ZA200505001B - 1,2,3-Trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia - Google Patents

Description

EE ——————————————————————— eee es eee 1,2,3-TRISUBSTITUTED ARYL, AND HETEROARYL DERIVATIVES AS MODULATORS OF METABOLISM

AND THE PRPPUYLAXIS AND TREATMENT OF DISORDERS RELATED THERETO SUCH AS DIABETES

AND HYPERGLYCEMIA

FIELD OF THE INVENTION

The present invention relates to certain 1,2,3-trisubstituted ary} and heteroaryl derivatives that are modulators of glucose metabolism. Accordingly, compounds of the present invention are useful in the prophylaxis or treatment of metabolic disorders and complications thereof, such as, diabetes and obesity.

BACKGROUND OF THE INVENTION

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

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

The etiology of the different types of diabetes is not the same; however, everyone with diabetes has two things in common: overproduction of glucose by the liver and little or no ability to move glucose out of the blood into the cells where it becomes the body's primary fuel.

People who do not have diabetes rely on insulin, a hormone made in the pancreas, to move glucose from the biood into the ceils of the body. However, people whe have diabetes cither don't produce insulin or can't efficiently use the insulin they produce; therefore, they can't move glucose into their cells. Glucose accumulates in the blood creating a condition called hyperglycemia, and over time, can cause serious health problems.

Diabetes is a syndrome with interrelated metabolic, vascular, and neuropathic components. The metabolic syndrome, generally characterized by hyperglycemia, comprises alterations in carbohydrate, fat and protein metabolism caused by absent or markedly reduced insulin secretion and/or ineffective insulin action. The vascular syndrome consists of "abnormalities in the blood vessels leading to cardiovascular, retinal and renal complications.

Abnormalities in the peripheral and autonomic nervous systems are also part of the diabetic syndrome.

People with IDDM, which accounts for about 5% to 10% of those who have diabetes, don't produce insulin and therefore must inject insulin to keep their blood glucose levels normal.

IDDM is characterized by low or undetectable levels of endogenous insulin production caused by destruction of the insulin-producing B cells of the pancreas, the characteristic that most readily

J distinguishes IDDM from NIDDM. IDDM, once termed juvenile-onset diabetes, strikes young and older adults alike.

Approximately 90 to 95% of people with diabetes have Type II (or NIDDM). NIDDM subjects produce insulin, but the cells in their bodies are insulin resistant: the cells don't respond properly to the hormone, so glucose accumulates in their blood. NIDDM is characterized by a relative disparity between endogenous insulin production and insulin requirements, leading to ’ elevated blood glucose levels. In contrast to IDDM, there is always some endogenous insulin production in NIDDM; many NIDDM patients have normal or cven elevated blood insulin levels, while other NIDDM patients have inadequate insulin production (Rotwein, R. et al. N.

Engl. J. Med. 308, 65-71 (1983)). Most people diagnosed with NIDDM are age 30 or older, and half of all new cases are age 55 and older. Compared with whites and Asians, NIDDM is more ' common among Native Americans, African-Americans, Latinos, and Hispanics. In addition, the onset can be insidious or even clinically inapparent, making diagnosis difficult.

The primary pathogenic lesion on NIDDM has remained elusive. Many have suggested that primary insulin resistance of the peripheral tissues is the initial event. Genetic epidemiological studies have supported this view. Similarly, insulin secretion abnormalities have: = been argued as the primary defect in NIDDM. 1t is likely that both phenomena are important contributors to the disease process (Rimoin, D. L., et. al. Emery and Rimoin's Principles and

Practice of Medical Genetics 3" Ed. 1:1401-1402 (1996)).

Many people with NIDDM have sedentery lifestyles and are obese; they weigh approximately 20% more than the recommended weight for their height and build. Furthermore, obesity is characterized by hyperinsulinemia and insulin resistance, a feature shared with

NIDDM, hypertension and atherosclerosis.

Obesity and diabetes are among the most common human health problems in industrialized societies. In industrialized countries a third of the population is at least 20% overweight. In the United States, the percentage of obese people has increased from 25% at the end of the 1970s, to 33% at the beginning the 1990s. Obesity is one of the most important risk factors for NIDDM. Definitions of obesity differ, but in general, a subject weighing at least 20% more than the recommended weight for his/her height and build is considered obese. The risk of developing NIDDM is tripled in subjects 30% overweight, and three-quarters with NIDDM are overweight.

Obesity, which is the result of an imbalance between caloric intake and energy expenditure, is highly correlated with insulin resistance and diabetes in experimental animals and human. However, the molecular mechanisms that are involved in obesity-diabetes syndromes. are not clear. During early development of obesity, increase insulin secretion balances insulin resistance and protects patients from hyperglycemia (Le Stunff, et al. Diabetes 43, 696-702 (1989)). However, after several decades, B cell fimction deteriorates and non-insulin-dependent

"diabetes develops in about 20% of fhe obese population (Pederson, P. Diab. Metab. Rev. 5, 505- 509 (1989)) and (Brancati, F. L., et al,, Arch. Intern. Med. 159, 957-963 (1999)). Given its high prevalence in modern societies, obesity ‘has thus become the leading risk factor for NIDDM (Hill,

J. O., et al., Science 280, 1371-1374 (1998)). However, the factors which predispose a fraction of patients to alteration of insulin secretion in response to fat accumulation remain unknown.

Whether someone is classified as overweight or obese is generally determined on the basis of their body mass index (BMI) which is calculated by dividing body weight (kg) by height squared (). Thus, the units of BMI are kg/m” and it is possible to calculate the BMI range associated with minimum mortality in each decade of life. Overweight is defined asa

BMI in the range 25-30 kg/m’, and obesity as a BMI greater than 30 kg/m’ (see TABLE below). There are problems with this definition in that it does not take into account the proportion of body mass that is muscle in relation to fat (adipose tissue). To account for this, obesity can also be defined on the basis of body fat content: greater than 25% and 30% in males aud females, respectively.

CLASSIFICATION OF WEIGHT BY

© BODY MASS INDEX (BMI) 35.0-39.9 Coontiy (Class 1

As the BMI increases there is an increased risk of death from a variety of causes that is independent of other risk factors. The most common diseases with obesity are cardiovascular disease (particularly hypertension), diabetes (obesity aggravates the development of diabetes), gall bladder disease (particularly cancer) and diseases of reproduction. Research has shown that even a modest reduction in body weight can correspond to a significant reduction in the risk of developing coronary heart disease.

Compounds marketed as anti-obesity agents include Orlistat (XENICAL™) and

Sibutramine. Orlistat (a lipase inhibitor) inhibits fat absorption directly and tends to produce a high incidence of unpleasant (though relatively harmless) side-effects such as diarrhea.

Sibutramine (a mixed 5-HI/noradrenaline reuptake inhibitor) can increase blood pressure and heart rate in some patients. The serotonin releaser/reuptake inhibitors fenfluramine

+ (Pondimin™) and dexfenfluramine (Redux™) have been reported to decrease food intake and body weight over a prolonged period (greater than 6 months). However, both products were withdrawn after reports of preliminary evidence of heart valve abnormalities associated with their use. Accordingly, there is a need for the development of a safer anti-obesity agent.

Obesity considerably increases the risk of developing cardiovascular diseases as well.

Coronary insufficiency, atheromatous disease, and cardiac insufficiency are at the forefront of the cardiovascular complication induced by obesity. It is estimated that if the entire population had an ideal weight, the risk of coronary insufficiency would decrease by 25% and the risk of cardiac insufficiency and of cerebral vascular accidents by 35%. The incidence of coronary diseases is doubled in subjects less than 50 years of age who are 30% overweight. The diabetes patient faces a 30% reduced lifespan. After age 45, people with diabetes are about three times more likely than people without diabetes to have significant heart disease and up to five times more likely to have a stroke. These findings emphasize the inter-relations between risks factors for

NIDDM and coronary heart disease and the potential value of an integrated approach to the prevention of these conditions based on the prevention of these conditions based on the prevention of obesity (Perry, L. J., et al., BMJ 310, 560-564 (1995).

Diabetes has also been implicated in the development of kidney disease, eye diseases and nervous-system problems. Kidney disease, also called nephropathy, occurs when the kidney's "filter mechanism” is damaged and protein leaks into urine in excessive amounts and eventually the kidney fails. Diabetes isalsoa leading cause of damage to the retina at the back of the eye and increases risk of cataracts and glaucoma. Finally, diabetes is associated with nerve damage, especially in the legs and feet, which interferes with the ability to sense pain and contributes to serious infections. Taken together, disbates complications are one of the nation's leading causes of death.

SUMMARY OF THE INVENTION

The present invention is drawn to compounds, which bind to and modulate the activity of a GPCR referred to herein as RUP3, and uses thereof. The term RUP3, as used herein, includes the human sequences found in GeneBank accession number XM_066873, naturally-occurring allelic variants, mammalian orthologs, and recombinant mutants thereof.

A preferred human RUP3 for use in screening and testing of the compounds of the invention is provided in the nucleotide sequence of Seq. ID.No:1 and the corresponding amino acid sequence in Seq. ID.No:2.

One aspect of the present invention encompasses 1,2,3-trisubstituted aryl and heteroaryl derivatives as shown in Formula (Ia):

Ri

Ho

Ary” NN A yA LD (Ia) or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

A and B are independently C;; alkylene optionally substituted with 1 to 4 methyl groups;

Dis 0, S, S(0), S(O), CRsR; or N-Ry;

V is selected from the group consisting of Cy.3 alkylene, ethynylene and Cy» heteroalkylene wherein each are optionally substituted with 1 to 4 substituents selected from the group . consisting of Cy.5 alkyl, Cy.4 alkoxy, carboxy, cyano, Cia haloalkyl and halogen; or Vis absent;

W is NR, O, S, S(O) or S(O); or W is absent;

X is N or CRs;

Y is N or CRg; 7 is selected from the group consisting of C,.5 acyl, Chr.s acyloxy, C4 alkoxy, Cis alkyl, Cy alkylcarboxamide, C;.4 alkylthiocarboxamide, Cy4 alkylsulfonamide, C14 alkylsulfinyl, Cy. alkylsulfonyl, Cy alkylthio, C14 alkylthioureyl, Cy. alkylureyl, amino, Cr alkylamino, C;4 dialkylamino, carbo-C; alkoxy, carboxamide, carboxy, cyano, Cis diacylamino, C, ¢ dialkylcarboxamide, C14 dialkylthiocarboxamide, Cos dialkylsulfonamide,

C,., dialkylsulfonylamino, formyl, C14 haloalkoxy, C14 haloalkyl, C14 haloalkylcarboxamide,

C,.4 haloalkylsulfinyl, Ci.4 haloalkylsulfonyl, C4 haloalkylthio, halogen, aryl, heterocyclic, heteroaryl, hydroxyl, hydroxylamino, nitro and tetrazolyl, wherein Cy.g alkyl and Cys acyl are each optionally substituted with 1,2, 3 or 4 groups selected from the group consisting of Cy.5 acyl, Cy.5 acyloxy, Ci alkoxy, C14 alkylcarboxamide, Cy.4 alkylsulfonamide, Cy.4 alkylsulfinyl, C,4 alkylsulfonyl, C;.4 alkylthio, Cy. alkylureyl, amino, C,., alkylamino, Cp4 dialkylamino, carbo-C ¢-alkoxy, carboxamide, carboxy, cyano, formyl, C4 haloalkoxy, Ci4 haloalkylsulfinyl, Ci.4 haloalkylsulfonyl, C14 haloalkylthio, halogen, hydroxyl, hydroxylamino and nitro; or

Z is a group of Formula (A):

H

AA

Mere,

A)

wherein:

Ry is H, Cy. alkyl or Cs cycloalkyl; and Rg is H, nitro or nitrile;

Ar, is aryl or heteroaryl wherein each are optionally substituted with Rg-Ry3;

R, is selected from the group consisting of H, Cys acyloxy, Cp alkenyl, C14 alkoxy, Cis alkyl, Cy. alkylcarboxamide, Cys alkynyl, Cy alkylsulfonamide, Ci. alkylsulfinyl, Cr alkylsulfonyl, Cy alkylthio, Cy 4 alkylureyl, amino, Cy.4 alkylamino, C, ¢ dialkylamino, carboxamide, cyano, Cs cycloalkyl, Cys dialkylcarboxamide, Cy.¢ dialkylsulfonamide, halogen, Cy. haloalkoxy, Cy. haloalkyl, Ci4 haloalkylsulfinyl, Ci4 haloalkylsulfonyl, Ci haloalkylthio and hydroxyl;

R, is selected from the group consisting of H, Cys acyl, Cis acyloxy, C;.4 alkoxy, Cis alkyl, C4 alkylcarboxamide, C4 alkylthiocarboxamide, C; 4 alkylsulfinyl, Ci4 alkylsulfonyl,

C, alkylthio, amino, carbo-C, alkoxy, carboxamide, carboxy, cyano, Cs¢-cycloalkyl, Cag dialkylcarboxamide, Cy 4 haloalkoxy, Ci.4 haloalkyl, halogen, heteroaryl, hydroxyl and phenyl; and wherein Cy. alkyl, heteroaryl and phenyl are each optionally substituted with 1 to substituents selected from the group consisting of Cs acyl, Cis acyloxy, Cis alkoxy, Cis alkyl, C,4 alkylamino, C;4 alkylcarboxamide, Cy4 alkylthiocarboxamide, C14 alkylsulfonamide, C4 alkylsulfinyl, C;4 alkylsulfonyl, C,4 alkylthio, C14 alkylthioureyl, C14 alkylureyl, amino, carbo-Cy.¢-alkoxy, carboxamide, carboxy, cyano, Cs. ¢-cycloalkyl, Cs ¢- cycloalkyl-C; s-alkylene, Ca.s-cycloalkyl-C,.s-heteroalkylene, C, 5 dialkylamino, Co dialkylcarboxamide, Cy.4 dialkylthiocarboxamide, Cy. dialkylsulfonamide, Cy alkylthioureyl, C:4 haloalkoxy, C4 haloalkyl, C14 haloalkylsulfinyl, C4 haloalkylsulfonyl,

C4 haloalkyl, C4 haloalkylthio, halogen, heterocyclic, hydroxyl, hydroxylamino and nitro; or

Ry is ~Ar,-Ar; wherein Ar, and Ar; are independently aryl or heteroaryl each optionally substituted with 1 to 5 substituents selected from the group consisting of H, Cys acyl, C15 acyloxy, Ci alkoxy, Cys alkyl, Ci4 alkylcarboxamide, C;.4 alkylthiocarboxamide,

Cy. alkylsulfinyl, Cy 4 alkylsulfonyl, C;4 alkylthio, amino, carbo-C; -alkoxy, carboxamide, carboxy, cyano, Cs s-cycloalkyl, C,s dialkylcarboxamide, C14 haloalkoxy, C;.4 haloalkyl, . halogen, hydroxy! and nitro; or

R; is a group of Formula (B): : : OR oA Ris ®) wherein:

Rs is Cys alkyl or Cs cycloalkyl; and Ry; is F, Cl, Br or CN; or

R; is a group of Formula (C):

rid Car, . (©) wherein:

Gis C=0, CR1sRy7, O, S, S(O), S(O); where Ris and Ry; are independently

H or C,¢ alkyl; and

Ar, is phenyl or heteroaryl optionally substituted with 1 to 5 substituents selected from the group consisting of Cy 5 acyl, Cy.5 acyloxy, Ci.4 alkoxy, Cy alkyl, Cy 4 alkylcarboxamide, Ci4 ’ alkylthiocarboxamide, Cy 4 alkylsulfonamide, C4 alkylsulfinyl, C14 alkylsulfonyl, Ci4 alkylthio, C4 alkylthioureyl, C:.4 alkylureyl, amino, carbo-Cy.¢-alkoxy, carboxamide, carboxy, cyano, C, s-cycloalkyl, Cs. dialkylcarboxamide, C14 dialkylthiocarboxamide, Cy. dialkylsulfonamide, Cy4 alkylthioureyl, C14 haloalkoxy, Ci. haloalkyl, C14 haloalkylsulfinyl,

C,.4 haloalkylsulfonyl, C4 haloalkyl, Cy4 haloalkylthio, halogen, heteroaryl, hydroxyl, hydroxylamino and nitro; : Rj is H, Cy.5 alkyl, Ci.4 alkoxy, halogen or hydroxyl;

R, is H or Cy. alkyl;

Rs and Rg are independently H, Cs alkyl or halogen;

R, is selected from the group consisting of Cys acyl, C15 acyloxy, Co alkenyl, Ci4 alkoxy, Cy.q alkyl, C4 alkylamino, Cy. alkylcarboxamide, C4 alkynyl, Cy.4 alkylsulfonamide, C; 4 alkylsulfinyl, C4 alkylsulfonyl, C4 alkylthio, C14 alkylureyl, amino, arylsulfonyl, carbo-C; alkoxy, carboxamide, carboxy, cyano, Cs cycloalkyl, Cy : dialkylamino, C,.¢ dialkylcarboxamide, Cs. diatkylsulfonamide, halogen, C;4 haloalkoxy, Ci. 4 haloalkyl, C;4 haloalkylsulfinyl, C14 haloalkylsulfonyl, Cy haloalkylthio, heterocyclic, beterocyclicsulfonyl, heteroaryl, hydroxyl, nitro, Cs oxo-cycloalkyl, phenoxy, phenyl, sulfonamide and sulfonic acid, and wherein Cy.5 acyl, Cy4 alkoxy, Cis alkyl, Ci4 alkylsulfonamide, alkylsulfonyl, arylsulfonyl, heteroaryl, phenoxy and phenyl are each optionally substituted with 1 to 5 substituents selected independently from the group consisting of C;.s acyl, Cys acyloxy, Cas alkenyl, C;.4 alkoxy, Cys alkyl, C14 alkylcarboxamide, C, 5 alkynyl, C,4 alkylsulfonamide, C14 alkylsulfinyl, C, 4 alkylsulfonyl,

C14 alkylthio, Cy.4 alkylureyl, carbo-C;.¢c-alkoxy, carboxamide, carboxy, cyano, Cis cycloalkyl, Cy dialkylcarboxamide, halogen, C; 4 haloalkoxy, C4 haloalkyl, C;.4 haloalkylsulfinyl, C,_4 haloalkylsulfonyl, C4 haloalkylthio, heteroaryl, heterocyclic, hydroxyl, nitro and phenyl; or

Rs is a group of Formula (D): : 2 Alb Rig

} wherein: “p” and “r” are independently 0, 1, 2 or 3; and

Rig is H, Cis acyl, Cy.6 alkenyl, Cig alkyl, Cis alkylcarboxamide, C,. ¢ alkynyl, C,, alkylsulfonamide, carbo-C; ¢-alkoxy, carboxamide, carboxy, cyano, Cs cycloalkyl, C, ¢ dialkylcarboxamide, halogen, heteroaryl or phenyl, and wherein the heteroaryl and phenyl are each optionally substituted with 1 to 5 substituents selected independently from the group consisting of

Cy. alkoxy, amino, Cy alkylamino, C, alkynyl, Co dialkylamino, halogen,

C1. haloalkoxy, C,.4 haloalkyl and hydroxyl; and

Ryo-Ry; are independently selected form the group consisting of Cys acyl, Crs acyloxy, Css alkenyl, C, 4 alkoxy, Cy.5 alkyl, C4 alkylcarboxamide, C,. alkynyl, C,, alkylsulfonamide, "Cy alkylsulfinyl, C4 alkylsulfonyl, C4 alkylthio, Cy4 alkylureyl, carbo-Ci ¢-alkoxy, carboxamide, carboxy, cyano, Cs cycloalkyl, C, ¢ dialkylcarboxamide, halogen, Cia haloalkoxy, C;.4 haloalkyl, C;.4 haloalkylsulfinyl, C4 haloalkylsulfonyl, C;4 haloalkylthio, hydroxyl and nitro; or two adjacent Ryo-Ry; groups together with Ar, formas, 60r7 membered cycloalkyl, cycloalkenyl or heterocyclic group wherein the 5, 6 or 7 membered ° group is optionally substituted with halogen.

Some embodiments of the present invention include pharmaceutical compositions comprising at least one compound of the present invention and a pharmaceutically acceptable carrier.

Some embodiments of the present invention include methods for prophylaxis or treatment of a metabolic disorder in an individual comprising administering to the individual a therapeutically effective amount uf a vornpound of the present invention of a pharmaccutical composition thereof.

Some embodiments of the present invention include methods of controlling or decreasing weight gain of an individual comprising administering to the individual a therapeutically effective amount of a compound of the present invention or pharmaceutical composition thereof.

Some embodiments of the present invention include methods of modulating a RUP3 receptor comprising contacting the receptor with a compound of the present invention.

Some embodiments of the present invention include methods of modulating a RUP3 receptor in an individual comprising contacting the receptor with a compound of the present invention. In some embodiments, the compound is an agonist. In some embodiments, the compound is an inverse agonist.

Some embodiments of the present invention include methods of modulating a RUP3 receptor in an individual comprising contacting the receptor with a compound of the present invention wherein the modulation of the RUP3 receptor is prophylaxis or treatment of a metabolic disorder.

Some embodiments of the present invention include methods of modulating a RUP3 receptor in an individual comprising contacting the receptor with a compound of the present invention wherein the modulation of the RUP3 receptor controls or reduces weight gain of the individual.

Some embodiments of the present invention include the use of compounds of the present invention for production of a medicament for use in prophylaxis or {reatment of 2 metabolic disorder.

Some embodiments of the present invention include the use of compounds of the present invention for production of a medicament for use in controlling or decreasing weight gain in an individual.

One aspect of the present invention pertains to compounds of the present invention, as described herein, for use in methods of treatment of the human or animal body by therapy.

One aspect of the present invention pertains to compounds of the present invention, as described herein, for use in methods of prophylaxis or treatment of a metabolic disorder of the human or animal body by therapy.

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

One aspect of the present invention pertains to methods of producing a pharmaceutical compositions comprising admixing at least one compound of the present invention and a pharmaceutically acceptable carrier.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1A shows RT-PCR analysis of RUP3 expression in human tissues. A total of twenty-two (22) human tissues were analyzed.

Figure 1B shows the cDNA Dot-Blot analysis of RUP 3 expression in human tissues.

Figure 1C shows analysis of RUP3 by RT-PCR with isolated huyman pancreatic islets of Langerhans.

Figure 1D shows analysis of RUP3 expression with cDNAs of rat origin by RT-PCR.

Figure 2A shows a polyclonal anti-RUP3 antibody prepared in Rabbits.

Figure 2B shows the expression of RUP3 in insulin-producing { cells of pancreatic islets.

Figure 3 shows finctional activities of RUP3 In vitro.

Figure 4A shows a RUP3 RNA blot.

Figure 4B shows RUP3 agonist, Compound B84, stimulates CAMP production in

HIT cells, at a level comparable to that seen with the adenyl cyclase activator forskolin.

Figure 4C shows RUP3 agonist, Compound B84, stimulates insulin secretion in HIT cells exposed to 15 mM glucose, at a level comparable to that seen with the adenylcyclase activator forskolin.

Figure 4D shows two RUP3 compounds, Compounds A48 und A51 (at 10 pM concentration), and the enhanced glucose-dependent insulin release compared to control.

Figure SA shows the In vivo effects of a RUP3 agonist (Compound B70) on glucose homeostasis in mice and specifically the effect by a RUP3 agonistina dose-dependent manner on the lowering of blood glucose after glucose challenge.

Figure 5B shows the acute response of db mice to a RUP 3 agonist and Ex-4. Figure 5B shows Compound B70 and Ex-4 significantly reduces glucose levels compared to vehicle control.

Figure 6 shows a representative scheme for the syntheses of compounds of the present invention.

DEFINITIONS

The scientific literature that has evolved around receptors has adopted a number of terms to refer to ligands having various effects on receptors. For clarity and consistency, the following definitions will be used throughout this patent document.

AGONISTS shall mean moieties that activate the intracellular response when they bind to the receptor, or enhance GTP binding to membranes.

AMINO ACID ABBREVIATIONS used hercin are set out in Tahle 1:

ETC 7S EY SE woe | me | k wore | aw | wn emacs | aw |p — ome | ows | oc “owmacam | ow | ® ome | ox | oo evo | ov | 6 wsmone | ws | om ~ wowwors | me | 1 woe | ww | or owe | ow | x wmowe | wer [om moans | ms | 0 F mous | wo | rp

ER ES RS meow | mw |r

Cmwroma | we | ow twosww | tw | oY

CHEMICAL GROUP, MOIETY OR RADICAL:

The term “Cys acyl” denotes an alkyl radical attached to a carbonyl wherein the definition of alkyl has the same definition as described herein; some examples include formyl, acetyl, propionyl, butanoyl, iso-butanoyl, pentanoyl, hexanoyl, heptanoyl, and the like.

The term “Cys acyloxy” denotes an acyl radical attached to an oxygen atom wherein acyl has the same definition has described herein; some examples include acetyloxy, propionyloxy, butanoyloxy, iso-butanoyloxy and the like. :

The term “Ca.¢ alkenyl” denotes a radical containing 2 to 6 carbons wherein at least one carbon-carbon double bond is present, some embodiments are 2 to 4 carbons, some embodiments are 2 to 3 carbons, and some embodiments have 2 carbons. Both E and Z isomers are embraced by the term “alkenyl.” Furthermore, the term “alkenyl” includes di- and tri-alkenyls. Accordingly, if more than one double bond is present then the bonds may be all Z or Z or a mixtures of £ and Z. i Examples of an alkenyl include vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3- pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, S-hexanyl, 2,4-hexadienyl and the like.

The term “Cy.4 alkoxy” as used herein denotes a radical alkyl, as defined : herein, attached directly to an oxygen atom. Example include methoxy, ethoxy, »-

PrOpoXy, iso-propoxy, n-butoxy, t-butoxy, iso-butoxy and the like.

The term “Cy. alkyl” denotes a straight or branched carbon radical containing 1 to 8 carbons, some embodiments are 1 to 6 carbons, some embodiments are 1 to 3 carbons, and some embodiments are 1 or 2 carbons. Examples of an alkyl include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, t-butyl, amyl, t-amyl, n-pentyl and the like.

The term “Cy; alkylcarboxamido™ denotes a single alkyl group attached to an amide, wherein alkyl has the same definition as found herein. The Cis alkylcarboxamido may be represented by the following: 0 0]

QA Nr aliyl Sens alkyl

Examples include N-methylcarboxamide, N-ethylcarboxamide, N~(iso- propyl)carboxamide and the like. oo

The term “C;-Cs alkylene” refers to a divalent straight carbon group, such as, ~CH,-, -CH,CHy-, -CH,CH,CHy-.

The term “C4 alkylsulfinyl” denotes an alkyl radical attached to a sulfoxide radical of the formula: -S(O)- wherein the alkyl radical has the same definition as described herein. Examples include methylsulfinyl, ethylsulfinyl and the like.

The term “Cj.4 alkylsulfonamide” refers to the groups 0,0 Qo. ° a Soy Or alkyl Sys alg

The term “C4 alkylsulfonyl” denotes an alkyl radical attached fo a sulfone radical of the formula: -S{O),- wherein the alkyl radical has the same definition as described herein, Examples include methylsulfonyl, ethylsulfonyl and the like.

The term “C4 alkylthio” denotes an alkyl radical attached to a sulfide of the formula: -S- wherein the alkyl radical has the same definition as described herein.

Examples include methylsulfanyl (i.e, CHsS-), ethylsulfanyl, isopropylsulfanyl and the like.

The term “Cy4 alkylthiocarboxamide” denotes a thicamide of the following formulae: tS] Ss

Ta alien ENN alkyl

H H

The term “Cj.4 alkyithioureyl” denotes the group of the formula: -NC(8S)N- wherein one are both of the nitrogens are substituted with the same or different alkyl group and alkyl has the same definition as described herein. Examples of an alkylthiourey! include, CH;NHC(O)NH-, NH,C(O)NCHj-, (CH); N(O)NH-, (CH5);N(O)NH-, (CH3),N(O)NCHs-, CH;CH,NHC(O)NH-, CH;CH,NHC(O)NCHs-, and the like.

The term “Cj. alkylureyl” denotes the group of the formula: -NC(O)N- wherein one are both of the nitrogens are substituted with the same or different alkyl group wherein alkyl has the same definition as described herein. Examples of an alkylureyl include, CH;NHC(O)NH-, NH,C(O)NCH-, (CH;),N(O)NH-, (CH,),N(O)NH-, (CH3),N(O)NCHj-, CH;CH,NHC(O)NH-, CH;CH,NHC(O)NCHs-, and the like.

The term “Cy. alkynyl” denotes a radical containing 2 to 6 carbons and at least one carbon-carbon triple bond, some embodiments are 2 to 4 carbons, some embodiments are 2 to 3 carbons, and some embodiments have 2 carbons. Examples of an alkynyl include ethynyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3- butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3- hexynyl, 4-hexynyl, 5-hexynyl and the like. The term “alkynyl” includes di- and tri- ynes. ~The term “amino” denotes the group NHa.

The term “Cy, alkylamino” denotes one alkyl radical attached fo an amino radical wherein the alkyl radical has the same meaning as described herein. Some examples include methylamino, ethylamino, propylamino and the like.

The term “aryl” denotes an aromatic ring radical containing 6 to 10 ring carbons. Examples include phenyl and naphthyl. ’

The term “arylalkyl” defines a C;-C, alkylene, such as —CHy~, -CH,CHj;~ and the like, which is further substituted with an ary] group. Examples of an “arylalkyl” include benzyl, phenethylene and the like.

The term “arylcarboxamido” denotes a single aryl group attached to the amine of an amide, wherein aryl has the same definition as found herein, The example is N-phenyicarboxamide.

The term “arylureyl” denotes the group -NC(O)N- where one of the nitrogens are substituted with an aryl.

The term “benzyl” denotes the group —CHCgHs.

The term “carbo-C,.¢-alkoxy” refers to an alkyl ester of a carboxylic acid, wherein the alkyl group is Cy.s. Examples include carbomethoxy, carboethoxy, carboisopropoxy and the like.

The term “carboxamide” refers to the group -CONH,.

The term “carboxy” or “carboxyl” denotes the group —CO,H; also referred to as a carboxylic acid.

The term “cyano” denotes the group —CN .

The term “Cs; cycloalkenyl” denotes a non-aromatic ring radical containing 3 to 6 ring carbons and at least one double bond; some embodiments contain3 to 5 carbons; some embodiments contain 3 to 4 carbons. Examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentenyl, cyclohexenyl, and the like,

The term “Cs cycloalkyl” denotes a saturated ring radical containing 3 to 6 carbons; some embodiments contain 3 to 5 carbons; some embodiments contain 3 to 4 carbons. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term “Cs cycloalky}-Cy;-alkylene” denotes a saturated ring radical containing 3 to 6 carbons bonded to a C,.s-alkylene as described herein; some embodiments contain 3 to 5 carbons; some embodiments contain 3 to 4 carbons.

Examples include cyclopropyl-CHa-, cyclopropyl-CH;CHz-, cyclobutyl-CHa-, cyclopentyl-CHj-, cyclohexyl-CILp-, and the like.

The term “Cas diacylamino” denotes an amino group bonded with two acyl groups defined herein wherein the acyl groups may be the same or different, such as: 0)

M—Craaliyt ¢—N

J—Cis alkyl 0)

Represented dialkylamino groups include diacetylamino, dipropionylamino, acetylpropionylamino and the like.

The term “C,.¢ dialkylamino” denotes an amino substituted with two of the same or different alkyl radicals wherein alkyl radical has the same definition as described herein. Some embodiments are Cz4 dialkylamino groups. Some examples incInde dimethylamino, methylethylamino, diethylamino and the like.

The term “C4 dialkylcarboxamido” or “Ci4 dialkylcarboxamide”denotes two alkyl radicals, that are the same or different, attached to an amide group, wherein alkyl has the same definition as described herein. A C4 dialkylcarboxamido may be represented by the following groups: 0] (@]

PS a alkyl S ~ ay alkyl

Cy.4 alkyl C14 alkyl .

Examples of a dialkylcarbozamide include N,N-dimethylcarboxamide, N-methyl-N- ethylcarboxamide and the like.

The term “Cj.¢ dialkylsulfonamide” refers to one of the following groups shown below: 0 0 0 0 op SOs alkyl S “ys alkyl

Cig alkyl C1.a alkyl .

The term “C,4 dialkylthiocarboxamido” or “Cy.4 dialkylthiocarboxamide” denotes two alkyl radicals, that are the same or different, attached to a thioamide group, wherein alkyl has the same definition as described herein. A Ci4 dialkylthiocarboxamido may be represented by the following groups:

S S oN NO alkyl So alkyl

C4 alkyl Cq4 alkyl . "Examples of a dialkylthiocarboxatnide include N.N-dimethylthiocarboxamide, N- methyl-N-ethylthiocarboxamide and the like. - The term “Cy dialkylsulfonylamino™ refers to an amino group bonded with {two Cy alkylsulfonyl groups as defined herein.

The term “ethynylene” refers to the carbon-carbon triple bond group as represented below: 3 —— 2

The term “formyY” refers to the group —-CHO.

The term “Cs.4 haloalkoxy” denotes a haloalkyl, as defined herein, that is directly attached to an oxygen to form a difluoromethoxy, trifluoromethoxy, 2,2,2- trifluoroethoxy, pentafluoroethoxy and the like. "The term “C;.4 haloalkyl” denotes an alkyl group, defined herein, wherein the alkyl is substituted with one halogen up to fully substituted represented by the formula

C, Fant; When more than one halogen is present they may be the same or different and selected from F, CL, Br or I. Some embodiments are 1 to 3 carbons. Examples include fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, 2,2,2- triftuoroethyl, pentafluoroethyl and the like.

The term “Cy. haloalkylcarboxamide” denotes an alkylcarboxamide group, defined herein, wherein the alkyl is substituted with one halogen up to fully substituted represented by the formula CF and “n” is 1, 2, 3 or 4. When more than one halogen is present they may be the same or different and selected from F, Cl, Br or I. Examples include 2-flucroacetyl, 2,2-difluoroacetyl, 2,2,2-trifluoroacetyl, 2-chloro-2,2- difluoroacetyl, 3,3,3-triflucropropionyl, 2,2,3,3,3-pentafluoropropionyl and the like.

The term “Cs haloalkylsulfinyl” denotes a haloalkyl radical attached to a sulfoxide of the formula: ~-S(O)- wherein the alkyl radical has the same definition as described herein. Examples include trifluoromethylsulfinyl, 2,2,2-trifluoroethylsulfinyl, 2,2-difluoroethylsulfinyl and the like.

The term “Cy.4 haloalkylsulfonyl” denotes a haloalkyl attached to a sulfone of the formula: -S(O),- wherein haloalkyl has the same definition as described herein.

Examples include trifluoromethylsulfonyl, 2.2.2 4rifluoroethylsulfonyl, 2,2- . diftuoroethylsulfonyl and the like.

The term “C4 haloalkylthie” denotes an alkylthio radical substituted with one or more halogens. Examples include trifluoromethylthio, 1,1-difluoroethylthio, 2,2.2-trifluoroethylthio and the like.

The term “halogen” or “halo” denotes to a fluoro, chloro, bromo or iodo group.

The term “Cy heteroalkylene” refers to a Cia alkylene bonded to a heteroatom selected from O, S, S(O), (0); and NIL Some represented examples include the groups of the following formulae: oo wo dd IUNYS OF CA px S ° PON eR and the like ‘

The term “heteroaryl” denotes an aromatic ring system that may be a single: ring, two fused rings or three fused rings containing carbons and at least one Ting heteroatom selected from O, S and N. Examples of heteroaryl groups include, but not limited to, pyridyl, benzofuranyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, quinoline, benzoxazole, benzothiazole, 1H-benzimidazole, isoquinoline, quinazoline, quinoxaline, 1H-imidazolyl, [1,24]triazolyl, [1,2,3]triazolyl, [1,2.4ltriazolyl, pyrrolyl, pyrazolyl, 1H-pyrazolyl, imidazolyl, oxazolyl, oxazolyl, [1.3 4Joxadiazolyl. [1,3,4]thiadiazolyl, [1,2,4]oxadiazolyl, [1,2,4]thiadiazolyl, tetrazolyi, i,3-divx0-1,3- dihydro-isoindolyl, [1,2,3]thiadiazol-4-yl and the like. :

The term “heterocyclic” denotes a non-aromatic carbon ring (i.e., cycloalkyl or cycloalkenyl as defined herein) wherein one, two or three ring carbons are replaced a heteroatom, such as, O, S, N, wherein the N can be optionally substituted with H,

C4 acyl or C;4 alkyl, and ring carbon atoms optionally substituted with oxo or a thiooxo thus forming a carbonyl or thiocarbonyl group. The heterocyclic group is a 3., 4-, 5-, 6- or 7-membered containing ring. Examples of a heterocyclic group include but not limited to aziridin-1-yl, aziridin-2-yl, azetidin-1 -yl, azetidin-2-yl, azetidin-3-yl, piperidin-1-yl, piperidin-4-yl, morpholin-4-yl, piperzin-1-yl, piperzin-4- yl, pyrrolidin-1-yl, pyrrolidin-3-yl, [1,3]-dioxolan-2-yl and the like. Additional examples of heterocyclic groups are shown in Tables 2B, 2C, 2D, 2E, 2F and 2G, infra.

The term “heterocycliccarboxamido” denotes a heterocyclic group with a ring nitrogen where the ring nitrogen is bonded directly to the carbonyl forming an amide. Examples include:

O 0) Oo ‘S0NAS 80

Lo , , and the like.

The term “heterocyclicsulfonyl” denotes a heterocyclic group with a ring nitrogen where the ring nitrogen is bonded directly to an SO, group forming an sulfonamide. Examples include:

QP RV RV

TN TY) LA

Lo , , and the like.

The term “hydroxyl” refers to the group -OH.

The term “hydroxylamine” refers to the group -NHOH.

The term “nitro” refers to the group -NO,.

The term “Cy 0xo-cycloalkyl” refers to a C4 cycloalkyl, as defined herein, : wherein one of the ring carbons is replaced with a carbonyl. Examples of C4 0x0- : cycloalkyl include but are not limited to: 2-oxo-cyclobutyl, 3-oxo-cyclobutyl, 3-0xo- cyclopentyl, 4-oxo-cyclohexyl, and the like and represented the following structures . respectively: oF ML Sx 0 0 hu ho, he ~ CL of , oO , O , OC , ~~” and 0

The term “perfluoroalkyl” denotes the group of the formula -CoFan; stated differently, a perfluoroalkyl is an alkyl as defined herein herein wherein the alkyl is fully substituted with fluorine atoms and is therefore considered a subset of haloalkyl.

Examples of perfluoroalkyls include CFs, CF,CFs, CF.CF,CF3, CF(CFa)y,

CF,CF,CF,CF;, CF,CF(CF3),, CF(CF5)CF,CF; and the like.

The term “phenoxy” refers to the group CeHsO-.

The term “phenyl” refers to the group CeHs-.

The term”sulfonic acid” refers to the group —SO:H.

The term “tetrazolyl” refers to the five membered heteroaryl of the following formulae:

A N=N ‘Was No Ns

In some embodiments, the tetrazolyl group is further substituted at either the 1 or 5 position resepectively.

The term “thiol” denotes the group —SH.

CODON shall mean a grouping of three nucleotides (or equivalents to nucleotides) which generally comprise a nucleoside (adenosine (A), guanosine (G), cytidine (C), uridine (U) and thymidine (T)) coupled to a phosphate group and which, when translated, encodes an amino acid.

COMPOSITION shall mean a material comprising at least two compounds or two components; for example, and not limitation, a Pharmaceutical Composition is a Composition.

COMPOUND EFFICACY shall mean a measurement of the ability of a compound to inhibit or stimulate receptor fimetionality, as opposed to receptor binding affinity.

CONSTITUTIVELY ACTIVATED RECEPTOR shall mean a receptor subject to constitutive receptor activation, ‘

CONSTITUTIVE RECEPTOR ACTIVATION shall mean stabilization of a receptor in the active state by means other than binding of the receptor with its endogenous ligand or a : chemical equivalent thereof.

CONTACT or CONTACTING shall mean bringing at least two moieties together, whether in an in vitro system or an in vivo system. . ENDOGENOUS shall mean a material that a mammal naturally produces.

ENDOGENOUS in reference to, for example and not limitation, the term “receptor” shall mean that which is naturally produced by a mammal (for example, and not limitation, a human) or a virus.

In contrast, the term NON-ENDOGENOUS in this context shall mean that which is not naturally produced by a mammal (for example, and not limitation, a human) or a virus. For example, and not limitation, a receptor which is not constitutively active in its endogenous form, but when manipulated becomes constitutively active, is most preferably referred to herein as a “non-endogenous, constitutively activated receptor.” Both terms can be utilized to describe both “in vivo” and “in vitro” systems. For example, and not a limitation, in a screening approach, the endogenous or non-endogenous receptor may be in reference to an in vitro screening system. As a further example and not limitation, where the genome of a mammal has been manipulated to include a non-endogenous constitutively activated receptor, screening of a candidate compound by means of an in vivo system is viable.

INDIVIDUAL as used herein refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.

INHIBIT or INHIBITING, in relationship to the term “response” shall mean that a response is decreased or prevented in the presence of a compound as opposed to in the absence of the compound.

INVERSE AGONISTS shall mean moieties that bind the endogenous form of the receptor or to the constitutively activated form of the receptor, and which inhibit the baseline intracellular response initiated by the active form of the receptor below the normal base level of activity which is observed in the absence of agonists or partial agonists, or decrease GTP binding to membranes. Preferably, the baseline intracellular response is inhibited in the presence of the inverse agonist by at least 30%, more preferably by at least 50%, and most preferably by at least 75%, as compared with the baseline response in the absence of the inverse agonist.

LIGAND shall mean an endogenous, naturally occurring molecule specific for an endogenous, naturally occurring receptor.

As used herein, the terms MODULATE or MODULATING shall mean to refer to an increase or decrease in the amount, quality, response or effect of a particular activity, function or molecule.

PHARMACEUTICAL COMPOSITION shall mean a composition comprising at’ least one active ingredient, whereby the composition is amenable to investigation for a specified, efficacious outcome in 2 mammal (for example, and not limitation, a human). Those of ordinary skill in the art will understand and appreéiate the techniques appropriate for-determining whether an active ingredient has a desired efficacious outcome based upon the needs of the artisan.

DETAILED DESCRIPTION

Compound Of The Present Invention

One aspect of the present invention pertains to certain 1,2,3-trisubstituted aryl and heteroaryl derivatives as shown in Formula (Ia):

Ry

Wy

AN ANN A

Arq Ww N™y\ z LD (Ta) or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein A, B, D,V,W,X,

Y, Z Ar, and R, are as described herein, supra and infra.

It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. " One aspect of the present invention encompasses N-oxides of 1,2,3-trisubstituted aryl and heteroaryl derivatives of Formula (1a).

One aspect of the present invention encompasses 1,2,3-trisubstituted aryl and heteroaryl derivatives as shown in Formula (Ia) wherein W is NR4 and compounds may be represented by Formula (Tb) as shown below:

Rq

Hy

AV N NS NT A

R, Z pb P (Ib) wherein each variable in Formula (Ib) has the same meaning as described herein. In some embodiments, R, is H. In some embodiments, R4 is CH; or CH,CHa.

One aspect of the present invention encompasses 1,2,3-trisubstituted aryl and heteroaryl derivatives as shown in Formula (Ta) wherein W is O, (i.e., an oxygen atom) and compounds may be represented by Formula (Ic) as shown below:

Ry

Ay .

Ary” a NPS NA z LD {c) wherein each variable in Formula (Ic) has the same meaning as described herein.

One aspect of the present invention encompasses 1,2,3-trisubstituted aryl and heteroaryl derivatives as shown in Formula (Ia) wherein W is S, S(O) or S(O), and compounds may be represented by Formulae (id), (Te) and (If) respectively as shown below: : Ri Ry Ry

SUPE! C3

A> Ae N A ar AN Nn — A ai ON NT A

Zz 8B (e) zZ B— 0 0 Z B~ (Id) (Ie) . a wherein each variable in Formulae (Id), (Ie) and (If) has the same meaning as described herein.

One aspect of the present invention encompasses 1,2,3 trisubstituted aryl and heteroaryl derivatives as shown in Formula (Ia) wherein W is absent and compounds may be represented by Formula (Ig) as shown below:

R4

Py

SNPS z LD (Ig) wherein each variable in Formula (Ig) has the same meaning as described herein. In some embodiments, compounds of the present invention are of Formula (Ig) wherein V is absent and accordingly these componnds may be represented by Formula (Ih) as shown below: . Ry oN M

MN A z BD (Th) wherein each variable in Formula (Th) has the same meaning as described herein.

One aspect of the present invention encompasses 1,2,3-trisubstituted aryl and heteroaryl derivatives as shown in Formula (Ia) wherein W is absent and V is ethynylene.

Compounds may be represented by Formula (Ii) as shown below:

Ry

NON v

Pas NA

Ars Zz B— D (1) wherein each variable in Formula (Ti) has the same meaning as described herein.

Tn some embodiments, V is C; ; alkylene optionally substituted with 1 to 4 substituents selected from the group consisting of C3 alkyl, C14 alkoxy and halogen. In some embodiments, V is a methylene group (i.e., -CH;-). In some embodiments, V is an ethylene group (i.e., -CH,CH,-). In some embodiments, V is a methylene and W is an oxygen atom. In some embodiments, V is methylene and W is a NR, group. In some embodiments,

V is methylene and W is a NH group. In some embodiments, V is ethylene and W is an oxygen atom. In some embodiments, V is ethylene and W is a NR, group. In some embodiments, V is ethylene and W is a NH group.

Tn some embodiments, V is C;., heteroalkylene optionally substituted with 1 to 4 substituents selected from the group consisting of C5 alkyl, C4 alkoxy and halogen. In some embodiments, V is -OCH,CH;-. In some embodiments, V is “OCH,CH,- and W is an oxygen atom and may be represented by the formula: -OCH,CH,0-. In some embodiments,

Vis -OCH,CH,- and W is a NH group and may be represented by the formula: -

OCH,CH,NH-.

In some embodiments, V is absent and may be represented by Formula (Tj) as shown below:

Ri

A

Ary Ww ANAS N~ A

Co I \ as an wherein each variable in Formula (Ij) has the same meaning as described herein.

In some embodiments, A and B are both methylene wherein A and B are optionally substituted with 1 to 2 methyl groups and therefore form a four-membered nitrogen containing ring. In some embodiments, compounds of the invention may be represented by

Formula (Ik) as shown below:

Ry

Py

AIS ANS

ATW N"\ z \-D (Ik) wherein each variable in Formula (IK) has the same meaning as described herein. In some embodiments, D is -CHR-.

In some embodiments, A is ethylene and BR is methylene wherein A is optionally substituted with 1 to 4 methyl groups and B is optionally substituted with 1 to 2 methyl groups. In some embodiments, compounds of the invention may be represented by Formula (Im) as shown below:

Rq oo M

Ar ANS N

Zz Ly (Tm) : wherein each variable in Formula (Im) has the same meaning as described herein. In some embodiments, D is -CHR,-. In some embodiments, R; is C,_, alkylsulfonyl.

In some embodiments, A is propylene and B is methylene wherein A is optionally substituted with 1 to 4 methyl groups and B is optionally substituted with 1 to 2 methyl : groups. In some embodiments, compounds of the invention may be represented by Formula (In) as shown below:

XL

X= M

Ary” Saas D : (In) wherein each variable in Formula (In) has the same meaning as described herein. In some embodiments, D is -CHR-.

Tn some embodiments, A and B are both ethylene wherein A and B are optionally substituted with 1 to 4 methyl groups. In some embodiments, compounds of the invention may be represented by Formula (To) as shown below:

XL

7 / z Ub (To) wherein each variable in Formula (Io) has the same meaning as described herein. In some embodiments, D is -CHRg-.

In some embodiments, A is propylene and B is ethylene wherein A and B are optionally substituted with 1 to 4 methyl groups. In some embodiments, compounds of the invention may be represented by Formula (Ip) as shown below:

Ry xP .

Ar WSS a)

SEAN

(Ip) wherein each variable in Formula (Ip) has the same meaning as described herein. In some embodiments, D is -CHR;-.

Tn some embodiments, A and B are both propylene wherein A and B are optionally substituted with 1 to 4 methyl groups. In some embodiments, compounds of the invention may be represented by Formula (Iq) as shown below:

XL

XZ M

Ary” AS NN z NI (lq)

/ wherein each variable in Formula (Iq) has the same meaning as described herein. In some embodiments, D is -CHR3-.

Tn some embodiments, D is O, S, S(O) or S(O). Tn some embodiments, D is §, S(O) or S(O),; and A and B are independently optionally substituted with 1 or 2 methyl groups. In some embodiments, A and B are ethylene groups. In some embodiments, A and B are ethylene groups substituted with 2. methyl groups and D is an oxygen atom (i.e., forming a 2,6-dimethyl-morpholin-4-yl group). .

Tn some embodiments, D is CRRa.

In some embodiments, R; is selected from the group consisting of H, C15 acyl, Cys acyloxy, C4 alkoxy, Cys alkyl, C4 alkylcarboxamide, Cy. alkylthiocarboxamide, C;4 alkylsulfinyl, C14 alkylsulfonyl, C;4 alkylthio, amino, carbo-C, s-alkoxy, carboxamide, carboxyl, Ca. cycloalkyl, C4 haloalkoxy, C4 haloalkyl, halogen and hydroxyl.

Tn some embodiments, R, is selected from the group consisting of C(O)CHa,

C(O)CH,CHs, C(O)CH,CH,CH3, C(O)CH(CHs),, C(O)CH,CH,CH,CH,, OC(O)CHa,

OC(O)CH,CH;, OC(O)CH,CH,CH,, OCH;, OCH,CH;, OCH,CH,CH;, OCH(CHa),,

OCH,(CH,),CH,;, CH,, CH,CHs, CH,CH,CHj, CH(CH,),, CH(CH;)(CH,CHa),

CH,(CH_),CHjs, CH,(CH,),CH;, C(O)NHCH;, C(O)NHCH,CH;, C(O)NHCH,CH,CHs,

C(O)NHCH(CHa),, C(O)NHCH,(CH,),CH;, CO,CH;, CO,CH,CH;, CO,CH,CH;CHs,

CO,CH(CHs), and CO,CH,(CH,),CHs.

In some embodiments, R; is selected from the group consisting of C(O)CHs,

C(O)CH,CH,, C(0)CH,CH,CH;, C(O)CH(CHs),, C(O)CH,CH,CH,CHs, OC(O)CH;,

OC(0)CH,CH;, OC(0)CH,CH,CH;, OCH, OCH,CH;, OCH;CH,CH,, OCH(CHa)., :

OCH,(CH,),CH;, CH;, CH,CH;, CH,CH,CH;, CH(CH;);, CH(CH1)(CH,CH;),

CH,(CH,),CH,, CH;(CH,);CH;, C(O)NH,, CO,CH;, CO,CH,CH;, CO,CH,CH,CHs,

CO,CH(CHs),, CO,CH,(CH,),CHj, and CO,H.

In some embodiments, R; is selected from the group consisting of SCHs, SCH,CHs,

SCH,CH,CH;, SCH(CHj;),, SCH,(CH,),CHj, S(O)CH;, S(O)CH,CH;, S(O)CH,CH,CHj,

S(O)CH(CHs),, S(O)CH;(CH,),CHs, S(0),CH;, S(0),CH,CHs, $(0),CH,CH,CHj,

S(0),CH(CHs),, S(0),CH,(CH,).CHs,, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, " OCR,, OCHF,, CF, CHF, and F.

In some embodiments, R, is selected from the group consisting of S(0).CHs,

S(0),CH,CH, S(0),CH,CH,CH;, S(0),CH(CH;),, S(0),CH;(CH_),CH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxyl, and F.

In some embodiments, R; is C13 alkyl, or heteroaryl each optionally substituted with 1 to 5 substituents selected from the group consisting of C, 5 acyloxy, C, 4 alkoxy, C, 5 alkyl,

C4 alkylsulfonyl, carbo-C,.s-alkoxy, carboxamide, carboxy, Cs ¢-cycloalkyl, Ca ¢-cycloalkyl-

C,s-alkylene, C;-cycloalkyl-C, ;-heteroalkylene, and hydroxyl.

Tn some embodiments, R, is selected from the group consisting of CH, OCH,

CH,CH,OCH;, CH,OCH,CH,, CH,0CH,CH,CH;, CH,CH,0CH;CHj,

CH,CH,0CH,CH,CHj, CH,0CH(CHa),, CH,OCH,CH(CHs),, CH,CO,H, CH.CH,CO,H,

CH,OH, CH,CH,0H and CH,CH,CH,OH.

In sorae embodiments, R; is Cys alkyl, heteroaryl or phenyl each optionally substituted with 1 to 5 substituents selected from the group consisting of Cys acyl, Cis acyloxy, Cy4 alkoxy, Cy alkyl, Cy 4 alkylamino, Ci. alkylcarboxamide, Cy.4 ’ alkylthiocarboxamide, C;_4 alkylsulfonamide, Cy.4 alkylsulfinyl, Cy.4 alkylsulfonyl, Cis alkylthio, C4 alkylthioureyl, C,.4 alkylureyl, amino, carbo-C,¢-alkoxy, carboxamide, carboxy, cyano, Cs ¢-cycloalkyl-C; s-heteroalkylene, C, 5 dialkylamino, C6 dialkylcarboxamide, C,_4 dialkylthiocarboxamide, C,.¢ dialkylsulfonamide, C;.4 alkylthioureyl, C14 haloalkoxy, C;.4 haloalkyl, C; 4 haloalkylsulfinyl, C;4 haloalkylsulfonyl,

Ci haloalkyl, Cy.4 haloalkylthio, halogen, heterocyclic, hydroxyl, hydroxylamine and nitro.

In some embodiments, R, is selected from the group consisting of CH,OCHs,

CH,CH,0CH;, CH,0CH,CH,, CH,O0CH,CH,CH;, CH,CH,OCH,CHs,,

CH,CH,OCH,CH,CH,, CH,OCH(CH,),, CH,OCH,CH(CH;),, CH,CO,H, CH,CH,CG,H,

CH,0H, CH,CH,0H and CH,CH,CH,OH. : . In some embodiments, R; is selected from the group consisting of CH,SCHj,

CH,SCH,CHs, CH,SCH,CH,CHj;, CH,SCH(CHs;),, CH,SCH,(CH,),CH;, CH,CH,SCH,,

CH,CH,SCH,CH;, CH,CH,SCH,CH,CH,, CH,CH,SCH(CH,);, CH,CH,SCH;(CH,),CHj, CH,S(O)CHs, CH,S(0)CH,CHs, CH,S(0)CH,CH, CH, CH,S(0)CH(CH;),,

CH, S(O)CH,(CH,),CH;, CH,CH,S(O)CH;, CH,CH,5(0)CH;CHs,

CH,CH,S(0O)CH,CH,CH;, CH,CH,S(0)CH(CH;),, CH,CH,S(O)CH>{(CH,),CHs,

CH, S(0),CH;, CH,S(0),CH,CH;, CH,S(0),CH,CH,CH;, CH,S(0),CH(CH;).,

CH,S(0),CH,(CH,),CH;, CH,CH,S(0),CH;, CH,CH,S(0),CH,CH;,

CH,CH,S(0),CH,CH,CH,, CH,CH,S(0),CH(CH), and CH,CH,S(0),CH,(CH,),CHs.

In some embodiments, Rs, is selected from the group consisting of CH;OCH,- cyclopropyl, CH;OCH,-cyclobutyl, CH,OCH,-cyclopentyl, CH,OCH;-cyclohexyl,

CH,0CH,CH,-cyclopropyl, CH; OCH,CH,-cyclobutyl, CH,OCH,CH,-cyclopentyl,

CH,OCH,CH,-cyclohexyl, CH,CH,OCH,-cyclopropyl, CH,CH,OCH,-cyclobutyl,

CH,CH,0OCH,-cyclopentyl, CH,CH,OCH,-cyclohexyl, CH,CH,OCH,CH;-cyclopropyl,

CH,CH,OCH,CH;-cyclobutyl, CH,CH,OCH,CH,-cyclopentyl and CH,CH,OCH,CH;- cyclohexyl.

In some embodiments, R, is selected from the group consisting of 1,2,4-oxadiazol-3- yl, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-triazol-5-yl and 1,2,4-triazol-1-yl, 3- methyl-1,2,4-o0xadiazol-5-yl, 3-methyl-1,2,4-oxadiazol-5-yl, 3-ethyl-1,2 4-oxadiazol-5-yl, 5- ethyl-1,2,4-0xadiazol-3-yl, 5-methyl-1,3,4-oxadiazol-2-yl, 5-ethyl-1,3,4-oxadiazol-2-yl, 3-

methyl-1,2,4-triazol-5-yl, 3-ethyl-1,2,4-triazol-5-yl, 3-methyl-1,2,4-triazol-1-y1, 3-ethyl-1,2,4~ triazol-1-yl, 5-methyl-1,2 4-friazol-1-yl and 5-ethyl-1,2,4-triazol-1-yl.

Tn some embodiments, R, is selected from the group consisting of 1,2,4-oxadiazol-3- yl, 1,2,4-0xadiazol-5-yl, 1,3 ,4-oxadiazol-2-yl, 3-methyl-1,2,4-oxadiazol-5-yl, 3-ethyl-1,2,4- " oxadiazol-5-yl, 3-isopropyl-1,2,4-oxadiazol-5-yl, 3-propyl-1 2 A-oxadiazol-5-yl, 3-t-butyl- 1,2,4-oxadiazol-5-yl, and 3-cyclopropyl-1 ,2,4-0xadiazol-5-yl.

Tn some embodiments, Ry is selected from the group consisting of 3-methyl-1,2,4- oxadiazol-5-yl, 3-ethyl-1,2,4-oxadiazol-5-yl, 3-propyl-1 2 A-oxadiazol-5-yl, 3-isopropyl- 1,2,A-oxadiazol-5-y1, 3-butyl-1,2,4-0xadiazol-5-yl, and 3-(t-butyl)-1,2,4-0xadiazol-5-yl.

Tn some embodiments, R, is a heteroaryl comprising 5-atoms in the aromatic ring and are represented by the following formulae:

TABLE 2A [3° E% [3 Cw Cs? 0” s” N” AM N° ) > H s > > —_% N= 3 Nemo N= Ned

SHES HES HES EN

N= 2 N= NY FY oN i Ny S Ny NH NaN

Zr WJC and NF wherein the 5-membered heteroaryl is bonded at any available position of the ring, for example, a imidazolyl ring can be bonded at one of the ring nitrogens (i.e., imidazol-1-y1 group) or at one of the ring carbons (i.e., imidazol-2-yl, imidazol-4-yl or imiadazol-5-yl group).

In some embodiments, R, is a 5-membered heteroaryl optionally substituted with 1 to 4 substituents selected from the group consisting of C5 acyl, Cys acyloxy, Ci4 alkoxy, Cis alkyl, C4 alkylamino, C,4 alkylcarboxamide, C; 4 alkylthiocarboxamide, C;.4 alkylsulfonamide, C;4 alkylsulfinyl, C4 alkylsulfonyl, C,4 alkylthio, C,4 alkylthioureyl, Ci» alkylureyl, amino, carbo-C,_-alkoxy, carboxamide, carboxy, cyano, C,¢-cycloalkyl-Cy s- heteroalkylene, C,; dialkylamino, Cy dialkylcarboxamide, C4 dialkylthiocarboxamide, Cs. dialkylsulfonamide, C,.4 alkylthioureyl, C,4 haloalkoxy, C;.4 haloalkyl, C14 haloalkylsulfinyl,

C,.4 haloalkylsulfonyl, C4 haloalkyl, Cy 4 haloalkylthio, halogen, heterocyclic, hydroxyl, hydroxylamino and nitro. :

Tn some embodiments, compounds of the present invention are of the following formula:

Ry ‘

PN Y

Ari” A

RS

Rs wherein R, is a 5-membered heteroaryl optionally substituted with 1 to 4 substituents selected from the group consisting of Cy 5 acyl, Cs acyloxy, C14 alkoxy, Crs alkyl, C;.4 alkylamino,

C1 alkylcarboxamide, Cy.4 alkylthiocarboxamide, Ci4 alkylsulfonamide, Ci.4 alkylsulfinyl,

C4 alkylsulfonyl, Cy alkylthio, Ci4 alkylthioureyl, Ci.4 alkylureyl, amino, carbo-Ci¢- alkoxy, carboxamide, carboxy, cyano, C,¢-cycloalkyl-C.s-heteroalkylene, C, g dialkylamino,

C, ¢ dialkyloarboxamide, Cy.4 dialkylthiocarboxamide, Cy. diallkylsulfonamide, Cis alkylthioureyl, Ci.4 haloalkoxy, Ci4 haloalkyl, Cy.4 haloalkylsulfinyl, Ci4 haloalkylsulfonyl,

C,.4 haloalkyl, Cy. haloalkylthio, halogen, heterocyclic, hydroxyl, hydroxylamino and nitro; and R; is hydrogen or C;4 alkyl.

In some embodiments, R, is a 5-membered heteroaryl optionally substituted withlor - 2 substituents selected from the group consisting of Cys alkyl, C;.4 haloalkyl and halogen; and

Rj is hydrogen.

In some embodiments, R, is a 5-membered heteroaryl optionally substituted with lor 2 Cs alkyl substituents; and R; is hydrogen.

Tn some embodiments, R; is a 5-membered heteroaryl optionally substituted with

CH,, CH,CHs, CH(CHs),, CH,CH;CHj, C{CHs)s; and Rs is hydrogen.

Tn some embodiments, R, is a fused heteroaryl group containing to aromatic rings wherein at least one is a heteroaryl ring, such as, benzofuranyl, benzimidazole, benzoxazole, benzothiazole, indole, benzothiophenyl. In some embodiments, R, is a benzofuran-2-yl group.

In some erbodiments, R, is a heterocyclic represented, for example, by the formulae in TABLE 2B.

TABLE 2B "Ng AV 2, MN 2 - 2

AF ATT Ae Ao ey ees

N—/ N=4 oA oH Ao i: ’ 1 h >

Cys alkyl, Cy alkyl, _ Cioalkyl, » Cis at, “24

N—/ 2 N—/ ~ + — = / oA / oA fo) 0K 0} (0) , S s 0) s S 5

Cis alkyl Cis alkyl

J ND?

A 0 oA Aso \ )

H and H .

Tt is understood that any one of the heterocyclic groups shown in TABLES 2B to 2E may be bonded at any available ring carbon or ring nitrogen as allowed by the respective formula. For example, a 2,5-dioxo-imidazolidinyl group may be bonded at the ring carbon or at either of the two ring nitrogens to give the following formulae respectively:

Y N pl \ PN

Ao oA Ie oA 1

H : H ; An

In some embodiments, R, is a heterocyclic represented, for example, by the formulae in TABLE 2C. : TABLE 2C

H, H, H, H, 0

N= 2, Ne NT N=

A’ Se % so so Ao 3 2 1 ?

Cr. alkyl, Cr alkyl, Cioalkyl, > Craalkyl,

NS NDS — —~ pl — =. JP —y P a= Pate «= p 's) 0 , Ss , 0) and Ss .

Tn some embodiments, R, is a heterocyclic represented, for example, by the formulae in TABLE 2D.

TABLE 2D .

H H Cys alkyl Cigalkyl, MP

N22 Ng } al = os oA Ass oA Ss oA s

H 3 0 and S .

In some embodiments, R; is a heterocyclic represented, for example, by the formulae in TABLE 2E.

TABLE 2E

H, x H, Ls Cisalkyl, A Cigakyl, >

N-— . N— ~ ~ — = Ag =A As = S = s (@] , S , [e] and S .

In some embodiments, R, is a heterocyclic represented, for example, by the formulae in TABLE 2F wherein the Cy.¢ alkyl group on the respective ring nitrogen atoms may be the : same or different.

TABLE 2F

Cig alkyl at Graal, ot oA | Hy

Cg alkyl and Cipalkyl

Tn some embodiments, R; is a heterocyclic represented, for example, by the formulae in TABLE 2G wherein the C; ¢ alkyl group on the respective ring nitrogen atoms may be the same or different.

TABLE 2G

Cralil, hd Cra ally Pn Cra all, Pn ns Gl o&

Crgakyl , C1. alkyl and Cigakyl

In some embodiments, D is CR;R; and R; is -Ar,-Ar; wherein Ar, and Ar; are independently aryl or heteroaryl optionally substituted with 1 to 5 substituents selected from the group consisting of Cy.s acyl, Cys acyloxy, Cr.4 alkoxy, Cy alkyl, C14 alkylcarboxamide, . Cy4 alkylthiocarboxamide, C,4 alkylsulfinyl, Cy.4 alkylsulfonyl, C4 alkylthio, amino, carbo-

C..¢-alkoxy, carboxamide, carboxy, cyano, Cse-cycloalkyl, Cy. dialkylcarboxamide, C14 : haloalkoxy, C,.; haloalkyl, halogen, hydroxyl and nitro. In some embodiments, Ar, is a heteroaryl and Ar; is phenyl. In some embodiments, compounds of the present invention are represented by Formula (Ir) as shown below:

Rq4 xy

Ar?” VS Ww ANAS N—A 4 LAC Arar,

Rs (fr) wherein each variable in Formula (Ir) has the same meaning as described herein. In some embodiments, compounds of the present invention are of Formula (Ir) wherein Rs is H.

In some embodiments, Ar; is a heteroaryl comprising S-atoms in the aromatic ring and are represented by the following formulae:

TABLE 3

Ars L322 Ara TB, Arg T_2, Arg 2 Arg 22

SLU NNT Np 5 > ’ H » > ’

EE SHE. RS TN

SH QU N° NE °

I oS RY NS Td

NS GAL Ne © Ny S Ny NH

Arg Ars Arg Aa

Mis wh Ma She

Ars

N=N $7 i ne 7

Ars and hd wherein the 5-mexmbered heteroaryl is bonded at any available position of the ring, for example, a imidazolyl ring can be bonded at one of the ring nitrogens (i.e., imidazol-1 =yl . group) or at one of the ring carbons (i.e., imidazol-2-yl, imidazol-4-y1 or imiadazol-5-yl " group) and Ar; is bonded to any remaining available ring atom.

Tn some embodiments, Ar; is a heteroaryl and Ar; is phenyl. In some embodiments, the heteroaryl and phenyl are optionally substituted with 1 to 5 substituents selected from the.’ : group consisting of H, C, 4 alkoxy, Cs alkyl, Cy.4 alkylcarboxamide, Ci4 alkylsulfinyl, C14 alkylsulfonyl, C,4 alkylthio, C4 haloalkoxy, C,.4 haloalkyl, halogen, hydroxyl and nitro. :

Tn some embodiments, D is CR;R; and R, is Formula (B): ’

OR

Ne

Re

B) wherein:

Ris is Cry alkyl or Cag cycloalkyl; and Ris is F, Cl, Br or CN. In some embodiments,

Ris is Cis alkyl and Rs is F, Cl or CN. : ' In some embodiments, D is CR,R3 and R; is Formula (C): or an © wherein:

Gis C=0, CRysR17, O, S, S(O), S(O); where Rig and R,; are independently H or Cys alkyl; and Ar, is phenyl or heteroaryl optionally substituted with 1 to 5 substituents selected from the group consisting of Cys acyl, Cys acyloxy, C4 alkoxy, Cy; alkyl, C14 alkylcarboxamide,

C..4 alkylthiocarboxamide, Ci4 alkylsulfonamide, C;4 alkylsulfinyl, C4 alkylsulfonyl, Ci.4 alkylthio, Cy alkylthioureyl, C14 alkylureyl, amino, carbo-C;.s-alkoxy, carboxamide, carboxy, cyano, Cs.s-cycloalkyl-C;.s-heteroalkylene, Ca dialkylcarboxamide, Ci4 dialkylthiocarboxamide, C, dialkylsulfonamide, C4 alkylthioureyl, C14 haloalkoxy, C14 haloalkyl, C4 haloalkylsulfinyl, Ci4 haloalkylsulfonyl, C4 haloalkyl, C4 haloalkylthio, halogen, heteroaryl, hydroxyl, hydroxylamino and nitro.

In some embodiments, R, is Formula (C) wherein G is C=0, CR1eRy7, 0, 8, S(0),

S(0),; wherein R;¢ and Ry7 are independently H or Cy.; alkyl; and Ary is phenyl or heteroaryl optionally substituted with 1 to 5 substituents selected from the group consisting of Cy4 alkoxy, C15 alkyl, Cy4 haloalkoxy, C,.4 haloalkyl, and halogen.

In some embodiments, (3 is C=0, CH; or O. In some embodiments, G is S, S(O) or

S(0),.

Tn some embodiments, Ary is selected from the group consisting of pyridinyl, - pyridazinyl, pyrimidinyl and pyrazinyl. In some embodiments, Ar, ig 2-pyridyl.

In some embodiments, compounds of the present invention are represented by

Formula (Is) as shown below:

Ry . xy

Ary” Ny A pa

IW

Rs (Is) wherein each variable in Formula (Is) has the same meaning as described herein.

Tn some embodiments, D is CR,R, Ry is Formula (C) and G is C=0, CRyeR;7 01 O.

Tn some embodiments, Ar, is phenyl optionally substituted with 1 to 5 substituents selected from the group consisting of C:.< acyl. Cis acyloxy, C4 alkoxy, Cys alkyl, Cis alkylearboxamide, Ci alkylthiocarboxamide, C;4 alkylsulfonamide, C: 4 alkylsulfinyl, C14 alkylsulfonyl, C,4 alkylthio, Ci.4 alkylthioureyl, C; 4 alkylureyl, amino, carbo-Cy_g-alkoxy, carboxamide, carboxy, cyano, Cs.s-cycloalkyl-Cy s-heteroalkylene, C,.¢ dialkylcarboxamide,

C, 4 dialkylthiocarboxamide, C.. dialkylsulfonamide, C4 alkylthioureyl, C4 haloalkoxy, Ci- 2 haloalkyl, C, 4 haloalkylsulfinyl, C14 haloalkylsulfonyl, C;.4 haloalkyl, C14 haloalkylthio, halogen, heteroaryl, hydroxyl, hydroxylamino and nitro.

In some embodiments, Ar, is phenyl optionally substituted with 1 to 5 substituents selected from the group consisting of Cys acyl, C4 alkoxy, Cis alkyl, C4 alkylcarboxamide,

C1.4 alkylsulfonamide, C4 alkylsulfinyl, C4 alkylsulfonyl, C, 4 alkylthio, carboxamide, Cy4 haloalkoxy, C;.4 haloalkyl, C,_4 haloalkylsulfinyl, Ci4 haloalkylsulfonyl, C, 4 haloalkyl, halogen and hydroxyl.

Tn some embodiments, Ar, is phenyl optionally substituted with 1 to 5 substituents selected from the group consisting of Cys acyl, C4 alkoxy, Cig alkyl, Cy. alkylsulfinyl, Cy.4 )

alkylsulfonyl, C4 alkylthio, C,., haloalkoxy, C,_, haloalkyl, C;4 haloalkyl, halogen and hydroxyl.

In some embodiments, Ar, is heteroaryl optionally substituted with 1 to 5 substituents selected from the group consisting of Cys acyl, Cys acyloxy, Cis alkoxy, Cis alkyl, C14 alkylcarboxamide, C4 alkylthiocarboxamide, C, 4 alkylsulfonamide, Cy4 alkylsulfinyl, C4 alkylsulfonyl, C4 alkylthio, C;_, alkylthioureyl, C; 4 aTkylureyl, amino, carbo-C; s-alkoxy, carboxamide, carboxy, cyano, Cs ¢-cycloalkyl-C, s-heteroalkylene, Cp dialkylcarboxamide,

C4 dialkylthiocarboxamide, C, 4 dialkylsulfonamide, C,4 alkylthioureyl, C,.4 haloalkoxy, C;. 4 haloalkyl, C4 haloalkylsulfinyl, C4 haloalkylsulfonyl, C;.4 haloalkyl, C;4 haloalkylthio, halogen, heteroaryl, hydroxyl, hydroxylamino and nitro.

In some embodiments, Ar, is heteroaryl optionally substituted with | to 5 substituents selected from the group consisting of Cy.5 acyl, C4 alkoxy, C, alkyl, C; 4 alkylcarboxamide,

C4 alkylsulfonamide, C4 atkylsulfingl, C4 alkylsulfonyl, C,.4 alkylthio, carboxamide, C4 haloalkoxy, C;4 haloalkyl, C, 4 haloalkylsulfinyl, C,4 haloalkylsulfonyl, C, 4 haloalkyl, halogen and hydroxyl.

In some embodiments, Ar, is heteroaryl optionally substituted with 1 to 5 substituents selected from the group consisting of C,.5 acyl, C;4 alkoxy, C,.s alkyl, Ci alkylsulfinyl, C;4 alkylsulfonyl, C;.4 alkylthio, C;.4 haloalkoxy, C, 4 haloalkyl, C, 4 haloalkyl, halogen and hydroxyl.

In some embodiments, Ar, is a 5-membered heteroaryl, for example, as shown in

TABLE 2A supra. In some embodiments, Ar, is a 6-membered heteroaryl, for example, the 6-membered heteroaryls as shown in TABLE 4:

TABLE 4

SECC i R i! , C7 s Ln , No? , oe OF 0d

Nan Lon LA Ne? wherein the heteroaryl group is bonded at any ring carbon. In some embodiments, Ar, is selected from the group consisting of pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl. In some embodiments, Ar, is 2-pyridyl. In some embodiments, D is CRyRs, R, is Formula (C),

G is CR;6R17 and Ry and R;5 are independently H or C,._; alkyl.

In some embodiments, D is CR;R3, R, is Formula (C) and G is S, S(O) or S(O).

In some embodiments, Ar; is phenyl optionally substituted with 1 to 5 substituents selected from the group consisting of Cys acyl, Cy. acyloxy, Cy. alkoxy, Cs alkyl, C14 alkylcarboxamide, C, 4 alkylthiocarboxamide, Cy alkylsulfonamide, C;4 alkylsulfinyl, Cy.4

~ alkylsulfonyl, C14 alkylthio, Cy alkylthioureyl, Cy. alkylureyl, amino, carbo-Cy.¢-alkoxy, carboxamide, carboxy, cyano, Cs ¢-cycloalkyl-Cy.s-heteroalkylene, Cas dialkylcarboxamide,

C4 dialkylthiocarboxamide, C, ¢ dialkylsulfonamide, Ci alkylthioureyl, Ci.4 haloalkoxy, Cy. , haloalkyl, C, 4 haloalkylsulfinyl, Cy 4 haloalkylsulfonyl, C14 haloalkyl, C4 haloalkylthio, halogen, heteroaryl, hydroxyl, hydroxylamino and nitro.

In some embodiments, Ar, is phenyl optionally substituted with 1 to 5 substituents selected from the group consisting of Cys acyl, C14 alkoxy, Cs alkyl, Cy 4 alkylcarboxamide,

C14 alkylsulfonamide, C;.4 alkylsulfinyl, C14 alkylsulfonyl, C14 alkylthio, carboxamide, C,.4 haloalkoxy, C;.4 haloalkyl, C14 haloalkylsulfinyl, C14 haloalkylsulfonyl, Ci4 haloalkyl, halogen and hydroxyl.

In some embodiments, Az, is phenyl optionally substituted with 1 to 5 substituents selected from the group consisting of Cy.s acyl, Cy alkoxy, Cis alkyl, Cy.4 alkylsulfinyl, C14 alkylsulfonyl, C4 alkylthio, Ci4 haloalkoxy, C14 haloalkyl, Cy4 haloalkyl, halogen and . hydroxyl.

Tn some embodiments, Ar, is heteroaryl optionally substituted with 1 to 5 substituents selected from the group consisting of Cys acyl, Ci. acyloxy, Ci. alkoxy, Cis alkyl, C4 alkylcarboxamide, Cy4 alkylthiocarboxamide, Ci.4 alkylsnlfonamide, C4 alkylsulfinyl, Ci4 alkylsulfonyl, C14 alkylthio, C4 alkylthioureyl, C14 alkylureyl, amino, carbo-Cy.¢-alkoxy, carboxamide, carboxy, cyano, Cs ¢-cycloalkyl-Cys-heteroalkylene, Co dialkylcarboxamide,

C4 dialkylthiocarboxamide, C, 6 dialkylsulfonamide, C14 alkylthioureyl, Cy 4 haloalkoxy, Ci. 4+ haloalkyl, C4 haloalkylsulfinyl, C, 4 haloalkylsulfonyl, C4 haloalkyl, Cy4 haloalkylthio, halogen, heteroaryl, hydroxyl, hydroxylamine and nitro.

In some embodiments, Ar, is heteroaryl optionally substimted with 1 io 5 substituents selected from the group consisting of Cys acyl, Cy alkoxy, Cis alkyl, C,4 alkylcarboxamide,

C4 alkylsulfonamide, C, 4 alkylsulfinyl, C4 alkylsulfonyl, Ci4 alkylthio, carboxamide, C; 4 haloalkoxy, C14 haloalkyl, C,, haloalkylsulfinyl, C4 haloalkylsutfonyl, C;.4 haloalkyl, halogen and hydroxyl.

Tn some embodiments, Ar, is heteroaryl optionally substituted with 1 to 5 substituents selected from the group consisting of Cy.5 acyl, C4 alkoxy, Ci.s alkyl, Cy4 alkylsulfinyl, Ci4 alkylsulfonyl, Cy.4 alkylthio, C;4 haloalkoxy, C14 haloalkyl, C4 haloalkyl, halogen and hydroxyl. In some embodiments, Ary is a S-membered heteroaryl, for example, as shown in

TABLE 2A, supra.

In some embodiments, Ar, is a 6-membered heteroaryl, for example, as shown in “TABLE 4, supra.

In some embodiments, Ar, is selected from the group consisting of pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl. In some embodiments, Ar, is 2-pyridyl.

In some embodiments, R; is EL.

. In some embodiments, D is N-R,. In some embodiments, R; is selected from the group consisting of H, Cys acyl, Cys alkyl, Ci4 alkylcarboxamide, C4 alkylsulfonyl, carbo-

C.¢-alkoxy, carboxamide, Cs ¢-cycloalkyl and Cy 4 haloalkyl. In some embodiments, Ryis selected from the group consisting of C(O)CHs, C(O)CH,CH;, C(O)CHCH,CH;,

C(O)CH(CHs),, C(O)CH,CH,CH,CH;, CH;, CH,CHs, CH,CH,CHs, CH(CHa)s,

CH(CH,)(CH,CH3;), CH,(CH,),CH;, CH(CH,);CHs, C(O)NHCH, C(O)NHCH,CHa,

C(O)NHCH,CH,CHj, C(O)NHCH(CHs),, C(O)NHCH,(CH,),CHs, CO,CHj, CO,CH,CHs,

CO,CH,CH,CH;, CO,CH(CH,), and CO,CH,(CH,),CHs. In some embodiments, R, is selected from the group consisting of S(0),CHa, S(0).CH,CHs, S(0),CH,CH,CHs;

S(O),CH(CH,)., S(0),CH,(CH,),CHs, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

CH,CF,, CF; and CHF.

In some embodiments, D is N-R, and R; is H, or carbo-C;.¢-alkoxy. In some . embodiments, R, is selected from the group consisting of CO,CHs, CO.CH,CHj,

CO,CH,CH,CH;, CO,CH(CHS), and CO,CH,(CH,),CH;. In some embodiments, R, is Cys alkyl optionally substituted with 1 to 5 substituents selected from the group consisting of Cis alkylsulfonyl, carbo-C;.s-alkoxy, and carboxy. In some embodiments, R, is CH,CO,Et, or -

CH,CH,CO,H. In some embodiments, R, is selected from the group consisting of

CH,CH,S(0),CHj, CH,CH,S(0),CH;CHj, CH,CH,S(0),CH,CH,CHj,

CH,CH,S(0),CH(CH); and CH,CH,S(0),CH,(CH,),CH.

In some embodiments, D is N-R, wherein R; is Cy. alkyl, heteroaryl or phenyl optionally substituted with 1 to 5 substituents selected from the group consisting of Cy.s acyl, * Cys acyloxy, Cy alkoxy, Cys alkyl, C4 alkylamino, C4 alkylcarboxamide, Cy 4 alkylthiocarboxamide, Cy alkylsuifonamide, C, alkyisulfinyi, C, alkyisuifonyl, Cis alkylthio, Cy. alkylthioureyl, C, 4 alkylureyl, amino, carbo-C,.s-alkoxy, carboxamide, carboxy, cyano, Cs¢-cycloalkyl-Cy s-heteroalkylene, C; 5 dialkylamino, C;5 dialkylcarboxamide, C,4 dialkylthiocarboxamide, C,.¢ dialkylsulfonamide, C;.4 alkylthioureyl, C,.4 haloalkoxy, C; 4 haloalkyl, C;4 haloalkylsulfinyl, C,4 haloalkylsulfonyl,

C,4 haloalkyl, C;.4 haloalkylthio, halogen, heterocyclic, hydroxyl, hydroxylamino and nitro.

In some embodiments, R, is selected from the group consisting of CH,CH,OCH;,

CH,CH,OCH,CH;, CH,CH,0CH,CH,CH,, CH,CO,H, CH,CH,CO,H, CH,CH,OH and

CH,CH,CH,OH. In some embodiments, R; is selected from the group consisting of

CH,CH,SCH,, CH,CH,SCH,CH;, CH,CH,SCH,CH,CH;, CH,CH,SCH(CHs),,

CH,CH,SCH,(CH,),CH;, CH,CH,S(0)CH,, CH,CH,S(0)CH,CHs,

CH,CH,S(O)CH,CH,CH,;, CH;CH,S(0)CH(CHs),, CH,CH,S(O)CH,(CH,),CHs,

CH,CH,S(0),CHs, CH,CH,S8(0),CH,CH;, CH,CH,S(0),CH,CH,CH,

CH,CH,S(0);CH(CH,), and CH,CH,S(0),CH,(CH,),CH;. In some embodiments, Rs is selected from the group consisting of 1,2,4-oxadiazol-3-yl, 1,2 4-oxadiazol-5-y1, 1,3,4-

oxadiazol-2-y, 1,2,4-triazol-5-yl and 1,2,4-triazol-1-yl, 3.methyl-1,2,4-oxadiazol-5-yl, 3- methyl-1,2,4-oxadiazol-5-yl, 3-ethyl-1,2,4-oxadiazol-5-yl, 3.-ethyl-1,2,4-oxadiazol-5-yl, 5- methyl-1,3,4-oxadiazol-2-yl, 5-ethyl-1,3 A-oxadiazol-2-yl, 3.methyl-1,2,4-triazol-5-yl, 3- ethyl-1,2,4-triazol-5-yl, 3-methyl-1,2,4-triazol-1-vl, 3.ethyl-1,2,4-triazol-1-yl, 5-methyl-1,2,4- triazol-1-yl and 5-ethyl-1,2 4-triazol-1-yl.

Tn some embodiments, D is N-R, and Rj is -Ar;-ATs wherein Ar, and Ar; are independently aryl or heteroaryl optionally substituted with 1 to 5 substituents selected from the group consisting of H, Cys acyl, Cis acyloxy, Ci alkoxy, Cis alkyl, Cie alkylcarboxamide, C4 alkylthiocarboxamide, Ci.4 alkylsulfinyl, C4 alkylsulfonyl, C14 alkylthio, amino, carbo-Cy.s-alkoxy, carboxamide, carboxy, cyano, Cse-cycloalkyl, Cos dialkylcarboxamide, C14 haloalkoxy, C14 haloalkyl, halogen, hydroxyl and nitro. . In some embodiments, compounds of the present invention are represented by Formula (It) as shown below:

Rq >

PS

Z YL No AT Arg t) wherein each variable in Formula (It) has the same meaning as described herein. In some : embodiments, Ar, is a heteroaryl and Ar; is phenyl. In some embodiments, the heteroaryl and phenyl are optionally substituted with 1to 5 substituents selected from the group consisting of

H, C.. alkoxy. Ci alkyl, Cia alkylcarbozamide, C4 alkylsulfinyl, Cy alkylsulfonyl, C14 alkylthio, Cy haloalkoxy, Cys haloalkyl, halogen, hydroxyl and nitro.

Tn some embodiments, D is N-R; wherein R; is Formula (C):

YY” Sarg ©) wherein:

Gis C=O or CRcR,7; where Ris and Ry; are independently H or Cy.¢ alkyl; and Ary is phenyl or heteroaryl optionally substituted with 1 to 5 substituents selected from the group consisting of C,.5 acyl, Cys acyloxy, Cy 4 alkoxy, C4 alkyl, C,4 alkylcarboxamide, C,4 alkylthiocarboxamide, Cy 4 alkylsulfonamide, C;.4 alkylsulfinyl, C, 4 alkylsulfonyl, Ci. alkylthio, C; 4 alkylthioureyl, C,.4 alkylureyl, amino, carbo-C,g-alkoxy, carboxamide, carboxy, cyano, Cs ¢-cycloalkyl-C,.;-heteroalkylene, Cy. dialkylcarboxamide, C4 dialkylthiocarboxamide, C,.¢ dialkylsulfonamide, C14 alkylthioureyl, C, baloalkoxy, C14 haloalkyl, C,., haloalkylsulfinyl, Cy 4 haloalkylsulfonyl, C4 haloalkyl, C;.4 haloalkylthio,

halogen, heteroaryl, hydroxyl, hydroxylamino and nitro. In some embodiments, compounds of the present invention are represented by Formula (Iu) as stiown below:

Ry . >

Ar; A Ww ANAS N= A : z LN I. Ary (Tu) wherein each variable in Formula (Tu) has the same meaning as described herein.

In some embodiments, D is N-Rs, Rj is Formula (C) and G is C=0. In some embodiments, Ar, is phenyl optionally substituted with 1 to 5 substituents selected from the group consisting of Cy.5 acyl, Cys acyloxy, C4 alkoxy, Cy alkyl, C4 alkylcarboxamide, C14 alkylthiocarboxamide, C;4 alkylsulfonamide, C4 alkylsulfinyl, C4 alkylsulfonyl, Ci4 alkylthio, Cy alkylthioureyl, C; alkylureyl, amino, carbo-Cy ¢-alkoxy, carboxamide, carboxy, cyano, Cs ¢-cycloalkyl-C, s-heteroalkylene, Cys dialkylcarboxamide, C4 dialkylthiocarboxamide, C, ¢ dialkylsulfonamide, C,.4 alkylthioureyl, C4 haloalkoxy, Ci.4 haloalkyl, C;_4 haloalkylsulfinyl, C,4 haloalkylsulfonyl, C;4 haloalkyl, C4 haloalkylthio, ; halogen, heteroaryl, hydroxyl, hydroxylamino and nitro. In some embodiments, Ar, is phenyl optionally substituted with 1 to 5 substituents selected from the group consisting of Cis acyl,

C14 alkoxy, Cs alkyl, C;4 alkylcarboxamide, C;4 alkylsulfonamide, C;4 alkylsulfinyl, C14 alkylsulfonyl, C,, alkylthio, carboxamide, C.4 haloalkoxy, C4 haloalkyl, C4 haloalkylsulfinyl, C, 4 haloalkylsulfonyl, C4 haloalkyl, halogen and hydroxyl. In some embodiments, Ar, is phenyl optionally substituted with 1 to 3 substituents selected from the group consisting of Cys acyl, Ci alkoxy, Cy alkyl, Ci4 alkylsulfinyl, C,; alkylsulfonyl, C4 alkylthio, C,.4 haloalkoxy, C4 haloalkyl, C;_ haloalkyl, halogen and hydroxyl. In some embodiments, Ar, is heteroaryl optionally substituted with 1 to 5 substituents selected from the group consisting of C,_s acyl, C,.s acyloxy, C,.4 alkoxy, C, alkyl, C,4 alkylcarboxamide,

C14 alkylthiocarboxamide, C,.4 alkylsulfonamide, C; 4 alkylsulfinyl, C4 alkylsulfonyl, Cia alkylthio, Cy 4 alkylthioureyl, C;.4 alkylureyl, amino, carbo-C;_s-alkoxy, carboxamide, carboxy, cyano, C; s-cycloalkyl-C, ;-heteroalkylene, Cs dialkylcarboxamide, C;.4 dialkylthiocarboxamide, C, ¢ dialkylsulfonamide, C,4 alkylthioureyl, C; 4 haloalkoxy, Ci.4 haloalkyl, C,4 haloalkylsulfinyl, C;4 haloalkylsulfonyl, C,, haloalkyl, C, 4 haloalkylthio, halogen, heteroaryl, hydroxyl, hydroxylamino and nitro. In some embodiments, Ar, is heteroaryl optionally substituted with 1 to 5 substituents selected from the group consisting of

C15 acyl, C4 alkoxy, Cis alkyl, C4 alkylcarboxamide, C, 4 alkylsulfonamide, C;_4 alkylsulfinyl, C,, alkylsulfonyl, C,4 alkylthio, carboxamide, C,4 haloalkoxy, C4 haloalkyl,

Ci haloalkylsulfinyl, C;.4 haloalkylsulfonyl, C,, haloalkyl, halogen and hydroxyl. In some embodiments, Ar; is heteroaryl optionally substituted with 1to 5 gubstituents selected from the group consisting of Cis acyl, Cy4 alkoxy, C,5 alkyl, C14 alkylsulfinyl, Ci. alkylsulfonyl,

C14 alkylthio, C;.4 haloalkoxy, C,4 haloalkyl, Ci4 haloalkyl, halogen and hydroxyl. In some embodiments, Ars is a 5-membered heteroaryl, for example, as shown in TABLE 2A, supra.

In some embodiments, Ar, is a 6-membered heteroaryl, for example, as shown in TABLE 4, supra. In some embodiments, Ary is selected from the group consisting of pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl. In some embodiments, Ar, is 2-pyridyl.

Tn some embodiments, D is N-R, wherein Rj is Formula (C) and G is CRyeR17. In some embodiments, Ar, is phenyl optionally substituted with 1 to 5 substituents selected from the group consisting of Cys acyl, Cy.5 acyloxy, Cy.4 alkoxy, Cys alkyl, C14 alkylcarboxamide,

C4 alkylthiocarboxamide, C4 alkylsulfonamide, C4 alkylsulfinyl, C14 alkylsulfonyl, Cy.4 alkylthio, C4 alkylthioureyl, C4 alkylureyl, amino, carbo-Cy.¢-alkoxy, carboxamide, carboxy, cyano, Cs g-cycloalkyl-C; s-heteroalkylene, C,.¢ dialkylcarboxamide, Ci4 dialkylthiocarboxamide, Cys dialkylsulfonamide, C.4 alkylthioureyl, C14 haloalkoxy, Cis haloalkyl, C;4 haloalkylsulfinyl, C;4 haloalkylsulfonyl, Cy.4 haloalkyl, C14 haloalkylthio, halogen, heteroaryl, hydroxyl, hydroxylamino and nitro. In some embodiments, Ary is phenyl optionally substituted with 1 to 5 substituents selected from the group consisting of Cy.s acyl,

C..4 alkoxy, Cys alkyl, Ci alkylcarboxamide, C4 alkylsulfonamide, Cy alkylsulfinyl, Ci4 alkylsulfonyl, C4 alkylthio, carboxamide, C;4 haloalkoxy, Ci.4 haloalkyl, Cry haloalkylsulfinyl, C,.4 haloalkylsulfonyl, Cy.4 haloalkyl, halogen and hydroxyl. In some embodiments, Ar, is phenyl optionally substituted with 1 to 5 substituents selected from the group consisting of Cys acyl, Cy alkoxy, Cy alkyl, Ci alkylsulfinyl, C;4 alkylsulfonyl, C14 alkylthio, Ci haloalkoxy, C;.4 haloalkyl, C;.4 haloalkyl, halogen and hydroxyl. In some embodiments, Ar, is heteroaryl optionally substituted with 1 to 5 substituents selected from the group consisting of Cys acyl, Cy.s acyloxy, Ci4 alkoxy, Cy alkyl, C14 alkylcarboxamide,

C.. alkylthiocarboxamide, Cy4 alkylsulfonamide, C4 alkylsulfinyl, Cy alkylsulfonyl, Ci.4 alkylthio, Cy. alkylthioureyl, Cy alkylureyl, amino, carbo-C;.¢-alkoxy, carboxamide, carboxy, cyano, Cs ¢-cycloalkyl-Cy.s-heteroalkylene, Cs. dialkylcarboxamide, Ci4 dialkylthiocarboxamide, C,.¢ dialkylsulfonamide, C;4 alkylthioureyl, C;.4 haloalkoxy, Ci haloalkyl, Cy4 haloalkylsulfinyl, C;_4 haloalkylsulfonyl, C14 haloalkyl, C;.4 haloalkylthio, halogen, heteroaryl, hydroxyl, hydroxylamino and nitro. In some embodiments, Ary is heteroaryl optionally substituted with 1 to 5 substituents selected from the group consisting of

Cs acyl, C4 alkoxy, Cy alkyl, Ci4 alkylcarboxamide, C;4 alkylsulfonamide, Cis alkylsulfinyl, C, 4 alkylsulfonyl, Cy 4 alkylthio, carboxamide, C;4 haloalkoxy, C14 haloalkyl,

C, haloalkylsulfinyl, Cy. haloalkylsulfonyl, C;_4 haloalkyl, halogen and hydroxyl. In some embodiments, Ar; is heteroaryl optionally substituted with 1 to 5 substituents selected from the group consisting of Cys acyl, C14 alkoxy, Cys alkyl, C14 alkylsulfinyl, C4 alkylsulfonyl,

C14 alkylthio, C;.4 haloalkoxy, Cy.4 haloalkyl, Cy 4 haloalkyl, halogen and hydroxyl. In some embodiments, Ar, is 2 5-membered heteroaryl, for example, as shown in TABLE 2A, supra.

In some embodiments, Ar, is a 6-membered heteroaryl, for example, as shown in TABLE 4, supra. In some embodiments, Ar, is selected from the group consisting of pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl. In some embodiments, Ar, is 2-pyridyl. In some embodiments, D is N-R, wherein R, is Formula (C), G is CRieR17 and Rye and Ry, are independently H or C,., alkyl.

Tn some embodiments, Z is selected from the group consisting of Cys acyl, Cys alkyl,

C4 alkylcarboxamide, amino, cyano, Cs diacylamino, Cy.¢ dialkylsulfonamide, formyl, halogen, heterocyclic, and nitro wherein Cy.g alkyl and Cys acyl are each optionally substituted with 1, or 2 groups selected from the group consisting of C4 dialkylmino, hydroxy, and halogen.

Tn some embodiments, Z is selected from the group consisting of nitro, amino, formyl, NHC(O)CFs, Br, NEC(O)CHa, N(C(O)CHs)z, N(S(0).CHa)z, CHs, [1,3]dioxolan-2- yl, CH,OH, CH,N(CHj),, and C(O)CH,.

In some embodiments, Z is selected from the group consisting of Cy.s acyl, Cis acyloxy, Ci. alkoxy, Cy. alkyl, C4 alkylcarboxamide, Cy alkylthiocarboxamide, C4 alkylsulfonamide, C;.4 alkylsulfinyl, C4 alkylsulfonyl, C,4 alkylthio, Ci4 alkyithioureyl, Ci4 alkylureyl, carboxamide, carboxy, cyano, aryl, C;4 haloalkyl, C;.4 haloalkylcarboxamide, heteroaryl, hydroxyl, hydroxylamino, nitro and tetrazolyl, wherein Cs alkyl is optionally substituted with 1, 2, 3 or 4 groups selected from the group consisting of Cs acyl, Cy. acyloxy, Cy. alkoxy, C4 alkylcarboxamide, C,, alkylsulfonamide, C, 4 alkylsulfinyl, Ci alkylsulfonyl, C4 alkylthio, Cy 4 alkylureyl, amino, carbo-C; ¢-alkoxy, carboxamide, carboxy. cyano, formyl, C,_, haloalkoxy, C;.4 haloalkylsulfinyl, C4 haloalkylsulfonyl, C4 haloalkyithio, halogen, hydroxyl, hydroxylamino and nitro.

In some embodiments, Z is selected from the group consisting of Cs acyl, C14 alkoxy, Cj. alkyl, C4 alkylcarboxamide, Cy alkylthiocarboxamide, Cy4 alkylthioureyl, Ci4 alkylureyl, carboxamide, carboxy, cyano, aryl, C,4 haloalkyl, C,, haloalkylcarboxamide, _ heteroaryl, hydroxyl, hydroxylamino, nitro and tetrazolyl.

In some embodiments, Z is a heterocyclic group. In some embodiments, Z is a 5- membered heterocyclic group containing two oxygen atoms.

In some embodiments, Z is an alkyl group optionally substituted C, 4-dialkylamino or hydroxy.

In some embodiments, Z is selected from the group consisting of formyl,

NHC(0)CH;, NHC(O)CH,CH;, NHC(O)CH(CHa),, CH;, CH,CH;, CH(CHa),,

CH,CH,CH,CH3, NHC(O)CF;, carboxy, CFs, CF,CF3, nitro and 1H-tetrazol-5-yl.

Tn some embodiments, Z is selected from the group consisting of carboxy, CFs, nitro and 1H-tetrazol-5-yl.

In some embodiments, Z is [1,3]-dioxolan-2-yl.

In some embodiments, Z is a formyl group.

In some embodiments, Z is a carboxy group.

In some embodiments, Z is a -CH,OH group.

In some embodiments, Z is a -CH,N(CH3), group.

In some embodiments, Z is Formula (A):

H H

Sy AN NE No Ry : Nr Rs

A) wherein:

Ry is H, Cys alkyl or Cs cycloalkyl; and Rg is H, nitro or nitrile. In some embodiments, Ry is H or C, 5 alkyl.

In some embodiments, R; is selected from the group consisting of H, C,4 alkoxy, Cis alkyl, C,.¢ alkynyl, amino, C;.¢ cycloalkyl and C;4 haloalkyl. In some embodiments, Ry isH or amino. :

In some embodiments, R; is selected from the group consisting of H, C,.¢ alkyl, and amino.

In some embodiments, Ar, is aryl optionally substituted with Rg-R;3. In some embodiments, Ar, is phenyl.

In some embodiments, Ar is heteroaryl. In some embodiments, Ar- is heieroaryl optionally substituted with Rg5-R;3. In some embodiments, Ar; is a heteroaryl selected from

TABLE 2A. In some embodiments, Ar, is a heteroaryl selected from TABLE 4 or an N-oxide thereof. In some embodiments, compounds of the invention are of Formula (Iv):

R

(5) Oorl X x,

ReRpy—e YY ANAS A

A Tw N77 z }-D (Iv) . wherein A, B,D, V, W, X,Y, Z, Ry, Ro, Ry, Ry; and R;; have the same meaning as described herein, supra and infra.

In some embodiments, Ar is heteroaryl and Ry is selected from the group consisting of H, Cys acyl, C14 alkoxy, C;.s alkyl, C4 alkylcarboxamide, C, 4 alkynyl, C4 alkylsulfonamide, Cy alkylsulfinyl, C, alkylsulfonyl, C, alkylthio, carboxamide and sulfonamide. . Tn some embodiments, Ro is selected from the group consisting of C15 acyl, Cis alkoxy, Cy. alkyl, C,4 alkylcarboxamide, C,.¢ alkynyl, C4 alkylsulfonamide, Cy 6 dialkylsulfonamide, C4 alkylsulfinyl, Cy. alkylsulfonyl, C; alkylthio, amino, arylsulfonyl,

Cs dialkylamino, C, s dialkylsulfonamide, and carboxamide.

In some embodiments, Rs is selected from the group consisting of C(O)CHa,

C(O)CH,CHs, C(O)CH,CH,CH;, C(O)CH(CHS,),, C(O)CH,CH,CH,CHj;, OCHs, OCH,CHs,

OCH,CH,CH;, OCH(CHs),, OCH,CH,CH,CH;, CH,, CH,Cli3, CH,CH,CH;, CH(CH3);,

CH(CH;)(CH,CHj;), CH,(CH,),CHj, CH,(CHy);CHs, CHy(CH,),CHs, CH;(CH,)sCHs,

C(O)NHCH;, C(O)NHCH,CH3, C(O)NHCH,CH,CHj, C(O)NHCH(CH;);, C=CH,

S(0),NHCHS, S(0),NHCH,CH;, S(0),NHCH,CH,CHj, S(0),NHCH(CHa)s,

S(O), NHCH,(CH,),CH;, S(O), NHCH(CH;)CH,CHs, S(O),N(CHa),, S(O).N(EL)(CHy),

S(0),CHs, $(0),CH,CHs3, S(0),CH,CH,CH, S(0)CH(CHz)z, S(0).CH,(CH;),CH;,

S(0),CH(CH;)CH,CH,, SCH,, SCH,CH;, SCH,CH,CH;, SCH(CHs),, SCH;(CH,),CHs, amino, S(O),Ph, N(CH),, N(CH3)(Et), N(Et), and C(O)NH,.

In some embodiments, Ry is selected from the group consisting of cyano, Cs cycloalkyl, halogen, C;4 haloalkoxy, C,.4 haloalkyl, C;4 haloalkylsulfonyl, and Ci4 haloalkylthio.

In some embodiments, R; is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cl, F, Br, OCF;, OCHF,, OCH,CF;, CFs, CHF,

CH, CFs, SCF;, SCHF; and SCH,CF:.

In some embodiments, K; is selected from the group consisting of CN, COsMe,

CO,Et, S(0),CHs, S(0),CFs, N(CH,),, N(Et),, C(O)NHCH,, C(O)NHEt, C(O)N(CHs),, OH,

OCH, and OFEt.

In some embodiments, Ry, is selected from the group consisting of heterocyclic, heterocyclicsulfonyl, heteroaryl, hydroxy, Cs; oxo-cycloalkyl, phenoxy and phenyl.

In some embodiments, R; is selected from the group consisting of C,.5 acyl, C14 alkoxy, C,.s alkyl, C;4 alkylcarboxamide, C,.¢ alkynyl, C;4 alkylsulfonamide, Cia alkylsulfinyl, C4 alkylsulfonyl, C;4 alkylthio, carboxamide, halogen and sulfonamide.

In some embodiments, Ry is selected from the group consisting of C(O)CHa,

C(O)CH,CH3, C(O)CH,CH,CH3, C(O)CH(CHs;),, C(O)CH,CH,CH,CH;, OCHs, OCH,CHj,

OCH,CH,CHj;, OCH(CHa;),, OCH,CH,CH,CH,, CH;, CH,CH,, CH,CH,CH;, CH(CH,)s,

CH(CH;)(CH,CHs), CH5(CH,),CH;, CHy(CH;);CHs, CH,(CH,),CHs, CH>(CH;)sCHs,

C(O)NHCH3;, C(O)NHCH,CH;, C(O)NHCH,CH,CH;, C(O)NHCH(CH:)s,

C(O)NHCH(CH;),CHs, CCH, S(0),NHCH,, S(0),NHCH,CH3, S(0),NHCH,CH,CH;,

S(O), NHCH(CHs),, 8(0).NHCH,(CH,),CH;, $(0),NHCH(CH;)CH,CH;, S(O)CH;,

S(O)CH,CHs, S(O)CH,CH,CHs, S(O)CH(CHa),, S(O)CH,(CH,),CHs,

S(O)CH(CH;)CH,CHs, $(0),CH, S(0).CH,CH;, S(0).CH,CH,CHs, S(0),CH(CHa)z,

S(0),CH,(CH,),CH, S(0),CH(CH;)CH,CHj;, SCH;, SCH,CHs, SCH,CH,CHs, SCH(CHs), and SCH,(CH,),CHa.

Tn some embodiments, R,, is selected from the group consisting of amino, arylsulfonyl, carboxy, cyano, Cs 4 cycloalkyl, halogen, C14 haloalkoxy, C;.4 haloalkyl and C;4 haloalkylthio.

Tn some embodiments, Ry is selected from the group consisting of phenylsulfonyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, CL, F, Br, OCF, OCHF,, OCH,CF3, CFs,

CHF,, CH,CFs, SCF;, SCHF, and SCH,CF.

Tn some embodiments, Ry is selected from the group consisting of heterocyclic, . heteroaryl, C47 0xo-cycloalkyl, phenoxy and phenyl. In some embodiments, Rs is selected from the group consisting of morpholin-4-yl, thiomorpholin-4-y}, 1-0%0-1A*-thiomorpholin-4- yl, 1,1-Dioxo-1A’~thiomorpholin-4-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl, 4-ethyl- piperazin-1-yl, 4-propyl-piperazin-1-yl, piperidin-1-yl, pyrrolidin-1-yl, 2,5-dioxo- imidazolidin-4-yl, 2,4-dioxo-thiazolidin-5-yl, 4-ox0-2-thioxo-thiazolidin-5-yl, 3-methyl-2,5-" dioxo-imidazolidin-4-yl, 3-methyl-2,4-dioxo-thiazolidin-5-yl, 3-methyl-4-oxo0-2-thioxo- thiazolidin-5-y1, 3-ethyl-2,5-dioxo-imidazolidin-4-yl, 3-ethyl-2,4-dioxo-thiazolidin-5-yl, and 3-ethyl-4-oxo0-2-thioxo-thiazolidin-5-yl.

In some embodiments, Ry is selected from the group consisting of 1H-imidazol-4-yl, [1,2,4]triazol-1-yl, [1,2,3]triazol-1-yl, [1,2,4]triazol-4-yl, pyrrol-1-yl, pyrazol-1-yl, 1H~ pyrazol-3-yl, imidazol-1-vl, oxazol-3-yl, oxazol-2-yl, [1,3,4]oxadiazol-2-y1, [1,3 4]thiadiazol- 2-y1, [1,2,4]oxadiazol-3-yl, [1,2,4]thiadiazol-3-v1, tetrazol-i-yl, pyrimidin-3-vi, pyrimidin-2- yl, pyrimidin-4-yl, pyridazin-3-yl, pyridazin-4-yl, pyrazin-2-yl, 1,3-dioxo-1,3-dihydro- isoindol-2-yl and [1,2,3]thiadiazol-4-yl.

In some embodiments, Ry is Cy alkyl or C,.4 alkoxy optionally substituted with 1 to substituents selected independently from the group consisting of Cy.4 alkoxy, C14 alkylcarboxamide, C4 alkylsulfonamide, Cy. alkylsulfinyl, C4 alkylsulfonyl, C;4 alkylthio, carbo-C;.s-alkoxy; carboxamide, carboxy, cyano, heterocyclic, hydroxyl and phenyl.

In some embodiments, Ry is Cy alkylsulfonyl optionally substituted with 1 to 5 substituents selected independently from the group consisting of C,.4 alkoxy, carboxamide, heteroaryl, heterocyclic and phenyl.

In some embodiments, Rs is C,, alkylsulfony] substituted with the heteroaryl group.

In some embodiments, the heteroaryl is selected from the group consisting of 1H-imidazol-4- yl, [1,2,41triazol-1-yl, [1,2,3}triazol-1-yl, [1,2,4]triazol-4-yl, pyrrol-1-yl, pyrazol-1-yl, 1H- pyrazol-3-yl, imidazol-1-yl, oxazol-5-yl, oxazol-2-yl, [1,3,4]oxadiazol-2-yl, [1,3,4]thiadiazol-

2-y1, [1,2,4loxadiazol-3-y1, [1,2,4]thiadiazol-3-yl, tetrazol-1-yl, pyrimidin-5-yl, pyrimidin-2- yl, pyrimidin-4-y1, pyridazin-3-yl, pyridazin-4-yl, pyrazin-2-yl, 1,3-dioxo-1,3-dihydro- isoindol-2-yl and {1,2,3]thiadiazol-4-y1.

In some embodiments, Ry is arylsulfonyl, heteroaryl, phenoxy or phenyl optionally substituted with 1 to 5 substituents selected independently from the group consisting of Ci.5 acyl, Cy 4 alkoxy, Cy. alkyl, C, 4 alkylsulfonamide, C; 4 alkylsulfinyl, C,4 alkylsulfonyl, Cy 4 alkylthio, carboxamide, carboxy, cyano, halogen, C,4 haloalkoxy, C4 haloalkyl, Cy.4 haloalkylthio and hydroxyl.

In some embodiments, Rs is arylsulfonyl, heteroaryl, phenoxy or phenyl each optionally substituted with 1 to 5 substituents selected independently from the group consisting of C14 alkoxy, Cy; alkyl, cyano, halogen, C;4 haloalkoxy, C,.4 haloalkyl and hydroxyl.

In some embodiments, Ry is a heterocyclic group as described herein.

In some embodiments, Ry is a heterocyclic group represented by the formulae shown in Table 2B, supra. In some embodiments, Ry is a heterocyclic group represented by the formulae shown in Table 2C, supra. In some embodiments, Ry is a heterocyclic group represented by the formulae shown in Table 2D, supra. In some embodiments, Ryisa heterocyclic group represented by the formulae shown in Table 2E, supra. In some embodiments, Ry is a heterocyclic group represented by the formulae shown in Table 2F, supra. In some embodiments, Ry is a heterocyclic group represented by the formulae shown in Table 2G, supra. . In some embodiments, R; is of Formula (D): ] whore, 0 ®) wherein: “p” and “r” are independently 0, 1, 2 or 3; and Ry; is H, C,.s acyl, Cy alkenyl, Cys alkyl, C,.4 alkylcarboxamide, Crs alkynyl, C,,4 alkylsulfonamide, carbo-C,¢-alkoxy, carboxamide, carboxy, cyano, Cs cycloalkyl, C,¢ dialkylcarboxamide, halogen, heteroaryl or phenyl, and wherein the heteroaryl or phenyl may be optionally substituted with 1 to 5 substituents selected independently from the group consisting of C,_4 alkoxy, amino, Cys alkylamino, C, alkynyl, C, ¢ dialkylamino, halogen, C; 4 haloalkoxy, C,.4 haloalkyl and hydroxyl.

In some embodiments, Ry is of Formula (D) wherein “p” and “r” are independently 0, or 1; and Ry; is H, carbo-C, alkoxy, heteroaryl or phenyl, and wherein the heteroaryl and phenyl are each optionally substituted with 1 to 5 substituents selected independently from the group consisting of Cy4 alkoxy, amino, C4 alkylamino, Cz alkynyl, C,. dialkylamino, halogen, C; 4 haloalkoxy, C4 haloalkyl and hydroxyl.

In some embodiments, p=0andr=0.

Tn some embodiments, Ry; is phenyl optionally substituted with 1 to 5 substituents selected independently from the group consisting of C4 alkoxy, amino, C14 alkylamino, C6 alkynyl, C, 5 dialkylamino, halogen, Cy haloalkoxy, Cy.4 haloalkyl and hydroxyl.

In some embodiments, p =0and r= 1.

Tn some embodiments, Ry; is carbo-Cys-alkoxy or carboxy.

In some embodiments, p= 0and r= 0.

Tn some embodiments, Ryg is heteroaryl or phenyl optionally substituted with 1 to 5 substituents selected mdependently from the group consisting of C4 alkoxy, amino, Ci4 alkylamino, C,.¢ alkynyl, Cos dialkylamino, halogen, Ci4 haloalkoxy, Ci. haloalkyl and hydroxyl. In some embodiments, the heteroaryl is selected from the group consisting of 1H- imidazol-4-y1, [1,2,4]triazol-1-y}, [1,2,3]triazol-1-yl, [1,2,4]triazol-4-y1, pyrrol-1-yl, pyrazol- 1-yl, 1H-pyrazol-3-yl, imidazol-1-yl, oxazol-5-yl, oxazol-2-yl, [1,3,4]oxadiazol-2-l, [1,3 ,4]thiadiazol-2-yl, [1,2,4]oxadiazol-3-yl, [1,2,4]thiadiazol-3-yl, tetrazol-1-yl, pyrimidin-5- - vy], pyrimidin-2-yl, pyrimidin-4-yl, pyridazin-3-yl, pyridazin-4-yl, pyrazin-2-yl, 1,3-dioxo-1,3- dihydro-isoindol-2-yl and [1,2,3]thiadiazol-4-yl.

Tn some embodiments, p=2 and r=1. In some embodiments, Rig is H, Cys acyl or

Cy alkyl.

Tn some embodiments, Ryo-Rys are independently Cys acyl, Cis alkoxy, Ci. alkyl, Ci. 4 alkylcarboxamide, Cy, alkylureyl, carbo-C, alkoxy, carboxamide, carboxy, cyano, Cas cycloalkyl, halogen, C14 haloalkoxy and C4 haloaliyl.

In some embodiments, one or two R;o-Rys groups are independently halogen. In some embodiments, one Ryo-R;3 group is a halogen.

Tn some embodiments, Ar; is phenyl and Rs is substituted at the para position on the phenyl.

Tn some embodiments, Art; is phenyl optionally substituted with Ro, Ripand Ry. In some embodiments, the compounds of the invention are of Formula (Iw):

Ry pL wf) ANA

Ry } Lob (Iw) wherein A, B,D, V, W, X,Y, Z, R, have the same meaning as described herein, supra and infra, and Ry is cyano, carbo-Cy¢-alkoxy, carboxy, Cs. dialkylamino, Ci 4 alkylcarboxamide,

C,.¢ dialkylsulfonamide, Cy alkylsulfonyl, hydroxyl, G 4 alkoxy, 5-membered heteroaryl, 6-

membered heteroaryl, or heterocyclic, wherein the 6-membered heteoaryl is optionally an N- oxide; and Ry, and Ry; are independently H or halogen. In some embodiments, Rs is cyano, carbomethoxy, carboethoxy, carboisopropoxy, carboxy, dimethylamino, diethylamino, methylethylamino, C(O)NHCH;, C(O)NHCH,CH;, C(O)NH(CHs)z, $(0),CHs,

S(0),CH,CHj, hydroxyl, OCHs, [1,2,4]triazol-4-yl, thiazol-2-yl, 3H-imidazol-4-yl, 1H- imidazol-2-yl, 1H-imidazol-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 1-oxy-pyridin-2-yl, 1-oxy-pyridin-3-yl, 1-oxy-pyridin-4-yl, or 2-0xo-oxazolidin-4-yl. In some embodiments, Rio . is H and Ry; is F.

In some embodiments, Ar, is phenyl and two adjacent Ryp-Ry; groups forma 5, 6 or 7 membered cycloalkyl, cycloalkenyl or heterocyclic group with the phenyl group wherein the 5, 6 or 7 membered group is optionally substituted with halogen.

In some embodiments, Ar; is phenyl and two adjacent R;o-Ry; groups forma 5, 6 or 7 membered cycloalkyl group with the phenyl group and is of the formulae shown below:

TABLE 5

Li 0 oC ol ‘ Z a a wherein “a” is 1, 2 or 3 to give a 5, 6 or 7 membered cycloalkyl fused together with the phenyl group where two of the ring carbons are shared between the cycloalkyl and phenyl group. In some embodiments, the cycloalkyl is optionally substituted with halogen. In some embodiments, the halogen is fluorine.

In some embodiments, Ar, is phenyl and two adjacent Ryo-Ry; groups forma 5, 6 or 7 membered cycloalkenyl group with the phenyl group and is of the formulae shown m TABLE and has at least one carbon-carbon ring double bond present that is not part of the phenyl group (i.e., cycloalkenyl), for example, 1H-Indenyl and dihydro-naphthyl. In some embodiments, the cycloalkenyl is optionally substituted with halogen. In some embodiments, the halogen is fluorine.

In some embodiments, Ar; is phenyl and two adjacent R;o-R;; groups forma 5, 6 or 7 heterocyclic group with the phenyl group and is of the formulae in TABLE 5 wherein one or more ring cycloalkyl carbons are replaced by a O, S, S(O), S(O), NH or N-C, 4-alkyl group.

In some embodiments, the heterocyclic group is optionally substituted with halogen. In some embodiments, the halogen is fluorine.

In some embodiments, Ar; is phenyl and two adjacent R;o-R;; groups forma 5 membered heterocyclic group with the phenyl group. In some embodiments, the 5 membered heterocyclic group with the phenyl group together form a 2,3-dihydro-benzofuran-5-yl or benzo[1,3]dioxol-5-yl group. In some embodiments, the two adjacent groups forma 6 membered heterocyclic group with the phenyl group. In some embodiments, the 6 membered heterocyclic group with the phenyl group together form a 2.3 dihydro-benzo[1,41dioxin-6-y1 or 2,3-dihydro-benzo[1,4]dioxin-2-yl group. In some epnbodiments, the two adjacent groups form a 7 membered heterocyclic group with the phenyl group. In some embodiments, the 7 membered heterocyclic group with the phenyl group together forma 3 A-dihydro-2H- benzo[b][1,4]dioxepin-7-yl group.

Tn some embodiments, Ar, is heteroaryl and two adjacent Rqo-Rqq groups formas, 6 or 7 membered cycloalkyl, cycloalkenyl or heterocyclic group with the heteroaryl group wherein the 5, 6 or 7 membered group is optionally substituted with halogen. In some embodiments, Ar, is a heteroaryl selected from TABLE 2A. In some embodiments, Ary is a heteroaryl selected from TABLE 4. In some embodiments, the two adjacent groups form a 5 membered heterocyclic group with the heteroaryl group. In some embodiments, the two adjacent groups form a 6 membered heterocyclic group with the heteroaryl group. In some embodiments, the two adjacent groups form a 7 membered heterocyclic group with the heteroaryl group.

Tn some embodiments, Rs is H, C15 acyl, Cis acyloxy, Cy. alkenyl, C14 alkoxy, Cis alkyl, C;.4 alkylcarboxamide, Cy.¢ alkynyl, Ci4 alkylsulfonamide, C;.4 alkylsulfinyl, Cis alkylsulfonyl, C,4 alkylthio, C14 alkylureyl, amino, arylsulfonyl, carbo-C; g-alkoxy, carboxamide, carboxy, cyano, Cas cycloalkyl, Cos dialkylcarboxamide, halogen, Cy haloalkoxy, Cy.4 haloalkyl, C,4 haloalkylsulfinyl, C,.4 haloalkylsulfonyl, C14 haloalkylthio, heterocyclic, hydroxyl, nitro, Cag oxo-cycloalkyl, sulfonamide and nitro.

Tn some embodiments, Rs and Rg are independently H or F.

In some embodiments, X is Iv and Y 1s CH.

In some embodiments, X is N and Y is CF.

In some embodiments, X is CH and Y is N.

In some embodiments, X and Y are N.

Tn some embodiments, X and Y are CH.

In some embodiments, X is CH and Y is CF.

Some embodiments of the present invention include compounds illustrated in TABLES A, B,

C, D and E; these TABLES are shown below.

TABLE A

Chemical Name

Al N= 1-[6-(4-Tmidazol-1 -yl-phenoxy)-5-

AY i. pitro-pyrimidin-4-yl]-piperidine-4-

TL lL carboxylic acid ethyl ester

NN

NO, Oo. 0 ‘

A2 N-NT NN 1-[6-(2-Methyl-5-trifluoromethyl-2H- : Fac AA pyrazol-3-yloxy)-5-nitro-pyrimidin-4- o N yl]-piperidine-4-carboxylic acid ethyl

NO, oO ester 10]

A3 xP 1-[6-(4-Methanesulfonyl-phenoxy)-5- - 7) NSN nitro-pyrimidin-4-y1]-piperidine-4-

NN carboxylic acid ethyl ester 0)

Ad aL NSN 1-[6-(Benzo[1,2,5)oxadiazol-5-

N= oN yloxy)-S-nitro-pyrimidin-4-yl]-

NO 0 piperidine-4-carboxylic acid ethyl 2 ~ ester —

AS | oo | 1-{6-[4-(2-Methoxycarbonyi-acetyl)- are} NTN phenoxy]-5-nitro-pyrimidin-4-yl} - o AA piperidine-4-carboxylic acid ethyl i

NO, lo ester

Oo

A6 N-NT NN 1-[5-Amino-6-(2-methyl-5-

Fa 21 A trifluoromethyl-2H-pyrazol-3-yloxy)-

Q N pyrimidin-4-ylj-piperidine-4-

NH Oo carboxylic acid ethyl ester ©)

A7 N-NT NN 1-[6-(2-Methyl-5-trifl thyl ’ y. uoromethyl-2H-

FCA APA pyrazol-3-yloxy)-5-(2,2,2-trifluoro- lo) y NH Ow acetylamino)-pyrimidin-4-y1]-

CFs L piperidine-4-carboxylic acid ethyl ester ‘

Chemical Name

A8 He Propionic acid 1-[2-amino-5-formyl-

N-N NSN 6-(2-methyl-5-trifluoromethyl-2H- :

FC Ah o pyrazol-3-yloxy)-pyrimidin-4-yl]-

Shot L A piperidin-4-yl ester

A9 N-NT NN 4-{6-(2-Methyl-5-trifluoromethyl-2H-

FIC CAAA NN N pyrazol-3-yloxy)-5-nitro-pyrimidin-4-

NO, \UN_O yl]-piperazine-1-~carboxylic acid ethyl 2 I . - ester

A10 NNT NN 1-[6-(2-Methyl-5-trifluoromethyl-2H-

FaC< AAA pyrazol-3-yloxy)-5-nitro-pyrimidin-4~ © NO LS yl]-piperidine-4-carboxylic acid 2 . methyl ester 0

NB 7 ~~ .

All N-N" NSN 2,6-Dimethyl-4-[6-(2-methyl-5-

FOL AA trifluoromethyl-2H-pyrazol-3-yloxy)-

NO, NO 5-nitro-pyrimidin-4-y1]-morpholine

Al12 N-NT NSN 0 1-[6-(2-Mthyl-5-trifluoromethyl-2H-

Fo A AA om pyrazol-3-yloxy)-5-nitro-pyrimidin-4-

NO y1}-piperidine-3-carboxylic acid ethyl . 2 ester :

Az N-NT NN | 1-[6-(2-Methy1-5-trifluoromethyl-2H-

FCN A pyrazol-3-yloxy)-5-nitro-pyrimidin-4-

I. © N H yI]-piperidine-4-carboxylic acid

NO: N~ ethylamide 0 :

Al4 NNT NSN 1-[6-(2-Methyl-5-phenyl-2H-pyrazol-

OA AA, 3-ylony)Spitco-pyrimidin 431}

NO piperidine-4-carboxylic acid ethy 2 Co eter 0

AlS NNT NIN 4-(2-Miethyl-5-triftuoromethyl-2H-

FCA Ay pyrazol-3-yloxy)-5-nitro-6-piperidin-

NO, ) 1-yl-pyrimidine

(Cmpd# [~~ Structure | _ Chemical Name \

Al6 CF; NTN 1-[5-Nitro-6-(2-trifluoromethyl-

NN benzyloxy)-pyrimidin-4-yl]- piperidine-4-carboxylic acid ethyl

NO, Oo. ester

Oo

Al7 NSN 1-{5-Nitro-6-(3-trifluoromethyl-

FC NN benzyloxy)-pyrimidin-4-yl}-

NO, lo ~ piperidine 4-carboxylic acid ethyl

O

A138 NSN 1-[5-Nitro-6-(4-trifluoromethyl- joaan eA piperidine-4-carboxylic acid ethy

FsC NO: Or | PP ester ) 0

A19 N-N" NN 1-[5-Bromo-6-(2-methyl-5-

Fac AN oN trifluoromethryl-2H-pyrazol-3-yloxy)-

Br o pyrimidin-4-y1]-piperidine-4- ~ carboxylic acid ethyl ester 0

A20 N-N" NN 1-[5-Acetylamino-6-(2-methyl-5-

FaC A oN trifluoromethyl-2H-pyrazol-3-yloxy)- . pyrimidin-4-y1}-piperidine-4- °N NH oor carboxylic acid ethyl ester i 0 i

A21 N-N" NSN 1-[5-Diacetylamino-6-(2-methyl-5-

Fa Al oy N trifluoromethyl-2H-pyrazol-3-yloxy)- or pyrimidin-4-yl]-piperidine-4- " 0) carboxylic acid ethyl ester

T 0

A22 N-N” NSN : 1-[6-(2-Methy]-5-trifluoromethyl-2H-

FO {AAA pyrazol-3-yloxy)-5-nitro-pyrimidin-4-

NO. 1 yl]-piperidine-4-carboxylic acid 2 CO,H

A23 NSN 1-{5-Nitro-6-[2-(2-trifluoromethyl-

NN phenyl)-ethoxy]-pyrimidin-4-y1} -

CF3 NO, ow piperidine-4-carboxyhic acid ethyl ester

(Copd# | Swuotre | ChemicalNamo

A24 JON NSN 1-{5-Nitro-6-[2-(3-trifluoromethyl-

FC oN oW phenyl)-ethoxy] pyrimidin4y, ” piperidine-4-carboxylic acid ethy

NO, Or ester

Oo

A25 N-N" NN 1-[5-Di-(methunesulfonyl)amino-6-

Fae oN (2-methyl-5-trifluoromethyl-211- o. N © our pyrazol-3-yloxy)-pyrimidin-4-yl]- i. 37 do piperidine-4-carboxylic acid ethyl

I 170 © ester

A26 JQ NSN 1-[5-Nitro-6-(3-trifluoromethyl-

FaC NN phenoxy)-pyrimidin-4-yl]-piperidine-

NOs Ow 4-carboxylic acid ethyl ester o

A27 N-N" NSN 1-[5-Methyl-6-(2-methyl-5-

F3C “oA trifluoromethyl-2H-pyrazol-3-yloxy)- :

Oo — pyrimidin-4-y1]-piperidine-4- carboxylic acid ethyl ester

O

A28 NSN 1-[5-Nitro-6-(2-trifluoromethyl- oN phenoxy)-pyrimidin-4-yl]-piperidine-

CFs NO, ow 4-carboxylic acid ethyl ester } oO

A29 F “1 NSN 1-[5-Nitro-6-(4-trifluoromethyl-

NN : phenoxy)-pyrimidin-4-yl]-piperidine-

NO, ou 4-carboxylic acid ethyl ester le]

A30 TL NSN 1-[6-(4-Fluoro-phenoxy)-5-nitro-

NN pyrimidin-4-yl]-piperidine-4-

NO, our carboxylic acid ethyl ester

Oo /

A31 N-N NSN 1-[6-(2,5-Dimethyl-2H-pyrazol-3-

AA, yloxy)-5-nitro-pyrimidin-4-yl}-

NO. 0 piperidine-4-carboxylic acid ethyl 2 9% ~~ ester oO

A32 Br NSN 1-[6-(4-Bromo-phenoxy)-5-nitro-

PN pyrimidin-4-yl]-piperidine-4- arboxylic acid ethyl ester

NO, Ol on RaIDORY od

O

A33 cl NSN 1-[6-(4-Chloro-phenoxy)-5-nitro- oN pyrimidin-4-yl]-piperidine-4-

NOs OL, our carboxylic acid ethyl ester

O

NH,

A34 1-[6-(4-Carbamoyl-phenoxy)-5- © NSN nitro-pyrimidin-4-yl]-piperidine-4- oN . carboxylic acid ethyl ester

NO, ou .

Oo

A35 S@\ NSN : 1-{6-[4-(2-Methoxy-ethyl)- 0 OPN phenoxy]-5-nitro-pyrinidin-4-y1}-

NO, ow piperidine-4-carboxylic acid ethyl ester 18]

A36 IR : 1-[6-(4-Cyclopentyl-phenoxy)-5- : NSN nitro-pyrimidin-4-yl]-piperidine-4-

NAA NTN | carboxylic acid ethyl ester

NO, NANO : 6]

A37 Ch In {-[5-Nitro-6-(4-pyrrol-1-yl-

TCL NSN phenoxy)-pyrimidin-4-yl}- 0 NN piperidine-4-carboxylic acid ethyl

NO, oe ester 0) lo

A38 ~ 1-[6-(4-Benzoyl-phenoxy)-5-nitro-

NSN pyrimidin-4-yl]-piperidine-4-

NN carboxylic acid ethyl ester

NO; ou

A39 Os 1-{6-[4-(4-Hydroxy-

S NN benzenesulfonyl)-phenoxy]-5-nitro- j@ TL AA pyrimidin-4-yl}-piperidine-4-

HO O N carboxylic acid ethyl ester

NO2 Oo 0 ag | NC 4 1-[6-(4-Cyano-biphenyl-4-yloxy)-

NSN 5nitro-pyrimidin-4-yl]-piperidine- $ lL 4-carboxylic acid ethyl ester oN

NO, os ' — 0

Adl AP 1-[6-(2-Amino-4-ethanesulfonyl-

N N phenoxy)-5-nitro-pyrimidin-4-yI}-

OPN piperidine-4-carboxylic acid ethyl -. ester

NH, NO Lor : 0) o ) a2 | H A) 1-{6-[4-(5-Hydroxy-pyrimidin-2-

SN NIN yl)-phenoxy]-5-nitro-pyrimidin-4- i y1}-piperidine-4-carboxylic acid oN ethyl ester

NG, Oo

Oo as Cg” | 1-[5-Nitro-6-(4-sulfo-phenoxy)-

HO” NN pyrimidin-4-yl}-piperidine-4-

INN carboxylic acid ethyl ester

NO, our 0] .

Ad4 Ne & IR 1-[5-Nitro-6-(4-[1,2Alriazol-1-yl- > IQR N “N phenoxy)-pyrimidin-4-yl]-

OPN piperidine-4-carboxylic acid ethyl

NO, Oo ester

X

HoN Pe

A45 NTN 1-[6-(4-Carbamoylmethyl- 0] OPN phenoxy)-5-nitro-pyrimidin-4-yl]- piperidine-4-carboxylic acid ethyl

NO; oO ester

Gad | Swe | Chemical Name

Ad6 0 1-{6-[4-(1,3-Dioxo-1,3-dihydro-

N Je isoindol-2-y1)-phenoxy]-5-nitro-

TL NSN pyrimidin-4-yl}-piperidine-4-

O NN carboxylic acid ethyl ester

O a7 | © 4 1-[6-(4Methoxy-biphenyl-4-

NN yloxy)-5-nitro-pyrimidin-4-yl}- 4 PP piperidine-4-carboxylic acid,

NN ethyl ester

NO, O._~

Oo

A48 QW 1-{6-[4-(2,5-Dioxo-imidazolidin- un, MH 4-y])-phenoxy]-5-nitro-

NSN pyrimidin-4-yl}-piperidine-4-

O oP carboxylic acid ethyl ester

NO, or

Oo .

A49 N-NT NN 4-(4,4-Difluoro-piperidin-1-yl)- ¢ FCA AAA 6~(2-methyl-5-trifluoromethyl- 2H -pyrazol-3-yloxy)-5-nitro~

NO, F "YO:

E pyrimidine

Oo _~

AS0 ~ : 1-{5-Nitro-6-[4-(4-0x0-

NN | cyclohexyl)-phenoxy]-pyrimidin- lL 4-yl1}-piperidine-4-carboxylic oN acid ethyl ester

NO» Oo

OC

A51 ~ 1-{5-Nitro-6-{4-(3-0x0-butyl)- 0 N"=N phenoxy]-pyrimidin-4-y1}- oN piperidine-4-carboxylic acid : NO, Ow ethyl ester

O

A52 0 1-[5-Nitro-6-(4-propionyl ~ -[5- -6-(4-propionyl-

N ~N phenoxy)-pyrimidin-4-yl]-

OPN piperidine-4-carboxylic acid

NO, Lou ethyl ester oO

Gp Smowe | Chomical Name

A53 SEN 1-{5-Nitro-6-(4-[1,2,3]thiadiazol-

Z NTN 4-yl-phenoxy)-pyrimidin-4-yl]-

AA piperidine-4-carboxylic acid

O N°” ethyl ester

NO2 os 0

A54 S@\ NSN 1-{G-[4-(2-Hydroxy-ethyl)-

HO =z phenoxy]-5-nitro-pyrimidin-4- © OL 1}-piperidine-4-carboxylic acid

NO (0) yi;-pipe - 2 ~ ethyl ester 0

AS5 ? : {4-[6-(4,4-Difluoro-piperidin-1- ® CJ NN y1)-5-nitro-pyrimidin-4-yloxy|-

NN phenyl} -phenyl-methanone ’ NO, gm : F

A56 9 9 3-{4-]6-(4,4-Difluoro-piperidin- oy NSN 1-yl)-5-nitro-pyrimidin-4-yloxy]- oN phenyl} -3-oxo-propionic acid thyl ester

NO, le ety

F

AST | QL° | 2-{6-(4.4-Difluoro-piperidin-1- ~-S- & NTN . yD-5-nitro-pyrimidin-4-yloxy]-5- . :

GA oN 7) | ethanesulfonyl-phenylamine

NHz NO; F !

F

AS8 ~ 4-(4-Cyclopentyl-phenoxy)-6-

N =N (4,4-difluoro-piperidin-1-yI)-5- oN nitro-pyrimidine

NO, F

A59 RY va a 1-[6-(2,6-Dichloro-4- - NN methanesulfonyl-phenoxy)-5- 0" nitro-pyrimidin-4-yl]-piperidine-

Ql NO, oe 4-carboxylic acid ethyl ester

A60 0 1-{6-[4-(4-Chloro-benzoyl)-

NSN phenoxy]-5-nitro-pyrimidin-4-

Cl oN yi} ‘piperidine 4-carborylo acid

NO, Or y 0

A61 0 IN 1-{6-[4-(4-Hydroxy-benzoyl)- “ NN phenoxy]-5-nitro-pyrimidin-4- ao AAA yl}-piperidine-4-carboxylic acid

HO © N thyl est

NO, or ethyl ester

O

A62 NTN, NSN 1-[6-(4-Cyanomethyl-phenoxy)- x NPN 5-nitro-pyrimidin-4-yl]-

NO, Lo ~ piperidine-4-carboxylic acid ethyl ester

Oo

A63 2 IR (4-{6-[42Methanesulfonyl-

NSN ethyl)-piperazin-1-yl]-5-nitro-

OPV pyrimidin-4-yloxy} -phenyl)-

NO, LUN PN phenyl-methanone oho!

A64 0 Py 4-(4-{6-[4-(2-Methanesulfonyl-

See! N SN ethyl)-piperazin-1-yl]-5-nitro- lo 0 NINN | pyrimidin4-yloxy}-phenyl)- © NO Neg” | butan-2-one oo

Oo O

A65 Cw ~ 3-(4-{6-[4-(2-Methanesulfonyl- ag! N ~N ethyl)-piperazin-1-yl}-5-nitro-

OPN pyrimidin-4-yloxy}-phenyl)-3-

NO, LUN EN oxo-propionic acid methyl ester 00 /

A66 i. N-N NSN 4-(4-Methyl-piperidin-1-y1)-6-(2- 8 AAA, methyl-5-trifluoromethyl-2H-

NO, $Y pyrazol-3-yloxy)-5-nitro- pyrimidine ’

A67 fod NT NTN 4-(4-Bromo-piperidin-1-yI)-6-(2- 3 AAA, methyl-5-trifluoromethyl-2H-

NO 1. pyrazol-3-yloxy)-5-nitro- 2 Br p imidine

Gp Smee | Choodl Neme

AGS N-N" NN 4-(2-Methyl-5-trifluoromethyl-

Fa A oP 2H-pyrazol-3-yloxy)-5-nitro-6- 1S Sg (4-propyl-piperidin-1-y1)- 2 » oq pyrimidine :

A69 N-y” NN 1-[62-Methyl-5-

FaC—< AA trifluoromethyl-2H-pyrazol-3- 0 Le yloxy)-5-nitro-pyrimidin-4-yI}-

NO NH piperidine-4-carboxylic acid i amide

AT0 CXL NSN 1-[5-Nitro-6-(2-0x0-2H-

SN oN : chromen-6-yloxy)-pyrimidin-4- yl]-piperidine-4-carboxylic acid

NO, or ethyl ester 0

ATL o=< 1. NSN 1-[5-Nitro-6-(2-0xo0- : 0) PN benzo 1,3]Joxathiol-6-yloxy)-

NO, ou pyrimidin-4-yl}-piperidine-4- x carboxylic acid ethyl ester

AT2 CC) ~ 1-[6-(9H-Carbazol-2-yloxy)-5-

NN nitro-pyrimidin-4-y1]-piperidine- 2

N SO N 4-carboxylic acid ethyl ester

NO, Oo

C

AT3 C) Nh 1-[5-Nitro-6-(9-0x0-9H-fluoren-

OY BY 2.yloxy)-pyrimidin-4-y1J

AN piperidine-4-carboxylic acid o NO; Oo ethyl ester 0

A74 9 NIN 1-{5-Amino-6-[4-(3-0xo-butyl)- 2 AL phenoxy] pyrimidin-4-yl}- 0) N piperidine-4-carboxylic acid

NH, or ethyl ester 0)

ATS 3S NSN 1-[6-[4-(3-Oxo-butyl)-phenoxy]- >. AL 5-(2,2,2-trifluoro-acetylamino)- 0) N pyrimidin-4-yl]-piperidine-4-

ON Oo carboxylic acid ethyl ester

CFs ol

Chemical Name

AT6 HQ ~ 1-{5-Amino-6-[4-(hydroxy- 2) N N phenyl-methyl)-phenoxy]-

J PN pyrimidin-4-yl}-piperidine-4-

NHy Ow carboxylic acid ethyl ester oO ~

AT77 0 1-{6-(2-Benzoyl-5-methoxy- = NN phenoxy)-5-nitro-pyrimidin-4- a I A NS y1]-piperidine-4-carboxylic acid 0 N ethyl ester 0 NO, Oo” 0]

A78 CIN NSN 1-[6-(6-Chloro-pyridin-3-yloxy)-

TL Pe 5-nitro-pyrimidin-4-y1]-

NN piperidine-4-carboxylic acid

NO, ou ethyl ester oO ~ .

AT ¢ pg! i 1-{6-(Benzo[1,3]dioxal-S-yloxy)- lo} oN 5-nitro-pyrimidin-4-yl}-

NO, oe piperidine-4-carboxylic acid ethyl ester 0

A80 Ge NN 1-[6-(4-Benzyloxy-phenoxy)-5- 0 APN ie pind J pipers. : -carboxylic acid ethyl ester

NO; ou ~ y o) ~~

A81 J QR NSN 1-[6-(3-Morpholin-4-yl- rN oN phenoxy)-5-nitro-pyrimidin-4- o/ NO, Ow yl}-piperidine-4-carboxylic acid ethyl ester

O

F3CS

A82 8 TL NSN 1-[5-Nitro-6-(4-

NN trifluoromethylsulfanyl-

NO, ou phenoxy)-pyrimidin-4-yl]- piperidine-4-carboxylic acid 0 ethyl ester

F2CO A

As3 3 TL NSN 1-[5-Nitro-6-(4-

S08 a

NO o pyrimidin-4-yl]-piperidine-4- 2 x ~ carboxylic acid ethyl ester

Gm Smee | Comical Name

ABA Q 1-[6-(4-Benzoyl-phenoxy)-3-

NN (2,2,2-trifluoro-acetylamino)- ® 4 AA pyrimidin-4-yl]-piperidine-4-

Oo N . carboxylic acid ethyl ester 0 <0 Oo”

CF3 O

AS85 Q {4-[5-Nitro-6-(4-propyl-

Cl $¢ N“SN piperidin-1-yl)-pyrimidin-4~ oN yloxy]-phenyl}-phenyl-

SPN methanone

NO,

A86 o” {4-Methoxy-2-]5-nitro-6-(4-

NIN propyl-piperidin-1-yl)-pyrimidin- 4 AA 4-yloxyl-phenyl}-phenyl- oO SPN methanone re

ART Q 4 {4-[5-Nitro-6-(4-propyl-

A NSN piperidin-1-yl)-pyrimidin-4-

NN yloxy]-phenyl}-butan-2-one

NO; SN

Ass | JN | 5:Nitro-4-(4-propyl-piperidin-1-

FINAN NIN | 16 (4-11,2 Althiadiazol A-yl- nN oN | phenoxy)-pyrimidme

NO; SUN

A89 QoQ 3-{4-[5-Nitro-6-(4-propyl- oN), NSN piperidin-1-y1)-pyrimidin-4-

OPN yloxy]-phenyl}-3-oxo-propionic

NO, SPN acid methyl ester

A90 QL 5 Ethanesulfonyl-2-[5-nitro-6-(4- ~-S NSN propyl-piperidin-1-yl)-pyrimidin-

AA 4-yloxy]-phenylamine

O N

NH, NO SPR

Copd# | Swowe | Chomioal Name

A91 uP 4-[4-(3-Tsopropyl- - TL NEN [1,2,4]oxadiazol-5-yl)-piperidin- x 1-y1]-6-(4-methanesulfonyl- 0 N as

N phenoxy)-pyrimidine-5- i = 4 carbonitrile / O-N

A92 NS N 1-[6~(4-Difluoromethoxy-

Ow, benzyloxy)-5 _miteo-pyrimidn-1

NO e) yl]-piperidine-4-carboxylic aci

HF,CO 2 ~ ethyl ester 0)

A93 NSN 1-[6-(3-Difluoromethoxy-

OPN benzyloxy)-5-nitro-pyrimidin-4-

NO, oo yl}-piperidine-4-carboxylic acid ethyl ester

OCF,H o} /

A%4 N-N NSN 2-{1-[6-(2-Methyl-5-

FCCLA AA trifluoromethyl-2H-pyrazol-3- -

NO, Ny yloxy)-5-nitro-pyrimidin-4-y1]-

OH piperidin-4-yl} ethanol /

A95 Fo ON NSN 3-{1-[6-(2-Methyl-5- 8 = oN trifluoromethyl-2H-pyrazol-3-

NO, SN yloxy)-5-nitro-pyrimidin-4-y1]-

COxH piperidin-4-yl}-propionic acid

ASE i Non” NTN GeTdm{ ML ih 1b 1) pe EIN 4-|4~(4-Methyi-Denzyi)-

F LAA piperidin-1-yl]-6-2-methyl-5-

NO, Lr \ trifluoromethyl-2H-pyrazol-3- yloxy)-5-nitro-pyrimidine

N-NT ND a

A97 F.C ~ N N o 4~(3-Methanesulfonyl-pyrrolidin- 8 = oN 2.0 1-y1)-6-(2-methyl-5-

NO, - \ trifluoromethyl-2H-pyrazol-3- yloxy)-S-nitro-pyrimidine ’

A98 F ec NSN 4-(2-Methyl-5-trifluoromethyl-

C= oN 2H-pyrazol-3-yloxy)-5-nitro-6-

NO, [4-(2-trifluoromethyl-phenoxy)-

O piperidin-1-yl]-pyrimidine -

CF3 7s

A99 F eC N NSN 4-(2-Methyl-5-trifluoromethyl- 3 = NN NZ 2H-pyrazol-3-yloxy)-5-nitro-6-

NO, g [4-(pyridin-2-ylsulfany))-

S piperidin-1-yl]-pyrimidine

Cp Smowe | Comical Name

A100 Q 4'-(4-Benzoyl-phenoxy)-3'-nitro-

SN 3,4,5,6-tetrahydro-2H- o a [1,2 bipyridinyl-4-carboxylic acid ethyl ester

NO2 Ol our

Oo

A101 Q 3-Nitro-4'-[4-(3-0x0-butyl)- ~N phenoxy]-3,4,5,6-tctrahydro-2H-

ONAN [1,2 bipyridinyl-4-carboxylic * acid ethyl ester :

NO, our y 0

OO © ?

A102 4'-[4-(2-Metboxycarbonyl- ~o ~N acetyl)-phenoxy]-3"-nitro-3,4,5,6- 0" NN tetrahydro-2H-[ 1,2" bipyridinyl-

NO, our 4-carboxylic acid ethyl ester oO

A103 AL 4-(2-Amino-4-ethanesulfonyl- ~-S “N : phenoxy)-3"-nitro-3,4,5,6-

I ZNY ttrabycro ZF {1,2 Toipyridinyl-

NHs NO» Su ow 4-carboxylic acid ethyl ester a 0]

Atos + N= | 4-(4-Imidazol-1-yl-phenoxy)-3'- : NN SN nitro-3,4,5.6-tewahydro-2H- > | [1,27bipyridinyl-4-carboxylic

O N | acid ethyl ester

NOz Oo” : @]

A105 N-NT NSN 4-(2-Methyl-5-trifluoromethyl-

FLA Ah 2H-pyrazol-3-yloxy)-5-nitro-6-

NO. {CL (4-trifluoromethyl-piperidin-1- 2 CFs yl)-pyrimidine

A106 N-N" NSN 4-(2-Methyl5-triffuoromethyl-

Feo Ah 2H-pyrazol-3-yloxy)-5-nitro-6-

Io 1 2 (4-phenylsulfany]-piperidin-1- 2 it yI)-pyrimidine cm Smee | CemicalName

A107 NSN 1-[6-(3-Ethynyl-phenoxy)-3-

PN nitro-pyrimidin-4-yl]-piperidine- . NO, Lo % 4-carboxylic acid ethyl ester

[0] .

As cl NSN {-[6-(4-Chiloro-2-fluoro- oN phenoxy)-5-nitro-pyrimidin-4- yl}-piperidine-4-carboxylic acid

F NO Oo ethyl ester

Oo

F ~

A109 N“SN 1-[6-(2,4-Difluoro-phenoxy)-5-

PN nitro-pyrimidin-4-yl}-piperidine-

F NO, Lo — 4-carboxylic acid ethyl ester 0]

A110 Br NSN 1-[6-(4-Bromo-2-fluoro-

PN phenoxy)-5-nitro-pyrimidin4- - yl]-piperidine-4-carboxylic acid -

F NO, ou ethyl ester 0)

Alll 2) NSN 4-(3-Bthynyl-phenoxy)-5-nitro-6- , oN (4-propyl-piperidin-1-yl)-

NO, pyrimidine

Al12 | CN NN | 4-(4-Ciloro-2-fluoro-phenoxy)- ] i - !

No N ! 5 -nitro-6-(4-propyl-pipenidin-1-

F NO, y)-pyrimidine

A113 F NSN 4-(2,A-Difluoro-phenoxy)-5-

PN nitro-6-(4-propyl-piperidin-1-yD-

F NO; SPN pyrimidine

All4 Br NS N 4-(4-Bromo-2-fluoro-phenoxy)- oN 5-nitro-6-(4-propyl-piperidin-1-

E NOs SPR yl)-pyrimidine @] .

Alls 3'-Nitro-2'-[4-(3-oxo-butyl)-

SL NS phenoxy]-3,4,5,6-tetrahydro-2H- 0” NN [1,4bipyridinyl-4-carboxylic

NO, 0 wr acid ethyl ester

Oo

Cmpd# | ~~ = Stuctwe | Chemical Name

Al16 Q 4{4-(3"Nitro4-propyl-3,4,5,6-

NT tetrahydro-2H-[1,4 Tbipyridinyl- : o lz N 2"-yloxy)-phenyl]-butan-2-one

NO, SUN

A117 Q 2'-(4-Benzoyl-phenoxy)-3'-nitro-

CC 0) NT 3,4,5,6-tetrahydro-2H- o lz N [1,4bipyridinyl-4-carboxylic

NO, OL our acid ethyl ester (0)

A118 9 4(4-{5-Nitro-6-[4-(pyridin-2-

NN ylsulfanyl)-piperidin-1-y1}- oN N N7 pyrimidin-4-yloxy}-phenyl)-

NO, CL, 3 . butan-2-one

A119 2 [4-(3"-Nitro-4-propyl-3,4,5,6- ® 2] NT tetrahydro-2H-[1,4"Tbipyridinyl- o L~ N 2'-yloxy)-phenyl]-phenyl- : NO SPN methanone )

A120 1 4-(4-{5-Nitro-6-[4-(2-

See! NSN trifluoromethyl-phenoxy)-

API py | perdi ly pymimidind

NO, NN N | yioxy}-phenyi)-butan~Z-one

CF,

A121 R nN 4-(4-{6-[4-(3-Mithyl-

See! NSN [1,2,4]oxadiazol-5-y1)-piperidin- oN 1-y1]-5-nitro-pyrimidin-4-yloxy}-

NO, OL 0 phenyl)-butan-2-one

N <

A122 2? nN (4-{6-[4-(3-Methyl-

N a [1,2,4]oxadiazol-5-yl)-piperidin- oN 1-y1]-5-nitro-pyrimidin-4-yloxy} -

NO, OL 0. phenyl)-phenyl-methanone

NY

(Camp | Swotwe | Chemical Name

A123 O 1-{6-[4-(4-Fluoro-benzoyl)-

Cl 4 NN phenoxy]-5-nitro-pyrimidin-4-

E PN yi} ‘piperidine 4 carboxylic acid

NO, Ol ou ethyl ester lo}

A124 7 (4-Fluoro-phenyl)-{4-[5-nitro-6- : NSN (4-propyl-piperidin-1-y1)- . OPN pyrimidin-4-yloxy]-phenyl}- : SUN methanone

NO, / oN .

A125 N-N" NN A-J4-(3-Methyl-]1,2,4]Joxadiazol-

FCA AA 5.y1)-piperidin-1-yl]-6-(2-

NO OL methyl-5-trifluoromethyl-2H- 2 =N d r— pyrazol-3-yloxy)-5-nitro-

O-N pyrimidine

A126 © N-NT NN 4-(4-Methoxymethyl-piperidin-1-

FLA y1)-6-(2-methyl-5-

NO SY 0 trifluoromethyl-2H-pyrazol-3- 2 \ yloxy)-5-nitro-pyrimidine

A127 Q IR 4-{A-[6-(A-Methoxymethy]-

See! NSN piperidin-1-yl)-5-nitro-

PN pyrimidin-4-yloxy]-phenyl}-

SU butan-2-one

NO2 SN

A128 | N-N" NN 4-[4-(2-Methoxy-ethyl)- piperidin-1-yl}-6-2-methyl-5-

NO, Ol trifluoromethyl-2H-pyrazol-3- o— yloxy)-5-nitro-pyrimidine

A129 0 IR 4-{4-[6-(4-Bthoxymethyl-

BAe! NSN piperidin-1-yl)-5-nitro-

NN pyrimidin-4-yloxy]-phenyl}-

NO butan-2-one 2 O__

A130 F NSN 4-(2,4-Difluoro-phenoxy)-5- : PN _ nitro-6-[4-(pyridin-2-ylsulfanyl)- ) Lo, SH £) piperidin-1-yl}-pyrimidine

Cap] Swe | Chemical Name

Al31 OMe (4-Methoxy-2- {S-pitro-6-[4-

NSN (pyridin-2-ylsulfany])-piperidin-

AP 1-yl]-pyrimidin-4-yloxy}- o bo 1 0) phenyl)-phenyl-methanone soles

A132 FZ NSN 4-(2,4-Difluoro-phenoxy)-6-(4-

SN NN ethoxymethyl-piperidin-1-y1)-5-

FE NO; Lo nitro-pyrimidine

No

Al33 o 4-{A-[6-(4-

N"SN Cyclopropylmethoxymethyl-

TEN piperidin-1-y1)-5-nitro- pyrimidin-4-yloxy]-phenyl}~

NO» o_ 4 butan-2-one

A134 q 4-{4-{5-Nitro-6-(4- 0, NN propoxymethyl-piperidin-1-y)-

NN pyrimidin-4-yloxy]-phenyl} - 8 butan-2-one

NO, o wi

A135 g 1-{4-6-(4-Methoxymethyl- : XL NN piperidin-1-yl)-5-nitro-

ANN pyrimidin-4-yloxy]-phenyl}-

NO, Sy 0 gthanone f AY ‘ !

SE RE i

A136 | 9 4-{4-[2-Nitro-3-(4-propyl-

Shae! piperidin-1-yl)-phenoxy]- o N phenyl}-butan-2-one

NO,

A137 Q 1-{4-[2-Nitro-3-(4-propyl-

Yu piperidin-1-yl)-pbenoxy]- 0 N phenyl}-ethanone

NO,

A138 Q {4-[2-Nitro-3-(4-propyl- ® 4 piperidin-1-yl)-phenoxy]- 0 N phenyl} -phenyl-methanone

NO, SON

[Cop | Swe | Chemical Name

A139 Q 9 3-{4-[2-Nitro-3-(4-propyl-

MeO piperidin-1-y1)-phenoxyj- o N phenyl}-3-oxo-propionic acid

NO, SUN methyl ester

A140 0 4-{4-[6-(4-Butoxymethyl-

NN piperidin-1-y1)-5-nitro-

PN ' pyrimidin-4-yloxy]-phenyl}-

NO, $¢ 0) butan-2-one

Al41 Q 4-{A-[6-4-Tsobutoxymethyl-

NSN piperidin-1-y1)-5-nitro- . oN pyrimidin-4-yloxy]-phenyl}-

NO, Oley butan-2-one

A142 Q (4-Fluoro-phenyl)-[4-(3'-nitro-4-

SN : propyl-3,4,5,6-tetrahydro-2H-

E O07 NPN [1,2bipyridinyl-4"-yloxy)-

NO; SUN phenyl]-methanone

A143 3 4-[4-(3'Nitro-4-propyl-3,4,5,6- aael J § tetrahydro-2H-[1,2Thipyridinyl-

NG AA | 4'-yloxy)-phenyl]-butan-2-one

NO; PN ) f

Al44 NN 3'-Nitro-4-propyl-4'-(4~ he TL (SN [1,2,4]triazol-1-yl-phenoxy)- 0” ON 3,4,5,6-tetrahydro-2H- lo, SUN [1,2 bipyridinyl

Al45 o 1-{2-Nitro-3-[4-(3-0xo-butyl)- phenoxy]-phenyl}-piperidine-4- 0 N carboxylic acid ethyl ester } NO, Jo

LS

@® 65 PCT/US2004/001267

Cmpd# [ ~~ Souewe | ~~ ChemicalName |]

Al46 Oo 1-[3-(4-Benzoyl-phenoxy)-2- or Cl os nitro-phenyl]-piperidine4- x oA N carboxylic acid ethyl ester

NO2 O_

O

@] . . ET

Al47 {4-[6-(4-Ethoxy-piperidin-1-yl)- loge! NSN 5-nitro-pyrimidin-4-yloxy]- 2 oN N phenyl} -(4-fluoro-phenyl)-

NO, 1 J methanone

Al48 N-NT NN 1-{6-(2-Methyl-5-

Fac LL AA tritluoromethyl-2H-pyrazol-3- 0 TL yloxy)-5-nitro-pyrimidin-4-y1|-

NO2 OH piperidin-4-ol

Al49

Q 1-[6-(4-Acetyl-phenoxy)-5-nitro- ae! NSN pyrimidin-4-yl]-piperidine-4- oP N carboxylic acid ethyl ester

NO, Oo 0

A150 Q (1-{6-[4-(4-Fluoro-benzoyl)-

NZN phenoxy]-5-nitro-pyrimidin-4-

E oN N F y1}-piperidin-4-yl)-(4-fluoro- henyl)-methanone

NO, P 0]

AlS1 py IN | ++ {6-[4-(+-Fluoro-benzoyl)- !

CL NZTN piperidin-1-yl}-3-mtro- i x oN N F | pynmidin--yloxy}-phenyl)- butan-2-one

NO, 0]

Al52

AP Pg 4-(4-Methanesulfonyl-phenoxy)-

Pd N ~~ N ni ETA rae

Ag ; S-nitro-6-[4-(pyridin-2 oN N NZ | ylsulfanyl)-piperidin-1-yl]-

NO; sx pyrimidine

AMENDED SHEET

( PCT/US2004/001267

Cmpd# | Structure Chemical Name

Al53 02 a 4-(4-Methanesulfonyl-phenoxy)- - NN 5-nitro-6-[4-(pyridin-4- 0 NN i$ ylsulfanyl)-piperidin-1-yl}- pyrimidine

NO, S ANY

Als54 0.0 ~~ 4-(4-Methanesulfonyl-phenoxy)-

ASF NN 5-nitro-6-(4-phenylsulfany! ~~ | AA piperidin-1-yl)- 0 TL 23 pyrimidine

NO2 S

A155 FaC™> NSN 1-[5-Nitro-6-(4-

Ah trifluoromethylsulfanyl-

Oo N

NO. a phenoxy)-pyrimidin-4-yl]- © ~~ piperidine-4-carboxylic acid 0 ethyl ester

A156 xP = 5-[1,3]Dioxolan-2-yl-4-[4-(3- - TL N =N isopropyl-[1,2,4]oxadiazol-5-yl)-- 0” ON piperidin-1-yl]-6-(4- methanesulfonyl-phenoxy)- oo Ny pyrimidine

J O-N

A157 QP IN 4-[4-(3-Isopropyl- “ XL NSN [1,2,4]uxadiazol-5-yl)-piperidin- o ZN 1-y1]-6-(4-methanesulfonyl-

Cl N phenoxy)-pyrimidine-5-

H "O = — carbaldehyde

O-N i

Ass. gN | 5-13]Dioxolan 21H = NTN | isopropyi-{1,2,4]oxadiazol-3-y1)-

LL piperidin-1-y1}-6-(4- 0 N [1,2,3]thiadiazol-4-yl-phenoxy)- oo Ny ( pyrimidine —/ O-N

A159 Jen 4-[4-(3-Tsopropyl-

Z NSN [1,2,4]oxadiazol-5-yl)-piperidin- lz 1-y1}-6-(4-[1,2,3]thiadiazol-4-yl- © N phenoxy)-pyrimidine-5-

Ho Ny carbaldehyde

O-N

AMENDED SHEET

Cm@[ Swewe | ChemiolNeme

A160 aN 4-]4-(3-Isopropyl- = NN [1,2,4]oxadiazol-5-yl)-piperidin- ! 1-y13-6-(4-[1,2,3]thiadiazol-4-y1- oY °N mids phenoxy)-pyrimidine-5-

Ho Yo oN, { carboxylic acid

O-N

A161 JEN [4-[4~(3-Isopropyl- = NIN [1,2,4loxadiazol-5-y1)-piperidin- 2 1-y1]-6-(4-1,2,3 lthiadiazol-4-yl- 0 N phenoxy)-pyrimidin-5-yl}-

HO Ny { methanol

O-N

A162 JEN [4-]4-(3-Isopropyl- = NN [1,2,4]oxadiazol-5-yl)-piperidin-

LL 1-y1]-6-(4-[1,2,3]thiadiazol-4-yl~ > N phenoxy)-pyrimidin-5-ylmethyl]-- ~N =N, { dimethyl-amine \ o-N ¥

Al63 Ye N ~ 4-{4-(3-tert-Butyl- - TL N “N [1,2,4]oxadiazol-5-yl)-piperidin- x oN 1-y1]-6-(6-methanesulfonyl-

NO SU pyridin-3-yloxy)-5-nitro- 2 = —& pyrimidine

O-N

Aled Rg’ Je A-{4-(3-Isopropyi-

Lo 2 NSN | [1,2 4Joxadiazol S-y) piperidin- oN 1-y1]-6-(4-methanesulfonyl-

CN SU phenoxy)-2-methyl-pyrimidine- od — S-carbonitrile

O-N

A165 XU NR 1-[4-J4-(3-Tsopropyl- - TL NSN [1,2,4]oxadiazol-5-yl)-piperidin- 0" FN 1-y1]-6-(4-methanesulfonyl-

GU phenoxy)-pyrimidin-5-yi}- 0 Z h—( ethanone

O-N

A

TABLE B

[Crmpd# | ~~ Structure | Chemical Name

Bl NSN 1-{6-[(Benzo[1,3]dioxol-5-ylmethyl)- 0 NPN amino]-5 -nitro-pyrimidin-4-yl}- cIJ H NO, Oo piperidine -carboxylic acid ethyl 0

B2 NSN 1-[5-Nitro-6-(3,4,5-trimethoxy-

HaCO NINN benzylamino)-pyrimidin-4-y1}-

H i . sa = . . y i

HsCO NO; Oo piperidine-4 carboxylic acid ethy

OCHg 0} ~ .

B3 NN (5-Nitro-6-piperidin-1-yl-pyrimidin-

FsC NON 4-y1)-3 -trifluoromethyl-benzyl)-

H NOg amine “>

B4 CFs NN 1-[5-Nitro-6-(2-trifluoromethyl- -

NTN benzylamino)-pyrimidin-4-y1]-

H NO, oOo piperidine-4-carbonylic acid ethyl } ro) [= . ~~

BS N=N 1-[5-Nitro-6-(4-trifluoromethyl- jog em benzylamino)-pyrimidin-4-yl}-

FoC NO, oo piperidine 4-sarbonylie acid ethyl 0) >

B6 N°TN : | 1-[5-Nitro-6-(3-trifluoromethyl-

FaC NNN | benzylamino) pyrimidin4-yi]-

H NO, O_- piperidine-4-carboxylic acid ethyl ester

O

~~

B7 CFs NON (5-Nitro-6-piperidin-1-yl-pyrimidin-

OARS A-y1)-(2-trifluoromethyl-benzyl)-

H NO, amine ~ :

BS NN (5-Nitro-6-piperidin-1-yl-pyrimidin-

JOR RNS 4-y1)-(4-triflucromethyl-benzy1)-

N"=N 1-[5-Amnino-6-(3-trifluoromethyl-

NSN benzylamino)-pyrimidin-4-yl]-

H NH, Oo piperidine-4-carboxylic acid ethyl

CFs 0 ester

Campa? | Smowre | Chemical Name ~~ .

B10 NN 1-5-Amino-6-(4-trifluoromethyl-

NPN ‘benzylamino)-pyrimidin-4-yl]-

EC H NH, oo piperidine-4-carboxylic acid ethyl 3 ester 0}

B11 ~L NSN 1-[6-(4-Bromo-phenylamino)-5-nitro-

NIN pyrimidin-4-yl}-piperidine4-

H No, Ole < carboxylic acid ethyl ester 0]

FaC

B12 | °° 7. NSN 1.[5-Nitro-6-(4-trifluoromethyl-

Ahn phenylamino)-pyrimidin-4-y1]-

N NO, 0 % piperidine-4-carboxylic acid ethyl ester 0 ~

B13 @\ NN 1[6-(Methyl-phenyl-amino)-5-nitro-

NPN pyrimidin-4-yl]-piperidine-4-

I No, ou carboxylic acid ethyl ester 0] 0 =

B14 FaC 1g NSN 1[5-Nitro-6-(4-trifluoromethoxy-

NNN phenylamino)-pyrimidin-4-ylI- :

H No, ow piperidine-4-carboxylic acid ethyl ester 0)

Io i F x !

Bl: SP NTN | 1-[6-(4-Fhuoro-phenylamino)-5-nitro-

SAN ; pyrimidm-4-yl] -pipendine-4- '

H no, Or carboxylic acid ethyl ester

Oo

F ‘ .

B16 ~ 1-[6~(3,5-Diflucro-phenylamino)-5-

N°=N nitro-pyrimidin-4-yl]-piperidine-4- . NPN carboxylic acid ethyl ester

H- NO, our oO

Cl

B17 ~~ 1-[6-(3,5-Dichloro-phenylamino)-5-

N° N nitro-pyrimidin-4-yl)-piperidine-4- cl N AAA N carboxylic acid ethyl ester

H No, o_- oO oO N ~~ N A .

Big | 4 ig \ 1-[6-(Benzo[1,3]dioxol-5-ylamino)-5- 0 NPN nitro-pyrimidin-4-y1}-piperidine-4-

H NO; Oo carboxylic acid ethyl ester :

O

FCO 2

B19 ’ NSN 1-[6-(2-Bromo-4-trifluoromethoxy-

NTN phenylamino)-5-nitro-pyrimidin-4-

Br H No, Ou~ yll-piperidine-4-carboxylic acid ethyl le]

NN

B20 ] 1-[6-(2-Fluoro-phenylamino)-5-nitro-

NSN : pyrimidin-4-yl]-piperidine-4-

F H NO; Oo carboxylic acid ethyl ester 0

NSN

B21 JQ PS 1-{6-(3-Fluoro-phenylamino)-5-nitro-

F NP N pyrimidin-4-yl]-piperidine4- .

H No, O._~ carboxylic acid ethyl ester 0

B22 PP 1-{6-[(2-Fluoro-phenyl)-methyl-

NTN amino}-5-nitro-pyrimidin-4-y1}-

F | NO Oo piperidine-4-carboxylic acid ethyl 0 ester

NSN

B23 2 1 1-[6~(Ethyl-phenyl-amino)-5-nitro- ! VE pyrimidin-4-y1}-piperidine-4- i NO» (ONgPs carboxylic acid ethyl ester ~Y cl NSN

B24 XL ] 1-{6-[(4-Chloro-phenyl)-methyl-

NNN amino]-5-nitro-pyrimidin-4-y1}- l' NO, ou piperidine-4-catbonylic acid ethyl [5) 0) ~

B25 N Py 1-[6-(4-Difluoromethyl- of NTN benzylamino)-5-nitro-pyrimidin-4-

EHC H No, O.~ | yl]-piperidine-4-carboxylic acid ethyl 2 0 ester ~

B26 ° LN 1-{6-[(2,3-Dihydro-benzo[1,4]dioxin- ( OR BN 6-ylmethyl)-amino]-5-nitro- 0 NO, Oo pyrimidin-4-yl}-piperidine-4- 0 carboxylic acid ethyl ester

Cd | Swewe | CoomioalNeme \ ~~ . Lo.

B27 NN . | 1-{6-](2,3-Dihydro-benzo[ 1 4]dioxin-

ONAN 2 yimethiy})-amino] -5-nitro-

H No, Ou pyrimidin-4-y1}-piperidine-4- © 5 carboxylic acid ethyl ester

B28 NSN 1-{6-[(2,3-Dihydro-benzofuran-5-

NE yimethyl)-amino]-5-nitro-pyrimidin- o NO, Or 4-y1}-piperidine-4-carboxylic acid . ethyl ester 0 ~~ ~~

B29 00 N™=n 1-{6-[(6-Fluoro-4H-

NN ‘benzo[1,3]dioxin-8-ylmethyl)-

H No, ow amino]-5-nitro-pyrimidin-4-y1}-

E piperidine-4-carboxylic acid ethyl 0 ester

Q

B30 C Xu NSN 1-[6(3,4-Dihydro-2H- o NA benzo[b][1 4]dioxepin-7-ylamino)-5-

H No 0 nitro-pyrimidin-4-y1]-piperidine-4- 2 ~ carboxylic acid ethyl ester. 6) 0 0 .

B31 hd 1-{6-]4-(Morpholine-4-sulfony])- rN” Cl. NSN phenylamino]-5-nitro-pyrimidin-4- oA NSN yi} -piperidine-4-carboxylic acid ethyl

Lo =

C

~ :

B12 NN | 1-{6-(2,2-Difluoro-benzo[1,3]dioxol- i Io) NNN 4-ylamino)-5-nitro-pyrimidin-4-y1]- gO H NO, or piperidine-4-carboxylic acid ethyl

F ester 0

O ~

B33 F( Ig N N 1-[6~(2,2-Difluoro-benzo[1,3]dioxol-

FO NPN 5-ylamino)-5-nitro-pyrimidin-4-yl|-

HNO, ow piperidine-4-carboxylic acid ethyl ester 0} ~

B34 ‘ag N Ph 1-{6-(1,1-Dioxo-1H-1A5- 0-3 NPN benzo[blthiophen-6-ylamino)-5-nitro-

H NO, o~ pyrimidin-4-y}]-piperidine-4- o carboxylic acid ethyl ester

Cp# | Smome | ChomoName

B35 N N 1-{6-{(Furan-3-ylmethyl)-amino]-5- ‘od NPN nitro-pyrimidin-4-yl}-piperidine-4- = H No, OL carboxylic acid ethyl ester o . ~~ .

B36 N N 1-{6-[2-(4-Methoxy-phenoxy)-

Orn ethylamino]-5-nitro-pyrimidin-4-y1}- ~o H No, Ow piperidine 4-oarboxylic acid ethyl

O . ~

B37 FN~ NSN 1-{6-[2-(5-Methoxy-1H-indol-3-y1)-

NTN ethylamino]-5-nitro-pyrimidin-4-yl}~

H No, Oo piperidine-4-carboxylic acid ethyl —-0 0 ester 0 ~ .

B38 C XL NSN (3,4-Dihydro-2H- o NTN benzo[b][1,4]dioxepin-7-yl)-[5-nitro-

H No Cl 6-(4-propyl-piperidin-1-yl)- . 2 pyrimidin-4-yl]-amine

NSN

B39 2. PP (3-Fluoro-phenyl)-{5-nitro-6-(4-

F NN propyl-piperidin-1-yl)-pyrimidin-4-

H NO, yl]-amine

NSN

B40 JQ! Pi (3-Methoxy-phenyl)-[5-nitro-6-(4~

MeO NTN propyl-piperidin-1-yl)-pyrimidin-4-

H NOs yl]-amine ~~

B41 JQ NN 1-{6-[(3-Fluoro-phenyl)-methyl-

F NN amino]-5-nitro-pyrimidn-4-y1}-

I Vo O~ piperidine-4-carboxylic acid ethyl

Fo) ester

Oo

B42 ~ 1-[6-(4-Benzoyl-phenylamino)-5- 2] 2] NSN nitro-pyrimidin-4-yl]-piperidine-4-

NN : carboxylic acid ethyl ester

H No, ow 0 ~

B43 NGAGE! PP 1-{6-[4-(1,1-Dioxo-11"-

Io] NN thiomorpholin-4-ylmethyl)-

NO, O._~ | phenylamino}-5-nitro-pyrimidin-4- 0 yl}-piperidine-4-carboxylic acid ethyl ester

CE Smee | Chemical Name

B44 %P ~ 1-[6-(4-Methanesulfonyl- < TL NSN phenylamino)-5-nitro-pyrimidin-4-

NN N yl _piperidine~4-carboxylic acid ethyl

H NOs fe) ~ ester 0]

BAS RY 1{6-(4-Dimethylsulfamoyl- “N” Ag! NN phenylamino)-5-nitro-pyrimidin-4-

NNN : J1]-piperidine-4-carboxylic acid ethyl

H No, our ester 0 ~ . :

B46 JQ! NN 1-[6-(3-Methoxy-phenylamino)-5- 07 NP N nitro-pyrimidin-4-yl-piperidine-4-

H NO, Oo” carboxylic acid ethyl ester 0) ~ .

B47 N N 1-[6-(2-Methoxy-phenylamino)-5-

NN nitro-pyrimidin-4-yl]-piperidine-4-

JO H No, Oo carboxylic acid ethyl ester 0]

B48 Fs 1-[6-(3,5-Bis-trifluoromethyl- 2 N ~N phenylamino)-5-nitro-pyrimidin-4-

FaC N AA N y1]-piperidine-4-carboxylic acid ethyl

H No N Oo | ester 0

OM .

B49 © ~ | 1-[6-(2,5-Dimethoxy-phenylamino)-

NEN 5 nitro-pyrimidin-4-yl]-piperidine-4-

NIN carboxylic acid ethyl ester ome! NO; or 0) ~

B50 o N N 1[6-(3.5 -Dimethoxy-benzylamino)-

Me NAN 5-nitro-pyrimidin-4-yl]-piperidine-4-

H No; Oo carboxylic acid ethyl ester

OMe 0] ~

BS1 MeO NEN [5-Nitro-6-(4-propyl-piperidin-1-y1)- © NOUN pyrimidin-4-yl]-(3,4,5-trimethoxy-

MeO NO> benzyl)-amine

OMe ’

op Smee | ChemioalNamo

B52 NSN (3.5 Dimethoxy-benzyl)-{5-nitro-6-

MeO NONN (4-propyl-piperidin-1-yl)-pyrmidin-

H NO; 4-yl}-amine

OMe

O i ‘4

B53 (4-{5-Nitro-6-[4-(pyridin-2- ® $ NSN ylsulfanyl)-piperidin-1-yl|-pyrimidin-

NN 7) Y 4-ylamino} -phenyl)-phenyl-

H nN 0, LL PN methanone

O . .

B54 ~~ 4- {5-Nitro-6-[4-(2-trifluoromethyl-

NN phenoxy)-piperidin-1-yl]-pytimidin-

NTN A-ylamino}-phenyl)-phenyl-

H NO, S% Ig methanone

CFs

NC ~ . . .

B55 TL NN" N 1-]6-(4-Cyano-phenylamino)-5-nitro-

NAP N pyrimidin-4-yl}-piperidine-4--

H No, Lo carboxylic acid ethyl ester ~~ 0)

OM

B56 ® 1-[6-(3,5-Dimethoxy-phenylamino)-

N ~N 5-nitro-pyrimidin-4-yl]-piperidine-4~

MeO NN carboxylic acid ethyl ester ~~

H' No, o- o!

BS7 NS | 1-[6-(4-sec-Butyl-phenylamino)-5-

IN | nitro-pyrimidin-4-yl]-piperidine-4-

NTN carboxylic acid ethyl ester

H NO, oO oO ~

B58 C2 N N 1-[6-(4-Heptyl-phenylamino)-5-nitro-

NTN pyrimidin-4-yl]-piperidine-4-

H No, ou carboxylic acid ethyl ester } O 10]

B59 2'-(4-Benzoyl-phenylamino)-3"-nitro- ® ¢ NTS 3,4.5 6-tetrahydro-2H-

N” NN [1,4Tbipyridinyl-4-carboxylic acid

H No, Lo ethyl ester

(Copd# | Studre | Chemical Name

Ba0 MeO OMe ~~ 1-[5-Nitro-6-(3,4,5-trimethoxy- y@} N ~N phenylamino)-pyrimidin-4-yl]-

MeO NS N piperidine-4-carboxylic acid ethyl ester

H no, Ow

O

~~ .

B61 ~~ N N 1-{5 -Nitro-6-(4-pentyl-phenylamino)-

NNN pyrimidin-4-yl]-piperidine-4-carboxylic

H No, Ko O_~ acid ethyl ester . . . eo)

B62 “2 NSN 1-{6-[4-(3-Carboxy-propyD)-

Oo \ AF N phenylamino}-5-nitro-pyrimidin-4-y1}-

N NO; Or piperidine-4-carboxylic acid ethyl ester 8}

CN

B63 : ~~ 1-{6-[4-(Cyano-phenyl-methyl)-

CC $ N SN phenylamino]-5-nitro-pyrimidin-4-yl}-

NN piperidine-4-carboxylic acid ethyl ester

H No, ou 0

B64 J-[6-(4-Cyclohexyl-phenylamino)-5- © NSN nitro-pyrimidin-4-yl]-piperidine-4-

NP N carboxylic acid ethyl ester

H No, oe s /=N | .

B65 Ne | 1[5-Nitro-6-(4-[1,2,4]triazol-1-y1- 1 N N phenylamino)-pyrimidin-4-y1]- :

NPN piperidine-4-carboxylic acid ethyl ester

H NO. oO 0) 0.0

B66 | _ JE ~ 1-[5-Nitro-6-(4- 3C TL N N trifluoromethanesulfonyl-phenylamino)-

NN pyrimidin-4-yl]-piperidine-4-carboxylic

H NO, oo acid ethyl ester

O

Cmp@ | Smowe | Chemical Name

B67 | se | 1 [5-Nitro-6-(4-[1,2,3]thiadiazol-4-yl-

NN phenylamino)-pyrimidin-4-yl]-

NPN piperidine-4-carboxylic acid ethyl ester 0

B68 oP ~ [6-(4-Bthoxymethyl-piperidin-1-yl)-5- dg Ag)! NSN nitro-pyrimidin-4-yL]-(4- xX NIN methanesulfonyl-phenyl)-amine

H No, ho

B69 N. \ ~~ [5-Nitro-6-(4-propyl-pipendin-1-yl)- he CL NSN pytimidin-4-yl]-(4-[1,2,4]triazol-1-yl- 4

SS NEN phenyl)-amine

H NO2 SPN r=

B70 N © \ a ’ {5-Nitro-6-[4-(pyridin-2-ylsulfanyl)- 1 @ NSN piperidin-1-y1]-pyrimidin4-yl}<4-

YY LL 0) [1,2,4]triazol-1-yl-phenyl)-amine . >

B71 N N (2-Fluoro-phenyl)- {6-[4-(3-methyl-

NN [1,2 Aloxadiazol-5-y])-piperidin-1-y1]-5-

F H No, N nitro-pyrimidin-4-yl} -amine - Da .

O-N 00 :

B72 8 ~ | (4-Methanesulfonyl-phenyl)-{6-[4-(3-

TL NN methyl-[1,2,4]oxadiazol-5-yl)-piperidin-

NN 1-y1]-5-nitro-pyrimidin-4-yl}-amine

H No, _N od /=N

B73 NON ~~ {6-[4-(3-Methyl-[1,2,4]oxadiazol-5-y1)-

CL NSN piperidin-1-yl]-5-nitro-pyrimidin-4-y1}

NN (4-[1,2,4]triazol-1-yl-phenyl)-amine i No, No

F/

O-N o S

B74 Lr TL NSN 1-{5-Nitro-6-[4-(4-trifluoromethyl-

FsC NN phenoxy)-phenylamino)-pyrimidin-4- : NO, 0 yi}-piperidine-4-carboxylic acid ethyl ester

Gm# | Smewe | ChemicalNeme

B75 NSN {6-[4-(3-Ethyl-[1,2,4]oxadiazol-5-y1)-

NTN piperidin-1-yl)-5-nitro-pyrimidin-4-y1}-

F H.No, NJ (2-fluoro-phenyl)-amine

Y/ v

O-N r=N

B76 Ne N ~ {6-[4-(2-Methoxy-phenylsulfanyl)-

TL NSN piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-

Np NPN (4-]1,2.41friazol-1-y1-phenyl)-amine

H' No, SN

Je 0.0

B77 ad ~~ (4-Methanesulfonyl-phenyl)- {5-nitro-6- - Ag NSN [4-(pyridin-2-ylsulfanyl)-piperidin-1-

OL I» yl]-pyrimidin-4-yl} -amine

HNO, sN’ } NSN ;

B78 2 ) (3-Methoxy-phenyl)-{5-nitro-6-{4- - 0) OL j® (pyridin-2-ylsulfanyl)-piperidin-1-yl}-

H No, oN pyrimidin-4-y1}-amine 0) NN

B79 CI 1 Benzo[1,3]dioxol-5-yl-[S-nitro-6-(4- ! oO NPN propyl-piperidin-1-y1)-pyrimidin-4-y1}-

H NO, amine

TRO Ny :

B8Y SN | (4-Fluoro-phenyl)-{1-[5-nitro-6-(4- tN TL N“N ~ [1,2,4]trazol-1-yl-phenylamino)-

NSN F | pyrimidin-4-yl]-piperidin-4-y1}-

H | methanone

NO; o)

N= , Ca

B81 SN ~ [5-Nitro-6-(4-phenylsulfanyl-piperidin-

N° TL NZN 1-y1)-pyrimidin-4-y1}-(4-[1,2,4}triazol-

NNN 1-yl-phenyl)-amine

HNO, S

NTN

B82 i (4-Fluoro-phenyl)-{1-[6-(2-fluoro-

NSA F phenylamino)-5-nitro-pyrimidin-4-yl]-

FH NO, piperidin-4-yl}-methanone lo)

CCropd# | © Stuotwre | Chemical Name

B83 N-n" NPN 1-[6-(2-Methyl-5-phenyl-2H- {YA N pyrazol-3-ylamino)-5-nitro-

N N pyrimidin-4-yl}-piperidine-4-

NO2 Or carboxylic acid ethyl ester 0}

B84 QP (4-Methanesulfonyl-phenyl)-{5- -S NZ N nitro-6-(4-phenylsulfanyl- § piperidin-1-yl)-pyrimidin-4-y1]-

M6, amie

H No, s

BSS

QP (4-Methanesulfonyl-phenyl)- {5-

NSN nitro-6-|4-(pyridin-2-yloxy)- zs z piperidin-1-yl]-pyrimidin-4-y1}-

N N bg amine

H NQOo o SN .

B86 UP {6-[4-(4-Fluoro-phenoxy)- - NSN piperidin-1-yl]-5-nitro-pyrimidin-

NTN F 4-y1}(4-methanesulfonyl-

H NO, OT . phenyl)-amine 0.0

B87 hd (4-Methanesulfonyl-phenyl)-{5- - TL NSN nitro-6-[4-(pyridin-4-yloxy)-

NN 0) piperidin-1-yi]-pyrimidin-4-y1} -

H NO 5 , = I amie

B88 2 Pg | (&Methanesuifonyl-phenyl-{3- s XL NSN | nitro-6-[4-(pyrimidm-2-yloxy)-

NTN Y | piperidin-1-yl]-pyrimidin-4-yl}- :

H NO, BY | amine 0.0

B89 hed ~~ (4-Methanesulfonyl-phenyl)- {5- - ZL NSN nitro-6-{4-(pyridin4-ylsul fanyl)-

NTN je) piperidin-1-y1]-pyrimidin-4-y1}-

H NO, g A | amine

B90 5Y% ~ (4-Methanesulfonyl-phenyl)-{6- dg Ag N ~N [4-(4-methoxy-phenylsulfanyl)-

NTN OMe | piperidin-1-yl}-5-nitro-pyrimidin-

H No, CL, Ly 4-yl}-amine

“Cop | Stwwomre | ChemicalName 00 a

BO1 RA PR [6-(4-Benzenesulfonyl-piperidin- - AQ! NSN 1-y1)-5-nitro-pyrimidin-4-y1]-(4-

NINN methanesulfonyl-phenyl)-amine

H No, s oo 0)

B92 a ~ {4-[6-(4-Methanesulfonyl- ~ TL N “N phenylamino)-5-nitro-pyrimidin- . DAD o 4¥1-piperazin 1 v1} acetic acid ~~

B93 N°=N (2-Fluoro-phenyl)-{5-nitro-6-|4-

NY N* (pyridin-2-ylsulfanyl)-piperidin~

FH Nop WAG 1-y1}-pyrimidin-4-yl}-amine ~~

B94 NN 2-Methoxy-phenyl)- {5-nitro-6-[4-

YO) hg (pyridin-2-ylsulfanyl)-piperidin-

OMe! NO, EN 1-yl}-pyrimidin-4-yl}-amine |: 0.0

B95 JY ~ (4-Methanesulfonyl-phenyl)-(5-

ZL NSN nitro-6-{4-[3-(3-trifluoromethyl-

NTN CF; | phenyl)-[1,2,4]oxadiazol-5-y1]-

H No, N CO) piperidin-1-yl}-pyrimidin-4-yl)- amin . ON )

Bog | AP ~~ £6143 Fihy1[1,2 Alowadianol- d XL N =N | 5-yl)-piperidin-1-yl]-5-nitro-

NTN pyrimidin4-yl}(4

H NO, N methanesulfonyl-phenyl)-amine - »

O-N

Oo 0

B97 Og ~ (6~{4-[5~(4-Fluoro-phenyT)-

Xl NSN [1,3 4]oxadiazol-2-y]]-piperidin-

NPN 1-31}-5-nitro-pyrimidin-4-yl)-(4-

H NO, 0 LO) methanesulfonyl-phenyl)-amine

N-N oO, 0

B98 % A (4-Methanesulfonyl-phenyl)-[5-

TL NSN nitro-6-(4-pyridin-2-ylmethyl-

NTN NZ piperidin-1-y])-pyrimidin-4-y1]-

H NO2 x amine

“Gop | Smwhwe [| CremicalName

S

B99 - TL NZN 4-{4-(3-Tsopropyl-

NTN [1,2,4]oxadiazol-5-y])-piperidin-

H i N 1-y1]-6-(4-methylsulfanyl-

N - Ye phenylamino)-pyrimidine-5-

O-N carbonitrile

Ny ) . ny

B100 ci—\ \ 1-{6-[4-(4,5-Dichloro-itmidazol-

NN 1-y1)-phenylamino}-5-nitro-

Cl NAN pyrimidin-4-yl} -piperidine-4-

H No, Lo < carboxylic acid ethyl ester

O

O NN . Cs

B101 4 ig PP Benzo[1,3]dioxol-5-y1-{5-nitro-6- 0 SAS! NY [4-(pyridin-2-ylsulfanyl)-

Ho Nop LAA piperidin-1-yl}-pyrimidin-4-y1}- amine ~ :

B102 N Ph . (4-Fluoro-phenyl)-{1-[6-(2-

NN fluoro-phenylamino)-5-nitro-

F H No, pyrimidin-4-yl]-piperidin-4-y1}- : 0 methanone

B103 { 3g $ . {1-[6-(Benzo[1,3]dioxol-5-

Oo NN ylamino)-5-nitro-pyrimidin-4-yl]-

NO, piperidin-4-y1} -(4-fluoro-phenyl)- fo methanone ~~

B104 | Ql NX _ | (2,3-Diftuoro-phenyl)-{5-nitro-6-

FF" "NY TL XJ |4-(pyridin-2-yisulfanyl)-

FH no, 5X \ piperidin-1-y1]-pyrimidin-4-y1}- ! amine } E ~

B105 NN (2,4-Difluoro-phenyl)-{5-nitro-6-

NNT NA [-pyridin-2-ylsulfany)-

F H No, JEN piperidin-1-yl]-pyrimidin-4-yl}- amine

F

B106 yy (2,5-Difluoro-phenyl)- {5-nitro-6-

NN [4-(pyridin-2-ylsulfanyl)-

NIN NT piperidin-1-y1]-pyrimidin-4-y1}~

F H NO, S a amine

Q. 0

B107 Ys! PP 1-[6-(4-Benzenesulfonyl-

Cr XL N N phenylamino)-5-nitro-pyrimidin-

NS N 4-yl]-piperidine-4-carboxylic acid

H NO, Oo ethyl ester

[Cmpd# | Stuctwe | Chemical Name

B108 Fo IC). NSN 1-[5-Nitro-6-(2-trifluoromethyl-

N NN 3H-benzoimidazol-5-ylamino)-

H H No, or pyrimidin-4-y1]-piperidine4- 3d carboxylic acid ethyl ester ~ §

B109 FF JQ! NN 1-{5-Nitro-643-(1,1,2,2-

Hog ae! tetrafluoro-ethoxy)-

FF H NO LL. o._- phenylamino]-pyrimidin-4-y1}- “nw piperidine4-carboxylic acid ethyl 0 . ester

B110 RY {6-[4-(4-Todo-phenoxy)- - <u NSN piperidin-1-ylj-5-nitro-pyrimidin-

NSN 4-y1}-(4methanesulfonyl-

H No, gH Lr phenyl)-amine 0 0

Bill NY (2-Fluoro-4-methanesulfonyl- “ NSN phenyl)-{6-[4~(3-isopropyl-

NN [1,2,4]oxadiazol-5-y1)-piperidin-

EF H NO, On 1-y1}-5-nitro-pyrimidin-4-y1}- ~ poi amine

O-N 0 0

B112 NY {6-[4-(3-Ethyl-[1,2,4]oxadiazol- - A gt NSN 5-y1)-piperidin-1-yl]-5-nitro-

NTN pyrimidin-4-y1}-(2-fluoro-4-

H methanesulfonyl-phenyl)-amine i NO NN,

STN

0

BI113 A IR (4-Methanesulfonyl-pheriyl)-{5- dd TL N ~N nitro-6-[4~(3-propyl-

NN [1,2,4]oxadiazol-5-y1)-piperidin-

H NO, KL _N 1-y1]-pyrimidin-4-yl} -amine

Sal

Q,,0

B14 ¥ A {6-[4-(3-Cyclopropylmethyl-

ZL NSN [1,2 AJoxadiazol-5-y1)-piperidin-

NN 1-y1]-5-nitro-pyrimidin-4-y1}-(4-

NO, ~ methanesulfonyl-phenyl)-amine

O-N

“Grp | Swews | ChomioalName

B115 Ye ~ {6-{4~(3-Isopropyl- - TL NTN [1,2,4]oxadiazol-5-y1)-piperidin-

NNN 1-y1]-5-nitro-pyrimidin-4-y1}-(4-

H No , SU methanesulfonyl-phenyl)-amine

On]

B116 AP an {6-[4-(3-Cyclopropyl- - CL NSN [1,2,4]oxadiazol-5-y1)-piperidin-

NNN 1-y1]-5-nitro-pyrimidin-4-y}}-(4-

H methanesulfonyl-phenyl)-amine

NO; _N 4 d

O-N

Bur | ~ (4-Methanesulfonyl-phenyl)-(5- - TL NTN nitro-6-{4-[3-(3-rifluoromethyl-

NSN CF, | phenyl-[1,24Joxadiazol-5-yi]-

H No ln e piperidin-1-yl} -pyrimidin-4-yl)- 2 z ,

J) amme

O-N 0)

B118 8 ~ } 4-[4-(3-Isopropyl- - TL NPN [1,2,4Joxadiazol-5-yl)-piperidin-

N” XN 1-y1]-6~(4-methanesulfinyl-

H | Os phenylamino)-pyrimidine-5-

N c WL carbonitrile

O-N 0.0

BI119 KP . {(4-Methanesulfonyl-phenyl)-{5-

CT LL noon i miro-6-{4-(4-mfiuoromethoxy- x NNN OCF3 | phenoxy)-piperidin-1-y1}-

H No, o pyrimidin-4-y1}-amine

Q 0

B120 4 ~ 4-[4-(3-Tsopropyl- - i ® NN [1,2,4]oxadiazol-5-y1)-piperidin-

N” XN 1-y1}-6-(4-methanesulfonyl-

H N phenylamine)-pyrimidine-5-

N ~ Ne carbonitrile

O-N

Q 0

B121 hd 1-{1-[6-(2-Fluoro-4- . - N SN methanesulfonyl-phenylamino)-5-

NNN nitro-pyrimidin-4-yl]-piperidin-4-

FH No SPP yl}-hexan-1-one

Gp | Smmwe | ChomoalNeme

B122 QP ~~ 1-{1-[6-(4-Methanesulfonyl- - 7. NSN phenylamino)-5-nitro-pyrimidin-

NN 4-y1]-piperidin-4-yl}-hexan-1-one

H No, er 8}

O

B123 SY IR {6-[4-(3-tert-Butyl- ~ N “N [1,2,4]oxadiazol-5-yl)-piperidin-

NPN 1-y1]-5-nitro-pyrimidin-4-y1}-(2-

F H no SE! fluoro-4-methanesulfonyl- 2 - —& phenyl)-amine

O-N a. SUR SE

B124 Ny IN {6-[4-(3-tert-Butyl- - XL NSN [1,2,Aloxadiazol-5-yl)-piperidin-

NP 1-y1}-5-nitro-pyrimidin-4-yl} (4-

H NO, On we methanesulfonyl-phenyl)-amine

O-N

Q 0

B125 Pi: - [6-(4-Benzofuran-2-yl-piperidin- ig NSN 1-yl)-5-nitro-pyrimidin-4-yl]-(4-

NNN methanesulfonyl-phenyl)-amine

H No, o) { ‘ .

B126 | XO ~ A-(3-Fhuoro-4-methanesulfonyl- “NY i N ~N | phenylamine) 6-11-(3-iscpropyl-

SAA [1.2,4]oxadiazol-5-y1)-piperidin-

H on Su N 1-y1J-pyrimidine-5-carbonitrile ! O- X ( oO

B127 Pi ~ {6-[4-(3-Isopropyl-

Tl NSN [1,2,4]oxadiazol-5-yl)-piperidin-

SNONTN 1-y1}-5-nitro-pyrimidin-4-y1}-(5-

H NO, N methanesulfonyl-pyridin-2-yl)- ~ — amine

O-N 0 OF

B128 J: ~ (3-Fluoro-4-methanesulfonyl-

NN phenyl)-{6-[4-(3-isopropyl-

NTN [1.2 A]oxadiazol-5-yl)-piperidin-

H No, _N + 1-y1}-5-nitro-pyrimidin-4-yl}- / amine

O-N

CepF [Sew [ ClomwiNeme o

B129 XP {6-14-(3-Tsopropyl- - TL NN [1,2,4Joxadiazol-5-y1)-piperidin- x NON 1-y1)-5-nitro-pyrimidin-4-y1}-(6-

H No SE methanesulfonyl-pyridin-3-y1)- 2 = — amine

O-N

B130 NSN 42, 3-Difluoro-phenylamino)-6-

FF” NNN [4-(3-isopropyl-[1,2,4]oxadiazol-

F H oN N 5-yl)-piperidin-1-yl]-pyrimidine- ~ — 5-carbonitrile

O-N

B131 h ~~ 4-(2,5-Difluoro-phenylamino)-6-

N ~N [4-(3-isopropyl-[1,2,4]oxadiazol-

NNN S-yl)-piperidin-1-y1]-pyrimidine-

F H oN On — 5-carbonitrile

S

B132 - TL NSN 4-J4-(3-Isopropyl-

NPN [1,2,4]oxadiazol-5-yl)-piperidin-

H oN Ol 1-y1]-6-(4-methylsulfanyl- ¢ —{ phenylamino)-pyrimidine-5-

O-N carbonitrile 0 0

B133 Nd 4-[4-(3-Isopropyl- 5 ~

Ag! NSN [1,2,4Joxadiazol-5-yl)-piperidin-

NNN | 1-y1]-6-(4-methanesulfonyl- : H con | ' phenylamino)-pyrimidiie-5- ~NL | carbonitrile

O-N

SN S Ca

B134 < TL NSN 4-(4-Hexauoyl-piperidin-1-y1)-6-

ES NNN (6-methylsulfanyl-pyridin-3-

H oN ylamino)-pyrimidine-3- . carbonitrile

O

0 0

B135 YON ~ 4-(4-Hexanoyl-piperidin-1-y1)-6- - TL N N (6-methanesulfonyl-pyridin-3- x NEN ylansino)-pyrimidine-5-

CN carboniirile

(Cmpa# | Stowe | Chemical Name

B136 “ CL. NSN 4.-[4-(3-Isopropyl-

N NSN [1,2,4]oxadiazol-5-y1)-

H ¢N Ol piperidin-1-y1]-6-(6- > — methylsulfanyl-pyridin-3-

O-N ylamino)-pyrimidine-5- carbonitrile

B137 AP N ~ 4-[4~(3-Isopropyl- “ TL NN [1,2,4]oxadiazol-5-y1)- x NNN piperidin-1-y1]-6-(6-

H methanesulfonyl-pyridin-3-

CN N . Ea. =) ylamino)-pyrimidine-5- :

O-N carbonitrile

B138 XP a 1-[4-[4-(3-Isopropyl- s TL NSN [1,2,4]oxadiazol-5-y1)-

N” SN piperidin-1-y1]-6-(4-

H Ol methanesulfonyl-phenylamino)- 0 ~ py pyrimidin-5-yI]-cthanone

O-N

O

B139 Uy N ~~ 1-[4-[4-(3-Isopropyl- 7” ~ .

TL N N [1,2,4]oxadiazol-5-y1)-

SSN N piperidin-1-yi]-6-(6-

H Ol methanesulfonyl-pyridin-3- iS > —( ylamino)-pyrimidin-5-y1]-

O-N ethanone

TABLE C

Cmpd# Structure | Chemical Name ~~

Cl N Pi 1-(5-Nitro-6-phenyl-pyrimidin-4-yl)-

N piperidine-4-carboxylic acid ethyl ester

NO, Oo.

O

~~

C2 : NN 1{6-Naphthalen-2-yl-5-nitro-

O 7 N pyrimidin-4-yl)-piperidine-4-carboxylic

NO2 Oo acid ethyl ester

C 3 ~

C3 NN 1-[6-(4-Methanesulfonyl-phenyl)-5- 0 7 ~N nitro-pyrimidin-4-yl]-piperidine-4- 0:8 NO, Oo carboxylic acid ethyl ester o)

FCS .

C4 N N 1-(6-Benzofuran-5-yl-5-nitro-

J ZN pyrimidin-4-y1)-piperidine-4-carboxylic 0 NO, Ow acid ethyl ester 0 — = SA

C5 N N 1-{5-Nitro-6-(3-trifluoromethyl-

FaC ZN phenyl) pyrimidin-4-yl]-piperidine-4-

NO» Oo carboxylic acid ethyl ester © 0

PCS

C6 NN 1-[6<(4-Methoxy-phenyl)-S-nitro-

N pyrimidin-4-yl]-piperidine-4-carboxylic

HCO NO, oO” acid ethyl ester ©

N"SN

C7 i 4~(A-Buty-piperidin-1-yl)-6-furan-3-yl-

SOA S-pitro-pyrimidine = NO, ~

C8 a TN 1-[6-(3-Chloro-phenyl)-5-nitro-

Oo pyrimidin-4-yl]-piperidine-4-carboxylic

NO, On acid ethyl ester } 0) ~~ co oMe N Ph 1-[6-(2,6-Dimethoxy-phenyl)-5-nitro-

PS NY pyrimidin-4-yl]-piperidine-4-carboxylic

A om 0) NNO acid ethyl ester ! 0

N™~N .

C10 [ 1-(6-Naphthalen-1-yl-5-nitro- ® N pyrimidin-4-yl)-piperidine-4-carboxylic

NO, Oo. acid ethyl ester :

J } ~

C11 3 Ph 1-[6-(4-Methylsulfanyl-phenyl)-5-nitro- oL N pyrimidin-4-yl]-piperidine-4-carboxylic s NO, OL” acid ethyl ester ! lo} ~~ .

C12 HN Pi 1-(2',4'-Dihydroxy-5-nitro-

N NY N [4,5 Tbipyrimidiny}-6-yl)-piperidine-4-

H ot Ni NO2 Oo” carboxylic acid ethyl ester

Cap] Swe | Chemical Name

NR

C13 N“=N 1-[6(4-Methanesulfonyl-phenyl)-5-

ZN nitro-pyrimidin-4-y1]-prperidine-4-

Ng NO, Oo carboxylic acid ethyl ester 00 0 . ~

C14 NN 1-[6-(3,5-Ris-trifluoromethyl-phenyl)-

FsC NN 5-nitro-pyrimidin-4-yl]-piperidine-4-

NO, Ou carboxylic acid ethyl ester

CF3 o

C15 Ls NSN 1-(6-Dibenzothiophen-4-yl-5-nitro- ll N pyrimidin-4-y1)-piperidine-4-carboxylic ® NO, Oo ~ acid ethyl ester 0]

NSN

C16 1 1-[6-(3,5-Dimethyl-isoxazol-4-y1)-5-

NT ZN nitro-pyrimidin-4-yl]-piperidine-4- [o) NO, oOo carboxylic acid ethyl ester. 0 ;

NN . . ca

C17 \ 1-(5-Nitro-6-thiophen-2-yl-pyrimidin-4- ‘ ro N yl)-piperidine-4-carboxylic acid ethyl

YY No, ow ester 0 > cig NN | 1-[6+(3,5-Dichloro-phenyl)}-5-nitro- ! ZN . pyrimidin-4-y1]-piperidine-4-carboxylic

NO, ow acid ethyl ester cl o)

C19 &) 0 NON | 1(6-Dibenzofiran-4-yl-5-nitro-

Zz N pyrimidin-4-yl)-piperidine-4-carboxylic ® NO, our acid ethyl ester 6] ~ :

C20 NN 1-[6-(3,5-Dimethyl-phenyl)-5-nitro-

ZN pyrimidin-4-yl]-piperidine-4-carboxylic

NO, Oo acid ethyl ester

Cmpd# | ~~ Structwe | Chemical Name

Pt

C21 NN 1-[6-(4-Acetyl-phenyl)-5-nitro-

ZN pyrimidin-4-yl]-piperidine-4-carboxylic ¢) NO, Oo acid ethyl ester 0 ~

C22 N N 1-[6-(4-Ethanesulfonyl-phenyl)-5-nitro- o | = ZN pyrimidin-4-yl]-piperidine-4-carboxylic o X ge NO, Oo acid ethyl ester

A 0

Par

C23 , N Ph 1{6-(2-Fluoro-biphenyl-4-yl)-5-nitro- ® N pyrimidin-4-y1}-piperidine-4-carboxylic

NO, oOo” acid ethyl ester ® !

P3

C24 UP N Ph 1-[6-(3-Methanesulfonyl-phenyl)-5- - N nitro-pyrimidin-4-yl}-piperidine-4-

NO, ou carboxylic acid ethyl ester 0 : ~~

C25 N Py 1-{6-[4-(2-Carboxy-ethyl)-pheny]-5-

Neogs N nitro-pyrimidin-4-y1}-piperidine-4-

HO,C NO, ou carboxylic acid ethyl ester 0 i”

C26 IR NX 1 1-{6-[4-(2-Methoxycarbonyl-ethyl)- ; YY NT | phenyl]-5-nitro-pyrimidin-4-y1}- ay NO, oe piperidine-4-carboxylic acid methyl = | ester 0] c27 NSN 1-66

PP -{ -[4-(2-Methoxycarbonyl-ethyl)- on N phenyl]-5-nitro-pyrimidin-4-yl}-

MeO,C NO, O._~ | Piperidine-4-carboxylic acid ethyl ester

TABLED

Chemical Name

D1 NSN 1-[5-Nitro-6-(2-trifluoromethyl-

Fs phenylethynyl)-pyrimidin-4-y1}-

NO, Ow piperidine-4-carboxylic acid ethyl ester

Oo

D2 NSN 1-(5-Niitro-6-phenylethynyl- — NY pyrimidin-4-yl)-piperidine-4-

NO, LA ro carboxylic acid ethyl ester oO > .

D3 NON 1-[5-Nitro-6-(4-trifluoromethyl-

ZN phenylethynyl)-pyrimidin-4-yl-

NO, Ow piperidine-4-carboxylic acid ethyl ® ester

FsC o + PC) ]

D4 N N 1-(5-Nitro-6-m-tolylethynyl- 2 YN pyrimidin-4-y1)-piperidine-4-

NO» Oo carboxylic acid ethyl ester 0] ) ~~ :

D5 N N 1-[6-(2 -Fluoro-phenylethynyl)-5-

E ZN nitro-pyrimidin-4-yl]-piperidine-4-

NO; Oo carboxylic acid ethyl ester 0}

Dé N nN | 1-{5-Nitro-6-(3-trifluoromethyl-

CE 2 YN | phenylethynyl)-pyrimidin-4-y1]- aC NO» OL | piperidine-4-carboxylic acid ethyl 0 | ester

TABLE E

- ~

El aR NAN 5-Nitro-4-(5-phenyl-

Oo sPVN NZ [1,3,4]oxadiazol-2-ylsulfanyl)-6-[4-

NO» 5X (pyridin-2-ylsulfanyl)-piperidin-1- yl]-pyrimidine

Some embodiments of the present invention include a pharmaceutical composition comprising at least one compound according to any of the compound embodiments disclosed herein and a pharmaceutically acceptable carrier.

Additionally, compounds of Formula (Ia) encompass all pharmaceutically acceptable solvates, particularly hydrates, thereof. The present invention also encompasses diastereomers as well as optical isomers, e.g. mixtures of enantiomers including racemic mixtures, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds of Formula (Ia). Separation of the individual isomers or selective synthesis of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art.

INDICATIONS

In addition to the foregoing beneficial uses for compounds of the present invention disclosed herein, compounds of the invention are useful in the prophylaxis or treatment of additional diseases. Without limitation, these include the following.

The most significant pathologies in Type II diabetes are impaired insulin signaling at its target tissues (“insulin resistance”) and failure of the insulin-producing cells of the pancreas to secrete an appropriate degree of insulin in response to a hyperglycemic signal.

Current therapies to treat the latter include inhibitors of the B-cell ATP-sensitive potassium: - channel to trigger the release of endogenous insulin stores, or administration of exogenous insulin. Neither of these achieves accurate normalization of blood glucose levels and both carry the tisk of inducing hypoglycemia. For these reasons, there has been intense interest in the development of pharmaceuticals that function ina glucose-dependent action, i.e. potentiators of glucose signaling. Physiological signaling systems which function in this manner are well-characterized and include the gut peptides GLP1, GIP and PACAP. These hormones act via their cognate G-protein coupled receptor to stimulate the production of cAMP in pancreatic B-cells. The increased cAMP does not appear to result in stimulation of insulin release during the fasting or preprandial state. However, a series of biochemical targets of cAMP signaling, including the ATP-sensitive potassium charnel, voltage-sensitive potassium channels and the exocytotic machinery, are modified in such a way that the insulin secretory response to a postprandial glucose stimulus is markedly enhanced. Accordingly, agonists of novel, similarly functioning, B-cell GPCRs, including RUP3, would also stimulate the release of endogenous insulin and consequently promote normoglycemia in Type II diabetes.

Tt is also established that increased cAMP, for example as a result of GLP1 stimulation, promotes B-cell proliferation, inhibits B-cell death and thus improves islet mass.

This positive effect on B-cell mass is expected to be beneficial in both Type II diabetes, where insufficient insulin is produced, and Type I diabetes, where B-cells are destroyed by an inappropriate autoimmune response.

\

T is also well-established that metabolic diseases exert a negative influence on other physiological systems. Thus, there is often the codevelopment of multiple disease states (e.g. type I diabetes, type II diabetes, inadequate glucose tolerance, msulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, obesity or cardiovascular disease in “Syndrome X”) or secondary diseases which clearly occur secondary to diabetes (e.g. kidney disease, peripheral neuropathy). Thus, it is cxpected that effective treatment of the diabetic condition will in tum be of benefit to such interconnected disease states.

Some embodiments of the present invention include a method for prophylaxis or treatment of a metabolic disorder or complications thereof in an individual comprising administering to the individual a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof. In some embodiments, the metabolic disorder or complications thereof is type I, type Il diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia syndrome X, or metabolic syndrome. In some embodiments, the metabolic disorder is type II diabetes. In some embodiments, the metabolic : disorder is hyperglycemia. In some embodiments, the metabolic disorder is hyperlipidemia.

Tn some embodiments, the metabolic disorder is hypertriglyceridemia. In some embodiments, ! the metabolic disorder is type I diabetes. In some embodiments, the metabolic disorder is dyslipidemia. In some embodiments, the metabolic disorder is syndrome X. In some embodiments, the individual is a mammal. In some embodiments, the mammal is a human.

Some embodiments of the present invention include a method of controlling or decreasing weighi gain of an individual comprising administering to the individual a therapeutically effective amount of a compound of the present invention or pharmaceutical composition thereof. In some embodiments, the mdividual is a mammal. In some embodiments, the mammal is a human. In some embodiments, the human has a body mass index of about 18.5 to about 45. In some embodiments, the human has a body mass index of about 25 to about 45. In some embodiments, the human has a body mass index of about 30 to about 45. In some embodiments, the human has a body mass index of about 35 to about 45.

One aspect of the present invention pertains to a compound of Formula (12), as described herein, for use in a method of treatment of the human or animal body by therapy. © Some embodiments of the present invention include a method of modulating a RUP3 receptor comprising contacting the receptor with a compound of the present invention.

Some embodiments of the present invention include a method of modulating a RUP3 receptor in an individual comprising contacting the receptor with a compound of the present , invention. In some embodiments, the compound is an agonist. In some embodiments, the compound is an inverse agonist.

Some embodiments of the present invention include 2 method of modulating 2a RUP3 receptor in an individual comprising contacting the receptor with a compound of the present invention wherein the modulation of the RUP3 receptor is prophylaxis or treatment ofa metabolic disorder and complications thereof. In some embodiments, the metabolic disorder is type I, type II diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypeririglyceridemia, hypercholesterolemia, dyslipidemia syndrome X, or metabolic syndrome. In some embodiments, the metabolic disorder is type II diabetes. In some embodiments, the metabolic disorder is hyperglycemia. In some embodiments, the metabolic disorder is hyperlipidemia. In some embodiments, the metabolic disorder is hypertriglyceridemia. In some embodiments, the metabolic disorder is type I diabetes. In some embodiments, the metabolic disorder is dyslipidemia. Tn some embodiments, the metabolic disorder is syndrome X. In some embodiments, the individual is a mammal. In some embodiments, the mammal is a human.

Some embodiments of the present invention include a method of modulating a RUP3 receptor in an individual comprising contacting the receptor with a compound of the present invention wherein the modulation of the RUP3 receptor controls or reduces weight gain of the « individual. In some embodiments, the individual is a mammal. In some embodiments, the mammal is a human. In some embodiments, the human has a body mass index of about 18.5 to about 45. Tn some embodiments, the human has a body mass index of about 25 to about 45. Tn some embodiments, the human has a body mass index of about 30 to about 45. In "some embodiments, the human has a body mass index of about 35 to about 45.

Some embodiments of the present invention include the use of a compound of the present invention for production of a medicament for use in prophylaxis or treatment of a metabolic disorder. In some embodiments, the metabolic disorder is type TI diabetes, inadequate glucose tolerance, insulin resistance, hyperglycerma, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia syndrome X, or metabolic syndrome.

Some embodiments of the present invention include the use of a compound of the present invention for production of a medicament for use in controlling or decreasing weight gain in an individual. In some embodiments, the individual is a mammal. In some embodiments, the mammal is 2 human. Tn some embodiments, the human has a body mass index of about 18.5 to about 45. In some embodiments, the human has a body mass index of about 25 to about 45. In some embodiments, the human has a body mass index of about 30 to about 45. In some embodiments, the human has a body mass index of about 35 to about 43.

Compounds of the present invention are identified as an agonist or an inverse agonist using methods known to those skilled in art, such as an assay as described in Example 1.

Accordingly, representative examples of compounds of the present invention that are agonists include the following: [6-(4-Benzenesulfonyl-piperidin-1-y1)-5 nitro-pyrimudin-4-yl]-(4-methanesulfonyl-phenyl)- amine; {A-{6-(4-Methanesulfony)-phenylarina)-5-nitro-pyrimidin-4-yl]-piperazin-1-y1}- acetic acid ethyl ester; (2-Fluoro-phenyl)-{5 -nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl}- : pyrimidin-4-yl}-amine; 1-{6-(4-Imidazol-1-y)-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester; 1-[5-Nitro-6-(4-[1,2,4}triazol-1 —yl-phenoxy)-pyrimidin-4-yl]- piperidine-4-carboxylic acid ethyl ester; {6-[4-(4-Fluoro-phenoxy)-piperidin-1 -y1}-5-nitro- pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine; {6-[4-(3- Isopropyl 1,2,4]oxadiazol-5- yl)-piperidin-1-y1}-5 -nitro-pyrimidin-4-yl} -(4-methanesulfonyl-phenyl)-amine; {6-[4-(3-

Cyclopropyl-[1,2 Aloxadiazol-5-y1)-piperidin-1 ~y1}-5-nitro-pyrinidin-4-y1}-(4~ methanesulfonyl-phenyl)-amine; (4-Methanesulfonyl-phenyl)~(5-nitro-6-{4-[3-(3- trifluoromethyl-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl} pyrimidin-4-yl)-amine; {6-[4- (3-Ethyl-{1,2 4]oxadiazol-5-y1)-piperidin-1-y1]-5 -nitro-pyrimidin-4-y1}-(2-fluoro-phenyl)- amine; (2-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(3 -isopropyl-[1,2,4]oxadiazol-5-y1)- piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-amine; {6-[4-(3-Ethyl-[1,2,4]oxadiazol-5-y1)- piperidin-1-y1]-5-nitro-pyrimidin-4-y1} -(2-fluoro-4-methanesulfonyl-phenyl)-amine; (4-

Methanesulfonyl-phenyl)-{5 -nitro-6-[4-(3-propyl-{1,2,4Joxadiazol-5 -yl)-piperidin-1-yl]- pyrimidin-4-y1}-amine; {6-[4-(3 —Cyclopropylmethyl-{1,2,4]oxadiazol-5-yl)-piperidin-1-y1}-5- nitro-pyrimidin-4-y1}-(4-methanesulfonyl-phenyl)-amine; (4-Methanesulfonyl-phenyl)-{5- nitro-6-[4-(pyridin-4-yloxy)-piperidin-1 -yl]-pyrimidin-4-y1}-amine; (4-Methanesulfonyl- phenyl)- {5-nitro-6-[4-(pyrimidin-2-yloxy)-piperidin-1 -yl]-pyrimidin-4-y1}-amine; 1-[6-(4-

Carbamoyimethyl-phcnoxy)-S-nitre-pyrimidin-4-v1] -piperidine-4-carhoxylic acid ethyl ester; 1-{6-[4~(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-phenoxy]-3 -nitro-pyrimidin-4-yl} -piperidine- 4-carboxvlic acid ethyl ester; 4'-[A~(2-Methoxycarbonyl-acetyl)-phenoxy]-3 "-nitro-3,4,5,6- tetrahydro-2H-[1,2 Tbipyridinyl-4-carboxylic acid ethyl ester; {6-[4-(2-Methoxy- phenylsulfanyl)-piperidin-1-y1]-5-nitro-pyrimidin-4-yl} «(4-[1,2,4]triazol-1-yl-phenyl)-amine; 4'-(2-Amino-4-ethanesulfonyl-phenoxy)-3'-nitro-3 4.5, 6-tetrahydro-2H-[1,2'Tbipyridinyl-4- carboxylic acid ethyl ester; 4'-(4-Imidazol-1-yl-phenoxy)-3'-nitro-3 4,5,6-tetrahydro-2H- [1,2'Tbipyridinyl-4-carboxylic acid ethyl ester; (4-Methoxy-2-{5-nitro-6-[4-(pyridin-2- ylsulfanyl)-piperidin-1-y1]-pyrimidin-4-yloxy} -pheny!)-phenyl-methanone; 4-{4-[6-(4-

Cyclopropylmethoxymethyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-phenyl} -butan-2-one; 4-{A-[5 ‘Nitro-6-(4-propoxymethyl-piperidin-1-yl)-pyrimidin-4-yloxy]-phenyl} -butan-2-one; 4-{4-[6-(4-Butoxymethyl-piperidin-1-y1)-5 -nitro-pyrimidin-4-yloxy]-phenyl}-butan-2-one; 4- {4-[6-(4-Tsobutoxymethyl-piperidin-1-y1)-5-nitro-pyrimidin-4-yloxy]} -phenyl}-butan-2-one; {1-[6-(Benzo[ 1,3]dioxol-5-ylamino)-5 -nitro-pyrimidin-4-yl]-piperidin-4-y1} -(4-fluoro- phenyl)-methanone; (2,3-Difluoro-phenyl)- {5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-

§1j-pyrimidin-4-yl} -amine; (2,4-Diftuoro-phenyl)- {5-nitro-6-[4-(pyridin-2-ylsulfanyl)- piperidin-1-ylj-pyrimidin-4-yl} -amine; 1-{2-Nitro-3-[4-(3 -oxo-butyl)-phenoxy]-phenyl}- piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Acetyl-phenoxry)-5 -pitro-pyrimidin-4-y1}- piperidine-4-carboxylic acid ethyl ester; 3'Nitro-2'-[4-(3-0x0-butyl)-phenoxy]-3 4,5,6- tetrahydro-2H-[ 1,4 Thipyridinyl-4-carboxylic acid ethyl ester; 4-(4-{5 ~Nitro-6-[4-(pyridin-2- ylsulfanyl)-piperidin-1-yl}-pyrimidin-4-yloxy} -phenyl)-butan-2-one; 4-(4-{5-Nitro-6-[4-(2- trifluoromethyl-phenoxy)-piperidin-1-yl] -pyrimidin-4-yloxy} -phenyl)-butan-2-one; 4-(4-{6- [4-(3-Methyl-[ 1,2, 4loxadiazol-5-y1)-piperidin-L-yl]-5-nitro-pyrimidin-4-yloxy}-pheny)- butan-2-one; 4-(2,4-Difluoro-phenoxy)-5 —nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl}- pyrimidine; 4-(4- {6-[4-(4-Fluoro-benzoyl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yloxy}- phenyl)-butan-2-one; 4-(4-Methanesulfonyl-phenoxy)-5 -nitro-6-[4-(pyridin-2-ylsulfanyl)- cyclohexyl]-pyrimidine; 4-(4-Methanesulfonyl-phenoxy)-5 -nitro-6-f4<4pyridin-4-ylsulfanyl)- cyclohexyl]-pyrimidine; 4-(4-Methanesulfonyl-phenoxy)-5-nitro-6-(4-phenylsulfanyl- cyclohexyl)-pyrimidine; 1-{6-[(Benzo[ 1,3]dioxol-5-ylmethyl)-amino]-5-nitro-pyrimidin-4- yl} -piperidine-4-carboxylic acid ethyl ester; 1-{6-[4~(1,1-Dioxo-1°-thiomorpholin-4- ylmethyl)-phenylamino]-5-nitro-pyrimidin-4-y1} -piperidine-4-carboxylic acid ethyl ester; 1- [6-(4-Methanesulfonyl-phenylamino)-5 -nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Dimethylsulfamoyl-phenylamino)-5 -nitro-pyrimidin-4-y1]-piperidine-4-- ’ carboxylic acid ethyl ester; 1-[6-(3-Methoxy-phenylamino)-5-nitro-pyrimidin-4-yi}- piperidine-4-carboxylic acid ethyl ester; 1-[6-(2-Methoxy-phenylamino)-5-nitro-pyrimidin-4- yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Methanesulfonyl-phenoxy)-5-nitro- pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-{6-[4-(2-Methoxycarbonyl-acetyl)- phenoxy]-3-nitro-pyrimidin-4-y1}-piperidine-4 carhoxylic acid ethyl ester; 1-[6-(2-Amino-4- ethanesulfonyl-phenoxy)-5-nitro-pyrimidin-4-yl] -piperidine-4-carboxylic acid ethyl ester; 1- [6-(2,5-Dimethoxy-phenylamino)-5 -nitro-pyrimidin~4-yl)-piperidine-4-carboxylic acid ethyl ester; (4 {5-Nitro-6.[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl] pyrimidin-4-ylamino}-pheny])- phenyl-methanone; 1-[6-(4-Cyclohexyl-phenylamino)-5-nitro-pyrimidin-4-y1)-piperidinc-4- carboxylic acid ethyl ester; 1-[5 ~Nitro-6-(4-]1,2,4]triazol-1-yl-phenylamino)-pyrimidin-4-y1]- piperidine-4-carboxylic acid ethyl ester; 1-{5 -Nitro-6-(4-trifluoromethanesulfonyl- phenylamino)-pyrimidin-4-y1]-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(4- [1,2,3]thiadiazol-4-yl-phenylamino)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; [6-(4-Ethoxymethyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yl] -(4-methanesulfonyl-phenyl)- amine; [5-Nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yl]-(4-[1,2,4]triazol-1-y}-phenyl)- amine; {5-Nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl} (4-[1,2 ]triazol- 1-yl-phenyl)-amine; (2-Fluoro-phenyl)- {6-[4-(3-methyl-[1,2,4]oxadiazol-5-y)-piperidin-1- y1]-5-nitro-pyrimidin-4-yl}-amine; (4-Methanesulfonyl-phenyl)-{6-[4-(3-methyl- [1,2,4]oxadiazol-5-y1)-piperidin-1-yl]-5-nitro-pyrimidin-4-y1}-amine; {6-[4-(3-Methyl-

[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-y1} -(4-[1,2 4]triazol-1-yl-phenyl)- amine; (4-Methanesulfonyl-phenyl)-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl}- pyrimidin-4-yl}-amine; (3-Methoxy-phenyl)- {5-nitro-6-[4-(pyridin-2-ylsulfany})-piperidin-1- yl]-pyrimidin-4-yl}-amine; 1-[6-(Benzo[ 1,3]dioxol-5-ylamino)-5-nitro-pyrimidin-4-yl]- piperidine-4-carboxylic acid ethyl ester; 1-[6-(2-Fluoro-phenylamino)-5 -nitro-pyrimidin-4- yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(3 —Fluoro-phenylamino)-5-nitro-pyrimidin- 4-yl}-piperidine-4-carboxylic acid ethyl ester; 146-(3 ,4-Dihydro-2H-benzo[b][ 1,4]dioxepin- : 7-ylamine)-5-nitro-pyrimidin-4-y!]-piperidine-4-carboxylic acid ethyl ester; 1-{6-[4- (Morpholine-4-sulfonyl)-phenylamino]-5-nitro-pyrimidin-4-yl} -piperidine-4-carboxylic acid ethyl ester; Benzo[1,3]dioxol-5-y1-[5 -nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-y1]- arming; (4-Fluoro-phenyl)-{1-[5 nitro-6-(4-[1,2,4]triazol-1 -yl-phenylamino)-pyrimidin-4-y1}- piperidin-4-yl}-methanone; [5-Nitro-6-(4-phenylsulfanyl-piperidin-1-yl)-pyrimidin-4-y1|-(4- [1,2,4]triazol-1-yl-phenyl)-amine; (4-Fluoro-phenyl)-{1-[6-(2-fluoro-phenylamino)-5-nitro- pyrimidin-4-yl]-piperidin-4-yl}-methanone; (4-Methanesulfonyl-phenyl)-[5-nitro-6-(4~ phenylsulfanyl-piperidin-1-yl)-pyrimidin-4-yl]-amine; (4-Methanesulfonyl-phenyl)-{5-nitro- 6-[4-(pyridin-2-yloxy)-piperidin-1-yI]-pyrimidin-4-yl}-amine; (4-Methanesulfonyl-phenyl)- {5-nitro-6-[4-(pyridin-4-ylsulfanyl)-piperidin-1-yl} -pyrimidin-4-yl} -amine; (4-

Methanesulfonyl-phenyl)-{6-[4-(4-methoxy-phenylsulfanyl)-piperidin-1-y1]-5 -nitro- pyrimidin-4-yl}-amine; 2-Methoxy-phenyl)-{5-nitro-6- [4-(pyridin-2-ylsulfanyl)-piperidin-1- y1]-pyrimidin-4-yl}-amine; (4-Methanesulfonyl-phenyl)-(5-nitro-6- {4-[3-(3-trifluoromethyl- pheny1)-[1,2,4Joxadiazol-5-yl]-piperidin-1-y1} -pyrimidin-4-yl)-amine; {6-[4-(3-Ethyl- [1,2,4loxadiazol-5-y1)-piperidin-1-y1}-5 -nitro-pyrimidin-4-y1}-(4-methanesulfonyl-phenyl)- amine; (6-{4-[5-(4-Fluoro-phenyl)-{1,3,4]oxadiazol-2-yl}-piperidin-1 1 S.nitro-pyrimidin- 4-y1)-(4-methanesulfonyl-phenyl)-amine; (4-Methanesulfonyl-phenyl)-[3 -nitro-6-(4-pyridin- 2-ylmethyl-piperidin-1-yl)-pyrimidin-4-yl]-amine; 1-{6-[4-(2,5-Dioxo-imidazolidin-4-y1)- phenoxy]-5 -nitro-pyrimidin-4-y1}-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(4- propionyl-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(4- [1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1- [6-[4-(3-Oxo-butyl)-phenoxy]-5 ~(2,2,2-trifluoro-acetylamino)-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester; 1-[6-(2-Benzoyl-5-methoxy-phenoxy)-5 ~nitro-pyrimidin-4-yl]- piperidine-4-carboxylic acid ethyl ester; 3-Nitro-4'-[4-(3-ox0-butyl)-phenoxy]-3.4.5,6- tetrahydro-2H-[1,2'Tbipyridinyl-4-carboxylic acid ethyl ester; 1-[6-(4-Dimethyl sulfamoyl- phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-{6-[4-(4,5-

Dichloro-imidazol-1-yl)-phenylamino]-5-nitro-pyrimidin-4-yl} -piperidine-4-carboxylic acid ethyl ester; Benzo[ 1,3]dioxol-5-yl-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl}- pyrimidin-4-yl1}-amine; (4-Fluoro-phenyl)-{1-[6-(2-fluoro-phenylamino)-5-nitro-pyrimidin-4- yl]-piperidin-4-y1}-methanone; (2,5-Difluoro-phenyl)- {5-nitro-6-[4-(pyridin-2-ylsulfanyl)-

piperidin-1-y1}-pyrimidin-4-yl} -amine; 1-{5-Nitro-6-[4-(3-oxo-butyl)-phenoxy]-pyrimidin-4- y1}-piperidine-4-carboxylic acid ethyl ester; 4-[4-(3 Jsopropyl-[1,2,4]oxadiazol-5-y1)- piperidin-1-y1}-6-(4-methanesulfonyl-phenoxy)-pyrimdime-5-carbonitrile; 5-[1,3]Dioxolan-2- y1-4-[4-(3-isopropyl-{1,2,4]oxadiazol-5 -yl)-piperidin-1-yl]-6-(4-methanesulfonyl-phenoxy)- pyrimidine; 4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5 ~yl)-piperidin-1-y1]-6-(4-methanesulfonyl- phenoxy)-pyrimidine-5-carbaldehyde; 5-{1,3 {Dioxolan-2-yl-4-[4-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-1-y1}-6-(4-1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidine; 4-)4- (3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl] -6-(4-[1,2,3]thiadiazol-4-yl-phenoxy)- pyrimidine-5-carbaldehyde; 4-[4-(3-Tsopropyl-[1,2,4loxadiazol-5-yl)-piperidin-1-y1]-6-(4- [1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidine-5-carboxylic acid; [4-[4-(3-Isopropyl- [1,2,4]oxadiazol-5-y1)-piperidin-1-yt}-6-(4-[1 2,3]thiadiazol-4-yl-phenoxy)-pyrimidin-5-y1}- methanol; [4-{4-(3 “Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-y1]-6-(4-1,2,3]thiadiazol-4- yl-phenoxy)-pyrimidin-5-ylmethyl]-dimethyl-amine; 4-[4-(3 -Isopropyl-[1,2,4]oxadiazol-5- yl)-piperidin-1-y1]-6-(4-methylsulfanyl-phenylamino)-pyrimidine-5 -carbontirile; 4-[4-(3- '

Tsopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfinyl-phenylamino)- ‘ pyrimidine-5~carbonitrile; (4-Methanesulfonyl-phenyl)-{5-nitro-6-[4-(4-trifluoromethoxy- phenoxy)-piperidin-1-yl}-pyrimidin-4-yl} -amine; 4-J4-(3-Isopropyl-[1,2,4]oxadiazol-5-y)- piperidin-1-yl]-6-(4-methanesulfonyl-phenylamino)-pyrimidine-5-carbonitrile; 1-{1-[6-(2-

Fluoro-4-methanesulfonyl-phenylamino)-5 ~nitro-pyrimidin-4-yl}-piperidin-4-y1} ~hexan-1- one; 1-{1-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-y1}-piperidin-4-yl}- hexan-1-one; {6-[4-(3-tert-Butyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4- y1}-(2-fluoro4-methanesulfonyl-phenyl)-amine; {6-[4~(3-tert-Butyl-[1,2,4]oxadiazol-5-yl)- piperidin-1-y11-5-nitro-pyrimidin-4-y1}(4-methanesnlfonyl-phenyl}-amine; [6-(4-

Benzofuran-2-yl-piperidin-1-y1)-5-nitro-pyrimidin-4-y1]-(4-methanesulfonyl-phenyl)-amine and 5-Nitro-4-(5-phenyl-{1,3,4)oxadiazol-2-ylsulfanyl)-6-[4-(pyridin-2-yisul fanyl)-piperidin- 1-yl]-pyrimidine.

Representative examples of compounds of the present invention that are inverse agonists include the following: 1-{6-[4~(2-Carboxy-ethyl)-phenyl]-5-nitro-pyrimidin-4-yl} -piperidine-4-carboxylic acid ethyl ester; 1-{6-[4-(2-Methoxycarbonyl-ethyl)-phenyl]-5-nitro-pyrimidin-4-y1}- piperidine-4-carboxylic acid methyl ester; 1-{6-[4-(2-Methoxycarbonyl-ethyl)-phenyl]-5 - nitro-pyrimidin~4-y1}-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(2- trifluoromethyl-phenylethynyl)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-(5-

Nitro-6-phenylethynyl-pyrimidin-4-yl)-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6- (4-triflucromethyl-phenylethynyl)-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; 1- (5-Nitro-6-m-tolylethynyl-pyrimidin-4-yl)-piperidine-4-carboxylic acid ethyl ester; 1-[6-(2-

Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-y1}-piperidine-4-

carboxylic acid ethyl ester; 1-[6-(Benzo[1,2,5]oxadiazol-5-yloxy)-5-nitro-pyrimidin-4-yI]- piperidine-4-carboxylic acid ethyl ester; 1-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3- yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid methyl ester; 2,6-Dimethyl-4-[6- (2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yi}-morpholine; 1~{6~ [4-(5-Hydroxy-pyrimidin-2-y1)-phenoxy}-5-nitro-pyrimidin-4-yl} -piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(4-sulfo-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4'-Methoxy-biphenyl-4-yloxy)-5-nitro-pyrimidin-4-yl}-piperidine-4- carboxylic acid ethyl ester; 4-(4,4-Difluoro-piperidin-1-y1)-6-(2-methyl-5-tniflucromethyl-2H- pyrazol-3-yloxy)-5-nitro-pyrimidinc; 1-{5-Nitro-6-[4-(4-oxo-cyclohexyl)-phenoxy]- pyrimidin-4-y1}-piperidine-4-carboxylic acid ethyl ester; 1-{6-[4-(2-Hydroxy-ethyl)- phenoxy]-5-nitro-pyrimidin-4-y1}-piperidine-4-carboxylic acid ethyl ester; 1-[6~(2-Methyl-5- trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl}-piperidine-3-carboxylic acid ethyl ester; 1-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]- piperidine-4-carboxylic acid ethylamide; 1-[6-(2-Methyl-5-phenyl-2H-pyrazol-3 -yloxy)-5- " nitro-pyrimidin-4-yl1]-piperidine-4-carboxylic acid ethyl ester; 4-(2-Methyl-5-trifluoromethyl- 2H-pyrazol-3-yloxy)-5-nitro-6-~piperidin-1-yl-pyrimidine; 1-[5-Acetylamino-6-(2-methyl-5- triftuoromethyl-2H-pyrazol-3-yloxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[5 ‘Diacetylamino-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3 yloxy)-pyrimidin-4-yl]- piperidine-4-carboxylic acid ethyl ester; 1-[6-(2-Methyl-S-trifluoromethyl-2H-pyrazol-3- yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid; 1-{5-Nitro-6-[2-(2- triflucromethyl-phenyl)-ethoxy]-pyrimidin-4-y1} -piperidine-4-carboxylic acid ethyl ester; 1- {5-Nitro-6-[2-(3-trifluoromethyl-phenyl)-ethoxy]-pyrimidin-4-y1} -piperidine-4-carboxylic acid ethyl ester; 1-[5-Di-(methanesulfonyhamino-6-(2-methyl-S-triftucromethyl 2H -pyrazel- 3-yloxy)-pyrimidm-4-y1}-piperidine-4-carboxylic acid ethyl ester; 1-[53-Nitro-6-(3- trifluoromethyl-phenoxy)-pyrimidin-4-y1]-piperidine-4-carboxylic acid ethyl ester; 1-[5-

Methyl-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester; 1-[5-Nitro-6-(2-trifluoromethyl-phenoxy)-pyrimidin-4-y1]- piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(4-trifluoromethyl-phenoxy)-pyrimidin- 4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6~(4-Fluoro-phenoxy)-5-nitro-pyrimidin-4- yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6~(2,5-Dimethyl-2H-pyrazol-3-yloxy)-5-nitro- pyrimidin-4-y1]-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(2-oxo- benzo[1,3]oxathiol-6-yloxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6- (9H-Carbazol-2-yloxy)-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; 1-[5-

Nitro-6-(9-oxo-9H-fluoren-2-yloxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-{5-Amino-6-[4-(3-oxo-butyl)-phenoxy]-pyrimidin-4-y1}-piperidine-4-carboxylic acid ethyl ester; 1-{5-Amino-6-[4-(hydroxy-phenyl-methyl)-phenoxy}-pyrimidin-4-y1}-piperidine-4- carboxylic acid ethyl ester; 1-[6-(6-Chloro-pyridin-3-yloxy)-5-nitro-pyrimidin-4-y1]-

piperidine-4-carboxylic acid ethyl ester; 1-[6-(Benzof1,3]dioxol-5-yloxy)-5-nitro-pyrimidin- 4-y1]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-B enzyloxy-phenoxy)-5-nitro- pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-{6-(4-Bromo-phenoxy)-5-nitro- pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Chloro-phenoxy)-5-nitro- pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Carbamoyl-phenoxy)-5- nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; 1-{6-[4-(2-Methoxy-cthyl)- phenoxy]-S-nitro-pyrimidin-4-y1} -piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Benzoyl- phenoxy)-5-nitro-pyrimidin-4-yl|-piperidine-4-carboxylic acid ethyl ester; 1-{6-[4-(4-

Hydroxy-benzenesulfonyl)-phenoxy] -5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; 1-{5-Amino-6-(2-methyl-5 -trifluoromethyl-2H-pyrazol-3 ~yloxy)-pyrimidin-4-yl]- piperidine-4-carboxylic acid ethyl ester; 1-[6-(2-Methyl-5 rifluoromethyl-2H-pyrazol-3- yloxy)-5 -(2,2,2-trifluoro-acetylamino)-pyrimidin-4-yl] -piperidine-4-carboxylic acid ethyl ester; Propionic acid 1-[2-amino-5-formyl-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3- yloxy)-pyrimidin-4-yl]-piperidin-4-yl ester; 4-{6-(2-Methyl-5 Arifluoromethyl-2H-pyrazol-3- yloxy)-5-nitro-pyrimidin-4-yl]-piperazine-1-carboxylic acid ethyl ester; 1-[6-(4'-Cyano- biphenyl-4-yloxy)-5 -nitro-pyrimidin-4-y1]-piperidine-4-carboxylic acid ethyl ester; {4-[6- (4,4-Difluoro-piperidin-1-y1)-5 -nitro-pyrimidin-4-yloxy]-phenyl}-phenyl-methanone; 3-{4- [6-(4,4-Difluoro-piperidin-1-yl)-5 -nitro-pyrimidin-4-yloxy]-phenyl}-3 -oxo-propionic acid methyl ester; 2-[6-(4,4-Difluoro-piperidin-1-y1)-5 -nitro-pyrimidin-4-yloxy}-5-ethanesulfony}- phenylamine; 4-(4-Cyclopentyl-phenoxy)-6-(4,4-difluoro-piperidin-1-yl)-5-nitro-pyrimidine; 1-[6-(2,6-Dichloro-4-methanesulfonyl-phenoxy)-5 -nitro-pyrimidin-4-y1]-piperidine-4- carboxylic acid ethyl ester; 1-{6-[4-(4-Chloro-benzoy!)-phenoxy]-5-nitro-pyrimidin-4-y1}- piperidine-4-carboxylic acid ethyl ester; 1-{6-T4-( 4-HAydroxy-benzovl)-phenoxy]-5-nitro- pyrimidin-4-y1}-piperidine-4-carboxylic acid ethyl ester; 1-[6(4-Cyanomethyl-phenoxy)-5- nitro-pyrimidin-4-y1}-piperidine-4-carboxylic acid ethyl ester; (4-{6-[4-(2-Methanesulfonyl- ethyl)-piperazin-1-yl]-3-nitro-pyrimidin-4-yloxy} -phenyl)-phenyl-methanone; 4-(4-{6-[4-(2-

Methanesulfonyl-ethyl)-piperazin-1-yl]-5-nitro-pyrimidin-4-yloxy} -phenyl)-butan-2-one; 3~ (4-{6-14-(2-Methanesulfonyl-ethyl)-piperazin-1-yl]-5 -nitro-pyrimidin-4-yloxy}-phenyl)-3- oxo-propionic acid methyl ester; 4-(4-Methyl-piperidin-1-y1)-6-(2-methyl-5-trifluoromethyl- 2H-pyrazol-3-yloxy)-5-nitro-pyrimidine; 4~(4-Bromo-piperidin-1 -y1)-6-(2-methyl-5- trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidine; 4-(2-Methyl-5 ~trifluoromethyl-2H- pyrazol-3-yloxy)-5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidine; 1-{5 -Nitro-6-(2- trifluoromethyl-benzyloxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[5-

Nitro-6-(3-trifluoromethyl-benzyloxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(4-trifluoromethyl-benzyloxy)-pyrimidin-4-yl] -piperidine-4-carboxylic acid ethyl ester; 1-]5-Bromo-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-pyrimidin- 4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(2-Methyl-5 Arifluoromethyl-2H-pyrazol-

3.yloxy)-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid amide; 1-{5-Nitro-6-(2-oxo- 2H-chromen-6-yloxy)-pyrimidin-4-yl] -piperidine-4-carboxylic acid ethyl ester; 1-{6-(3-

Morpholin-4-yl-phenoxy)-5 _nitro-pytimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1- £5. Nitro-6-(4-triftuoromethylsulfanyl-phenoxy)-pyrimidin-4-yl]- piperidine 4-carboxylic acid ethyl ester; 1-5 Nitro-6-(4-trifluoromethoxy-phenoxy)-pyrimidin-4-yl|-piperidine-4- carboxylic acid ethyl ester; 1-[6-(4-Benzoyl-phenoxy)-5 -(2,2,2-rifluoro-acetylamino)- pyrimidin-4-y1]-piperidine-4-carboxylic acid ethyl ester; {4-[5 “Nitro-6-(4-propyl-piperidin-1- yl)-pyrimidin-4-yloxy|-phenyl}-phenyl-methanone; {4-Methoxy-2-[5-nitro-6-(4-propyl- piperidin-1-yl)-pyrimidin-4-yloxy} -phenyl}-phenyl-methanone; 4-{4-[5-Nitro-6-(4-propyl- piperidin-1-y1)-pyrimidin-4-yloxy]-phenyl}-butan-2-one; 5-Nitro-4-(4-propyl-piperidin-1-y1)- 6-(4-[1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidine; 3.-{4-[5-Nitro-6-(4-propyl-piperidin-1 y)- pyrimidin-4-yloxy]-phenyl}-3-oxo-propionic acid methyl ester; 5-Ethanesulfonyl-2-[5-nitro- 6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yloxy|-phenylamine; Benzo[1,3]dioxol-5-yl-[5-nitro- 6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yl}-amine; 1-[6-(4-Difluoromethoxy-benzyloxy)-5- nitro-pyrimidin-4-y1]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(3-Fthynyl-phenoxy)-5- nitro-pyrimidin-4-y1]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Chloro-2-fluoro- phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(2,4-Difluoro- phenoxy)-5-nitro-pyrimidin-4-yl] -piperidine-4-carboxylic acid ethyl ester; 1-[6~(4-Bromo-2- fluoro-phenoxy)-5 -nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; 4-(3-

Ethyny!-phenoxy)-5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidine; 4-(4-Chloro-2-fluoro- phenoxy)-5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidine; 4~(2,4-Difluoro-phenoxy)-5-nitro-6- (4-propyl-piperidin-1-yl)-pyrimidine;1-[6-(3 Difluoromethoxy-benzyloxy)-5-nitro-pyrimidin- 4-yij-piperidine-4-carbuxylic acid ethyl oster; ATA (A Methyl-benzyl)-pineridin-1 y11-6-(2- methyl-3-trifluoromethyl-2H-pyrazol-3 -yloxy)-5-nitro-pyrimidine; 4-(3-Methanesulfonyl- pyrrolidin-1-y1)-6-(2-methyl-5 -rifluoromethyl-2H-pyrazol-3 -yloxy)-5-nitro-pyrimidine; 4-(2-

Methyl-5-trifluoromethyl-2H-pyrazol-3 -yloxy)-5-nitro-6- [4-(2-trifluoromethyl-phenoxy)- piperidiri-1-yl]-pyrimidine; 4-(2-Methyl-S rifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-6-[4- (pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidine; 1-[6-(4-Cyclopentyl-phenoxy)-5-nitro- pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-5 -Nitro-6~(4-pyrrol-1-yl- phenoxy)-pyrimidin-4-yl] -piperidine-4-carboxylic acid ethyl ester; 4'-(4-Benzoyl-phenoxy)- 3'nitro-3,4,5 ,6-tetrahydro-2H-[1,2"Tbipyridinyl-4-carboxylic acid ethyl ester; 4-(2-Methyl-5- trifluoromethyl-2H-pyrazol-3-yloxy)-5 ~nitro-6-(4-trifluoromethyl-piperidin-1-yl)-pyrimidine; 4-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5 -nitro-6-(4-phenylsulfanyl-piperidin-1- yl)-pyrimidine; 4-(4-Bromo-2-fluoro-phenoxy)-5 -nitro-6-(4-propyl-piperidin-1-yl)- pyrimidine; 4-[4-(3"Nitro-4-propyl-3,4,5,6-tetrahydro-2H-[ 1,4 Tbipyridinyl-2"-yloxy)- phenyl]-butan-2-one; 2'-(4-Benzoyl-phenoxy)-3'-nitro-3 ,4,5,6-tetrahydro-2H- [1,4'Tbipyridinyl-4-carboxylic acid ethyl ester; (5-Nitro-6-piperidin-1-yl-pyrimidin-4-y1)-(3-

trifluoromethyl-benzyl)-amine; 1.5-Nitro-6-(2-trifluoromethyl-benzylamino)-pyrimidin-4- y1]-piperidine-4-carboxylic acid ethyl ester; 1-3 Nitro-6-(4-trifluoromethyl-benzylamino)- pyrimidin-4-y1]-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(3-trifluoromethyl- benzylamino)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; (5-Nitro-6-piperidin- 1-yl-pyrimidin-4-y1)-(2-trifluoromethyl-benzyl)-amine; [4-(3'-Nitro-4-propyl-3 ,4,5,6- tetrahydro-2H-[ 1,4 Tbipyridinyl-2"-yloxy)-phenyl]-phenyl-methanone; (4-{6-14-(3-Methyl- 11,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5 -nitro-pyrimidin-4-yloxy} -phenyl)-phenyl-methanone; 1-{6-[4-(4-Fluoro-benzoyl)-phenoxy]-5 -nitro-pyrimidin-4-y!} -piperidine-4-carboxylic acid otha cster, (4-Fhuoro-phenyl)-{4-[5-nitro-6-(4- propyl piperidin-1-y1)-pyrimidin-4-yloxy]- phenyl}-methanone; 4-[4-(3-Methyl-{1 ,2,4]oxadiazol-5-yl)-piperidin-1-yl] -6-(2-methyl-5- trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidine; 4-(4-Methoxymethyl-piperidin-1- y1)-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3 -yloxy)-5-nitro-pyrimidine; 4-{4-[6-(4-

Methoxymethyl-piperidin-1-y1)-5-nitro-pyrimidin-4-yloxy]-phenyl} -butan-2-one; 1-{5-Nitro- 6-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenylamino] -pyrimidin-4-y1} -piperidine-4-carboxylic acid ethyl ester; 1-(5 “Nitro-6-phenyl-pyrimidin-4-yl)-piperidine-4-carboxylic acid ethyl ester; 1~ (6-Naphthalen-2-y1-5 -nitro-pyrimidin-4-y1)-piperidine-4-carboxylic acid ethyl ester; 4-[4-(2-

Methoxy-ethyl)-piperidin-1-y1}-6-(2-methyl-5 -triftuoromethyl-2H-pyrazol-3-yloxy)-5-nitro- pyrimidine; 4- {4-[6-(4-Bthoxymethyl-piperidin-1-yI)-5 -nitro-pyrimidin-4-yloxy]-phenyl}- butan-2-one; 4.[4-(3"Nitro-4-propyl-3,4,5,6-tetrahydro-2H-[1 2 Toipyridinyl-4'-yloxy)- phenyl}-butan-2-one; 31.Nitro-4-propyl-4'-(4-]1,2,4]triazol-1-yl-phenoxy)-3,4,5,6-tetrahydro- 2H-[1,2"Tbipyridinyl; 1-{3 -(4-Benzoyl-phenoxy)-2-nitro-phenyl]-piperidine-4-carboxylic acid ethyl ester; {4-[6-(4-Ethoxy-piperidin-1 ~y1)-5-nitro-pyrimidin-4-yloxy]-phenyl} -(4-fluoro- ' phcnyl)-methanone; 1-16-(2-Methyl-5-frifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro- pyrimidin-4-y1]-piperidin-4-ol; 2-{1-[64(2-Methyl-5 Arifluoromethyl-2H-pyrazol-3-yloxy)-3- nitro-pyrimidin-4-yl}-pipenidin-4-yl} —ethanol; 3-{1-[6-(2-Methyl-5-trifluoromethyl-2H- pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperidin-4-yl}-propionic acid; (1-{6-[4-(4-Fluoro- benzoyl)-phenoxy]-5 -nitro-pyrimidin-4-y1}-piperidin-4-y1)-(4-fluoro-phenyl)-methanone; 1- [5 Nitro-6-(4-trifluoromethylsulfanyl-phenoxy)-pyrimidin-4-y1] -piperidine-4~carboxylic acid ethyl ester; 1-[5-Nitro-6-(3 ,4,5-trimethoxy-benzylamino)-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester; (5-Nitro-6-piperidin-1 ~yl-pyrimidin-4-y1)-(4-trifluoromethyl- benzyl)-amine; 1-[5 -Amino-6-(3-trifluoromethyl-benzylamino)-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester; 1-[5 -Amino-6-(4-trifluoromethyl-benzylamino)-pyrimidin-4-y1}- piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Bromo-phenylamino)-5-nitro-pyrimidin-4- yl}-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(4-trifluoromethyl-phenylamino)- pyrimidin-4-y1]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(Methyl-phenyl-amino)-5-nitro- pyrimidin-4-y1]-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(4-trifluoromethoxy- phenylamino)-pyrimidin-4-y1}-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Fluoro-

\ phenylamino)-5 -nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-{6-[(2,3-

Dihydro-benzo[ 1,4]dioxin-6-ylmethyl)-amino]-5-nitro-pyrimidin-4-yl} -piperidine-4- carboxylic acid ethyl ester; 1-{6-[(2,3 “Dihydro-benzo[ 1 4]dioxin-2-ylmethyl)-amino]-5-nitro- pyrimidin-4-y1} -piperidine-4-carboxylic acid ethyl ester; 1-{6-[(2.3 _Dihydro-benzofuran-5- ylmethy!)-amino]-5-nitro-pyrimidin-4-y1} -piperidine-4-carboxylic acid ethyl ester; 1-{6-[(6-

Fluoro-4H-benzo[ 1,3]dioxin-8-ylmethyl)-amino}-5 -nitro-pyrimidin-4-y1}-piperidine-4- carboxylic acid ethyl ester; 1-[6-(2,2-Difluoro-benzo[1,3]dioxol-4-ylamino)-5-nitro- } pyrimidin-4-yi]-piperidine-4-carboxylic acid ethyl ester; 1-{6-(2,2-Difluoro-benzo[1,3]dioxol- 5-ylamino)-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; 1{6-(1,1-Dioxo 1H-1A-benzo[b]thiophen-6-ylamino)-5-nitro-pyrimidin-4-y1]-piperidine-4-carboxylic acid ethyl ester; 1-{6-[(Furan-3-ylmethyl)-amino]-5 -nitro-pyrimidin-4-yl} -piperidine-4-carhoxylic acid ethyl ester; 1-{6-[2-(4-Methoxy-phenoxy)-ethylamino]-5 -nitro-pyrimidin-4-yl}- piperidine-4-carboxylic acid ethyl ester; 1-{6-[2-(5-Methoxy-1H-indol-3-y1)-ethylamino]-5- nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; (3,4-Dihydro-2H- benzo[b][1,4]dioxepin-7-y1)-[5-nitro-6-(4-propyl-piperidin-1-y1)-pyrimidin-4-y1]-amine; (3-

Fluoro-phenyl)-[5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yl}-amine; (3-Methoxy- phenyl)-[5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yl]-amine; 1-{6-[(3-Fluoro-phenyl)- methyl-amino]-5-nitro-pyrimidin-4-y1} -piperidine-4-carboxylic acid ethyl ester; 1-[6-(4~ - Benzoyl-phenylamino)-5-nitro-pyrimidin-4-y1} -piperidine-4-carboxylic acid ethyl ester; 1-[6- (3,5-Bis-trifluoromethyl-phenylamino)-5 -nitro-pyrimidin-4-yl] -piperidine-4-carboxylic acid ethyl ester; 1-[6-(3,5-Dimethoxy-benzylamino)-5-nitro-pyrimidin-4-y1]-piperidine-4- carboxylic acid ethyl ester; 1-[6-(4-Heptyl-phenylamino)-5 -nitro-pyrimidin-4-yl]-piperidine- 4-carboxylic acid ethyi ester; 2'-(4-Benzoyl-phenylamino)-3'-nitro-3,4,5 ,G-tetrahydro-2H- [1,4 Tbipyridinyl4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(3,4,5-trimethoxy-phenylamino)- pyrimidin-4-y1]-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(4-pentyl- phenylamino)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-{6-[4-(3-Carboxy- . propyl)-phenylamino]-5-nitro-pyrimidin-4-y1} -piperidine-4-carboxylic acid ethyl ester; [S-

Nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yl]-(3,4,5-trimethoxy-benzyl)-amine; (3,5-

Dimethoxy-benzyl)-[5-nitro-6-(4-propyl-piperidin-1-yI)-pyrimidin-4-yl]-amine; (4-{5-Nitro- 6-[4-(2-trifluoromethyl-phenoxy)-piperidin-1-yl}-pyrimidin-4-ylamino} -phenyl)-phenyl- methanone; 1-[6-(3,5-Difluoro-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(3,5-Dichloro-phenylamino)-5 -nitro-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester; 1-[6-(2-Bromo-4-trifluoromethoxy-phenylamino)-5-nitro- pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-{6-[(2-Fluoro-phenyl)-methyl- amino]-5-nitro-pyrimidin-4-yl} -piperidine-4-carboxylic acid ethyl ester; 1-[6-(Ethyl-phenyl- amino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-{6-[(4-Chloro- phenyl)-methyl-amino}-5-nitro-pyrimidin-4-y1} -piperidine-4-carboxylic acid ethyl ester; 1-[6-

(4-Difluoromethyl-benzylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Cyano-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6~(3,5-Dimethoxy-phenylamino)-S-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6~(4-sec-Butyl-phenylamino)-5-nitro-pyrimidin-4-y1]-piperidine-4- carboxylic acid ethyl ester; 1-{6-[4-(Cyano-phenyl-methyl)-phenylamino]-5-nitro-pyrimidin- 4-y1}-piperidine-4-carboxylic acid ethyl ester; 1-{5-Nitro-6-[4-(4-trifluoromethyl-phenoxy)- phenylamino]-pyrimidin-4-yl} -piperidine-4-carboxylic acid ethyl ester; 1-[6-(2-Methyl-5- phenyl-2H-pyrazol-3-ylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Renzenesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(2-trifluoromethyl-3H-benzoimidazol-5-ylamino)-pyrimidin-4- yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Methanesulfonyl-phenyl)-5-nitro- pyrimidin-4-yl}-piperidine4-carboxylic acid ethyl ester; 1-(6-Benzofuran-5-yl-5-nitro- pyrimidin-4-yl)-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(3-triflucromethyl- phenyl)-pyrimidin-4-y1}-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Methoxy-phenyl)-5- nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 4-(4-Butyl-piperidin-1-y1)-6- furan-3-yl-5-nitro-pyrimidine; 1-[6~(3-Chloro-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4- - carboxylic acid ethyl ester; 1-[6-(2,6-Dimethoxy-phenyl)-5 -nitro-pyrimidin-4-yl]-piperidine- 4-carboxylic acid ethyl ester; 1-(6-Naphthalen-1-yl-5-nitro-pyrimidin-4-yl)-piperidine-4- carboxylic acid ethyl ester; 1-[6-(4-Methylsulfanyl-phenyl)-5 -nitro-pyrimidin-4-y1]- piperidine-4-carboxylic acid ethyl ester; 1-(2'4'-Dihydroxy-5-nitro-[4,5"Tbipyrimidinyl-6-y1)- piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Methanesulfonyl-phenyl)-5 -nitro-pyrimidin- 4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(3,5 -Bis-trifluoromethyl-phenyl)-5-nitro- pyrimidin-4-y1]-piperidine-4-carboxylic acid ethyl ester; 1-(6-Dibenzothiophen-4-y1-5-nitro- pyrimidin-4-y1)-piperidine-4-carboxylic acid ethyl ester; 4-( 2.4-Difluoro-phenoxy)-6-(4- ethoxymethyl-piperidin-1-yl)-5-nitro-pyrimidine; 1-{4- [6-(4-Methoxymethyl-piperidin-1-yi)- 5-nitro-pyrimidin-4-yloxy]-phenyl} -ethanone; 4-{4-[2-Nitro-3-(4-propyl-piperidin-1 yl) phenoxy]-phenyl}-butan-2-one; 1-{4~[2-Nitro-3-(4-propyl-piperidin-1-yl)-phenoxy] -phenyl}- ethanone; {4-[2-Nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-phenyl} -phenyl-methanone; 3- {4-[2-Nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-phenyl} -3-oxo-propionic acid methyl ester; (4-Fluoro-phenyl)-[4-(3 “nitro-4-propyl-3,4,5,6-tetrahydro-2H-[1,2"Tbipyridinyl-4"-yloxy)- phenyl]-methanone; 1-[6-(3,5-Dimethyl-isoxazol-4-y1)-5-nitro-pyrimidin-4-yl}-piperidine-4- carboxylic acid ethyl ester; 1-(5 -Nitro-6-thiophen-2-yl-pyrimidin-4-yl)-piperidine-4- carboxylic acid ethyl ester; 1-[6-(3,5-Dichloro-phenyl)-5 -nitro-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester; 1-(6-Dibenzofuran-4-yl-5-nitro-pyrimidin-4-y1)-piperidine-4- carboxylic acid ethyl ester; 1-[6-(3,5-Dimethyl-phenyl)-5 -nitro-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester; 1-[6-(4-Acetyl-phenyl)-5 -nitro-pyrimidin-4-y1]-piperidine-4- carboxylic acid ethyl ester; 1-[6-(4-Ethanesulfonyl-phenyl)-5 -pitro-pyrimidin-4-yl}-

piperidine-4-carboxylic acid ethyl ester; 1-[6-(2-Fluoro-biphenyl-4-yl)-5-nitro-pyrimidin-4- yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(3-Methanesulfonyl-phenyl)-5-nitro- pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(2-Fluoro-phenylethynyl)-5- nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester and 1-[5-Nitro-6-(3- trifluoromethyl-phenylethynyl)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester.

Pharmaceutical compositions .

Some embodiments of the present invention include a method of producing a pharmaceutical composition comprising admixing at least one compound according to any of the compound embodiments disclosed herein and a pharmaceutically acceptable carrier.

A compound of the present invention can be formulated into pharmaceutical compositions using techniques well known to those in the art. Suitable pharmaceutically- acceptable carriers, outside those mentioned herein, are available to those in the art; for example, see Remington’s Pharmaceutical Sciences, 16™ Edition, 1980, Mack Publishing Co., (Oslo et al., eds.) and the most current version.

While it is possible that, for use in the prophylaxis or treatment, a compound of the. . “invention may in an alternative use be administered as a raw or pure chemical, it is preferable however to present the compound or active ingredient as a pharmaceutical formulation or composition further comprising a pharmaceutically acceptable carrier.

The invention thus further provides pharmaceutical formulations comprising a compound of the invention or a pharmaceutically acceptable salt or derivative thereof together with one or more pharmaceutically acceptable carriers therefor and/or prophylactic ingredients. The carrier(s) must he "aceentahle” in the sense of heing compatible with the other ingredients of the formulation and not overtly deleterious to the recipient thereof.

Pharmaceutical formulations include those suitable for oral, rectal, nasal, topical (includmg buccal and sub-lingual), vaginal or parenteral (including intramuscular, sub- cutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation.

The compounds of the invention, together with a conventional adjuvant, carrier, or diluent, may thus be placed into the form of pharmaceutical formulations and mit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, gels or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.

For oral admunistration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are capsules, tablets, powders, granules or a suspension, with conventional additives such as lactose, mannitol, corn starch or potato starch; with binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or ' gelatins; with disintegrators such as corn starch, potato starch or sodium carboxymethyl- cellulose; and with lubricants such as talc or magnesium stearate. The active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable pharmaceutically acceptable carrier.

The dose'when using the compounds of Formula (Ia) can vary within wide limits, and as is customary and is known to the physician, it is to be tailored to the individual conditions in each individual case. It depends, for example, on the nature and severity of the illness to be treated, on the condition of the patient, on the compound employed or on whether an acute or chronic disease state is treated or prophylaxis is conducted or on whether further active compounds are administered in addition to the compounds of the Formula (Ia).

Representative doses of the present invention include, about 0.01 mg to about 1000 mg, about 0.01 to about 750 mg, about 0.01 to about 500 mg, 0.01 to about 250 mg, 0.01 mg to about 200 mg, about 0.01 mg to 150 mg, about 0.01 mg to about 100 mg, and about 0.01 mg to about 75 mg. Multiple doses may be administered during the day, especially when relatively large amounts are deemed to be needed, for example 2, 3 or 4, doses. Tf appropriate, depending on individual behavior and as appropriate from the patients physician or care-giver ’ it may be necessary to deviate upward or downward from the daily dose.

The amount of active mgredient, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will ultimately be at the discretion of the attendant physician or clinician. In general, one skilled in the art understands how to extrapolate in vivo data obtained in a model system, typically an animal model, to another, such as a human. Typically, animal models include, but are not limited to, the rodents diabetes models as described in Example 6, infra (other animal models have been reported by Reed and Scribner in Diabetes, Obesity and

Metabolism, 1, 1999, 75-86). In some circumstances, these extrapolations may merely be based on the weight of the animal model in comparison to another, such as a mammal, preferably a human, however, more often, these extrapolations are not simply based on weights, but rather incorporate a variety of factors. Representative factors include the type,

age, weight, sex, diet and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles of the particular compound employed, whether a drug delivery system is utilized, on whether an acute or chronic disease state is being treated or prophylaxis is conducted or on whether further active compounds are administered in addition to the compounds of the Formula (Ia) and as part of a drug combination. The dosage regimen for treating a disease condition with the compounds and/or compositions of this invention is selected in accordance with a variety factors as cited above. Thus, the actual dosage regimen employed may vary widely and thercfore may deviate from a preferred dosage regimen and one skilled in the art will recognize that dosage and dosage regimen outside these typical ranges can be tested and, where appropriate, may be used in the methods of this invention.

The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations. The daily dose can be divided, especially when relatively large amounts are administered as deemed appropriate, into several, for example 2, 3 or 4, part administrations.

If appropriate, depending on individual behavior, it may be necessary to deviate upward or downward from the daily dose indicated.

The compounds of the present invention can be administrated in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either a compound of the invention or a pharmaceutically acceptable salt of a compound of the invention.

For preparing pharmaceutical compositions from the compounds of the present . invention, the selection of a suitable pharmaceutically acceptable carrier can be either solid, liquid or a mixture of both. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component.

In tablets, the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted to the desire shape and size.

The powders and tablets may contain varying percentage amounts of the active compound. A representative amount in a powder or tablet may contain from 0.5 to about 90 percent of the active compound; however, an artisan would know when amounts outside of this range are necessary. Suitable carriers for powders and tablets are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low meltmg wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it.

Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.

For preparing suppositories, a low melting wax, such as an admixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogenous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.

Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable dituent or solvent, for example, as a solution in 1 3-hutanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The compounds according to the present invention may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The pharmaceutical compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilizing and thickening agents, as desired.

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

Also included are solid form preparations which are intended to be converted, shorfly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and ermulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

For topical administration to the epidermis the compounds according to the invention may be formulated as ointments, creams or lotions, or as a transdermal patch.

Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated. . with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.

Formulations suitable for topical administration in the mouth include lozenges comprising active agent in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray. The formulations may be provided in single or multi-dose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension.

In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump.

Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurized pack with a suitable propellant. If the compounds of the Formula (Ia) or pharmaceutical compositions comprising them are administered as aerosols, for example as nasal aerosols or by inhalation, this can be carried out, for example, using a spray, a nebulizer, a pump nebulizer, an inhalation apparatus, a metered inhaler or a dry powder inhaler. Pharmaceutical forms for administration of the compounds of the Formula (Ia) as an aerosol can be prepared by processes well-known to the person skilled in the art. For their preparation, for example, solutions or dispersions of the compounds of the Formula (Ia) in water, water/alcohol mixtures or suitable saline solutions can be employed using customary additives, for example benzyl alcohol or other suitable preservatives, absorption ethancers for increasing the bioavailability, solubilizers, dispersants and others, and, if appropriate, customary propellants, for example include carbon dioxide,

CEC’s, such. as, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane; and the like. The aerosol may conveniently also contain a + surfactant such as lecithin. The dose of drug may be controlled by provision of a metered valve.

In formulations intended for administration to the tespiratory tract, including intranasal formulations, the compound will generally have a small particle size for example of the order of 10 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization. When desired, formulations adapted to give sustained release of the active ingredient may be employed.

Alternatively the active ingredients may be provided in the form of a dry powder, for example, a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethy! cellulose and polyvinylpyrrolidone (PVP).

Conveniently the powder carrier will form a gel in the nasal cavity. The powder composition . may be presented in unit dose form for example in capsules or cartridges of; e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.

The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing i discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge fisclf or it can be the appropriate number of any of these in packaged form. :

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

The term "prodrug" refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems,"

Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed.

Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference.

Combination Therapy/Prophylaxis

While the compounds of the invention can be administered as the sole active pharmaceutical agent as described herein above, they can also be used in combination with one or more agents belonging to the class of drugs known as a-glucosidase inhibitors, aldose reductase inhibitors, biguanides, HMG-CoA reductase inhibitors, squalene synthesis inhibitors, fibrate compounds, LDL catabolism enhancers and angiotensin converting enzyme (ACE) inhibitors. a.-Glucosidase inhibitors belong to the class of drugs which competitively inhibit digestive enzymes such as a-amylase, maltase, o-dextrinase, sucrase, etc. in the pancreas and or small intesting. The reversible inhibition by a-glucosidase inhibitors retard, diminish or otherwise reduce blood glucose levels by delaying the digestion of starch and sugars. Some representative examples of o-glucosidase inhibitors include acarbose, N-(1,3-dihydroxy-2- propyl)valiolamine (generic name; voglibose), miglitol, and a-glucosidase inhibitors known in the art.

The class of aldose reductase inhibitors are drugs which inhibit the first-stage rate- limiting enzyme in the polyol pathway that prevent or arrest diabetic complications. In the hyperglycemic state of diabetes, the utilization of glucose in the polyol pathway is increased and the excess sorbitol accumulated intracellularly as a consequence acts as a tissue toxin and hence evokes the onset of complications such as diabetic neuropathy, retinopathy, and nephropathy. Examples of the aldose reductase inhibitors include tolurestat; epalrestat; 3,4- : dihydro-2,8-diisopropyl-3-thioxo-2H-1,4-benzoxazine-4-acetic acid; 2,7-difluorospiro(OH- fluorene-9,4'-imidazolidine)-2',5"-dione (generic name: imirestat); 3-[(4-bromo-2- flurophenyl)methy]-7-chloro-3,4-dihydro-2,4-dioxo-1(2H)-quinazoline acetic acid (generic name: zenarestat); 6-fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1 -benzopyran-4,4'- imidazolidine]-2-carboxamide (SNK-860); zopolrestat; sorbinil; and 1-[(3-bromo-2- benzofuranyl)sulfonyl]-2,4-imidazolidinedione (M-16209), and aldose reductase inhibitors known in the art.

The biguanides are a class of drugs that stimulate anaerobic glycolysis, increase the sensitivity to insulin in the peripheral tissues, inhibit glucose absorption from the intestine, suppress of hepatic gluconeogenesis, and inhibit fatty acid oxidation. Examples of bignanides include phenformin, metformin, buformin, and biguanides known in the art. .

Statin compounds belong to a class of drugs that lower blood cholesterol levels by inhibiting hydroxymethylglutalyl CoA (HMG-CoA) reductase. HMG-CoA reductase is the rate-limiting enzyme in cholesterol biosynthesis, A statin that inhibits this reductase lowers serum LDL concentrations by upregulating the activity of LDL receptors and responsible for clearing LDL from the blood. Examples of the statin compounds include rosuvastatin, pravastatin and its sodium salt, simvastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin, and HMG-CoA reductase inhibitors known in the art.

Squalene synthesis inhibitors belong to a class of drugs that lower blood cholesterol levels by inhibiting synthesis of squalene. Examples of the squalene synthesis inhibitors include (S)-ai~[Bis[2,2-dimethyl-1-oxopropoxy)methoxy] phosphinyl]-3- phenoxybenzenebutanesulfonic acid, mono potassium salt (BMS-188494) and squalene synthesis inhibitors known in the art.

Fibrate compounds belong to a class of drugs that lower blood cholesterol levels by inhibiting synthesis and secretion of triglycerides in the liver and activating a lipoprotein lipase. Fibrates have been known to activate peroxisome proliferators-activated receptors and induce lipoprotein lipase expression. Examples of fibrate compounds include bezafibrate, beclobrate, binifibrate, ciplofibrate, clinofibrate, clofibrate, clofibric acid, etofibrate, fenofibrate, gemfibrozil, nicofibrate, pirifibrate, ronifibrate, simfibrate, theofibrate, and fibrates known in the art.

LDL (low-density lipoprotein) catabolism enhancers belong to 2 class of dmgs that lower blood cholesterol levels by increasing the number of LDL (low-density lipoprotein) receptors, examples include IDL catabolism enhancers known in the art.

Angiotensin converting enzyme (ACE) inhibitors belong to the class of drugs that partially lower blood glucose levels as well as lowering blood pressure by inhibiting angiotensin converting enzymes. Examples of the angiotensin converting enzyme inhibitors include captopril, enalapril, alacepril, delapril; ramipril, lisinopril, imidapril, benazepril, ceronapril, cilazapril, enalaprilat, fosinopril, moveltopril, perindopril, quinapril, spirapril, temocapril, trandolapril, and angiotensin converting enzyme inhibitors known in the art.

Tnsulin secretion enhancers belong to the class of drugs having the property fo promote secretion of insulin from pancreatic B cells. Examples of the insulin secretion : enhancers include sulfonylureas (SU). The sulfonylureas (SU) are drugs which promote secretion of insulin from pancreatic 3 ceils by transmitting signals of insulin secretion via ST receptors in the cell membranes. Examples of the sulfonylureas include tolbutamide; chlorpropamide; tolazamide; acetohexamide; 4-chloro-N-[(1-pyrolidinylamino) carbonyl]- benzenesulfonamide (generic name: glycopyramide) or its ammonium salt; glibenclamide (elyburide); gliclazide; 1-butyl-3-metanilylurea; carbutamide; glibonuride; glipizide; gliquidone; glisoxepid; glybuthiazole; glibuzole; glyhexamide; glymidine; glypinamide; phenbutamide; tolcyclamide, glimepiride, and other insulin secretion enhancers known in the art. Other insulin secretion enhancers include N-[[4-(1-methylethyl)cyclohexyl)carbonyl}-D- phenylalanine (Nateglinide); calcium (2S)-2-benzyl-3-(cis-hexahydro-2- isoindolinylcarbonyl)propionate dihydrate (Mitiglinide, K AD-1229); and other insulin secretion enhancers known in the art.

Thiazolidinediones belong to the class of drugs more commoningly known as TZDs.

Examples of thiazolidinediones include rosiglitazone, pioglitazone, and thiazolidinediones known in the art.

Some embodiments of the invention include, a pharmaceutical composition comprising a compotmd of Formula (Ia) or a pharmaceutically acceptable salt thereof in combination with at least one member selected from the group consisting of an a-glucosidase inhibitor, an aldose reductase inhibitor, a biguanide, a HMG-CoA reductase inhibitor, a squalene synthesis inhibitor, a fibrate compound, a LDL catabolism enhancer and an "angiotensin converting enzyme inhibitor. In another embodiment, the pharmaceutical composition is a compound of Formula (Ia) or a pharmaceutically acceptable salt thereof in combination with a HMG-CoA reductase inhibitor. In still another embodiment, the HMG-

CoA reductase inhibitor is selected from the group consisting of prevastatin, simvastatin, lovastatin, atorvastatin, fluvastatin and lipitor.

In accordance with the present invention, the combination can be used by mixing the respective active components either all together or independently with a physiologically acceptable carrier, excipient, binder, diluent, etc., as described herein above, and administering the mixture or mixtures either orally or non-orally as a pharmaceutical composition. When a compound or a mixture of compounds of Formula (Ia) are administered as a combination therapy or prophylaxis with another active compound the therapeutic agents can be formulated as a separate pharmaceutical compositions given at the same time or at different times, or the therapeutic agents can be given as a single composition.

Other Utility

Another object of the present invention relates to radiolabelled compounds of

Formula (Ia) that would be usefirl not only in radio-imaging but also in assays, both in vitro and 1n vivo, for focalizing and quantitating KUP3 in. lissue samples, including human, and for identifying RUP3 ligands by inhibition binding of a radiolabelled compound. It is a further object of this invention to develop novel RUP3 assays of which comprise such radiolabelled compounds.

Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to *H (also written as T), 'C, C, °F, "I, ®Br, '*’L, I, 1257 1311 5Br. "Br, 0, 1*N, **S and "Br. The radionuclide that is incorporated in the instant radiolabelled compounds will depend on the specific application of that radiolabelled compound. Thus, for in vitro RUP3 labeling and competition assays, compounds that incorporate *H, “C, 1, I, **S or ®Br will generally be most useful. For radio-imaging . applications ''C, *F, %°L, "21, 1, 1, "Br, "Br or "Br will generally be most useful.

It is understood that a “radio-labelled ” or “labelled compound” is a compound of

Formula (Ia) that has incorporated at least one radionuclide; In some embodiments, the radionuclide is selected from the group consisting of °H, **C, "#1, **S and "Br; In some embodiments, the radionuclide *H or *C. Moreover, it should be understood that all of the atoms represented in the compounds of the invention can be either the most commonly occurring isotope of such atoms or the more scarce radio-isotope or nonradio-active isotope.

Synthetic methods for incorporating radioisotopes into organic compounds including those applicable to those compounds of the invention are well known in the art and include incorporating activity levels of tritium into target molecules include: A. Catalytic

Reduction with Tritium Gas - This procedure normally yields high specific activity products and requires halogenated or unsaturated precursors. B. Reduction with Sodium

Borohydride IH] - This procedure is rather inexpensive and requires precursors containing reducible functional groups such as aldehydes, ketones, lactones, esters, and the like. C.

Reduction with Lithium Aluminum Hydride [*H ] - This procedure offers products at almost theoretical specific activities. It also requires precursors containing reducible functional groups such as aldehydes, ketones, lactones, esters, and the like. D. Tritium Gas Exposure

Labeling - This procedure involves exposing precursors containing exchangeable protons to tritium gas in the presence of a suitable catalyst. E. N-Methylation using Methyl Iodide [’H] - This procedure is usually employed to prepare O-methyl or N-methyl CH) products by treating appropriate precursors with high specific activity methyl iodide CH). This method in general allows for high specific activity, such as about 80-87 Ci/mmol.

Synthetic methods for incorporating activity levels of 1 into target molecules include: A. Sandmeyer and like reactions — This procedure transforms an aryl or heteroaryl amine into a diazonium salt, such as a tetrafluoroborate salt, and subsequently to >I labelled compound using Na'®1. A represented procedure was reported by Zhu, D.-G. and co-workers inJ. Org. Chem. 2002, 67, 943-948. B. Ortho *Todination of phenols — This procedure . allows for the incorporation of 1 at the ortho position of a phenol as reported by Collier, T.

L. and co-workers in J. Labelled Compd Radiopharm. 1999, 42, S264-5266. C. Aryl and heteroaryl bromide exchange with ***I— This method is generally a two step process. The first step is the conversion of the aryl or heteroaryl bromide to the corresponding tri-alkyltin intermediate using for example, a Pd catalyzed reaction [i.e. Pd(Ph;P),] or through an aryl or heteroaryl lithium, in the presence of a tri-alkyltinhalide or hexaalkylditin [e.g., (CH3);SnSn(CH3)s]. A represented procedure was reported by Bas, M.-D. and co-workers in ~~

J. Labelled Compd Radiopharm. 2001, 44, S280-S282.

A radiolabelled RUP3 compound as described herein can be used in a screening assay to identify/evaluate compounds. In general terms, a newly synthesized or identified compound (i.e., test compound) can be evaluated for its ability to reduce binding of the “radiolabelled compound of Formula (Ia)” to the RUP3 receptor. Accordingly, the ability of a test compound to compete with the “radio-labelled compound of Formula (Ia)” for the binding to the RUP3 receptor directly correlates to its binding affinity.

The labelled compounds of the present invention bind to the RUP3 receptor.

In one embodiment the labelled compound has an ICs; less than about 500 pM, in another embodiment the labelled compound has an ICs less than about 100 pM, in yet another embodiment the labelled compound has an ICs less than about 10 pM, in yet another embodiment the labelled compound has an ICs less than about 1 uM, and in still yet another embodiment the labelled inhibitor has an ICs, less than about 0.1

HM.

Other uses of the disclosed receptors and methods will become apparent to those in the art based upon, inter alia, a review of this patent docurnent.

This application claims priority benefit of U.S. Provisional Application Number 60/440,394, filed January 14, 2003; U.S. Provisional Patent Application Number 60/449,829, filed February 24, 2003, U.S. Provisional Patent Application Number 60/453,390, filed March 6, 2003, and U.S. Non-Provisional Patent Application No. 60/470,875, filed May 14, 2003; wherein each are hereby incorporated by reference in their entirety.

The following examples are given to illustrate the invention and are not intended to -. be inclusive in any manner:

EXAMPLES

The compounds of the present invention and their syntheses are further illustrated by the following examples. The examples are provided to further define the invention without, however, limiting the invention to the specifics of these examples.

Example 1 96-well Cyclic AMP membrane assay for RUP3

Materials: 1) Adenlyl cyclase Activation Flashplate Assay kit from Perkin Elmer — 96 wells (SMP004B) and "I tracer (NEX130) which comes with the kit. Keep in refrigerator, in a box, and do not expose the Flashplates to light. 2) Phosphocreatine — Sigma P-7936 3) Creatine Phosphokinase --- Sigma C-3755 4) GTP — Sigma G-8877 5) ATP- Sigma A-2383 : 6) IBMX — Sigma I-7018 7) Hepes — 1M solution in distilled water — Gibco #15630080 8) MgCl2 — Sigma M-1028- 1M Solution 9) NaCl Sigma — $6546 — 5M Solution

10) Bradford Protein Assay Kit — Biorad # 5000001 11) Proclm 300- Sigma #4-8126

Binding Buffer - filter through 45- micron Nalgene filter and keep in refrigerator. All buffers and membranes should be kept cold (in ice bucket) while performing assay. mM Hepes, pH7.4 1 mM MgC12 100 mM NaCl 2X Regeneration Buffer (make in binding buffer): 20 uM Phosphocreatine (1.02 gm/200 ml binding buffer) 20 units Creatine phosphokinase (4 mg/200 ml) 20 uM GTP (make up 10.46 mg/ml in binding buffer and add 200 ul /200 mt) 0.2 mM ATP (22.04 mg/200 mt) . 100 mM IBMX (44.4 mg IBMX dissolved in 1 ml 100% DMSO first and then add the entire amount to 200 ml of buffer).

Regeneration buffer can be aliquotted into 40-45 ml portions (in 50 ml sterile tubes) and kept frozen for up to 2 months. Simply put the tube in a beaker with room temperature water to thaw out the regeneration buffer on the day of the assay. :

A. Assay procedure 1} Pipet 50 ul regeneration buffer in all 96 wells using Matrix 1250 8-channel pipettor. 2) Pipet 5 ul DMSO in columns 1 and columns 11 and 12. 3) Pipet 50 ul cAMP standards in columms 11 and 12 in this format: 50 pmole/well for row A, 25 pmole/well for row B, 12.5 pmol/well for row C, 5 picomol/well for row }

D, 2.5 pmole/well for row E, 1.25 pmole/well for row F, 0.5 pmole/well for row G, and 0 pmole/well (buffer only) for row H. 4) Pipet 5 ul compounds from each well of a compound dilution plate, for IC50s, using the following dilution scheme:

Well H: 400 uM compound (final concentration of compound in reaction mix = 5/100 x 400 uM = 20 uM i

EE _

Well G: 1:10 dilution of Well H (i.e. 5ul compound from well H + 45 ul 100% DMSO) (final concentration = 2 uM)

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

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

Well D: 1:10 dilution of well E (final concentration = 0.002 uM) ‘Well C: 1:10 dilution of well D (final concentration = 0.0002 uM

Well B: 1:10 dilution of well C (final concentration = 0.00002 uM) ’ Well A:1:10 dilution of well B (final concentration = 0.000002 uM)

ICsy8 or ECsps are done in triplicate. One Flashplate can therefore be set up to handle 3 compounds. (i.c., columns 2, 3, and 4 are for compound #1, columns 5, 6, and 7 are - for compound #2, and columns 8, 9, and 10 are for compound #3.) 5) Add 50 ul of RUP3 membranes to all wells inn Columns 2 to 10. (Prior to the start of the assay, the frozen membrane pellets for both RUP3 and CMV (cells transfected with an expression plasmid containing no RUP3 sequences), are suspended in binding buffer, usually 1 ml binding buffer for 1 plate of membranes. The membranes are kept in ice all the time, and a polytron (Brinkmann polytron, model #

PT-3100) is used (setting 6-7, for 15-20 seconds) to obtain a homogeneous membrane suspension.) Protein concentration is determined by Bradford protein assay kit using instructions given in the kit, using the standard supplied with the kit as a reference.

The protein concentration of the membranes is adjusted with binding buffer, so that 50 ul membranes — 15 ug protein (i.e. 0.3 mg/ml protein). 6) Incolumn 1, Wells A, B, C, and D, add 50 ul RUP3 membranes. To wells E, F, G, : and H, add 50 ul CMV membranes, (CMV membranes being of the same protein concentration as the RUP3 membranes). 7) Incubate 1 hour at room temperature with agitation on a rotating platform shaker.

Cover with foil while shaking. 8) After 1 hour, add (to all 96 wells), 100 ul of the '*I tracer in detection buffer supplied with the Flashplate kit plus proclin, made up in the following manner:

Pipet per 10 ml per Flashplate: 100 ml of detection buffer + 1 ml '*I + 0.2 ml of Proclin ( the proclin helps to stop the production of cAMP). Make a smaller quantity of detection buffer mix if you have fewer plates.

PCT/US2004/001267 9) Shake the plates on a rotating platform shaker for 2 hours, covering the plates with lead sheeting. 10) Seal the plates with the plastic film sealers provided with the Flashplate kit. 11) Count the plates using a TRILUX 1450 Microbeta Counter. See the door of the counter to determine which counting protocol to use. 12) Data is analyzed on the Arena Database according to the RUP3 non-fusion, ICs ECs for 96-well cAMP membrane assay, and the compound numbers and the concentrations of compounds must be entered by the user. : }

B. Membrane Cyclase Criteria 1) Signal to Noise: .

An acceptable signal-to-noise ratio for RUP3 can vary from 4 to 6. The raw cpms are approximately 1800 to 2500 for RUP3 and 3500-4500 for CMV. The cpm (or ultimately pmoles of cAMP/well) cannot be outside the standard curve, and should not approach well A of the standard curve (50 pmole/well) and well H (no cAMP).

Generally, the pmoles of cAMP produced by RUP3 receptor are around 11 to 13 pmele/well (for 15 uglwell protein), and for CMV are between 2 to 3 pmolefwell (for ug protein /well). 2) Standard curve:

The slope should be linear and the error bars for duplicates should be very small. The receptor and CMV controls cannot be off scale of the standard curve, as described above. If the receptor controls are off the high end of the standard curve,i.e. 50 + pmole/well or higher, one must repeat the experiment using less protein. However, such a case has not been observed with transiently transfected RUP3 membranes (10 ug DNA/15 cm plate, using 60 ul Lipofectamine, and preparing membranes after 24 hour of transfection.) 3) The ICs, or ECsq curve should be at 100% (+ or — 20%) of control RUP3 membranes at the top, and should go down to 0 (or up to 20%) at the bottom. The standard error of the triplicate determinations should be + or — 10%.

PCT/US2004/001267

C. Stimulation of cAMP in HIT-T15 cells

HIT-T15 (ATCC CRL#1777) is an immortalized hamster insulin-producing cell line.

These cells express RUP3 and therefore can be used to assess the ability of RUP3 ligands to stimulate or inhibit cAMP accumulation via its endogenously expressed receptor. In this assay, cells are grown to 80% confluence and then distributed into a 96-well Flashplate (50,000 cells/ well) for detection of cAMP via a “cAMP Flashplate Assay” (NEN, Cat #

SMP004). Briefly, cells are placed into anti-cAMP antibody-coated wells that contain either vehicle, the test ligand(s) at a concentration of interest, or 1 uM forskolin. The latter is a direct activator of adenylyl cyclase and serves as a positive control for stimulation of cAMP in HIT-T15 cells. All conditions are tested in triplicate. After a 1 hour incubation to allow for stimulation of cAMP, a Detection Mix containing ***I-cAMP is added to each well and the plate is allowed to incubate for another 1 hour. The wells are then aspirated to remove unbound *I-cAMP. Bound "*T-cAMP is detected using a Wallac Microbeta Counter. The : amount of cAMP in each sample is determined by comparison to a standard curve, obtained. by placing known concentrations of cAMP in some wells on the plate.

D. Stimulation of insulin secretion in HIT-T1S5 cells :

It is known that stimulation of cAMP in HIT-T'15 cells causes an increase in insulin secretion when the glucose concentration in the culture media is changed from 3mM to 15 mM. Thus, RUP2 ligands can also be tested for their ability to stimulate glucose-dependent insulin secretion (GSIS) in HIT-T15 cells. In this assay, 30,000 cells/well in a 12-well plate are incubated in culture media containing 3 mM glucose and no serum for 2 hours. The media is then changed; wells receive media containing either 3 mM or 15 mM glucose, and in both cases the media contains either vehicle (DMSO) or RUP3 ligand at a concentration of interest. Some wells receive media containing 1 uM forskolin as a positive control. All conditions are tested in triplicate. Cells are incubated for 30 minutes, and the amount of insulin secreted into the media is determined by ELISA, using a kit from either Peninsula

Laboratories (Cat # ELIS-7536) or Crystal Chem Inc. (Cat # 90060).

E. Stimulation of insulin secretion in isolated rat islets

As with HIT-T15 cells, it is known that stimulation of cAMP in isolated rat islets causes an increase in insulin secretion when the glucose concentration in the culture media is changed from 60 mg/dl to 300 mg/dl. RUP3 is an endogenously expressed GPCR in the

T/US2004/001267 insulin-producing cells of rat islets. Thus, RUP3 ligands can also be tested for their ability to . stimulate GSIS in rat islet cultures. This assay is performed as follows:

A. Select 75-150 islet equivalents (TEQ) for each assay condition using a dissecting microscope. Incubate overnight in low-glucose culture medium. (Optional.)

B. Divide the islets evenly into triplicate samples of 25-40 islet equivalents per sample. Transfer to 40 jm mesh sterile cell strainers in wells of a 6-well plate with 5 ml of low (60 mg/dl) ghicose Krebs-Ringers Buffer (KRB) assay medium.

C. Incubate 30 minutes (1 hour if overnight step skipped) at 37°C and 5% CO,.

Save the supernatants if a positive control for the RIA is desired.

D. Move strainers with islets to new wells with 5ml/well low glucose KRB. This is the second pre-incubation and serves to remove residual or carryover insulin from the culture medium. Incubate 30 minutes.

E. Move strainers to next wells (Low 1) with 4 or 5 ml low glucose KRB. Incubate @ 37° C for 30 minutes. Collect supernatants into low-binding polypropylene - tubes pre-labelled for identification and keep cold.

F. Move strainers to high glucose wells (300mg/dl, which is equivalent to ’ 16.7mM). Incubate and collect supernatants as before. Rinse islets in their strainers in low-glucose to remove residual insulin. If the rinse if to be collected for analysis, use one rinse well for each condition (i.e. set of triplicates.)

G. Mave strainers to final wells with low-glucose assay medinm (Low 2). Incubate and collect supernatants as before.

H. Keepmg cold, centrifuge supernatants at 1800rpm for 5 minutes @ 4-8°C to remove small islets/islet pieces that escape the 40mm mesh. Remove all but lower 0.5 — 1 ml and distribute in duplicate to pre-labelled low-binding tubes.

Freeze and store at <-20° C until insulin concentrations can be determined.

I Insulin determinations are done as above, or by Linco Labs as a custom service, using their rat insulin RIA (Cat. # RI-13K).

Example 2

A. RT-PCR analysis of RUP3 expression in human tissues (Figure 1A).

RT-PCR was applied to determine the tissue distribution of RUP3. Oligonucleotides used for PCR had the following sequences: 7047: 5°-CATTGCCGGGCTGTGGTTAGTGTC-3’ (forward primer), (SEQID

NO:3); : 7048: 5’-GGCATAGATGAGTGGGTTGAGCAG:3® (reverse primer), (SEQ ID

NO:4); . and the human multiple tissue cDNA panels (M1C, Clontech) were used as templates (1 ng cDNA per PCR amplification). Twenty-two (22) human tissues were analyzed. PCR. was performed using Platinum PCR SuperMix (Life Technologies, Inc.; manufacture instructions were followed) in a 50 pl reaction by the following sequences: step 1, 95°C for 4 min; step 2, 95°C for 1 min; step 3, 60°C for 30 sec; step 4, 72°C for 1 min; and step 5, 72°C for 7 min. Steps 2 through 4 were repeated 35 times.

The resulting PCR reactions (15 ul) were loaded on a 1.5% agarose gel to analyze the

RT-PCR products, and a specific 466 base-pair DNA fragment representing RUP3 was specifically amplified from cDNA of pancreas origin. Low expression was also evident in subregions of brain.

B. cDNA Dot-Blot analysis of RUP3 expression in human tissues (Figure 1B).

Results from RT-PCR analysis were further confirmed in cDNA dot-blot analysis. In this assay, a dot-blot membrane containing cDNA. from 50 human tissues (Clontech) was hybridized with a **P-radiolabelled DNA probe having sequences derived from human

RUP3. Hybridyzation signals were seen in pancreas and fetal liver, suggesting these tissues express RUP3. No significant expression was detected in other tissues analyzed.

C. Analysis of RUP3 by RT-PCR with isolated human pancreatic islets of Langerhans (Figure 1C).

Further analysis of RUP3 by RT-PCR with isolated human pancreatic islets of

Langerhans showed robust expression of RUP3 in islet cells but not in control samples.

D. Analysis of RUP3 expression with cDNAs of rat origin by RT-PCR (Figure 1D).

RUP3 expression was further analyzed with cDNAs of rat origin by RT-PCR technique. Tissue cDNAs used for this assay were obtained from Clontech except those for hypothalamus and islets, which were prepared in house. Concentrations of each cDNA sample were normalized via a control RT-PCR analysis of the house-keeping gene GAPDH before assaying for RUP3 expression. Oligonucleotides used for PCR had the following sequences: rat RUP3 (“rRUP3”) forward: 5’-CATGGGCCCTGCACCTITCTTTG-3’ (SEQID

NO:5); rRUP3 reverse: 5’-GCTCCGGATGGCTGATGATAGTGA-3’ (SEQ ID NO:6).

PCR was performed using Platinum PCR SuperMix (Life Technologies, Inc.; manufacture instructions were followed) in a 50 pl reaction by the following sequences: step 1, 95°C for 4 min; step 2, 95°C for 1 min; step 3, 60°C for 30 sec; step 4, 72°C for 1 min; and step 5, 72°C for 7 min. Steps 2 through 4 were repeated 35 times.

The resulting PCR reactions (15 pl) were loaded on a 1.5% agarose gel to analyze the

RT-PCR products, and a specific 547 base-pair DNA fragment representing rat RUP3 was specifically amplified from cDNA of pancreas origin, revealing a similar expression profile with human, Of particular note, robust expression was seen in isolated islets and hypothalamus, ‘

Example 3

RUP3 protein expression is restricted to p cell lineage of pancreatic islets (Figure 2).

A. A polyclonal anti-RUP3 antibody was prepared in rabbits (Figure 2A).

Rabbits were immunized with an antigenic peptide with sequence derived from rat

RUP3 (“rRUP3”). The peptide sequence was RGPERTRESAYHIVTISHPELDG and shared . 100% identity with mouse RUP3 in the corresponding region. A cysteine residue was incorporated at the N-terminal end of this antigenic peptide to facilitate KLH crosslinking before injecting into rabbits. The resulting antisera (“anti-rRUP3”) and the corresponding preimmune sera (“pre-rRUP3") were tested for immune reactivity to mouse RUP3 in immunobloting assays (lanes 1 thought 4). In this assay, the GST-RUP3 fusion protein was readily recognized by the anti-rRUP3 antisera (lane 4), but not by the preimmune sera (lane 2). The immunoreactive signal could be efficiently eliminated when the immunobloting assay was performed in the presence of excess antigenic peptide (lane 6).

B. RUP3 expression in insulin-producing B cells of pancreatic islets (Figure 2B).

Rat pancreas was perfused with 4% paraformaldehyde (PFA) in PBS and embedded in OCT embedding medium. Ten micron sections were prepared, fixed on glass slides, and immunostained with either pre-rRUP3 (Figure 2B, panel ag) or with anti-rRUP3 antisera (Figure 2B, panels c and e) followed by secondary staining with donkey anti-rabbit IgG conjugated to the fluorochrome Cy-3, Each section was also co-immunostained with a

PCT/US2004/001267 monoclonal anti-insulin antibody (Santa Cruz, Figure 2B, panels b and d) in primary staining followed by a secondary staining with donkey anti-mouse IgG conjugated with FITC, or with a goat anti-glucagon antibody (Santa Cruz, Figure 2B, panel f) and donkey anti-goat IgG coupled to FITC. Immunofluorescent signals were examined under a fluorescent microscope.

RUP3 was found expressed in insulin producing cells (panels ¢ and d), but not in glucagons producing cells (panels e and f). These data demonstrated that RUP3 is expressed in 8 cells but not in o cells of the rat pancreatic islets. Analogous results were obtained when mouse pancreatic sections were investigated for RUP3 expression.

Example 4

Functional Activities of RUP3 In Vitro (Figure 3).

It was established that RUP3 stimulates the production of cAMP by cotransfection of 293 cells with: (1) a CRE-Luciferase reporter, wherein the ability to stimulate the production of firefly luciferase depends on increased cAMP in cells, and (2) an expression plasmid encoding the human form of RUP3 (Figure 3A). Note that cells co-transfected with an expression plasmid containing no RUP3 sequences (“CMV” in Figure 3A) produce very little luciferase activity, whereas cells transfected with an expression plasmid encoding RUP3 (“RUP3” in Figure 3A) have at least a 10-fold increase in luciferase activity. This indicates that RUP3 stimulates the production of cAMP when introduced into 293 cells. This property of RUP3 is conserved across species, because hamster RUP3 stimulates luciferase activity . when introduced into 293 cells in a manner analogous to that described for human RUP3 (Figure 3B). ‘

It is established that, when cAMP is increased in insuiim-producing cells of the pancreas, these cells exhibitan enhanced ability to secrete insulin when glucose concentrations rise. To test whether RUP3 might impart enhanced glucose-dependent insulin release, retrovirus containing human RUP3 was used to generate Tué6 cells that express high levels of RUP3. Tub cells produce insulin, but do not express appreciable levels of RUP3 and do not normally exhibit an increase in insulin release when increased glucose is presentin the culture media. As shown in Figure 3C, Tus cells transduced with a control virus that contains no receptor are still able to produce insulin, but do not show an increase in insulin secretion when the concentration of glucose in the culture media is shifted from 1 mM to 16 : mM. By contrast, Tu6 cells transduced with RUP3-containing retrovirus display significant glucose-dependent insulin secretion (Figure 3C).

Example 5

Functional Activities of RUP3 Agonists In Vitro (Figure 4).

To demonstrate that RUP3 agonists stimulate endogenously expressed RUP3 in insulin-producing cells, two in vitro models can be used. In the first of these, RUP3 agonists are used to stimulate HIT-T15 cells, which express RUP3 at significant levels, as indicated in the Northern blot shown in Figure 4A. Moreover, these cells are known to exhibit enhanced glucose-dependent insulin release when intracellular cAMP concentrations are elevated. In the example shown in Figure 4B, the RUP3 agonist Compound B84 stimulates cAMP production in HIT cells, at a level comparable to that seen with the adenyl cyclase activator _ forskolin. This indicates that Compound B84 is a very robust stimulator of cAMP in HI't-

T1S5 cells. In the example shown in Figure 4C, Compound B84 also stimulates insulin secretion in HIT cells exposed to 15 mM glucose, once again at a level comparable to that seen with the adenyl cyclase activator forskolin. This indicates that Compound B84 is a very robust potentiator of insulin secretion in HIT-T15 cells.

Isolated rat islets are the other in vitro model used to demonstrate the efficacy of

RUP3 agonists. In this model, agents that induce cAMP are not expected to stimulate insulin secretion when glucose concentrations are low (e.g. 60 mg/dl). However, when glucose concentrations are increased (e.g. to 300 mg/dl), these agents are expected to enhance insulin secretion to levels above those seen with glucose alone. In the example shown in Figure 4D, both RUP3 agonists (Compounds 48 and 51 at 10 uM concentration) enhanced glucose dependent insulin release. Moreover, the level of enhancement was comparable to that seen with 25 tM GLP-1, a gut hormone known to act on islets in this manner.

Example 6

In vivo effects of RUP3 agonists on glucose homeostasis in mice,

A. Oral Glucose tolerance test (0GTT) (Figure 5A).

Male C57bl/6N mice at age of 8 weeks were fasted for 18 hours and randomly : grouped (n=11) to receive a RUP3 agonist (Compound B70) at indicated doses, or with control extendin-4 (ex-4, 1 pg/kg), a GLP-1 peptide analog known to stimulate glucose- dependent insulin secretion. Compound B70 was delivered orally via a gavage needle (p.o. volume at 100 pl). Control Ex-4 was delivered intraperitoneally. Thirty minutes after administration of test compound and control ex-4, mice were administered orally with dextrose at 5 g/kg dose. Levels of blood glucose were determined at the indicated time points using Glucometer Elite XI. (Bayer). Figure SA shows the mean glucose concentration averaged from eleven animals in each treatment group. These results demonstrated that the

RUP3 agonist, Compound B70, lowered blood glucose in a dose-dependent manner in mice after challenged with glucose.

B. Acute response of db mice to RUP3 agonist (Figure 5B). '

Male db mice (C57BL/KsOlahsd-Leprdb, diabetic, Harlan) at age of 10 weeks were randomly grouped (n=6) to receive vehicle (oral gavage), Compound B70 (60 mg/kg, oral gavage), or Ex-4 (1 ng/kg, intraperitoneally). After compound administration, food was removed and blood glucose levels were determined at indicated times as shown in Figure 5B.

Reduction in blood glucose at each time point was expressed as percentage of original glucose levels, averaged from six animals for each group. These animals had blood glucose levels (fed state) of 300-400 mg/dl, significantly higher than non-diabetic wild type animals.

Treatment with Compound B70 or Ex-4 significantly reduced glucose levels compared to vehicle control as shown in Figure 5B. These data demonstrated that the RUP3 agonist had efficacy in improving glucose homeostasis in diabetic animals.

Example 7

CRE-Luciferase Assay in 293 Cells 293 cells were plated in 96-well tissue culture plates at a concentration of 20,000 cells per well. The following day, the cells are transfected with a mixture of pCRE-Luc (Stratagene, Cat. # 219076), the indicated expression plasmid, and pEGFP-N1 (Clontech, Cat. # 6085-1) at a ratio of 5:1:0.25 using Lipofectamine Reagent (Invitrogen, Cat. #18324-020) according to the manufacturer’s directions. pEGFP-N1 encodes a “green fluorescent protein” and was used as a control to determine that most cells were successfully transfected. After 24-48 hr, the cells were lysed in situ with 100 ul/ well reconstituted T.uclite buffer (Luclite.

Reporter Gene Assay Kit, Packard, Cat. # 6016911), according to the manufacturer’s . directions. Afier a 10 minute incubation in the dark, luminescence was measured using a

TRILUX 1450 Microbeta Counter (Wallac).

Example 8

Generation of Tu6/ RUP3 Stable Lines

To produce Tub cells that express RUP3 at high levels, a retrovirus bearing an expression cassette for RUP3 was generated. Briefly, RUP3 coding sequence was cloned into the retroviral vector pPLNCX2 (Clontech, Cat # 6102-1). The amphotropic packaging cell line PT-67 (Clontech, K1060-D) was then transfected with either the parental vector pLNCX2 or pLNCX2/RUP3 using Lipofectamine and stable lines were established using guidelines provided by the PT-67 vendor. Retrovirus-containing supematant was obtained by collecting media from the resultant stables according to the manufacturer’s directions. Tu6 cells, ina 10

"cm dish, were then infected with retrovirus by incubating in a solution of 1 ml viral supermatant/ 9 ml culture media containing 40 ug/ml polybrene for 24 hours. The medium was then changed to culture media containing 300 ug/ml G418. G418-resistant clones were ultimately created by virtue of the neomycin-resistance gene cassette present in the pLNCX2 vector, thus indicating the successful integration of retrovirus into the Tub genome. The expression of RUP3 in the Tu6/RUP3 G418-resistant colonies was confirmed by Northern blot.

Example 9

Insulin secretion, Tub Stables ‘

To measure insulin secretion from rodent insulin-producing cell lines, cells were first cultured overnight in serum-free, glucose-deficient media. The following morning, the cells were then placed in the same media supplemented with either 1 mM or 16 mM glucose. After an incubation of 4 hours, the media was collected and analyzed for insulin content using a Rat

Insulin Enzyme-Immunoassay (EIA) System (Amersham Pharmacia Biotech, Cat. # RPN 2567). Typically, the assay was performed using multiple dilutions of sample media in order. to ensure that the sample measurements fell within the boundaries of the standard curve (generated using known amounts of insulin), as recommended by the manufacturer.

Example 10

RUP3 RNA Blot

To determine the expression of RUP3 in insulin-producing or non islet cells, the following cell lines were obtained and cuifured according to guidelines provided by American

Type Culture Collection or the indicated provider.

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Total RNA was isolated from each of these cell lines using TRIZOL (lovitrogen, Cat # 15596-018), subjected to electrophoresis through an agarose/formaldehyde gel and an RNA blot was prepared using standard molecular biological techniques. A radiolabelled RUP3 probe, corresponding to the full-length coding sequence of RUP3, was prepared using a :

Prime-It IT Random Primer Labeling Kit (Stratagene, Cat # 300385). The denatured probe, 10 ml ExpressHyb solution (Clontech, Cat # 8015-2) and the RNA blot were incubated in a hybridization oven, washed and exposed to film using standard molecular biology practices. :

Example 11 .

Receptor Binding Assay

In addition to the methods described herein, another means for evaluating a test compound is by determining binding affinities to the RUP3 receptor. This type of assay generally requires a radiolabelled ligand to the RUP3 receptor. Absent the use of known ligands for the RUP3 receptor and radiolabels thereof, compounds of Formula (Ia) can be labelled with a radioisotope and used in an assay for evaluating the affinity of a test compound to the RUP3 receptor.

A radiolabelled RUP3 compound as described herein can be used in a screening assay to identify/evaluate compounds. In general terms, a newly synthesized or identified compound (i.e., test compound) can be evaluated for its ability to reduce binding of the “radiolabelled compound of Formula (Ia)” to the RUP3 receptor. Accordingly, the ability to compete with the “radio-labelled compound of Formula (a) or Radiolabelled RUP3

Ligand for the binding to the RUP3 receptor directly correlates to its binding affinity of the test compound to the RUP3 receptor.

ASSAY PROTOCOL FOR DETERMINING RECEPTOR BINDING FOR RUP3:

A. RUP3 RECEPTOR PREPARATION 293 cells (human kidney, ATCC), transiently transfected with 10 ug human RUP3 receptor and 60 ul Lipofectamine (per 15-cm dish), were grown in the dish for 24 hours (75% confluency) with a media change and removed with 10 ml/dish of Hepes-EDTA buffer ( 20mM Hepes + 10 mM EDTA, pH 7.4). The cells were then centrifuged in a Beckman

Coulter centrifuge for 20 minutes, 17,000 rpm (JA-25.50 rotor). Subsequently, the pellet was resuspended in 20 mM Hepes + 1 mM EDTA, pH 7.4 and homogenized with a 50- ml

Dounce homogenizer and again centrifuged. After removing the supernatant, the pellets were stored at -80°C, until used in binding assay. When used in the assay, membranes were thawed on ice for 20 minutes and then 10 mL of incubation buffer (20 mM Hepes, 1 mM MgCl,,100 mM NaCl, pH 7.4) added. The membranes were then vortexed to resuspend the crude membrane pellet and homogenized with a Brinkmann PT-3100 Polytron homogenizer for 15 seconds at setting 6. The concentration of membrane protein was determined using the BRL

Bradford protein assay.

B. BINDING ASSAY

For total binding, a total volume of 50ul of appropriately diluted membranes (diluted in assay buffer containing 50mM Tris HCI (pH 7.4), 10mM MgCl,, and 1lmM EDTA; 5-50ug protein) is added to 96-well polyproylene microtiter plates followed by addition of 100ul of assay buffer and 50ul of Radiolabelled RUP3 Ligand. For nonspecific binding, 50 ul of assay buffer is added instead of 100ul and an additional 50ul of 10uM cold RUP3 is added before 50ul of Radiolabelled RUP3 Ligand is added. Plates are then incubated at room temperature for 60-120 minutes. The binding reaction is terminated by filtering assay plates through a Microplate Devices GF/C Unifilter filtration plate with 2 Brandell 96-well plate - harvestor followed by washing with cold 50 mM Tris HCI, pH 7.4 containing 0.9% NaCl.

Then, the bottom of the filtration plate are sealed, 50ul of Optiphase Supermix is added to } each well, the top of the plates are sealed, and plates are counted in a Trilux MicroBeta scintillation counter. For compound competition studies, instead of adding 100ul of assay buffer, 100ul of appropriately diluted test compound is added to appropriate wells followed by addition of 50ul of Radiolabelled RUP3 Ligand.

C. CALCULATIONS

The test compounds are mitjally assayed at 1 and 0.1 uM and then at a range of concentrations chosen such that the middle dose would cause about 50% inhibition of a

Radio-RUP3 Ligand binding (i.e., ICs). Specific binding in the absence of test compound (Bo) is the difference of total binding (Bt) minus non-specific binding (NSB) and similarly specific binding (in the presence of test compound) (B) is the difference of displacement binding (Bp) minus non-specific binding (NSB). ICs, is determined from an inhibition response curve, logit-log plot of % B/Bg vs concentration of test compound.

K; is calculated by the Cheng and Prustoff transformation:

K;i=ICs/ (1+ [LYKp) where [L] is the concentration of a Radio-RUP3 Ligand used in the assay and Kp is the dissociation constant of 2 Radio-RUP3 Ligand determined independently under the same binding conditions.

CHEMISTRY

SYNTHESES OF COMPOUNDS OF THE PRESENT INVENTION

EXAMPLE 12

Tilustrated syntheses for compounds of Formula (Ia) are shown in Figure 6 where the symbols have the same definitions as used throughout this disclosure. The preparation of N- oxides is well know in the art, which include, but not limited to pyridines, pyrimidines and the like. For example, N-oxides can be prepared at normal or elevated pressure, in the presence of an oxidizing agent, such as, hydrogen peroxide, peracetic acid, perbenzoic, m- chloroperbenzoic acid (mCPBA), ozone, oxygen and the like, in the presence or absence of solvent, such as chloroform, dichlormethane, acetic acid, trifluoroacetic acid, and the like or mixtures thereof.

Chemistry: Proton nuclear magnetic resonance (*H NMR) spectra were recorded on ' a Varian Mercury Vx-400 equipped with a 4 nucleus auto switchable probe and z-gradient or a Bruker Avance-400 equipped with a QNP (Quad Nucleus Probe) or a BBI (Broad Band

Tnverse) and z-gradient. Chemical shifts are given in parts per million (ppm) with the residual solvent signal used as reference. NMR abbreviations are used as follows: s = singlet, d = doublet, t = triplet, g = quartet, m= multiplet, br = broad. Microwave irradiations were carried out using the Smith Synthesizer (Personal Chemistry). Thin-layer chromatography (TLC) was performed on silica gel 60 Fass (Merck), preparatory thin-layer chromatography - (prep TLC) was preformed on PK6F silica gel 60 A 1 mm plates (Whatman), and colunm chromatography was carried out on a silica gel column using Kieselgel 60, 0.063-0.200 mm (Merck). Evaporation was done in vacuo on a Buchi rotary evaporator. Celite 545 ® was used during palladium filirations.

LCMS specs: 1) PC: HPLC-pumps: LC-10AD VP, Shimadzu Inc.; HPLC system controller:

SCL-10A VP, Shimadzu Inc; UV-Detector: SPD-10A VP, Shimadzu Inc; Autosampler: CTC

HTS, PAL, Leap Scientific; Mass spectrometer: API 150EX with Turbo Ion Spray source,

AB/MDS Sciex; Software: Analyst 1.2. 2) Mac: HPLC-pumps: LC-8A VP, Shimadzu Inc;

HPLC system controller: SCL-10A. VP, Shimadzu Inc.

UV-Detector: SPD-10A VP, Shimadzu Inc; Autosampler: 215 Liquid Handler, Gilson Inc;

Mass. spectrometer: API 150EX with Turbo Ion Spray source, AB/MDS Sciex

Software: Masschrom 1.5.2.

Compound Al

1-{6-(4-Imidazol-1-yl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester: General Method 1.

A mixture of 1-(6-chloro-5-nitro-pyrimidin-4-yl)-piperidine-4-carboxylic acid ethyl ester (63 mg, 0.2 mmol), 4-imidazol-1-yl-phenol (42 mg, 0.26 mmol) and potassium carbonate (36 mg, 0.26 mmol, 1 equivalent) in anhydrous DMF (1 ml) was heated to 90 °C overnight. The resulting residue was purified by Flash Chromatography (hexanes:ethyl acetate = 1:1) to give 1-[6-(4-Imidazol-1 -yl-phenoxy)-5-nitro-pyrimidin-4-yl] -piperidine-4-carboxylic acid ethyl ester [A1] as a yellow solid (80 mg, 92 %). 'H NMR (CDCl;, 400 MHz) 8 1.28 (t, 3H), 1.80- 1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 3.22 (t, 2H), 3.964.03 (m, 2H), 4.15 (4, 2H), 7.38-7.42 (m, 2H), 7.46 (t, 1H), 7.55-7.59 (m, 3H), 8.17 (s, 1H), 8.90-8.92 (m, 1H).

Exact mass calculated for C,H, NeUs 438.17, found 439.2 (MH).

The intermediate 1-(6-chloro-5-nitro-pyrimidin-4-yl)-piperidine-4-carboxylic acid ethyl ester was prepared by following general method 2,

General Method 2: Addition of Substituted piperidines to dichloro-5-nitropyrimidine. .

Compound 2,6-dichloro-5-nitropyrimidine (500 mg, 2.57 mmol) was dissolved in dichloromethane (40 ml) and cooled to 0 °C. To this was added diisopropylethyl amine (0.54 ml, 3.08 mmol) followed by a solution of piperidine-4-ethyl-ester (3.69 mmol) in dichloromethane (5 ml) dropwise. The mixture was stirred at 0 °C for 1 hour and then concentrated in vacuo. Flash chromatography (hexanes:ethyl acetate = 1:1) provided

Compound Ala, 1-(6-chloro-5-nitro-pyrimidin-4-yl)-piperidine-4-carboxylic acid ethyl ester as a yellow solid (466 mg, 60 %). "HNMR (DMSO, 400 MHz) 8 1.57-1.63 (m, 2H), 1.91- 1.95 (m, 2H), 2.72-2.74 (m, 1H), 3.17(t, 2H). 3.60 (s, 3H), 3.84-3.89 (m, 2H), 8.46 (s, 1H).

Exact mass calculated for C,,H;:CIN,O. 300.06, found 301.2 (MH). : Compounds A2-A155 were prepared in an analogous manner as described for Compound Al, supra. ' Compound A2 1-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]- piperidine-4-carboxylic acid ethyl ester. General Method 3: 4,6-dichloro-5-nitro pyrimidine (5.00 g, 25.7 mmol) and diisopropylethylamine (7.66 ml, 43.9 mmol) were dissolved in dichloromethane (17.0 ml). The mixture was stirred in an ice bath and 4-ethyl ester piperidine (3.33 ml, 43.9 mmol) dissolved in dichloromethane (17.0 ml) was added dropwise. The mixture was warmed to room temperature and after 30 min. the desired product was observed by LCMS m/z 315 (M+H"). The solvent was removed under reduced pressure, the crude dissolved in dioxane (20 ml), sequentially, diisopropylethylamine (6.31 ml, 36.22 mmol) and 2-Methyl-5-trifluoromethyl-2H-3-hydroxypyrazole(3.60 g, 21.73 mmol) were added and the mixture was heated at 90 °C for 18 h. Work up yielded a crude red oil.

Purification by Flash Chromatography (0-35% diethyl ether/ hexane). Yield 58.47 % yellow solid. "H NMR 400MEz DMSO & (ppm): 8.34 (s, 1H); 6.71 (s, 1H); 4.07 (m, 2H); 3.88 (, 2H); 3.70 (s, 3H); 3.27 (i, 2H); 2.72 (m, 1H); 1.94 (m, 2H); 1.62 (m, 2H); 1.18 (¢, 3H).

LCMS (EST) m/z 444.3 (MAE, 100%)

Compomd A3 1-[6-(4-Methanesulfonyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester

Following the general procedure [method 1] compound A3 was obtained as a yellow solid (52%). "HNMR (CDCl, 400 MHz) 5 1.28 (t, 3H), 1.80-1 96 (tn, 2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 3.35-4.05 (m, 16H), 4.15 (q, 2H), 7.55-7.58 (mn, 2H), 7.62-7.66 (m, 1H), 7.88-7.92 (m, 2H), 7.95 (s, 1H). Exact mass calculated for CH, N6O6S 532.21, found 533.3 ov)

Compound A4 : 1-[6-(Benzo[1,2,5] oxadiazol-5-yloxy)-5-nitro-pyrimidin-4-yI} -piperidine-4-carboxylic acid ethyl ester

Following the general procedure, [method 1] compound A4 was obtained as a brown solid (65 %). "BNMR (CDCls, 400 MHz) & 1.28 (t, 3H), 1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 4.02-4.05(m, 2H), 4.14 (q, 2H), 7.22 (d, 1H), 7.60 (s, 1H), 7.82 (d, 1H), 8.16 (s, 1H). Exact mass calculated for C,sH,sNeOg 414.13, found 415.3 (MH).

Compound AS 1-{6-[4-(2-Methoxycarbonyl-acetyl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4- carboxylic acid ethyl ester: [method 1]

Flash chromatography (hexanes:ethyl acetate = 2:1) provided compound AS as a yellow solid (250 mg, 65 %). "HNMR (CDCls, 400 MHz) § 1.28 (t, 3H), 1.78-1.88 (m, 2H), 1.95-2.05 (m, 2H), 2.62-2.70 (m, 1H), 3.22 (t, 2H), 3.76 (s, 2H), 4.00 (s, 3H), 4.02-4.08 (m, 2H), 4.18 (q, 2H), 7.25 (d, 2H), 8.00 (d, 2H), 8.22 (5, 1H). Exact mass calculated for C;,H4N4O3 472.16, found 473.4 (MH).

Compound A6

1-[5-Amino-6-(2-methyl-5-triftuoromethyl-2H-pyrazol-3-yloxy)-pyrimidin-4-yl}- piperidine-4-carboxylic acid ethyl ester: General Method 4:

A2 (100 mg, 0.225 mmol) was dissolved in ethanol (8.0 ml), 5% Pd/C (0.1 mmol) was added to the reaction vessel with stirring. The mixture was purged with hydrogen and after 15 min the desired product A6 was observed by T.CMS. Filtration followed by solvent removal under reduced pressure yielded a solid that was purified by filtration through a silica plug using 50% ethyl acetate/hexane as solvent. Yield 32.13%. ‘H NMR 400 MHz DMSO 8 (ppm): 8.34 (s, 1H); 6.71 (s, 1H); 4.07 (m, 2H); 3.88 (d, 2H); 3.70 (s, 2H); 3.30 (s, 3H); 3.23 (m, 2H); 2.72 (m, 1H); 1.95 (m, 2H); 1.62 (m, 2H); 1.17 (t, 3H). LCMS (EST) m/z 415.3 MH’, 100%) . Compound A7 1-[6-(2-Methyl-5-trifinoromethyl-2H-pyrazol-3-yloxy)-5-(2,2,2-trifluoro-acetylamino)- pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester;

General Method 5:

A6 (50 mg, 0.12 mmol) and diisopropylamine (0.83 ml, 0.476 mmol) were dissolved in anhydrous dichloromethane (2.0 ml), and excess (CF4CO0),0 was added dropwise at 0 °C.

Stirring at room temp. was maintained for 12 hours. Purification by RP-HPLC. Yield 46 % white solid. 'H NMR 400MHz DMSO 8 (ppm): 8.36 (s, 1H); 6.73 (s, 1H); 4.06 (m, 2H); 3.89 (@, 2H); 3.72 (s, 310); 3.23 (mw, 2H); 2.73 (m, 1H); 1.97 (m, 2H); 1.62 (m, 2H); 1.17 ¢, 3H).LCMS (ESI) m/z 511.3 (MH, 100%)

Compound A8 )

Propionic acid 1-[2-amino-5-formyl-6-(2-methyl-5-trifiluoromethyl-2H-pyrazol-3-yloxy)- pyrimidin-4-yl]-piperidin-4-yl ester;

General Method 6: 4,6-dichloro-2-amino-5-formylpyrimidine (1.90 g, 9.89 mmol) and diisopropylethylamine (3.30 ml, 18.95 mmol) were dissolved in anhydrous 1,4-dioxane (25.0 ml). The mixture was stirred on an ice bath and 4-ethyl ester piperidine (1.46 ml, 9.47 mmol) dissolved in dioxane (25.0 ml) was added dropwise. The mixture attained room temperature and after 30 min. the desired product was observed by LCMS m/z 313 (M+H"). The solvent was removed under reduced pressure, and the crude residue dissolved in dioxane (20 ml), to it were added diisopropylethylamine (6,31 ml, 36.22 mmol) and 2-Methyl-5 -trifluoromethyl-2H-pyrazol-3- ol (3.95 g, 23.77 mmol). The mixture heated at 90 °C for 18 h. Aqueous work up yielded a pale orange solid. Recrystalization from ether and hexanes, followed by filtration of the solid yielded white crystals. Yield 50.28%, 'H NMR 400MHz DMSO (ppm): 9.90 (s, 1H); 7.42

(d, 2H); 6.76 (s, 1H); 4.09 (m, 2H); 3.95 (4, 2H); 3.76 (5, 3H); 3.09 (m, 2H); 2.63 (m, 1H); 1.90 (m, 2H); 1.66 (m, 2H); 1.19 (t, 3H). LCMS (ESD) m/z 443 (M+H", 100 %)

Compound A9 4-[6-(2-Methyl-5-trifluoromethyi-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yI]- " piperazine-1-carboxylic acid ethyl ester; [method 3]. Purification by Flash Chromatography (5-30% ethyl acetate / hexane). Yield 33 % yellow oil. 'H NMR 400MHz DMSO & (ppm): 8.38 (s, 1H); 6.71 (s, 1H); 4.04 (mm, 2H); 3.88 (d, 2H); 3.70 (s, 311); 3.54 (m, 2H); 3.42 (m, 2H); 3.29 (m, 2H) 1.18 (t, 3H). LCMS (ESD m/z 446,2 (M'H', 100%)

Compound A10 1-[6~(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]- piperidine-4-carboxylic acid methyl ester; [method 3]. Flash chromatography (hexanes:ethyl acetate = 2:1) provided compound A10 as a yellow solid (173 mg, 30 %). "H NMR (CDCls, 400 MHz) 5 1.80-1.88 (m, 2H), 2.02-2.12. (m, 2H), 2.72-2.74 (m, 1H), 3.72 (s, 3H), 3.78 (s, 3H). 3.94-4.06 (m, 2H), 6.49 (s, 1H), 8.25 (s, 1H). Exact mass calculated for C;¢H;7FsNOs 430.12, found 431.4 (ME).

Compound All 2,6-Dimethyl-4-[6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4- yll-morpholine; {method 3j. Purification by Flash Chromatography (0-30% ethyl acetate / hexane).

Yield 57 % yellow oil. "H NMR 400MHz DMSO 3 (ppm): 8.37 (s, 1H); 6.71 (s, 1H); 3.83 (m, 2H); 3.72 (s, 3H); 3.62 (m, 2H); 2.81 (m, 2H); 1.12 (t, 6H). LCMS (ESI) m/z 403 (MH, 100%)

Compound A12 : 1-[6-(2-Methy}-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]- piperidine-3-carboxylic acid ethyl ester; [method 3]. Purification by Flash Chromatography (0-50% ethyl acetate / hexane).

Yield 50 % yellow oil. 'H NMR 400 MHz DMSO 8 (ppm): 8.36 (s, 1H); 6.72 (s, 1H); 4.08 : (m, 2H); 3.98 (m, 2H); 3.72 (s, 3H); 3.58 (m, 1H); 3.45 (m, 1H); 2.69 (m, 1H); 1.99 (m, 1H); 1.76 (m, 2H); 1.57 (m, 1H); 1.17 (t, 3H). LCMS (ESI) m/z 445 (MH, 100%)

Compound Al13

1-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl}- piperidine-4-carboxylic acid ethylamide; [method 1] . Purification by HPLC. Yield 16 %. 1 NMR 400 MHz CDCl; 8 (ppm): 8.17 (5,

TH); 6.43 (s, LED; 4.06 (mm, 26); 3.72 (5, 3H); 3.12 (m, 2H); 2.58 (m, 3H); 1.88 (m, 4H).

LCMS (EST) m/z 416.1 (M+, 100 %)

Compound Al4 1-[6-(2-Miethyl-5-phenyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester; [method 1]. The product was purified by column chromatography on silica (Biotage) using hexane! ethyl acetate (7:3). "H NMR 400MHz CDCl; 8 (ppm): 8.23 (s, 1H, pyrimidine); 7.78 (d, 2H), 7.40-7.35 (dd, 2H), 6.50 (s, 1H), 4.20 (q, 2H), 4,10-4.00 (m, 2H), 3.78 (s, 3H), 3.30- 3.20 (m, 2H), 2.70-2.60 (m, 1H), 2.10-2.00 (m, 2H), 2.95-2.80 (mm, 2H), 1.30 (t, 3H). LCMS (ESI) for Cp2H,NeOs: m/z 453.2 M + H", 100 %)

Compound Al15 4-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-uitro-6-piperidin-1-yl-pyrimidine; [method 3]. The product was purified by Preparatory TLC using hexane/ ethyl acetate (7:3). 'H NMR 400MHz CDCl; 6 (ppm): 8.20 (s,1H, pyrimidine); 6.45 (s, 1H); 3.80 (s, 3H, CH;), 3.60-3.50 (m, 4H); 1.75-1.60 (m, SH). LCMS (ESI) for C;4H;sF3N¢O5: m/z 373 M +H", 100 %)

Compound A16 1-[5-Nitro-6-(2-trifluoromethyl-benzyloxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; General Method 7: 1-(6-chloro-5-nitropyrimidine-4-yl) -piperidine-4-carboxylic acid ethyl ester 1 (0.22 g, 0.63 mmol) and 2-(trifluoromethanol) benzyl alcohol (0.11 g, 1.26 mmol) were dissolved in DMF at room temperature. Sodium hydride (30 mg, 1.26 mmol) was added and the mixture was stirred at 40 °C for 30 minutes. Diluted the mixture with 10 % aq. HC, and extracted twice with EtOAc. The combined organic extracts were washed with water and brine, dried over anhydrous Na,SO,, and concentrated in vacuo. The residue was purified by preparatory

L.CMS. 'H NMR, 400MHz, CDCl;, 6 (ppm): 8.20 (s, 1H); 7.63 (t, 2H); 7.55 (t, 1H); 7.39 (, 1H); 5.63 (s, 2H); 4.13 (q, 2H); 3.95 (d, 2H); 3.14 (t, 2H); 2.54 (m, 1H); 1.98 (m, 2H); 1.79 (m, 2H); 1.24 (t, 3H). LCMS (ESI) for CH, FsN,Os: m/z 454 (M+H', 100 %)

Compound A17

1-[5-Nitro-6-(3-trifluoromethyl-benzyloxy)-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; [method 7]. The residue was purified by preparatory TLC using hexane/ethyl acetate (3/1, v/v). "H NMR, 400MHz, CDCl, 5 (ppm): 8.22 (s, 1H); 7.66 (s, 1H); 7.58 (t, 2H); 7.49 (1, 1H); 5.52 (s, 2H); 4.15 (q, 2H); 3.62 (m, 2H); 3.15 (¢, 2H); 2.60 (m, 1H); 2.00 (m, 2H); 1.80 (m, 2H); 1.27 (t, 3H). LCMS (BSI) for CoH FaN,Os: m/z 469 (MH, 100 %)

Compound A18 1-[5-Nitro-6-(4-triflaoromethyl-benzyloxy)-pyrimidin-4-ylj-piperidine-4-carboxylic acid ethyl ester; [method 7.]. Lhe residue was purified by preparatory TLC using hexane/ethyl acetate(3/1, v/v). 'H NMR, 400MHz, CDCl, & (ppm): 8.20(s, 1H); 7.62(d, 2H); 7.52(d, 2H); 5.52(s, 2H); 4,11(q, 2H); 3.96(m, 2H); 3.15(t, 2H); 2.58(m, 1H); 2.01 (wm, 2H); 1.81(m, 2H); 1.25(t, 3H).

LCMS (ESI) for CoH, FaN,Os: m/z 454 (MAH, 100 %)

Compound A19 1-[5-Bromo-6-(2-methyl-5-triflnoromethyl-2H-pyrazol-3-yloxy)-pyrimidin-4-yl}- piperidine-4-carboxylic acid ethyl ester; General Method 8.

A mixture of 1-[6-(2-methyl-5-rifluoromethyl-2H-pyrazol-3.yloxy)-pyrimidin-4-y1]- piperidine-4-carboxylic acid ethyl ester (150 mg, 0.37 mmol) and NBS (65 mg, 0.37 mmol) in

DMF (3 ml) was stirred at 60 °C for 2 days. The mixture was quenched with sodium thiosulfate, and extracted with ethyl acetate. The combined organic layer was dried with anhydrous sodium sulfate and concentrated in vacuo. Flash chromatography (hexanes:ethyl acetate = 3:1) provided compound A19 as a white solid (100 mg, 37 %). "HNMR (CDCl, 400 MHz) d 1.28 (t, 3H), 1.78-1.88 (m, 2H), 1.95-2.05 (m, 2H), 2.57-2.62 (m, 1H), 3.17 (t, 2H), 3.81 (s, 3H), 4.18 (q, 2H), 4.22-4.33 (m, 2H), 6.41 (s, 1H), 8.22 (5, 1H). Exact mass calculated for Cy7H;,BrFN;0; 477.06, found 478.0 (MH).

Compound A20 1-[5-Acetylamino-6~(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-pyrimidin-4-yl]- piperidine-4-carboxylic acid ethyl ester and :

Compound A21 1-[S-Diacetylamino-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)- pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester

General Method 9: :

A mixture of compound A6 (100 mg, 0.24 mmol) and acetic anhydride (0.1 ml, 1 mmol) in pyridine (5 ml) was heated to 60 °C for three days. The mixture was concentrated in vacuo. /

Flash chromatography (Hexanes:ethyl acetate = 1:1) provided compound A20a (7 mg, 7%) and A20b (40 mg, 34 %) both as a yellow oil. Compound A20a "HNMR (CDCl, 400 MHz) 8 1.33 (t, 3H), 1.77-1.85 (wm, 2H), 1.95-2.05 (m, 2H), 2.22 (s, 3H), 2.55-2.62 (m, 1H), 3.16 (1, 2H), 3.76 (s, 3H), 4.06-4.22 (m, 4H), 6.24 (5, 1H), 6.50 (s, 1H), 8.22 (s, 1H). Exact mass calculated for CyoHy4F3NsO4 456:17, found 457.2 (MH). Compound A20b "H NMR (CDCl, 400 MHz) § 1.25 (1, 311), 1.77-1.85 (m, 2H), 1.95-2.05 (m, 2H), 2.37 (s, 6H), 2.55- 2.62 (m, 1H), 3.18 (t, 2H), 3.66 (s. 3H), 4.06-4.22 (m, 4H), 6.24 (s, 1H), 6.31 (s, 150), 8.25 (5, 1H). Exact mass calculated for Cy HasFsN¢Os 498.18, found 499.4 (M+H). :

Compound A22 1-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yll- piperidine-4-carboxylic acid; [method 3]. Purification of part of the crude by HPLC. Yield 8.58 % yellow solid. "H NMR. 400MHBz DMSO 8 (ppm): 8.33 (s, TH); 6.71 (s, 1H); 3.88 (m, 2H); 3.70 (s, 3H); 3.22 (m, 2H); 2.63 (m, 1H); 1.93 (m, 2H); 1.59 (m, 2H). LCMS (ESI) m/z 417 (MH, 100 %)

Compound A23 : 1-{5-Nitro-6-[2-(2-trifluoromethyl-phenyl)-ethoxy]-pyrimidin-4-yl}-piperidine-4- carboxylic acid ethyl ester; [method 7]. The residue was purified by preparatory TLC using hexane/ethyl acetate (9/1,v/v). '"H NMR, 400MHz, CDCl, & (ppm): 8.63 (s,1H); 7.45 (m, 4H); 4.16 (q,2H); 4.03 (mm, 2H); 3.89 ( t, 2H); 3.08 (t, 2H); 3.20 (t, 2H); 2.55 (m, 1H); 2.03 (m, 2H); 1.80 (m, 2H); 1.28 (t, 3H). LCMS (ESI) for C,;HyFsN,Os: m/z 468 (M+H, 100 %)

Compound A24 1-{5-Nitro-6-[2-(3-triflnoromethyl-phenyl)-ethoxy]-pyrimidin-4-yl}-piperidine-4- carboxylic acid ethyl ester; . [method 7]. The residue was purified by preparatory TLC using hexane/ethyl acetate (9/1, v/v). '"H NMR, 400MHz, CDCl, 8 (ppm): 8.63 (s,1H); 7.45 (m, 4H); 4.16 (q,2H); 4.03 (m, 2H); 3.89 (t, 2H); 3.08 (t, 2H); 3.20 (t, 2H); 2.55 (m, 1H); 2.03 (m, 2H); 1.80 (m, 2H); 1.28 (t, 3H). LCMS (ESI) for Cy H,:F:N,Os: m/z 468 (M+H", 100 %)

Compound A25 1-[5-Di-(methanesulfonyl)amino-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)- pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; General Method 10: '

Compound A6 (150 mg, 0.36 mmol) was dissolved in dichloromethane (5 ml). To this was added DIEA (0.125 ml) and methane sulfonic anhydride (94 mg, 0.54 mmol). The mixture was stirred at room temperature for 24 hours, quenched with water and extracted with dichloromethane. The combined organic layer was dried in vacuo and purified by HPLC to give compound A25 as a yellow solid (24 mg, 12 %). IINMR (CDCls, 400 MHz) 8 1.28 (t, 3H), 1.80-1.95 (m, 2H), 2.05-2.15 (m, 2H), 2.60-2.68 (m, 1H), 3.38 (1, 2H), 3.50 (s, 6H), 3.79 (s, 3H), 4.17(q, 2H), 4 444.55 (m, 2H), 6.24 (s, 1H), 8.22 (s, 1H). Exact mass calculated for

CoHnsF3 NOs; 570.12, found 571.3 (MED.

Compound A26

J-{5-Nitro-6-(3-trifluoromethyl-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; [method 1]. The residue was purified by colurm chromatography (Biotage) using 10 % hexane/ethyl acetate. 'H NMR, 400MHz, CDCl, 8 (ppm): 8.16 (s, 1H); 7.53 (tm, 2H); 7.41 (5, 1H); 7.02 (d, 1H); 4.16 (q, 2H); 4.01 (m, 1H); 3.21 (t, 2H); 2.97 (5, 9H); 2.90 (s, 9H); 2.63 " (m, 1H); 2.02 (m, 2H); 1.85 (m, 4H); 1.27 (t, 3H). LCMS (EST) for CigH1FaN4Os: m/z 440

MH, 100 %)

Compound A27 1-[5-Methy}-6-(2-methy}-5-trifluoromethyl-2H-pyrazol-3-yloxy)-pyrimidin-4-yij- piperidine-4-carboxylic acid ethyl ester; General Method 11.

A mixture of A19 (100 mg, 0.21 mmol), methyl boronic acid (25 mg, 0.42 mmol), dichlorobis(triphenylphosphine)palladium (II) (15 mg, 0.021 mmol) and potassium carbonate (87 mg, 0.62 mmol) m dry DMF (5 ml) was heated to 100 °C under nitrogen overnight. The mixture was cooled to Toom temperature, quenched with water and extracted with ethyl acetate. The combined organic layer was dried with anhydrous sodium sulfate and concentrated in vacuo. Flash chromatography (hexanes:ethyl acetate = 3:1) provided compound A27 as an oil (20 mg, 23 %). "HNMR (CDCls, 400 MHz) 5 1.28 (t, 3H), 1.82-1.94 (mm, 2H), 1.97-2.05 (m, 2H), 2.23 (s, 3H), 2.57-2.62 (m, 1H), 3.02 (t, 2H), 3.77 (5, 3H), 3.82- 3.88 (m, 2H), 4.18 (q, 2H), 6.34 (s, 1H), 8.22 (s, 1H). Exact mass calculated for

C53 NsO; 413.17, found 414.4 (MH).

Compound A28 1-{5-Nitro-6-(2-trifluoromethyl-phenoxy)-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester;

[method 1]. The residue was purified by column chromatography (Biotage) using 10 % hexane/ethyl acetate. Yield 74 %. "H NMR. 400MHz, CDCl, 8 (ppm): 8.14 (s, 1H); 7.70 (4, 1H); 7.62 (t, 1H); 7.38 (t, 1H); 7.26 (d, 1H); 4.17 (q, 2H); 4.03 (m, 2H); 3.23 (t, 2H); 2.63 (m, 1H); 2.04 (m, 2H); 1.85 (m,2H); 1.28 (t 3H). LCMS (EST) for C,sH15FsN4Os: m/z 440 (MAH, 100 %)

Compound A29 1-{1-[5-Nitro-6-(4-trifluoromethyl-phenoxy)-pyrimidin-4-yl|-piperidin-4-carboxylic acid ethyl ester [method 1]. The residue was purified by column chromatography (Biotage) using 10 % hexane/ethyl acetate. Yield 58 %. IH NMR, 400 MHz, CDCls, 6 (ppm): 8.01 (s, 1H); 7.47 (4, 2H); 6.93 (d, 2H); 4.16 (g, 2H); 4.05 (m, 2H); 3.23 (t, 2H); 2.66 (m, 1H); 2.09 (m, 2H); 1.93 (m 2H); 1.28 (t, 3H). LCMS (ESI) for CsHi0:FsNJOs: m/z 440 (MAH, 100 %)

Compound A30 1-[6-(4-Fluoro-phenoxy)-5-nitro-pyrimidin-4-yl|-piperidine-4-carboxylic acid ethyl ester; [method 1]. Yield 0.016 g, 16 %. Yellow solid. IH NMR. 400MHz CDCl, § (ppm): 8.17 (s, 1H); 7.10 (m, 4H); 4.18 (q, 2H); 4.03 (mm, 2H); 3.22 (tm, 2H); 2.63 (m 1H); 2.03 (m, 2H); 1.84 (m, 2H); 1.29 (m, 3H) . LCMS (ESD m/z 391 (MAH,100%)

Compound A31 . 1-[6-(2,5-Dimethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; [method 3]. The product was purified by column chromatography on silica (Biotage) using hexane/ ethyl acetate (7:3). 'H NMR 400MHz CDCl; (ppm): 8.23 (s,1H, pyrimidine); 5.97 (s, 15D), 4.20 (q, 2H), 4.10-4.00 (m,2H), 3.50 (s,3H), 3.30-3 20 (m, 2H), 2.70-2.60 (m, 1H), 2.10 (5, 3H), 2.00 (m,2H), 1.95-1.90 (m, 2H), 1.30 (t, 3H). LCMS (ESD) for C;7HxNOs: m/z 391.3 (M +H", 100 %)

Compound A32 1-[6-(4-Bromo-phenoxy)-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; [method 1]. The solvent was removed in vacuo and the residue purified by preparatory thin layer chromatography [SiO,; EtOAc/hexane; 50:50]. Yield 0.010 g, 9 %. Yellow solid.'H

NMR 400MHz CDCl: 8 (ppm): 8.17 (s, 1H); 7.52 (d, 2H); 7.03 (d, 28); 4.17 (g, 2H); 4.02 (mn, 2); 3.22 (mm, 2H); 2.63 (m, 1H); 2.02 (m, 2H); 1.84 (m, 2H); 1.29 (m, 3H)

LCMS (EST) mvz 452,453 QM-+H",100%) ’ Compound A33 1-[6-(4-Chloro-phenoxy)-S-nitro-pyrimidin-d-yl|-piperidine-4-carboxylic acid ethyl ester; [method 1]. Yield 0.009g, 9%. Yellow solid. HI NMR 400MHz CDCl, § (ppm): 8.17 (s, 1H); 7.37 (d, 2H); 7.08 (d, 2H); 4.17 (mm, 2H); 4.03 (m, 2H); 3.22 (m, 2H); 2.64 (m, 1H); 2.03 (m, 2H); 1.84 (m, 2H); 1.29 (m, 3H). LCMS (ESD) m/z 407 (M+H, 100%)

Compound 'A34 1-[6-(4-Carbamoyl-phenoxy)-S-nitro-pyrimidin-4-yI}-piperidine-4-carboxylic acid ethyl ester;

General Method 1a: A mixture of compound 7 (63 mg, 0.2 mmol), 4-hydroxybenzene carboxamide (35 mg, 0.26 mmol) and potassium carbonate (36 mg, 0.26 mmol) in DMF (1 ml) was heated in microwave for 9 minutes at 80 °C. Following the general procedure, compound A34 was obtained as a yellow solid (65 %). HINMR (CDCls, 400 MHz) 5 1.19 (&, 3H), 1.70-1.80 (m, 2H), 1.98-2.03 (m, 2H), 2.65-2.80 (m, 1H), 3.22 (t, 2H), 3.82-3.96 (m, : - 2H), 4.07 (q, 2H), 7.25 (d, 2H), 7.40 (s, 1H), 7.92 (d, 2H), 8.00 (s, 1H), 8.20 (s, 1H). Exact mass calculated for C;sHaNsOg 415.15, found 416.2 (MED.

Compound A35

J-{6-4-(2-Mcthoxy-ethyl)-phenoxy)-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; [method 1a]. Following the general procedure, compound A35 was obtained as a yellow solid (71 %). "HNMR (CDCls, 400 MHz) 8 1.28 (t, 3H), 1.70-1.80 (m, 2H), 1.98-2.03 (m, 2H), 2.65-2.75 (m, 1H), 2.94 (t, 2H), 3.22 (t, 2H), 3.37 (5, 3H), 3.62 (4, 2H), 3.96-4.03 (m, 2H), 4.15 (gq, 2H), 7.05 (4, 2H), 7.25 (d, 2H), 8.17 (s, 1H). Exact mass calculated for

Cy H,eN4O¢ 430.19, found 431.4 (MH).

Compound A36 1-[6-(4-Cyclopentyl-phenoxy)-5-nitro-pyrimidin-4-y1j piperidine-4-carboxylic acid ethyl ester; [method 1a]. Following the general procedure, compound A36 was obtained as a yellow solid (58%). "HNMR (CDCl,, 400 MHz) 5 1.28 (t, 3H), 1.58-1.92 (mm, 8H), 1.98-2.15 (m,

4H), 2.65-2.75 (m, 1H), 3.00 (quintet, 1H), 3.22 (t, 2H), 3.96-4.03 (1, 2H), 4.15 (q, 2H), 7.04 (d, 2H), 7.25 (d, 2H), 8.18 (s, 1H). Exact mass calculated for Cp3HzsNiOs 440.21, found 441.2 (MH).

Compound A37 1-[5-Nitro-6-(4-pyrrol-1-yl-phenoxy)-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; [method 1a]. Following the general procedure, compound A37 was obtained as a yellow solid (77 %). "HNMR. (CDCls, 400 MHz) & 1.28 (t, 3H), 1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 3.22 (t, 2H), 3.96-4.03 (m, 2H), 4.15 (q, 2H), 6.36 (d, 2H), 7.04 (4, 2H), 7.19 (d, 2H), 7.40 (d, 2H), 8.18 (s, 1H). Exact mass calculated for CpHzNsOs 437.17, found 438.2 (MH). _

Compound A38 1-[6-(4-Benzoyl-phenoxy)-5-nitro-pyrimidin-4-ylj-piperidine-4-carboxylic acid ethyl esters; : [method 1a]. Following the general procedure, compound A38 was obtained as a yellow solid (70 %). "HNMR (CDCl,, 400 MHz) § 1.28 (t, 3H), 1.80-1.96 (m, 2H), 2.00-2.08 (mm, 2H), 2.65-2.75 (m, 1H), 3.22 (t, 2H), 3.96-4.03 (m, 2H), 4.15 (q, 2H), 7.24-7.28 (m, 2H), 7.46-7.51 (m, 2H), 7.58-7.62 (m, 1H), 7.78-7.82 (in, 2H), 7.87-7.90 (m, 2H), 8.21 (s, 1H).

Exact mass calculated for C;sH,4N,O6 476.17, found 477.2 (ME).

Compound A39 1-{6-[4-(4-Hydroxy-benzenesulfonyl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4- carboxylic acid ethyl ester; [method 1a]. Following the general procedure, compound A39 was obtained as a yellow solid (51 %). "HNMR (CDCl, 400 MHz) § 1.28 (t, 3H), 1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 3.22 (1, 2H), 3.96-4.03 (m, 2H), 4.15 (q, 2H), 6.82 (d, 2H), 7.25 (d, 2H), 7.78 (d, 2H), 7.96 (d, 2H), 8.13 (s, 1H). Exact mass calculated for C,4HzN4OsS 528.13, found 529.2 (MH).

Compound A40 1-[6-(4"-Cyano-biphenyl-4-yloxy)-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; [method 1a]. Following the general procedure, compound A40 was obtained as a yellow solid. "HNMR (CDCl;, 400 MHz) § 1.28 (t, 3H), 1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65-

2.75 (m, 1H), 3.22 (t, 2H), 3.96-4.03 (mn, 2H), 4.15 (gq, 2H), 7-24-7.26 (m, 2H), 7.61-7.78 (m, 6H), 8.19 (s, 1H). Exact mass calculated for CpsH,sN;Os 473.17, found 473.3 (MH).

Compound A41 : 1-[6-(2-Amino-4-ethanesulfonyl-phenoxy)-5-nitro-pyrimidin-4-yI]-piperidine-4- carboxylic acid ethyl ester; [method 1a]. Following the general procedure, compound A41 was obtained as a yellow solid. "HNMR (CDCls, 400 MHz) 5 1.28 {t, 3H), 1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65- 2.75 (m, 1H), 3.14 (q, 2H), 3.40 (t, 2H), 3.96-4.03 (m, 2H), 4.18 (q, 2H), 7.18 (d, 2H), 7.68 (d, 1H), 7.72 (d, 1H), 8.06 (s, 1H), 10.35 (s, 2H). Exact mass calculated for CyoH,sNs0,S 479.15, found 480.0 (MH"). :

Compound A42 1-{6-[4-(5-Hydroxy-pyrimidin-2-yl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4- carboxylic acid ethyl ester; [method 1a]. Following the general procedure, compound A42 was obtained as a yellow solid. "HNMR (CDCls, 400 MHz) & 1.28 (t, 3H), 1.80-1.96 (m, 2H), 2.00-2.08 (1m, 2H), 2.65- 2.75 (m, 1H), 3.14 (q, 2H), 3.40 (t, 2H), 3.96-4.03 (m, 2H), 4.18 (q, 2H), 7.36 (d, 2H), 8.20 (s, 1H), 8.38 (d, 2H), 8.77 (s, 2H). Exact mass calculated for C;;H::N¢QOg 466.16, found 467.2

Compound A43 . 1-[5-Nitro-6-(d-sulfo-phenoxy)-pyrimidin-4-yl-piperidine-d-carboxylic acid ethyl ester; [method 1a]. Following the general procedure, compound A43 was obtained as a yellow solid. "HNMR (CDCl:, 400 MHz) & 1.28 (1. 3H), 1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65- 2.75 (m, 1H), 3.14 (q, 2H), 3.40 (t, 2H), 3.70-3.82 (m, 2H), 4.05 (gq, 2H), 7.12 (d, 2H), 7.60 (d, 2H), 8.20 (5, 1H). Exact mass calculated for C,sH;oN,OSNa 474.08, found 475 (M+H").

Compound A44 1-[5-Nitro-6-(4-[1,2,4]triazo}-1-yl-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; [method 1a]. Following the general procedure, compound A44 was obtained as a yellow solid. '"H NMR (CDCls, 400 MHz) § 1.28 (t, 3H), 1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65- 2.75 (m, 1H), 3.22 (t, 2H), 3.96-4.03 (m, 2H), 4.15 (q, 2H), 7.33 (d, 2H), 7.73 (d, 2H), 8.17 (s, 2H), 8.69 (s, 1H). Exact mass calculated for CoH, N;05 439.16, found 440.4 (MH).

Compound A45 1-[6~(4-Carbamoylmethyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; [method 1a]. Following the general procedure, compound A45 was obtained as a yellow - solid. "H NMR (CDCl, 400 MHz) 5 1.28 (t, 3H), 1.80-1.96 (m, 2ED), 2.00-2.08 (m, 2H), 2.65- 2.75 (m, 1H), 3.22 (t, 2H), 3.60 (s, 2H), 3.96-4.03 (m, 2H), 4.15 (q, 2H), 7.17(d, 2H), 7.38 (4, 2H), 8.17 (s, 1H). Exact mass calculated for CagHyps NO 429.16, found 430.3 (MH).

Compound A46 1-{6-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-phenoxy]-5-nitro-pyrimidin-4-y1}- . piperidine-4-carboxylic acid ethyl ester; [method 1a]. Following the general procedure, compound a46 was obtained as a yellow solid. "HNMR (CDCl,, 400 MHz) § 1.28 (t, 3H), 1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65- 2.75 (m, 1H), 3.22 (t, 2H), 3.60 (5, 2H), 3.96-4.03 (mn, 2H), 4.15 (q, 2H), 7.26-7.29 (m, 2H), 7.52-1.55 (m, 2H), 7.82 (dd, 2H), 7.94 (dd, 2H), 8.19 (s, 1H). Exact mass calculated for

Catl23Ns0 517.16, found 518.3 (ME).

Compound A47 } 1-[6-(4'-Methoxy-biphenyl-4-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; [method 1a]. Following the general procedure, compound A47 was obtained as a yellow solid. '"H NMR (CDCls, 400 MHz) 5 1.28 (t, 3H), 1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65- 2.75 (m, 1H), 3.22 (t, 2H), 3.60 (s, 2H), 3.85 (s, 3H), 3.96-4.03 (m, 2H), 4.15 (q, 2H), 6.96 (d, 2H), 7.17(d, 2H), 7.54 (d, 2H), 7.60 (d, 2H), 8.17 (s, 1H). Exact mass calculated for

CisHa6N, 05 478.19, found 479.2 (MED).

Compound A48 1-{6-[4-(2,5-Dioxo-imidazolidin-4-yl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4- carboxylic acid ethyl ester; [method 1a]. Following the general procedure, compound A48 was obtained as a yellow solid. "H NMR (CDCl, 400 MHz) § 1.28 (t, 3H), 1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65- 2.75 (m, 1H), 3.22 (t, 2H), 3.60 (s, 2H), 3.96-4.03 (1m, 2H), 4.15 (q, 2H), 5.16 (s, 1H), 5.30 (s, 1H), 5.60 (s, 1H), 7.26 (4, 2H), 7.43 (d, 2H), 8.16 (s, 1H). Exact mass calculated for

Ca1HzNeO7 470.15, found 471.1 (MH).

Compound A49

£(4,4-Diftuoro-piperidin-1-y1)-6-(2-methyl-5-triffuoromethyl-2H-pyrazol-3-yloxy)-5- nitro-pyrimidine; [method 2 followed by method 3]. Purification by HPLC yielded a yellow solid.

Yield 54.71%. 1H NMR 400 MHz CDCl, 3 (ppm): 8.29 (s, 1H); 6.52 (5, 1H); 3.80 (5, 3H); 3.71 (m, 2H); 2.11 (m, 2H); 2.01 (m, 4H). LCMS (BSI) m/z 409.2 (MH, 100%)

Compound AS0 1-{5-Nitro-6-[4-(4-0x0-cyclohexyl)-phenosy]-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; [method 1a]. Following the general procedure, compound AS0 was obtained as a yellow solid (45 %). "HNMR (CDCls, 400 MHz) 5 1.28 (t, 3H), 1.80-2.05 (m, 6H), 2.21-2.24 (1m, 2H), 2.52-2.56 (m, 2H), 2.65-2.75 (m, 1H), 3.22 (t, 2H), 3.60 (s, 2H), 3.96-4.03 (m, 2H), 4.15 (q, 2H), 7.10 (d, 2H), 7.26 (d, 2H), 8.17 (s, 1H). Exact mass calculated for C,H: N4Os 468.2, found 469.2 (MH).

Compound A51 1-{5-Nitro-6-[4-(3-oxo-butyl)-phenoxy]-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; [method 1a]. Following the general procedure, compound A51 was obtained as a yellow solid (61 %). "HNMR (CDCl, 400 MHz) 5 1.28 (t, 3H), 1.80-1.96 (m, 2H), 2.00-2.08 (m, \ 2H), 2.16 (s, 3H), 2.65-2.75 (m, 1H), 2.72-2.78 (m, 2H), 2.82-2.90 (m, 2H), 3.22 (t, 2H), 3.60 (s, 2H), 3.96-4.03 (m, 2H), 4.15 (q, 2H), 7.02 (4, 2H), 7.22 (d, 2H), 8.17 (s, 1H). Exact mass calculated for CHeN.O5 442.19, found 443.0 (MH).

Compound AS2 1-[5-Nitro-6-(4-propionyl-phenoxy)-pyrimidin-4-yl]-piperidine4-carboxylic acid ethyl ester; ! [method 1a]. Following the general procedure, compound A52 was obtained as a yellow solid (70 %). "HNMR (CDCl,, 400 MHz) 8 1.28 (t, 3H), 1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 3.01 (g, 2H), 3.22 (t, 2H), 3.96-4.03 (m, 2H), 4.15 (q, 2H), 7.21(d, 2H), 8.02 (d, 2H), 8.17 (s, 2H). Exact mass calculated for Cy H,,N,Os 428.17, found 429.3 (MH).

Compound A53 1-[5-Nitro-6-(4-[1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester;

[method 1a]. Following the general procedure, compound AS3 was obtained as a yellow solid (57 %). "HNMR (CDCls, 400 MHz) 5 1.28 (t, 3H), 1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 3.22 (t, 2H), 3.96-4.03 (m, 2H), 4.15 (gq, 2H), 7.28 (d, 2H), 8.10 (d, 2H), 8.19 (5, 1H), 8.64 (s, 1H). Exact mass calculated for CaoHaoNeOsS 456.12, found 457.2

QE").

Compound AS4 1-{6-4-(2-Hydroxy-ethyl)-phenoxy|-S-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; [method 1a]. Following the general procedure, compound A54 was obtained as a yellow solid. "HNMR (CDCls, 400 MHz) 8 1.28 (t, 3H), 1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65- 2.75 (m, 1H), 2.88 (1, 2H), 3.05 (t, 0.5H), 3.22 (t, 2H), 3.87 (t, 2H), 3.96-4.03 (m, 2H), 4.15 (g, 2H), 4.55 (t, 0.580), 7.07(d, 2), 7.22 (d, 2H), 8.15 (s, 1H). Exact mass calculated for

CoH2aN4 05 416.17, found 417.3 (MED.

Compound A55 {4-[6-(4,4-Difluoro-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxyl-phenyl}-phenyl- methanone;

General Procedure 2 followed by method 1a. Flash column chromatography [Hexane:Ethyl Acetate=1:1] provided the intermediate as a yellow oil (444 mg, 84 %). H

NMR 400MHz CDCl, 5(ppm): 8.40(s, 1H); 3.70(sb, 41); 2.1(t, 4H). Exact mass calculated for CsH,CIF,N,0, 278.04, LCMS (EST) m/z 279.3(M+H, 100%). [method 1a]. HPLC provided compound A55 as yellow solid (26 mg, 59%). "HNMR 400MEz CDCl, 5(ppm): 8.25(s,1H); 7.90(dd,2H);7 80(dd, 2H); 7.61(td, 1H); 7.50( td, 2H); 7.26(d,2H); 3.75 (sb, 4H);2.15 (qu,4H). Exact mass calculated for CopHys FaN4O4 440.13,

LCMS (ESD) m/z 441.3(M+I, 100 %).

Compound AS6 3-{4- [6-(4,4-Difluoro-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-phenyl}-3-oxo-propionic acid methyl ester; [method 1a]. HPLC provided compound A56 as yellow solid (10 mg, 24 %). 11 NMR 400MHz CDC}; 8(ppm): 8.21(s,1H); 8.04(d,2H);7.24(d, 2H); 4.01(s, 2H); 3.75 (sb, 4H);2.15(q,4H); 2.00(sb,3H). Exact mass calculated for C;oHis F,N,O4 436.12, LCMS (ESI) m/z 437.3 (M+, 100 %).

Compound A57

2-[6-(4,4-Difluoro-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-5-ethanesulfonyl- phenylamine; [method 1a]. HPLC provided compound A57 as yellow oil (31mg, 70 %). '"H NMR 400MHz

CDCl; 8 (ppm): 10.35 (s,1H); 8.18 (5,1H); 7.85 (s,1H); 7.63 (d, 1H); 7.19 (d, 1H); 3.78 (5, 4H); 3.16 (q, 2H); 2.20 (q,4H); 1.21 (sb,3H). Exact mass calculated for CH; F3NsOsS 443.11, LCMS (ESI) m/z 444.3 (MH, 100 %).

Compound A58 4-(4-Cyclopentyl-phenoxy)-6-(4,4-difluoro-piperidin-1-yl)-5-nitro-pyrimidine; [method 1a]. HPLC provided compound A58 as yellow solid (20 mg, 50 %). "H NMR 400

MHz CDCl; 8(ppux): 8.21 (s,1H); 7.25 (d,2H); 7.06 (d, 2H); 3.70 (5, 4H); 3.03 (4,18); 2.10 (sb, 4h); 1.80 (d,2H); 1.71 (t,2H); 1.60 (sb, 4H). Exact mass calculated for C;oHz, FaN,O; 404.17, LCMS (ESI) m/z 405.2 (MH, 100%).

Compound A59 1-[6-(2,6-Dichloro-4-methanesulfonyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4- . carboxylic acid ethyl ester; [method 1a]. Following the general procedure, compound A59 was obtained as a yellow solid (52 %). "H NMR (CDCl,, 400 MHz) § 1.28 (t, 3H), 1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 3.35-4.05 (m, 16H), 4.15 (q, 2H), 7.55-7.58 (1m, 2H), 7.62-7.66 (m, 1H), 7.88-7.92 (m, 2H), 7.95 (s, 1H). Exact mass calculated for C,,H3,NsOeS 532.21, found 533.3 (MH).

Compound A60 . 1-{6-[4-(4-Chloro-benzoyl)-phenoxy]-5-nitro-pyrimidin-4-y1}-piperidine-4-carboxylic acid ethyl ester; [method 1a]. Following the general procedure, compound A60 was obtained as a yellow solid (52 %). "HNMR (CDCls, 400 MHz) 5 1.28 (t, 3H), 1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 3.35-4.05 (m, 16H), 4.15 (q, 2H), 7.55-7.58 (m, 2H), 7.62-7.66 (mm, 1H), 7.88-7.92 (m, 2H), 7.95 (s, 1H). Exact mass calculated for C,sH:,NsOeS 532.21, found 533.3 (MH).

Compound A61 1-{6-[4-(4-Hydroxy-benzoyl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; ]

I 144 [method 1a]. Following the general procedure, compound A61 was obtained as a yellow solid (52 %). "H NMR (CDCl;, 400 MHz) § 1.28 (t, 3H), 1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 3.35-4.05 (m, 16H), 4.15 (g, 2H), 7.55-7.58 (m, 2H), 7.62-7.66 (m, 1H), 7.88-7.92 (m, 2H), 7.95 (s, 1H). Exact mass calculated for CaHzNsOsS 532.21, found 533.3 (MH).

Compound A62 1-[6-(4-Cyanomethyl-phenoxy)-5-nitro-pyrimidin-4-yll ~piperidine-4-carboxylic acid ethyl ester; [method 1a]. Following the genera) procedure, compound A62 was obtained as a yellow solid (52 %). "HNMR (CDCls, 400 MHz) 5 1.28 (t, 3H), 1.80-1.96 (1m, 2H), 2.00-2.08 (m, : 2H), 2.65-2.75 (wm, 1H), 3.35-4.05 (m, 16H), 4.15 (q, 2H), 7.55-7.58 (m, 2H), 7.62-7.66 (mm, 1H), 7.88-7.92 (m, ZH), 7.95 (8, 1H). Exact mass calculated for Cy H3nNeO,S 532.21, found 533.3 (MEH).

Compound A63 @-{6- [4-(2-Methanesulfonyl-ethyl)-piperazin-1-yl]-5-nitro-pyrimidin-4-yloxy}-phenyl)- phenyl-methanone;

General Procedure 2 followed by method 1a. Flash colunm chromatography Methanol:

Dichloromethane=1:9] provided the intermediate monochloro compound as red oil (124 mg, %). Exact mass calculated for C1 H;<CIN;O,S 349.06, LCMS (EST) m/z 350.1(M+H", 100 %). [method 1a]. Flash column chromato graphy [Hexane: Ethyl Acetate=2:1 then Methanol:

Dichloromethane=1:9] provided compound A63 as yellow oil (7 mg, 14 %). "HNMR

A00MHz CDCl: 8(ppm): 8.13 (d,2H); 7.91 (¢,2H); 7.80 (d, 2H); 7.60 (d, 1H): 7.50 (d, 2H); 7.21 (t, 1H); 4.03 (m, 2H); 3.71 (db, 6H); 3.31 (sb, 2H); 3.08 (5,3H); 3.00 (5,2H). Exact mass calculated for CpgH,s N5OgS 511.15, LCMS (ESD m/z 512.1 (MH, 100%).

Compound A64 . 4-(4-{6- [4-(2-Methanesulfonyl-ethyl)-piperazin-1-yl]-5-nitro-pyrimidin-4-yloxy}- phenyl)-butan-2-one; [method 1a]. Flash column chromatography [Hexane: Ethyl Acetate=2:1 then Methanol:

Dichloromethane=1:9] provided compound A64 as yellow oil (6 mg, 13 %) 'H NMR 400MHz CDCl; 8(ppm): 8.20 (s,1H); 7.21 (d,2H); 7.05 (d, 2H); 3.63 (s, 4H); 3.20 (d, 2H); 3.03 (s,3H); 2.90 (m, 4H); 2.80 (t, 2H); 2.61 (sb, 4H); 2.18 (s, 3H). Exact mass calculated for

Cy Hy N;06S 477.17, LCMS (ESI) m/z 478.1 (M+H', 100%).

© Compound A65 3-(4-{6-{4-(2-Methanesulfonyl-ethyl)-piperazin-1-yl|-5-nitro-pyrimidin-4-yloxy}- phenyl)-3-oxo-propionic acid methyl ester; [method 1a]. Flash column chromatography [Hexane: Ethyl Acetate=2:1 then Methanol:

Dichloromethane=1:9] provided compound A65 as yellow oil (7 mg, 14 %). "HNMR

A400MEz CDCI, S(ppm): 8.20 (s, 1H); 8.02 (d, 2H); 7.26 (4,280); 4.01 (d, 2H); 3.73 (5, TH); 3.10 (sb, SH). Exact mass calculated for Cp1HysNsOsS 507.14, LCMS (ESI) m/z 508.2 (MAH, 100%).

Compound A66 4-(4-Methyl-piperidin-1-yl)-6-(2-methy}-5-trifluoromethyl-2 H-pyrazol-3-yloxy)-5-nitro- pyrimidine; : [method 2 followed by general method 3]. Purification by HPLC yielded A66 as a yellow solid. Yield: 18 %. "H NMR 400MHz CDCl; 8 (ppm): 8.10 (5, 1H); 6.36 (s, 1H); 3.95 (d, 2H); 3.65 (s, 3H); 2.93 (m, 2H); 1.62 (m, 3H); 1.14 (m, 2H); 0.85 (rm, 3H). LCMS (ESD) m/z 387

MH", 100%)

Compound A67 4-(4-Bromo-pipexidin-1-yl)-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro- pyrimidine; [method 2 followed by general method 3]. Final purification by HPLC yielded an orange solid. Yield 22 %.'H NMR 400MHz CDCl, & (ppm): 8.31 (s, 1H); 6.51 (s, 1H); 4.41 (m, 1H); 3.84 (m, 2H); 3.81 (s, 3H); 3.66 (m, 2H); 2.17 (m, 2H); 1.98 (m, 2H). LCMS (ESI) m/z 453 (MH, 100%)

Compound A638 4-(2-Methy)-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-6-(4-propyl-piperidin-1-yl)- pyrimidine; fmethod 1a]. provided compound A68 as yellow solid (501 mg, 55 % yield). "TH NMR 400MHz CDCl; § (ppm): 8.25 (s, 1H); 6.51 (5, 1ED); 4.13 (dt, 2H); 3.80 (s, 3H); 3.07 (td, 2H); 1.82 (d, 2H); 1.63-1.56 (m, 1H); 1.40-1.22 (m, 6H); 0.93(t, 3H). Exact mass calculated for

Cy7H,, FaNgO; 414.16, LCMS (ESI) m/z 415.3 (M+H', 100%).

Compound A69 1-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl}- piperidine-4-carboxylic acid amide;

[method 3]. Purification by HPLC yielded a yellow solid. Yield 16 %. 'H NMR 400 MHz

CDCl, § (ppm): 8.17 (s. 1H); 6.43 (s, 1H); 4.06 (m, 2H); 3.72 (5, 3H); 3.12 (mm, 2H); 2.58 (m, 3H); 1.88 (m, 4H). LCMS (ESD m/z 416.1 (M+H, 100 %)

Compound A70 1-[5-Nitro-6-(2-0x0-2H-chromen-6-yloxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester: [method 1a]. Following the general procedure, compound A70 was obtained as a yellow solid (43 %). "HNMR (CDCl, 400 MHz) § 1.28 (t, 3H), 1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65-2.75 (tu, LH), 4.02-4.05(m, 2H), 4.14 (q, 2H), 6.38 (d, 1H), 7.02 (d, 1H), 7.10 (s, 1H), 7.42 (d, 1H), 7.63 (d, 1H), 8.13 (s, 1H). Exact mass calculated for Cu HaoN,O; 440.13, found 441.3 (ME). :

Compound A71 1-[5-Nitro-6-(2-0x0-benzo[1,3]oxathiol-6-yloxy)-pyrimidin-4-yI|-piperidine-4-carboxylic . acid ethyl ester; ] [method 1a]. Following the general procedure, compound A71 was obtained as a yellow solid (34 %). "H NMR (CDCl;, 400 MHz) § 1.28 (t, 3H), 1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 4.02-4.05(m, 2H), 4.14 (q, 2D), 7.02 (d, 1H), 7.15 (5, 1H), 7.40 (4, 1H), 8.14 (s, 1H). Exact mass calculated for CsH;sN4,07S 446.09, found 447.0 (MH).

Compound AT2 1- [6-(9H-Carbazol-2-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; [method 1a]. Following the general procedure, compound A72 was obtained as a yellow solid (89 %). 'H NMR (CDCls, 400 MHz) 5 1.28 (t, 3H), 1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 4.02-4.05(m, 2H), 4.14 (q, 2H), 6.90 (d, 1H), 7.00 (d, 1H), 7.03-7.08 (m, 1H), 7.30-7.36 (m, 2H), 7.78-7.82 (m, 2H), 8.12 (s, 1H), 8.26 (s, 1H). Exactmass calculated for CpqHa3NsO; 461.17, found 462.3 (MH).

Compound A73 1-[5-Nitro-6-(9-0xo-9H-fluoren-2-yloxy)-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; [method 1a). Following the general procedure, compound A73 was obtained as a yellow solid (84 %). "HNMR (CDCls, 400 MHz) d 1.28 (t, 3H), 1.80-1.96 (m, 2H), 2.00-2.08 (m,

2H), 2.65-2.75 (mn, 1H), 4.02-4.05(m, 2H), 4.14 (q, 2H), 7.20-7.25 (m, 3H), 7.40-7.60 (m, 4H), 8.16 (s, 1H). Exact mass calculated for CosH»N4Os 474.15, found 475.1 (MED).

Compound A74 1-{5-Amino-6-[4-(3-oxo-butyl)-phenoxy]-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester

General method 12:

A51 (348 mg, 0.786 mmol) was dissolved in ethyl acetate (10 mL), palladium on activated carbon (10wt — degussa type) was added and the mixture purged with Hy. The reaction was monitored by LCMS and after completion the crude was filtered through celite and activated carbon. Purification by HPLC afforded Compound A74 as a light yellow oil. Yield: 26 %. H

NMR 400MHz CDCl; 8 (ppm): 8.14(s, 1H); 7.26 (4, 2H); 7.05 (4, 2H); 6.38 (s, 2H); 4.19 (m, 2H); 3.88 (d, 2H); 3.17 (m, 2H); 2.94 (m, 2H); 2.81 (m, 2H); 2,63 (m, 1H); 2.18 (5, 3H); 2.14 (d, 2H); 1.91 (m, 2H); 1.30 (t, 3H). LCMS (ESI) m/z 413.4 (MH, 100 %).

Compound A75 1-[6-[4-(3-Oxo-butyl)-phenoxy]-5-(2,2,2-trifluoro-acetylamino)-pyrimidin-4-yIl- piperidine-4-carboxylic acid ethyl ester;

General method 13:

A74 (61 mg, 0,148 mmol) and diisopropylethylamine (84 ml, 0.484 mmol) were dissolved in dichloromethane and trifluoroacetic anhydride (0.51 mi, 0.363 mmol) was added. The mixture was stirred at room temperature for 3 hours and LCMS indicated the desired product.

Purification by HPLC yielded light yellow oil. Yield 72.97%. ‘H NMR 400MHz CDCl; 8 . (ppm): 8.21 (s, 1H); 8.14 (s, 1H); 7.20 (d, 2H); 7.00 (d, 2H); 4.15 (m, 4H); 3.13 (m, 2H); 2.89 (mo, 2H); 2.77 (mm, 2H); 2.57 (m, 2H): 2,15 (5, 3H): 1.99 (m, 2H); 1.77 (m, 2H); 1.26 (t, 3H).

LCMS (ESI) m/z 509.2 (M+H", 100%)

Compound A76 1-{5-Amino-6-[4-(hydroxy-phenyl-methyl)-phenoxy]-pyrimidin-4-yl}-piperidine-4- carboxylic acid ethyl ester; [method 12] . Purification by HPLC yielded oil. Yield 8 %. *H NMR 400MHz CDCl: & (ppm): 8.05 (s, 1H); 7.38 (m, 8H); 7.12 (d, 2H); 5.86 (5, 1H); 4.18 (m, 2H); 3.99 (s, 2H); 3.80 (d, 2H); 2.94 (m, 2H); 2.55 (m, 1H); 2.09 (m, 2H); 1.88 (m, 2H); 1.29 (t, 3H). LCMS (ESD m/z 449.3 (MH, 100%)

Compound A77

1- [6-(2-Benzoyl-5-methoxy-phenoxy)-S-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; [method 1a). Following the general procedure, compound A77 was obtained as a yellow solid (52 %). "HNMR. (CDCls, 400 MHz) § 1.28 (t, 3H), 1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65-2.75 (tm, 1H), 3.35-4.05 (m, 16H), 4.15 (9, 2H), 7.55-7.58 (m, 9H), 7.62-7.66 (m, 1H), 7.88-7.92 (m, 211), 7.95 (s, 1H). Exact mass calculated for CH NOS 532.21, found 533.3 (MH).

Compound A78 1-6-(6-Chloro-pyridin-3-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; [method 1a]. HPLC provided compound A78 as yellow solid (63 mg, 61 %). "HNMR 400MHz CDCl; § (ppm): 8.20 (d,1H); 8.08 (s, 1H); 7.43 (dd, 1H); 7.30 (d, 1H); 4.09 (4, 21); 3.95 (dt,2H); 3.15 (td, 2H); 2.55 (m, 1H); 1.95 (dt, 2H); 1.77 (td, 2H); 1.19 (t, 3H). Exact mass calculated for C,7FsCI NsO5 407.10, LCMS (ESI) m/z 408.3 (M+, 100 %).

Compound A79 1-[6-(Benzo [1,3] dioxol-5-yloxy)-5-nitro-pyrimidin-4-yI]-piperidine-4-carboxylic acid ethyl ester; [method 1a]. Following the general procedure, compound A79 was obtained as an oil (46 %). "HNMR (CDCls, 400 MIz) § 1.28 (t, 3H), 1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 4.02-4.05(m, 2H), 4.14 (gq, 2H), 6.00 (s, 2H), 6.57 (d, 1H), 6.60 (s, 1H), 6.80 (d, 1H), 8.16 (s, 1H). Exact mass calculated for C;5HzoN404 416.13, found 417.0 (MH").

Compound A80 1-[6-(4-Benzyloxy-phenoxy)-5-nitro-pyrimidin-4-yl}-piperidine4-carboxylic acid ethyl ester; [method 1a]. Following the general procedure, compound A80 was obtained as a yellow solid (25 %). "HNMR (CDCl; 400 MHz) d 1.28 (t, 3H), 1.80-1.96 (m, 2H), 2.00-2.08 (m, ' 2H), 2.65-2.75 (m, 1H), 4.02-4.05(mm, 2H), 4.14 (q, 2H), 5.04 (5, 2H), 6.94-7.05 (m, 4H), 7.27-7.41 (m, 5H), 8.19 (s, 1H). Exact mass calculated for C,sH,N,Og 478.19, found 479.1 (MID).

Compound A81 1-[6~(3-Morpholin-4-yl-phenoxy)-5-nitro-pyrimidin-4-ylj-piperidine-4-carboxylic acid ethyl ester;

[method 1a]. Following the general procedure, compound A81 was obtained as an oil (84 %). "HNMR (CDCl, 400 MHz) 5 1.28 (t, 3H), 1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 3.20-3.35 (m, 6H), 3.82-3 84 (m, 2H), 3.98-4.05(m, 2H), 4.14 (g, 2H), 6.75-6.80 (m, 2H), 6.95-6.99 (mm, 1H), 7.32-7.38 (m, 1H), 8.17 (s, 1H). Exact mass calculated for

Cy HN505 457.20, found 458.3 (MH).

Compound A82 1-[5-Nitro-6-(4-trifluoromethylsulfanyl-phenoxy)-pyrimidin-4-ylj-piperidine-4- carboxylic acid ethyl ester; [method 1a]. Following the general procedure, compound A82 was obtained as a yellow solid (32 %). "HNMR (CDCl;, 400 MHz) 6 1.28 (t, 3H), 1.80-1.96 (m, 2H), 2.00-2.08 (wm, 2H), 2.65-2.75 (m, 1H), 4.02-4.05(m, 2H), 4.14 (q, 2H), 7.26 (d, 2B), 7.68 (d, 2H), 8.17 (s, 1H). Exact mass calculated for C;oHigFsN,OsS 472.1, found 473.1 (MI). )

Compound A83 1-[5-Nitro-6-(4-trifluoromethoxy-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; [method 1a). Following the general procedure, compound A83 was obtained as a yellow solid (79 %). "H NMR (CDCls, 400 MHz) § 1.28 (t, 3H), 1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 4.02-4.05(m, 2H), 4.14 (q, 2H), 7.18 (4, 2H), 7.26 (4, 2H), 8.17 (s, 1H). Exact mass calculated for C;gH;sF3N;O5 456.13, found 457.1 (MH).

Compound A84 1-[6-( 4-Renzoyl-phenoxy)-5-(2,2,2-trifluoro-acetylamino)-pyrimidin-4-yl)-piperidine-4- carboxvlic acid ethyl ester; [method 13]. Purification by HPLC. 'H NMR 400 MHz CDCl; 8 (ppm): 8.20 (s, 1H); 7.97 (s. 1H); 7.79 (d, 2H); 7.72 (d, 2H); 7.52 (m, 1H); 7.41 (m, 2H); 7.13 (d, 2H); 4.09 (m, 4H); 3.11 (m, 2H); 2.53 (m, 1H); 1.94 (m, 2H); 1.72 (m, 2H); 1.19 (1, 3H). LCMS (ESI) m/z 543.5 (M+H, 100 %)

Compound A85 {4-[5-Nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yloxy]-pheny}}-phenyl-methanone;

General Procedure 2 followed by method 3.

Intermediate: 'H NMR 400MHz CDCl, 8(ppm): 8.26(s, 1H); 4.035(d, 2H); 2.94(id, 2H); 1.73(dt, 2H); 1.50 (m, 1H); 1.27 (m, 2H); 1.18 (m, 2H); 1.12 (dd, 2H); 0.84(t, 3H). Exact mass calculated for Ci, H,7CIN,O, 284.10, LCMS (ESI) m/z 285.0(M+H", 100%).

[method 1]. HPLC provided compound A85 as yellow oil (77 mg, 69 % yield). "H NMR 400MHz CDCl; & (ppm): 8.01(s, 1H); 7.71 (dd,2H); 7.62 (dd, 2H); 7.41 (tt, 111); 7.30 (dt, 2H); 7.07 (dt,3H); 3.92 (d, 2H); 2.86 (td,2H); 1.62 (dd, 2H); 1.39 (m, 1H); 1.14 (dt, 2H); 1.06 (t,2H); 1.06 (q, 2H); 0.72 (3H). Exact mass calculated for C,sHasN,Os 446.20, LCMS (EST) m/z 447.2 (M+H", 100%).

Compound A86 {4-Methoxy-2-[5-nitro-6-(4-propyl-piperidin-1-yI)-pyrimidin-4-yloxy] -phenyl}-phenyl- methanone; [method 1]. HPLC provided compound A86 as orange oil (67 mg, 57 % yield). "H NMR 400MHz CDCl; S(ppin): 7.88 (s, 1H); 7.50 (dd, 210); 7.40 (5,110); 7.37 (tt,111); 7.30 (t,1H); 7.22 (t,2H); 6.71 (dd,1H); 6.625 (d, 1H); 3.81 (d, 2H); 3.71 (5,3H); 2.81 (td, 2H); 1.58 (dd, 2H); 1.36 (m, 1H); 1.16 (dt, 2H); 1.06 (td,2H); 1.01 (dd, 2H); 0.73 (t,3H). Exact mass calculated for C,sH,sN,05 476.21, LCMS (ESI) m/z 476.9(M-+H", 100 %).

Compound A87 4-{4-[5-Nitro-6-(4-propyl-piperidin-1-y))-pyrimidin-4-yloxy]-phenyl}-butan-2-one; [method 1]. HPLC provided compound A87 as yellow solid (62 mg, 59 % yield). "H NMR 400MHz CDCl, 8(ppmy): 8.08 (s, 1H); 7.13 (d,2H); 6.95 (,2H); 4.00 (d, 2H); 2.96 (td,2H); 2.82 (1,2H); 2.69 (t, 2H); 2.07 (s, 3H); 1.71 (dd, 2H); 1.48 (m, 1H); 1.27 (m, 2H); 1.17 (m, 4H); 0.83 (t,3H). Exact mass calculated for C2HsN,04 412.21, LCMS (ESD) m/z 413.4 (M+HY, 100 %).

Compound ASS 5-Nitro-4-(4-propyl-piperidin-1-yl)-6-(4-[1,2,3] thiadiazol-4-yl-phenoxy)-pyrimidine; [method 1]. HPLC provided compound A88 as yellow solid (61 mg, 56 % yield). '"H NMR 400 MHz CDCl; & (ppm): 8.56 (s, 1H); 8.11 (s, 1H); 8.02 (d, 2H); 7.22 (d,2H); 4.03 (4, 2H); 2.96 (td,2H); 1.73 (dd, 2H); 1.48 (m, 1H); 1.27 (m, 2H); 1.2 (m, 4H); 0.84 (t,3H). Exact mass calculated for CyoH,NeO; $426.15, LCMS (ESI) m/z 427.1 (M+H", 100 %).

Compound A89 3-{4-[5-Nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yloxy]-phenyl}-3-oxo-propionic acid methyl ester; [method 1]. HPLC provided compound A89 and A89a [enol] as yellow solid (12 mg, 4 mg, 18 % yield)."H NMR 400 MHz CDCl, § (ppm): A89: 8.08 (s, 1H); 7.94 (d, 2H); 7.18 (d, 2H); 4.02 (d, 2H); 3.92 (s,2H); 3.68 (s,3H); 2.96 (td,2H); 1.72 (dd, 2H); 1.50 (m, 1H); 1.26 (m,

PCT/US2004/001267 2H); 1.17 (m, 4H); 0.83 (t,3H). A89a: 8.08(s, 1H); 7.94(d, 2H); 7.75(dd, 2H); 7.12 (dd,2H); 5.57(s, 1H); 4.02 (d, 2H); 3.73 (s,3H); 2.96 (1,2H); 1.72 (d, 2H); 1.51(m, 1H); 1.26 (m, 2H); 1.18 (m, 4H); 0.83 (t,3H). Exact mass calculated for C,,HyeN4Os442.19, LCMS (EST) m/z 443 3(M+H", 100%).

Compound A90 .

S-Ethanesulfonyl-2-[5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yloxy]- phenylamine; (method 1]. HPLC provided compound A92 as yellow solid (60 mg, 53 % yield). "H NMR 400MHz CDCl; 8 (ppm):10.2 (s, 1H); 7.97 (s, 1H); 7.63 (d, 1H); 7.61 (s, 1H); 7.11 (d, 1H); 3.13 (td, 2H); 3.04 (q, 2H); 1.81 (d, 2H); 1.59 (m, 1H); 1.28 (m, 2H); 1.2 (m, 411); 0.84 (t, 3H). Exact mass calculated for C,0H,,NsOs S 449.17, LCMS (EST) m/z 450.3 (MH, 100 %).

Compound A91 4-[4-(3-Isopropyl-{1,2,4] oxadiazo}-5-yl)-piperidin-1-y1]-6-(4-methanesulfonyl-phenoxy)- pyrimidine-5-carbonitrile; 4,6-Dichloro-pyrimidine-5-carbonitrile (254 mg, 1.47 mmol) was dissolved in DMF (3 mL).

K,CO; (203 mg, 1.47 mmol) and phenoxy methyl sulfone (253 mg, 1.47 mmol) were added to the solution at 0 °C. The reaction was stirred for 30 min. The completion of the reaction was

Judged with TLC (EtOAc: Hex =1:1, R= 0.82). After the completion of the reaction, were added the oxodiimidazol (340 mg, 1.47 mmol) and K,CO; (406 mg, 2.94 mmol) to the reaction at 0 °C. The reaction was warmed to rt and stirred for 30 min. The reaction was heated to 40 °C and maintained for 1 h. The reaction was cooled to 13, poured in to H,0 {50 mL) and exiracted with EtOAc (50 mL, two times). The EtOAc was dried over MgSO; and concentrated under vacuum. The crude product was purified over SiO, (EtOAc : Hex=1 * 1, Ry=0.39) to afford the desired compound ( 523 mg; 76.1%). "H-NMR (DMSO-d): 8.32 (1H, 5), 8.02 (2H, J =4.3 Hz, — d), 8.00 (2H, T=4.3 Hz, d), 4.68 (2H, m), 3.50 (2H, m), 3.32 (1H, m), 3.44 (3H, 5), 3.05 (1H, m), / 2.22 (2H, m), 1.83 (2H, T= 17Hz, d), 1.25 (6H, J = 7 Hz, d) ppm. LCMS: 469.4, 384.9, 357.2.

The starting material, 4,6-Dichloro-pyrimidine-5-carbonitrile, used in the preparation of

Compound A91 was prepared in the following manner: To a solution of 5-fomyl-4,6- dichloropyrimidine (3.6 g, 20.3 mmol) in EtOAc (50 ml), was added a solution of NH,OH-HCl (141 g, 20.3 mmol) in H,O (30 ml) followed by AcONa (1.67 g, 20.3 mmol) at rt. After stirring for 2h, the reaction was washed with H,0O (50 ml, two times) and dried over MgSO,. The EtOAc was concentrated under vacuum to afford the crude iminohydroxy compound (3.51 g, 90.2%).

The crude compound was used for next step without further purification. The iminchydroxy compound (3.51 g, 18.3 mmol) was dissolved in SOCI, (20 ml) at 0 °C and stirred for 30 min.

The reaction was warmed to rt and maintained for 3h. The reaction was poured into H,0 (100 g)

PCT/US2004/001267 portionwise and stirred for 30 min. The precipitate was filtered, washed with H,O (100 ml.) and dried under vacuum to afford 4,6-Dichloro-pyrimidine-5-carbonitrile (2.99g, 91%). "H-NMR (DMSO-d): 8.53 ppm; LCMS: not detectable.

Compound A92 1-[6-(4-Difluoromethoxy-benzyloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; ) [Method 7]. The residue was purified by preparatory LCMS. 'H NMR, 400 MHz, CDCl, 6 (ppm): 8.19 (s, 1H); 7.38 (d, 2H); 7.08 (d, 2H); 6.47 (m, 1H); 5.43 (s, 2H); 4.12 (q, 2H); 3.93 (m, 2H); 3.12 (m, 2H); 2.56 (m, 1H); 1.96 (m, 2H); 1.76 (m 2H); 1.23 (t, 3H). LCMS (ESD for CooHpF; Ni Og m/z 452 (MH, 100 %).

Compound A93 1-[6-(3-Difluoromethoxy-benzyloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl! ester; [Method 7]: The residue was purified by preparatory LCMS. 'H NMR, 400MEz, CDCl, § . (ppm): 8.16 (s, 1H); 7.29 (t, 1H); 7.17 (d, 1H); 7.11 (s, 1H); 7.00 (d, 1H); 6.45 (m, 1H); 5.40 (s, 2H); 4.08 (q, 2H); 3.89 (m, 2H); 3.08 (m, 2H); 2.52 (m, 1H); 1.92 (m, 2H); 1.74 (m 2H); 1.19 (t, 3H). LCMS (ESI) for CyoF,,F,N,Of: m/z 452 (MH, 100 %).

Compound A9%4 : 2-{1-[6-(2-Methy)-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl]- piperidin-4-vI ethangl; : [methds 2 followed by 3]. Purification by HPLC yielded brownish oil. Yield 21 %. 'H NMR 400MHz CDCl 8 (ppm): 8.50 (s, 1H); 6.76 (s, 1H); 4.37 (d, 2H); 4.04 (s, 3H); 3.99 (tn, 2H); 3.33 (t, 2H); 1.82 (m, 8H). LCMS (ESD) mvz 417 (M=H", 100 %) -

Compound A95 3-{1-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl}- piperidin-4-yl}-propionic acid; [method 2 followed by 3]. Purification by HPLC yielded brownish solid. Yield 21 %. 'H

NMR 400 MHz CDCl; 8 (ppm): 8.20 (s, LH); 6.45 (s, 1H); 4.07 (d, 2H); 3.74 (s, 3H); 3.01 (m, 2H); 2.33 (m, 2H); 2.19 (m, 2H); 1.58 (m, 4H); 1.28 (m, 4H). LCMS (ESD m/z 459 (M+, 100 %)

Compound A96

4-[4-(4-Methyl-benzyl)-piperidin-1-yi]-6-(2-methyl-5-triftuoromethyl-2H-pyrazol-3- yloxy)-5-nitro-pyrimidine; [method 2 followed by 3]. Purification by Flash Chromatography yielded an yellow oil. }

Yield 29 %. *H NMR 400MHz CDCl; 8 (ppm): 8.25 (s, 1H); 7.11 (wm, 2H); 7.04 (m, 2H); 6.51 (s, 1H); 4.12 (m, 2H); 3.79 (s, 3H); 3.03 (t, 2H); 2.57 (d, 2H); 2.34 (5, 3H); 1.83 (m, 3H); 1.33 (m, 2H). LCMS (ESI) m/z 477 (M+H", 100 %)

Compound A97 4-(3-Methanesulfonyl-pyrrolidin-1-yl)-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3- yloxy)-5-nitro-pyrimidine; [methods 2 and 3]. Purification by HPLC yiclded brownish oil. Yield 30 %. LCMS (ESD) m/z 438 (MH, 100%)

Compound A98 4-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-6-[4-(2-frifluoromethyl- phenoxy)-piperidin-1-yl}-pyrimidine; [methods 2 and 3]. Purification by HPLC yielded ‘orange solid. Yield 77 %. "H NMR 400

MHz CDCl; 8 (ppm): 8.29 (s, 1H); 7.1 (d, 1H); 7.51 (t, 1H); 7.02 (m, 2H); 6.54 (s, 1H); 3.82 : (m, 7TH); 2.09 (m, SH). LCMS (ESI) m/z 533.1 (M+H", 100 %) :

Compound A99 4-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-6-[4-(pyridin-2-ylsulfanyl)- piperidin-i-yij-pyrimidine; [methods 2 and 3]. Purification by HPLC yielded A99 as a brown oil. Yield 12 %. 'H NMR 400MHz CDCl; 8 (ppm): 8.31 (s, 1H); 6.54 (s, 1H); 4.22 (d, 2H); 3.82 (s, 3H); 3.12 (m, 2H); 2.40 (m, 1H); 2.03 (m, 2H); 1.72 (m, 2H). LCMS (ESI) m/z 482.1 (M+H, 100 %)

Compound A100 4'-(4-Benzoyl-phenoxy)-3'-nitre-3,4,5,6-tetrahydro-2H-[1,2'|bipyridinyl-4-carboxylic acid ethyl ester; [method 1a}. Purification by HPLC provided compound A100 as yellow solid (43 mg, 41 %}. "H NMR 400MHz CDCl; 8(ppm): 7.84 (d,1H); 7.81 (s, 2H); 7.73 ( d, 2H); 7.52 (t,1H); 7.41 (q,2H); 7.17 (d, 2H); 6.57 (d, 1H); 4.10 (q, 2H); 3.48 (dt,2H); 3.03 (td, 2H); 2.50 (m, 5H); 1.96 (dd, 2H); 1.81 (td, 2H); 1.21 (t, 3H). Exact mass calculated for C;sH,sN:05475.17

LCMS (ESD m/z 476.0 (M+H", 100%).

Compound A101 3'-Nitro-4'-[4-(3-0x0-butyl)-phenoxy]-3,4,5,6-tetrahydro-2H-[1,2'[bipyridinyl-4- carboxylic acid ethyl ester; [method 1]. Purification by HPLC provided compound A101 as yellow oil (49 mg, 49 %). ‘1 “NMR 400MHz CDCl; 8(ppm): 7.89 (d,1H); 7.21 (4, 2H); 7.05 (d, 2H); 6.60 (d,1H); 4.19 (q,2H); 3.56 (dt, 2H); 3.12 (td, 2H); 2.91 (4, 2H); 2.78 (12H); 2.59 (t, 1H); 2.17 (s, 3H); 2.04 (dd, 2H); 1.89 (m, 2H); 1.30 (t, 3H). Exact mass calculated for CoH N30 441.19 LCMS (EST) m/z 442.5 (M+H", 100%).

Compound A102 } 4'-[4-(2-Methoxycarbonyl-acetyl)-phenoxy]-3'-nitro-3,4,5,6-tetrahydro-2H- [1,2']bipyridinyl-4-carboxylic acid ethyl ester; [method 1a]. HPLC provided compound A102 as yellow solid (28 mg, 27 %). "H NMR 400MHz CDCl; § (ppm): 8.03 (d, ZH); 7.92 (d, 1H); 7.24 (d, 2H); 6.65 (d, 1H); 4.19 (q, 2H); 3.57 (dd, 2H); 3.12 (td, 2H); 2.62 (s, 3H); 2.59 (m, 1H); 2.05 (dd, 2H); 1.90 (m, 2H); 1.30(, 3H). Exact mass calculated for C,3H,sN305 471.16 LCMS (ESD m/z 472.4 (M+H, 100 %). © ’

Compound A103 4'-(2-Amino-4-ethanesulfonyl-phenoxy)-3'-nitro-3,4,5,6-tetrahydro-2H-[1,2'|bipyridinyl- 4-carboxylic acid ethyl ester; [method 1a]. HPLC provided compound A103 as brown solid (61 mg, 57 %). "HNMR 400MHz CDCl; 8(ppm): 9.83 (s,1H); 7.97 (d, 1H); 7.45 (dd, 1H); 7.10 (d,1H); 6.76 (d, 1H); 4.10 (q,2H); 3.45 (d, 2H); 3.16 (m, 4H); 2.69 (mm, 1H); 1.93 (d,2H); 1.69 (t, 2H); 1.18 (1,3H); 1.12 (t, 3H). Exact mass calculated for C,HyeN,O, S 478.15 LCMS (ESI) m/z 479.2 (M+H', 100 Y%).

Compound A104 4'-(4-Imidazol-1-yl-phenoxy)-3"-nitro-3,4,5,6-tetrahydro-2H-[1,2' | bipyridinyl-4- carboxylic acid ethyl ester; [method 1a]. HPLC provided compound A104 as brown oil (64 mg, 65 %). "HNMR 400MHz CDCl; § (ppm): 8.85 (s, 1H); 7.90 (d, 1H); 7.57 ( d, 1H); 7.53 (dd,2H); 7.45 (d, 1H); 7.41 (dd, 2H); 4.20 (q, 2H); 3.56 (d, 2H); 3.13 (td, 2H); 2.60 (m, 1H); 2.06 (dd, 2H); 1.90 (td, 2H); 1.30 (t, 3H). Exact mass calculated for C»,H,,N505437.17 LCMS (ESI) m/z 438.3(M-+H", 100%).

Compound A105

4-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-6-(4-trifluoromethyl- piperidin-1-yI)-pyrimidine; [method 2 followed by 3]. Purification by HPLC yielded orange oil.. Yield 41 %. 'H NMR 400MHz CDCl; 8 (ppm): 8.31 (s, 1H); 6.54 (s, 1H); 4.22 (d, 2H); 3.82 (s, 3H); 3.12 (m, 2H); 2.40 (m, 1H); 2.03 (m, 2H); 1.72 (m, 2H). LCMS (ESI) m/z 481.1 (MH, 100%)

Compound A106 4-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-6-(4-phenylsulfanyl- piperidin-1-yD)-pyrimidine; [method 3]. Purification by HPLC yielded A106 as an orange solid. Yield 55 %. "HNMR 400MHz CDCl; 8 (ppm): 8.28 (5, 1H);7.47 (my, 2H); 7.34 (1, 2H), 6.53 (s, 1H); 4.03 (d, 2IT); 3.82 (s, 3H); 3.42 (m, 1H); 3.33 (m, 2H); 2.09 (m, 3H); 1.74 (m, 2H). LCMS (ESD) m/z 481.1 (MAH, 100 %)

Compound A107 1-[6-(3-Ethynyl-phenoxy)-5-nitro-pyrimidin-4-yI]-piperidine-4-carboxylic acid ethyl : ester; [method 1a]. Purification by by semi preparatory HPLC afforded the pure product in 50 %.

TH NMR, 400MHz, CDCl, 8 (ppm): 8.12 (s, 1H); 7.30 (m, 2H); 7.19 (s, 1H); 7.06 (m, 1H); 4.10 (q, 2H); 3.95 (m, 2H); 3.14 (m, 2H); 3.03 (5, 1H); 2.56 (m, 1H); 1.95 (m, 2H); 1.76 (m, 2H); 1.20 (t, 3H). LCMS (ESI) for Cy0H0N,O0s: m/z 396 (M+H, 100 %).

Compound A108 1-[6-(4-Chloro-2-fluoro-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; {method 1a]. Purified by semi preparatory HPLC afforded the pure product in 42 %. 'H

NMR, 400MHz, CDCls, § (ppm): 8.00 (s, 1H); 7.06 (m, 3H); 4.02 (q, 2H); 3.86 (m, 2H); 3.07 (m, 2H); 2.48 (m, 1H); 1.87 (m, 2H); 1.69 (m, 2H); 1.12 (t, 3H). LCMS (ES)) for

CisH;CIEN,O5: m/z 424 (MH, 100 %).

Compound A109 1-[6-(2,4-Difluoro-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; [method1a]. purified by semi preparatory HPLC afforded the pure product in 34 %.

PCT/US2004/001267 'H NMR, 400MHz, CDCl,, 5 (ppm): 8.14 (s, 1H); 7.15 (m, 1H); 6.89 (m, 2H); 4.14 (q, 2H); 3.98 (m, 2H); 3.19 (m, 2H); 2.60 (m, 1H); 2.00 (m, 2H); 1.82 (m, 2H); 1.24 (t, 3H). LCMS (ESD) for CysH1sFoN,0s: m/z 408 (MH, 100 %).

Compound A110 : 1-]6-(4-Bromo-2-fluoro-phenoxy)-5-nitro-pyrimidin-4-ylj-piperidine-4-carboxylic acid ethyl ester; [method 1a}. purified by semi preparatory HPLC afforded the pure product in 41 %. ‘H

NMR, 400MHz, CDCls, 5 (ppm): 8.07 (s, 1H); 7 .26(m, 2H); 7.02 (t, 1H); 4.09(q, 2H); 3.94 (m, 2H); 3.14 (m, 2H); 2.55 (m, 1H); 1.95 (m, 2H); 1.76 (m, 2H); 1.19 (t, 3H). LCMS (ESI) for C;gH;sBrFN,O5: m/z 468 (M-+HY, 100 %).

Compound A111 4-(3-Ethynyl-phenoxy)-5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidine; [method 1a]. purified by semi preparatory HPLC afforded the pure product in 28 %. 'H

NMR, 400MHz, CDCl, 6 (ppm): 8.07 (s, 1H); 7.28 (m, 2H); 7.19 (m, 1H); 7.05 (m, 1H);. : - 4.00 (m, 2H); 3.01 (s, 1H); 2.93 (m, 2H); 1.71 (m, 2H); 1.48 (m, 1H); 1.28 (m, 2H); 1.16 (m, 4H); 0.83 (t, 3H). LCMS (BSI) for CyoHz5N,05: m/z 366 (MH, 100 %).

Compound A112 4-(4-Chloro-2-fluoro-phenoxy)-5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidine; : [method 1a]. Purified by semi preparatory HPLC afforded the pure product in 39 %. 'H

NMR, 400MHz, CDCl, 8 (ppm): 2.04 (5, 1D); 7.13 (a, 3H); 4.01 (m, 25); 2.94 (m, ZH); 1.71 (m, 2H); 1.49 (m, 1H); 1.28 (m, 2H); 1.16 (m, 4H); 0.82 (t, 3H). LCMS (ESI) for

CisHoCIFN.O;: mvz 394 (MH, 100 %).

Compound A113 4-(2,4-Difluoro-phenoxy)-5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidine; [method 1a]. purified by semi preparatory HPLC afforded the pure product in 54 %. 'H :

NMR, 400MHz, CDCl;, 6 (ppm): 8.04 (s, 1H); 7.10 (m, 1H); 6.85 (m, 2H); 4.00 (m, 2H); 2.94 (m, 2H); 1.71 (m, 2H); 1.49 (m, TH); 1.28 (m, 2H); 1.16 (m, 4H); 0.82 (t, 3H).LCMS (ESI) for C1sHaoF;N4O5: m/z 378(M+H", 100 %).

Compound A114 4-(4-Bromo-2-fluere-phenoxy)-5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidine; [method 1a]. purified by semi preparatory HPLC afforded the pure product in 62 %. 'H

NMR, 400MHz, CDCls, & (ppm): 8.15 (s, 1H); 7.35 (m, 21D); 7.12 (¢, 1H); 4.10 (m, 2H);

3.10 (m, 2H); 1.81 (m, 2H); 1.59 (m, 1H); 1.36 (m, 2H); 1.26 (m, 4H); 0.93 (t, 3H). LCMS (ESD) for CigHyoBrFN,0:: m/z 438 (M+H', 100 %).

Compound A115 3'-Nitro-2'-[4-(3-ox0-butyl)-phenoxy}-3,4,5,6-tetrahydro-2H-[1,4"|bipyridinyl-4- carboxylic acid ethyl ester;

General Procedure 2:

Intermediate monochloro as a yellow oil (128 mg, 80 % vield).Exact mass calculated for

CisHia CIN,0,4 320.06, LCMS (ESD) m/z 320.8(M+H", 100%). [method 1a]. HPLC provided compound A119 as yellow oil (44 mg, 50 %). 'H NMR 400MHz CDCl; (ppm): 8.30 (d,1H); 7.42 (d, 2H); 7.18 ( d, 2H); 6.40 (d, 1H); 4.34 (g, 2H); 3.95 (dt, 2H); 3.36 (td, 2H); 3.10(t, 2H); 2.96 (t, 2H); 2.74 (m, 1H); 2.34 (5, 3H); 2.20 (dt, 2H); 2.05 (id, 2H); 1.44 (t, 3H). Exact mass calculated for CH N3Og441.19 LCMS (ESI) m/z 442.3 (MAH, 100%).

Compound A116 4-[4-(3'-Nitro-4-propyl-34,5,6-tetrahydro-2H-[1,4'|bipyridinyl-2'-yloxy)-phenyl]-butan- . 2-one; {method 1a]. HPLC provided compound A116 as yellow oil (34 mg, 32 %)."H NMR 400MHz CDCI; §(ppm): 8.09 (d,1H); 7.24 (d, 2H); 7.00 (d, 2H); 6.15 (d,1H); 3.80 (d, 2H); 3.06 (td, 2H); 2.91 (t,2H); 2.77 (t, 2H); 1.77 (4, 2H); 1.51 (m, 1H); 1.36-1.22 (m, 6H); 0.8 (t,3H). Exact mass calculated for C,3HsN30,411.22 LCMS (ESD) m/z 412.4 (M+H", 100 %).

Compound A117 ) 2'-(4-Benzoyl-phenoxy)-3'-nitro-3,4.5,6-tetrahydro-2H-[1,4'|bipyridinyl-d-carboxylic acid ethyl ester; [method 1a]. HPLC provided compound A117 as yellow oil (37 mg, 39 %). "H NMR 400MHz CDCl; 8(ppm): 8.24 (d,1H); 7.97 (d, 2H); 7.86 (d, 2H); 7.68 (t,1H);7.57(t, 2H); 7.27 (d, 2H); 6.36 (d,1H); 4.23 (q, 2H); 3.87 (dt, 2H); 3.23 (td, 2H); 2.66-2.60 (m, 1H); 2.08 (dt, 2H); 1.92 (td, 2H); 1.33 (t,3H). Exact mass calculated for C,¢H;sN30¢475.17 LCMS (ESD) m/z 476.2(M+H, 100%).

Compound A118 4-(4-{5-Nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yloxy}-phenyl)- butan-2-one; } [method 1a]. The crude was dissolved in dichloromethane and purified by preparative TLC. [SiO;; 20/80 EtOAc/hexanes]. Yield 37 mg, 48 %. Yellow solid. "H-NMR (400 MHz, .

PCT/US2004/001267 © CDC) 5 (ppm) 8.36 (, 1H); 8.1 (s, 1H); 7.42 (ddd, 160); 7.11 (am, 3H); 6.95 (m, 3H); 4.12 (heptet, 1H); 3.94 (it, 2H); 3.33 (m, 2H); 2.84 (m, 2H); 2.70 (m, 2H); 2.15 (m, 2H); 2.08 (s, 3H); 1.75 (m, 2H). LCMS (ESD, m/z 480 (M+H*, 100%)

Compound A119 . [4-(3'-Nitro-4-propyl-3,4,5,6-tetrahydro-2H-[1,4'| bipyridiny}-2'-yloxy)-phenyl]-phenyl- methanone;

General Procedure 2: Intermediate monochloro as a yellow oil (142 mg, 80 % yield). Exact mass calculated for CigHyy CIN,0,354.04, LCMS (EST) m/z 355.2(M+H", 100%). method 1a]. HPLC provided compound A119 as yellow solid (26 mg, 29 %). "H NMR. 400MHz

CDCl; 8(ppm): 8.33 (d,1H); 8.07 (d, 2H), 7.94 (4, 2H); 7.77 (m,1H); 7.65 (t, 2H); 7.37 (d, 2H); 6.44 (d,1H); 3.96 (d, 2H); 3.28 (td, 2H); 1.95 (d, 2H); 1.71-1.65 (m, 1H); 1.51-1.38 (m, 6H); 1.1 (t,3H). Exact mass calculated for CusH2N304 445.20 LCMS (ESD m/z 446.0(M+H", 100 %).

Compound A120 4-(4-{5-Nitro-6-[4-(2-trifluoromethyl-phenoxy)-piperidin-1-yl|-pyrimidin-4-yloxy}- phenyl)-butan-2-one; ‘ [method 2 followed by method 1]. Yield 0.173 g, 83 %. Yellow solid. "Hf NMR 400MHz

CDCl; 4 (ppm): 8.30 (s, 1H); 7.53 (m, 1H); 7.42 (m, 1H);6.93 (m, 2H); 4.75 (m, 1H); 3.77 (m, 2H); 3.56 (m, 2H); 1.95 (m, 4H). LCMS (ESI) m/z 403 (M+H",100%) [method 1a]. Compound A120 purified through a silica plug [SiO,; EtOAc/hexane; 20:80]. ‘

Yicld 0.067 g, 85 %. Yellow oil. "H NMR 400MHz CDCl; § (ppm): 8.12 (s, 1H); 7.53 (m, 1H); 7.42 (m, 1H); 7.15 (tm, 2H); 6.97 (m, 4H); 3.72 (m, 2H); 3.60 (m, 2H); 2.82 (m, 2H); 2.70 (m, 3H); 2.08 (m, 4H); 1.97 (m, 4H). LCMS (ESD) m/z 531 (M+H",100 %)

Compound A121 4-(4-{6-[4-(3-Methyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yloxy}- phenyl)-butan-2-one; [method 1]. Purification by HPLC. Yield 52 %. Yellow solid. 'H NMR 400MEz CDCl; 8 (ppm): 8.11 (5, 1HD);); 7.17 (d, 2H); 6.98 (4, 2H); 4.06 (d, 2H); 3.23 (t, 2H); 3.12 (d, 2H); 3.00 (m, 2H); 2,85 (t, 2H); 2.72 (t, 2H); 2.10 (s, 3H); 1.81 (m, 4H); 1,28 (m, 2H); 0.84 (t, 6H).

LCMS (ESI) m/z 453 (M+H", 100 %) [method 1a]. Purification by HPLC yielded a yellow solid. Yield 62 %. 'H NMR 400MHz

CDCl; 8 (ppm): 8.13 (s, 1H); 7.15 (d, 2H); 6.98 (d, 2H); 4.02 (d, 2H); 3.22 (m, 3H); 2.83 (t, .

2H); 2,70 (t, 2H); 2.33 (s, 3H); 2.10 (m, SH); 1.04 (m, 2H). LCMS (ESI) m/z 453.2 (M+H,

Compound A122 (4-{6-[4-(3-Methyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yloxy}- phenyl)-phenyl-methanone;

Purification by HPLC yielded yellow solid. Yield 68 %. 'H NMR 400MHz CDCl, 8 (ppm): 8.04 (s, 1H); 7.71 (d, 2H); 7.61 (d, 2H); 7.41 (m, 1H); 7.30 (m,2H); 7.08 (m, 2H); 3.92 (d, 2H); 3.13 (m, 3H); 2.21 (5, 3H); 2,02 (m, 2H); 1.83 (m, 2H). LCMS (ESI) m/z 487.1 (M+H", 100 %)

Compound A123 1-{6-[4-(4-Fluoro-benzoyl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; [method 1]. HPLC provided compound A123 as yellow solid (85 mg, 86 % yield). "H NMR. 400MHz CDCl; 8 (ppm): 8.13 (s,1H); 7.79 (d, 2H); 7.76 (d, 2H); 7.20 (d, 2H); 7.10 (d,2H); 4.09 (q, 2H); 3.96 (dt,2H); 3.15 (td, 2H); 2.59-2.52 (m, 1H); 1.96 (dt, 2H); 1.77 (td, 2H); 1.19 (t,3H). Exact mass calculated for C,sH,s FN,Os 494.16, LCMS (ESI) m/z 495.1 (M+H, 100 %).

Compound A124 (4-Fluoro-phenyl)-{4-[5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yloxy]-phenyl}- methanone; [method 1]. HPLC provided compound A124 as yellow solid (69 mg, 84 % yield). '"H NMR 400MHz CDCl; 8(ppm): 8.10 (s, 1H); 7.78 (d. 2H); 7.76 (d, 2H); 7.19 (4, 2H); 7.09 (it, 2H); 4.03 (d, 2H); 2.96 (td, 2H); 1.73 (dd, 2H); 1.51(m, 1H); 1.37 (m, 2H); 1.21 (m, 2H); 1.15(m, 2H); 0.83 (t, 3H). Exact mass calculated for CpsH,sFN,0, 464.19, LCMS (ESD m/z 465.2 (M+H", 100%).

Compound A125 4-[4-(3-Methyl-[1,2 4] oxadiazo}-5-yl)-piperidin-1-yl]-6-(2-methyl-5-trifluoromethyl-2H- pyrazol-3-yloxy)-5-nitro-pyrimidine; [method 3]. Purification by HPLC yielded yellow oil. Yield 38 %. ‘H NMR 400MHz CDCl, 3 (ppm): 8.16 (s, 1H); 6.38 (s, 1H); 3.98 (d, 2H); 3.65 (5, 3H); 3.21 (m, 3H); 2.26 (s, 3H); 2.08 (m, 2H); 1.89 (m, 2H). LCMS (ESI) m/z 417 (M-+H*, 100 %)

Compound A126 4-(4-Methoxymethyl-piperidin-1-yI)-6-(2-methyl-5-trifluoromethyl-2B-pyrazol-3-yloxy)-

S-nitro-pyrimidine; [method 3]. Purification by HPLC yielded A126 as a yellow oil. Yield 21 %. 'H NMR 400MHz CDCl; 8 (ppm): 8.05 (s, 1H); 6.30 (s, 1H); 3.93 (d, 2H); 3.59 (s, 3H); 3.15 (s, 3H); 3.07 (m, 2H); 2,89 (m, 2H); 1.69 (m, 3H); 1.15 (m, 2H). LCMS (ESD) m/z 417 (M+H", 100%)

Compound A127 4-{4-[6-(4-Methoxymethyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-phenyl}-butan-2- one; [method 1a]. Purification by HPLC yielded A127 as a yellow solid. Yield 19 %. "TH NMR 400 MHz CDCl, 8 (ppm): 8.04 (s, 1H); 7.07 (d, 2H); 6.91 (d, 2H); 3.98 (d, 2H); 3.22 (s, 3H); 3.14 (d, 2H); 2.92 (m, 2H); 2,76 (mm, 2H); 2.64 (m, 2H); 2.02 (s, 3H); 1.74 (m, 3H); 1,20 (m, 2H). LCMS (ESI) m/z 414.45 (M-HH', 100 %)

Compound A128 4-{4-(2-Methoxy-ethyl)-piperidin-1-yl]-6-(2-methy)-5-trifluoromethyl-2H-pyrazol-3- yloxy)-5-nitro-pyrimidine; [method 2 followed by 1a]. Purification by HPLC yielded orange solid. Yield 41 %. 'H

NMR 400 MHz CDCl, 8 (ppm): 8.11 (s, 1H); 6.36 (s, 1H); 3.97 (d, 2H); 3.65 (s, 3H); 3.33 (m, 2H); 3.22 (5, 3H); 2,93 (m, 2H); 1.69 (m, 3H); 1.43 (m, 2H); 1.16 (m, 2H). LCMS (ESI) m/z 431.1 (M+H", 100 %)

Compound A129 4-{4-[6-(4-Ethoxymethyl-piperidin-1-yl)-5-nitro-pyrimidin-4-vloxy] -phenyl}-butan-2- one; . [method 1a] A129 was purified by HPLC. 'H NMR 400MHz CDCl; & (ppm): 8.00 (s, 1H), 7.10 (d, 2H), 6.80 (d, 2H), 3.90 (m, 2H), 3.30 (q, 2H), 3.15 (4, 2H), 2.90 (m, 2H),2.70 (t, 2H), 2.60 (t, 2H), 2.00 (s, 3H) 1.70 (m, 3H), 1.20 (m, 2H), 1.00 (t, 2H). LCMS (ESI) for

CHpsN4Os: m/z 429.0 (M + HY, 100 %)

Compound A130 4-(2,4-Difluorc-phenoxy)-5-nitro-6-[4-(pyridin-2-ylsulfanyl)- piperidin-1-yl]-pyrimidine; [method 1a] A130 was purified by semi preparatory HPLC afforded the pure product in 73 %. 'H NMR, 400MHz, CDCl, § (ppm): 8.67 (d, 1TH); 8.10(s, 1H); 7.80 (t, 1H); 7.42 (d, 1H);

7.31(t, 1H); 7.11 (m, 1H); 6.88 (m, 2H); 4.12 (m, 1H); 3.99 (m, 2H); 3.29 (m, 2H); 2.14 (m, 2H); 1.76 (m, 2H). LCMS (EST) for CooH17F,N50,S: m/z 445 (MAH, 100 %).

Compound A131 (4-Methoxy-2-{5-nitro-6-[4-(pyridin-2-ylsultanyl)-piperidin-1 -yI}-pyrimidin-4-yloxy}- phenyl)-phenyl-methanene; [method 1a] Purified by semi preparatory LCMS afforded the pure product in 38 %. 'H

NMR, 400 MHz, CDCl, 6 (ppm): 8.55 (d, 1H); 7.98 (s, 1H); 7.62 (m, 3H); 7.46 (m, 2H); 7.31 (m, 31); 7.15 (m, 1H); 6.80 (m, 1H); 6.72 (d, 1H); 4.05 (m, 1H); 3.86 (m, 2H); 3.82 (s, 3H, -OCHs); 3.22 (m, 2H); 2.09 (m, 2H); 1.70 (m, 2H). LCMS (ESI) for CaH,sNsOsS: m/z 543 (M+H', 100 %).

Compound A132 4-(2,4-Difluoro-phenoxy)-6-(4-ethoxymethyl-piperidin-1-yI)-5-nitro-pyrimidine; [method 1]. crude product was purified by HPLC to afford yellow oil (35.4 mg, 27 %). 'H

NMR 400MHz CDCl; § (ppm): 8.20 (s, 1H), 7.20 (m, 1H), 6.80 (d, 2H),7.00-6.90 (m, 2H),4.10 (m, 2H), 3.50 (d, 2H), 3.10 (m, 2H), 2.00 (m, 1H), 1.90 (m, 2H), 1.40 (m, 2H), 1.20 (t, 3H). LCMS (ESI) for CigH0FN,O4: m/z 395.1 (M +H, 100 %)

Compound A133 ’ 4-{4-16-(4-Cyclopropylmethoxymethyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]- phenyl}-butan-2-one; [method 2 followed by method 1a]. Purification by HPLC yielded yellow solid. Yield 53 %. 'H NMR 400 MHz CDC, 5 (ppm): 7.97 (s, 1H);); 7.02 (d, 2H); 6.84 (d, 2H); 3.92 (4, 21); 3.13 (m, 2H); 3.07 (m, 2H); 2.86 (m, 2H); 2,71 (m, 2H); 2.57 (m, 2H); 1.56 (s, 3H); 1.70 (m, 3H); 1.13 (m, 2H); 0.85 (m, 1H); 0.34 (m, 2H); 0.01 (m, 2H). LCMS (ESI) m/z 455.2 (M+H", 100 %)

Compound A134 4-{4-[5-Nitro-6-(4-propoxymethyl-piperidin-1-yl)-pyrimidin-4-yloxy]-phenyl}-butan-2- one; [method 2 followed by 1a). Purification by HPLC yielded yellow solid. Yield 22 %. 'H i

NMR 400MHz CDCl, 8 (ppm): 8.03 (s, 1H);); 7.08 (d, 2H); 6.90 (d, 2H); 3.98 (d, 2H); 3.24 (t 2H); 3.16 (d, 2H); 2.92 (m, 2H); 2,76 (m, 2H); 2.63 (m, 2H); 2.01 (5s, 3H); 1.74 (m, 3H); 1.45 (m, 2H); 1.19 (m, 2H); 0.78 (t, 3H). LCMS (ESI) m/z 443.3 M-+H', 100 %)

Compound A135 1-{4-[6-(4-Methoxymethyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-phenyl}-ethanone; [method 1a]. Yield 12 %. "H NMR 400MHz CDCl; 8 (ppm): 8.03 (s, 1H);); 7.89 (d, 2H); 7.10 (4, 2H); 3.99 (4, 2H); 3.21 (t, 3H); 3.13 (mm, 2H); 2.93 (m, 2H); 2,47 (s, 3H); 1.75 (m, 3H); 1.19 (m, 2H). LCMS (ESD m/z 387 (MH, 100%)

Compound A136 4-{4-[2-Nitro-3-(4-propy}-piperidin-1-yl)-phenoxy]-phenyl}-butan-2-one;

Following general procedure 1, compound A136 was obtained as a yellow oil (70 %). "HNMR (CDCl;, 400 MHz) 8 0.70 (t, 3H), 1.04-1.17 (m, 7H), 1.53(d, 2H), 1.97 (s, 3H), 2.54 2.70 (m, 611), 3.10(d, 2H), 6.36 (d, 2H), 6.69 (d, 18), 6.77 (d, 2H), 6.96 (d, 2H ), 7.04(t, 1H).

Exact mass calculated for C,qHaoN,O4 410.22, found 411.2 (MED).

Compound A137 1-{4-[2-Nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-phenyl}-ethanone;

Following the general procedure 1, compound A137 was obtained as a yellow solid (11 %)‘ - "HNMR (CDCls, 400 MHz) 6 0.82 (t, 3H), 1.17-1.28 (m, 7H), 1.64 (d, 2H), 2.50 (s, 3H), 2.67 (t, 2H), 3.20 (d, 2H), 6.58 (d, 1H), 6.89 (d, 1H), 6.98 (d, 2H), 7.24 (t, 1H), 7.88 (d, 2H).

Exact mass calculated for Ca2H;6N,0,4 382.19, found 383.3 MI).

Compound A138 {4-[2-Nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-phenyl}-phenyl-methanone;

The intermediate monofinoro was made by method 2. It was obtained as a yellow solid (88% yield). "HNMR (CDCl, 400 MHz) 5 0.88 (t, 3H), 1.24-1.33 (m, 7H), 1.71 (m. 2H), 2.74 (t, 2H), 3.23 (d, 2H), 6.77(t, 1H), 6.87 (4. 1H). 7.30 (d, 1H). Exact mass calculated for

C14H1sFN,0; 266.14, found 297.0 (MH).

Following the general procedure 2, compound A138 was obtained as a yellow oil (72 %). "HNMR (CDCls, 400 MHz) 8 0.75 (t, 3H), 1.10-1.24 (m, 7H), 1.59-1.62 (m, 2H), 2.67 (t, 2H), 3.20 (d, 2H), 6.59 (d, 1H), 6.88 (d, 1H), 6.95 (d, 2H), 7.21 (t, 1H), 7.34 (t, 2H ), 7.44 (t,1H), 7.63 (d, 2H), 7.68 (d, 2H). Exact mass calculated for CoHN; 04 444.20, found 445.1(MHY).

Compound A139 3-{4- [2-Nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-phenyl}-3-oxo-propionic acid methyl ester; [method 1]. Following the general procedure, compound A139 was obtained as a yellow solid (6 %). "HNMR (CDCl,, 400 MHz) § 0.71 (t, 3H), 0.99-1.16 (m, 7H), 1.54 (m, 2H),

2.33-2.35 (m, 2H), 2.62 (m, 2H), 3.68 (s, 3H), 6.74 (d, 1H), 6.96 (d, 2H), 7.06 (d, 1H), 7.37 (t, 1H), 7.83(d, 2H). Exact mass calculated for C,,H,5N,O¢ 440.19, found 399.2 MH.

Compound A140 4-{4-[6-(4-Butoxymethyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-phenyl}-butan-2- one; [method 1a]. Purification by HPLC yielded yellow oil. Yield 41 %. "H NMR 400MLLz CDCl; (ppm): 8.03 (s, 1H);); 7.08 (d, 2H); 6.89 (d, 2H); 3.97 (d, 2H); 3.27 (t, 2H); 3.16 (d, 2H); 2.90 (m, 2H); 2,76 (t, 2H); 2.63 (1, 2H); 2.02 (s, 3H); 1.74 (m, 1H); 1,70 (d, 2H); 1,41 (m, 2H); 1,22 (m, 4H); 0.78 (t, 3H). LCMS (ESD) m/z 457 (M'H", 100%)

Compound A141 4-{4-[6-(4-Isobutoxymethyl-piperidin-1-y})-5-nitro-pyrimidin-4-yloxy]-phenyl}-butan-2- one; [method 1a]. Purification by HPLC yielded yellow oil, Yield 45 %. "H NMR A00MHz

CDCls8 (ppm): 8.11 (s, 1H);); 7.17 (d, 2H); 6.98 (d, 2H); 4.06 (d, 2H); 3.23 (t, 2H); 3.12 (d, - 2H); 3.00 (m, 2H); 2,85 (t, 2H); 2.72 (t, 2H); 2.10 (s, 3H); 1.81 (m, 4H); 1,28 (m, 2H); 0.84 (t, 6H). LCMS (ESI) m/z 457 (MH, 100 %)

Compound A142 (4-FInoro-phenyl)-[4-(3'-nitro-4-propy}-3,4,5,6-tetrahydro-2H-[1,2'|bipyridinyl-4'- yloxy)-phenyl]-methanone;

General Procedure Z provided the monochioro intermediate as yellow crystal (484 mg, 66 % yield). "H NMR 400MHz CDCl 3 (ppm): 8.21(d, 1H); 6.91(d, 1H); 3.62(d, 2H); 3.09 (td, 2H); 1.89 (d,2H); 1.61 (m, 1H); 1.50-1.34 (m,6H); 1.03 (t, 3H). Exact mass calculated for

CisHys CIN;O, 283.11, LCMS (EST) m/z 284.3(M-+H", 100%). [method 1a]. HPLC provided compound A142 as tan solid (34 mg, 37 % yield). "H NMR 400MHz CDCl; 8 (ppm): 7.83 (d, 1H); 7.78 (d, 2H); 7.75 (d, 2H); 7.15 (d, 2H); 7.11 (d, 2H); 6.58 (4, 1H); 3.51 (d, 2H); 2.97 (td, 2H); 1.73 (dd, 2H); 1.49-1.42 (m, 1H); 1.31-1.17 (m, 6H); 0.84 (t, 3H). Exact mass calculated for CHa FN;0, 463.19, LCMS (ESD m/z 464.0(M+H", 100%).

Compound A143 4-[4-(3"-Nitro-4-propyl-3,4,5,6-tetrahydro-2H-[1,2'Ibipyridinyl-4'-yloxy)-phenyl]-butan- 2-one; :

[method 1a]. HPLC provided compound A143 as yellow solid (57 mg, 70 % yield). "H NMR 400MHz CDCl; 3(ppm): 7.75 (d, 1H); 7.11 (d, 2H); 6.95 (d, 2H); 6.46 (d, 2H); 3.46 (d, 2H); 2.90 (td, 2H); 2.81 (t, 2H); 2.68(t, 2H); 2.07.(s, 3H); 1.69 (m, 2H); 1.43-1.38 (m, 1H); 1.29- 1.16 (1m, 6H); 0.83 (t,3H). Exact mass calculated for C,H, N50, 411.22, LCMS (ESD) m/z 412.0 (M+H", 100%).

Compound A144 3'-Nitro-4-propyl-4'-(4-[1,2,4]triazol-1-yl-phenoxy)-3,4,5,6-tetrahydro-2H- [1,2']bipyridinyl; ’ [method 1a]. HPLC provided compound A144 as yellow solid (46 mg, 56 % yield). "H NMR 400MHz CDCls 8 (ppm): 8.62(s, 1H); 8.08 (5, 1H); 7.72(d, 1H); 7.58 (d, 2H); 7.18 (d, 2H); 6.49 (d, 1H); 3.43(d, 2H); 2.89 (td, 2H); 1.66 (d, 2H); 1.42-1.35 (m, 1H); 1.25-1.11 (m, 6H); 0.79 (t,3H). Exact mass calculated for C,H, NO; 408.19, LCMS (ESD m/z 409.0 (M-+H", © 100%). :

Compound A145 1-{2-Nitro-3-[4-(3-0x0-butyl)-phenoxy]-phenyl}-piperidine-4-carboxylic acid ethyl ester;

The intermediate monofluoro was made by method 2. It was obtained as a yellow solid (90 % yield). "HNMR (CDCls, 400 MHz) & 1.20 (t, 3H), 1.77-1.93 (m, 4H), 2.35 (m, 1H), 2.73-2.79 (t, 2H), 3.18-3.22 (wm, 2H), 4.08 (q, 2H), 6.77-6.86 (m, 2H), 7.25-7.31 (m, 1H). Exact mass calculated for C,,H,;,FN,0, 296.12, found 297.2. Following general procedure 1, compound

A145 was obtained as a yellow oil (61 %). "HNMR (CDCl, 400 MHz) 6 1.19 (t, 3H), 1.77- 1.83(m, 2H), 1.88-1.92(m, 2H), 2.07(s, 3H), 2.30-2.33 (m, 1H), 2.66-2.82(m, 6H), 3.18- 3.22(m, 2H), 4.07 (q, 2H), 6.50 (d, 1H), 6.79 (d, 1H ), 6.88(d, 2H), 7.08(d, 2H), 7.16(t, 1H).

Exact mass calculated for C,4H.eN-O; 440.19, found 441.1 (MH.

Compound A146 1-[3-(4-Benzoyl-phenoxy)-2-nitro-phenyl]-piperidine-4-carboxylic acid ethyl ester; [method 2]. Intermediate was obtained as a yellow solid (90 % yield). ‘HNMR (CDCl, 400

MHz) § 1.20 (t, 3H), 1.77-1.93 (m, 4H), 2.35 (m, 1H), 2.73-2.79 (t, 2H), 3.18-3.22 (m, 2H), 4.08 (q, 2H), 6.77-6.86 (m, 2H), 7.25-7.31 (m, 1H). Exact mass calculated for Ci14H,7FN; 04 296.12, found 297.2 (MH). Following the general procedure 1, compound A146 was obtained as a yellow solid (44 %). "HNMR (CDCl, 400 MHz) 5 1.20 (t, 3H), 1.80-1.91 (m, 4H), 2.37(m, 1H), 2.74-2.81(m, 2H), 3.22-3.25 (m, 2H), 4.10 (q, 2H), 6.68(d, 1H), 6.93 (d, 1H), 7.02 (d, 2H), 7.29 (t, 1H), 7.42(t, 1H), 7.52(d, 1H), 7.70(d, 2H), 7.76(d, 2H). Exact mass calculated for C,7H,6N,O5 474.18, found 475.2 MH.

Compound A147 {4-[6-(4-Ethoxy-piperidin-1-yI)-5-nitro-pyrimidin-4-yloxy]-phenyl}-(4-fluoro-phenyl)- methanone; [method 1a]. Purification by HPLC. Yield 24 %. "H NMR 400MHz CDCl; 8 (ppm): 8.03 (s, 1H);); 7.66 (m, 4H); 7.07 (m, 2H);6.98 (m, 2H); 3.65 (m, 2H); 3.48 (m, 1H); 3.39 (q, 2H); 3.25 (m, 2H); 1.77 (m, 2H); 1.56 (m, 2H); 1.06 (t, 3H). LCMS (ESI) m/z 467 (MH, 100%)

Compound A148 1-[6-(2-Methy}-5-triftuoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-d-yl]-piperidin- ’ 4-91 [method 3]. Purification by HPLC. Yield 35 % yellow oil. "H NMR 400MHz DMSO & (ppm): 8.26 (s, 1H); 6.67 (5, LH); 4.82 (s, 1H); 3.75 (m, 2H); 3.68 (s, 3H); 3.31 (m, 2H); 1.76 (m, 2H); 1.41 (m, 2H). LCMS (EST) m/z 389 (M'H", 100%)

Compound A149 1-[6-(4-Acetyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester. [method 1a]. The mixture was purified by HPLC to give compound A149 as a yellow solid (57 mg, 70 %). "HNMR (CDCl,, 400 MHz) § 1.28 (t, 3H), 1.80-1.90 (m, 2H), 1.98-2.03 (mm, 2H), 2.62 (s, 3H), 3.22 (t, 2H), 3.97-4.03 (m, 2H), 4.17 (q, 2H), 7.25 (d, 2H), 8.02 (d, 2H), 8.17 (s, 1H). Exact mass calculated for CaoH2N4O5 414.15, found 415.2 (MH).

Compound A150 (1-{6-{4-(4-Fluoro-benzayl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidin-4-yl)-(4-flaoro- phenyl}-methanone [method la]. Purification by HPLC. Yield 40 % of a yellow solid as TFA salt. 'H NMR 400MHz CDCl, 3 (ppm): 10.0 (s, 1H); 8.19 (s, 1H); 8.01 (m, 2H); 7.91 (m, 2H); 7.76 (m, 4H); 7.19 (m, 2H); 7.09 (m, 4H); 4.06 (d, 2H); 3.52 (m, 1H); 3.25 (m, 2H); 1.88 (m, 4H).

LCMS (ESD m/z 545.4 (MH, 100 %) :

Compound A151 4-(4-{6-[4-(4-Fluoro-benzoyl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yloxy}-phenyl)-butan- 2-one [method 1a]. Purification by HPLC yielded yellow solid. Yield 62 %. "H NMR 400MHz

CDCl; 8 (ppm): 8.25 (s, 1H); 8.04 (m, 2H); 7.26 (m, 4H); 7.10 (d, 2H); 4.19 (m, 2H); 3.61 (m, ’

J

PCT/US2004/001267 @® 166 1H);3.35 (m, 2H); 2.96(t; 2H); 2.83 (t, 2H); 2.21 (s, 3H); 2.00 (m, 4H). LCMS (ESD) m/z 493.4 MH", 100%)

Compound A152 4-(4-Methanesulfonyl-phenoxy)-5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]- pyrimidine [method 1a]. The crude was dissolved in DMF and purified by HPLC. Yellow solid. Yield 66 mg, 72 %. "H-NMR (400 MHz, CDCl,) 8(ppm): 8.43 (m, 1H); 8.12 (s, 111); 7.94 (tt, 2H); 7.49 (ddd, 1H); 7.28 (tt, 2H), 7.15 (m, 1H); 7.01 (m, 1H); 4.10 (heptet, 1H); 3.96 (it, 21); 3.34 (m, 2H); 3.00 (s, 3H); 2.15 (m, 2H); 1.75 (m, 2H). LCMS (ESI), m/z 488 (M+H+, 100%)

Compound A153 4-(4-Methanesulfonyl-phenoxy)-5-nitro-6-[4-(pyridin-4-ylsulfanyl)-piperidin-1-yl}- pyrimidine [method 1a]. The crude was dissolved in dichloromethane and purified by HPLC. Yellow solid. Yield 85 mg, 87 %. "H-NMR (400 MHz, CDCl.) 8(ppm): 8.41 (m, 2H); 8.10(s, 1H); .- 7.94 (m, 2H); 7.79 (mm, 2H); 7.33 (m, 2H); 4.02 (iy, 3H); 3.37 (mw, 2H); 3.06 (s, 3H); 2.20 (im, 2H); 1.78 (m, 2H). LCMS (ESD), m/z 488 (M+H", 100 %)

Compound A154 4-(4-Methanesulfonyl-phenoxy)-5-nitro-6-(4-phenylsulfanyl-piperidin-1-yl)- pyrimidine [method 1a]. The crude was dissolved in dichloromethane and purified by HPLC. Yellow solid. Yield 80 mg, 83 %. 'H-NMR (400 MHz, CDCl) 8(ppm): 7.97 (s, 1H); 7.78 (my, 2H); 7.21 (m, 2H); 7.15 (m, 3H); 7.08 (m, 2H); 3.80 (m, 2H); 3.16 (heptet, 1H); 3.06 (m, 2H); 2.86 (s, 3H); 1.87 (m, 2H); 1.50 (m, 2H). LCMS (ESI), m/z 487 (M+H", 100%)

Compound A153 1-[5-Nitro-6-(4-trifluoromethylsulfanyl-phenoxy)-pyrimidin-4-yl]-piperidine—i- carboxylic acid ethyl ester : [methed 1a]. yellow solid (92 %). 'H NMR (CDCl,, 400 MHz) 6 1.28 (t, 3H), 1.79 (m, 2H), 1.98 (m, 2H), 2.58 (m, 1H), 3.18 (t, 2H), 3.85 (m, 2H), 4.10 (q, 2H), 7.58 (d, 2H), 7.67 (d, 1H), 8.09 (s, 1H), 10.13 (5, 1H). Exact mass calculated for CsHoF3N:0,8S 471.45, found 472.1 (MH).

Compound A156

AMENDED SHEET

5-[1,3]Dioxolan-2-yl-4-[4-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-1-yI]-6-(4- methanesulfonyl-phenoxy)-pyrimidine

Using the method described herein Compound A156 was prepared. The crude mixture was purified by flash chromatography, eluted with 50% ethyl acetate/hexane to afford Compound

A156 (316.5mg, 67.8%). 'H NMR 400MHz CDCl, & (ppm): 8.24 (5, 1H), 7.93 (d, 2H), 7.26(d, 2H), 5.95(s, 1H), 4.10 (m, 2H), 3.96 (m, 2H), 3.17 (q, 1H), 3.02 (s,3H), 2.14 (m, 2H), 1.95 (m, 2H), 1.28 (d, 6H). LCMS (ESI) for CoaHaoNs06S: m/z 516.3 (M +H, 100%)

Compound A157 4-{4-(3-Isopropyl-[1,2,4|oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfonyl-phenoxy)- pyrimidine-5-carbaldehyde

Compound A156 was hydrolyzed using HCI aq in a mixture of acetone/acetonitrile to give

Compound A157 (30.0mg, 93.72%); "H NMR 400MHz CDCl, 6 (ppm):10.3(s, 1H), 8.17 (s, 1H), 7.96 (4, 2H), 7.32(d, 2H), 4.12 (m, 2H),3.30 (mm, 2H),3.22 (m,1H), 3.00(s, 3H), 3.00 (q,13), 2.06 (m, 2H), 2.00 (m, 2H), 1.27 (d, 6H). LCMS (ESI) for C,,H,sNsOsS: m/z 472.2

M+H", 100%).

Compound A158 5-[1,3]Dioxolan-2-yl-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yIj-6-(4- [1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidine

White solid, "H NMR 400MHz CDC); 8 (ppm): 8.62 (s, 1H), 8.31(s, 1H), 8.08(d, 2H), 7.28(4, 2H), 6.06(s, 1H), 4.24 (m, 2H), 4.13 (m, 2H), 4.04 (m, 2H), 3.23 (m, 2H), 3.07(q, 1H), 2.20 (m, 21), 2.02 (im, 2IT), 1.33 (4, 68); LCMS (ESI) for CysHpyN;O,4S: miz 522.3 (M +H, 100%).

The intermediate 4-chloro-3-[1,3]dioxolan-2 -yl-6-(4-[1,2,3]thiadiazol-4-yl-phenoxy)- pyrimidine was prepared usmg the following method: Phosphorus Oxychoride (200 ml, 2184.8mmol) was added drop wise (additional funnel) in DMF at 0 °C, and stirred for 1 hour, treated with 4,6 dihydroxypyridimidine (50.0g, 446.1 mmol) and stirred for half hour at room temperature. The heterogeneous mixture was refluxed for 3 hours. The volatiles were removed at reduce pressure, and the residue was poured in ice water and extract with chloroform and diethylether, wash with sodium bicarbonate and concentrate under high vacuum. The resulting mixture was purified on silica (CH,Cl,) to afford 4,6-dichloro- pyrimidine-5-carbaldehyde as a yellow solid (54.0 g). 'H NMR 400MHz CDCl, 6 (ppm): 10.3 (s, 1H, aldehyde), 8.7 (s,1H, pyrimidine).

Compound 4,6-Dichloro-pyrimidine-5-carbaldehyde (8.6g, 0.049mmol), anhydrous ethylene glycol (8.2ml) and p-Toluene-sulfonic acid (150mg) were mixture in benzene (200 mL) and heated under reflux for 3 hours. Concentrate under high vacuum, worked up with chloroform, water, sodium bicarbonate and sodium chloride, concentrate. The reaction mixture was purified on silica (CH,CL,) to give 4,6-Dichloro-5-[1,3]dioxolan-2-yl-pyrimidine (8.86g, 82.5%). "HNMR 400MHz CDC, § (ppm): 8.8 (s, 1H), 6.3 (s,1H), 4.3 (m, 211), 4.1(m, 2H).

To a mixture of 4,6-dichloro-5-[1,3]dioxolan-2-yl-pyrimidine (100.0 mg, 0.45mmol) and added Potassium Carbonate (80.62mg, 0.45mmol) in DMF (5m) cooled to 0° C was added a solution of 4-[1,2,3]-thiadiazol-4-yl-phenol (DMF) drop wise. The resulting mixture was stirred at room temperature for 30 minutes to give 4-chloro-5-[1,3]dioxolan-2-yl-6-(4- [1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidine. LCMS (ESI) for CysH;{CIN,O;S: m/z 362.9 M +H’, 100%).

Compound A159 4-[4-(3-Isopropyl-[1,2,4] oxadiazol-5-yD)-piperidin-1-yI}-6-(4-[1,2,3]thiadiazol-4-y1- phenoxy)-pyrimidine-5-carbaldehyde

White solid (18.01 mg, 25.9%); "HNMR 400MHz CDCl; & (ppm): 10.7(s, 15), 8.67 (s, 1H), 8.26(s, 1H), 8.14(d, 2H), 7.34(d, 2H), 4.19 (m, 2H), 3.40 (m, 2H), 3.26 (m, 1H), 3.07(g, 1H), "... 2.20 (m, 2H), 2.02 (m, 2H), 1.33 (d, 6H). LCMS (ES) for CpsHpN;058: m/z 478.2 M +H, 100%).

Compound A160 4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-y1]-6-(4-[1,2,3] thiadiazol-4-yl- phenoxy)-pyrimidine-5-carboxylic acid

White solid (3.8 mg, 13.63%); ‘H NMR 400 MHz MeOD 6 (ppm): 9.23 (s, LH), 8.13(d, 2H) 8.06(s,1H),, 7.29(d, 2H), 4.61 (m, 2H), 3.30 (m, 2H), 3.05(q, 1H), 2.15 (m, 2H), 1.97 (m, 2H), © 1.32 (d, 6H); LCMS (ESI) for Co:H.:N-0,S: m/z 494.3 M+H", 100%).

Compound A161 [4-[4-(3-Isopropyl-[1,2,4]oxadiazo)-5-yl)-piperidin-1-yl]-6-(4-[1,2,3] thiadiazol-4-yl- phenoxy)-pyrimidin-5-yl]-methanol

Yellow solid (17.5mg, 85.03%); 'H NMR 400MHz CDCl, § (ppm): 8.63 (s, 1H), 8.31(s,1H), 8.11(d, 2H), 7.27(d, 2H),4.77 (s,2H), 4.23 (m, 2H), 3.28 (m, 2H), 3.28 (m, 1H), 3.07(q, 1H), 2.21 (m, 2H), 2.03 (m, 2H), 1.34 (d, 6H); LCMS (ESI) for CpsH,sN;05S: m/z 480.3 (M + H', 100%) :

Compound A162 [4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-[1,2,3] thiadiazol-4-y}- phenoxy)-pyrimidin-5-ylmethyl]-dimethyl-amine

White solid, (4.2mg, 15.83%), LCMS (ESI) for CysH:N;0,S: m/z 507.3 (M + H*, 100%).

Compound A163 4-[4-(-tert-Butyl-[1,2.4] oxadiazol-5-yl)-piperidin-1-ylJ-6-(6-methanesulfonyl-pyridin-3- yloxy)-5-nitro-pyrimidine

Compound A163 was prepared using the general procedure for the addition of amine to pyrimidine; yellow solid (82mg, 81%). 'H NMR 400MHz CDCl; 8(ppm): 8.60(s, 1H); 8.19(s, 1H); 8.18(d,1H); 7.79(d,1H); 4.12(db,2H); 3.39-3.29(m,3H); 3.26(s,3H); 2.22(db, 2H); 2.06-2.02(m, 2H); 1.36(s,9H) Exact mass calculated for Cp Has N 4068 503.16,

LCMS (ESI) m/z 504.2(M+H", 100%).

Compound A164 4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl|-6-(4-methanesulfonyl-phenoxy)- 2-methyl-pyrimidine-5-carbonitrile : ' To a solution of 4-chloro-6-(4-methanesulfonyl-phenoxy)-2-methyl-pyrimidine-5- carbonitrile (80.0 mg, 0.25 mmol) and 4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidine (107.1 mg, 0.50 mmol) in DMF (1 mL) was added potassium carbonate (68.3 mg, 0.50 mmol) and the resulting mixture was left stirring for 2 hours at room temperature. Worked up with ethyl acetate, sodium bicarbonate, dried with magnesium sulfate and evaporated. The crude product was crystallized with ethyl acetate/hexane over night and filtered off to afford

Compound A164 as a yellow solid (30.6mg). LCMS (ESI) for CsH,6Ns0,S: m/z 483.3 (M +

H', 100%), 'H NMR 400MHz CDCl; 5 (ppm): 8.00 (d, 2H), 7.38 ( d, 2H), 4.82 (mn, 2H), 3.45 (m, 2H), 3.31 (m, 1H), 3.10 (s, 3H), 3.08 (m, 1H), 2.35 (s, 3H), 2.24(m, 2H), 2.03 (m, 2H), 1.34(d, 6H).

Compound A165 1-[4~[4-(3-Isopropyl-{1,2,4] oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfonyl- phenoxy)-pyrimidin-5-yl]-ethanone : To a solution of 1-[4-chloro-6-(4-methanesulfonyl-phenoxy)-pyrimidin-5-yl]- ethanone (0.21 mmol, 70 mg) and 4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidine (0.21 mmol, 49 mg) in N,N-dimethy] formamide (500 uL) was added potassium carbonate (.21 : mmol, 29 mg). The mixture was microwaved at 100 °C for 150 seconds. Is progress was monitored by thin layer chromatography and LCMS. The reaction was treated with water and the desired compound was extracted in ethyl acetate. Organic layer was evaporated in vacuo.

Purification by HPLC provided Compound A165 as a white solid (20 mg, 20%). "H-NMR (400 MHz, CDCls) 8(ppm): 8.24 (s, 1H); 8.01 (d, 2H); 7.32 (d, 2H); 4.02 (m, 2H); 3.22 (m,

3H); 3.10 (m, 1H); 3.08 (s, 3H); 2.69 (s, 3H), 2.18 (m, 2H), 2.02 (m, 2H); 1.35 (d, 6H).

LCMS (ESI), m/z 486.3 (M+H+, 100%).

EXAMPLE 13

SYNTHESES OF COMPOUNDS OF THE PRESENT INVENTION

Compound B1 1-{6-][(Benzo[1,3] dioxol-5-ylmethyl)-amino]-5-nitro-pyrimidin-4-yl}-piperidine-4- carboxylic acid ethyl ester; General Method 14.

Starting material, {6-chloro-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester was prepared by general method 2. A mixture of 6-chloro~5-nitro-pyrimidin-4-yl}- piperidine-4-carboxylic acid ethyl ester (63 mg,0.2 mmol), amine (1.1 eqv, 33 mg, 0.22 mmol) and potassium carbonate (1.1 eqv, 31 mg,0.22 mmol) in DMF (1 ml) was stirred at 100 °C for 3 minutes in Smith microwave Synthesiser, HPLC purification afforded compound

B1 as yellow oil (59 mg, 54 %). "H NMR 400MHz CDCl; § (prm): 8.58 (5, 1H); 8.01 (s, 1H); 6.63 (d, 2H); 6.61 (s, 1H); 5.79 (s, 2H); 4.51 (d, 2H); 3.99 (q, 2H) 3.70 (dt, 2H); 3.10 (id, 2H); 2.48 (m, 1X); 1.88 (dt, 2H); 1.70 (td, 2H); 1.09 (, 3H). Exact mass calculated for C,oH,s

N;Os 429.16, LCMS (ESI) m/z 430.0 (M+H", 100%).

Compound B2 1- [5-Nitro-6-(3,4,5-trimethoxy-benzylamino)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; . [method 14]. Filtered the reaction mixture and the filtrate was purified by semi preparatory

HPLC afforded the pure product m 28 % yield. ‘H NMR, 400MHz, CDCls, § (ppm): 8.71 (m, 1H); 8.07 (s, 1H); 7.10 (s, 2H); 6.42 (5, 2H); 4.56 (d, 2H); 4.02 (q, 2H); 3.71 (s, 6H); 3.69 (s, 3H); 3.16 (m, 2H); 2.52 (m, 1H); 1.91 (m, 2H); 1.74 (m, 2H); 1.12 (t, 3H). LCMS (EST) for

CaaHasNsO7: m/z 475(M-+H, 100 %).

Compound B3 (5-Nitro-6-pip eridin-1-yl-pyrimidin-4-yl)-(3-trifluoromethyl-benzyl)-amine; [method 14]. The product was purified by Preparatory TLC using hexane/ ethyl acetate (9:1). 'H NMR 400MHz CDCl, § (ppm): 8.65 (8); 8.05 (s, 1H, pyrimidine); 7.65 (d, 1H); 7.50 (m, 2H); 7.40 (d, 1H); 5.00(s, 2H); 3.50 (m, 4H), 1.80 (s, NH); 1.75-1.60 (m, 5H)

Compound B4 1-[5-Nitro-6-(2-trifluoromethyl-benzylamino)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester;

[method 14]. The residue was filtered through a silica plug [SiO,; EtOAc/hexane; 50:50] and solvent removed in vacuo. Yield 0.143 g, 50 %. Yellow oil. 'H NMR 400MHz CDCl; S(ppm): 8.63 (m, 1H); 8.07 (s, 1H); 7.68 (m, 1H); 7.53 (m, 2H); 7.40 (m, 1H); 5.01 (m, 2H); 4.17 (m, 2H); 3.89 (m, 2H); 3.21 (m, 2H); 2.63 (m, 1H); 2.03 (m, 2H); 1.85 (m, 2H); 1.28 (m, 3H).

LCMS (EST) m/z 390 (M+H", 100 %)

Compound BS 1-[S-Nitro-6-(4-trifluoromethyl-benzylamino)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; [method 14]. Solvent was removed in vacuo and residue was purified by preparatory TLC. [SiO,; EtOAc/hexaue; 10:90]. Yield 0.227 g 73 %. Yellow oil. '"H NMR 400MHz CDCl, 8 (ppm): 8.69 (m, 1H); 8.06 (s, 1H); 7.60 (d, 2E); 7.45 (d, 2H); 4.87 (m, 2H); 4.17 (m, 2H); 3.90 (m, 2H); 3.22 (m, 2H); 2.64 (m, 1H); 2.03 (m, 2H); 1.85 (m, 2H); 1.28 (m, 3H)

Compound B6 1-5-Nitro-6-(3-triftuoromethyl-benzylamino)-pyrimidin-4-yl]-piperidine-4-carboxylic'. acid ethyl ester; [method 14]. Solvent was removed in vacuo and residue was purified by preparatory TLC, [SiO,; EtOAc/hexane; 10:90. Yield 0.177g, 65 %. Yellow solid. "H NMR 400MHz CDCl; ’ 8(ppm): 8.69 (m, 1H); 8.06 (s, 1H); 7.61 (mm, 1H); 7.54 (m, 2H); 7.48 (m, 1H); 4.87 (m, 2H); 4.17 (m, 2H); 3.90 (m, 2H); 3.22 (m, 2H); 2.64 (m, 1H); 2.03 (m, 2H); 1.85 (m, 2H); 1.28 (m, 3H)

Compound B7 (5-Nitro-6-piperidin-1-yl-pyrimidin-4-yl)(2-trifluoromethyl-benzyl)-amine; [method 14]. The product was purified by Preparatory TLC using hexane/ ethyl acetate 6:1). 'H NMR 400MHz CDCl, (ppm): 8.65 (s); 8.05 (s, 1H, pyrimidine); 7.65 (d, 1H); 7.50 (m, 2H); 7.40 (d, 1H); 5.00(s, 2H); 3.50 (m, 4H,), 1.80 (s, NH),1.75-1.60 (m, 5H) . Compound BS (5-Nitro-6-piperidin-1-yl-pyrimidin-4-y))-(4-triftuoromethyl-benzyl)-amine;

The product was purified by Preparatory TLC using hexane/ ethyl acetate/dichloromethane (8:1:1). "H NMR 400MHz CDCl; 6 (ppm): 9.05 (s); 8.05 (s,1H, pyrimidine); 7.70 (d, 2H); 7.50 (d, 2H); 4.90 (s, 2H); 3.40 (m,4H,), 1.75-1.60 (.m, 6H). .

Compound BY : /

1-[5-Amino-6-(3-trifluoromethyl-benzylamino)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; General Method 15.

Di-substituted-5-nitropyrimidine (180 mg, 0.4 mmol) was dissolved in ethyl acetate (5 mL) and flushed with N; gas. Palladium catalyst [5 %, Pd/C] was added and hydrogen gas was introduced into the mixture. The reaction mixture was stirred for 4 hours at room temperature.

The reaction mixture was filtered through Celite and the solvent was removed under vacuo.

Yield 0.158 g, 94 %. White solid. "H NMR 400MHz CDCl; S(ppm): 8.69 (m, 1H); 8.06 (s, 1H); 7.61 (m, 1H); 7.54 (m, 2H); 7.48 (m, 1H); 4.87 (m, 2H); 4.17 (m, 2H); 3.90 (m, 2H); 3.22 (m, 2H); 2.64 (m, 1H); 2.03 (m, 2H); 1.85 (m, 2H); 1.28 (mn, 3H). LCMS (ESI) m/z 424

M+H",100%)

Compound B10 1-[5-Amino-6-(4-trifluoromethyl-benzylamino)-pyrimidin-4-ylj-piperidine-4-carboxylic : acid ethyl ester; [method 15]. Yield 0.121 g, 72 %. White solid. 'H NMR 400MEz CDCl; §(ppm): 8.13 (s, 1H); 7.58 (d, 2H); 7.46 (d, 2H); 4.75 (m, 2H); 4.17 (m, 2H); 3.43 (m, 2H); 2.86 (m, 2H); 2.49 (m, 1H); 2.05 (mm, 2H); 1.86 (m, 2H); 1.29 (m, 35). LCMS (ESD m/z 424 (MH, 100%)

Compound B11 1- [6-(4-Bromo-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-d-carboxylic acid ethyl ester; General Method 16. [6-chloro-5-nitro-pyrimidin-4-yl] -piperidine-4-carboxylic acid ethyl ester (415 mg, 1.32 mmoi) and 4-bromoaniline (309 mg, 1.80 mmol) were dissolved in anhydrous 1,4-dioxane (0.5-1 ml) and irradiated in a sealed microwave reaction tube at 250 °C for 300 seconds. The reaction mixture was passed through a silica plug [SiOs; EtOAc/hexane; 20:80]. Yield 0.070 g, 12 %. Yellow solid. 'H NMR 400MHz CDCl; & (ppm): 9.98 (s, 1H); 8.03 (s, 1H); 7.41 (m, 2H); 7.17 (m, 2H); 4.09 (m, 2H); 3.83 (m, 2H); 3.16 (m, 2H); 2.77 (m, 1H); 1.97 (m, 2H); 1.78 (m, 2H); 1.20 (m, 3H). LCMS (ESI) m/z 451, 452 (MH, 100 %)

Compound B12 1-[5-Nitro-6-(4-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; [Method 16]. Yield 0.010g, 14%. Yellow solid. *H NMR 400MHz CDCl; § (ppm): 10.11 (s, 1H); 8.07 (s, 1H); 7.69 (d, 2H); 7.54 (4, 2H); 4.09 (m, 2H); 3.84 (m, 2H); 3.17 (m, 2H); 2.58 (m, 1H); 1.97 (m, 2H); 1.79 (m, 2H); 1.20 (m, 3H). LCMS (ESI) m/z 440 (M+H", 100 %)

Compound B13 1-[6-(Methyl-phenyl-amino)-5-nitro-pyrimidin-4-yI}-piperidine-d-carboxylic acid ethyl ester; [method 16] Yield 0.062 g, 93 %. Yellow solid. "H NMR 400MHz CDCl; §(ppm): 8.09 (s, 1H); 7.33 (m, 2H); 7.17 (m, 3H); 4.14 (m, 2H); 3.92 (m, 2H); 3.54 (5, 3H); 3.19 (m, 2ED); 2.58 (m, 1H); 1.99 (m, 2H); 1.83 (m, 2H); 1.26 (m, 3H). LCMS (ESD) m/z 386 (M+H", 100 %)

Compound B14 1-[5-Nitro-6-(4-trifluoromethoxy-phenylamino)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; [Method 16]. Yield 0.066 g, 92 %. Yellow solid. '"H NMR 400MHz CDC]; 8(ppm): 10.09 (s, 1H); 8.11 (s, 1H); 7.63 (d, 2H); 7.22 (d, 2H); 4.17 (m, 2H); 3.91 (m, 2H); 3.25 (m1, 2H); 2.66 (m, 1H); 2.05 (m, 2H); 1.86 (m, 2H); 1.28 (m, 3H). LCMS (ESI) m/z 456 (MHI, 100%)

Compound B15 \ 1-[6-(4-Fluoro-phenylamino)-5-nitro-pyrimidin-4-yI}-piperidine-4-carboxylic acid ethyl : ester; [Method 16]. Yield 0.071 g, 100 %. Yellow solid. 'H NMR 400MHz CDCl, S(ppm): 10.01 (s, 1H); 8.08 (s, 1H); 7.50 (m, 2H); 7.06 (wm, 2H); 4.16 (m, 2H); 3.90 (mm, 2H); 3.23 (m, 2H); 2.65 (m, 1H); 2.03 (m, 2H); 1.86 (m, 2H); 1.27 (m, 3H). LCMS (ESD m/z 390 (M-+H",100%)

Compound B16 1-[6-(3,5-Difluoro-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; ’ [Method 16]. Yield 0.066 g, 89 %. Yellow solid. "H NMR 400MHz CDCI: §(ppmy): 10.13 (s, 1H); 8.15 (s, 1H); 7.29 (m, 2H); 6.60 (m, 1H); 4.16 (m, 2H); 3.90 (m, 2H); 3.22 (m, 2H); 2.64 (m, 1H); 2.03 (m, 2H); 1.84 (m, 2H); 1.27 (m, 3H). LCMS (ESI) m/z 408 (M+H" ,100%)

Compound B17 1-[6-(3,5-Dichloro-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; [Method 16]. Yield 0.023 g, 33 %. Yellow solid. "H NMR 400MHz CDCl, 8(ppm): 10.08 (s, 1H); 8.16 (s, 1H); 7.62 (m, 2H); 7.15 (m, 1H); 4.17 (m, 2H); 3.91 (m, 2H); 3.23 (m, 2H); 2.66 (m, 1H); 2.05 (m, 2H); 1.85 (m, 2H); 1.28 (m, 3H). LCMS (ESD m/z 440 (M-+H", 100%)

Compound B18

1-[6-(Benzo[1,3] dioxol-5-ylamino)-5-nitro-pyrimidin-4-yl}-piperidine-d-carbogylic acid ethyl ester; [Method 16]. The solvent was removed in vacuo and the residue purified by preparatory TLC [8i02; EtOAc/hexane; 20:80]. Yield 0.063 g, 70 %. Orange oil. "H NMR 400MHz CDCl, 8(ppm): 9.96 (s, 1H); 8.09 (s, 1H); 7.17 (s, 1H); 6.81 (m, 2H); 5.98 (s, 2H); 4.16 (gq, 2H); 3.91 (m, 2K); 3.24 (m, 2H); 2.64 (m, 1H); 2.04 (m, 2H); 1.86 (m, 2H); 1.27 (m, 3H). LCMS (ESI) m/z 416 (M+H", 100 %)

Compound B19 : 1-[6-(2-Bromo-4-triftuoromethoxy-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine4- carboxylic acid ethyl ester; [Method 16]. The reaction mixture was passed through a silica plug {SiO2; EtOAc/hexane; 10:90]. Yield 0.020 g, 24 %. Yellow solid. Hl NMR. 400MHz CDCl; §(ppm): 10.21 (s, 1H); 8.28 (m, 1H); 8.06 (s, 1H); 7.42 (m, 1H); 7.17 (m, 1H); 4.09 (m, 2H); 3.85 (m, 3.85); 3.18 (m, 2H); 2.55 (m, 1H); 1.98 (m, 2H); 1.79 (m, 2H); 1.20 (m, 3H). LCMS (ESD) m/z 535, 536

MH, 100 %)

Compound B20 } 1-[6-(2-Flnoro-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; [Method 16]. The solvent was removed in vacuo and the residue was purified by preparatory

TLC [SiO,; EtOAc/hexane; 20:80]. Yield 0.016 g, 22 %. Yellow oil. Hl NMR 400MHz

CDCl; (ppm): 10.11 (5, 1H); 8.16 (m, 2H); 7.15 (m, 3H); 4.16 (m, 2H); 3.92 (m, 2H); 3.25 (m, 2H); 2.65 (m, 1H); 2.03 (m, 2H); 1.86 (m, 2H); 1.28 (m, 3H). LCMS (ESI) m/z 390 (M+HT,100%)

Compound B21 1-[6-(3-Fluoro-phenylamino)-5-nitro-pyrimidin-4-yl] -piperidine-4-carboxylic acid ethyl ester; [Method 16]. The reaction mixture was passed through a silica plug [SiO2; EtOAc/hexane; 20:80]. Yield 0.034 g, 43 %. Yellow solid. 'H NMR 400MHz CDCl; 8(ppm): 10.12 (s, 1H); 8.14 (s, 1H); 7.63 (m, 1H); 7.31 (m, 1H); 7.23 (mn, 1H); 6.87 (m, 1H); 4.17 (mm, 2H); 3.91 (m, 2H); 3.24 (m, 2H); 2.65 (m, 1H); 2.05 (m, 2H); 1.86 (m, 2H); 1.28 (m, 3H). LCMS (ESI) m/z 390 (MH, 100%)

Compound B22 ’ .

1-{6-[(2-Fluoro-phenyl)-methyl-amino}-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethy] ester; - [Method 16]. purified by preparatory TLC [Si02; EtOAc/hexane; 20:80]. Yield 0.018 g, 23 %. Yellow oil. "H NMR 400MEz CDCl; 3(ppm): 8.09 (s, 1H); 7.14 (m, 2H); 7.03 (m, 2H); 4.15 (m, 2H); 3.93 (m, 2H); 3.51 (5, 3H); 3.20 (m, 2H); 2.60 (m, 1H); 2.00 (m, 2H); 1.83 (m, 2H); 1.27 (m, 3H). LCMS (ESI) m/z 404 (M+H*,100%)

Compound B23 1-[6-(Kthyl-phenyl-amino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; : [Method 16]. The solvent was removed in vacuo and the residue purified by preparatory 'I'L.C [Si0,; EtOAc/hexane; 20:80]. Yield 0.008 g, 8 %. Yellow oil. 'H NMR 400MHz CDCl; 8(ppm): 8.13 (s, 1H); 7.32 (m, 2H); 7.20 (m, 2H); 7.12 (m, 1H); 4.14 (m, 4H); 3.86 (m, 2H); 3.14 (m, SED); 2.57 (tm, 1H); 1.98 (m, 2H); 1.83 (m, 2H); 1.24 (m, 4H). LCMS (ESD m/z 400 . (M+H,100%)

Compound B24 1-{6-[(4-Chloro-phenyl)-methyl-amino]-5-nitro-pyrimidin-4-yl}-piperidine-d-carboxylic acid ethyl ester; [Method 16]. The solvent was removed in vacuo and the residue purified by preparatory TLC [Si0;; EtOAc/hexane; 20:80]. Yield 0.008 g, 8 %. Yellow oil. *H NMR 400MHz CDCl, $(ppm): 8.10 (s, 1H); 7.29 (d, 2H); 7.10 (d, 2H); 4.15 (m, 2H); 3.93 (m, 2H); 3.52 (s, 3H); 3.21 {m, ZH); 2.56 (m, 1H); 2.01 (m, 2H); 1.85 (m, 2H); 1.26 (m, 3H) . LCMS (ESI) m/z 420 (M+H",100%)

Componnd B25 1- [6-(4-Difluoromethyl-benzylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; [method 14]. HPLC provided compound B25 as yellow oil (58 mg, 64 %). *H NMR 400

MHz CDCl; 8 (ppm): 8.48 (s, 1H); 8.13 (s, 1H); 7.27 (4, 2H); 7.05 (4, 2H); 4.72 (4, 2H); 4.10 (9, 2H); 3.80 (dt, 2H); 3.25 (td, 2H); 2.60 (m, 1H); 2.00 (dt, 2H); 1.84 (td, 2H); 1.19 (t, 3H).

Exact mass calculated for C,oHy, F,N;Os 451.17, LCMS (ESD m/z 452.1(M+H", 100%). )

Compound B26 1-{6-[(2,3-Dihydro-benzo [1,4] dioxin-6-ylmethyl)-amino]-5-nitro-pyrimidin-4-yl}- piperidine-4-carboxylic acid ethyl ester;

[method 14]. HPLC provided compound B26 as yellow solid (62 mg, 56 %). 'H NMR 400MHz CDCl, 8 (ppm): 8.86 (s,1H); 8.28 (s, 1H); 6.95 (d,1H); 6.93 (s, 1H); 6.89 (d, 1H); 4.75 (d,2H); 4.25 (q, 2H); 3.96 (dt, 4H); 3.87 (dt, 2H); 3.38 (td, 2H); 2.75 (m,1H); 2.15 (dt,2H); 1.98 (td, 2H); 1.35 (t, 3H). Exact mass calculated for C21Has NsOg 443.18, LCMS (ESD m/z 444.6(M+H", 100%).

Compound B27 1-{6-[(2,3-Dihydro-benzo[1,4] dioxin-2-ylmethyl)-amino]-5-nitro-pyrimidin-4-y1}- piperidine-4-carboxylic acid ethyl ester; [method 14]. HPLC provided compound B27 as yellow solid (62 mg, 56 %). '"H NMR. 400M2 CDCI; 8(pprm): 8.86 (s, 1H); 8.28 (s, 1H); 6.95 (d, 1H); 6.93 (s, 1H); 6.89 (d, 1H); 4.75 (d, 2H); 4.25 (q, 2H); 3.96 (dt, 4H); 3.87 (dt, 2H); 3.38 (td, 2H); 2.75 (m, 1H); 2.15 (dt, 2H); 1.98 (td, 2H); 1.35 (t, 3H). Exact mass calculated for Cy Hys NsOg 443.18, LCMS (ESD) m/z 444.6(M+H", 100%).

Compound B28 1-{6-(2,3-Dihydro-benzofuran-5-ylmethyl)-amino]-5-nitro-pyrimidin-4-yl}-piperidine-4- carboxylic acid ethyl ester; [method 14]. HPLC provided compound B28 as yellow solid (62 mg, 57 %). "HNMR 400MHz CDCl; 8(ppm): 8.47(s, 1H); 8.02(s, 1H); 7.12(s, 1H); 7.02(d, 1H); 6.68(d, 1H); 4.62(d, 2H); 4.50(t, 2H); 4.09(q, 2H); 3.81(dt, 2H); 3.15(d, 2H); 3.12(t, 2H); 2.55(m, 1H); 1.95(dt, 2H); 1.77(td, 2H); 1.19(t, 3H). Exact mass calculated for Cy Hys NsOs 427.19, LCMS (ESD) m/z 428.1(M+H', 100%).

Compound B29 1-{6-[(6-Fluoro-4H-henzo[1,3] dioxin-8-ylmethyl)-amino]-5-nitro-pyrimidin-4-yl}- piperidine-4-carboxylic acid ethyl ester; ' [method 14]. HPLC provided compound B29 as yellow solid (77 mg, 67 %). 'H NMR 400MHz CDCl; 8(ppm): 8.92 (s,1H); 8.09 (s, 1H); 6.88 (dd, 1H); 6.58 (dd, 1H); 5.22 (s,2FD); 4.80 (s, 2H); 4.68 (d, 2H); 4.09 (q, 2H); 3.80 (d, 2H); 3.19 (td, 2H); 2.57 (m, 1H); 1.96 (dt, 2H); 1.79 (td, 2H); 1.19 (i, 3H). Exact mass calculated for CatH24 FNsO5 461.17, LCMS (ESI) m/z 462.3 (M+H', 100 %).

Compound B30 1-[6-(3,4-Dihydro-2H-benzo[b] [1,4] dioxepin-7-ylamino)-5-nitro-pyrimidin-4-yI}- piperidine-4-carboxylic acid ethyl ester;

[Method 16]. The solvent was removed in vacuo and the residue purified by preparatory TLC [Si0;; EtOAc/hexane; 20:80]. Yield 0.069 g, 71 %. Yellow oil. '"H NMR 400 MHz CDCl; 3 (ppm): 9.96 (s, LH; 8.09 (s, 1H); 7.24 (m, 1H); 7.04 (m, 1H); 6.95 (m, 1H); 4.22 (m, 6H); 3.90 (m, 2H); 3.22 (m, 2H); 2.63 (m, 1H); 2.19 (m, 2H); 2.03 (m, 2H); 1.85 (mm, 2H); 1.26 (m, 3H). LCMS (ESI) m/z 444 (M+H",100 %) )

Compound B31 1-{6-[4-(Morpholine-4-sulfonyl)-phenylamino}-5-nitro-pyrimidin-4-yl}-piperidine-d- carboxylic acid ethyl ester; [Method 16]. The solvent was removed in vacuo and the residue purified by preparatory TL.C [Si0y; EtOAc/hexane; 20:80]. Yield 0.030 g, 29 %. Yellow oil. '"H NMR 400MHz CDCl3 6 . (ppm): 10.29 (s, 1H); 8.19 (s, 1H); 7.89 (d, 2H); 7.74 (4, 2H); 4.17 (m, 2H); 3.91 (m, 2H); 3.75 (m, 3.75); 3.27 (m, 2H); 3.02 (m, 6H); 2.66 (m, 1H); 2.07 (m, 2H); 1.87 (m, 2H); 1.28 (m, 4H). LCMS (ESI) m/z 521 (M+H", 100%)

Compound B32 ’ 1-[6-(2,2-Difluoro-benzo[1,3] dioxol-4-ylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester; [Method 16]. purified by preparatory TLC [SiO,; EtOAc/hexane; 20:80]. Yield 0.069 g, 74 %. Yellow solid. "H NMR 400MHz CDCl; 8 (ppm): 10.06 (s, 1H); 8.10 (s, 1X0); 7.61 (s, 1H); 7.25 (s, 1H); 7.04 (m, 2H); 4.17 (m, 2H); 3.91 (m, 2H); 3.25 (m, 2H); 2.65 (m, 1H); 2.05 (m, 2H); 1.87 (m. 2H); 1.28 (m, 3H). LCMS (ESI) m/z 452 (M+H', 100 %)

Compound B33 ’ 1-[6-(2.2-Diftuoro-benzo[1.3]dioxol-5-ylamino)-5-nitro-pyrimidin-4-vl]-piperidine-4- carboxylic acid ethyl ester; [Method 16]. Preparatory TLC [SiO2; FtOAc/hexane; 20:80]. Yield 0.048g, 50%. Yellow solid. '"H NMR 400MHz CDCl; 8(ppm): 9.87 (s, 1H); 8.13 (5, 1H); 7.67 (m, 1H); 7.25 (s, 1H); 7.09 (m, 1H); 6.92 (m, 1H); 4.17 (m, 2H); 3.92 (m, 2H); 3.26 (m, 2H); 2.66 (m, 1H); 2.06 (m, 2H); 1.88 (m, 2H); 1.58 (m, 2H); 1.28 (m, 3H). LCMS (ESD) m/z 452 (MH, 100 %)

Compound B34 1-[6-(1,1-Dioxoe-1H-1A -benzo[b] thiophen-6-ylamino)-5-nitro-pyrimidin-4-yl]-piperidine- 4-carboxylic acid ethyl ester; [Method 16]. preparatory TLC [SiO2; EtOAc/hexane; 20:80]. Yield 0.021 g, 22 %. Yellow solid. "H NMR 400MHz CDCl, § (ppm): 10.23 (s, 1H); 8.35 (m, 1H); 8.07 (s, 1H); 7.51 (m,

1H); 7.21 (m, 1H); 7.08 (m, 1H); 6.57 (m, 1H); 4.05 (q, 2H); 3.79 (m, 2H); 3.13 (m, 2H); 2.53 (m, 1H); 1.93 (m, 2H); 1.74 (m, 2H); 1.15 (m, 3H). LCMS (EST) m/z 460 (M+H",100%)

Compound B35 1-{6-[(Furan-3-ylmethyl)-amino]-5-nitro-pyrimidin-4-yl}-piperidine-d-carboxylic acid ethyl ester; [method 14]. HPLC provided compound B35 as yellow solid (46 mg, 61 %). "HNMR 400MHz CDCl; 8(ppm): 8.71(s, 1H); 8.16(s, 1H); 7.44(s,1H); 7.37(d, 1H); 6.35(d, 1H); 4.59(d,2H); 4.11(q,2H); 3.82(dt, 2H); 3.26(td, 2H); 2.61(m, 1H); 2.00(dt, 25); 1.84(td, 2H); 1.20(t, 3H). Exact mass calculated for Ci7H NsOs 375.15, LCMS (EST) m/z 376.1 (MH, 100%).

Compound B36 1-{6-]2-(4-Methoxy-phenoxy)-ethylamino]-5-nitro-pyrimidin-4-yl}-piperidine-4- carboxylic acid ethyl ester; [method 14]. HPLC provided compound B36 as yellow solid (77 mg, 69 %). *H NMR 400MHz CDCl; 8 (ppm): 9.22 (s,1H); 8.26 (s, 1H); 6.90 (d,2H); 6.87 (d, 2H); 4.20 (t,2H); 4.19 (t,2H); 4.04 (q, 2H); 3.93 (dt,2H); 3.79 (8,3H); 3.39 (td, 2H); 2.72 (m, 1H); 2.11 (dt, 2H); 1.94 (td, 2H); 1.30 (t, 3H). Exact mass calculated for CH, NsOg 445.20, LCMS (ESD m/z 446.2 (M+H', 100 %).

Compound B37 1-{6-[2-{5-Miethoxy-iH-indol-3-yl)-ethylamine]-5-nitro-pyrimidin-4-yl}-piperidine-d- . carboxylic acid ethyl ester; [method 14]. HPLC provided compound B37 as yellow solid (63 mg, 54 %). "H NMR 400MHz CDCl; 8 (ppm): 8.47 (s,1H); 8.04 (s, 1H); 7.91 (5, 1H); 7.19 (d,1H); 7.01 (dd, 2H); 6.80 (dd, 1H); 4.08 (q, 2H); 3.84 (dt,2H); 3.78 (5, 3H); 3.13 (td, 2H); 3.03 (t,2H); 2.54 (m, 5H); 1.94 (dt, 2H); 1.76 (td, 2H); 1.18 (t, 3H). Exact mass calculated for Cas3H3Ns05 468.21 (BSD) m/z 469.2, 100 %).

Compound B38 . (3,4-Dihydro-2H-benzo[b][1,4] dioxepin-7-yl)- [5-nitro-6-(4-propyl-piperidin-1-yl)- pyrimidin-4-ylj-amine; } [Method 16]. preparatory TLC [SiO,; EtOAc/hexane; 20:80]. Yield 0.003 g, 3 %. Yellow oil. 'H NMR 400MHz CDCl, § (opm): 9.78 (s, 1H); 7.87 (s, 1H); 6.85 (m, 1H); 6.74 (m, 1H);

4.00 (m, 4H); 3.71 (m, 2H); 2.86 (m, 2H); 1.97 (m, 2H); 1.58 (m, 2H); 1.12 (m, 2H); 1.03 (m, 6H); 0.69 (m, 3H). LCMS (ESI) m/z 414 (M+H", 100 %)

Compound B39 (3-Fluoro-phenyl)-[5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yl]-amine; [Method 16]. The solvent was removed in vacuo and the residue purified by preparatory T1.C [Si0;; EtOAc/hexane; 20:80]. Yield 0.007 g, 9 %. Yellow oil. "H NMR 400MHz CDCl,

S(ppm): 10.11 (s, 1H); 8.08 (s, 1H); 7.59 (m, 1H); 7.26 (m, 1H); 7.20 (m, 1H); 6.82 (m, 1H); 3.90 (m, 2H); 3.04 (m, 2H); 1.76 (m, 2H); 1.56 (m, 1H); 1.29 (m, 2H); 1.20 (m, 4H); 0.86 (m, 3H). LCMS (BST) m/z 360 (M+H, 100 %)

Compound B40 (3-Methoxy-phenyl)-[S-nitro-6-(4-propyl-piperidin-1-yI)-pyrimidin-4-yl}-amine; [Method 16]. The solvent was removed in vacuo and the residue purified by preparatory TLC [Si0O,; EtOAc/hexane; 20:80]. Yield 0.002 g, 2 %. Yellow oil. "H NMR 400MHz CDCl,

S(ppm): 10.04 (s, 1H); 8.04 (s, 1H); 7.21 (m, 2H); 7.04 (m, 1H); 6.67 (m, 1H); 3.87 (m, 2H); 3.75 (s, 3H); 3.02 (m, 2H); 1.74 (m, 2H); 1.49 (m, 1H); 1.27 (m, 2H); 1.19 (m, 4H); 0.84 (m, 3H). LCMS (ESI) m/z 404 (M+H",100%) -

Compound B41 1-{6~[(3-Fluoro-phenyl)-methyl-amino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; ) [Method 16]. The solvent was removed in vacuo and the residue purified by preparatory TLC [Si0;; EtOAc/hexane; 20:80]. Yield 0.023 g, 30%. Light brown oil. 'H NMR 400MHz CDCl, (ppm): 8.13 (s, 1H); 7.26 (m. 1H); 6.88 (m, 3H); 4.13 (gq, 2H); 3.91 (m, 2H); 3.53 (s, 3H); 3.19 (m, 2H); 2.58 (m, 1H); 1.99 (m, 2H); 1.81 (m, 2H); 1.24 (m, 3H). LCMS (ESI) m/z 404 (M+H",100%)

Compound B42 1-[6-(4-Benzoyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; [Method 16]. The solvent was removed in vacuo and the residue purified by preparatory TLC [SiO,; EtOAc/hexane; 20:80]. Yield 0.059 g, 65 %. Light yellow solid. "H NMR 400MHz

CDCl; § (ppm): 10.31 (5, 1H); 8.21 (s, 1H); 7.89 (m, 2H); 7.82(m, 4H); 7.61 (m, 1H); 7.50 (m, 2H); 4.19 (q, 2H); 3.94 (m, 2H); 3.27 (m, 2H); 2.67 (m, 1H); 2.08 (m, 2H); 1.89 (m, 2H); 1.29 (m, 3H). LCMS (ESI) m/z 476 (M+H",100%)

Compound B43 1-{6-[4-(1,1-Dioxo-11"-thiomorpholin-4-ylmethyl)-phenylamino]-5-nitro-pyrimidin-4- yl}-piperidine-4-carboxylic acid ethyl ester; [Method 16]. The solvent was removed in vacuo and the residue purified by preparatory TLC [SiO,; EtOAc/hexane; 50:50]. Yield 0.055 g, 56 %. Yellow oil. "H NMR 400MHz CDCl, 8(ppm): 10.09 (s, LH); 8.11 (s, 1H); 7.55 (d, 2H); 7.31 (d, 2H); 5.29 (s, 1H); 4.15 (m, 2H); 3.89 (m, 2H); 3.63 (m, 2H); 3.22 (m, 2H); 3.01 (m, 6H); 2.64 (mm, 1H); 2.03 (m, 2H); 1.84 (m, 2H); 1.25 (m, 4H). LCMS (ESD) m/z 519 (M+H",100%)

Compound B44 1-[6-(4-Methanesulfonyl-phenylamine)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; [Method 16]. The solvent was removed in vacuo and the residue purified by preparatory TLC [SiO;; EtOAc/hexane; 50:50]. Yield 0.032 g, 37 %. Yellow solid. "H NMR 400MHz CDC]; & . (ppm): 10.21 (s, 1H); 8.11 (5, 1H); 7.83 (m, 4H); 4.09 (m, 2H); 3.84 (m, 2H); 3.18 (m, 2H); 2.99 (s, 3H); 2.59 (m, 1H); 1.98 (wm, 2H); 1.79 (m, 2H); 1.20 (m, 3H). LCMS (ESI) m/z 450 (M-H,100%)

Compound B45 1-[6-(4-Dimethylsulfamoyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester; [Method 16]. The solvent was removed in vacuo and the residue purified by preparatory TLC [SiO,; EtOAc/hexane; 40:60]. Yield 0.060 g, 57 %. Yellow solid. 'H NMR 400MHz CDCl,

B(ppm): 10.20 (s, 1H); 8.10 (s, 1H); 7.79 (d, 2H); 7.68 (d, 2H); 4.09 (g, 2H); 3.84 (m. 2H): 3.18 (m, 2H); 2.64 (s, 6H); 2.57 (m, 1H); 1.98 (m, 2H); 1.79 (m, 2H); 1.20 (m, 3H). LCMS (ESD) m/z 479 (M+H",100%)

Compound B46 1-[6~(3-Methoxy-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; [Method 16]. purified by preparatory TLC. [SiO,; 2:3 EtOAc/hexanes]. Yield 75 mg, 84 %.

Yellow solid. "H-NMR (400 MHz, CDCl;) 8(ppm): 10.15 (s, 1H); 8.16 (s, 1H); 7.24 (m, 2H); 7.11 (m, 1H); 6.88 (m, 1H); 4.10 (q, 2H); 3.92 (m, 2H); 3.82 (5, 1H); 3.17 (m, 2H); 2.62 (heptet, 1H); 2.09 (m, 2H); 1.95 (m, 2H); 1.25 (t, 3H). LCMS (BSI), m/z 401 (M+H", 100%)

Compound B47 1-[6~(2-Methoxy-phenylamino)-5-nitro-pyrimidin-4-yl] -piperidine-4-carboxylic acid : ethyl ester; [Method 16]. purified by preparatory TLC. [Si0; 15/85 EtOAc/hexanes]. Yield 56 mg, 63 %. Yellow solid. "H-NMR (400 MHz, CDCl.) 8(ppm): 10.57 (s, 1H); 8.41 (m, 1H); 8.18 (s, 1H); 7.15 (m, 1H); 7.0 (m, 1H); 4.21 (q, 2H); 3.92 (m, 5H); 3.25 (m, 2H); 2.63 (m, 2H); 2.08 : (m, 2H); 1.88 (on, 2H); 1.24 (m, 3H). LCMS (ESD, m/z 401 (M+H, 100%) : Compound B48 1-[6-(3,5-Bis-trifluoromethyl-phenylamino)-5-nitro-pyrimidin-4-ylj-piperidine-4- carboxylic acid ethyl ester; [Method 16]. Purified by flash chromatography. [Silica Gel 60; 20/80 EtOAc/hexanes].

Yield 89 mg, 80 %. Yellow solid. "H-NMR (400 MHz, CDCl) 8 (ppm): 10.23 (5, 1H); 8.20 (m, 3H); 7.65 (5, 1H); 4.20 (m, 2H); 3.92 (m, 2H); 3.15 (m, 2H); 2.68 (heptet, 1H); 2.10 (m, 2H); 1.94 (m, 2H); 1.30 (t, 3H). LCMS (ESD), m/z 507 (MAH, 100%)

Compound B49 1-[6-(2,5-Dimethoxy-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; [Method 16]. purified by preparatory TLC. [SiO;; 20/80 EtOAc/hexanes]. Yield 61 mg, 64 %. Orange solid. "H-NMR (400 MHz, CDCl) & (ppm): 10.61 (5, 1H); 8.24 (s, 1H); 8.17 (s, 1H); 6.84 (d, 1H); 6.62 (dd, 1H); 4.17(q, 2H); 3.92 (m, 5H); 3.80 (s, 3H); 3.23 (m, 2H); 2.63 (heptet, 1H); 2.10 (m, 2H); 1.84 (m, 2H); 1.25 (t, 3H). LCMS (ESI), m/z 431 (M-+H", 100 %) :

Compound B50 1-[6-(3,5-Dimethoxy-benzylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; [method 14]. Semi preparatory HPLC afforded the pure product in 28 %. 'H NMR, 400MEHz,

CDCl, & (ppm): 8.85 (m, 1H); 8.32 (s, 1H); 7.50 (s, 1H); 6.73 (d, 2H); 6.63 (t, 1H); 4.96 (d, 2H); 4.40 (q, 2H); 4.13 (m, 2H); 4.03 (5, 6H); 3.45 (m, 2H); 2.86 (m, 1H); 2.26 (m, 2H); 2.08 (m, 2H); 1.50 (i, 3H). LCMS (ESI) for CpHyeNsO5: m/z 475(M+H, 100 %).

Compound B51 [5-Nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-y]] ~(3,4,5-trimethoxy-benzyl)-amine; [method 14]. semi preparative HPLC afforded the pure product in 16 %. 'H NMR, 400MHz,

CDCl, 6 (ppm): 8.81(m, 1H); 8.05(s, 1H); 7.07 (s, 1H); 6.39 (s, 2H); 4.53 (d, 2H); 3.76 (m,

1H); 3.67 (s, 6H); 3.66 (s, 3H); 3.01 (m, 2H); 1.68 (d, 2H); 1.12 (m, 6H); 0.72 (t, 3H). LCMS (ESD) for CpHyN5Os: miz 445 (M+H, 100 %).

Compound B52 (3,5-Dimethoxy-benzyl)-|5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yl}-amine; [method 14]. Semi preparative HPLC afforded the pure product in 20 %. 'H NMR, 400MHz,

CDCls, 8 (ppm): 8.66 (m, 1H); 8.11 (s, 1H); 7.30 (s, 1H); 6.54 (d, 2H); 6.43 (t, 1H); 4.76 (d. 2H); 3.96 (m, 1H); 3.83 (s, 6H); 3.12 (m, 2H); 1.84 (m, 2H); 1.38 (m 2H); 1.30 (m 4H); 0.95 (t; 3H). LCMS (ESI) for C;HysNsO4: m/z 415 (MH, 100 %).

Compound B53 (4-{5-Nitro-6- [4-(pyridin-2-ylsulfanyl)-piperidin-1-yl] -pyrimidin-4-ylamino}-phenyl)- phenyl-methanone; [Method 16]. purified by preparative TLC. [SiOs; 30/70 EtOAc/hexanes]. Yield 42 mg, 51 %. Yellow solid. "H-NMR (400 MHz, CDCls) 8(ppm): 10.3 (s, 1H); 8.44 (d, 1H); 8.20 (s, 1H); 7.87 (m, 2H); 7.81 (m, 4H); 7.59 (m, 1H); 7.50 (m, 3H); 7.18 (d, 1H); 7.01 (d, 1H); 4.22 (heptet, 1H); 3.92 (m, 2H); 3.45 (dt, 2H); 2.26 (m, 2H); 1.86 (m, 2H). LCMS (ESI), m/z 513 (MEER, 100%)

Compound B54 (4-{5-Nitro-6-[4-(2-trifiuoromethyl-phenoxy)-piperidin-1-yl]-pyrimidin-4-ylamino}- phenyl)-phenyl-methanone;

Method 16]. residue purified by preparatory TLC [SiO,; EtOAc/hexane; 20:80]. Yield 0.057 g, 68 %. Yellow solid. 'H NMR 400 MHz CDCI, 8 (ppm): 10.24 (s, 1H); 8.13 (s, 1H); 7.80 (on. 2H); 7.74 (m, 4H); 7.52 (m, 2H); 7.42 (m, 4H); 6.95 (m, 2H); 4.78 (mm, 1H); 3.64 (m. 4H): 2.02 (m, 4H). LCMS (ESI) m/z 564 (M-+H", 100 %) " Compound B55 1-[6-(4-Cyano-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; [Method 16]. residue purified by preparatory TLC [SiO;; EtOAc/hexane; 20:80]. Yield 0.035 g, 40 %. Yellow solid. '"H NMR 400MHz CDCl; §(ppm): 10.19 (s, 1H); 8.10 (s, 1H); 7.76 (d, 2H); 7.58 (d, 2H); 4.09 (q, 2H); 3.83 (m, 2H); 3.17 (m, 2H); 2.58 (m, 1H); 1.97 (m, 2H); 1.78 (m, 2H); 1.19 (m, 3H) LCMS (ESI) m/z 397 (M+H",100%)

Compound B56

1-[6-(3,5-Dimethoxy-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; [Method 16]. residue purified by preparatory TLC [SiO,; EtOAc/hexane; 20:80]. Yield 0.070 8, 73 %. Orange solid. "H NMR 400MHz CDC]; § (ppm): 9.84 (s, 1H); 7.91 (s, 1H); 6.60 (d, © 2H); 6.10 (t, 1H); 3.954 (q, 2H); 3.69 (m, 2H); 3.58 (s, 6H); 3.01 (m, 2H); 2.42 (m, 1H); 1.82 (m, 2H); 1.63 (m, 2H); 1.05 (m, 3H). LCMS (ESI) m/z 432 (M+H",100%)

Compound B57 1-[6-(4-sec-Butyl-phenylamino)-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; [Method 16]. residue purified by preparatory ‘I'LC | 5103 EtOAc/hexane; 20:80]. Yield 0.088 8, 93 %. Orange oil. "FH NMR 400MHz CDCl; § (ppm): 10.10 (s, 1H); 8.14 (s, 1H); 7.50 (d, 2H); 7.21 (d, 2H); 4.19 (q, 2H); 3.94 (m, 21); 3.26 (mm, 2H); 2.63 (m, 2H); 2.06 (m, 2H); 1.87 (m, 2H); 1.61 (m, 2H); 1.27 (m, 6H); 0.86 (m, 3H). LCMS (ESD) m/z 428 (MAH, 100 %)

Compound B58 1-[6-(4-Heptyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; [Method 16]. residue purified by preparatory TLC [SiO5; EtOAc/hexane; 20:80]. Yield 0.092 g, 89 %. Orange oil. 'H NMR 400MHz CDCl; §(ppm): 10.05 (s, 1H); 8.09 (s, 1H); 7.43 (d, 2H); 7.18 (d, 2H); 4.16 (q, 2H); 3.90 (m, 2H); 3.22 (m, 2H), 2.60 (m, 3H); 2.02 (m, 2H); 1.84 (m, 2H); 1.27 (m, 13H); 0.87 (m, 3H). LCMS (ESD m/z 470 (M+H", 100 %)

Compound B59 2'-(4-Benzoyl-phenylamino)-3'-nitro-3.4,5,6-tetrahydro-2H-[1,4'Thipyridinyl-4- carboxylic acid ethyl ester. General Method 17.

A mixture of 2, 4-dichloro-3-nitro-pyridine (77 mg, 0.4 mmol), 4-benzoyl-aniline (1.0 eqv, 7 9mg, 0.4 mmol) and potassium carbonate (1.4 eqv, 78 mg, 0.56 mmol) in DMF (1 ml) was stirred in a sealed vessel at 150 °C for 30 mins under microwave irradiation. HPLC provided intermediate compound 2-[4-benzoyl-anilino]-4-dichloro-3-nitro-pyridine as brown solid (58 mg, 41 % yield). Exact mass calculated for C,gH;,CIN;O; 353.06, LCMS (ESD m/z 353.6(M+H", 100%). [method 14]. RP-HPLC provided compound B59 as orange solid (26 mg, 27 % vield). 'H

NMR 400MHz CDCl, (ppm): 9.55 (s, 1H); 7.89 (d, 3H); 7.74 (d, 2H); 7.57 (t, 1H); 7.46 (t, : 2H); 7.32 (d, 2H); 6.50 (d, 1H); 4.12 (q, 2H); 3.63 (d, 2H); 3.26 ( t, 2H); 2.63-2.58 (m, 1H);

2.04( 4, 2H); 1.94 (td, 2H); 1.21(t, 3H). Exact mass calculated for C;H>sN4Os 474.19, LCMS (ESD m/z 475.3 (M+H", 100%).

Compound B60 i 1-[5-Nitro-6-(3,4,5-trimethoxy-phenylamino)-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; [Method 16]. purified by preparatory TLC. [SiO,; 30/70 EtOAc/hexanes].Yield 42 mg, 41 %. Orange oil. "H-NMR (400 MHz, CDCl,) 8(ppm): 9.97 (s, 1H); 8.05 (5, 1H); 6.77 (5, 2H); 4.08 (q, 2H); 3.81 (m, 11H); 3.17 (t, 2H); 2.58 (heptet, 1H); 1.97 (t, 2H); 1.78 (q, 2H); 1.19 (t, 3H). LCMS (ESD, m/z 462 (M+H+, 100%)

Compound B61 1-[5-Nitro-6-(4-pentyl-phenylamino)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; [Method 16]. purified by preparatory TLC. [SiO,; 20/80 EtOAc/hexanes]. Yield 79 mg, 81 %. Yellow oil. "H-NMR (400 MHz, CDCl) & (ppm): 9.99 (5, 1H); 8.00 (s, 1H); 7.38 (d, 2H); 7.12 (4, 2H); 4.09 (q, 2H); 3.83 (m, 2H); 3.15 (m, 2H); 2.55 (m, 3H); 1.95 (m, 2H); 1.79 (m, 2H); 1.53 (m, 2H); 1.24 (m, 7H); 0.81 (t, 3H). LCMS (ESI), m/z 442 (M+H', 100 %)

Compound B62 1-{6-[4-(3-Carboxy-propyl)-phenylamino]-5-nitro-pyrimidin-4-y1}-piperidine-4- carboxylic acid ethyl ester; [Method 16]. purified by preparatory TLC. [SiO,; 30/70 EtOAc/hexanes]. Yield 67 mg, 67%. Yellow solid. "H-NMR (400 MHz, CDC1;) & (ppm): 10.08 (s, 1H); 8.13 (s, 1H); 7.49 (d, 2H); 7.22 (d. 2H): 4.18 (q. 2H); 3.92 (m, 2H); 3.25 (m, 2H); 2.68 (m, 3H); 2.40 (1, 2H); 2.06(m, 2H); 1.96 (m, 2H); 1.88 (m, 2H); 1.27 (t, 3H). LCMS (ESD), m/z 458 (M+H", 100 %)

Compound B63 1-{6-[4-(Cyano-phenyl-methyl)-phenylamino]-5-nitro-pyrimidin-4-yl}-piperidine-4- carboxylic acid ethyl ester; [Method 16]. Dry crude B63 was purified by Biotage Horizon 2 [12+M column; 30/70

EtOAc/hexanes]. Yield 93 mg, 87 %. Yellow film. "H-NMR (400 MHz, CDCl;) §(ppm): 10.13 (s, 1H); 8.13 (s, 1H); 7.64 (tt, 2H); 7.36 (m, TH); 5.31 (s, 1H); 4.17 (q, 2H); 3.92 (m, 2H); 3.25 (m, 2H); 2.66 (heptet, 1H); 2.06 (m, 2H); 1.88(m, 2H); 1.28 (t, 3H). LCMS (ESD, m/z 486 (M+H", 100 %)

Compound B64 1-[6-(4-Cyclohexyl-phenylamine)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; [Method 16]. Crude B64 was purified by preparatory TLC [SiO2; 20/80 EtOAc/hexanes].

Yield 55 mg, 55 %. Yellow solid. "H-NMR (400 MHz, CDCl) 8(ppm): 9.99 (s, 1H); 8.04 (s, 1H); 7.38 (it, 2H); 7.16 (m, 2H); 4.09 (mn, 2H); 3.84 (m; 2H); 3.16 (m, 2H); 2.56 (heptet, 1H); 2.43(m, 1H); 1.95 (m, 2H); 1.79 (m, 8H); 1.31 (m, 2H), 1.20(t, 5H). LCMS (ESI), m/z 453 (M+H', 100%)

Compound B65 1-|5-Nitro-6-(4-|1,2,4] triazol-1-yl-phenylamino)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; [Method 16]. Crude B65 was purified by flash chromatography [Silica Gel 60; 30/70

EtOAc/hexanes]. Yield 53 mg, 55 %. Yellow solid. "H-NMR (400 MHz, CDCl) 8(ppm): 10.42 (s, 1H); 8.56 (s, 1H); 8.15 (s, 1H); 8.11 (5, 1H); 7.79 (it, 2H); 7.71 (tt, 2H); 4.17 (q, 2H); 3.93 (m, 2H); 3.26 (m, 2H); 2.66(heptet, 13); 2.05 (m, 2H); 1.87 (m, 2H); 1.27 (wm, 3H).

LCMS (ESI), m/z 438 (M-+H", 100 %)

Compound B66 1-[5-Nitro-6-(4-trifluoromethanesulfonyl-phenylamino)-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester; [Method 16]. Purified by flash chromatography [Silica Gel 60; 30/70 EtOAc/hexanes].

Yield 34 mg, 31 %. Yellow solid. "H-NMR (400 MHz, CDCl) 8(ppm): 10.72 (s, 1H); 8.16 (s, 1H); 7.98 (m, 4H); 4.10 (q, 2H); 3.85 (m, 2H); 3.20 (m, 2H); 2.60 (heptet, 1H); 1.99 (m, 2H); 1.81(m, 2H); 1.19 (m. 3H). LCMS (ESI), m'z 503 (M=H", 100 %)

Compound B67 1-[5-Nitro-6-(4-[1,2,3|thiadiazol-4-yl-phenylamino)-pyrimidin-4-yi]-piperidine-4- carboxylic acid ethyl ester; [Method 16]. purified by flash chromatography [Silica Gel 60; 30/70 EtOAc/hexanes].

Yield 39 mg, 39 %. Yellow solid. "H-NMR (400 MHz, CDCl) 8 (ppm): 10.48 (s, 1H); 8.65 (s,1H); 8.18 (s, 1H); 8.08 (it, 2H); 7.80 (tt, 2H); 4.16 (q, 2H); 3.94 (m, 2H); 3.26 (m, 2H); 2.66(heptet, 1H); 2.06 (m, 2H); 1.89 (m, 2H); 1.28 (t, 3H).

Compound B68

[6-(4-Ethoxymethyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yl]-(4-methanesulfonyl-phenyl)- amine; [Method 16]. purified by HPLC [Semi-Prep]. Yield 13 mg, 17 %. Yellow solid. JH-NMR (400 MHz, CDCls) 8(ppm): 10.13 (s, 1H); 7.99 (s,1H); 7.73 (m, 4H); 3.79 (m, 2H); 3.3 (q, 2H); 3.11 (d, 2H); 2.95 (m, 2H); 2.86 (s, 3H); 1.77(m, 3H); 1.18 (mm, 2H); 1.02 (m, 3H).

LCMS (ESI), m/z 436 (M+H", 100 %)

Compound B69 [5-Nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yt]-(4-[1,2,4] triazol-1-yl-phenyl)- amine; [Method 16]. purified by preparatory TLC [SiO,; 50/50 EtOAc/hexanes]. Yield 27 mg, 27 %.

Yellow solid. "H-NMR (400 MHz, CDCl3) 6 (ppm): 10.17 (s, 1H); 8.47 (s,1H); 8.07 (5, 1H); 8.04 (s, 1H); 7.73 (it, 2H); 7.63 (tt, 2H); 3.89 (m, 2H); 3.05 (m, 2H); 1.76(m, 2H); 1.40 (m, 1H); 1.24 (m, 6H); 0.85 (t, 3H). LCMS (ESD), m/z 408 (M+H, 100%)

Compound B70 : {5-Nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-d-yl}-(4-[1,2,4] triazol-1-yl- phenyl)-amine; [Method 16]. The crude was purified by HPLC. Yield 52 mg, 55 %. Yellow solid. "H-NMR (400 MHz, CDCls) 3 (ppm): 10.18 (s, 1H); 8.47 (5, 1H); 8.37 (m, 1H); 8.09 (s, 1H); 8.04 (s, 1H); 7.72 (tt, 2H); 7.63 (it, 2H); 7.43 (ddd, 1H); 7.12 (it, 1H); 6.94 (m, 1H); 4.15 (heptet, 1H); 3.85 (m, 2H); 3.37 (m, 2H); 2.19 (m, 2H); 1.79 (m, 2H). LCMS (ESD), m/z 476 (M+H", 100 %)

Compound B71 (2-Fluoro-phenyl)-{6-[4-(3-methyl-[1,2 4] oxadiazol-5-y})-piperidin-1-yI]-5-nitro- pyrimidin-4-yl}-amine; [Method 16]. Purified by HPLC. Yield 33 mg, 38%. Yellow solid. "H-NMR (400 MHz,

CDCl) 8 (ppm): ): 10.01 (s, 1H); 8.09 (s, 1H); 7.63 (t, 1H); 7.28 (m, 1H); 7.16 (m, 2H); 3.98 (m, 2H); 3.41 (m, 2H); 3.33 (heptet, 1H); 2.36 (s, 3H); 2.23 (m, 2H); 2.05 (m, 2H). LCMS (EST), m/z 399 (M+H', 100% )

Compound B72 (4-Methanesulfonyl-phenyl)-{6-[4-(3-methyl- [1,2,4}0xadiazo}-5-yl)-piperidin-1-yI}-5- nitro-pyrimidin-4-yl}-amine;

[Method 16]. yellow solid. Yield 15.2%. "H NMR 400MHz CDCl; 8 (ppm): 10.5 (s, 1H); 8.49 (s, 1H); 8.2 (dd, 4H); 4.26 (d, 2H); 3.64 (m, 2H); 3.60 (m, 1H); 3.33 (s, 3H); 2,67 (5, 3H); 2.5 (d, 2H); 2.33 (m, 2H). LCMS (ESI) m/z 460,2 MH", 100%)

Compound B73 {6-[4-(3-Methyl-[1,2,4] oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-y1}-(4- [1,2,4}triazol-1-yl-phenyl)-amine; [Method 16]. yellow solid. Yield 11 %. "H NMR 400MHz CDCl; 8 (ppm): 10 (s, 1H); 8.41 (s, 1H);); 8.02 (s, 1H); 7.97 (s, 1H); 7.64 (d, 2H); 7.55 (d, 2H); 3.84 (d, 2H); 3.24 (m, 2H); 3.20 (m, 1H); 2.25 (5, 3H); 2,09 (d, 2H); 1.90 (m, 2H). LCMS (ESD) m/z 449,2 (M'H", 100%)

Compound B74 1-{5-Nitro-6-[4-(4-trifluoromethyl-phenoxy)-phenylamino]-pyrimidin-4-yl}-piperidine- 4-carboxylic acid ethyl ester; . [Method 16]. residue purified by preparatory TLC [Si02; EtOAc/hexane; 20:80]

Yield 0.057g, 56 %. Yellow solid. "H NMR 400MHz CDCL; § (ppm): 10.23 (s, 1H); 8.25 (s, 1H); 7.72 (m, 4H); 7.20 (m, 4H); 4.30 (q, 2H); 4.05 (m, 2H); 3.37 (m, 2H); 2.78 (m, 1H); 2.18 (m, 2H); 2.00 (m, 2H); 1.40 (m, 3H). LCMS (ESI) m/z 532 (M+H",100%)

Compound B75 } {6~ [4-(3-Ethyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(2-fluoro- phenyl)-amine; [Method 16]. The desired product was observed by LCMS m/z 414 (M+H"). Purification by

RP-HPLC.Yield 69 %."H NMR 400MHz CDCl; § (ppm): 10.00 (s, 1H); 8.11 (s,1H); 8.09 (m. 1); 7.12 (m, 3H); 3.97 (d, 2H); 3.29 (m, 2H); 3.26 (m, 1H); 2.65 (m, 2H); 2.18 (m, 2H); 2.06 (m, 2H); 1.29 (t, 3H). LCMS (ESI) m/z 414 (M+H", 100%)

Compound B76 {6-[4-(2-Methoxy-phenylsulfanyl)-piperidin-1-yl]-5-nitro-pyrimidin-4-y1}-(4- [1,2,4]triazol-1-yl-pheny])-amine; [Method 16]. Yield 43 %. Yellow solid. '"H NMR 400MHz CDCl; § (ppm): 9.98 (s, 1H); 8.33 (s, 1H);); 7.91 (d, 2H); 7.57 (d, 2H); 7.47 (d, 2H); 7.20 (m, 1H); 7.09 (m, 2H); 6.70 (m, 2H); 3.69 (s, 3H); 3.33 (m, 1H); 3.10 (m, 2H); 1.85 (m, 2H); 1.51 (m, 4H). LCMS (ESD m/z 505 (M+H", 100 %)

Compound B77

(4-Methanesulfonyl-phenyl)-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]- pyrimidin-4-yl}-amine

Crude B77 was purified by flash chromatography [Silica gel 60; 50/50 EtOAc/hexanes].

Yield 49 mg, 50 %. Yellow solid. "H-NMR (400 MHz, CDCls) 8(ppm): ): 10.25 (s, 1H); 8.13 (s, 1H); 7.85 (m, 4H); 7.64 (it, 1H); 7.43 (m, 1H); 7.11 (d, 1H); 6.95 (m, 1H); 4.15 (m, 1H); 3.85(m, 2H); 3.38 (m, 2H); 2.99 (5s, 3H); 2.19 (m, 2H); 1.79 (m, 2H). LCMS (ESI), m/z 487 (MH, 100% )

Compound B78 (3-Methoxy-phenyl)-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl}-pyrimidin-4-y1}- amine : [Method 16]. The crude mixture was purified by preparatory TLC [SiO,; 20/80

EtOAc/hexanes].

Yield 70 mg, 87 %. Yellow solid. "H-NMR (400 MHz, CDCl;) & (ppm): 10.25 (s, 1H); 8.55 (m, 1H); 8.25 (s, 1H); 7.60 (ddd, 1H); 7.40 (m, 2H); 7.38 (s, 1H); 7.29 (d, 1H); 7.22 (d, 1H); 7.12 (mm, 1H); 4.33 (heptet, 1H); 4.01 (m, 2H); 3.94 (s, 3H); 3.54 (m, 2H); 2.36 (m, 2H); 1.98 : (m, 2H). LCMS (ESI), m/z 439 (M-+H, 100% ) . Compound B79

Benzo [1,3]dioxo}-5-yl-[5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yI]-amine. [Method 16]. Residue purified by preparatory TLC [SiO,; EtOAc/hexane; 20:80]. Yield 0.005 g, 6 %. Yellow oil. "H NMR 400MHz CDCl, 3(ppm): 9.92 (s, 1H); 8.01 (s, 1H); 7.13 (m, 1H); 6.78 (m, 1H); 6.72 (m, 1H); 5.92 (s, 2H); 3.87 (m, 2H); 3.02 (m, 2H); 1.74 (m, 2H); 1.48 (m, 1H); 1.27 (m, 2H); 1.18 (m, 4H); 0.84 (m, 3H). LCMS (ESD m/z 386 (M+H",100%)

Compound B80 (4-Fluoro-phenyl)-{1-[S-nitro-6-(4-[1,2,4]triazol-1-yl-phenylamino)-pyrimidin-4-yI]- piperidin-4-yl}-methanone

Purification by HPLC. Yield 56 %. yellow solid TFA salt. '"H NMR 400MHz CDCl; 8 (ppm): 11.61 (s, 3H); 10.3 (s, 1H); 9.18 (s,1H); 8.39 (s, 1H); 8.18 (5, 1H); 8.01 (m, 2H); 7.84 (d, 2H); 7.74 (d, 2H); 7.19 (t, 2H); 4.07 (d, 2H); 3.67 (m, 1H); 3.47 (m, 2H); 2.05 (m, 4H). LCMS (ESI) m/z 489.4 (M'H', 100%)

Compound B81 [5-Nitro-6-(4-phenylsulfanyl-piperidin-1-yl)-pyrimidin-4-yI]-(4-[1,2,4]triazol-1-yl- phenyl)-amine

[Method 16]. product precipitated from the crude asa yellow solid. It was filtered and washed with hexane. Yield 36 %. 'H NMR 400MHz CDCl; 5 (ppm): 10.17 (8, 1H); 8.57 (s, 1H); 8.10 (d, 2H); 7.76 (d, 2H); 7.66 (d, 2H); 7.42 (m, 25); 7.29 (m, 3H); 3.89 (m, 2); 3.39 (m, 1H);3.27 (m, 2H); 2.06(m; 2H); 1.71 (m, 2H). LCMS (ESD) m/z 475.3 (M'H', 100%)

Compound B82 (4-Fluoro-phenyl)-{1-[6-(2-fluoro-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidin-d-yl}- methanone } [Method 16]. Purification by HPLC. Yield 17 %. red oil. 'H NMR. 400MHz CDCl; 8 (ppm): 9.92 (s, 1H); 7.96 (s, 1H); 7.79 (m, 2H); 7.46 (m, 1H); 7.17 (m, 1H); 7.02 (m, 4H); 3.86 (, 2H); 3.46 (mu, 1H); 3.31 (m, 2H); 1.86 (m, 4H). LCMS (HSI) m/z 440.4 (M'H', 100%)

Compound B83 1-[6-(2-Methyl-5-phenyl-2H-pyrazel-3-ylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4- : carboxylic acid ethyl ester [Method 16]. Purification by HPLC yielded orange solid Yield 30 %. "H NMR 400MHz

CDCl3 8 (ppm):, 8.34 (s, 1H); 7.90 (m, 2H); 7.68 (d, 3H); 7.04 (s, 1H); 4.32 (m, 2H);.4.11 (5, 3H); 4.06 (m, 2H); 3.44 (m, 2H); 2.83 (m, 1H); 2.22 (m, 2H); 2.04 (m, 2H); 1.41 (t, 3H).

LCMS (EST) m/z 452 (MH, 100%)

Compound B34 (4-Methanesulfonyl-phenyl)-[5-nitro-6-(4-phenylsulfanyl-piperidin-1-yl)-pyrimidin-4- yij-amine [Method 16]. Purification by HPLC yielded yellow solid. Yield 9 %. 'H NMR 400MHz

CDCl; 8 (ppm): 10.0 (s, 1H); 8.00 (s, 1H); 7.75 (d. 2H): 7.68 (d, 2H); 7.26 (m, 2H); 7.14 (m, 3H); 3.73 (4, 2H); 3.22 (m, 1H); 3.13 (m, 2H); 2.87 (s. 3H); 1.91 (m, 2H); 1.55 (m, 2H).

LCMS (ESI) m/z 486 (M'H', 100%)

Compound B85 (4-Methanesulfonyl-phenyl)-{5-nitro-6-[4-(pyridin-2-yloxy)-piperidin-1-yl}-pyrimidin-d- yl}-amine [Method 16]. as yellow solid (68 mg, 72 %). "H NMR 400MHz CDCl, o(ppm): 10.2 (s, 1H); 8.13 (s, 1H); 8.12 (d, 1H); 7.87 (d, 2H); 7.83 (d, 2H); 7.60 (t, 1H); 6.87 (t,1H); 6.73 (d, 1H); 5.29 (m,1H); 3.76-3.70 (m,2H); 3.56-3.51 (m,2H); 2.99 (s,3H); 2.10-2.05 (m, 2H); 1.95-1.90 (m,2H). Exact mass calculated for Cy, Hp, NOsS 470.14, LCMS (ESD m/z 471. 4(M+H,

Compound B86: {6~[4-(4-Fluoro-phenoxy)-piperidin-1-yl}-5-nitro-pyrimidin-4-y1}-(4-methanesulfonyl- phenyl)-amine [method 16] afforded compound B86 as yellow solid (58 mg, 60 %). "H NMR 400MHz

CDCl; 8(ppm): 10.2 (s, 1H); 8.13 (s, 1H); 7.87 (d, 2H); 7.81 (d, 2H); 6.92(m, 2H); 6.82 (m,2H); 4.50 (m,1H); 3.71-3.65 (m,2H); 3.54-3.51 (m,2H); 2.99 (s,3H); 1.99-1.91 (m 2H).

Exact mass calculated for CHa, FN;O5S 487.13, LCMS (ESI) m/z 488. 3(M+H", 100%).

Compound B87 (4-Methanesulfonyl-phenyl)-{5-nitro-6-|4-(pyridin-4-yloxy)-piperidin-1-yl]-pyrimidin-4- yl}-amine

Method 16 afforded compound B87 as yellow solid (56 mg, 60 %). "H NMR 400MHz CDCl, 8(ppm): 10.2(s, 1H); 8.68 (d, 2H); 8.17(s,1H); 7.88 (d, 2H); 7.83(d, 2H); 7.26 (d, 2H); 4.96 (m,1H); 3.76-3.69 (m,2H); 3.62-3.57 (m,2H); 3.00 (5,30); 2.21-2.15 (m 2H); 2.03-1.99 (m,2H). Exact mass calculated for Cy; Hy, NgOsS 470.14, LCMS (ESD) my/z 471. 2(M+H", 100%).

Compound BSS (4-Methanesulfonyl-phenyl)-{5-nitro-6-[4-(pyrimidin-2-yloxy)-piperidin-1-yl}- pyrimidin-4-yl}-amine .

Method 16 afforded compound B88 as a yellow solid (69 mg, 73 %). *H NMR 400MHz

CDCl; 8(ppm): 10.2 (s, 1H); 8.52 (d, 2H); 8.14(s,1H); 7.88 (d, 2H); 7.83 (d, 2H); 6.96(t, 11D); 5.34 (m,1H); 3.79-3.72 (m,2H); 3.58-3.52 (m,2H); 2.99 (s,3H); 2.14-2.08 (m 2H); 2.02-1.93 (m,2H). Exact mass calculated for C,H,: N-O-S 471.13. LCMS (ESD m/z 472.0(M~+H". 100%).

Compound B89 (4-Methanesulfonyl-phenyl)-{5-nitro-6-[4-(pyridin-4-ylsulfanyl)-piperidin-1-yI]- pyrimidin-4-yl}-amine

Method 16 afforded compound B89 as a yellow solid (52 mg, 54 %). ‘H NMR 400MHz

CDCl; 8(ppm): 10.1(s, 1H); 8.56(d, 2H); 8.17(s, 1H); 7.89 (d, 2H); 7.83(d, 2H); 7.53(d, 2H); 3.92-3.89(m,2H); 3.84(m, 1H); 3.44-3.38(m,2H); 3.00(s,3H); 2.26-2.22(m 2H); 1.94- 1.88(m,2H). Exact mass calculated for C,H, N6O,S; 486.11, LCMS (ESI) m/z 487.2 (M-+H",

@® 191 PCT/US2004/001267

Compound B90 (4-Methanesulfonyl-phenyl)-{6-[4-(4-methoxy-phenylsulfanyl)-piperidin-1-yl]-5-nitro- pyrimidin-4-yl}-amine

Method 16 afforded compound B90 as a as yellow solid (50 mg, 49 %). 'H NMR 400MIiz

CDCl; 8(ppm): 10.2(s, 1H); &8.11(s,1H); 7.87 (d, 2H); 7.80(d, 2H); 7.34(d, 2H); 6.79(d,2H); 3.86-3.83(m, 2H); 3.74(s,3H); 3.22-3.12(m,3H); 2.99(s,3H); 1.99-1.95(m 2H); 1.66- 1.57(m,2H). Exact mass calculated for Cy3HzsNsOsS, 515.13, LCMS (ESD mv/z 516. 1(M+H?, 100%).

Compound B91 [6-(4-Benzenesulfonyl-piperidin-1-yI)-5-nitro-pyrimidin-4-yl|-(4-methanesalfonyl- phenyl)-amine

Method 16 afforded compound B91 a as yellow solid (51 mg, 50 %). '"H NMR 400MIz

CDCl; 5(ppm): 10.2(s, 1H); 8.12(s,1H); 7.87 (d, 2H); 7.81(d,211); 7.79(d, 2H); 7.64(t, 1H); 7.53(t,1H); 4.01(m,2H); 3.17(m, 1H); 3.08-3.04(m,2H); 2.99(s,31); 2.08-2.04(m 2H); 1.82- 1.78(m,2H). Exact mass calculated for C2aHpNsOeS; 517.11, LCMS (EST) m/z 518.3(M~+H", 100%).

Compound B92 {4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperazin-1-yl}-acetic acid ethyl ester [Method 16]. afforded compound B92 as a yellow solid (45 mg, 48 %). "H NMR 400MHz

CDCl, 8 (ppm): 10.2(s, 1H); 8.18(s, 1H); 7.88 (d, 2H); 7.81 (d, 2H); 4.21(q,2H); 3.86-3.83 (m,6H); 3.46-3.43 (m, 4H); 3.00 (s,3H); 1.23 (t, 3H). Exact mass calculated for C;sHasNsOeS 464.15, LCMS (ESI) m/z 465.3 (M+H", 100%).

Compound B93 (2-Fluaro-pheny lj {5-nitro-6-{4-(pyridin-2-y lsulfanyl)-piperidin-1-y1j-py rimidin-4-» 1; - amine [Method 16]. The crude was dissolved in dichloromethane and purified by preparative TLC. [SiO,; 15/85 EtOAc/hexanes]. Yellow solid. Yield 7 mg, 10 %. "H-NMR (400 MHz, CDCl;) (ppm): 10.07 (s, 1H); 8.37 (d, 1H); 8.13(m, 1H); 8.08 (s, 1H); 7.43 (ddd, 1H); 7.07 (m, 4H); 6.94 (m, 1H); 4.15 (heptet, 1H); 3.85 (m, 2H); 3.36 (m, 2H); 2.18 (m, 2H); 1.79 (m, 2H).

LCMS (ESI), m/z 427 (M+H", 100 %)

Compound B94

AMENDED SHEET

Ou ————————

® 192 PCT/US2004/001267 (2-Methoxy-phenyl)-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-ylj-pyrimidin-4-yl}- amine [Method 16]. purified Ly preparative TLC. [S102; 15/85 EtOAc/hexanes]. Yellow solid.

Yield 42 mg, 56 %. "H-NMR (400 MHz, CDCl) § (ppm): 10.51 (s, 1H); 8.36 (d, 2H); 8.10(s, 1H); 7.42 (ddd, 1H); 7.10 (d, 1H); 7.03 (ddd, 11); 6.87 (d, 1H); 4.14 (heptet, 1H); 3.85 (m, 5H); 3.35 (m, 2H); 2.17 (m, 2H); 1.78 (mn, 2H) LCMS (FST), m/z 438 (M+Ht, 100%)

Compound B95 (4-Methanesulfonyl-phenyl)-(5-nitro-6-{4-[3-(3-trifluoromethyl-phenyl)- [1,2,4]oxadinzol-5-yl]-piperidin-1-yl}-pyrimidin-4-yl)-amine

Following the general procedure 16, compound B95 was obtained as a yellow solid (61 %).

H NMR (CDCl, 400 MHz) b 2.06-2.10 (m, 2H), 223-2 27 (m, 2H), 2.99 (s, 3H), 3.31-3.38 (mn, 3H), 3.96-3.99 (m, 2H), 7.55 (t, 1H), 7.70 (d, 1H), 7.86 (dd, 4H), 8.16 (5, 1H), 8.20 (d, 1H), 8.28 (5, 1H), 10.2 (5, 1H). Exact mass calculated for C;5Hz,FiN,OsS 589.1, found 590.4 (MH).

Compound B96 {6-]4-(3-Ethyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitre-pyrimidin-4-yl}-(4- methanesulfonyl-phenyl)-amiune

Following the general procedure 16, compound B96 was obtained as a yellow solid (31 %). '"H NMR (CDCl, 400 MHz) & 1.25 (t, 3H), 2.06-2.10 (m, 2H), 2.23-2.27 (m, 2H), 2.70 (q, 2H), 2.99 (s, 3H), 3.31-3.38 (m, 3H), 3.96-3.99 (m, 2H), 7.84 (dd, 4H), 8.14 (s, 1H), 10.2 (5, 1H). Exact mass calculated for C,cH,3N;Os8 473.1, found 474.2 (MH).

Compound B97 (6-{4-[5-(4-Fluoro-phenyl)-[1,3 4]oxadiazol-2-yl]-piperidin-1-yl}-5-nitro-pyrimidin-4-yl)- (+-methanesulfonyl-phenyl)-amine

Following the general procedure 16, compound B97 was obtained as a yellow solid (93 Ja). 'H NMR (CDCl, 400 MHz) 6 2.06-2.10 (tm, 2H), 2.23-2.27 (mm, 2H), 2.99 (5, 3H), 3.31-3.38 (m, 3H), 3.96-3.99 (m, 2H), 7.24 (dd, 2H), 7.96 (dd, 4H), 8.04-8.08 (m, 2H), 8.25 (s, 1H), 10.3 (s, 1H). Exact mass calculated for C;4H2,FN;OsS 539.14, found 540.3 (MH.

Compound B98 . (4-Methanesulfonyl-phenyl)-[S-nitro-6-(4-pyridin-2-ylmethyl-piperidin-1-yl)-pyrimidin- 4-yl]-amine

AMENDED SHEET

Following the general procedure 16, Compound B98 was obtained as a yellow solid (95 %). "HNMR (CDCl,, 400 MHz) 5 1.36-1.47 (m, 2H), 1.69-1.72 (m, 2H), 2.12-2.18 (m, 1H), 2.99 (s, 3H), 3.00-3.05 (m, 2H), 3.91-3.94 (m, 2H), 7.52 (d, 1H), 7.65 (dt, 1H), 7.85 (dd, 4H), 8.11 (s, 1H), 8.17 (dt, 1H), 8.82 (d, 1H), 10.2 (s, 1H). Exact mass calculated for

CpH24N:0,S 468.1, found 469.4 (MH).

Compound B99 : 4-[4-(3-Isopropyl-[1,2,4] oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methylsulfanyl- phenylamino)-pyrimidine-5-carbonitrile

Following the general procedure, Compound B99 was prepared. "H-NMR (DMSO-d): 9.38 (114, 5), 8.21 (IIL, 5), 7.47 (2H, J=4.3 Hz, d), 7.23 (211, T = 4.3 I1z, d), 4.50 (2H, m), 3.35 (217, m), 3.02 (1H, m), 2.51 (3H, 5), 2.18 (2H, m), 1.79 (2H, m) 1.83 (6H, J = 7Hz, d) ppm. LCMS: 436.3,351.9,324.4,270.2.

Compound B100 1-{6-[4-(4,5-Dichloro-imidazo}-1-yl)}-phenylamino]-5-nitro-pyrimidin-4-yl}-piperidine-4- carboxylic acid ethyl ester [Method 16]. yellow solid (40 mg, 49 %). ‘HNMR (CDCls, 400 MHz) 5 1.28 (t, 3H), 1.87 (m, 2H), 2.06 (m, 2H), 2.66 (m, 1H), 3.26 (t, 2H), 3.93 (m, 2H), 4.17 (q, 2H), 7.37 (m, 250), 7.54 (s, 1H), 7.82 (m, 2H), 8.17 (5, 1H), 10.23 (s, 1H). Exact mass calculated for

Cu1H, CLN,04 506.34, found 506.2 (MH). '

Compound Bidi

Benzo[1,3]dioxol-5-yl-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl}-pyrimidin-4- yi}-amine [Method 16]. orange solid (9 mg, 14 %). "HNMR (CDCl;, 400 MHz) 5 1.78 (m, 2H), 2.17 (m, 2H), 3.35 (m, 2H), 3.83 (m, 2H), 4.14 (m, 1H), 5.92 (m, 2H), 6.75 (mm, 2H), 6.94 (m, 1H), 7.11 (m, 1H), 7.19 (m, 1H), 7.42 (m, 1H), 8.02 (s, 1H), 8.36 (m, 1H), 9.91 (s, 1H). Exact mass calculated for CyqH,,N404S 452.49, found 453.2 (MH).

Compound B102 (4-Fluoro-phenyl)-{1-[6-(2-fluoro-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidin-4-y1}- methanone [Method 16]. yellow solid (16mg, 44%). "HNMR (CDCl;, 400 MHz) 5 1.89 (m, 4H), 3.26 (m, 2H), 3.51 (m, 1H), 3.96 (m, 2H), 7.10 (m, 5H), 7.92 (m, 2H), 8.08 (5, 1H), 8.13 (m, 1H), 10.06 (s, 1H). Exact mass calculated for C,H,,N,O5S 439.41, found 440.3 MH.

Compound B103 {1-[6-(Benzo[1,3]dioxol-5-ylamino)-5-nitro-pyrimidin-4-yl]-piperidin-4-yl}-(4-flaoro- phenyD-methanone [Method 16]. orange solid (20 mg, 53 %). "HNMR (CDCl,, 400 MHz) 3 1.89 (m, 4H), 3.26 (m, 2H), 3.51 (m, 1H), 3.96 (m, 211), 5.92 (s, 2H), 6.76 (mm, 211), 7.10 (m, 3H), 7.92 (m, 2H), 8.03 (s, 1H). 9.91 (s. 11. Exact mass calculated for CrHo0FNsOs 465.43. found 466.3 (ME?)

Compound B104 (2,3-Difluoro-phenyl)-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4- yl}-amine [Method 16]. yellow solid (5 mg, 8 %). "HNMR (CDCl, 400 MHz) 5 1.78 (m, 2H), 2.17 (m, 2H), 3.35 (m, 2H), 3.83 (m, 2H), 4.14 (m, 1H), 6.94 (mm, 2H), 7.03 (m, 1H), 7.10 (m, 1H), 7.42. (m, 1H), 7.89 (mm, 1H), 8.08 (s, 1H), 8.37 (in, 1H), 10.05 (s, 1H). Exact mass calculated for CaoH;gF,N:Q,S 444.46, found 444.9 (M+H).

Compound B105 (2,4-Difluoro-phenyl)-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4- yl}-amine [Method 16]. yellow solid (12 mg, 19 %). "HNMR (CDCl, 400 MHz) § 1.78 (m, 2H), 2.17 (m, 2H), 3.35 (m, 2H), 3.83 (m, 2H), 4.14 (m, 1H), 6.85 (m, 2H), 6.93 (m, 1H), 7.10 (m, 1H), 7.42 (m, 1H), 7.89 (m, 1H), 8.05 (5, 1H), 8.37 (m, 1H), 9.91 (s, 1H). Exact mass calculated for CoH, :F:N¢O,S 444 46, found 445.4 (M=H).

Compound B106 (2,5-Diftuoro-phenyl)-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl}-pyrimidin-4- yl}-amine [Method 16]. yellow solid (3 mg, 5 %). "HNMR (CDCls, 400 MHz) 5 1.78 (m, 2H), 2.17 (m, 2H), 3.35 (m, 2H), 3.83 (mm, 2H), 4.14 (m, 1H), 6.73 (m, 1H), 6.93 (m, 1H), 7.03 (m, 1H), - 7.11 (m, 1H), 7.42 (m, 1H), 8.13 (s, 1H), 8.25 (m, 1H), 8.37 (m, 1H), 10.25 (s, 1H). Exact mass calculated for C,oH15F,N:O,S 444.46, found 445.3 (M+HD).

Compound B107

PCT/US2004/001267 1-[6-(4-Benzenesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yI] -piperidine-4-carboxylic acid ethyl ester [Method 16]. yellow solid (32 mg, 39 %). "HNMR (CDCls, 400 MHz) § 1.22 (t, 3H), 1.80 (m, 2H), 2.00 (m, 2H), 2.60 (m, 1H), 3.20 (t, 2H), 3.85 (m, 2H), 4.12 (q, 2H), 7.48 (mn, 3H), 7.78 (d, 2H), 7.90 (m, 4H), 8.11 (s, 1H), 10.19 (s, 1H). Exact mass calculated for

CodHsN5O4S 511.55, found 512.3 (MH).

Compound B108 1-[5-Nitro-6-(2-triftuoromethyl-3H-benzoimidazol-5-ylamino)-pyrimidin-4-yl]-

Piperidine-4-carboxylic acid ethyl ester [Method 16]. yellow solid (11mg, 14%). "HNMR (CDCl, 400 MHz) 6 1.40 (t, 3H), 2.00 (m, 2H), 2.18 (m, 2H), 2.79 (m, 1H), 3.39 (t, 2H), 4.06 (m, 2H), 4.30 (q, 2H), 7.43 (m, 1H), 7.65 (m, 1H), 7.95 (m, 1H), 8.26 (m, 2H), 10.40 (s, 1H). Exact mass calculated for CooH,oFN,O, 479.41, found 480.3 (MI).

Compound B109 1-{5-Nitro-6-3-(1,1,2,2-tetrafluoro-ethoxy)-phenylamino}-pyrimidin-4-yl}-piperidine-d- carboxylic acid ethyl ester [Method 16]. yellow solid (65 mg, 84 %). "HNMR (CDCl, 400 MHz) 8 1.36 (t, 3H), 1.96 (mm, 2H), 2.14 (m, 2H), 2.74 (m, 1H), 3.34 (m, 2H), 4.01 (m, 2H), 4.26 (a, 2H), 6.02 (m, 1H), 7.14 (m, 1H), 747 (m, 1H), 7.56 (m, 1H), 7.77 (m, 1H), 8.24 (5, 1H), 10.23 (s, 1H). Exact mass calculated for CyoH,,F,N;O5 487.40, found 488.2 (MH).

Compound B110 {6-[4-(4-Todo-phenoxy)-piperidin-1-yl|-5-nitro-pyrimidin-d-y1} -(4-methanesulfonyl- phenyl)-amine '

Yellow solid; yield 82.6%. H NMR 400MHz CDCl; § (ppm): 10.2 (5, 1H); 8.13 (s, 1H); 7.86 (m, 4H); 7.50 (m, 2H); 6.64 (m, 2H); 4.55 (m, 1H); 3.65 (m, 2H); 3.55 (rd, 2H); 2.98 (s, 3H); 1.96 (m, 4H). LCMS (ESI) m/z 596 (MH, 100%).

Compound B11i (2-Fluoro-4-methanesulfonyl-phenyl)-{6- [4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin- 1-yl]-S-nitro-pyrimidin-4-yI}-amine

Following the general procedure, Compound B111 was obtained as a yellow solid (38%). 'H NMR 400MHz CDCl; 8 10.3(s, 1H); 8.74(t, 1H); 8.17(s, 1H); 7.70 (d, 1H); 7.67(d, 1H); 3.95-3.92(m,2H); 3.33-3.27(m,2H); 3.29-3.23(m, 1H); 3.00(s,3H); 3.03-2.96(m, 1H);

2.19-2.11(m, 211); 2.03-1.96(m, 2H); 1.26(d, 611). Exact mass calculated for Cpr Hps FN/OsS 505.15, LCMS (EST) m/z 506. 2(M+H", 100%).

Compound B112 ’ {6-[4-(3-Ethyl-[1,2,4] oxadiazol-5-yl)-piperidin-1-yl}-5-nitro-pyrimidin-4-yi}-(2-fluoro-4- methanesulfonyl-phenyl)-amine

Following the general procedure, Compound B112 was obtained as a yellow solid (31%). "HNMR (CDCl, 400 MHz) 8 1.25 (t, 3H), 2.06-2.10 (m, 2H), 2.23-2.27 (m, 2H), : 2.70 (q, 2H), 2.99 (5, 3H), 3.31-3.38 (xn, 3H), 3.96-3.99 (m, 2H), 7.84 (dd, 4H), 8.14 (s, 1H), 10.2 (s, 1H). Exact mass calculated for CoHzN7058 473.1, found 474.2 MEH.

Compound B113 (4-Methanesulfonyl-phenyl)-{5-nitro-6-[4-(3-propy}[L,2,4Joxadiazol-5-yl)-piperidin-1- yll-pyrimidin-4-yl}-amine '

Following the general procedure, Compound B113 was obtained as a yellow solid (44%). "H NMR 400MHz CDCl, § 10.2(s, 1H); 8.13(s, 1H); 7.87 (d, 2H); 7.83(d, 2H); 3.92(m,2H); 3.32-3.29(m,2H); 3.26-3.23(m, 1H); 2.99(s,3H); 2.62(t, 2H); 2.19-2.15(m, 2H); 2.01-1.95(m, 2H); 1.69(se, 2H); 0.91(, 3H). Fxact mass calculated for Cz Has N7OsS 487.16,

LCMS (ESI) m/z 488 2(M+", 100%).

Compound B114 {6-[4-(3-Cyclopropylmethy}-[1,2,4loxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4- yI}-(4-methanesnlfonyl-phenyl)-amine

Following the general procedure, Compound B114 was obtained as a yellow solid (45%). "H NMR 400MHz CDCl § 10.2(s, 1H); 8.15(s, 1H); 7.87 (&, 2H); 7.78(d, 2H); 3.95(m,2H); 3.34-3.30(m,2H); 3.30-3.27(m, 1H); 3.00(s,3H); 2.57(d, 2H); 2.21-2.17(m, 2H); 2.04-1.96(m, 2H); 1.06-1.02(m, 1H); 0.53-0.48(m, 2H); 0.25-0.16(m, 2H). Exact mass calculated for CooHas N/OsS 499.16, LCMS (ESD m/z 500.5(M=+H", 100%).

Compound B115 {6-[4-(3-Isopropy}-[1,2 4loxadiazol-5-yl)-piperidin-1-y] -5-pitro-pyrimidin-4-y1}-(4- methanesulfonyl-phenyl)-amine )

Following the general procedure, Compound B115 was obtained as a yellow solid (76%). 'H NMR 400MHz CDCl; § 10.2 (s, 1H); 8.14 (s, 1H); 7.85 (dd, 4H); 3.92 (d, 2H), 3.27 (m, 3H); 3.0 (s, 3H); 2,14 (m, 2H); 1.99 (m, 2H); 1.25 (d, 6H).

LCMS (ESI) m/z 488 (M'H', 100%)

Compound B116 . {6-14-(3-Cyclopropyl-[1,2,4] oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4- methanesulfonyl-phenyl)-amine

Following the general procedure, Compound B116 was obtained as a yellow solid (83.6%). 'H NMR 400MHz CDCl, 8 10.2 (s, 1H); 8.14 (s, 1H); 7.86 (dd, 4H); 3.90 (d, 2H); 3.30 (m, 2H); 3.27 (m, 1H); 3.00 (s, 3H); 2.13 (m, 2H); 1.98 (m, 3H); 0.97 (m, 4H). LCMS (ESD m/z 486 (MH, 100%)

Compound B117 : (4-Methanesulfonyl-pheny})-(5-nitro-6-{4-[3-(3-trifluoromethyl-phenyl)- [1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-pyrimidin-4-yl)-amine

Following the general procedure, Compound B117 was obtained as a yellow solid (61%). "HNMR (CDCls, 400 MHz) & 2.06-2.10 (m, 2H), 2.23-2.27 (m, 2H), 2.99 (5, 3H), . 3.31-3.38 (m, 3H), 3.96-3.99 (m, 2H), 7.55 (t, 1H), 7.70 (d, 1H), 7.86 (dd, 4H), 8.16 (s, 1H),’ 8.20 (d, 1H), 8.28 (s, 1H), 10.2 (5, 1H). Exact mass calculated for CpsHy,F3N70sS 589.1, found 590.4 ME).

Compound B118 4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-y))-piperidin-1-y1]-6-(4-methanesulfinyl- phenylaminro)-pyrimidine-5-carbonitrile

Compound B99 was selectively oxidized using mCPBA to give Compound Bii8 as the sulfoxide, "H-NMR (DMSO-dq): 9.65 (1H, 5), 8.26 (1H, 5), 7.75 (2H, m), 7.63 (2H, m), 4.52 (2H, m). 3.45 (1H, m), 3.32 (2H. m), 3.04 (1H, m), 2.73 (3H, 5), 2.18 (2H. m). 1.79 2H, m) 1.18 (6H, J = THz, d) ppm. LCMS: 468.4, 384.1, 356.2, 302.1. :

Compound B119 (4-Methanesulfonyl-phenyl)-{5-nitro-6-[4-(4-trifluoromethoxy-phenoxy)-piperidin-1-yl]- pyrimidin-4-yl}-amine

A mixture of compound {6-chloro-5-nitro-pyrimidin-4-yi)-(4-methanesulfonyl-phenyl)-aminc (400 mg, 1.22 mmol), 4-(4-trifluoromethoxy-phenoxy)-piperidine (399 mg, 1.34 mmol) and potassium carbonate (336 mg, 2.44 mmol) in DMF (8 ml) was heated in an oil bath at 60°C for 2 hours. The crude mixture was cooled to 0°C and quenched with water. The solid was filtered off, rinsed with water and dried in vacuum oven to give product B119 as a yellow solid (604 mg, 90%). 1HINMR (CDCl3, 400 MHz) d 2.01-2.08 (m, 4H), 3.06 (s, 3H), 3.64-

3.66 (m, 2H), 3.73-3.75 (mm, 2H), 4.62-4.66 (m, 1H), 6.93 (d, 2H), 7.17 (d, 2H), 7.93 (dd, 4H), 8.21 (s, 1H), 10.2 (s, 1H). Exact mass calculated for CyaH5F3N5068 553.1, found 554.3

VEY).

Compound B120 4-[4-(3-Isopropyl-[1,2,4]cxadiazo}-5-yl)-piperidin-1-yl]-6-(4-methanesulfonyl- phenylamine)-pyrimidine-5-carbonitrile

Compound B99 was oxidized using mCPBA to give Compound B120 as the sulfone. "HNMR (DMSO-dg): 9.86 (1H, 5), 8.34 (1H, 8), 7.93 ~ 7.84 (411, m), 4.54 (2H, m), 3.50 ~ 3.39 (3H, m), 3.21 (3H, 5) 3.05 (1H, m), 2.21 (2H, m), 1.83 (2H, m) 1.27 (6H, J = THz, d) ppm. LCMS: 452.1, 437.2, 368.1, 340.0.

Compound B121 1-{1-[6-(2-Flnoro-4-methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yl|-piperidin-4~ yl}-hexan-1-one

The general procedure for the addition of Amine to pyrimidine afforded Compound 121; H

NMR, 400MHz, CDCl, 8 (ppm): 10.48(s, NH); 8.84(s, 1H); 8.23(s, 1H); 7.75(m, 2H); 3.98(m, 2H); 3.22(m, 2H); 3.06 (s, CH,); 2.69(m, 1H); 2.48(m, 2H); 1.99(m, 2H); 1.77(m, 2H), 1.59(m, 2H), 1.29(m, 4H), 0.89(t, 3H); LCMS (ESI) for C;;HaeFNs05S: m/z 493(M+H", 100 %).

Compound B122 . 1-{1-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidin-4-yl}- hexan-1-one

The general procedure for the addition of Amine to pyrimidine afforded Compound 122; 'H

NMR, 400MHz, CDCls, é (ppm): 10.2(s, NH); 8.20(s, 1H); 7.92(m, 4H); 3.98(m, 2H); 3.22(m, 2H); 3.06 (s, CHj); 2.69(m, 1H); 2.48(m, 2H); 1.99(m, 2H); 1.77(m, 2H), 1.59(m, 2H), 1.29(m, 4H), 0.89(t, 3H); LCMS (ESI) for Co,HyoNs05S: m/z 476(M-+H, 100 %).

Compound B123 {6-[4-(3-tert-Butyl-[1,2,4Joxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(2- fluoro-4-methanesulfonyl-phenyl)-amine

The general procedure for the addition of Amine to pyrimidine afforded Compound B123 as yellow oil (40mg, 51%). "H NMR 400MHz CDCl; d(ppm): 10.4(s,NH); 8.83(t, 1H); 8.25(s, 1H); 7.76 (t, 2H); 4.01(d,2H); 3.41-3.34(m, 2H); 3.32-3.28(m, 1H); 3.08(s,3H); 2.27-2.22(m, 2H); 2.11-2.04(m, 2H); 3.36(s, 9H). Exact mass calculated for:

CyHyr FN (O58 518.17, LCMS (ESD m/z 520. 4(M+H', 100%).

Compound B124 {6-[4-(3-tert-Butyl-[1,2,4] oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4- methanesulfonyl-phenyl)-amine

The general procedure for the addition of amine to pyrimidine afforded Compound 124 as a yellow solid, yield 90%; I NMR 400MHz CDCl, 8 (ppm): 10.2 (s, 1H); 8.23 (s, 1H); 7.97 (d, 2H); 7.76 (4, 2H); 4.02 (d, 2H); 3.44 (wm, 3H); 3.2 (s, 3H); 2,27 (m, 2H); 2.03 (mw, 2H); 1.37 (s, 9H); LCMS (ESD) m/z 502 (MH, 100%)

Compound B125 [6-(4-Benzofuran-2-yl-piperidin-1-yl)-5-nitro-pyrimidin-4-yl]-(4-methanesulfonyl- phenyl)-amine

The general procedure for the addition of amine to pyrimidine afforded Compound B125 as a yellow solid (82mg, 91%). "HNMR (CDCls, 400 MHz) 3 1.00 (s, 11D), 1.54 (m, 2H), 1.93 (m, 2H), 2.97 (s, 3H), 3.09 (m, 2H), 3.74 (m, 2H), 6.42 (s, 1H), 6.98 (m, 3H), 7.27 (4, 1H), . 7.32 (d, 1H), 7.66 (m, 4H), 7.97 (s, 1H). Exact mass calculated for CyoHy FoIN7O5 493.53, found 494.4 (M+).

Compound B126 4~(3-Fluoro-4-methanesulfonyl-phenylamino)-6-[4-(3-isopropyl-[1,2,4] oxadiazo}-5-yl)- piperidin-1-yl]-pyrimidine-5-carbonitrile

Compound B126 was obtained as a solid (30%). "HNMR (CDCl, 400 MHz) 5 1.34 (d, 6H), 2.01-2.08 (m, 2H), 2.23-2 27 (m, 2H), 3.06 (heptet, 1H), 3.22 (s, 3H), 3.30-3.34 (m, 1H), 3.46-3.50 (m, 2H), 4.704 77 (m, 2H), 7.33 (dd, 1H). 7.40 (s, 1H), 7.90 (i. 1H). 8.08 (dd. 1H), 8.38 (s, 1H). Exact mass calculated for Cz, H,FN;0;8 485.2, found 486.3 (MH).

Compound B127 {6-[4-(3-Isopropyl-[1,2,4]oxadiazo)-5-yl)-piperidin-1-yl}-5-nitro-pyrimidin-4-y}}-(5- methanesulfonyl-pyridin-2-y}-amine

Compound B127 was prepared by the general procedure for the addition of pyridinylsulfone to pyrimidine to give a solid (4 mg, 4%). 'H NMR 400MHz CDCl; 8(ppm): 10.5(s, NH); 8.86(s,1H); 8.74(d, 1H); 8.29(s,1H); 8.20(d, 1H); 4.02-3.99(m,2H); 3.40-3.28(m, 3H); 3.11(s,3H); 3.11-3.06(m, 1H); 2.26-2.22(m, 2H); 2.09-2.03(m, 2H); 1.33(d, 6H). Exact mass calculated for CoH, N §0sS 488.16, LCMS (ESI) m/z 489.3(M+H", 100%).

Compound B128 (3-Fluoro-4-methanesunlfonyl-phenyl)-{6- [4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin- 1-yl}-5-nitro-pyrimidin-4-yl}-amine

Compound B128 was prepared using the general procedure for the oxidation ofa sulfide to sulfone; yellow solid (9 mg, 36%). "H NMR 400MHz CDCl, 8(ppm): 10.3(s,NH); 8.25(s, 1H); 8.13(d, 1H); 7.92(t,1H); 7.40(d,1H); 4.00(db,2H); 3.41-3.29(m,3H); 3.23(s,3H);3.10-3.07(m, 1H); 2.26-2.24(m, 2H); 2.10-2.02(m,2H); 1.34(d,6H). Exact mass caloulated for CaHay FN 1058 505.15, LCMS (EST) m/z 506.3(M+H', 100%).

Compound B129 {6~[4-(3-Isopropyl-[1,2,4] oxadiazol-5-yl)-piperidin-1-yl}-5-nitro-pyrimidin-4-yl}-(6- methanesulfonyl-pyridin-3-yl)-amine

Compound B129 was prepared using the general procedure for the oxidation of a sulfide to sulfone; yellow solid (6 mg, 67%). "H NMR 400MHz CDCI; 5(ppm): 10.3(s,NH); 8.93(s, 1H); 8.52(d, 1H); 8.22(s,1H); 8.10(d, 1H); 4.00(db,2H); 3.41-3.31(m,3H); 3.23(s,3H); 3.08(qu, 1H); 2.27-2.23(m,2H); 2.10-2.04(m, 2H); 1.33(d,6H).Exact mass calculated for

CoH N OsS 488.16, LCMS (ESI) m/z 489.2(M+H", 100%).

Compound B130 4~(2,3-Difluoro-phenylamino)-6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]- pyrimidine-5-carbonitrile

To a solution of 4,6-dichloro-pyrimidine-5-carbenitrile (254 mg, 1.47 mmol) and 2,3- difluoroaniline (190 mg, 1.47 mmol) in DMF (3 mL) at 0 °C was added K,CO; (203 mg, 1.47 mmol). The completion of the reaction was monitored by TLC (EtOAc:Hex 1:1, R;= 0.90).

After the completion of the reaction, 4-(3-isopropyl-[1.2,4Joxadiazol-5-y1)-piperidine (340 mg, 1.47 mmol) and K,CO; (406 mg, 2.94 mmol) were added at 0°C. The reaction was warmed to rt and stirred for 30 min. The reaction was heated to 40°C and maintained for 1h. The reaction was cooled to rt, poured in to H,O (50 mL) and extracted with EtOAc (50 mL, two times). The

EtOAc was dried over MgSO, and concentrated under vacuum. The crude product was purified over SiO, (EtOAc:Hex = 1:1, R= 0.49) to afford Compound B130 ( 501 mg; 76.7 %). "H-NMR (DMSO-d): 9.60 (1H, 5), 8.28 (1H, 5), 7.45~7.29 (3H, m), 4.64 (2H, m), 3.59~3.52 (4H, m), 3.41~3.49 (2H, m), 2.29~2.25 (2H, b), 1.96~1.86 (2H, m), 1.39 (6H, d) ppm. LCMS: 426.43.

Compound B131 4-(2,5-Diflucro-phenylamino)-6-[4-(3-isopropyl-[1,2,4] oxadiazol-5-yl)-piperidin-1-yI]- pyrimidine-5-carbonitrile

To a solution of 4,6-Dichloro-pyrimidine-5-carbonitrile (254 mg, 1.47 mmol) and 2.5- difluoroaniline (190 mg, 1.47 mmol) in DMF (3 mL) at 0°C was added K,CO; (203 mg, 1.47 mmol). The completion of the reaction was monitored by TLC (EtOAc:Hex = 1:1, Ry= 0.90).

After the reaction was complete, 4-(3-isopropyl-[1,2.4Joxadiazol-5-yl)-piperidine (340 mg, 1.47 mmol) and K,CO; (406 mg, 2.94 mmol) were added at 0°C. The reaction was warmed to rt and stirred for 30 min. The reaction was heated to 40°C and maintained for 1 h. The reaction was cooled to rt, poured in to H,O (50 mL) and extracted with EtOAc (50 mL, two times). The

EtOAc was dried over MgSO, and concentrated under vacuum. The crude product was purified over SiO; (EtOAc:Hex = 1:1, R,= 0.44) to afford the desired Compound B131 (465 mg; 71 %). "H-NMR (DMSO-d): 9.32 (1H, s), 8.19 (1H, s), 7.40~7.08 (3H, m), 4.54 (2H, m), 3.48~3.32 (4H, m), 3.07~3.01 (2H, m), 2.18~2.14 (2H, b), 1.96~1.86 (2H, m1), 1.27 (611, d) ppm. LCMS: 426.43.

Compound B132 ‘ 4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yI)-piperidin-1-yl]-6-(4-methylsulfanyl-phenylamino)- pyrimidine-5-carbonitrile

Compound B132 was prepared by the general procedure for the addition of amine to pyrimidine as described herein using 4-chloro-6-(4-methylsulfanyl-phenylamino)-pyrimidine-5- carbonitrile and 4-(3-isopropyl-{ 1,2,4]oxadiazol-5-yl)-piperidine. "H-NMR (DMSO-d6): 9.38 (1H, 5), 8.21 (1H, 8), 7.47 H, I = 4.3 Hz, d), 7.23 (2H, I= 4.3 Hz, d), 4.50 (2H, m), 3.35 (2H, m), 3.02 (1H, m), 2.51 (3H, s), 2.18 (2H, m), 1.79 (2H, m) 1.83 (6H, J = THz, d) ppm. LCMS: 436.3, 351.9, 324.4,270.2.

Intermediate 4-chioro-6-(4-methylisuifanyi-phenyiamino)-pyrimidine-5-carboniirile was prepared in a similar manner as described herein using 4,6-dichloro-pyrimidine-5-carbonitrile and 4-methylsulfanyl-phenylamine. "H-NMR (DMSO-d6): 10.22 (1H, s), 8.53 (1H, 5) 7.43 (2H, m), 740 (2H, m), 2.49 (3H, s) ppm. LCMS: 277.0, 234.0, 149.0. .

Compound B133 4-[4-(3-Isopropy}-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfonyl- phenylamino)-pyrimidine-5-carbonitrile

To 2 solution of 4-[4-(3-isopropyl-{1,2,4]oxadiazol-5-y1)-pipcridin-1-y1]-6-(4- methylsulfanyl-phenylamino)-pyrimidine-5-carbonitrile (200mg, 0.46 mmol) in dichloromethane (5 mL) at 0°C was added 216 mg of m-CPBA (0.94 mmol). The reaction was stirred for 10 min and warmed to room temperature. The reaction was maintained for 2h at the same temperature and the completion of the reaction was judged by TLC. The reaction was concentrated under vacuum and purified over SiO, (ethyl acetate/ Hex = 1/1m R= 0.69) to afford Compound B133 (167 mg, 80%). "H-NMR (DMSO-d6): 9.86 (1H, s), 8.34 (1H, 5), 7.93 ~ 7.84 (4H, m), 4.54 (2H,

m), 3.50 ~3.39 (3H, m), 3.21 (3, 8) 3.05 (1H, m), 2.21 (2H, m), 1.83 (2H, m) 1.27 (6H, T=

THz, d) ppm. LCMS: 452.1, 437.2, 368.1, 340.0.

Compound B134 4-(4-Hexanoyl-piperidin-1-yl)-6-(6-methylsulfany}-pyridin-3-ylamino)-pyrimidine-5- carbonitrile 4-Chloro-6-(4-methylsulfanyl phenylamino)-pyrimidine-5-carbonitrile (150.00me, 0.54mmol) in DMF (2ml) was mixture with Potassium Carbonate (82.1mg, 0.59mmol), added 1-piperidin-4-yl-hexan-1-one hydrochloride (237.4mg, 1.08 mmol) in DMF (1ml) and lefl stirring at room temperature for 1 hour. Reaction was worked up with ethyl acetate, sodium bicarbonate, dried with magnesium sulfate, filtered and concentrate under high vacuum to afford a lithe yellow solid as product. Compound was recrystalized using hexane in ethyl acetate to afford Compound B134 (157mg). LCMS (ESD for Cpt NsOS: w/z 4254 M+

H', 100%). FL NMR 400MHz CDCl; 6 (ppm): 8.72 (d, 1H), 8.40 (s, 1H),7.97 (q,1H), 7.21 (s, \ELNH), 4.92 (m, 2H), 3.42 (m, 2H), 2.86 (m, 1H), 2.75 (s, 3H), 2.65 (t, 2H), 2.15 (m, 2H), 1.77 (m, 2H), 1.50(m, 250), 1.50 (m, 2H), 1.07 (¢, 3H).

Compound B135 4-(4-Hexanoyl-piperidin-1-yI)-6-(6-methanesulfonyl-pyridin-3-ylamino)- pyrimidine-5-carbonitrile 4-(A-Hexanoyl-piperidin-1-yl)-6-(6-methylsulfanyl-pyridin-3-ylamino)-pyrimidine-5- carbonitrile (100 mg, 0.236mmol) in chloroform was mixture with mCPBA (122.0mg, 0.71mmol) at 0 C under stirring, left reaction warmed up to room temperature and reacted for an additional 12 hours. Worked up with water (pH=10 using ammonium hydroxide as base), chloroform. sodium bicarbonate, dried with magnesium sulfate, concentrate under high vacuum and crystallized using hexane and ethyl acetate to afford Compound B135 as a solid (90mg, 84%). LCMS (ESI) for CHzeNs0,8: m/z 457.2 (M + HY, 100%). "HNMR 400MHz

CDCl; 5 (ppm): 8.87 (d, 1H), 8.46 (q, 1H), 8.32 (s,1H), 8.07(d,1H), 742 (s,1H, NH), 4.74 (m, 2H), 3.48 (m, 2H),3.21(s, 3H), 2.70 (m, 1H), 2.48 (t, 2H), 1.98 (mn, 2H), 1.58 (m, 2H), 1.27(m, 2H), 1.27 (m, 2H), 0.89 (t, 3H).

Compound B136 4-[4-(3-Isopropyl-[1,2,4] oxadiazol-5-yl)-piperidin-1-yl]-6-(6-methylsulfanyl-pyridin-3- ylamino)-pyrimidine-5-carbonitrile 4-Chloro-6-(6-methylsulfanyl-pyridin-3-ylamino)-pyrimidine-5-carbonitrile (80.00mg, 0.29mmol) in DMF (2ml) was mixture with Potassium Carbonate (79.62mg,

; ® WO 2004/065380 203 PCT/US2004/001267 0.58 mmol), added 4-(3-isopropyi-[ 1,2,4]oxadiazol-5-y})-piperidine hydrochloride (237.4 mg, 1.08 or 1.02 mmol) mn DMF (1ml) and left stirring at room temperature for 1 hour. Reaction was worked up with ethyl acetate, sodium bicarbonate, dried with magnesium sulfate, filtered and concentrate under high vacuum. Compound was recrystallized using hexane m ethyl acetate to afford Compound B136. 'H NMR 400MHz DMSO 3 (ppm): 9.48 (s, 1H), 8.55 (d, 1H), 8.35 (s, 1H), 8.19 (s, 1H), 7.77 (d, 1H), 7.26 (d,1H), 4.52(m, 2H), 3.48 (mm, 1H), 3.37 (m, 2H), 3.32 (s, 3H), 3.04 (m, 1H), 2.14 (m, 2H), 1.75 (m, 2H), 1.33 (d, 6H).

Compound B137 4-[4-(3-Isopropyl-[1,2,4|oxadinzol-5-yl)-piperidin-1-yl]-6-(6-methanesulfonyl- pyridin-3-ylamino)-pyrimidine-5-carbonitrile 4-[4-(3-Isopropyl-[ 1,2,4]oxadiazol-S-yl)-piperidin-1.yl -6-(6-methylsulfanyl-pyridin- 3-ylamino)-pyrimidine-3-carbonitrile (26.0mg, 0.06mmol) in chloroform was mixture with mCPBA (41.1mg, 0.24mmol) at 0°Cunder stirring, left reaction warmed up to room temperature and reacted for an additional 12 hours. Worked up with water (pH=10 using ammonium hydroxide as base), chloroform, sodium bicarbonate, dried with magnesium sulfate, concentrate under high vacuum and crystallized using hexane and ethyl acetate to afford Compound B137 as a solid (7.5 mg). 'H NMR 400MHz DMSO & (ppm): 8.88 (d, 1H), 8.55 (d, 1H), 8.35 (5, 1H), 8.08 (d, 1H), 7.44 (s, 1H), 4.72 (m, 2H), 3.48 (m, 1H), 3.30 (m, 1H), 3.22 (s, 3H), 3.08 (m, 1H), 2.23 (im, 2H), 2.03 (m, 2H), 1.33 (d, 6H).

Compound B138 1-[4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfonyl- phenylamino)-pyrimidin-5-yl]-ethanone

To a solution of 1-[4-Chloro-6-(4-methanesulfonyl-phenylamino)-pyrimidin-5-ylj- ethanone (0.21 mmol, 70 mg) and 4-(3-isopropyl-[1,2,4]Joxadiazol-5-y1)-piperidine hydrochloride (0.21 mmol, 49 mg) in N.N-dimethyl formamide (500 ul) was added potassium carbonate (0.21 mmol, 29 mg). The resulung mixrure was microwaved at 100 “C for 150 seconds. Its progress was monitored by thin layer chromatography and LCMS. The reaction was treated with water and the desired compound was extracted in ethyl acetate.

Organic layer was evaporated in vacuo. Purification by HPLC provided Compound B138 as a white solid (15 mg, 15%). "H-NMR (400 MHz, CDCl;) 8(ppm): 10.85 (s, 1H); 8.32 (5, : 1H); 7.92 (s, 4H); 4.07 (m, 2H); 3.40 (m, 2H); 3.29 (h, 1H); 3.09 (m, 1H); 3.07 (s, IH); 2.47 (s, 3H); 2.18 (m, 2H); 2.03 (m, 2H), 1.33 (d, 6H). LCMS (ESI), m/z 485.3 (M+HH, 100%).

Compound B139

AMENDED SHEET

1-[4-[4-(3-Isopropyl-[1,2,4] oxadiazol-5-yl)-piperidin-1-yi} -6-(6-methanesulfonyl- pyridin-3-ylamino)-pyrimidin-5-yl}-ethanone

To a solution of 1-[4-chloro-6-(6-methanesulfonyl-pyridin-3-ylamino)-pyrimidin-5- yl]-ethanone (0.21 mmol, 70 mg) and 4-(3 -isopropyl-[1,2,4]oxadiazol-5-y})-piperidine hydrochloride (0.21 mmol, 49 mg) in N,N-dimethyl formamide (500 ul) was added potassium carbonate (21 mmol, 29 mg). The mixture was microwaved at 100 °C for 150 seconds. Its progress was monitored by thin layer chromatography and LCMS. The reaction was treated with water and the desired compound was extracted in ethyl acetate. Organic layer was evaporated in vacdo. Purification by HPLC provided Compound B139 as a white solid (31 mg, 31%). '1-NMR (400 MHz, CDCls) 8(ppm): 10.9 (s, 1H); 8.90 (d, 18); 8.58 (4, 1H); 8.32 (s, 1H); 8.05 (d, 1H); 4.09 (m, 2H); 3.41 (m, 2H); 3.29 (b, 1H); 3.23(s, 3H); 3.09 (h, 1H); 2.48 (s, 3H), 2.18 (m, 2H), 2.02 (m, 2H), 1.35 (d, 6EDLCMS (ESI), m/z 486.3 (M+H, 100%).

EXAMPLE 14

SYNTHESES OF COMPOUNDS OF THE PRESENT INVENTION

Compound C1 1-(5-Nitro-6-phenyl-pyrimidin-4-yl)-piperidine-4-carboxylic acid ethyl ester

General Method 17. A mixture of 1-(6-chloro-3-nitropyrimidine-4-yl)-piperidine-4- carboxylic acid ethyl ester (0.157 g, 0.49 mmol), phenyl boronic acid (62.1 mg, 0.50 mmol), tetrakistriphenylphosphinepalladium(0) (11.6 mg), 2M Na,CO; (375 pL), DME/H,O/ethanol (7/3/2) (1239 pL) was heated in a microwave tube at 140 °C for 120 s in a microwave reactor.

The reaction mixture was cooled and filtered and the filtrate was partitioned between ethyl acetate and water. The organic layer was washed with 1N NaOH (2x) and brine, dried (Na,CO;) and evaporated. Flash column chromatography (Biotage, silica, 20 %

EtOAc/hexane) afforded the desired product C1 in 47 % yield. 'H NMR, 400MHz, CDCls, 6 (ppm): 8.63(s, 1H); 7.45(m, SH); 4.16(qg, 2H); 4.07(m, 2H); 3.20(t, 2H); 2.62(m, 1H); 2.03(m, © 2H); 1.84(m, 2H); 1.28(t, 3H). LCMS (ESI) for C;sH,0N404: m/z 356 (M-+H", 100 %)

Compound C2 1-(6-Naphthalen-2-y}-5-nitro-pyrimidin-4-yl)-piperidine-4-carboxylic acid ethyl ester [method 17]. Purification of the crude product by HPLC afforded the pure product. 'H NMR, 400MHz, CDCl,, 8 (ppm): 8.62(s, 1H); 7.93(s, 1H); 7.80 (m, 3H); 7.50(m, 3H}; 4.10(q, 2H); 3.99(m, 2H); 3.16 (t, 2H); 2.58(m, 1H); 1.98 (m, 2H); 1.21(t, 3H). LCMS (ESI) for

CpHyN,Og: m/z 406 (MH, 100 %)

" Compound C3 1-[6-(4-Methanesulfonyl-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; [method 17]. Purification of the crude product by preparatory LCMS afforded the pure product in 7 %. "H NMR, 400 MHz, CDCl, 5 (ppm): 8.66(s, 1H); 8.02(d, 1H); 7 66(d, 1H); 4.18(q, 2H); 4.05(m, 2H); 3.27(t, 2H); 3.09(s, 3H); 2.66(1n, 1H); 2.06(m, 2H); 1.88(m, 2H); 1.28(t, 3H). LCMS (ESI) for CyHyN,06S: m/z 434 (MAH, 100 %)

Compound C4 1-(6-Benzofuran-5-yl-5-nitro-pyrimidin-4-y})-piperidine-4-carboxylic acid ethyl ester; [method 17]. Flash column chromatography (Biotage, silica, 20 % EtOAc/hexane) afforded the product in 61 % yield. ‘H NMR, 400MHz, CDCls, § (ppm): 8.63(s, 1H); 7.66(d, 1H); 7.57(s, 1H); 7.54(d, 1H); 7.39(t, 1H); 7.28(t, 1H); 4.15(m, 4H); 3.22(t, 2H); 2.63(m, 1H); 2.04(m, 2H); 1.85(m, 2H); 1.28(t, 3H). LCMS (ESI) for CHzN4Os: m/z 396 QM+H, 100 %)

Compound C5 1-[5-Nitro-6-(3-trifluoromethyl-phenyl)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; [method 17]. Purification of the crude product by HPLC afforded the pure product in 11 %. 'H NMR, 400MHz, CDCls, & (ppm): 8.65 (s, 1H); 7.46 (q, 1H); 4.18 (q, 2H); 4.05 (m, 2H); 3.24 (m, 3H); 2.65 (m, 1H); 2.05 (m, 2H); 1.86 (m, 2H); 1.27 (t, 3H). LCMS (ESI) for

CHa N40, miz 370 (MH, 100 %)

Compound C6 1-[6-(4-Methoxy-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; [method 17]. Flash column chromatography (Biotage, silica, 20 % EtOAc/hexane) afforded the product in 24 % yield. "H NMR, 400MHz, CDCl,, 5 (ppm): 8.60(s, 1H); 7.47(d, 1H); 6.94(, 2H); 4.15(q, 2H); 4.03(m, 2H); 3.84(s, 2H); 3.17(m, 2H); 2.61(m, 1H); 1.96(m, 2H); 1.83(m, ZH); 1.27(i, 3H). LCMS (EST) for CisH,N,O05: nv'z 386 (MHI, 100 %)

Compound C7 4-(4-Butyl-piperidin-1-yD-6-furan-3-yl-5-nitro-pyrimidine; [method 17]. Flash column chromatography (Biotage, silica, 20 % EtOAc/hexane) afforded the product in 35 % yield. "TH NMR, 400MHz, CDCl, 8 (ppm): 8.55(s, 1H); 7.97(s, 1H);

7.46(s, 1H); 6.73(s, 2H); 4.16(q, 2H); 3.18 (m, 2H); 2.61(m, 1H); 2.01(m, 2H); 1.83(m, 2H); 1.27(t, 3H). LCMS (ESI) for C16HaN4Os: m/z 346 (M+H', 100 %)

Compound C8 1-[6-(3-Chloro-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester [method 17]. Purification of the crude product by HPLC afforded the pure product in 14 %. 'H NMR, 400MHz, CDCl,, 8 (ppm): 8.67(s, 1H); 7.47(m, 1H); 7.38(t, LF); 7.32(m, 1H); 4.18(q, 2H); 4.05 (m, 2H); 3.28 (1, 2H); 2.67(m, 1H); 2.07(m, 2H); 1.88(m, 2H); 1.28(t, 3H).

LCMS (ESD for CygH;5CIN,Oy: m/z 390 (MH, 100 %)

Compound C9 1-[6-(2,6-Dimethoxy-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; [method 17]. Purification of the crude product by HPLC afforded the pure product in 28 %. '"H NMR, 400MHz, CDCl, 8 (ppm): 8.79(s, 1H); 7.95(s, 3H); 7.40(t, 1H); 6.59(d, 2H); 4.18(q, 2H); 4.07 (m, 2H); 3.74 (s, 6H); 3.38 (t, 2H); 2.70(m, 1H); 2.10(m, 2H); 1.95(m, 2H); : 1.28(t, 3H). LCMS (ESI) for Cipl;sCIN4O4: m/z 390 (MH, 100 %)

Compound C10 1-(6-Naphthalen-1-yl-5-nitro-pyrimidin-4-yl)-piperidine-4-carboxylic acid ethyl ester; [method 17]. The reaction mixture was filtered through Celite and activated carbon and purified by preparatory LCMS. 'H NMR 400MHz CDCl; §(ppm): 8.75 (s, 1H); 7.96 (m, 1H); 7.90 (m, 2H}; 7.51 (m, 3H); 7.40 (m, 1H); 4.19 (m, 2H); 4.11 (m, ZH); 3.31 (m, ZH); 2.68 (m, 1H); 2.08 (m, 2H); 1.91 (m, 2H); 1.29 (m, 3H). LCMS (ESI) m/z 407 (M+H',100%)

Compound C11 1-[6-(4-Methylsulfanyl-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid . ethyl ester; [method 17]. The reaction mixture was filtered through Celite and activated carbon and purified by preparatory LCMS. "H NMR 400MHz CDCI, §(ppm): 8.68 (s, 1H); 7.41 (m, 2H); 7.28 {m, 2II); 4.18 (mn, 2H); 4.07 (mw, 2H); 3.27 (m, 2H); 2.66 {m, 1H); 2.52 (5, 3H); 2.03 (my, 2H); 1.85 (m, 2H); 1.29 (m, 3H). LCMS (ESI) m/z 403 (M+H',100%)

Compound C12 1-(2',4'-Dihydroxy-5-nitro-[4,5'|bipyrimidinyl-6-yl)-piperidine-4-carboxylic acid ethyl ester;

[method 17]. The reaction mixture was filtered through Celite and activated carbon and purified by HPLC w/TFA. Yield 0.015 g, 11 %. Yellow solid. "HNMR 400MHz CDCl;

C(ppm): 8.48, 7.33 (5, TED; 8.02 (5, LH); 4.07 (mm, 2H); 3.86 (m, 2H); 3.13 (m, 280; 2.65 (5, 2H); 2.55 (m, 1H); 1.93 (m, 2H); 1.74 (m, 2H); 1.18 (m, 3H). LCMS (ESI) m/z 391 (M-+H",100%) :

Compound C13 1-[6-(4-Methanesulfonyl-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; [method 17] Yield: 6 mg (4 %). 'H NMR, 400MHz, CDCl, 6 (ppm): 8.66(s, 1H); 8.02(d, 1H); 7.66(d, 111); 4.18(q, 2H); 4.05(m, 2H); 3.27(t, 2H); 3.09(s, 3H); 2.66(m, 1H); 2.06(m, 2H); 1.88(m, 21D); 1.28(t, 3H). LCMS (ESI) for C;sH,N,068: m/z 434 (M+H", 100 %)

Compound C14 1-[6~(3,5-Bis-trifluoromethyl-phenyl)-5-nitro-pyrimidin-4-yl|-piperidine-4-carboxylic acid ethyl ester; [method 17]. Purification of the crude product by preparatory LCMS afforded the pure product in 23 %. "H NMR, 400MHz, CDCl,, 8 (ppm): 8.64(s, 1H); 7.96(s, 3H); 4.18(q, 2H); 4.05(m, 2H); 3.25(t, 2H); 2.65(m, 1H); 2.05(m, 2H); 1.85(m, 4H); 1.28(t, 3H). LCMS (ESD) for CoH 1sFeN4O4: m/z 492 (MH, 100 %)

Compound C15 i-{6-Dibenzoihiophen-4-yi-5-nitro-pyrimidin-4-yl-pipcridine-4-carboxylic acid ethyl ester; ’ [method 17]. Purification of the crude product by preparatory LCMS afforded the pure product in 24 %. "H NMR, 400MHz, CDCl, 6 (ppm): 8.72(s, 1H); 8.20(d, 1H); 8.12 (m, 1H): 7.76(m, 1H); 7.45(m, 4H); 7.37(m, 1H); 4.14(q, 2H); 4.05(m, 2H); 3.27(t, 2H), 2.64(m, 11H); 2.03(m, 2H); 1.86(m, 2H); 1.25(t, 3H). LCMS (ESI) for C,HzN:04S: m/z 462 (MAH, 100 %)

Compound C16 1-[6~(3,5-Dimethyl-isoxazol-4-yl)-5-nitro-pyrimidin-4-yi]-piperidine-4-carboxylic acid ethyl ester; [method 17]. Purification of the crude product by preparatory LCMS afforded the pure product in 12 %. "H NMR, 400MHz, CDCl, § (ppm): 8.64(s, 1H); 4.18(q, 2H); 4.05(m, 2H); 3.25(t, 2H); 2.66(m, 1H); 2.35(s, 3H); 2-21(s, 3H); 2.05(m, 2H); 1.86(m, 2H); 1.28(t, 3H). :

LCMS (ESI) for C;7Hz NOs: m/z 375 (M+H", 100 %)

Compound C17 1-(5-Nitro-6-thiophen-2-yl-pyrimidin-4-yl)-piperidine-4-carboxylic acid ethyl ester; fmethod 17]. Purification of the crude product by preparatory LCMS afforded the pure product in 23%. ‘H NMR, 400MHz, CDCls, 8 (ppm): 8.56(s, 13); 7.58(d, 15); 7.47(d, 1H); 7.10¢t, 1H); 4.17(q, 2H); 4.09(d, 2H); 321(, 2H); 2.62(m, 1H); 2.03(m, 2H); 1.85(m, 2H); 1.28(t, 3H). LCMS (ESI) for C;¢H:gN,04S: m/z 362 (MAH, 100 %)

Compound C18 1-[6-(3,5-Dichloro-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; {method 17]. Purification of the crude product by preparatory LCMS afforded the pure product in 7 %. 'H NMR, 400MHz, CDCl, 8 (ppm): 8.59(s, 1H); 7.44(s, 1H); 7.30(s, ZH); 7.23(s, 1H); 4.14(q, 2H); 4.00(x, 2H); 3.21(m, 2H); 2.61(m, 1H); 2.02(m, 2H); 1.81(m, 2H); 1.25(t, 3H). LCMS (ESD) for CyeH1sN,0,S: m/z 362 (M+H', 100 %)

Compound C19 1-(6-Dibenzofuran-4-yl-5-nitro-pyrimidin-4-yl)-piperidine-4-carboxylic acid ethyl ester; [method 17]. Purification of the crude product by preparatory LCMS afforded the pure product in 17 %. "H NMR, 400MHz, CDCls, § (ppm): 8.77(s, 1H); 8.07(d, 1H); 7.96(d, 1H); 7.45(m, 4H); 7.36(t, 1H); 4.18(q, 2H); 4.08(m, 2H); 3.31(t, 2H); 2.69(m, 1H); 2.07(m, 2H), 1.92(m, 2H); 1.29(t, 3H). LCMS (ESI) for C,,H,N,Os: m/z 446 (M+H", 100 %)

Compound C20 1-[6-(3,5-Dimethyl-phenyl)-5-nitro-pyrimidin-4-yl] _piperidine-4-carboxylic acid ethyl ester; [method 17]. Purification of the crude product by preparatory LCMS afforded the pure product in 23 %. "H NMR, 400MHz, CDCl;, 8 (ppm): . 8.46(s, 1H); 6.93(s, 3H); 4.02(q, 2H); 3.89(m, 2H); 3.05(m, 2H); 2.47(m, 1H); 2.20(s, 6H); 1.88(m, 2H); 1.70(m, 4H); 1.18(t, 3H).

LCMS (ESI) for CygH;CIN,O,: m/z 384 (MAH, 100 %)

Compound C21 1-[6-(4-Acetyl-phenyl)-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester;

Filtered the reaction mixture and the filtrate was purified by semi preparatory HPLC afforded the pure product in 21 %. '"H NMR, 400MHz, CDCl, 5 (ppm): 8.63(s, 1H); 8.00(d, 2H); 7.57(d, 2H); 4.16(q, 2H); 4.03(m, 2H); 3.22(m, 2H); 2.64(s, 3H); 2.03(m, 2H); 1.85(m, 4H), 1.27(t, 3H). LCMS (ESI) for CooH,,N,Os: m/z 398 (M+H', 100 %) '

Compound C22 1-[6-(4-Ethanesulfonyl-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; [method 17]. Purification of the crude product by preparatory TLC using 20 %

EtOAc/hexane afforded the pure product in 21 %. "H NMR, 400MHz, CDCl, & (ppm): 8.63(s, 1H); 7.97(d, 2H); 7.67(d, 2H); 4.18(q, 2H); 3.22(m, 2H); 3.12(m, 3H); 2.65(m, 1H); 2.04(m, 2H); 1.85(m, 2H); 1.28(t, 3H). LCMS (ESI) for CpH,iN,06S: m/z 448 (M+H', 100 %)

Compound C23 1-[6~(2-Fluoro-biphenyl-4-yl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; [method 17]. purified by semi preparatory HPLC afforded the pure product in 14 %. nH

NMR, 400MHz, CDCl, § (ppm): 8.54(s, 1H); 7.35(m, 8H); 4.07(q, 2H); 3.96(m, 2H); 3.13(1, 2H); 2.53(m, 1H); 1.95(m, 2H); 1.77(m, 28); 1.19(t, 3H). LCMS (ES) for CoH, NOs: m/z 398 (MH, 100 %)

Compound C24 : 1-[6-(3-Methanesulfonyl-phenyl)-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; [method 17]. Purification of the crude product by flash column chromatography (Biotage,silica, 20 % FtOAc/hexane) afforded the pure product in 5 %. 'H NMR, 400MIz,

CDCl, 6 (ppm): 8.67(s, 1H); 8.07(m, 2H); 7.69(m, 2H); 4.18(q, 2H); 4.09(m, 2H); 3.29(%, 2H); 3.08(s, 3H); 2.71(m, 1H); 2.06(m, 2H); 1.87(m, 2H); 1.27(t, 3H). LCMS (ESI) for

C1sH2N406S: mvz 434(M~-H", 100 %) \

Compound C25 1-{6-[4-(2-Carboxy-ethyl)-phenyl]-5-nitro-pyrimidin-4-y1}-piperidine-4-carbexylic acid ethyl ester; } [method 17}. C25 was purified by preparatory IIPLC afforded the pure product in 24 %. BH

NMR, 400MHz, CDCl, 8 (ppm): 8.52(s, 1H); 7.33(d, 2H); 7.17(d, 2H); 4.07(m, 2H); 3.94(m, 2H); 3.10(t, 2H); 2.94(t, 2H); 2.64(t, 2H); 2.52(m, 1H); 1.40(t, 3H). LCMS (ESI) for

CoH NO: m/z 428(M+H", 100 %) :

Compound C26

1-{6-[4-(2-Methoxycarbonyl-ethyl)}-phenyl] -5-nitro-pyrimidin-4-yl}-piperidine-4- carboxylic acid methyl ester [method 17]. Purification of the residue by columm chromatography (silica, 20 %

EtOAc/hexane) afforded the pure product in 14 %. 'H NMR, 400MHz, CDCl, 6 (ppm): 8.55(s, 1H); 7.36(d, 2H); 7.19(d, 2H); 3.95(m, 2H); 3.64(s, 3H); 3.60(s, 3H); 3.1 1(m, 2H); 2.92(t, 2H); 2.57(t, 2H); 2.54(m, 1H); 1.95(m, 2H); 1.76(m, 2H). LCMS (ESI) for

Cy HN, Og: m/z 428 (MH, 100 %).

Compound C27 1-{6-[4-(2-Methoxycarbonyl-ethyl)-phenyl]-5-nitro-pyrimidin-4-yl}-piperidine-4- carboxylic acid ethyl ester. [method 17]. Purification of the residue by preparatory TLC (silica, 20 % EtOAc/hexane) afforded the pure product in 16 %. 'H NMR, 400MHz, CDCls, & (ppm): 8.55(s, 1H); 7.35(d, 2H); 7.19(d, 2H); 4.09(q, 2H); 3.96(m, 2H); 3.60(s, 3H); 3.11(m, 2H); 2.92(t, 2H); 2.57(t, 2H); 1.94(s, 3H); 1.77(m, 2H); 1.19(, 3H). LCMS (ESI) for C,H,eN,Og: m/z 442 (MHI, 100 %).

EXAMPLE 15

SYNTHESES OF COMPOUNDS OF THE PRESENT INVENTION

Compound D1 : 1-[5-Nitro-6-(2-trifluoromethyl-phenylethynyl)-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester. General Method 18. - 1-{6-chloro-5-nitro-pyrimidin-4-y1}-piperidine-4-carboxylic acid ethyl ester (100 mg, 0.317 mmol), PA(PPh,),Cl, (12 mg, 0.017 mmol) and copper(Diodide (5 mg, 0.026 mmol) were dissolved in diisopropylethylamine and stirred for 2 min. o-ethynyl-trifluoromethylbenzene (100 ul, 0.072 mmol) was added and the mixture stirred under N, at 70 °C for 18 hours. The yellow suspension turned black. After cooling to room temperature, the reaction mixture was diluted with chloroform (12 ml), passed through a celite plug and concentrated under vacuo.

Purification by Flash Chromatography (0-30% Ethyl acetate / Hexanes) gave Compound D1.

Yield 35 %. 'H NMR 400Miz CDCl; & (ppm): 8.58 (s, 1H); 7.78 (d, 1H); 7.71 {d, 1H); 7,56 (m, 2H); 4.16 (m, 2H); 4.01 (d, 2H); 3.21 (m, 2H); 2.63 (m, 1H); 2.03 (m, 2H); 1.84 (m, 2H); 1.26 (t, 3H). LCMS (ESD m/z 449 MH", 100 %)

Compound D2 1-(5-Nitro-6-phenylethynyl-pyrimidin-4-yI)-piperidine-4-carboxylic acid ethyl ester

[method 18]. Purification by HPLC yielded red oil. Yield 9 %. "H NMR 400MHz CDCl; § (ppm): 8.49 (s, 1H); 7.54 (4, 2H); 7.32 (d, 3H); 4.11 (m, 2H); 3.95 (d, 2H); 3.20 (m, 2H); 2.58 (m, 1H); 2.01 (mn, 2H); 1.80 (m, 2H); 1.21 (t, 3H). LCMS (ESI) m/z 381 (M-+H", 100 %)

Compound D3 1-[5-Nitro-6-(4-trifluoromethyl-phenylethynyl)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; [method 18]. Purification by HPLC. Yield 30 % brown solid. "H NMR 400MHz CDCl; 8 (ppm): 8.55 (s, 1H); 7.7 (d, 2H); 7.65 (d, 2H); 4.17 (m, 2H); 4.00 (d, 2H); 3.24 (m, 2H); 2.64 (m, 1H); 1.96 (m, 4H); 1.28 (t, 3H). LCMS (ESI) m/z 449 (M+H", 100%)

Compound D4 . 1-(5-Nitro-6-m-tolylethynyl-pyrimidin-4-yI)-piperidine-4-carboxylic acid ethyl ester;

Purification by HPLC. Yield 60 % brown solid. *H NMR 400MHz CDCl; 8 (ppm): 8.55 (5, 1H); 7.44 (d, 2H); 7.27 (d, 2H); 4.18 (m, 2H); 4.00 (d, 2H); 3.24 (m, 2H); 2.64 (m, 1H); 2.37 (s, 3H); 2.04 (m, 2H); 1.87 (m, 2H); 1.28 (t, 3H). LCMS (ESD) m/z 395 (M+H", 100 %)

Compound D5 1-[6~(2-Fluoro-phenylethynyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester;

H NMR 400MHz CDCl; § (ppm): 8.58 (s, 1H); 7.78 (d, 1H); 7.71 (d, 1H); 7,56 (m, 2H); 4.16 (m, 2H); 4.01 (d, 2H); 3.21 (m, 2H); 2.63 (m, 1H); 2.03 (m, 2H); 1.84 (m, 2H); 1.26 (1, 3H).

LCMS (ESI) m/z 449 (M+H", 100 %)

Compound D6 "1-[5-Nitro-6-(3-trifluoromethyl-phenylethynyl)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; [method 18]. Purification by Flash Chromatography (20-30 % Ethyl acetate/ Hexanes). Yield 42 %. "H NMR 400MHz CDCl; 3 (ppm): 8.55 (s, 1H); 7.87 (s, 1H); 7.78 (d, 1H); 7.68 (d, 1H); 7.55 (m, 1H); 4.19 (m, 2H); 4.00 (d, 2H); 3.23 (mn, 2H); 2.65 (m, 1H); 2.04 (m, 2H); 1.86 (m, 2H); 1.27 (t, 3H). LCMS (ESI) m/z 449 (MH, 100%)

EXAMPLE 16

SYNTHESES OF COMPOUNDS OF THE PRESENT INVENTION

S-Nitro-4-(S-phenyl-[1,3,4]oxadiazol-2-ylsulfanyl)-6-[4-(pyridin-2-ylsulfanyl)-piperidin- 1-yl]-pyrimidine '

Compound E1 [Method 16]. yellow solid (56 mg, 80 %). "HNMR (CDCl;, 400 MHz) 8 1.61 (m, 2H), 2.02 (tm, 2H), 3.22 (m, 2H), 3.69 (m, 2H), 3.98 (m, 2H), 6.87 (m, 1H), 6.94 (m, 1H), 7.30 (m, 4H), 7.72 (m, 2H), 7.89 (m, 1H), 8.20 (m, 11). Exact mass calculated for CHisN705S, 493.56, found 494.5 (MH).

The compounds in the above examples were screened in the Membrane Cyclase

Assay. Representative compounds are shown in the table below:

RUFP3 (ICs)

Compound Membrane Cyclase (uM) om

The other compounds in the Examples showed ICs, activities in the membrane cyclase assay less than about 500 pM.

Those skilled in the art will recognize that various modifications, additions, substitutions, and variations to the illustrative examples set forth herein can be made without departing from the spirit of the invention and are, therefore, considered within the scope of the invention. All documents referenced above, including, but not limited to, printed publications, » and provisional and regular patent applications, are incorporated herein by reference in their entirety.

Claims (3)

1. A PCT/US2004/001267 ® 213

   I. A compound of Formula (Ia): R, Ay Ary “a As NT A z % —D (Ia) or a pharmaceutically acceptable salt, hydrate or solvale thereof, wherein: A and B arc independently Cj. alkylenc optionally substituted with 1 to 4 methyl groups; D is S(O), CR;R; or N-Ry; V is selected from the group consisting of C,.3 alkylene, ethynylene and Cy.» heteroalkylene wherein each are optionally substituted with 1 to 4 substituents selected from the group consisting of C,_; alkyl, C, 4 alkoxy, carboxy, cyano, Cy; haloalkyl and halogen; or V is absent; W is NRy, O, S(O) or S(O); or W is absent; XisCRsorNandY is N; or XisNand Y is CRg or N; Z is selected from the croup consisting of CL: adh C2 anion Cop alhowy Coals © Ldlkvicarnonamide. © 2 alba Ithiocarnonamids CL alke izuifonamide. C4 alkylsulfinyl. Cy alkylsulfonyl, C,_; alkylthio. Cy alkylthioureyl. C4 alkylureyl. amino, C,.» alkylaming, C._ dialkylamino, carbo-C,¢-alkoxy. carboxamide, carboxy, cyano, Cy diacylamino, Cy ¢ dialkylcarboxamide, C4 dialkylthiocarboxamide, Cs, dialkylsulfonamide, C; 4 dialkylsulfonylamino, formyl,

   C,.; haloalkoxy, Cy haloalkyl, C, haloalkylcarboxamide, C4 haloalkylsulfinyl, C4 haloalkylsulfonyl, C, 4 haloalkylthio, halogen, heterocyclic, heteroaryl, hydroxyl, hydroxylamino, nitro and tetrazolyl, wherein Cy alkyl and C, s acyl are each optionally substituted with 1, 2. 3 or 4 groups selected from the group consisting of Cis acyl, Cyc acyloxy, C4 alkoxy, Cy alkylcarboxamide, C,_; alkylsulfonamide, C, 4 atkylsulfinyl, C,_; alkvisulfonyl. C, alkylthio, C4 alkylureyl, amino, C; , alkylamino, C4 dialkylamino, carbo-C, ¢-alkoxy, carboxamide, carboxy, cyano, J AMENDED SHEET

   PCT/US2004/001267 ® 214 formyl. C, | haloatkoxy. OC, haloalkylsulfinyl, C, , haloalkylsulfonyl. CC, haloalkyltiio, halogen, hydroxyl, hydroxytlamino and nitro; or

   7. is a group of Formula (A): NN YY TR Ne, 2, (A) wherein: Ry is H, C4 alkyl or Cs cycloalkyl; and Rg is H, nitro or nitrile; Ar, is aryl or heteroaryl wherein each are optionally substituted with Re-Ry3; R, is selected from the group consisting of H, C,.5 acyloxy, C, alkenyl, C4 alkoxy, Cg alkyl, Cy alkylcarboxamide, Ca 4 alkynyl, Cy, alkylsulfonamide, C4 alkylsulfinyl, C4 alkylsulfonyl, C,4 alkylthio, C,4 alkylureyl, C4 alkylamino, Cy 5 dialkylamino, carboxamide, cyano, Cs. cycloalkyl, C,.¢ dialkylcarboxamide, Cy dialkylsulfonamide, halogen, C,_ haloalkoxy, C, haloalkyl, C,4 haloalkylsulfinyl,

   C,.4 haloalkylsulfonyl, C, 4 haloalkylthio and hydroxyl; R, is selected from the group consisting of C5 acyl, C,.5 acyloxy, C4 alkoxy, C5 alkyl, Cy4 alkylcarboxamide, C, 4 alkylthiocarboxamide, C4 alkylsulfinyl, C4 alkylsulfonyl, C4 alkylthio, carbo-C, ¢-alkoxy, carboxy, cyano, Cs s~cycioalkyl, Co dialkyicarboxamide, C, baioalkoxy. Cy haloalkyl, halogen, heteroary hydro land phenyl: and wherein Co alkyl heteroan band phen are zach optionally substitgted with 1 ro 5 substituents selected from the croup consisting or C acy: C -acvion. CL alkony, Cy alnyl U aly lame. © alkylcarboxamide, C, alkylthiocarboxamide, C, alkylsulfonamide. C4 alkylsulfinyl, C,; alkylsulfonyl, C,_ alkylthio, Cy alkylthioureyl, C, 4 alkylureyl, amino, carbo-C, ¢-alkoxy, carboxamide, carboxy, cyano, Ci¢-cycloalkyl, Cs.¢- cycloalkyl-C, ;-alkylene, Cs 4-cycloalkyl-C; ;-heteroalkylene, Ca dialkylcarboxamide, C, dialkylthiocarboxamide, C4 dialkylsulfonamide, C4 alkylthioureyl, C4 haloalkoxy, C,_ haloalkyl, Cy haloalkylsulfinyl, C, 4 haloalkylsulfonyl, C,4 haloalkyl, C, haloalkyithio, halogen, heterocyclic, hydroxyl, hydroxylamine and nitro. or R, is -Ar,-Ar; wherein Ar, and Ar; are independently aryl or heteroaryl each optionally substituted with 1 to 5 substituents selected from the group consisting of AMENDED SHEET

   H, C,s acyl, Cys acyloxy, Cy4 alkoxy, Cy alkyl, Cis alkylcarboxamide, C14 alkylthiocarboxamide, Cis alkylsulfinyl, C4 alkylsulfonyl, C4 alkylthio, amino, carbo-C,.¢-alkoxy, carboxamide, carboxy, cyano, Cs¢-cycloalkyl, C26 dialkylcarboxamide, Ci.4 haloalkoxy, Cy.4 haloalkyl, halogen, hydroxyl and nitro; or R, is a group of Formula (B): Or ore (B) wherein: Ruais Cis alkyl or C4 cycloalkyl; and Rs is F, Cl, Bror CN; or R, is a group of Formula (C): idl Sar, © wherein: G is C=0, CR1eR17, 0, S, S(0), S(O)z; where Rys and Ry; are independently H or C,5 alkyl; and Ar, is phenyl or heteroaryl optionally substituted with 1 to 5 substituents selected from the group consisting of Cy.5 acyl, Cis acyloxy, C;.4 alkoxy, Cis alkyl, C14 alkylcarboxamide, C4 alkylthiocarboxamide, C4 alkylsulfonamide, Cy alkylsulfinyl, C14 alkylsulfonyl, Cy4 alkylthio, Ci alkylthioureyl, Ci alkylureyl, amino, carbo-C;s-alkoxy, carboxamide, carboxy, cyano, Css- cycloalkyl, C, ¢ dialkylcarboxamide, Cis dialkylthiocarboxamide, Cs. ¢ dialkylsulfonamide, C;4 alkylthioureyl, C14 haloalkoxy, Ci4 haloalkyl, C14 haloalkylsulfinyl, C,4 haloalkylsulfonyl, C14 haloalkyl, C,4 haloalkylthio, halogen, heteroaryl, hydroxyl, hydroxylamino and nitro; Rj is H, C5 alkyl, C4 alkoxy, halogen or hydroxyl; R4is H or Cys alkyl; Rs and Rg are independently H, C, 5 alkyl or halogen; R, is selected from the group consisting of Cs acyl, Cys acyloxy, Cas alkenyl, C,4 alkoxy, Cis alkyl, Cy 4 alkylamino, Cy, alkylcarboxamide, Cz6 alkynyl,

   Ci. alkylsulfonamide, Cy, alkylsulfinyl, C4 alkylsulfonyl, C,4 alkylthio, C14 alkylureyl, amino, arylsulfonyl, carbo-C, ¢-alkoxy, carboxamide, carboxy, cyano, Cis cycloalkyl, Ca.¢ dialkylamino, C, ¢ dialkylcarboxamide, Cs dialkylsulfonamide, halogen, C,.4 haloalkoxy, C;4 haloalkyl, C; 4 haloalkylsulfinyl, C14 haloalkylsulfonyl, C4 haloalkylthio, heterocyclic, heterocyclicsulfonyl, heteroaryl, hydroxyl, nitro, Cy oxo-cycloalkyl, phenoxy, phenyl, sulfonamide and sulfonic acid, and wherein C; 5 acyl, Cy. alkoxy, Cy.¢ alkyl, Cy 4 alkylsulfonamide, alkylsulfonyl, arylsulfonyl, heteroaryl, phenoxy and phenyl are each optionally substituted with 1 to 5 substituents selected independently from the group consisting of Cys acyl, Cis acyloxy, Cy. alkenyl, C4 alkoxy, Cys alkyl, C14 alkylcarboxamide, Cy alkynyl, Ci.4 alkylsulfonamide, Cy4 alkylsulfinyl, C,.4 alkylsulfonyl, Cy4 alkylthio, Cy.4 alkylureyl, carbo-C,.-alkoxy, carboxamide, carboxy, cyano, Cs cycloalkyl, Cas dialkylcarboxamide, halogen, C; 4 haloalkoxy, C4 baloalkyl, C, 4 haloalkylsulfinyl, C14 haloalkylsulfonyl, C4; haloalkylthio, heteroaryl, heterocyclic, hydroxyl, nitro and phenyl; or Ry is a group of Formula (D): Ayr th Rig 0} ®) wherein: “p” and “r” are independently 0, 1, 2 or 3; and Riz is H, Cys acyl, Cos alkenyl, Cy alkyl, C4 alkylcarboxamide, C; ¢ alkynyl, C;4 alkylsulfonamide, carbo-C,.¢- alkoxy, carboxamide, carboxy, cyano, Cs ¢ cycloalkyl, Cos ‘ dialkylcarboxamide, halogen, heteroaryl or phenyl, and wherein the heteroaryl and phenyl are each optionally substituted with 1 to 3 substituents selected independently from the group consisting of Cy4 . alkoxy, amino, Cy alkylamino, C, ¢ alkynyl, Cy; dialkylamino, halogen, C4 haloalkoxy, C;.4 haloalkyl and hydroxyl; and Rio-R;s are independently selected form the group consisting of Cy.5 acyl, Cis acyloxy, Cu alkenyl, C,4 alkoxy, Cg alkyl, C4 alkylcarboxamide,

   C,.¢ alkynyl, C4 alkylsulfonamide, C4 alkylsulfinyl, C4 alkylsulfonyl, C4 alkylthio, C,.4 alkylureyl, carbo-C, ¢-alkoxy, carboxamide, carboxy, cyano, Cig cycloalkyl, C,¢ dialkylcarboxamide, halogen, C;.4 haloalkoxy, C4 haloalkyl, C4 haloalkylsulfinyl, C,.4 haloalkylsulfonyl, C,. haloalkylthio, hydroxyl and nitro; or

   ® PCT/US2004/001267 two adjacent R p-R; groups together with Ar, form a 5. 6 or 7 membered cycioalkyl, cycioalkenyi or heterocyclic group wherein the 3,6 or 7 membered group is optionally substituted with halogen.
2. 2. The compound according to claim [ wherein W is NR.
3. 3 The compound according to claini 2 wherein Rois H

   4. The compound according to claim 2 wherein Ry is CH; or CH,CH;

   5. The compound according to claim 1 wherein W is O.

   6. The compound according to claim 1 wherein W is absent.

   7. The compound according to claim 1 wherein W is absent and V is ethynylene.

   8. The compound according to any one of claims 1 to 6 wherein V is -CHs- or -CH,C1H,.

   9. The compound according to any one of claims 1 to 6 wherein V is -OCH,CHs-.

   10. The compound according to any one of claims 1 to 6 wherein V is absent. 11 The compound according to any one of claims 1 to 10 wherein A is ethylene and B is methylene.

   12. THE compound accordimns IT amy OnE OI Sialme Lf luwmnerain AI Drom Ens ana B is methylene

   13. The compound according to any one of claims 1 to 10 wherein A and B are both ethylene wherein A and B are optionally substituted with 1 to 4 methyl groups.

   14. The compound according to any one of claims 1 to 13 wherein D is S(O). AMENDED SHEET

   ® PCT/US2004/001267 The compound according to any one of claims 1 to 13 where Ds CORR;

   16. The compound according to claim 15 wherein R, is selected from the group consisting of C5 acyl, C,.s acyloxy, C4 alkoxy, Cy alkyl, Cy4 alkylcarboxamide, C4 alkylthiocarboxamide, C, 4 alkylsulfinyl, C, 4 alkylsulfonyl, C, alkylthio, carbo C,, alkoxy, carboxyl, Us, cycloalkyl, C, 4 haloalkoxy, C4 haloalkyl, halogen and hudrosyl

   17. The compound according to claim 16 wherein R; is selected from the group consisting of C(O)CH;, C(O)CH,CH;, C(O)ClHL,CH,CH;, C(O)CH(CHs)o, C(O)CH,CHLCH,CH;3, OC(O)CH;, OC(O)YCH,CH;, OC(O)CH,CHLCH3, OCHs, OCH,CHj3;, OCH,CH,CHj;, OCH(CHj3)a, OCHA(CH1),CHs, CH3, CH,CHs, CH,CH,CHj3, CH(CH;),, CH(CH3)(CH2CH;), CHa(CH,)>CH;, CHA(CHa);CH;, CO,CH;3, CO,CH,CHj5, CO,CH,CH,CH3, CO.CH(CHj3),, CO2CHa(CH,),CH;, and CO,H.

   18. The compound according to claim 16 wherein R, is selected from the group consisting of §(0),CH3, S(0),CH,CH3, S(0),CH,CH,CHj3, S(O),CH(CH3)a, S{0)CH,(CH-1WCHa. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxyl, and

   F.

   19. The compound according to claim 15 wherein R, is C5 alkyl, or heteroaryl each nntinnally cohetitirtead with 1 4a § cuthetitiiants calactad fram the orn cancictinae nf optionally substituted with 1 to 5 substituents selected from the group consisting of Cs acyloxy. Cy alkoxy. C. alkyl C. alkyisulfonyl carbo-C- q-alkoxy carboxamide. carboxy, Co. -oyvcloalkyl, Co-cyveioaliny-C s-alkylene C.o-cveioalknt- C -heteroalkn iene. and ny dros:

   20. The compound according to claim 19 wherein R, is selected from the group consisting of CH,OCH;, CH,CH,0CHj;, CH,OCH,CHj3;, CH,0CH,CH.CH;, CH,CH-OCH,CHj, CH,CH,OCH,CH-CH,;, CH,OCH(CH3),, CH.OCH.CH(CH3),, CH,CO-H, CH,CH,CO,H, CH-OH, CH,CH,0OH and CH,CH,CH,0H.

   21. The compound according to claim 19 wherein R; is selected from the group consisting of CH.S(0).CH;. CH,S(0)-CH-CH;. CH,S(0),CH-CH-CH;:, CH-S(O)-CH(CHjs)-. CH,S5(0),CHA(CH;);CHs., CH,CH,S(0),CHs, CH,CH,S(0),CH,CHs. CH,CH,S(0),CH,CH,CH3, CH,CH,S(0}),CH(CHj),, AMENDED SHEET

   ® PCT/US2004/001267

   CH.CH.S(0)-CH.(CH.).CH;. CH.OCH;-cyclopropy!, CH.OCH--cyclobutyl, CH>UCH;-cyclopentyl, and CH-OCHa-cyctohexyl. 22, The compound according to claim 19 wherein R, is selected from the group consisting of 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 3-methyl 1,2,4 oxadiazol-5-yl, 3-ethyl-1,2 4-oxadiazol-5-yl, 3-1sopropyl-1,2,4-oxadiazol-5-yl, 3- propvi-1 7 4-oxadiazol-3-vi 3-r-butvi-1 2 doovadiazei-y-vl and s-cvelopropyl-1 2 4- oxadiazol-5-yl.

   23. The compound according to claim 15 wherein R, is -Ar,-Ar; wherein Ar, and Ar; arc independently aryl or heteroaryl each optionally substituted with 1 to 5 substituents selected from the group consisting of Cys acyl, C,_s acyloxy, C4 alkoxy, C, alkyl, Cy, alkylcarboxamide, C; 4 alkylthiocarboxamide, C, 4 alkylsulfinyl, C4 alkylsulfonyl, C4 alkylthio, amino, carbo-C, ¢-alkoxy, carboxamide, carboxy, cyano, Cs¢-cycloalkyl, C,¢ dialkylcarboxamide, C4 haloalkoxy, C;4 haloalkyl, halogen, hydroxy! and nitro.

   24. The compound according to claim 23 wherein Ar, is a heteroaryl and Ar; is phenyl.

   25. The compound according to claim 15 wherein R, is Formula (C): G idl “Ar, () wherein: GisC=0. CR.,R - O % 500 Sth: wherain RB. and R.- are Independently Hor C.- alka t. and Ar, is phenyl or heteroaryl optionally substituted with 1 to 5 substituents selected from the group consisting of C,4 alkoxy, Cig alkyl, Ci4 haloalkoxy, C,; haloalkyl, and halogen.

   26. The compound according to claim 25 wherein G is C=0, CH; or O.

   27. The compound according to claim 25 wherein G is S, S(O) or S(O),.

   28. The compound according to any one of claims 25 to 27 wherein Ar, is selected from the group consisting of pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl. AMENDED SHEET

   ® PCT/US2004/001267 29 The compound according to any one of claims25 to 28 wherein Ary is 2-pyridyl

   30. The compound according to any one of claims 25 to 29 wherein Ry, and R,; are both

   H.

   31. ‘The compound according to any one ot claims 15 to 30 wherein Ry is H.

   32. The compound according to any one of claims 41 to 13 wherein D is N-Ra.

   33. The compound according to claim 32 wherein R, is carbo-Cyg-alkoxy.

   34. The compound according to claim 33 wherein R; is selected from the group consisting of CO,CHj;. CO,CH-CH;. CO.CH.CH,CH,, CO,CH(CH3), and CO,CH,(CH2),CHs.

   35. The compound according to claim 32 wherein R, is Cy alkyl optionally substituted with 1 to 5 substituents selected from the group consisting of C, 4 alkylsulfonyl, carbo-C; ¢-alkoxy, and carboxy.

   36. The compound according to claim 35 wherein R, is CH.CO,Et, or CH,CH,CO,H.

   37. The compound according to claim 35 wherein R is selected from the group rnmetating AF CIT OT C/N CLI CT OTT QON CII CT. OT OT rN NY OWI CLT LULL 1oL iy ul lA LDN JIL 134 WM A20% 8 CRESAR SP AAT EA TE AER RASS ENE AACE IRA SE ESA EE PY CH-CH-S(O»CH(CH:)- and CH.CH-S(OV-CH-(CH-)-CHs. 38 The compound aloolling 0 any one of Gam: 1 we 37 wherein J is seeded rom the group consisting of Cs acyl, C4 alkyl. C4 alkylcarboxamide, amino, cyano. Cu diacylamino, Ca, dialkylsulfonamide, formyl. halogen. heterocyclic, and nitro wherein Cy alkyl and C5 acyl are each optionally substituted with 1, or 2 groups selected from the group consisting of C» 4 dialkylmino. hydroxy. and halogen.

   39. The compound according to claim 38 wherein Z is selected from the group consisting of nitro, amino, formyl, NHC(O)CF3, Br, NHC(O)CH;, N(C(O)CHs),, N(5(0)-CHj3)s.

   CH;. [1.3]dioxolan-2-v1, CH,OH. CH>N(CHjs)-. and C(O)CHx AMENDED SHEET

   3 PCT/US2004/001267 40 The compound according to any one of claims 1 to 39 wherem R, 1s selected from the group consisting of H and Cg alkyl. 41 The compound according to any one of claims 1 to 40 wherein Ar, is phenyl optionally substituted with Ry-R;. 42 I'he compound according to claim 41 wherein Ra. ie selected from the vrourn consisting of Cy 5 acyl, Cy 4 alkoxy, C4 alkyl, Cy; alkylcarboxamide, Cs. alkynyl, C4 alkylsulfonamide, C, dialkylsulfonamide, C, 4 alkylsulfinyl, C, ; alkylsulfonyl, C, 4 alkylthio, amino, arylsulfoniyl, Cs dialkylamino, C4 dialkylsulfonamide, and carboxamide.

   43. The compound according to claim 42 wherein Ry 1s selected from the group consisting of C{O)CHj, C(O)CH,CHj3, C(O)CH,CH,CH3, C(O)CH(CH3),, C(O)CH,CH,CH,CH;, OCH;, OCH,CHj;, OCH,CH,CH;, OCH(CH3),, OCH,CH,CH.CH;, CH;, CH,CH;, CH,CH2CH;, CH(CH3),, CH(CH;)(CH,CHs), CHa(CH,)-CH3, CH,(CH;);CH;3, CHy(CHa)4CH;, CHA(CH,)sCH;, C(O)NHCH;, C(O)NHCH,CHj;, C(O)NHCH,CH,CH;, C(O)NHCH(CHa;),, C=CH, S(O),NHCHj3;, S(O) NHCH.CH;, S(OBNHCH-CH.OH;, S(O)aNHCH(CHA)A, S(O)NHCH,(CH1),CH;, S(O);NHCH(CH;3)CH,CHs, S(O)-N(CH;)s, S(O), N(Et)(CHs), S(O),CH3, S(0).CH,CH3, S(0).CH.CH,CH;, S(0),CH(CHj),, S(0)-CH-(CH,),CH;, S(0).CH(CH;)CH,CH,3, SCH;, SCH,CH;, SCH.CH,CH;, SCH(CH.)a, SCHA(CH,)-CHj;, amino, S{C); Ph, N{Clis), N{CILYEL), N(Et), and C(ONH: +4 The compound acoording to Claim +7 wherein Robs selected Tom the srous consisting of cyano, Cs, cycloalkyl, halogen, C, haloalkoxy, Ci haloalkyl, Ci haloalkylsulfonyl, and C, 4 haloalkylthio.

   45. The compound according to claim 44 wherein Ry is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cl, F, Br, OCF3, OCHF,, OCH,CF,, CF;, CHF, CH.CF;, SCF:. SCHF- and SCH,CF-.

   46. The compound according to claim 41 wherein R. is selected from the group consisting of heterocyclic, heterocyclicsulfonyl, heteroaryl, hydroxy, C4.; oxo-cycloalkyl. phenoxy and phenyl. AMENDED SHEET

   PCT/US2004/001267 ® 222

   47. The compound according to claim 46 wherein Ry is selected from the group consisting ot morpholin-4-yl, thiomorpholin-4-yi, 1-ox0-1 _ -thiomorphoiin--yl, i,i-Dioxo- 1 “-thiomorpholin-4-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl, 4-ethyl-piperazin-1- vl, 4-propyl-piperazin-1-yl, piperidin-1-yl, pyrrolidin-1-yl, 2,5-dioxo-imidazolidin-4- yl, 2,4-dioxo-thiazolidin 5 yl, 4 oxo 2 thioxo thiazolidin-5-yl, 3-methyl-2,5-dioxo- imidazolidin-4-yl, 3-methyl-2.4-dioxo-thiazolidin-3-yl, 3-methyl-4-oxo-2-thioxo-~ thigzohidin-~-vl 3-ethvi-7 S-dioso-imidaszolidin-d-vi S-ettinv1-2 d-dioxo-thiazolidin-3- yl, and 3-cthyl-4-oxo-2-thioxo-thiazolidin-5-yl.

   48. The compound according to claim 46 wherein Ry is sclected from the group consisting of 1 H-imidazol-4-yl, [1,2,4]triazol-1-yl, [1,2,3]triazol-1-yl, [1,2,4]triazol-4- yl, pyrrol-1-yl, pyrazol-1-yl, 1H-pyrazol-3-yl, imidazol-1-yl, oxazol-5-yl, oxazol-2-yl, [1,3.4]oxadiazol-2-y], [1,3 .4]thiadiazol-2-yl, [1,2 4]oxadiazol-3-yl, [1,2,4]thiadiazol- 3-yl, tetrazol-1-yl, pyrimidin-5-yl, pyrimidin-2-yl, pyrimidin-4-yi, pyridazin-3-yI, pyridazin-4-yl, pyrazin-2-yl, 1,3-dioxo-1,3-dihydro-isoindol-2-yl and [1,2,3]thiadiazol-4-yl.

   49. The compound according to claim 41 wherein Ry is C,.g alkyl or C,_4 alkoxy optionally substituted with 1 to 5 substituents selected independently from the group consisting of Cs acyl, C4 alkoxy, C,, alkylcarboxamide, C4 alkylsulfonyl, carbo-

   C,.¢-alkoxy, carboxamide, carboxy, cyano, and hydroxyl.

   50. The compound according to claim 49 wherein R; is selected from the group consisting of CH,OCH; CH,OCH-CH:. CH-OCH-CH-CH: CH-OCH(CH-)- CH-OCH-(CH-)-CH: CH-CH-OCH; CH-CH-OCH-CH: CH-CH-OCH-CH-CH-

   CH-.CH-OCiLi Cit: and Ci1-Ci-0CH- CH: -.CH-

   51. The compound according to claim 41 wherein Ry is of Formula (D): Ahh Ri Oo (D} wherein: “p” and “r” are independently 0. or 1; and Rg is H. carbo-C, ¢-alkoxy. heteroaryl or phenyl. and wherein the heteroaryl and phenyl are each optionally substituted with 1 to 5 substituents selected independently from the group AMENDED SHEET j

   ® PCT/US2004/001267 consisting of C, alkoxy, amino, C_; alkylamino, C. alkonyl, Coy dialhylamino, nalogen, C4 haloalkoxy, C4 haloalky! and nydroayl.

   52. The compound according to claim 51 whereinp = Gand r = 0.

   53. I'he compound according to claim 52 wherein Ky 1s phenyl optionally substituted with 1 to S substituents sefecied independently from the group consisting of ©. alkoxy. amino, C,_; alkylamino. C,,, alkynyl, C4 dialkylamino, halogen, C4 huloalkoxy, Cy 4 haloalkyl und hydroxyl.

   54. The compound according to claim 51 whereinp = 0 and r+ 1.

   55. The compound according to claim 54 wherein Ris is carbo-C,_g-alkoxy or carboxy.

   56. The compound according to any one of claims 42 to 55 wherein Ry is substituted at the para position on the phenyl.

   57. The compound according to any one of claims 41 to 56 wherein Ryo-Ry3 are independently selected from the group consisting of C, < acyl. Cy 4 alkoxy. C, ¢ alkyl,

   C,.; alkylcarboxamide, C,4 alkylureyl, carbo-C, ¢-alkoxy, carboxamide. carboxy, cyano, Cs. cycloalkyl, halogen, C,4 haloalkoxy and C,_4 haloalkyl. 58 The compound according to any one of claims 41 to 56 wherein one or two BR BR groups are independently halogen.

   3G. The compound according to any ong of tlaims 40 10 SS wherein two adiacent R -R groups together with the phenyl] form a 3. 6 or 7 membered cycloalkyl. cycloalkenyl or heterocyclic group wherein the 5, 6 or 7 membered group is optionally substituted with halogen.

   60. The compound according to claim 59 wherein the heterocyclic group together with the phenyl group is a 2,3-dihydro-benzofuran-5-yl, benzo[1,3|dioxol-5-yl group, 2,3- dihydro-benzo[ 1,4]dioxin-6-yl, 2,3-dihydro-benzo[ 1,4 ]dioxin-2-yl group. 3.4- dihvdro-2H-benzo|b]| 1.4]dioxepin-7-yl group.

   61. The compound according to any one of claims 1 to 40 wherein Ar; is heteroaryl optionally substituted with R¢-R 3. AMENDED SHEET

   PCT/US2004/001267 62 The compound according to claim 61 wherein Ry is selected from the group consisting of Cy alkoxy, Cy alkyl, U4 alkylcarboxamide, C4 alkylsuifonyl, C4 haloalkyl, hydroxy, halogen, and phenyl

   63. The compound according to claim 62 wherein Ry is selected from the group consisting OCH3. OCH,CH;, OCH,CH>CH3, OCH(CH3),, OCHCHACHCH;, CH; CHLCH;, CHACH-C He CHOCO H = CHOCHMO HCH CHSC HS-OH- CHS(CHCH- CH:(CH1)4CHs, CHA(CH,)sCH;, C(O)NHCH;, C(O)NHCH,CHa, C(O)NHCH,CH.CH;, C(O)NHCH(CH,),, C(O)NHCH(CH,),CHj, S(0)-CH, $(0),CH,CHj, S(0),CH,CH,CHj, S(O),CH(CH:),, Cl, F, Br, CF, CHF, CH-CFj, and hydroxy. 64 The compound according to any one of claims 61 to 63 wherein Ryo-R,; are independently C5 acyl, C4 alkoxy, C,g alkyl, C4 alkylcarboxamide, C,.4 alkylureyl, carbo-C,.¢-alkoxy, carboxamide, carboxy, cyano, Cs cycloalkyl, halogen, C4 haloalkoxy and C,.4 haloalkyl.

   65. The compound according to any one of claims 61 to 63 wherein one or two Ryo-Ry3 groups are independently halogen.

   66. The compound according to any one of claims 1 to 65 wherein X is N and Y is CH.

   67. The compound according to any one of claims 1 to 65 wherein X is Nand Vis CF 68 Lhe compound according to any one of claims 1 to 62 wherem X is CHand Y 1s N

   69. The compound according to any one of claims 1 to 65 wherein X and Y are N

   70. The compound according to claim | wherein said compound is selected from the group consisting of: 1-[6-(4-Imidazol-1-yl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester; AMENDED SHEET

   PCT/US2004/001267 ® 225 1-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yioxy)-S-mtro-pyrimidin-4 ylj-pipenidine-4-carboxylic acid ethyl ester; 1-[6-(4-Methanesulfonyl-phenoxy)-3-nitro-pyrimidin-4-y1]-pipcridinc-4- carboxylic acid ethyl ester;

   1.[6-(Benzo|1,2,5 joxadiazol-5-yloxy)-5-nitro-pyrimidin-4 yl] piperidine 4 carboxylic acid ethyl ester; i-ih-jd-(2-Methovvearbonvi-acetvli-phenovel-snitro-puerimidin-d-vil- piperidine-4-carboxylic acid ethyl ester; 1-15 -Amino-6-(2 -methyl-S-trifluoromethyl-2H-pyrazol-3-yloxy) pyrimidin 4-yl}-piperidine-4-carboxylic acid ethyl ester; 1-|6-(2-Methyl-5-triflucromethyl-2 H-pyrazol-3-yloxy)-5-(2,2,2-trifluoro- acetylamino)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 4-[6-(2-Methyl -5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4- yl]-piperazine-1-carboxylic acid ethyl ester; 1-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4- yl]-piperidine-4-carboxylic acid methyl ester; 1-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4- yl]-piperidine-3-carboxylic acid ethyl ester; : 1-[6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4- yl]-piperidine-4-carboxylic acid ethylamide; 1-[6-(2-Methyl-5-phenyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidin-4-yl1]- piperidine-4-carboxylic acid ethyl ester; 1-15. Nitre-6-(2-riflucromethy! benzyloxy) pyrimidin 4 v1] piperidine 4 carboxylic acid ethyl ester: P-[3-Natro-6-( 3-trirluoromethyi-benzyviony -myrimidin-24-yv iH -riperidine ~~ carooha ic aad etna lester. 1-[53-Nitro-6-(4-trifluoromethyl-benzyloxy)-pyrimidin-4-yl]-piperidine-4- carboxylic acid cthyl ester; 1-[5-Bromo-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-pyrimidin- 4-yl]-piperidine-4-carboxylic acid ethyl ester; AMENDED SHEET

   1-[5-Acetylamino-6-(2-methyl-5 -trifluoromethyl-2H-pyrazol-3-yloxy)- pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[5-Diacetylamino-6-(2-methyl-5 rifluoromethyl-2H-pyrazol-3-yloxy)- pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-]6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3 -yloxy)-5-nitro-pyrimidin-4- yl] -piperidine-4-carboxylic acid; : 1- {5-Nitro-6-[2-( 2-trifluoromethyl-phenyl)-cthoxy] -pyrimidin-4-y1}- piperidine-4-carboxylic acid ethyl ester; 1-{5-Nitro-6-[2-(3-trifluoromethyl-phenyl) -ethoxy}-pyrimidin-4-y1}- piperidine-4-carboxylic acid ethyl ester; 1-[5-Di-(methanesulfonyl)amino-6-(2-methyl-5 Arifluoromethyl-2H-pyrazol- 3-yloxy)-pyrimidin4-yl] -piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(3 _trifluoromethyl-phenoxy)-pyrimidin-4-yi]-piperidine-4- carboxylic acid ethyl ester; 1-[5 -Methyl-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3 -~yloxy)-pyrimidin- 4-y1]-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(2-trifluoromethyl-phenoxy) -pyrimidin-4-yl]-piperidine-4- . carboxylic acid ethyl ester; 1-[5 Nitro-6-(4-trifluoromethyl-phenoxy)-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester; 1-[6-(4-Fluoro-phenoxy)-5 _nitro-pyrimidin-4-y1] -piperidine-4-carboxylic acid ethyl ester; 1-[6-(2,5-Dimethyl-2H-pyrazol-3-yloxy)-5 -nitro-pyrimidin-4-y1]-piperidine- 4-carboxylic acid ethyl ester; 1-[6-(4-Bromo-phenoxy)-5-nitro-pyrimidin-4-yi] -piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Chloro-phenoxy)-5 -nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Carbamoyl-phenoxy)-5 _nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-{6-[4-(2-Methoxy-ethyl)-phenoxy]-5-nitro-pyrimidin-4-y1} -piperidine-4- carboxylic acid ethyl ester; 1-[6-(4-Cyclopentyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester; 1-[5-Nitro-6-(4-pyrrol-1-yl-phenoxy)-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester; ee

   1-[6-(4-Benzoyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-{6-[4-(4-Hydroxy-benzenesulfonyl)-phenoxy]-5 -nitro-pyrimidin-4-yl}- piperidine-4-carboxylic acid ethyl ester; 1-[6-(4"-Cyano-biphenyl-4-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester; 1-[6-(2-Amino-4-ethanesulfonyl-phenoxy)-5-nitro-pyrimidin-4-yt}- piperidine-4-carboxylic acid ethyl ester; 1-{6-[4-(5-Hydroxy-pyrimidin-2-yl)-phenoxy]-5-nitro-pyrimidin-4-y1}~ piperidine-4-carboxylic acid ethyl ester; 1-5-Nitro-6-(4-sulto-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(4-[1,2,4iriazol-1-yl-phenoxy)-pyrimidin-4-yl|-piperidine-4- ‘carboxylic acid ethyl ester; 1-[6-(4-Carbamoylmethyl-phenoxy)-5-nitro-pyrimidin-4-yl}-piperidine-4- carboxylic acid ethyl ester; 1-{6-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-~yl)}-phenoxy]-5-nitro-pyrimidin-4- yl}-piperidine-4-carboxylic acid ethyl ester; ' 1-{6-(4'-Methoxy-biphenyl-4-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester; 1-{6-[4+(2,5-Dioxo-imidazolidin-4-yl)-phenoxy]-5 -nitro-pyrimidin-4-y1} - piperidine-4-carboxylic acid ethyl ester; 4-(4,4-Difluoro-piperidin-1-y1)-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3- yloxy)-5-nitro-pyrimidine; 1-{5-Nitro-6-[4-(4-ox0-cyclohexyl)-phenoxy]-pyrimidin-4-yl} -piperidine-4- carboxylic acid ethyl ester; 1-{5-Nitro-6-[4~(3-oxo-butyl)-phenoxy]-pyrimidin-4-y1}-piperidine-4- carboxylic acid ethyl ester; 1-[5-Nitro-6-(4-propionyl-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(4-{1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidin-4-yi}-piperidine-4- carboxylic acid ethyl ester; 1-{6-[4-(2-Hydroxy-ethyl)-phenoxy]-5-nitro-pyrimidin-4-y1} -piperidine-4- carboxylic acid ethyl ester; {4-[6-(4,4-Difluoro-piperidin-1-y1)-5-nitro-pyrimidin-4-yloxy]-phenyl}- - phenyl-methanone; }

   PCT/US2004/001267 ® 228 3-{4-[6-(4 4-Thfluoro-piperidin-1-y1)-5-nitro-pyrimidin-4-yloxy]-phenyl}-3- oxo-propionic acid methyl ester; 2-[6-(4,4-Diftuoro-piperidin-1-y1)-5-nitro-pyrimidin-4-yloxy}-5- ethanesulfonyl-phenylamine; 4 (4 Cyclopentyl phenoxy)-6-(4,4-difluoro-piperidin-1-yl)-5-nitro- pyrimidine; 1-16-17 6-Dichloro-d-methanesulfonvi-phenosv-S-nitto-pyrimidin-d-vil- piperidine-4-carboxylic acid ethyl ester;

   1.-{6 [4 (4 Chloro-benzoyl)-phenoxy]-5-nitro-pyrimidin-4-y1} -piperidine-4- carboxylic acid cthyl ester; 1-{6-[4-(4-Hydroxy-benzoyl)-phenoxy]-3-nitro-pyrimidin-4-yl} piperidine - 4~carboxylic acid ethyl ester; {-[6-(4-Cyanomethyl-phenoxy)-5-nitro-pyrimidin-4-yll-piperidine-4- carboxylic acid ethyl ester; (4-{6-[4-(2-Methanesulfonyl-ethy!)-piperazin-1-yl]-5-nitro-pyrimidin-4- yloxy}-phenyl)-phenyl-methanone; 4-(4-{6-[4-(2-Methanesulfonyl-ethyl)-piperazin-1-yl}-5-nitro-pyrimidin-4- yloxy}-phenyl)-butan-2-one; 3-(4-{6-[4-(2-Methanesulfonyl-ethyl)-piperazin-1-y1}-5-nitro-pyrimidin-4- yloxy}-phenyl)-3-oxo-propionic acid methyl ester; 4-(4-Methyl-piperidin-1-y1)-6-(2-methyl-5-trifluoromethy!-2H-pyrazol-3- yloxy)-3-nitro-pyrimidine; A-(4-Brome-piperidin-1-y1-6-(2-methy1-5-triflnoromethyl-2H-pyrazol-3- vloxy)-3 -nitro-pyrimidine: d- 2-Methyl-S-triflucromethyi-2H-pyrazol->-vioay s-3-nitre-6-(4-propyi- Dipenidin- A benvmmiding: 1-[5-Nitro-6-(2-oxo-2H-chromen-6-yloxy }-pyrimidin-4-ylj-piperidine-4- carboxylic acid ethyl] ester; 1-[5-Nitro-6-(2-0xo-benzo[ 1,3 Joxathiol-6-yloxy)-pyrimidin-4-yl}-piperidine- 4-carboxylic acid ethyl ester; 1-[6-(9H-Carbazol-2-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(9-ox0-9H-fluoren-2-yloxy)-pyrimidin-4-yl}-piperidine-4- carboxylic acid ethyl ester: AMENDED SHEET a 229 1-{5-Amino-6-[4-(3-oxo-butyl)-phenoxy]-pyrimidin-4-yl} -piperidine-4- carboxylic acid ethyl ester; 1-[6-[4-(3-Oxo-butyl)-phenoxy]-5-(2,2,2-triflucro-acetylamino)-pyrimidin-4- yl]-piperidine-4-carboxylic acid ethyl ester; 1-{5-Amino-6-[4-(hydroxy-phenyl-methyl)-phenoxy]-pyrimidin-4-y1}- piperidine-4-carboxylic acid ethyl cster; 1-[6-(2-Benzoyl-5-methoxy-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester; 1-[6-(6-Chloro-pyridin-3-yloxy)-5-nitro-pyrimidin-4-yl}-piperidine-4- carboxylic acid ethyl ester; 1-[6-(Benzo[ 1,3]dioxol-5-yloxy)-5-nitro-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester; 1-[6-(4-Benzyloxy-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-]6~(3-Morpholin-4-yl-phenoxy)-5-nitro-pyrimidin-4-yl}-piperidine-4- carboxylic acid ethyl ester; Nitro-6-(4-trifluoromethylsulfanyl-phenoxy)-pyrimidin-4-y1] -piperidine- 4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(4-trifluoromethoxy-phenoxy)-pyrimidin-4-yl}-piperidine-4- carboxylic acid ethyl ester; 1-[6-(4-Benzoyl-phenoxy)-5 -(2,2,2-triflucro-acetylamino)-pyrimidin-4-yl]- piperidine-4-carboxylic acid ethyl ester; {4-[5-Nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yloxy]-phenyl}-phenyl- methanone; {4-Methoxy-2-[5-nitro-6-(4-propyl-piperidin-1-y1)-pvrimidin-4-yloxy]- phenyl}-phenyl-methanone; : 4-{4-[5-Nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yloxy]-phenyl}-butan- 2-one; 5-Nitro-4-(4-propyl-piperidin-1-y1)-6-(4-[1,2,3}thiadiazol-4-yl-phenoxy)- pyrimidine; 3-{4-[5-Nitro-6~(4-propyl-piperidin-1-yl)-pyrimidin-4-yloxy]-phenyl } -3-oxo- propionic acid methyl ester; 5-Ethanesulfonyl-2-[5-nitro-6-(4-propyl-piperidin-1-y1)-pyrimidin-4-yloxy]- phenylamine; 1-[6-(4-Difluoromethoxy-benzyloxy)-5-nitro-pyrimidin-4-y1]-piperidine-4- carboxylic acid ethyl ester;

   1-{6-(3-Difluoromethoxy-benzyloxy)-5 _nitro-pyrimidin-4-yl] -piperidine-4- . carboxylic acid ethyl ester; 2-{1-{6-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3 -yloxy)-5 nitro-pyrimidin- 4-yl]-piperidin-4-yl}-ethanol; 3-{1-[6-(2-Methyl-5-trifluoromethyl-2H-pyra z0l-3-yloxy)-5-nitro-pyrimidin- 4-y1]-piperidin-4-yl}-propionic acid; 4-[4-(4-Methyl-benzyl)-piperidin-1-yl] -6-(2-methyl-5-trifluoromethyl-2H- pyrazol-3-yloxy)-5-nitro-pyrimidine; 4-3 -Methanesulfonyl-pyrrolidin-1-y1)-6-(2-methyl-5 rifluoromethyl-2H- pyrazol-3-yloxy)-5-nitro-pyrimidine; 4-(2-Methyl-5 ~trifluoromethyl-2H-pyrazol-3-yloxy)-5 -nitro-6-[4-(2- triflnoromethyl-phenoxy)-piperidin-1-yl]-pyrimidine; 4-(2-Methyl-5 -trifluoromethyl-2H-pyrazol-3-yloxy)-5 -nitro-6-[4-(pyridin-2- ylsulfanyl)-piperidin-1-y1]-pyrimidine; 4'-(4-Benzoyl-phenoxy)-3'-nitro-3,4,5 ,6-tetrahydro-2H-1,2"Tbipyridinyl-4- "carboxylic acid ethyl ester; -

   3. Nitro-4'-[4-(3-0xo-butyl)-phenoxy]-3 ,4,5,6-tetrahydro-2H- [1,2"Tbipyridinyl-4-carboxylic acid ethyl ester; 4'-[4-(2-Methoxycarbonyl-acetyl)-phenoxy]-3'-nitro-3,4,5 6-tetrahydro-2H- [1,2'bipyridinyl-4-carboxylic acid ethyl ester; : #-(2-Amino-4-ethanesulfonyl-phenoxy)-3-nitro-3,4,5,6-tetrahydro-2H- [1,2'Tbipyridinyl-4-carboxylic acid ethyl ester; 4'(4-Imidazol-1-yl-phenoxy)-3'-nitro-3 A.5,6-tetrahrydro-2H- [1,2 Tbipyridinyl-4-carboxylic acid ethyl ester; 4-(2-Methvl-5-trifluoromethyl-2H-pyrazol-3 -yloxy)-5-nitro-6-(4- trifluoromethyl-piperidin-1-yl)-pyrimidine; 4-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yloxy)-5 -nitro-6-(4- phenylsulfanyl-piperidin-1-yl)-pyrimidine; 1-[6-(3-Ethynyl-phenoxy)-5-nitro-pyrimidin-4-yl] -piperidine-4-carboxylic acid ethyl ester; . 1-[6-(4-Chloro-2-fluoro-phenoxy)-5 -nitro-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester; 1-[6-(2,4-Difluoro-phenoxy)-5-nitro-pyrimidin-4-yl] -piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Bromo-2-fluoro-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester; : 4-(3-Ethynyl-phenoxy)-5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidine;

   4-(4-Chloro-2-fluoro-phenoxy)-5 -nitro-6-(4-propyl-piperidin-1-y1)- pyrimidine; 4-(2,A-Difluoro-phenoxy)-5 nitro-6-(4-propyl-piperidin-1-y])-pyrimidine; 4~(4-Bromo-2-fluoro-phenoxy)-5 -nitro-6-(4-propyl-piperidin-1-y1)- pyrimidine; 3'-Nitro-2'[4-(3-0x0-butyl)-phenoxy]-3 A,5,6-tetrahydro-2H- [1,4Thipyrdinyl-4-carboxylic acid ethyl ester;

   4.[4-(3"-Nitro-4-propyl-3 4.5 6-tetrahydro-2H1-[ 1,4 Thipyridinyl-2-yloxy)- phenyl]-butan-2-one;

   2'.(4-Benzoyl-phenoxy)-3'-nitro-3.4,5 6-tetrabydro-2H-[1,4Tbipyridinyl-4- carboxylic acid ethyl ester; 4-(4-{5 “Nitro-6-[4-(pyridin-2-ylsul fanyl)-piperidin-1-yl]-pyrimidin-4- : : yloxy}-phenyl)-butan-2-one; [4-(3"Nitro-4-propyl-3,4,5,6-tetrahydro-2H-[ 1,4 Tbipyridinyl-2'-yloxy)- phenyl]-phenyl-methanone; 4-(4-{5-Nitro-6-[4-(2-triftuoromethyl-phenoxy)-piperidin-1-yl] ~pyrimidin-4- yloxy}-phenyl)-butan-2-one; 4-(4-{6-[4-(3-Methyl-[1,2,4]oxadiazol-5 ~y1)-piperidin-1-y1]-5-nitro~ pyrimidin-4-yloxy}-phenyl)-butan-2-one; (4-{6-14-(3 Methyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl}-5-nitro-pyrimidin- 4-yloxy}-phenyl)-phenyl-methanone; 1-{6-[4-(4-Fluoro-benzoyl)-phenoxy]-5 -nitro-pyrimidin-4-yl1} -piperidine-4- carboxylic acid ethyl ester; : (4-Fluoro-phenyl)-{4-[5 -nitro-6~(4-propyl-piperidin-1-y1)-pyrimidin-4- yloxy]-phenyl}-methanone: : 4-[4-(3 Methyl-[1,2,4]oxadiazol-5-y1)-piperidin-1-y1] -6~2-methyl-5- .trifluoromethyl-2H-pyrazol-3-yloxy)-5-nitro-pyrimidine; 4-(4-Methoxymethyl-piperidin-1-yl)-6-(2-methyl-5 -trifluoromethyl-2H- pyrazol-3-yloxy)-5-nitro-pyrimidine; 4-{4-[6-(4-Methoxymethyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]- phenyl} -butan-2-one; 4-[4-(2-Methoxy-ethyl)-piperidin-1-yl]-6<2-methyl-5-trifluoromethyl-2H- pyrazol-3-yloxy)-5-nitro-pyrimidine; 4-{4-[6-(4-Ethoxymethyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]- phenyl}-butan-2-one; 4-(2,4-Difluoro-phenoxy)-5-nitro-6-[4-(pyridin-2-yl sulfanyl)-piperidin-1-y1]- pyrimidine;

   PCT/US2004/001267 ® 232 (4-Methoxy-2- 1 Snitro-6-[4-(pyrdin-2 -y lsulfany)-piperidin-1-yl-pyrimidin- 4-yloxyj-phenyl)-phenyi-methanone, 4-(2,4-Difluoro-phenoxy)-6-(4-ethoxymethyl-piperidin-1-yl)-5-nitro- pyrimidine; 4 {4 [6 (4-Cyclopropylmethoxymethyl piperidin 1 yl} 5 nitro pyrimidin-4 yloxy]-phenyl} -butan-2-one; LILI Nitro-A-rd propos meth l-piperidin. iv Fepvrimidined-viosi- phenyl} -butan-2-one; 1-{4-[6 (4 Methoxymethy! piperidin-1 yl) 5 nitro pyrimidin 4 yloxy]- phenyl} -cthanonc; 4-{4-[6-(4-Butoxymethyl-piperidin-1-yl}-5-nitro-pyrimidin-4-yloxy]- phenyl}-butan-2-one; 4-14-[6-(4-Isobutoxymethyl-piperidin-1-yl)-5-nitro-pyrimidin4-yloxy|- phenyl} -butan-2-one; (4-Fluoro-phenyl)-{4-(3'-nitro-4-propy!-3,4,5,6-tetrahydro-2H- [1,2'Tbipyridinyl-4'-yloxy)-phenyl]-methanone; 4-14-(3"-Nitro-4-propyl-3.4,5,6-tetrahydro-2H-{ 1,2'|bipyridinyl-4'-yloxy)- phenyl}-butan-2-one; 3'-Nitro-4-propyl-4'-(4-{1.2 4]triazol-1-vl-phenoxy)-3.4.5.6-tetrahvdro-2 H-

   [1.2'|bipyridinyl; {4-[6-(4-Ethoxy-piperidin-1-yl1)-5-nitro-pyrimidin-4-yloxy]-phenyl} -(4- fluoro-phenyl)-methanone; 1-[6-(2-Methyl-5-trifluoromethy! 2H pyrazel-2 yloxy) 5 nitro-pyrimidinA- v1]-piperidin-4-ol: I-{a-rd-Acztvi-phenoxy -S-nitro-pyrimidin-=-yv1i-pinencine-—+-carbexy hic A013 II CSET AMENDED SHEET

   PCT/US2004/001267 ® 233 (1-16-[4-(4-Fluora-benzoyl)-phenoxy]-5-nitro-pyrimidin-4-y1} -piperidin-4- ylj-(4-tluoro-phenyij-methanonc; 4-(4-{6-[4-(4-Fluoro-benzoyl)-piperidin-1-yl}-5-nitro-pyrimidm-4-yloxy}- phenyl)-butan-2-one; 4-(4-Methanesulfonyl-phenoxy)-5 -nitro-6-[1-(pyridin-2-ylsulfanyl)- piperidin-1-yl]-pyrimidine; dd-Methanesculforvl-phienoswi-S-nit o-6-Td-peridin-d-vIsutfanviy- piperidin-1-yl|-pyrimidine; 4-[4-(3-Isopropyl-[1,2,4]oxadiazol -5 -y1)-piperidin-1-y1]-6-(4- methancsulfonyl phenoxy)-pyrimidine -5-carbonitriie; 5-[1.3]Dioxolan-2-yl-4-[4-(3-isopropyl-| 1,2,4 Joxadiazol-5-yl)-piperidin-1 - y1]-6-(4-methanesulfonyl-phenoxy)-pyrimidine; 4-14-(3-1sopropyl-[1,2,4}oxadiazol-5-yl)-piperidin-1-y1]-6-(4- methanesulfonyl-phenoxy)-pyrimidine--5-carbaldehyde; 5-[1,3]Dioxolan-2-yl-4-[4-(3-isopropyl-[ 1,2,4]oxadiazol-5-yl)-piperidin-1- y1]-6-(4-[1,2,3]thiadiazol-4-yI-phenoxy)-pyrimidine; 4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4- [1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidine-5-carbaldehyde; 4-[4-(3-Isopropyl-[1.2.4}oxadiazol-5-y1)-piperidin-1-yI1-6-(4-

   1,2.3]thiadiazol-4-yl-phenoxy)-pyrimidine-5-carboxylic acid, [4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin- 1-y1]-6-(4- [1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidin-5-yl}-methanol; [4-T1-{3-Tsopropyl-[1.2 4loxadiazel-5-y1}-piperidin-1-y1]-6-(4-

   {1.2 .3]thiadiazol-4-vl-phenoxy)-pyrimidin-3-vimethvl]-dimethyl-amine- A-d-Nferhanesulfonvi-phenovy-3-nitro-6-(L-phenyisulfanvi-piperidin- 1 -y i 4-[4-(3-tert-Butyi-[1,2.4Joxadiazol-3-v1)-piperidin-1-y1]-6-(6- methanesulfonyl-pyridin-3-yloxy)-5-nitro-pyrimidine; 4-[4-(3-Isopropyl-[1,2,4]Joxadiazol-5-yl)-piperidin-1-yl]-6-(4- methanesulfonyl-phenoxy)-2-methyl-pyrimidine-5-carbonitrilc: and 1-[4-[4-(3-Tsopropyl-]1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4- methanesulfonyl-phenoxy)-pyrimidin-5-yl}-ethanone; or a pharmaceutically acceptable salt. hydrate or solvate thereof

   71. The compound according to claim 1 wherein said compound is selected from the group consisting of: AMENDED SHEET

   PCT/US2004/001267 ® 234

   I-{6-{(Renza[1,3]dioxol-5-yImethyl)-amino]-S-nitro-pyrimidm-4-y i} - pipenidine-4-carboxylic acid ethyl ester,

   1-[5-Nitro-6-(3,4,5-trimethoxy-benzylamino)-pyrimidin-4-y1]-piperidine-4- carboxylic acid ethyl ester;

   1-[5-Nitro-6-(2-trifluoromethyl-benzylamino)-pyrimidin-4 yl] piperidine 4 carboxylic acid ethyl ester;

   Toi SNitro-6- d-trifluoromethvi-henzv laminod-pyrimidim-d-yii-piperidine-d.- carboxylic acid ethyl ester;

   [-[5-Nitro -6-(3-trifluoromethyl-benzylamino) pyrimidin-4-yl]- piperidine 4 carboxylic acid ethyl ester,

   1-]5-Amino-6-(3-trifluoromethyl-benzylamino)-pyrimidin-4-yl]-piperidine- 4-carboxylic acid ethyl] ester;

   1-[5-Amino-6-(4-trifluoromethyl-benzylamino)-pyrimidin-4-yl]-piperidine- 4-carboxylic acid cthyl ester;

   1-[6-(4-Bromo-phenylamino)-5-nitro-pyrimidin-4-ylj-piperidine-4- carboxylic acid ethyl ester;

   1-[S-Nitro-6-(4-trifluoromethyl-phenylamino)-pyrimidin-4-ylj-piperidine-4-- carboxylic acid ethyl ester;

   [-[6-(Methyl-phenyl-amino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester;

   1-[5-Nitro-6-(4-trifluoromethoxy-phenylamino)-pyrimidin-4-yl]-piperidine- 4-carboxylic acid ethyl ester;

   1 [6 {4 Fluoro phenylamine) 5 nitro pyrimidin 4 y!] piperidine 4 carboxylic acid ethyl ester;

   L-fe-t 3. 2-Difluore-phenyviamine ->-nitre-pyrimidin—-y li-pipendine-4- cartoons ic acid eth ester

   1-{6-(3.5-Dichloro-phenylamino)-3-nitro-pyrimidin-+-y1]-piperidine—4- carboxylic acid ethyl ester;

   1-[6-(Benzol 1,3 ]dioxol-5-ylamino)-5-nitro-pyrimidin-4-yl}-piperidine-4-- carboxylic acid ethyl ester;

   1-[6-(2-Bromo-4-trifluoromethoxy-phenylamino)-5-nitro-pyrimidin-4-yl]- piperidine-4-carboxylic acid ethyl ester;

   1-[6-(2-Fluoro-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester:

   AMENDED SHEET

   1-[6-(3-Fluoro-phenylamino)-5 nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-{6-[(2-Fluoro-phenyl)-methyl-amino]-5 _pitro-pyrimidin-4-y1}-piperidine- 4-carboxylic acid ethyl ester; 1-[6-(Ethyl-phenyl-amino)-5 _nitro-pyrimidin-4-y1]-piperidine-4-carboxylic acid ethyl ester; 1-{6-[( 4-Chloro-phenyl)-methyl-amino]-5-nitro-pyrimidin-4-y1} -piperidine- 4-carboxylic acid ethyl ester; 1-[6-(4-Difluoromethyl-benzylamino)-5 ~pitro-pyrimidin-4-yl]-piperidinc-4- carboxylic acid ethyl ester; 1-{6-[(2,3-Dihydro-benzo[ 1,4]dioxin-6-ylmethyl)-amino]-5 -nitro-pyrimidin- 4-y1}-piperidine-4-carboxylic acid ethyl ester; 1-{6-[(2,3-Dihydro-benzo[1,4] dioxin-2-ylmethyl)-amino]-5 -nitro-pyrimidin-- 4-y1}-piperidine-4-carboxylic acid ethyl ester; 1-{6-[(2,3 -Dihydro-benzofuran-5 -ylmethyl)-amino]-5 -nitro-pyrimidin-4-y1}- piperidine-4-carboxylic acid ethyl ester; 1-{6-[(6-Fluoro-4H-benzo[1,3]dioxin-8-ylmethyl)-amino]-5-nitro-pyrimidin- 3 4-y1}-piperidine-4-carboxylic acid ethyl ester; 1-[6-(3 ,A-Dihydro-2H-benzo[b][1,4]dioxepin-7-ylamino)-5-nitro-pyrimidin- 4-yl]-piperidine-4-carboxylic acid ethyl ester; Ki 1-{6-[4-(Morpholine-4-sulfonyl)-phenylamino]-5 -nitro-pyrimidin-4-yl}- piperidine-4-carboxylic acid ethyl ester; 1-[6-(2,2-Difluoro-benzo[ 1,3]dioxol-4-ylamino)-5-nitro-pyrimidin-4-yl}- piperidine-4-carboxylic acid ethyl ester; 1-[6-(2,2-Difluoro-benzo[1,3]dioxol-5 -ylamino)-5-nitro-pyrimidin-4-y1]- piperidine-4-carboxylic acid ethyl ester; 1-[6-(1,1-Dioxo-1H-14°-benzo[b]thiophen-6-ylamino)-5-nitro-pyrimidin-4- yl]-piperidine-4-carboxylic acid ethyl ester; 1-{6-[(Furan-3-yimethyl)-amino]-5 -nitro-pyrimidin-4-yl}-piperidine-4- carboxylic acid ethyl ester; 1-{6-[2-(4-Methoxy-phenoxy)-ethylamino]-5 -nitro-pyrimidin-4-yi}- piperidine-4-carboxylic acid ethyl ester; 1-{6-[2-(5-Methoxy-1H-indol-3 -yl)-ethylamino]-5 -nitro-pyrimidin-4-y1}- piperidine-4-carboxylic acid ethyl ester; (3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-y1)-[5 -nitro-6-(4-propyl-piperidin- 1-yl)-pyrimidin-4-yl}-amine; : :

   (3-Fluoro-phenyl)-[5 -nitro-6-(4-propyl-piperidin-1 -yD)-pyrimidin-4-yl]- amine; ) (3-Methoxy-phenyl)-[5 -nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yl]- amine; : 1-{6-[(3-Fluoro-phenyl)-methyl-amino]-5 -nitro-pyrimidin-4-yl}-piperidine~ 4-carboxylic acid ethyl ester; 1-[6-(4-Benzoyl-phenylamino)-5 -nitro-pyrimidin-4-y1}-piperidine-4- carboxylic acid ethyl ester; 1-{6-[4~(1,1-Dioxo-1)°-thiomorpholin-4-ylmethyl)-phenylamino]-5-nitro- pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Methanesulfonyl-phenylamino)-5 -nitro-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester; 1-[6-(4-Dimethylsulfamoyl-phenylamino)-5 -nitro-pyrimidin-4-y1]-piperidine- 4-carboxylic acid ethyl ester; 1-[6-(3-Methoxy-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4- } carboxylic acid ethyl ester; :

   1.[62-Methoxy-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester; 1-[6<(3,5-Bis-iriflucromethyl-phenylamino)-5 -nitro-pyrimidin-4-y1]- piperidine-4-carboxylic acid ethyl ester; 1-[6-(2,5 Dimethoxy-phenylamino)-5-nitro-pyrimidin-4-y1] -piperidine-4- carboxylic acid ethyl ester; 1-[6-(3,5-Dimethoxy-benzylamino)-5 -nitro-pyrimidin-4-y1]-piperidine-4- carboxvlic acid ethyl ester; [5-Nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-y1]-(3 4 S-trimethoxy- henzyl)-amine; (3,5-Dimethoxy-benzyl)-[5-nitro-6-(4-propyl-piperidin-1 -yl)-pyrimidin-4-y1]- amine; (4-{5-Nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-y1] -pyrimidin-4- ylamino}-phenyl)-phenyl-methanone; (4-{5-Nitro-6-[4-(2-trifluoromethyl -phenoxy)-piperidin-1-yl]-pyrimidin-4- ylamino} -phenyl)-phenyl-methanone; 1-[6-(4-Cyano-phenylamino)-5 -nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-[6-(3,5-Dimethoxy-phenylamino)-5-nitro-pyrimidin-4-yl] -piperidine-4- carboxylic acid ethyl ester;

   1-[6-(4-sec-Butyl-phenylamino)-5 -nitro-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester; 1-[6-(4-Heptyl-phenylamino)-5 -nitro-pyrimidin-4-yl1] -piperidine-4-carboxylic acid ethyl ester; .

   2'.(4-Benzoyl-phenylamino)-3-nitro-3,4,5,6-tetrahydro-2H-[ 1,4 Tbipyridinyl- 4-carboxylic acid ethyl cster; 1-[5-Nitro-6-(3 4 5-trimethoxy-phenylamino)-pyrimidin-4-y1]-piperidine-4- carboxylic acid ethyl ester; 1-[5 “Nitro-6-(4-pentyl-phenylamino)-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-{6-]4-(3-Carboxy-propyl)-phenylamino]-5 ~nitro-pyrimidin-4-yl}- piperidine-4-carboxylic acid ethyl ester; 1-{6-[4~(Cyano-phenyl-methyl)-phenylamino]-5 -nitro-pyrimidin-4-yl}- piperidine-4-carboxylic acid ethyl ester; 1-[6~(4-Cyclohexyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester; 1-[5-Nitro-6-(4-[1,2,4]triazol-1-yl-phenylamino)-pyrimidin-4-yl] -piperidine- 4-carboxylic acid ethyl ester; . 1-[5 ~Niitro-6-(4-trifluoromethanesulfonyl-phenylamino)-pyrimidin-4-yl]- ’ piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(4-[1,2,3]thiadiazol-4-yl-phenylamino)-pyrimidin-4-yl]- piperidine-4-carboxylic acid ethyl ester; [6~(4-Ethoxymethyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yl]-(4- methanesulfonyl-phenyl)-amine; : [5-Nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-y1]-(4-[1.2 4]triazol-1-v1- phenyl)-amine; {5-Nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-y1} ~(4- [1,2,4]triazol-1-yl-phenyl)-amine; (2-Fluoro-phenyl)-{6-[4-(3-methyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-y1]-5- nitro-pyrimidin-4-yl1}-amine; (4-Methanesulfonyl-phenyl)-{6-[4-(3-methyl-| 1,2,4]oxadiazol-5-yl)- piperidin-1-y1]-5-nitro-pyrimidin-4-yl} -amine; {6-[4-(3-Methyl-{1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4- y1}-(4-[1,2,4]triazol-1-yl-phenyl)-amine; 1-{5-Nitro-6-[4-(4-trifluoromethyl-phenoxy)-phenylamino]-pyrimidin-4-yl}- piperidine-4-carboxylic acid ethyl ester;

   {6-4-3 Ethyl-[1,2,4]oxadiazol-5-y1)-piperidin-1-y1]-5-nitro-pyrimidin-4- y1}-(2-fluoro-phenyl)-amine; {6-4-(2-Methoxy-phenylsulfanyl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl} - (4-[1,2,4]triazol-1-yl-phenyl)-amine; (4-Methanesulfonyl-phenyl)- {5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1- y1]-pyrimidin-4-yl}-amine; (3-Methoxy-phenyD)-{5 -nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-y1]- pyrimidin-4-yl} -amine; Benzo[1,3]dioxol-5-y1-5 -nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yl]- amine; (4-Fluoro-phenyl)-{ 1-[5-nitro-6-(4-| 2,4 triazol-1-yl-phenylamino)- pyrimidin-4-yl]-piperidin-4-yl}-methanone; [5-Nitro-6-(4-phenylsulfanyl-piperidin-1-yl)-pyrimidin-4-yl]-(4- [1,2,4}triazol-1-yl-phenyl)-amine; (4-Fluoro-phenyl)-{1-[6-(2-fluoro-phenylamino)-5-nitro-pyrimidin-4-yI}- piperidin-4-yl} -methanone; 1-[6-(2-Methyl-5-phenyl-2H-pyrazol-3-ylamino)-5-nitro-pyrimidin-4-yl]- piperidine-4-carboxylic acid ethyl ester; (4-Mcthancsulfonyl-phenyl)-{5-nitro-6-(4-phenylsulfanyl-piperidin-1-yl)- pyrimidin-4-y1]-amine; (4-Methanesulfonyl-phenyl)- {5-nitro-6-[4-(pyridin-2-yloxy)-piperidin-1-yl]- pyrimidin-4-yl}-amine; {6-[4-(4-Fluoro-phenoxy)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl} -(4- methanesulfonyl-phenyl)-amine; (4-Methanesulfonyl-phenyl)-{35-nitro-6-[4-(pyridin-4-vloxy)-piperidin-1-y1]- pyrimidin-4-yl}-amine; (4-Methanesulfonyl-phenyl)- {S-nitro-6-[4-(pyrimidin-2-yloxy)-piperidin-1- yl]-pyrimidin-4-yl}-amine; (4-Methanesulfonyl-phenyl)- {5-nitro-6-[4-(pyridin-4-ylsulfanyl)-piperidin-1- yll-pyrimidin-4-yl}-amine; (4-Methanesuifonyi-phenyl)- {6-{4-(4-methoxy-phenylsulfanyl)-piperidin-1- yi]-5-nitro-pyrimidin-4-yl} -amine; : [6-(4-Benzenesulfonyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yl]-(4- methanesulfonyl-phenyl)-amine; {4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperazin-1- yl}-acetic acid ethyl ester;

   (2-Fluoro-phenyl)-{5 -nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-y1}- pyrimidin-4-yl1}-amine; 2-Methoxy-phenyl)-{5 -nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]- pyrimidin-4-yl}-amine; (4-Methanesulfonyl-phenyl)-(5-nitro-6- {4-[3-(3 -trifluoromethyl-phenyl)- [1,2,4]oxadiazol-5-yI]-piperidin-1-y1} -pyrimidin-4-yl)-amine; {6-]4-(3-Fthyl-[1,2,4]oxadiazol-5 -y1)-piperidin-1-y1]-5-nitro-pyrimidin-4- ) y1}«(4-methanesulfonyl-phenyl)-amine; (6-{4-[5 -(4-Fluoro-phenyl)-[1,3,4]oxadiazol-2-yl}-piperidin-1-y1} -5-nitro- pyrimidin-4-yl)-(4-methanesulfonyl-phenyl)-amine; (4-Methanesulfonyl-phenyl)-{5 -nitro-6-(4-pyridm-2-ylmethyl-piperidin-1-y1)- pyrimidin-4-yl]-amine; 1-{6-[4-(4,5-Dichloro-imidazol-1-y1)-phenylamino}-5 -nitro-pyrimidin-4-yl}~ piperidine-4-carboxylic acid ethyl ester; Benzo 1,3]dioxol-5-y1-{5 -nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]- pyrimidin-4-yl}-amine; (4-Fluoro-phenyl)-{1-[6-(2-fluoro-phenylamino)-5-nitro-pyrimidin-4-y1]- piperidin-4-y1}-methanone; {1-[6-(Benzo[1,3]dioxol-5 -ylamino)-5-nitro-pyrimidin-4-yl]-piperidin-4-y1}- (4-fluoro-phenyl)-methanone; . (2,3-Difluoro-phenyl)-{5 -nitro~6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-y1]- pyrimidin-4-yl} -amine; ' (2,4-Difluoro-phenyl)- {5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-y1}- pyrimidin-4-yl} -amine;

   (2.5-Difluoro-phenyl)- {5 -nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]- ' pyrimidin-4-yl}-amine; 1-[6-(4-Benzenesulfonyl-phenylamino)-5-nitro-pyrimidin-4-y1}-piperidine-4- carboxylic acid ethyl ester; 1-[5-Nitro-6-(2-trifluoromethyl-3H-benzoimidazol-5-ylamino)-pyrimidin-4- yl]-piperidine-4-carboxylic acid ethyl ester; 1-{5-Nitro-6-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenylaminoj-pyrimidin-4-yi}- piperidine-4-carboxylic acid ethyl ester; {6-[4-(4-Todo-phenoxy)-piperidin-1-yl]-5-nitro-pyrimidin-4-y1}-(4- methanesulfonyl-phenyl)-amine; (2-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5- yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-amine;

   {6-[4-(3-Ethyl-[1,2,4Joxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4- © yl} (2-fluoro-4-methanesulfonyl-phenyl)-amine; (4-Methanesulfonyl-phenyl)- {5-nitro-6-{4-(3-propyl-[1,2,4]oxadiazol-5-yI)- piperidin-1-y1]-pyrimidin-4-y1}-amine; {6-[4~(3-Cyclopropylmethyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl}-5-nitro- : pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine; : {6-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-y1)-piperidin-1-y1]-5-nitro-pyrimidin- 4-y1}~(4-methanesulfonyl-phenyl)-amine; {6-[4-(3-Cyclopropyl-[1,2,4Joxadiazol-5-y1)-piperidin-1-yl}-5-nitro- pyrimidin-4-yl} -(4-methanesulfonyl-phenyl)-amine; A-{4-(3-Tsopropyl41,2,4|oxadiazol-5 -y1}-piperidin-1-y1]-6-(4-methylsultanyl- phenylamino)-pyrimidine-5-carbonitrile; 4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1 -yl]-6-(4- methanesulfinyl-phenylamino)-pyrimidine-5-carbonitrile; ’ (4-Methanesulfonyl-phenyl)-{5-nitro-6-[4-(4-trifluoromethoxy-phenoxy)- piperidin-1-yl]-pyrimidin-4-yl}-amine; 4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-y1]-6-(4- methanesulfonyl-phenylamino)-pyrimidine-5 —carbonitrile; 1-{1-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-y1]- piperidin-4-yl1}-hexan-1-one; 1-{1-[6~(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidin- 4-yl}-hexan-1-one; : {6-[4-(3-tert-Butyl-[1,2,4]oxadiazol-5-y1)-piperidin-1-yl]-5-nitro-pyrimidin- 4-y1}~(2-fluoro-4-methanesulfonyl-phenyl)-amine; {6-[4~(3-tert-Butyl-[1,2.4]oxadiazol-5-y1)-piperidin-1-y]-3-nitro-pyrimidin- 4-yl}-(4-methanesulfonyl-phenyl)-amine; [6-(4-Benzofuran-2-yl-piperidin-1-yl)-5-nitro-pyrimidin-4-y1]-(4- methanesulfonyl-phenyl)-amine; 4~(3-Fluoro-4-methanesulfonyl-phenylamino)-6-[4-(3-isopropyl- [1,2,4]oxadiazol-5-yl)-piperidin-1-y1]-pyrimidine-5-carbonitrile; {6-{4-(3-Isopropyi-{ 1,2,4joxadiazoi-5-yI)-piperidin-i-yi]-5-nitro-pyrimidin- 4-y1}-(5-methanesulfonyl-pyridin-2-yl)-amine; (3-Fluoro-4-methanesulfonyl-phenyl)- {6-[4-(3-isopropyl-[ 1,2,4]oxadiazol-5- yl)-piperidin-1-yl}-5-nitro-pyrimidin-4-y1} -amine; {6-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin- 4-yl}~(6-methanesulfonyl-pyridin-3-yl)-amine;

   PCT/US2004/001267 ® 241 4-(2 3-Nifluoro-phenylamina)-6-{4-(3-isopropyi-| 1 7 d]ovadiazal-5-yl)- pipendin-| -ylj-pyrimidine-5-carbonitrile; 4-(2,5-Difluoro-phenylamino)-6-{4-(3-1sopropyl-[ 1,2,4 Joxadiazol-5-yl})- piperidin-1-yl}-pyrimidine-5-carbonitrile; 4-[4-(3-Isopropyl-[1,2,4oxadiazol-5-y1)-pipcridin- | -yl]-6-(4-methylsulfanyl phenylamino)-pyrimidine-5-carbonitriie; Ald scleopropyi-i 1 djoxadiazol-N-vipinenidin- i ovij-ne(d. methanesulfonyl-phenylamino)-pyrimidine-5-carbonitrile; 4-(4-Hexanoyl piperidin -1-y1)-6-(6-methylsulfanyl-pyridin-3-ylamino)- pyrimidine-5-carbonitrile; 4-(4-Hexanoyl-piperidin-1-yl)-6-(6-methanesulfonyl-pyridin-3-ylamino)- pyrimidine-5-carbonitrile; 4-[4-(3-1sopropyl-[1,2.4Joxadiazol-5-y1)-piperidin-1-yl]-6-(6-methylsulfanyl- pyridin-3-ylamino)-pyrimidine-5-carbonitrile; 4-{4-(3-1sopropyl-{1,2,4]oxadiazol-5-yl)-piperidin-1-y1]-6-(6- methanesulfonyl-pyridin-3-ylamino)-pyrimidine-5-carbonitrile; 1-[4-[4-(3-Isopropyl-[1,2,4]oxadiazol-3-yl)-piperidin-{-yl]-6-(4- methanesulfonyl-phenylamino)-pyrimidin-5-ylj-ethanone; and 1-[4-[4-(3-Isopropyl-{1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(6- methanesulfonyl-pyridin-3-ylamino)-pyrimidin-5-yl]-ethanone; or a pharmaceutically acceptable salt, hydrate or solvate thereof.

   72. The compound according to claim 1 wherein said compound is selected from the croup consisting ot: Ca EINITO-AepREn SA TIMI = eT IDET IE = JETRO ID AD etn Ester I-(6-Naphthalen-2-y I-3-mitro-pyrimidin-4-v1j-piperidine-4-carboxy lic acid cthyl ester; 1-[6-(4-Methanesulfonyl-phenyl)-5-nitro-pyrimidin-4-yl}-piperidine-4- carboxylic acid ethyl ester; 1-(6-Benzofuran-5-yl-5-nitro-pyrimidin-4-y1)-piperidine-4-carboxylic acid ethyl ester: 1-|5-Nitro-6-(3-triflucromethyl-phenyl)-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethy! ester; 1-[6-(4-Methoxy-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester, 4-(4-Butyl-piperidin-1-yl)-6-furan-3-yl-5-nitro-pyrimidine; AMENDED SHEET

   1-{6-(3-Chloro-phenyl)-5 -nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid "ethyl ester; 1-[6-(2,6-Dimethoxy-phenyl)-5 -nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; 1-(6-Naphthalen-1-y1-5-nitro-pyrimidin-4-yl)-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Methylsulfanyl-pheny!)-5-nitro-pyrimidin-4-y1]-piperidine-4- carboxylic acid ethyl ester; 1-(2' 4'-Dihydroxy-5-nitco-[4, 5 Tbipyrimidinyl-6-yl)-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Methanesulfonyl-pbenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester; 1-[6-(3,5-Bis-trifluoromethyl-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester; 1-(6-Dibenzothiophen-4-y1-5-nitro-pyrimidin-4-yl)-piperidine-4-carboxylic : acid ethyl ester; 1-[6-(3,5-Dimethyl-isoxazol-4-y1)-5-nitro-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester; 1-(5-Nitro-6-thiophen-2-yl-pyrimidin-4-yl)-piperidine-4-carboxylic acid ethyl ester; : 1-[6-(3,5-Dichloro-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; ) : 1-(6-Dibenzofuran-4-yl-5-nitro-pyrimidin-4-y1)-piperidine-4-carboxylic acid ethyl ester; 1-[6-(3,5-Dimethyl-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester; ] 1-[6-(4-Acetyl-phenyl)-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester; 1-[6-(4-Ethanesulfonyl-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester; 1-{6-(2-Fiuoro-biphenyl-4-yi)-5 -nitro-pyrimidin-4-yij-piperidine-4- carboxylic acid ethyl ester; 1-[6-(3-Methanesulfonyl-phenyl)-5-nitro-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester; 1-{6-[4-(2-Carboxy-ethyl)-phenyl]-5-nitro-pyrimidin-4-yl} -piperidine-4- carboxylic acid ethyl ester;

   ® PCT/US2004/001267 1-16-[4-(2-Methoxycarhonyl-ethyl)-phenyl]-5-nitro-pyrimidin-4-yt] - pipendine-4-carboxyiic acid methyl ester; and 1-{6-[4-(2-Methoxycarbonyl-ethyl)-phenyli}-5-nitro-pyrimidin-4-y1} - piperidine 4 carboxylic acid ethyl ester; or a pharmaceutically acceptable salt, hydrate or solvate thereof.

   73. The compound according to claim 1 wherein said compound is sclected from the group consisting of: 1-[5-Nitro-6-(2-trifluoromethyl-phenylethynyl)-pyrimidin-4-ylj-piperidine-4- carboxylic acid ethyl ester; 1-(5-Nitro-6-phenylethynyl-pyrimidin-4-yl)-piperidine-4-carboxylic acid ethyl ester; 1-[5-Nitro-6-(4-trifluoromethyl-phenylethynyl}-pyrimidin-4-yl]-piperidine-4-- carboxylic acid ethyl ester; 1-(5-Nitro-6-m-tolylethynyl-pyrimidin-4-y1)-piperidine-4-carboxylic acid ethyl ester; 1-[6~(2-Fluoro-phenylethynyl)-5-nitro-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester; 1-| 5-Nitro-6-(3-triflucromethyl-phenylethynyl)-pyrimidin-4-yl]-piperidine-4- carboxylic acid ethyl ester; and 1-[5-Aming-6-(3-triflugromethyl-phenylethyny!} pyrimidin 4 v1] piperidine 4-carboxylic acid ethy] ester: or a pharmaceutically acceptable salt. hydrate or solvate therzof. 74 A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 73 and a pharmaceutically acceptable carrier. 75 The use an effective amount of a compound according to any one of claims 1 to 73 or a pharmaceutical composition of claim 74 for the production of a medicament to treat a metabolic disorder in an individual. AMENDED SHEET

   } PCT/US2004/001267 76 The use according to claim 75 wherein the metabolic disorder is type 1, type 11 diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, syndrome X or metabolic syndrome.

   77. I'he use according to claim /5 wherein the metabolic disorder is type il diabetes.

   78. The use of an effective amount of a compound according to any one of claims 1 to 73 or a pharmaceutical composition of claim 74 for the production of a medicament to control or decrease weight gain of an individual.

   79. The use of a compound according to any one of claims 1 to 73 for the production of a medicament to modulate a RUP3 receptor.

   80. The use of a compound according to any one of claims 1 to 73 for the production of a medicament to modulate a RUP3 receptor in an individual.

   81. The use according to claim 79 or 80 wherein the compound is an agonist.

   82. The use according to claim 79 or 80 wherein the compound is an inverse agonist.

   83. The use according to any one of claims 80 to 82 wherein the modulation of the RUP3 rarantnr ic neranhulavie af a metahnlic Aicardar LASS ed ts Pryupeiyy TLAMALY WL LL LULU LG Ll ovE LLL 84 The use according to claim 82 wherein the metabolic disorder 1s tape |. type il 213D2Ts. Inadequate THUCOSE TOITAnIE INSulln TRIISIENncE. NA peTen LET hyperlipidemia. hy pertriglyceridemia. hy percholesterolemia, dyslipidemia. syndrome X or metabolic syndrome.

   85. The use according to claim 83 wherein the metabolic disorder is type II diabetes.

   86. The use according to any one of claims 80 to 82 wherein the modulation of the RUP3 receptor controls or reduces weight gain of the individual.

   87. The use according to any one of claims 80 to 82 wherein the individual is a mammal.

   88. The use according to claim 87 wherein the mammal is a human. AMENDED SHEET

   7) PCT/US2004/001267

   89. A compound according to any one of claims 1 ta 73 or a pharmaceutical composition according to claim 74 for use in 2 method of treatment of the human or animal body by therapy

   90. A compound according to any one of claims I to 73 or a pharmaceutical composition according to claim 74 for use in a method of prophylaxis or treatment of a metabolic disorder of the human or animal body by therapy

   91. The method of producing a pharmaceutical composition admixing at least one compound according to any one of claims 1 to 73 and a pharmaceutically acceptable carrier.

   92. A compound according to any one of claims 1 to 73, substantially as herein described with reference to and illustrated in any of the examples and accompanying figures.

   93. A composition according to claim 74, substantially as herein described with reference to and illustrated in any of the examples and accompanying figures.

   94. A use according to any one of claims 75 to 88. substantially as herein described with reference to and illustrated in any of the examples and accompanying figures.

   9s. A substance or composition for use in a method of treatment according to claim 89 or claim 90, substantially as herein described with reference to and illustrated in any of the examples and accompanying figures. 96 Ametnod according to claim Yi substantial as nerem ascribed with reTerenis Ww and illustrated in any of the examples and accompanying figures. AMENDED SHEET oO ow > [iF Marker Leas ee = id Marker Brain th. gi Heart Heart cee a ee Brain Kid iy i a oo EY ep vi | Placenta ney Te Ske Re Lung Ml Liver 2 § Sy We NEE Ey EN Liver FE LS BER Sa I © 1 nlndol AMiania Lung 5 Rha JAR Sa SL [Preheat MW oncreas Lukiar x ig id noid EE Kidney Aye ERT Bt LB Pancreas

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