ESI MS m/e 408, M+Na + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.82 (d, J=8.3 Hz, 1 H), 7.39-7.59 (m, 2 H), 6.96-7.12 (m, 1 H), 4.79-5.11 (m, 1 H), 3.94-4.31 (m, 2 H), 3.42 (t, J=5.9 Hz, 2 H), 3.27 (s, 6 H), 2.70 (t, J=12.1 Hz, 2 H), 1.63-1.92 (m, 3 H), 1.46 (s, 9 H), 0.99-1.37 (m, 2 H).

Step B: Synthesis of N 2 -[1-(4-bromo-2-trifluoromethoxy-benzyl)-piperidin-4-ylmethyl]-N 4 ,N 4 -dimethyl-quinazoline-2,4-diamine dihydrochloride.

Using the procedure for the step B of example 37, the title compound was obtained.

ESI MS m/e 538, M (free)+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 13.13 (s, 1 H), 12.69 (brs, 1 H), 8.73 (t, J=6.3 Hz, 1 H), 8.19 (d, J=8.2 Hz, 1 H), 7.90 (d, J=7.6 Hz, 1 H), 7.45-7.73 (m, 4 H), 7.22-7.33 (m, 1 H), 4.10-4.24 (m, 2 H), 3.36-3.67 (m, 10 H), 2.61-2.86 (m, 2 H), 1.80-2.33 (m, 5 H).

N 2 -{1-[2-(4-Bromo-2-trifluoromethoxy-phenyl)-ethyl]-piperidin-4-ylmethyl}-N 4 ,N 4 -dimethyl-quinazoline-2,4-diamine dihydrochloride

Step A: Synthesis of N 2 -{1-[2-(4-bromo-2-trifluoromethoxy-phenyl)-ethyl]-piperidin-4-ylmethyl}-N 4 ,N 4 -dimethyl-quinazoline-2,4-diamine dihydrochloride

Using the procedure for the step B of example 37, the title compound was obtained.

ESI MS m/e 552, M (free)+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 13.16 (brs, 1 H), 8.74 (m, 1 H), 7.92 (d, J=8.2 Hz, 1 H), 7.67 (t, J=7.5 Hz, 1 H), 7.53 (d, J=7.6 Hz, 1 H), 7.22-7.46 (m, 5 H), 3.44-3.71 (m, 10 H), 3.26-3.39 (m, 2 H), 3.01-3.15 (m, 2 H), 2.63-2.86 (m, 2 H), 1.87-2.33 (m, 5 H).

N 2 -[1-(4-Bromo-2-trifluoromethoxy-benzyl)-pyrrolidin-3-yl]-N 4 ,N 4 -dimethyl-quinazoline-2,4-diamine dihydrochloride

A mixture of (2-chloro-quinazolin-4-yl)-dimethyl-amine obtained in step B of example 1 (5.1 g, 28.9 mmol) and 1-Benzyl-pyrrolidin-3-ylamine (5.1 g, 28.9 mmol) in BuOH (8 mL) was stirred at reflux for 26 hr, poured into saturated aqueous NaHCO 3 , and the aqueous layer was extracted with CHCl 3 (three times). The combined organic layer was dried over MgSO 4 , filtered, concentrated, and purified by flash chromatography (NH-silica gel, 10% to 16% EtOAc in hexane) to give N 2 -(1-benzyl-pyrrolidin-3-yl)-N 4 ,N 4 -dimethyl-quinazoline-2,4-diamine (3.37 g, 50%) as a pale yellow solid.

ESI MS m/e 348, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.80 (d, J=9.0 Hz, 1 H), 7.46 (m, 2 H), 7.18-7.38 (m, 5 H), 7.02 (ddd, J=8.3, 6.3, 1.9 Hz, 1 H), 5.30 (brs, 1 H), 4.59-4.75 (m, 1 H), 3.63 (d, J=2.5 Hz, 2 H), 3.25 (s, 6 H), 2.88 (dd, J=9.6, 6.6 Hz, 1 H), 2.70-2.81 (m, 1 H), 2.28-2.60 (m, 3 H), 1.64-1.78 (m, 1 H).

To a solution of N 2 -(1-benzyl-pyrrolidin-3-yl)-N 4 ,N 4 -dimethyl-quinazoline-2,4-diamine (3.3 g, 9.5 mmol) in MeOH (33 mL) was added Pd(OH) 2 (660 mg). The mixture was stirred at ambient temperature under hydrogen atmosphere for 13 hr, and stirred at 50° C. for 6 hr. The mixture was filtered, concentrated, and purified by medium-pressure liquid chromatography (NH-silica gel, 1% to 3% MeOH in CHCl 3 ) to give N 4 ,N 4 -dimethyl-N 2 -pyrrolidin-3-yl-quinazoline-2,4-diamine (2.3 g, 93%) as a yellow oil.

ESI MS m/e 258, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.82 (d, J=7.8 Hz, 1 H), 7.42-7.54 (m, 2 H), 7.03 (ddd, J=8.3, 6.4, 1.8 Hz, 1 H), 5.03 (brs, 1 H), 4.52 (brs, 1 H), 3.26 (s, 6 H), 2.83-3.24 (m, 4 H), 1.97-2.30 (m, 2 H), 1.57-1.77 (m, 1 H).

Step C: Synthesis of N 2 -[1-(4-bromo-2-trifluoromethoxy-benzyl)-pyrrolidin-3-yl]-N 4 ,N 4 -dimethyl-quinazoline-2,4-diamine dihydrochloride

Using the procedure for the step B of example 37, the title compound was obtained.

ESI MS m/e 510, M (free)+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 13.22 (brs, 1 H), 12.87 (s, 1 H), 9.68 (d, J=7.4 Hz, 1 H), 8.11 (d, J=8.4 Hz, 1 H), 7.95 (d, J=8.4 Hz, 1 H), 7.71 (t, J=8.3 Hz, 1 H), 7.43-7.63 (m, 3 H), 7.28-7.38 (m, 1 H), 4.94-5.15 (m, 1 H), 4.41 (s, 2 H), 4.00-4.17 (m, 1 H), 3.26-3.82 (m, 8 H), 3.00-3.16 (m, 1 H), 2.59-2.82 (m, 1 H), 2.18-2.37 (m, 1 H).

Using the procedure for the step A of example 81, the title compound was obtained.

ESI MS m/e 300, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.79 (d, J=8.4 Hz, 1 H), 7.45 (m, 2 H), 7.00 (ddd, J=8.4, 6.3, 1.9 Hz, 1 H), 4.80 (d, J=8.2 Hz, 1 H), 3.82-3.94 (m, 1 H), 3.24 (s, 6 H), 2.56 (d, J=6.2 Hz, 2 H), 2.14-2.28 (m, 2 H), 1.78-1.92 (m, 2 H), 0.95-1.42 (m, 7 H).

Step B: Synthesis of trans-4-bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexylmethyl]-2-trifluoromethoxy-benzamide hydrochloride.

Using the procedure for the step A of example 47, the title compound was obtained.

ESI MS m/e 566, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 13.48 (s, 1 H), 8.34 (d, J=7.5 Hz, 1 H), 7.83-7.94 (m, 2 H), 7.43-7.69 (m, 4 H), 7.20-7.29 (m, 1 H), 6.49-6.62 (m, 1 H), 3.72-3.93 (m, 1 H), 3.50 (s, 6 H), 3.39 (t, J=6.3 Hz, 2 H), 2.09-2.22 (m, 2 H), 1.85-1.98 (m, 2 H), 1.37-1.69 (m, 3 H), 1.08-1.28 (m, 2 H).

To a solution of 1-benzyl-piperidin-4-ylamine (2.00 g, 10.5 mmol) in THF (20 mL) was added (Boc) 2 O (2.52 g, 11.5 mmol). The mixture was stirred at ambient temperature for 40 min, and concentrated. To a solution of the residue in MeOH (20 mL) was added 20% Pd(OH) 2 (400 mg). The mixture was stirred at ambient temperature under hydrogen atmosphere for 20 hr. Additionally, 20% Pd(OH) 2 (400 mg) was added and the mixture was stirred at ambient temperature under hydrogen atmosphere for 7 hr, at 50° C. for 4.5 hr, and at ambient temperature for 12 hr, filtered through a pad of celite, and concentrated to give a white solid. A mixture of (2-chloro-quinazolin-4-yl)-dimethyl-amine obtained in step B of example 1 (1.10 g, 5.30 mmol) and the above solid (1.27 g, 6.34 mmol) in 2-propanol (11 mL) was stirred at reflux for 20 hr. The precipitate was collected by filtration, washed with 2-propanol, dissolved in 50% MeOH in CHCl 3 (60 mL). The solution was poured into saturated aqueous NaHCO 3 , and the aqueous layer was extracted with CHCl 3 (three times). The combined organic layer was dried over MgSO 4 , filtered, concentrated, and purified by flash chromatography (NH-silica gel, EtOAc to CHCl 3 ) to give [2-(4-amino-piperidin-1-yl)-quinazolin-4-yl]-dimethyl-amine (864 mg, 68%) as a colorless oil.

ESI MS m/e 272, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.79 (d, J=8.2 Hz, 1 H), 7.45-7.55 (m, 2 H), 6.96-7.05 (m, 1 H), 4.83 (d, J=13.4 Hz, 2 H), 3.26 (s, 6 H), 2.84-3.03 (m, 3 H), 1.85-1.95 (m, 2 H), 1.20-1.50 (m, 4 H).

Step B: Synthesis of 4-bromo-N-[1-(4-dimethylamino-quinazolin-2-yl)-piperidin-4-yl]-2-trifluoromethoxy-benzenesulfonamide.

Using the procedure for the step A of example 20, the title compound was obtained.

ESI MS m/e 574, M+H + ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.94 (d, J=8.7 Hz, 1 H), 7.80 (d, J=8.2 Hz, 1 H), 7.39-7.61 (m, 4 H), 6.98-7.07 (m, 1 H), 4.60-4.81 (m, 3 H), 3.39-3.61 (m, 1 H), 3.25 (s, 6 H), 2.98-3.08 (m, 2 H), 1.73-1.92 (m, 2 H), 1.33-1.54 (m, 2 H).

Structure

122

472 (M + H)

123

532 (M + H)

124

511 (M + H)

125

496 (M + H)

126

616 (M + H)

127

532 (M + H)

128

526 (M + H)

129

510 (M + H)

130

538 (M + H)

131

631 (M + H)

132

488 (M + H)

133

650 (M + H)

134

494 (M + H)

135

479 (M + H)

136

479 (M + H)

137

558 (M + H)

138

502 (M + H)

139

516 (M + H)

140

536 (M + H)

141

646 (M + H)

142

601 (M + H)

143

522 (M + H)

144

528 (M + H)

145

514 (M + H)

146

482 (M + H)

147

527 (M + H)

148

496 (M + H)

149

484 (M + H)

150

513 (M + H)

151

529 (M + H)

152

532 (M + H)

153

557 (M + H)

154

532 (M + H)

155

458 (M + H)

156

499 (M + H)

157

499 (M + H)

158

499 (M + H)

159

567 (M + H)

160

490 (M + H)

161

544 (M + H)

162

580 (M + H)

163

558 (M + H)

164

505 (M + H)

165

460 (M + H)

166

556 (M + H)

167

580 (M + H)

168

522 (M + H)

169

468 (M + H)

170

480 (M + H)

171

468 (M + H)

172

595 (M + H)

173

605 (M + H)

174

522 (M + H)

175

482 (M + H)

176

622 (M + H)

177

653 (M + H)

178

544 (M + H)

179

606 (M + H)

180

600 (M + H)

181

600 (M + H)

182

567 (M + H)

183

572 (M + H)

184

572 (M + H)

185

506 (M + H)

186

473 (M + H)

187

472 (M + H)

188

518 (M + H)

189

627 (M + H)

190

548 (M + H)

191

608 (M + H)

192

472 (M + H)

193

514 (M + H)

194

681 (M + H)

195

640 (M + H)

196

715 (M + H)

197

662 (M + H)

198

530 (M + H)

199

502 (M + H)

200

516 (M + H)

201

515 (M + H)

202

486 (M + H)

203

545 (M + H)

204

512 (M + H)

205

530 (M + H)

206

496 (M + H)

207

556 (M + H)

208

510 (M + H)

209

522 (M + H)

210

502 (M + H)

211

498 (M + H)

212

502 (M + H)

213

506 (M + H)

214

484 (M + H)

215

568 (M + H)

216

526 (M + H)

217

524 (M + H)

218

562 (M + H)

219

486 (M + H)

220

524 (M + H)

221

649 (M + H)

222

601 (M + H)

223

490 (M + H)

224

610 (M + H)

225

498 (M + H)

226

522 (M + H)

227

538 (M + H)

228

479 (M + H)

229

546 (M + H)

230

556 (M + H)

231

522 (M + H)

232

506 (M + H)

233

496 (M + H)

234

580 (M + H)

235

520 (M + H)

236

693 (M + H)

237

560 (M + H)

238

546 (M + H)

239

524 (M + H)

240

527 (M + H)

241

513 (M + H)

242

508 (M + H)

243

490 (M + H)

244

590 (M + H)

245

524 (M + H)

246

490 (M + H)

247

550 (M + H)

248

524 (M + H)

249

568 (M + H)

250

524 (M + H)

251

530 (M + H)

252

513 (M + H)

253

530 (M + H)

254

513 (M + H)

255

532 (M + H)

256

480 (M + H)

257

468 (M + H)

258

536 (M + H)

259

536 (M + H)

260

502 (M + H)

261

486 (M + H)

262

482 (M + H)

263

536 (M + H)

264

604 (M + H)

265

536 (M + H)

266

592 (M + H)

267

626 (M + H)

268

558 (M + H)

269

434 (M + H)

270

518 (M + H)

271

454 (M + H)

272

556 (M + H)

273

528 (M + H)

274

528 (M + H)

275

406 (M + H)

276

602 (M + H)

277

420 (M + H)

278

392 (M + H)

279

490 (M + H)

280

420 (M + H)

281

446 (M + H)

282

538 (M + H)

283

460 (M + H)

284

454 (M + H)

285

532 (M + H)

286

510 (M + H)

287

532 (M + H)

288

616 (M + H)

289

488 (M + H)

290

522 (M + H)

291

528 (M + H)

292

547 (M + H)

293

472 (M + H)

294

504 (M + H)

295

504 (M + H)

296

468 (M + H)

297

538 (M + H)

298

522 (M + H)

299

488 (M + H)

300

590 (M + H)

301

522 (M + H)

302

520 (M + H)

303

390 (M + H)

304

446 (M + H)

305

468 (M + H)

306

468 (M + H)

307

432 (M + H)

308

505 (M + H)

309

536 (M + H)

310

469 (M + H)

311

504 (M + H)

312

430 (M + H)

313

433 (M + H)

314

408 (M + H)

315

451 (M + H)

316

380 (M + H)

317

476 (M + H)

318

391 (M + H)

319

437 (M + H)

320

448 (M + H)

321

471 (M + H)

322

470 (M + H)

323

412 (M + H)

324

557 (M + H)

325

391 (M + H)

326

435 (M + H)

327

425 (M + H)

328

569 (M + H)

329

391 (M + H)

330

524 (M + H)

331

498 (M + H)

332

442 (M + H)

333

396 (M + H)

334

516 (M + H)

335

474 (M + H)

336

474 (M + H)

337

444 (M + H)

338

482 (M + H)

339

516 (M + H)

340

458 (M + H)

341

498 (M + H)

342

442 (M + H)

343

440 (M + H)

344

442 (M + H)

345

442 (M + H)

346

460 (M + H)

347

476 (M + H)

348

476 (M + H)

349

462 (M + H)

350

516 (M + H)

351

480 (M + H)

352

432 (M + H)

353

408 (M + H)

354

442 (M + H)

355

434 (M + H)

356

442 (M + H)

357

422 (M + H)

358

406 (M + H)

359

490 (M + H)

360

440 (M + H)

361

510 (M + H)

362

456 (M + H)

363

456 (M + H)

364

422 (M + H)

365

460 (M + H)

366

472 (M + H)

367

498 (M + H)

368

464 (M + H)

369

418 (M + H)

370

539 (M + H)

371

465 (M + H)

372

499 (M + H)

373

497 (M + H)

374

558 (M + H)

375

526 (M + H)

376

450 (M + H)

377

395 (M + H)

378

553 (M + H)

379

500 (M + H)

380

469 (M + H)

381

532 (M + H)

382

450 (M + H)

383

529 (M + H)

384

515 (M + H)

385

594 (M + H)

386

553 (M + H)

387

473 (M + H)

388

428 (M + H)

389

450 (M + H)

390

502 (M + H)

391

508 (M + H)

392

472 (M + H)

393

476 (M + H)

394

479 (M + H)

395

446 (M + H)

396

462 (M + H)

397

510 (M + H)

398

454 (M + H)

399

416 (M + H)

400

438 (M + H)

401

492 (M + H)

402

457 (M + H)

403

420 (M + H)

404

404 (M + H)

405

430 (M + H)

406

448 (M + H)

407

465 (M + H)

408

434 (M + H)

409

410 (M + H)

410

587 (M + H)

411

420 (M + H)

412

465 (M + H)

413

525 (M + H)

414

448 (M + H)

415

510 (M + H)

416

464 (M + H)

417

432 (M + H)

418

422 (M + H)

419

434 (M + H)

420

476 (M + H)

421

418 (M + H)

422

623 (M + H)

423

618 (M + H)

424

484 (M + H)

425

461 (M + H)

426

482 (M + H)

427

450 (M + H)

428

454 (M + H)

429

430 (M + H)

430

482 (M + H)

431

454 (M + H)

432

500 (M + H)

433

478 (M + H)

434

543 (M + H)

435

502 (M + H)

436

473 (M + H)

437

489 (M + H)

438

328 (M + H)

439

328 (M + H)

440

396 (M + H)

441

384 (M + H)

442

356 (M + H)

443

399 (M + H)

444

396 (M + H)

445

384 (M + H)

446

439 (M + H)

447

534 (M + H)

448

404 (M + H)

449

460 (M + H)

450

482 (M + H)

451

482 (M + H)

452

446 (M + H)

453

519 (M + H)

454

550 (M + H)

455

483 (M + H)

456

518 (M + H)

457

444 (M + H)

458

447 (M + H)

459

422 (M + H)

460

465 (M + H)

461

394 (M + H)

462

490 (M + H)

463

405 (M + H)

464

451 (M + H)

465

462 (M + H)

466

485 (M + H)

467

484 (M + H)

468

426 (M + H)

469

571 (M + H)

470

405 (M + H)

471

449 (M + H)

472

439 (M + H)

473

583 (M + H)

474

405 (M + H)

475

538 (M + H)

476

512 (M + H)

477

456 (M + H)

478

410 (M + H)

479

530 (M + H)

480

488 (M + H)

481

488 (M + H)

482

458 (M + H)

483

496 (M + H)

484

530 (M + H)

485

472 (M + H)

486

512 (M + H)

487

456 (M + H)

488

454 (M + H)

489

456 (M + H)

490

456 (M + H)

491

474 (M + H)

492

490 (M + H)

493

490 (M + H)

494

476 (M + H)

495

530 (M + H)

496

494 (M + H)

497

446 (M + H)

498

422 (M + H)

499

488 (M + H)

500

448 (M + H)

501

456 (M + H)

502

436 (M + H)

503

420 (M + H)

504

504 (M + H)

505

454 (M + H)

506

524 (M + H)

507

470 (M + H)

508

470 (M + H)

509

436 (M + H)

510

474 (M + H)

511

486 (M + H)

512

512 (M + H)

513

478 (M + H)

514

432 (M + H)

515

553 (M + H)

516

479 (M + H)

517

513 (M + H)

518

511 (M + H)

519

572 (M + H)

520

540 (M + H)

521

464 (M + H)

522

409 (M + H)

523

567 (M + H)

524

514 (M + H)

525

483 (M + H)

526

546 (M + H)

527

464 (M + H)

528

543 (M + H)

529

529 (M + H)

530

608 (M + H)

531

567 (M + H)

532

487 (M + H)

533

442 (M + H)

534

464 (M + H)

535

516 (M + H)

536

522 (M + H)

537

486 (M + H)

538

490 (M + H)

539

493 (M + H)

540

460 (M + H)

541

476 (M + H)

542

524 (M + H)

543

468 (M + H)

544

430 (M + H)

545

452 (M + H)

546

506 (M + H)

547

471 (M + H)

548

434 (M + H)

549

418 (M + H)

550

444 (M + H)

551

462 (M + H)

552

479 (M + H)

553

448 (M + H)

554

424 (M + H)

555

601 (M + H)

556

462 (M + H)

557

524 (M + H)

558

478 (M + H)

559

446 (M + H)

560

436 (M + H)

561

448 (M + H)

562

490 (M + H)

563

432 (M + H)

564

637 (M + H)

565

632 (M + H)

566

498 (M + H)

567

475 (M + H)

568

496 (M + H)

569

464 (M + H)

570

468 (M + H)

571

444 (M + H)

572

496 (M + H)

573

468 (M + H)

574

514 (M + H)

575

492 (M + H)

576

557 (M + H)

577

516 (M + H)

578

487 (M + H)

579

503 (M + H)

580

342 (M + H)

581

368 (M + H)

582

410 (M + H)

583

398 (M + H)

584

370 (M + H)

585

413 (M + H)

586

410 (M + H)

587

398 (M + H)

588

453 (M + H)

589

432 (M + H)

590

432 (M + H)

591

474 (M + H)

592

458 (M + H)

593

490 (M + H)

594

535 (M + H)

595

430 (M + H)

596

552 (M + H)

597

433 (M + H)

598

503 (M + H)

599

536 (M + H)

600

506 (M + H)

601

429 (M + H)

602

486 (M + H)

603

459 (M + H)

604

443 (M + H)

605

636 (M + H)

606

601 (M + H)

607

705 (M + H)

608

623 (M + H)

609

559 (M + H)

610

583 (M + H)

611

596 (M + H)

612

512 (M + H)

613

480 (M + H)

614

494 (M + H)

615

494 (M + H)

616

537 (M + H)

617

492 (M + H)

618

523 (M + H)

619

534 (M + H)

620

556 (M + H)

621

587 (M + H)

622

587 (M + H)

623

523 (M + H)

624

641 (M + H)

625

641 (M + H)

626

523 (M + H)

627

544 (M + H)

628

526 (M + H)

629

548 (M + H)

630

405 (M + H)

631

564 (M + H)

632

524 (M + H)

633

630 (M + H)

634

564 (M + H)

635

518 (M + H)

636

647 (M + H)

637

545 (M + H)

638

671 (M + H)

639

490 (M + H)

640

482 (M + H)

641

466 (M + H)

642

494 (M + H)

643

528 (M + H)

644

482 (M + H)

645

517 (M + H)

646

537 (M + H)

647

496 (M + H)

648

508 (M + H)

649

508 (M + H)

650

496 (M + H)

651

559 (M + H)

652

490 (M + H)

653

564 (M + H)

654

550 (M + H)

655

602 (M + H)

656

522 (M + H)

657

533 (M + H)

658

468 (M + H)

659

502 (M + H)

660

449 (M + H)

661

493 (M + H)

662

468 (M + H)

663

501 (M + H)

664

515 (M + H)

665

501 (M + H)

666

438 (M + H)

667

508 (M + H)

668

582 (M + H)

669

674 (M + H)

670

474 (M + H)

671

457 (M + H)

672

441 (M + H)

673

550 (M + H)

674

438 (M + H)

675

569 (M + H)

676

424 (M + H)

677

436 (M + H)

678

415 (M + H)

679

441 (M + H)

680

458 (M + H)

681

451 (M + H)

682

449 (M + H)

683

435 (M + H)

684

465 (M + H)

685

476 (M + H)

686

526 (M + H)

687

465 (M + H)

688

476 (M + H)

689

494 (M + H)

690

453 (M + H)

691

463 (M + H)

692

519 (M + H)

693

465 (M + H)

694

462 (M + H)

695

585 (M + H)

696

553 (M + H)

697

515 (M + H)

698

458 (M + H)

699

500 (M + H)

700

504 (M + H)

701

579 (M + H)

702

438 (M + H)

703

506 (M + H)

704

456 (M + H)

705

452 (M + H)

706

530 (M + H)

707

493 (M + H)

708

486 (M + H)

709

472 (M + H)

710

563 (M + H)

711

480 (M + H)

712

464 (M + H)

713

494 (M + H)

714

532 (M + H)

715

546 (M + H)

716

533 (M + H)

717

622 (M + H)

718

472 (M + H)

719

438 (M + H)

720

464 (M + H)

721

512 (M + H)

722

437 (M + H)

723

577 (M + H)

724

465 (M + H)

725

488 (M + H)

726

435 (M + H)

727

434 (M + H)

728

613 (M + H)

729

408 (M + H)

730

394 (M + H)

731

542 (M + H)

732

549 (M + H)

733

530 (M + H)

734

668 (M + H)

735

490 (M + H)

736

486 (M + H)

737

501 (M + H)

738

488 (M + H)

739

562 (M + H)

740

502 (M + H)

741

524 (M + H)

742

588 (M + H)

743

487 (M + H)

744

436 (M + H)

745

660 (M + H)

746

605 (M + H)

747

662 (M + H)

748

696 (M + H)

749

603 (M + H)

750

561 (M + H)

751

639 (M + H)

752

657 (M + H)

753

559 (M + H)

754

645 (M + H)

755

631 (M + H)

756

589 (M + H)

757

557 (M + H)

758

591 (M + H)

759

565 (M + H)

760

568 (M + H)

761

601 (M + H)

762

607 (M + H)

763

477 (M + H)

764

477 (M + H)

765

482 (M + H)

766

461 (M + H)

767

461 (M + H)

768

444 (M + H)

769

496 (M + H)

770

496 (M + H)

771

488 (M + H)

772

530 (M + H)

773

460 (M + H)

774

602 (M + H)

775

437 (M + H)

776

419 (M + H)

777

548 (M + H)

778

672 (M + H)

779

540 (M + H)

780

540 (M + H)

781

522 (M + H)

782

512 (M + H)

783

632 (M + H)

784

644 (M + H)

785

680 (M + H)

786

646 (M + H)

787

646 (M + H)

788

582 (M + H)

789

602 (M + H)

790

630 (M + H)

791

670 (M + H)

792

710 (M + H)

793

684 (M + H)

794

650 (M + H)

795

624 (M + H)

796

636 (M + H)

797

602 (M + H)

798

616 (M + H)

799

612 (M + H)

800

622 (M + H)

801

650 (M + H)

802

606 (M + H)

803

586 (M + H)

804

624 (M + H)

805

528 (M + H)

806

452 (M + H)

807

438 (M + H)

808

424 (M + H)

809

522 (M + H)

810

488 (M + H)

811

488 (M + H)

812

488 (M + H)

813

504 (M + H)

814

504 (M + H)

815

458 (M + H)

816

452 (M + H)

817

497 (M + H)

818

547 (M + H)

819

549 (M + H)

820

522 (M + H)

821

629 (M + H)

822

510 (M + H)

823

538 (M + H)

824

512 (M + H)

825

583 (M + H)

826

535 (M + H)

827

556 (M + H)

828

480 (M + H)

829

494 (M + H)

830

597 (M + H)

831

570 (M + H)

832

478 (M + H)

833

448 (M + H)

834

446 (M + H)

835

450 (M + H)

836

432 (M + H)

837

452 (M + H)

838

460 (M + H)

839

478 (M + H)

840

444 (M + H)

841

492 (M + H)

842

522 (M + H)

843

603 (M + H)

844

518 (M + H)

845

490 (M + H)

846

563 (M + H)

847

457 (M + H)

848

471 (M + H)

849

418 (M + H)

850

463 (M + H)

851

460 (M + H)

852

444 (M + H)

853

576 (M + H)

854

490 (M + H)

855

550 (M + H)

856

439 (M + H)

857

408 (M + H)

858

410 (M + H)

859

424 (M + H)

860

394 (M + H)

861

424 (M + H)

862

424 (M + H)

863

411 (M + H)

864

425 (M + H)

865

384 (M + H)

866

424 (M + H)

867

446 (M + H)

868

446 (M + H)

869

488 (M + H)

870

549 (M + H)

871

444 (M + H)

872

566 (M + H)

873

447 (M + H)

874

517 (M + H)

875

550 (M + H)

876

520 (M + H)

877

443 (M + H)

878

500 (M + H)

879

473 (M + H)

880

457 (M + H)

881

650 (M + H)

882

615 (M + H)

883

719 (M + H)

884

637 (M + H)

885

573 (M + H)

886

597 (M + H)

887

610 (M + H)

888

526 (M + H)

889

494 (M + H)

890

508 (M + H)

891

508 (M + H)

892

551 (M + H)

893

506 (M + H)

894

537 (M + H)

895

548 (M + H)

896

570 (M + H)

897

601 (M + H)

898

601 (M + H)

899

537 (M + H)

900

655 (M + H)

901

655 (M + H)

902

558 (M + H)

903

540 (M + H)

904

562 (M + H)

905

419 (M + H)

906

578 (M + H)

907

538 (M + H)

908

644 (M + H)

909

578 (M + H)

910

532 (M + H)

911

661 (M + H)

912

559 (M + H)

913

685 (M + H)

914

506 (M + H)

915

504 (M + H)

916

496 (M + H)

917

480 (M + H)

918

508 (M + H)

919

542 (M + H)

920

496 (M + H)

921

531 (M + H)

922

551 (M + H)

923

510 (M + H)

924

522 (M + H)

925

522 (M + H)

926

510 (M + H)

927

504 (M + H)

928

504 (M + H)

929

578 (M + H)

930

564 (M + H)

931

616 (M + H)

932

536 (M + H)

933

547 (M + H)

934

482 (M + H)

935

516 (M + H)

936

463 (M + H)

937

507 (M + H)

938

482 (M + H)

939

515 (M + H)

940

529 (M + H)

941

515 (M + H)

942

452 (M + H)

943

522 (M + H)

944

596 (M + H)

945

688 (M + H)

946

488 (M + H)

947

471 (M + H)

948

455 (M + H)

949

564 (M + H)

950

452 (M + H)

951

583 (M + H)

952

438 (M + H)

953

450 (M + H)

954

429 (M + H)

955

455 (M + H)

956

472 (M + H)

957

463 (M + H)

958

449 (M + H)

959

479 (M + H)

960

490 (M + H)

961

540 (M + H)

962

479 (M + H)

963

490 (M + H)

964

508 (M + H)

965

467 (M + H)

966

477 (M + H)

967

533 (M + H)

968

479 (M + H)

969

476 (M + H)

970

599 (M + H)

971

567 (M + H)

972

529 (M + H)

973

472 (M + H)

974

514 (M + H)

975

518 (M + H)

976

593 (M + H)

977

452 (M + H)

978

520 (M + H)

979

470 (M + H)

980

466 (M + H)

981

544 (M + H)

982

507 (M + H)

983

604 (M + H)

984

500 (M + H)

985

486 (M + H)

986

577 (M + H)

987

494 (M + H)

988

478 (M + H)

989

508 (M + H)

990

546 (M + H)

991

560 (M + H)

992

547 (M + H)

993

636 (M + H)

994

486 (M + H)

995

452 (M + H)

996

478 (M + H)

997

526 (M + H)

998

451 (M + H)

999

591 (M + H)

1000

479 (M + H)

1001

502 (M + H)

1002

448 (M + H)

1003

627 (M + H)

1004

422 (M + H)

1005

408 (M + H)

1006

556 (M + H)

1007

563 (M + H)

1008

544 (M + H)

1009

682 (M + H)

1010

504 (M + H)

1011

500 (M + H)

1012

515 (M + H)

1013

502 (M + H)

1014

576 (M + H)

1015

516 (M + H)

1016

538 (M + H)

1017

602 (M + H)

1018

501 (M + H)

1019

450 (M + H)

1020

674 (M + H)

1021

619 (M + H)

1022

676 (M + H)

1023

710 (M + H)

1024

617 (M + H)

1025

575 (M + H)

1026

653 (M + H)

1027

671 (M + H)

1028

659 (M + H)

1029

645 (M + H)

1030

603 (M + H)

1031

571 (M + H)

1032

605 (M + H)

1033

579 (M + H)

1034

582 (M + H)

1035

615 (M + H)

1036

621 (M + H)

1037

491 (M + H)

1038

491 (M + H)

1039

496 (M + H)

1040

475 (M + H)

1041

475 (M + H)

1042

458 (M + H)

1043

510 (M + H)

1044

510 (M + H)

1045

533 (M + H)

1046

544 (M + H)

1047

474 (M + H)

1048

616 (M + H)

1049

451 (M + H)

1050

433 (M + H)

1051

562 (M + H)

1052

686 (M + H)

1053

554 (M + H)

1054

554 (M + H)

1055

536 (M + H)

1056

526 (M + H)

1057

646 (M + H)

1058

658 (M + H)

1059

694 (M + H)

1060

660 (M + H)

1061

660 (M + H)

1062

596 (M + H)

1063

616 (M + H)

1064

644 (M + H)

1065

684 (M + H)

1066

724 (M + H)

1067

698 (M + H)

1068

664 (M + H)

1069

638 (M + H)

1070

650 (M + H)

1071

630 (M + H)

1072

626 (M + H)

1073

664 (M + H)

1074

620 (M + H)

1075

600 (M + H)

1076

638 (M + H)

1077

542 (M + H)

1078

466 (M + H)

1079

452 (M + H)

1080

438 (M + H)

1081

536 (M + H)

1082

502 (M + H)

1083

502 (M + H)

1084

502 (M + H)

1085

518 (M + H)

1086

518 (M + H)

1087

472 (M + H)

1088

466 (M + H)

1089

511 (M + H)

1090

561 (M + H)

1091

563 (M + H)

1092

536 (M + H)

1093

643 (M + H)

1094

524 (M + H)

1095

552 (M + H)

1096

526 (M + H)

1097

597 (M + H)

1098

549 (M + H)

1099

570 (M + H)

1100

494 (M + H)

1101

508 (M + H)

1102

611 (M + H)

1103

584 (M + H)

1104

492 (M + H)

1105

462 (M + H)

1106

460 (M + H)

1107

464 (M + H)

1108

446 (M + H)

1109

466 (M + H)

1110

474 (M + H)

1111

492 (M + H)

1112

458 (M + H)

1113

506 (M + H)

1114

536 (M + H)

1115

617 (M + H)

1116

532 (M + H)

1117

504 (M + H)

1118

577 (M + H)

1119

471 (M + H)

1120

485 (M + H)

1121

432 (M + H)

1122

458 (M + H)

1123

590 (M + H)

1124

504 (M + H)

1125

564 (M + H)

1126

453 (M + H)

1127

422 (M + H)

1128

424 (M + H)

1129

438 (M + H)

1130

408 (M + H)

1131

438 (M + H)

1132

438 (M + H)

1133

425 (M + H)

1134

439 (M + H)

1135

398 (M + H)

1136

438 (M + H)

1137

506 (M + H)

1138

376 (M + H)

1139

432 (M + H)

1140

454 (M + H)

1141

454 (M + H)

1142

491 (M + H)

1143

522 (M + H)

1144

455 (M + H)

1145

416 (M + H)

1146

419 (M + H)

1147

394 (M + H)

1148

366 (M + H)

1149

462 (M + H)

1150

377 (M + H)

1151

457 (M + H)

1152

456 (M + H)

1153

398 (M + H)

1154

543 (M + H)

1155

421 (M + H)

1156

555 (M + H)

1157

377 (M + H)

1158

510 (M + H)

1159

484 (M + H)

1160

382 (M + H)

1161

460 (M + H)

1162

460 (M + H)

1163

430 (M + H)

1164

468 (M + H)

1165

502 (M + H)

1166

444 (M + H)

1167

484 (M + H)

1168

428 (M + H)

1169

426 (M + H)

1170

428 (M + H)

1171

428 (M + H)

1172

446 (M + H)

1173

462 (M + H)

1174

462 (M + H)

1175

448 (M + H)

1176

502 (M + H)

1177

466 (M + H)

1178

376 (M + H)

1179

428 (M + H)

1180

420 (M + H)

1181

428 (M + H)

1182

408 (M + H)

1183

392 (M + H)

1184

476 (M + H)

1185

426 (M + H)

1186

496 (M + H)

1187

442 (M + H)

1188

442 (M + H)

1189

408 (M + H)

1190

446 (M + H)

1191

458 (M + H)

1192

484 (M + H)

1193

450 (M + H)

1194

404 (M + H)

1195

525 (M + H)

1196

483 (M + H)

1197

544 (M + H)

1198

512 (M + H)

1199

436 (M + H)

1200

381 (M + H)

1201

539 (M + H)

1202

486 (M + H)

1203

518 (M + H)

1204

436 (M + H)

1205

515 (M + H)

1206

501 (M + H)

1207

580 (M + H)

1208

539 (M + H)

1209

459 (M + H)

1210

414 (M + H)

1211

436 (M + H)

1212

488 (M + H)

1213

494 (M + H)

1214

458 (M + H)

1215

465 (M + H)

1216

432 (M + H)

1217

406 (M + H)

1218

496 (M + H)

1219

440 (M + H)

1220

424 (M + H)

1221

478 (M + H)

1222

406 (M + H)

1223

390 (M + H)

1224

416 (M + H)

1225

434 (M + H)

1226

451 (M + H)

1227

420 (M + H)

1228

396 (M + H)

1229

573 (M + H)

1230

434 (M + H)

1231

496 (M + H)

1232

450 (M + H)

1233

418 (M + H)

1234

408 (M + H)

1235

420 (M + H)

1236

462 (M + H)

1237

404 (M + H)

1238

609 (M + H)

1239

468 (M + H)

1240

436 (M + H)

1241

440 (M + H)

1242

418 (M + H)

1243

468 (M + H)

1244

440 (M + H)

1245

486 (M + H)

1246

475 (M + H)

1247

340 (M + H)

1248

382 (M + H)

1249

370 (M + H)

1250

342 (M + H)

1251

382 (M + H)

1252

370 (M + H)

1253

520 (M + H)

1254

390 (M + H)

1255

446 (M + H)

1256

468 (M + H)

1257

468 (M + H)

1258

505 (M + H)

1259

536 (M + H)

1260

469 (M + H)

1261

430 (M + H)

1262

433 (M + H)

1263

408 (M + H)

1264

380 (M + H)

1265

476 (M + H)

1266

391 (M + H)

1267

448 (M + H)

1268

471 (M + H)

1269

470 (M + H)

1270

412 (M + H)

1271

557 (M + H)

1272

435 (M + H)

1273

425 (M + H)

1274

569 (M + H)

1275

391 (M + H)

1276

524 (M + H)

1277

498 (M + H)

1278

396 (M + H)

1279

474 (M + H)

1280

474 (M + H)

1281

444 (M + H)

1282

482 (M + H)

1283

516 (M + H)

1284

458 (M + H)

1285

498 (M + H)

1286

442 (M + H)

1287

440 (M + H)

1288

442 (M + H)

1289

442 (M + H)

1290

460 (M + H)

1291

476 (M + H)

1292

476 (M + H)

1293

462 (M + H)

1294

516 (M + H)

1295

480 (M + H)

1296

408 (M + H)

1297

442 (M + H)

1298

434 (M + H)

1299

442 (M + H)

1300

422 (M + H)

1301

490 (M + H)

1302

440 (M + H)

1303

456 (M + H)

1304

422 (M + H)

1305

460 (M + H)

1306

472 (M + H)

1307

498 (M + H)

1308

464 (M + H)

1309

418 (M + H)

1310

539 (M + H)

1311

497 (M + H)

1312

558 (M + H)

1313

526 (M + H)

1314

450 (M + H)

1315

395 (M + H)

1316

553 (M + H)

1317

500 (M + H)

1318

532 (M + H)

1319

450 (M + H)

1320

529 (M + H)

1321

515 (M + H)

1322

594 (M + H)

1323

473 (M + H)

1324

428 (M + H)

1325

450 (M + H)

1326

502 (M + H)

1327

508 (M + H)

1328

472 (M + H)

1329

476 (M + H)

1330

479 (M + H)

1331

446 (M + H)

1332

420 (M + H)

1333

510 (M + H)

1334

454 (M + H)

1335

438 (M + H)

1336

492 (M + H)

1337

420 (M + H)

1338

404 (M + H)

1339

430 (M + H)

1340

448 (M + H)

1341

465 (M + H)

1342

434 (M + H)

1343

410 (M + H)

1344

587 (M + H)

1345

448 (M + H)

1346

510 (M + H)

1347

464 (M + H)

1348

432 (M + H)

1349

422 (M + H)

1350

434 (M + H)

1351

476 (M + H)

1352

418 (M + H)

1353

623 (M + H)

1354

618 (M + H)

1355

486 (M + H)

1356

463 (M + H)

1357

482 (M + H)

1358

452 (M + H)

1359

454 (M + H)

1360

432 (M + H)

1361

482 (M + H)

1362

454 (M + H)

1363

502 (M + H)

1364

489 (M + H)

1365

328 (M + H)

1366

354 (M + H)

1367

396 (M + H)

1368

384 (M + H)

1370

396 (M + H)

1371

404 (M + H)

1372

418 (M + H)

1373

420 (M + H)

1374

460 (M + H)

1375

444 (M + H)

1376

476 (M + H)

1377

521 (M + H)

1378

416 (M + H)

1379

538 (M + H)

1380

419 (M + H)

1381

522 (M + H)

1382

492 (M + H)

1383

472 (M + H)

1384

429 (M + H)

1385

622 (M + H)

1386

545 (M + H)

1387

555 (M + H)

1389

480 (M + H)

1390

482 (M + H)

1391

523 (M + H)

1392

480 (M + H)

1393

520 (M + H)

1394

573 (M + H)

1395

573 (M + H)

1396

627 (M + H)

1397

613 (M + H)

1398

532 (M + H)

1399

512 (M + H)

1400

391 (M + H)

1401

510 (M + H)

1402

633 (M + H)

1403

531 (M + H)

1404

468 (M + H)

1405

452 (M + H)

1406

468 (M + H)

1407

503 (M + H)

1408

523 (M + H)

1409

482 (M + H)

1410

494 (M + H)

1411

482 (M + H)

1412

531 (M + H)

1413

550 (M + H)

1414

536 (M + H)

1415

588 (M + H)

1416

508 (M + H)

1417

519 (M + H)

1418

488 (M + H)

1419

435 (M + H)

1420

479 (M + H)

1421

487 (M + H)

1422

501 (M + H)

1423

426 (M + H)

1424

494 (M + H)

1425

568 (M + H)

1426

660 (M + H)

1427

460 (M + H)

1428

424 (M + H)

1429

555 (M + H)

1430

427 (M + H)

1431

444 (M + H)

1432

435 (M + H)

1433

421 (M + H)

1434

451 (M + H)

1435

462 (M + H)

1436

512 (M + H)

1437

451 (M + H)

1438

462 (M + H)

1439

480 (M + H)

1440

439 (M + H)

1441

449 (M + H)

1442

505 (M + H)

1443

539 (M + H)

1444

487 (M + H)

1445

488 (M + H)

1446

565 (M + H)

1447

492 (M + H)

1448

442 (M + H)

1449

516 (M + H)

1450

465 (M + H)

1451

472 (M + H)

1452

458 (M + H)

1453

466 (M + H)

1454

450 (M + H)

1455

480 (M + H)

1456

518 (M + H)

1457

532 (M + H)

1458

580 (M + H)

1459

452 (M + H)

1460

498 (M + H)

1461

409 (M + H)

1462

563 (M + H)

1463

420 (M + H)

1464

535 (M + H)

1465

516 (M + H)

1466

476 (M + H)

1467

472 (M + H)

1468

487 (M + H)

1469

548 (M + H)

1470

512 (M + H)

1471

473 (M + H)

1472

648 (M + H)

1473

591 (M + H)

1474

645 (M + H)

1475

531 (M + H)

1476

619 (M + H)

1477

529 (M + H)

1478

563 (M + H)

1479

537 (M + H)

1480

540 (M + H)

1481

579 (M + H)

1482

463 (M + H)

1483

449 (M + H)

1484

432 (M + H)

1485

482 (M + H)

1486

482 (M + H)

1487

505 (M + H)

1488

516 (M + H)

1489

560 (M + H)

1490

523 (M + H)

1491

405 (M + H)

1492

534 (M + H)

1493

526 (M + H)

1494

526 (M + H)

1495

510 (M + H)

1496

498 (M + H)

1497

632 (M + H)

1498

570 (M + H)

1499

590 (M + H)

1500

618 (M + H)

1501

658 (M + H)

1502

672 (M + H)

1503

638 (M + H)

1504

612 (M + H)

1505

624 (M + H)

1506

590 (M + H)

1507

604 (M + H)

1508

598 (M + H)

1509

574 (M + H)

1510

424 (M + H)

1511

508 (M + H)

1512

474 (M + H)

1513

474 (M + H)

1514

474 (M + H)

1515

490 (M + H)

1516

490 (M + H)

1517

444 (M + H)

1518

438 (M + H)

1519

483 (M + H)

1520

535 (M + H)

1521

510 (M + H)

1522

601 (M + H)

1523

496 (M + H)

1524

420 (M + H)

1525

498 (M + H)

1526

521 (M + H)

1527

542 (M + H)

1528

466 (M + H)

1529

480 (M + H)

1530

583 (M + H)

1531

556 (M + H)

1532

464 (M + H)

1533

434 (M + H)

1534

434 (M + H)

1535

436 (M + H)

1536

418 (M + H)

1537

438 (M + H)

1538

446 (M + H)

1539

464 (M + H)

1540

430 (M + H)

1541

478 (M + H)

1542

575 (M + H)

1543

506 (M + H)

1544

476 (M + H)

1545

564 (M + H)

1546

478 (M + H)

1547

396 (M + H)

1548

410 (M + H)

1549

410 (M + H)

1550

410 (M + H)

1551

370 (M + H)

1552

410 (M + H)

1553

432 (M + H)

1554

474 (M + H)

1555

458 (M + H)

1556

490 (M + H)

1557

535 (M + H)

1558

430 (M + H)

1559

552 (M + H)

1560

433 (M + H)

1561

536 (M + H)

1562

506 (M + H)

1563

429 (M + H)

1564

486 (M + H)

1565

443 (M + H)

1566

636 (M + H)

1567

705 (M + H)

1568

559 (M + H)

1569

569 (M + H)

1570

480 (M + H)

1571

494 (M + H)

1572

496 (M + H)

1573

537 (M + H)

1574

494 (M + H)

1575

534 (M + H)

1576

587 (M + H)

1577

587 (M + H)

1578

523 (M + H)

1579

627 (M + H)

1580

627 (M + H)

1581

526 (M + H)

1582

524 (M + H)

1583

564 (M + H)

1584

647 (M + H)

1585

545 (M + H)

1586

671 (M + H)

1587

482 (M + H)

1588

466 (M + H)

1589

528 (M + H)

1590

482 (M + H)

1591

517 (M + H)

1592

537 (M + H)

1593

496 (M + H)

1594

508 (M + H)

1595

496 (M + H)

1596

564 (M + H)

1597

550 (M + H)

1598

602 (M + H)

1599

522 (M + H)

1600

533 (M + H)

1601

468 (M + H)

1602

502 (M + H)

1603

449 (M + H)

1604

493 (M + H)

1605

515 (M + H)

1606

440 (M + H)

1607

508 (M + H)

1608

582 (M + H)

1609

674 (M + H)

1610

474 (M + H)

1611

548 (M + H)

1612

438 (M + H)

1613

569 (M + H)

1614

441 (M + H)

1615

458 (M + H)

1616

449 (M + H)

1617

435 (M + H)

1618

465 (M + H)

1619

476 (M + H)

1620

526 (M + H)

1621

465 (M + H)

1622

476 (M + H)

1623

494 (M + H)

1624

453 (M + H)

1625

463 (M + H)

1626

519 (M + H)

1627

553 (M + H)

1628

501 (M + H)

1629

458 (M + H)

1630

502 (M + H)

1631

579 (M + H)

1632

506 (M + H)

1633

456 (M + H)

1634

530 (M + H)

1635

479 (M + H)

1636

590 (M + H)

1637

486 (M + H)

1638

472 (M + H)

1639

480 (M + H)

1640

464 (M + H)

1641

494 (M + H)

1642

532 (M + H)

1643

546 (M + H)

1644

608 (M + H)

1645

438 (M + H)

1646

466 (M + H)

1647

512 (M + H)

1648

423 (M + H)

1649

577 (M + H)

1650

434 (M + H)

1651

549 (M + H)

1652

530 (M + H)

1653

490 (M + H)

1654

486 (M + H)

1655

501 (M + H)

1656

562 (M + H)

1657

487 (M + H)

1658

660 (M + H)

1659

605 (M + H)

1660

662 (M + H)

1661

696 (M + H)

1662

639 (M + H)

1663

659 (M + H)

1664

647 (M + H)

1665

633 (M + H)

1666

543 (M + H)

1667

577 (M + H)

1668

551 (M + H)

1669

554 (M + H)

1670

477 (M + H)

1671

463 (M + H)

1672

446 (M + H)

1673

496 (M + H)

1674

496 (M + H)

1675

519 (M + H)

1676

530 (M + H)

1677

574 (M + H)

1678

437 (M + H)

1679

419 (M + H)

1680

548 (M + H)

1681

672 (M + H)

1682

540 (M + H)

1683

540 (M + H)

1684

524 (M + H)

1685

512 (M + H)

1686

632 (M + H)

1687

646 (M + H)

1688

648 (M + H)

1689

584 (M + H)

1690

632 (M + H)

1691

672 (M + H)

1692

686 (M + H)

1693

652 (M + H)

1694

626 (M + H)

1695

638 (M + H)

1696

618 (M + H)

1697

612 (M + H)

1698

588 (M + H)

1699

624 (M + H)

1700

438 (M + H)

1701

522 (M + H)

1702

488 (M + H)

1703

488 (M + H)

1704

488 (M + H)

1705

504 (M + H)

1706

504 (M + H)

1707

458 (M + H)

1708

452 (M + H)

1709

497 (M + H)

1710

549 (M + H)

1711

524 (M + H)

1712

615 (M + H)

1713

510 (M + H)

1714

434 (M + H)

1715

512 (M + H)

1716

535 (M + H)

1717

556 (M + H)

1718

480 (M + H)

1719

494 (M + H)

1720

597 (M + H)

1721

570 (M + H)

1722

478 (M + H)

1723

448 (M + H)

1724

448 (M + H)

1725

450 (M + H)

1726

432 (M + H)

1727

452 (M + H)

1728

460 (M + H)

1729

478 (M + H)

1730

444 (M + H)

1731

492 (M + H)

1732

524 (M + H)

1733

589 (M + H)

1734

490 (M + H)

1735

490 (M + H)

1736

563 (M + H)

1737

471 (M + H)

1738

578 (M + H)

1739

410 (M + H)

1740

424 (M + H)

1741

424 (M + H)

1742

424 (M + H)

1743

447 (M + H)

1744

384 (M + H)

1745

424 (M + H)

1746

434 (M + H)

1747

472 (M + H)

1748

520 (M + H)

1749

514 (M + H)

1750

470 (M + H)

1751

500 (M + H)

1752

482 (M + H)

1753

502 (M + H)

1754

490 (M + H)

1755

426 (M + H)

1756

683 (M + H)

1757

537 (M + H)

1758

588 (M + H)

1759

460 (M + H)

1760

477 (M + H)

1761

447 (M + H)

1762

509 (M + H)

1763

438 (M + H)

1764

464 (M + H)

1765

450 (M + H)

1766

383 (M + H)

1767

476 (M + H)

1768

396 (M + H)

1769

434 (M + H)

1770

416 (M + H)

1771

470 (M + H)

1772

410 (M + H)

1773

442 (M + H)

1774

394 (M + H)

1775

461 (M + H)

1776

476 (M + H)

1777

510 (M + H)

1778

544 (M + H)

1779

380 (M + H)

1780

437 (M + H)

1781

464 (M + H)

1782

394 (M + H)

1783