Title of Invention

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

Abstract The present invention relates to certain substituted aryl and heteroaryl derivative of Formula (I) that are modulators of metabolism, especially of the activity of a GPCR, referred to herein as RUP3. Accordingly, compounds of the present invention are useful in the treatment of metabolic-related disorders and complications thereof, such as, diabetes and obesity.
Full Text SUBSTITUTED ARYL AND HETEROARYL DERIVATIVES AS MODULATORS OF
METABOLISM AND THE PROPHYLAXIS AND TREATMENT OF DISORDERS
RELATED THERETO
FIELD OF THE INVENTION
The present invention relates to certain substituted aryl and heteroaryl derivatives that are
modulators of glucose metabolism. Accordingly, compounds of the present invention are useful in
the treatment of metabolic-related 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 blood into the cells of the body. However, people who have diabetes either 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 β cells of the pancreas, the characteristic that most readily 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 dont 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 even 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. It 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 3rd 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, β cell
function deteriorates and non-insulin-dependent diabetes develops in about 20% of the 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
(m2). Thus, the units of BMI are kg/m2 and it is possible to calculate the BMI range associated with
minimum mortality in each decade of life. Overweight is defined as 'a BMI in the range 25-30 kg/m2,
and obesity as a BMI greater than 30 kg/m2 (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 and females, respectively.

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 narketed 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-
HT/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 NI DDM 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, I. J., et al., 5MJ310, 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 is also a 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,
diabetes 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 AY288416, 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 certain substituted aryl and heteroaryl
derivatives as shown in Formula (I):

or pharmaceutically acceptable salt, solvate, hydrate or N-oxide thereof;
wherein:

A1 and A2 are independently C1-3 alkylene optionally substituted with one or more
substituents selected independently from the group consisting of C1-6 alkyl, C1-6 alkoxy, and carboxy;
D is CR1R2 or NR2, wherein R1 is selected from the group consisting of H, C1-6 alkyl, C1-6
alkoxy, halogen and hydroxyl;
E is N, C, or CR3, wherein R3 is H or C1-6 alkyl;
— is a single bond when E is N or CR3, or a double bond when E is C;
K is absent, C3-6 cycloalkylene, or C1-3 alkylene group each optionally substituted with one or
more substituents selected independently from the group consisting of C1-6 alkyl, C1-6 alkoxy, carboxy,
cyano, and halogen;
Q1 is NR4, O, S, S(O), or S(O)2, wherein R, is H, C1-6 acyl, C1-6 alkyl, C2-6 alkenyl, C2-6
alkynyl, C3-7 cycloalkyl, or C3-7-cycloaIkyl-C1-3-alkylene, wherein said C1-6 alkyl is optionally
substituted with one or more substituents selected independently from the group consisting of C1-6
acyl, C1-6 acyloxy, C2-6 alkenyl, C1-6 alkoxy, C1-6 alkyl, C1-6 alkylamino, C1-6 alkylcarboxamide, C2-6
alkynyl, C1-6 alkylsulfonamide, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6
alkylthiocarboxamide, C1-6 alkylthioureyl, C1-6 alkylureyl, amino, di-C1-6-alkylamino, C1-6
alkoxycarbonyl, carboxamide, carboxy, cyano, C3-6 cycloalkyl, di-C1-6-alkylcarboxamide, di-C1-6-
alkylsulfonamide, di-C1-6-alkylthiocarboxamido, C1-6 haloalkoxy, C1-6 haloalkyl, halogen, C1-6
haloalkylsulfmyl, C1-6 haloalkylsulfonyl, C1-6 haloalkylthio, hydroxyl, hydroxylamino and nitro;
Q2 is absent, NR5 or O, wherein R5 is H, C1-6 acyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7
cycloalkyl, or C3-7-cycloalkyl-C1-3-alkylene, wherein said C1-6 alkyl is optionally substituted with one
or more substituents selected independently from the group consisting of C1-6 acyl, C1-6 acyloxy, C2-6
alkenyl, C1-6 alkoxy, C1-6 alkyl, C1-6 alkylamino, C1-6 alkylcarboxamide, C2-6 alkynyl, C1-6
alkylsulfonamide, C1-6 alkylsulfinyl, C1- alkylsulfonyl, C1-6 alkylthio, C1-6 alkylthiocarboxamide, C1-6
alkylthioureyl, C1-6 alkylureyl, amino, di-C1-6-alkylamino, C1-6 alkoxycarbonyl, carboxamide, carboxy,
cyano, C3-6 cycloalkyl, di-C1-6-alkylcarboxamide, di-C1-6-alkylsulfonamide, di-C1-6-
alkylthiocarboxamido, C1-6 haloalkoxy, C1-6 haloalkyl, halogen, C1-6 haloalkylsulfinyl, C1-6
haloalkylsulfonyl, C1-6 haloalkylthio, hydroxyl, hydroxylamino and nitro;
W is N or CH;
X is N or CR6;
Y is N or CR7;
Z is N or CR8,
V is absent, C1-3 heteroalkylene, or C1-3 alkylene wherein each are optionally substituted with
one or more substituents selected independently from the group consisting of C1-3 alkyl, C1-6 alkoxy,
carboxy, cyano, C1-3 haloalkyl, and halogen;
R5, R7, and R8 are each independently selected from the group consisting of H, C1-6 acyl, C1-6
acyloxy, C2-6 alkenyl, C1-6 alkoxy, C1-6 alkyl, C1-6 alkylamino, C1-6 alkylcarboxamide, C2-6 alkynyl, C1-
6 alkylsulfonamide, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylthiocarboxamide, C1-

6 alkylthioureyl, C1-6 alkylureyl, amino, di-C1-6-alkylamino, C1-6 alkoxycarbonyl, carboxamide,
carboxy, cyano, C3-6 cycloalkyl, di-C1-6-alkylcarboxamide, di-C1-6-alkylsulfonamide, di-C1-6-
alkylthiocarboxamido, C1-6 haloalkoxy, C1-6 haloalkyl, halogen, C1-6 haloalkylsulfinyl, C1-6
haloalkylsulfonyl, C1-6 haloalkylthio, hydroxyl, hydroxylamino and nitro, wherein said C1-6 alkenyl,
C1-6 alkyl, C2-6 alkynyl and C1-6 cycloalkyl are each optionally substituted with one or more
substituents independently selected from the group consisting of C1-6 acyl, C1-6 acyloxy, C1-6 alkenyl,
C1-6 alkoxy, C1-6 alkyl, C1-6 alkylamino, C1-6 alkylcarboxamide, C1-6 alkynyl, C1-6 alkylsulfonamide,
C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylthiocarboxamide, C1-6 alkylthioureyl, C1-
6 alkylureyl, amino, di-C1-6-alkylamino, C1-6 alkoxycarbonyl, carboxamide, carboxy, cyano, C1-6
cycloalkyl, di-C1-6-alkylcarboxamide, di-C1-6-alkylsulfonamide, di-C1-6-alkylthiocarboxamido, C1-6
haloalkoxy, C1-6 haloalkyl, halogen, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6 haloalkylthio,
hydroxyl, hydroxylamino and nitro;
Ar is aryl or heteroaryl optionally substituted with R9, R10, R11, R12, and R13;
R9 is selected from the group consisting of C1-6 acyl, C1-6 acylsulfonamide, C1-6 acyloxy, C1-6
alkenyl, C1-6 alkoxy, C1-6 alkyl, C1-6 alkylamino, C1-6 alkylcarboxamide, C2-6 alkynyl, C1-6
alkylsulfonamide, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylthiocarboxamide, C1-6
alkylthioureyl, C1-6 alkylureyl, amino, aryl, arylcarbonyl, arylsulfonyl, di-C1-6-alkylamino,
carbamimidoyl, C1-6 alkoxycarbonyl, carboxamide, carboxy, cyano, C1-6 cycloalkyl, di-C1-6-
alkylcarboxamide, di-d.6-alkylsulfonamide, di-C1-6-alkylthiocarboxamido, guanidine, C1-6
haloalkoxy, C1-6 haloalkyl, halogen, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6 haloalkylthio,
heterocyclic, heterocyclicsulfonyl, heteroaryl, hydroxyl, hydroxylamino, nitro, C1-6 oxo-cycloalkyl,
phenoxy,. sulfonamide, sulfonic acid and thiol; and wherein each R9 is optionally substituted with one
or more substituents selected independently from the group consisting of C1-6
acylsulfonamide, C1-6 acyloxy, C1-6 alkenyl, C1-6 alkoxy, C1-6 alkyl, C1-6 alkylamino, C1-6
alkylcarboxamide, C1-6 alkynyl, C1-6 alkylsulfonamide, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6
alkylthio, C1-6 alkylthiocarboxamide, C1-6 alkylthioureyl, C1-6 alkylureyl, amino, aryl, arylcarbonyl,
arylsulfonyl, di-C1-6-alkylamino, C1-6 alkoxycarbonyl, carboxamide, carboxy, cyano, C3-6 cycloalkyl,
di-C1-6-alkylcarboxamide, di-C1-6-alkylsuIfonamide, di-C1-6-alkylthiocarboxamido, C1-6 haloalkoxy,
C1-6 haloalkyl, halogen, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6 haloalkylthio, heteroaryl,
heteroarylcarbonyl, heteroarylsulfonyl, heterocyclic, hydroxyl, hydroxylamino, and nitro;
R10, R11, R12,-and R13 are independently selected from the group consisting of C1-6 acyl, C1-6
acyloxy, C1-6 alkenyl, C1-6 alkoxy, C1-6 alkyl, C1-6 alkylamino, C1-6 alkylcarboxamide, C1-6 alkynyl, C1-
6 alkylsulfonamide, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylthiocarboxamide, C1-
6 alkylthioureyl, C1-6 alkylureyl, amino, di-C1-6-alkylamino, C1-6 alkoxycarbonyl, carboxamide,
carboxy, cyano, C3-6 cycloalkyl, di-C1-6-alkylcarboxamide, di-C1-6-alkylsulfonamide, di-C1-6-
alkylthiocarboxamido, C1-6 haloalkoxy, C1-6 haloalkyl, halogen, C1-6 haloalkylsulfinyl, C1-6
haloalkylsulfonyl, C1-6 haloalkylthio, hydroxyl, hydroxylamino, nitro, and thiol; or two adjacent R10,

R11, R-12, and R13 groups together with the atoms to which they are bonded form a 5, 6 or 7 member
cycloalkyl, 5, 6 or 7 member cycloalkenyl, or 5, 6 or 7 member heterocyclic group wherein the 5, 6 or
7 member group is optionally substituted with halogen or oxo; and
R2 is selected from the group consisting of H, C1-6 acyl, C1-6 acyloxy, C2-6 alkenyl, C1-6
alkoxy, C1-6 alkyl, C1-6 alkylamino, C1-6 alkylcarboxamide, C2-6 alkynyl, C1-6 alkylsulfonamide, C1-6
alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylthiocarboxamide, C1-6 alkylthioureyl, C1-6
alkylureyl, amino, aryl, arylcarbonyl, aryloxy, di-C1-6-alkylamino, carbamimidoyl, C1-6
alkoxycarbonyl, C3-7-cycloalkoxycarbonyl, carboxamide, carboxy, cyano, C3-6 cycloalkyl, di-C1-6-
alkylcarboxamide, di-C1-6-alkylsulfonamide, di-C1-6-alkylthiocarboxamido, guanidine, C1-6
haloalkoxy, C1-6 haloalkyl, halogen, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6 haloalkylthio,
heteroaryl, heteroaryl-C1-3-alkylene, heteroarylcarbonyl, heteroaryloxy, heterocycliccarboxamide,
hydroxyl, hydroxylamino and nitro; wherein each R2 is optionally substituted with one or more
substituents selected independently from the group consisting of C1-6 acyl, C1-6 acyloxy, C2-6 alkenyl,
C1-6 alkoxy, C1-6 alkyl, C1-6 alkylamino, C1-6 alkylcarboxamide, C2-6 alkynyl, C1-6 alkylsulfonamide,
C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylthiocarboxamide, C1-6 alkylthioureyl, C1-
6 alkylureyl, amino, aryl, di-C1-6-alkylamino, C1-6 alkoxycarbonyl, carboxamide, carboxy, cyano, C3-6
cycloalkyl, di-C1-6-alkylcarboxamide, di-C1-6-alkylsulfonamide, di-C1-6-alkylthiocarboxamido, C1-6
haloalkoxy, C1-6 haloalkyl, halogen, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6 haloalkylthio,
heterocyclic, heteroaryl, hydroxyl, hydroxylamino and nitro, and wherein C1-6 alkyl is further
optionally substituted with one or more substituents selected independently from the group consisting
of C1-6 acyl, C1-6 alkoxy, C1-6 alkylamino, C1-6 alkylcarboxamide, C1-6 alkylsulfonamide, C1-6
alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylureyl, amino, di-C1-6-alkylamino, C1-6
alkoxycarbonyl, carboxamide, carboxy, cyano, C3-6 cycloalkyl, di-C1-6-alkylcarboxamide, di-C1-6-
alkylsulfonamide, C1-6 haloalkoxy, C1-6 haloalkyl, halogen, C1-6 haloalkylsulfinyl, C1-6
haloalkylsulfonyl, C1-6 haloalkylthio, heterocyclic, hydroxyl, hydroxylamino and nitro.
One aspect of the present invention pertains to pharmaceutical compositions comprising at
least one compound of the present invention and a pharmaceutically acceptable carrier.
One aspect of the present invention pertains to methods for the treatment of a metabolic-
related disorder in an individual comprising administering to the individual in need of such treatment
a therapeutically effective amount of a compound of the present invention or a pharmaceutical
composition thereof.
One aspect of the present invention pertains to methods of decreasing food intake of an
individual comprising administering to the individual in need thereof a therapeutically effective
amount of a compound of the present invention or pharmaceutical composition thereof.
One aspect of the present invention pertains to methods of inducing satiety in an individual
comprising administering to the individual in need thereof a therapeutically effective amount of a
compound of the present invention or pharmaceutical composition thereof.

One aspect of the present invention pertains to methods of controlling or decreasing weight
gain of an individual comprising administering to the individual in need thereof a therapeutically
effective amount of a compound of the present invention or pharmaceutical composition thereof.
One aspect of the present invention pertains to 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 for the RUP3 receptor. In some embodiments, the
modulation of the RUP3 receptor is the treatment of a metabolic-related disorder.
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 reduces food intake of the individual.
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 induces satiety in the individual.
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.
One aspect of the present invention pertains to use of a compound of the present invention for
production of a medicament for use in the treatment of a metabolic-related disorder.
One aspect of the present invention pertains to use of a compound of the present invention for
production of a medicament for use in decreasing food intake in an individual.
One aspect of the present invention pertains to use of a compound of the present invention for
production of a medicament for use of inducing satiety in an individual.
One aspect of the present invention pertains to use of a compound 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 a compound of the present invention for use in
a method of treatment of the human or animal body by therapy.
One aspect of the present invention pertains to a compound of the present invention for use in
a method of treatment of a metabolic-related disorder of the human or animal body by therapy.
Some embodiments of the present invention pertain to methods wherein 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 abouT45. 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.
In some embodiments the individual is a mammal. In some embodiments the mammal is a
human.
In some embodiments, the metabolic-related disorder is hyperlipidemia, type 1 diabetes, type
2 diabetes mellitus, idiopathic type 1 diabetes (Type lb), latent autoimmune diabetes in adults
(LADA), early-onset type 2 diabetes (EOD), youth-onset atypical diabetes (YOAD), maturity onset

diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, coronary heart
disease, ischemic stroke, restenosis after angioplasty, peripheral vascular disease, intermittent
claudication, myocardial infarction (e.g. necrosis and apoptosis), dyslipidemia, post-prandial lipemia,
conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose,
metabolic acidosis, ketosis, arthritis, obesity, osteoporosis, hypertension, congestive heart failure, left
ventricular hypertrophy, peripheral arterial disease, diabetic retinopathy, macular degeneration,
cataract, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy,
metabolic syndrome, syndrome X, premenstrual syndrome, coronary heart disease, angina pectoris,
thrombosis, atherosclerosis, myocardial infarction, transient ischemic attacks, stroke, vascular
restenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertrygliceridemia, insulin resistance,
impaired glucose metabolism, conditions of impaired glucose tolerance, conditions of impaired
fasting plasma glucose, obesity, erectile dysfunction, skin and connective tissue disorders, foot
ulcerations and ulcerative colitis, endothelial dysfunction and impaired vascular compliance.
In some embodiments, the metabolic-related disorder is type I diabetes, type II diabetes,
inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia,
hypertriglyceridemia, hypercholesterolemia, dyslipidemia or syndrome X. In some embodiments, the
metabolic-related disorder is type II diabetes. In some embodiments, the metabolic-related disorder is
hyperglycemia. In some embodiments, the metabolic-related disorder is hyperlipidemia. In some
embodiments, the metabolic-related disorder is hypertriglyceridemia. In some embodiments, the
metabolic-related disorder is type I diabetes. In some embodiments, the metabolic-related disorder is
dyslipidemia. In some embodiments, the metabolic-related disorder is syndrome X.
One aspect of the present invention pertains to a method of producing a pharmaceutical
composition comprising admixing at least one compound, as described herein, and a pharmaceutically
acceptable carrier.
The inventions described in this application were made by Arena Pharmaceuticals, Inc as a
result of activities undertaken within the scope of a December 20, 2004 joint research agreement
between Ortho-McNeil Pharmaceutical, Inc. and Arena Pharmaceuticals, Inc.
Applicant reserves the right to exclude any one or more of the compounds from any of the
embodiments of the invention. Applicant additionally reserves the right to exclude any disease,
condition or disorder from any of the embodiments of the invention.
BRIEF DESCRIPTION OF THE ACCOMPANYING 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 human 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 P cells of pancreatic islets.
Figure 3 shows in vitro functional activities of RUP3.
Figure 4 shows a RUP3 RNA blot.
DETAILED DESCRIPTION OF THE 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 interact and activate the receptor, such as the RUP3
receptor and initiates a physiological or pharmacological response characteristic of that receptor. For
example, when moieties activate the intracellular response upon binding to the receptor, or enhance GTP
binding to membranes.


The term ANTAGONISTS is intended to mean moieties that competitively bind to the
reteptor at the same site as agonists (for example, the endogenous ligand), but which do not activate
the intracellular response initiated by the active form of the receptor, and can thereby inhibit the
intracellular responses by agonists or partial agonists. Antagonists do not diminish the baseline
intracellular response in the absence of an agonist or partial agonist.
CHEMICAL GROUP, MOIETY OR RADICAL:
The term "C1-6 acyl" refers to a C1-6 alkyl radical attached directly to the carbon of a
carbonyl group wherein the definition for alkyl is as described herein; some examples include,
but not limited to, acetyl, propionyl, n-butanoyl, iso-butanoyl, sec-butanoyl, t-butanoyl (also
referred to as pivaloyl), pentanoyl and the like.
The term "C1-6 acyloxy" refers to an acyl radical attached directly to an oxygen atom
[-OC(=O)-C1-6 alkyl] wherein acyl has the same definition has described herein; some
examples include but not limited to acetyloxy [-OC(=O)CH3], propionyloxy, butanoyloxy,
iso-butanoyloxy, sec-butanoyloxy, t-butanoyloxy and the like.
The term "C1-6 acylsulfonamide" refers to a C1-6 acyl attached directly to the nitrogen
of the sulfonamide, wherein the definitions for C1-6 acyl and sulfonamide have the same
meaning as described herein, and a C1-6 acylsulfonamide can be represented by the following
formula:

Some embodiments of the present invention are when acylsulfonamide is a C1-5
acylsulfonamide, some embodiments are C1-4 acylsulfonamide, some embodiments are C1-3
acylsulfonamide, and some embodiments are C1-2 acylsulfonamide. Examples of an
acylsulfonamide include, but not limited to, acetylsulfamoyl [-S(=O)2NHC(=O)Me],
propionylsulfamoyl [-S(=O)2NHC(=O)Et], isobutyrylsulfamoyl, butyrylsulfamoyl, 2-methyl-
butyrylsulfamoyl, 3-methyl-butyrylsulfamoyl, 2,2-dimethyl-propionylsulfamoyl,
pentanoylsulfamoyl, 2-methyl-pentanoylsulfamoyl, 3-methyl-pentanoylsulfamoyl, 4-methyl-
pentanoylsulfamoyl, and the like.
The term "C2-6 alkenyl" refers to 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 E or Z or a mixtures of E and Z. Examples of an alkenyl include vinyl, allyl, 2-butenyI, 3-
butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexanyl, 2,4-
hexadienyl and the like.

The term "C1-6 alkoxy" refers to an alkyl radical, as defined herein, attached directly
to an oxygen atom (i.e., -O-C1-6 alkyl). Examples include methoxy, ethoxy, n-propoxy, iso-
propoxy, n-butoxy, t-butoxy, iso-butoxy, sec-butoxy and the like.
The term "C1-6 alkyl" refers to a straight or branched carbon radical containing 1 to 6
carbons, some embodiments are 1 to 5 carbons, some embodiments are 1 to 4 carbons, some
embodiments are 1 to 3 carbons, and some embodiments are 1 or 2 carbons. Examples of an
alkyl include, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-
butyl, sec-butyl, n-pentyl, iso-pentyl, sec-pentyl, neo-pentyl, pent-3-yl, 2-methyl-but-1-yl,
1,2-dimethyl-prop-1-yl, n-hexyl, iso-hexyl, sec-hexyl, neo-hexyl, l-ethyl-2-methyl-prop-1-yl,
1,2,2-trimethyl-prop-1-yl, 1,1,2-trimethyl-prop-1-yl, 1-ethyl-1-methyl-prop-1-yl, 1,1-
dimethyl-but-1-yl, 1,2-dimethyl-but-1-yl, 2,3-dimethyl-but-1-yl, 2,2-dimethyl-but-1-yl, 1,3-
dimethyl-but-1-yl, hex-3-yl, 2-methyl-pent-1-yl, 3-methyl-pent-1-yl, and the like.
The term "C1-6 alkylamino" refers to one alkyl radical attached directly to an amino
radical (-HN-C1-6 alkyl) wherein the alkyl radical has the same meaning as described herein.
Some examples include, but not limited to, methylamino (i.e., -HNCH3), ethylamino, n-
propylamino, iso-propylamino, n-butylamino, sec-butylamino, iso-butylamino, t-butylamino, and
the like.
The term "C1-6 alkylcarboxamide" or "C1-6 alkylcarboxamido" refers to a single C1-
6 alkyl group attached to the nitrogen of an amide group, wherein alkyl has the same
definition as described herein. The C1-6 alkylcarboxamido may be represented by the
following:

Examples include, but not limited to, N-methylcarboxamide, N-ethylcarboxamide, N-n-
propylcarboxamide, N-iso-propylcarboxamide, N-n-butylcarboxamide, N-sec-
butylcarboxamide, N-iso-butylcarboxamide, N-t-butylcarboxamide and the like.
The term "C1-3 alkylene" refers to a C1-3 divalent straight carbon group. Examples of
a C1-3 alkylene group include, -CH2-, -CH2CH2-, and -CH2CH2CH2-. Other examples include,
=CH-, =CHCH2-, =CHCH2CH2- wherein these examples relate generally to "A2" when E is C
(i.e., a carbon atom).
The term "C1-6 alkylsulfinyl" refers to an alkyl radical attached directly to a sulfoxide
radical of the formula: -S(=O)- wherein the alkyl radical has the same definition as described
herein. Examples include, but not limited to, methylsulfinyl, ethylsulfinyl, n-propylsulfinyl,
iso-propylsulfinyl, n-butylsulfinyl, sec-butylsulfinyl, iso-butylsulfinyl, t-butyl, and the like.
The term "C1-6 alkylsulfonamide" refers to the groups


wherein C1-6 alkyl has the same definition as described herein.
The term "C1-6 alkylsulfonyl" refers to a alkyl radical attached to a sulfone radical of
the formula: -S(O)2- wherein the alkyl radical has the same definition as described herein.
Examples include, but not limited to, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, iso-
propylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl, iso-butylsulfonyl, t-butyl, and the like.
The term "C1-6 alkylthio" refers to a alkyl radical attached to a sulfide of the formula:
-S- wherein the alkyl radical has the same definition as described herein. Examples include,
but not limited to, methylsulfanyl (i.e., CH3S-), ethylsulfanyl, n-propylsulfanyl, iso-
propylsulfanyl, n-butylsulfanyl, sec-butylsulfanyl, iso-butylsulfanyl, t-butyl, and the like.
The term "C1-6 alkylthiocarboxamide" refers to an alkyl attached directly to a
thiocarboxamide group at either the nitrogen or at the carbon of the thiocarbonyl and has the
following respective formulae:

wherein C1-4 alkyl has the same definition as described herein.
The term "C1-6 alkylthioureyl" refers to the group of the formula:
-NC(=S)NH- wherein one are both of the nitrogens are independently substituted with the
same or different C1-6 alkyl groups and alkyl has the same definition as described herein.
Examples of an alkylthioureyl include, but not limited to, CH3NHC(S)NH-, NH2C(S)NCH3-,
(CH3)2N(S)NH-, (CH3)2N(S)NH-, (CH3)2N(S)NCHr, CH3CH2NHC(S)NH-,
CH3CH2NHC(S)NCH3-, and the like.
The term "C1-6 alkylureyl" refers to the group of the formula: -NC(=O)NH- wherein
one are both of the nitrogens are independently substituted with the same or different C1-6
alkyl group wherein alkyl has the same definition as described herein. Examples of an
alkylureyl include, but not limited to, CH3NHC(O)NH-, NH2C(O)NCH3-, (CH3)2N(O)NH-,
(CH3)2N(O)NH-, (CH3)2N(O)NCH3-, CH3CH2NHC(O)NH-, CH3CH2NHC(O)NCH3-, and the
like.
Theterm "C2-6 alkynyl" refers to a radical containing 2 to 6 carbons and at least one
carbon-carbon triple bond (-C=C-), some embodiments are 2 to 4 carbons, some embodiments
are 2 to 3 carbons, and some embodiments have 2 carbons (-C=CH). Examples of a C2-6 alkynyl
include, but not limited to, 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 C2-6 alkynyl includes di- and tri-ynes.
The term "amino" refers to the group -NH2.

The term "aryl" refers to an aromatic ring radical containing 6 to 10 ring carbons.
Examples include phenyl, naphthyl, and the like.
The term "arylcarbonyl" refers to an aryl group attached directly to the carbon of a
carbonyl group, wherein aryl has the same definition as described herein. Examples include
phenylcarbonyl (or also referred to as benzoyl), naphthalene-1-carbonyl, naphthalene-2-carbonyl,
and the like.
The term "aryloxy" refers to an aryl group attached directly to an oxygen atom [i.e.,
aryl-O-] wherein aryl has the same definition as described herein. Examples include, but not
limited to, phenoxy, naphthalen-1-yloxyl, naphthalen-2-yloxy, and the like.
The term "arylsulfonyl" refers to an aryl group attached directly to the sulfur of a
sulfonyl group [i.e., -S(=O)2-] wherein aryl has the same definition as described herein.
Examples include benzenesulfonyl, naphthalene-1-sulfonyl, naphthalene-2-sulfonyl, and the like.
The term "C1-6-alkoxycarbonyl" refers to an alkoxy group attached directly to the
carbon of a carbonyl and can be represented by the formula -C(=O)O-C1-6-alkyl, wherein the
C1-6 alkyl group is as defined herein. In some embodiments, the C1-6-alkoxycarbonyl group is
further bonded to a nitrogen atom and together form a carbamate group (e.g., NC(=O)O-C1-6-
alkyl). Examples include, but not limited to, methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, iso-propoxycarbonyl, butoxycarbonyl, sec-butoxycarbonyl, iso-
butoxycarbonyl, t-butoxycarbonyl, n-pentoxycarbonyl, iso-pentoxycarbonyl, t-
pentoxycarbonyl, neo-pentoxycarbonyl, n-hexyloxycarbonyl, and the like.
The term "carbamimidoyl" refers to a group of the following chemical formula:

The term "carboxamide" refers to the group -C(=O)NH2.
The term "carboxy" or "carboxyl" refers to the group -CO2H; also referred to as a
carboxylic acid group.
The term "cyano" refers to the group -CN.
The term "C3-7 cycloalkyl" refers to a saturated ring radical containing 3 to 7 carbons;
some embodiments contain 3 to 6 carbons ("C3-6 cycloalkyl"); some embodiments contain 3
to 5 carbons_("C3-5 cycloalkyl"); some embodiments contain 3 to 4 carbons ("C3-4
cycloalkyl"). Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopenyl,
cyclohexyl, cycloheptyl and the like.
The term "C3-7-cycloalkyl-C1-3-alkylene" refers to a C1-3 divalent straight chain
carbon group bonded to a C3-7-cycloalkyl group. Examples include, cyclopropylmethyl,
cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropyl-ethyl, 2-cyclobutyl-
ethyl, 2-cyclopentyl-ethyl, and the like.

The term "Cvrcycloalkoxy" refers to a cycloalkyl, as defined herein, attached
directly to an oxygen atom (i.e., -O-C3-7 cycloalkyl). Example include, but not limited to,
cyclopropoxy, cyclobutoxy, cyclopentoxy, and the like.
The term "C3-7-cycloalkoxycarbonyl" refers to a C3-7 cycloalkoxy group attached
directly to the carbon of a carbonyl group, and can be represented by the formula: -C(=O)O-
C3-7-cycloalkyl, wherein the cycloalkyl group has as described herein. In some embodiments,
the C3-7-cycloalkoxycarbonyl group is bonded to a nitrogen atom and together form a
carbamate group (e.g., NC(=O)O-C3-7-cycloalkyl). Examples include, but not limited to,
cyclopropoxycarbonyl, cyclobutoxycarbonyl, cyclopentoxycarbonyl, and the like.
The term "C3-6 cycloalkylene" refers to a divalent cycloalkyl radical, where
cycloalkyl is as defined herein, containing 3 to 6 carbons; some embodiments contain 3 to 5
carbons; some embodiments contain 3 to 4 carbons. In some embodiments, the two bonding
groups are on the same carbon, for example:

In some embodiments, the two bonding groups are on different carbons.
The term "di-C1-6rdialkylamino" refers to an amino substituted with two of the same or
different C1-6 alkyl radicals wherein alkyl radical has the same definition as described herein.
Some examples include, but not limited to, dimethylamino, methylethylamino, diethylamino,
methylpropylamino, methylisopropylamino, ethylpropylamino, ethylisopropylamino,
dipropylamino, propylisopropylamino and the like.
The term "di-C1-6-alkylcarboxamide" or "di-C1-6-alkylcarboxamido" refers to two
C1-6 alkyl radicals, that are the same or different, attached to an amide group, wherein alkyl
has the same definition as described herein. A di-C1-6-alkylcarboxamido can be represented
by the following groups:

wherein C1-6 has the same definition as described herein. Examples of a dialkylcarboxamide
include, but not limited to, N,N-dimethylcarboxamide, N-methyl-N-ethylcarboxamide, N,N-
diethylcarboxamide, N-methyl-N-isopropylcarboxamide, and the like.
The term "di-C1-6-alkylsulfonamide" refers to two C1-6 alkyl radicals, that are the
same or different, attached to a sulfonamide group, wherein alkyl has the same definition as
described herein. A di-C1-6-alkylsulfonamide can be represented by the following groups:


Examples include, but not limited to, dimethylsulfamoyl [-S(=O)2N(CH3)2],
ethylmethylsulfamoyl, methanesulfonyl-methyl-amino [-N(CH3)S(=O)2CH3], ethyl-
methanesulfonyl-amino [-N(CH2CH3)S(=O)2CH3], and the like.
The term "di-C1-6-alkylthiocarboxamido" or "di-C1-6-alkylthiocarboxamide"refers
to two C1-6 alkyl radicals, that are the same or different, attached to a thioamide group,
wherein alkyl has the same definition as described herein. A C1-6 dialkylthiocarboxamido can
be represented by the following groups:

Examples of a dialkylthiocarboxamide include, but not limited to, N,N-
dimethylthiocarboxamide, N-methyl-N-ethylthiocarboxamide and the like.
The term "guanidine" refers to a group of the following chemical formula:

The term "C1-6 haloalkoxy" refers to a haloalkyl, as defined herein, which is directly
attached to an oxygen atom. Examples include, but not limited to, difluoromethoxy,
trifluoromethoxy (OCF3), 2,2,2-trifluoroethoxy, pentafluoroethoxy and the like.
The term "C1-6 haloalkyl" refers to an alkyl group, defined herein, wherein the alkyl is
substituted with one halogen up to fully substituted, a fully substituted haloalkyl can be
represented by the formula CnL2n+1 wherein L is a halogen and "n" is 1,2,3,4, 5, or 6 and when
more than one halogen is present then they may be the same or different and selected from the
group consisting of F, CI, Br and I, in some embodiments, halogen is F. Examples of haloalkyl
groups include, but not limited to, fluoromethyl, difiuoromethyl, trifluoromethyl,
chlorodifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, and the like.
The term "Ci„6 haloalkylsulfinyl" refers to a C\.e haloalkyl radical directly attached to
the sulfur o£a~sulfoxide group of the formula: -S(=O)-, wherein the Q.6 haloalkyl radical has the
same definition as described herein. Examples include, but not limited to,
trifluoromethylsulfmyl, 2,2,2-trifluoroethylsulfmyl, 2,2-difluoroethylsulfinyl and the like.
The term "Ci_6 haloalkylsulfonyl" refers to a haloalkyl radical directly attached to the
sulfur of a sulfone group of the formula: -S(=O)2- wherein haloalkyl has the same definition as
described herein. Examples include, but not limited to, trifluoromethylsulfonyl, 2,2,2-
trifluoroethylsulfonyl, 2,2-difluoroethylsulfonyl and the like.

The term "d.6 haloalkylthio" refers to a haloalkyl radical directly attached to a
sulfur wherein the haloalkyl has the same meaning as described herein. Examples include,
but not limited to, trifluoromethylthio (i.e., CF3S-), 1,1-difluoroethylthio, 2,2,2-
trifluoroethylthio and the like.
The term "halogen" or "halo" refers to to a fluoro, chloro, bromo or iodo group.
The term "C1.3 heteroalkylene" refers to an alkylene bonded to a heteroatom selected
from -0-, -S-, -S(=O)-, -S(=O)2-, and -NH-. Some represented examples include, but not
limited to, the groups of the following formulae:

and the like.
The term "heteroaryl" refers to an aromatic ring system that may be a single ring, two
fused rings or three fused rings wherein at least one ring carbon is replaced with a heteroatom
selected from, but not limited to, the group consisting of O, S, N, and NH. Examples of
heteroaryl groups include, but not limited to, pyridyl, benzofuranyl, pyrazinyl, pyridazinyl,
pyrimidinyl, triazinyl, quinoline, benzoxazole, benzothiazole, liJ-benzimidazole, isoquinoline,
quinazoline, quinoxaline, pyrrole, indole, and the like. Other examples include, but not limited
to, heteroaryl groups in TABLE 3, TABLE 4, and the like.
The term "heteroaryl-C]_3-aIkylene" refers to a heteroaryl that is directly attached to an
alkylene group, wherein both heteroaryl and alkylene are the same as described herein.
Examples of a heteroaryl-C^-alkylene include, but not limited to, isoxazol-3-ylmethyl, isoxazol-
4-ylmethyl, isoxazol-5-ylmethyl, 2-isoxazol-3-yl-ethyl, 2-isoxazol-4-yl-ethyI, 2-isoxazol-5,-yl-
ethyl, [l,2,4]oxadiazol-3-ylmethyl, [l,2,4]oxadiazol-5-ylmethyl, 2-[l,2,4]oxadiazol-3-yl-ethyl, 2-
[l,2,4]oxadiazol-5-yl-ethyI, and the like.
The term "heteroarylcarbonyl" refers to a heteroaryl group attached directly to the
carbon of a carbonyl group, wherein heteroaryl has the same definition as described herein.
Examples include [l,2,4]oxadiazole-3-carbonyl, [l,2,4]oxadiazole-5-carbonyl, isoxazole-3-
carbonyl, israazole-4-carbonyl, isoxazole-5-carbonyl, furan-2-carbonyl, furan-3 -carbonyl, furan-
4-carbonyl, furan-5-carbonyl, thiophene-2-carbonyl, thiophene-3-carbonyl, pyridine-2-carbonyl,
pyridine-3-carbonyl, pyridine-4-carbonyl, and the like.
The term "heteroaryloxy" refers to a heteroaryl group attached directly to an oxygen
atom [i.e., heteroaryl-O-] wherein heteroaryl has the same definition as described herein.
Examples include, but not limited to, [l,2,4]oxadiazole-3-yloxy, [l,2,4]oxadiazole-5-yloxy,
isoxazole-3-yloxy, isoxazole-4-yloxy, isoxazole-5-yloxy, furan-2-yloxy, furan-3-yloxy,

thiophen-2-yloxy, thiophen-3-yloxy, pyridin-2-yloxy, pyridin-3-yloxy, pyridin-4-yloxy, and the
like.
The term "heteroarylsulfonyl" refers to an heteroaryl group attached directly to the
sulfur of a sulfonyl group [i.e., -S(=O)2-] wherein heteroaryl has the same definition as described
herein. Examples include, but not limited to, [l,2,4]oxadiazole-3-sulfonyl, [l,2,4]oxadiazole-5-
sulfonyl, isoxazoIe-3-sulfonyl, isoxazole-4-sulfonyl, isoxazole-5-sulfonyl, furan-2-sulfonyl,
furan-3-sulfonyl, thiophene-2-sulfonyl, thiophene-3-sulfonyl, pyridine-2-sulfonyl, pyridine-3-
sulfonyl, pyridine-4-sulfonyl, and the like.
The term "heterocyclic" refers to a non-aromatic carbon ring (i.e., cycloalkyl or
cycloalkenyl as defined herein) wherein one, two or three ring carbons are replaced by a
heteroatom selected from, but not limited to, the group consisting of-O-, -S-, -S(=O)-,
-S(=O)2-, and -NH-, and the ring carbon atoms are optionally substituted with oxo or thiooxo
thus forming a carbonyl or thiocarbonyl group respectively. The heterocyclic group can be a
3, 4, 5, 6 or 7-member 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,
[l,3]-dioxolan-2-yl and the like. Additional examples of heterocyclic groups are shown
below in TABLE 2:

It is understood that any one of the heterocyclic groups shown herein can be bonded at any
ring carbon or ring nitrogen as allowed by the respective formula unless otherwise specified.
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:


The term "heterocycliccarboxamide" or "heterocycliccarboxamido" refers to a
heterocyclic group, as defined herein, which has at least one nitrogen ring atom and the ring
nitrogen is bonded directly to the carbon of a carbonyl group forming an amide. Examples
include, but not limited to,

The term "heterocyclicsulfonyl" refers to a heterocyclic group, as defined herein,
which has at least one ring nitrogen and the ring nitrogen is bonded directly to the sulfur of a -
S(=O)2- group forming an sulfonamide group. Examples include, but not limited to,

The term "hydroxyl" refers to the group -OH.
The term "hydroxylamino" refers to the group -NHOH.
The term "nitro" refers to the group -N02.
The term "oxo" refers generally to a double bonded oxygen; typically "oxo" is a
substitution on a carbon and together form a carbonyl group.
The term "C3.6 oxo-cycloalkyl" refers to a C3^ cycloalkyl, as defined herein, wherein 1
or 2 of the ring carbons is substituted with an oxo group thus forming a carbonyl group.
Examples of oxo-cycloalkyl groups include, but are not limited to, 2-oxo-cyclobutyl, 3-oxo-
cyclobutyl, 3-oxo-cyclopentyl, 3-oxo-cyclohexyl, 2-oxo-cyclohexyl, 4-oxo-cyclohexyl, and the
like and represented by the following structures respectively:

The term "phenoxy" refers to the group C6H50-.
The term "phenyl" refers to the group C6H5-.
The term "sulfonamide" refers to the group -S(=O)2NH2.
The term"sulfonic acid" refers to the group -SO3H.
The term "thiol" refers to the group -SH.

COMPOSITION shall mean a material comprising at least two compounds or two components;
for example, and without limitation, a Pharmaceutical Composition is a Composition comprising a
compound of the present invention and a pharmaceutically acceptable carrier.
COMPOUND EFFICACY shall mean a measurement of the ability of a compound to inhibit or
stimulate receptor functionality, as opposed to receptor binding affinity.
CONTACT or CONTACTING shall mean bringing the indicated moieties together, whether
in an in vitro system or an in vivo system. Thus, "contacting" a RUP3 receptor with a compound of
the invention includes the administration of a compound of the present invention to an individual, for
example a human, having a RUP3 receptor, as well as, for example, introducing a compound of the
invention into a sample containing a cellular or more purified preparation containing a RUP3
receptor.
IN NEED OF TREATMENT as used herein refers to a judgment made by a caregiver (e.g.
physician, nurse, nurse practitioner, etc. in the case of humans; veterinarian in the case of animals,
including non-human mammals) that an individual or animal requires or will benefit from treatment.
This judgment is made based on a variety of factors that are in the realm of a caregiver's expertise, but
that includes the knowledge that the individual is ill, or will be ill, as the result of a disease, condition
or disorder that is treatable by the compounds of the invention. The term "treatment" also refers in
the alternative to "prophylaxis." Therefore, in general, "in need of treatment" refers to the judgment
of the caregiver that the individual is already ill, accordingly, the compounds of the present invention
are used to alleviate, inhibit or ameliorate the disease, condition or disorder. Furthermore, the phrase
also refers, in the alternative, to the judgment made by the caregiver that the individual will become
ill. In this context, the compounds of the invention are used in a protective or preventive manner.
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 a mammal (for example, without limitation, a human). Those of ordinary skill in the art will
understand and appreciate the techniques appropriate for determining whether an active ingredient has a
desired efficacious outcome based upon the needs of the artisan.
THERAPEUTICALLY EFFECTIVE AMOUNT as used herein refers to the amount of
active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue,
system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor
or other clinician, which includes one or more of the following:
(1) Preventing the disease; for example, preventing a disease, condition or disorder in an
individual that may be predisposed to the disease, condition or disorder but does not yet experience or
display the pathology or symptomatology of the disease,
(2) Inhibiting the disease; for example, inhibiting a disease, condition or disorder in an
individual that is experiencing or displaying the pathology or symptomatology of the disease,
condition or disorder (i.e., arresting further development of the pathology and/or symptomatology),
and
(3) Ameliorating the disease; for example, ameliorating a disease, condition or disorder in an
individual that is experiencing or displaying the pathology or symptomatology of the disease,
condition or disorder (i.e., reversing the pathology and/or symptomatology).
Compounds of the Present Invention:
One aspect of the present invention encompasses certain substituted aryl and heteroaryl
derivatives as shown in Formula (I):

or pharmaceutically acceptable salt, solvate, hydrate or N-oxide thereof; wherein Ar, V, Qh Q2, K, E,
— , Ai, A2, D', W, X, Y, and Z have the same definitions 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.

As used herein, "substituted" indicates that at least one hydrogen atom of the chemical group
is replaced by a non-hydrogen substituent or group, the non-hydrogen substituent or group can be
monovalent or divalent. When the substituent or group is divalent, then it is understood that this
group is further substituted with another substituent or group. When a chemical group herein is
"substituted" it may have up to the full valance of substitution; for example, a methyl group can be
substituted by 1, 2, or 3 substituents, a methylene group can be substituted by 1 or 2 substituents, a
phenyl group can be substituted by 1, 2, 3, 4, or 5 substituents, a naphthyl group can be substituted by
1, 2, 3, 4, 5, 6, or 7 substituents and the like. Likewise, "substituted with one or more substituents"
refers to the substitution of a group with one substituent up to the total number of substituents
physically allowed by the group. Further, when a group is substituted with more than one group they
can be identical or they can be different.
It is understood herein that where a moiety is said to be substituted, that moiety is meant to be
the one recited in the immediately preceding list of variables. For example, where a C^ alkyl group
is substituted by a substituent selected from another Ci_6 alkyl and other substitutents, subsequent
language of "wherein C1-6 alkyl is further optionally substituted" refers to the immediately preceding
C1-6 alkyl substitutent, as opposed to the original Ci.g alkyl group; such that the original C1-6 alkyl can
be substituted by another Q.6 alkyl which is itself further optionally substituted.
It is understood and appreciated that compounds of the invention may have one or more chiral
centers, and therefore can exist as enantiomers and/or diastereomers. The invention is understood to
extend to and embrace all such enantiomers, diastereomers and mixtures thereof, including, but not
limited to, racemates. Accordingly, some embodiments of the present invention pertain to compounds
of Formula (I) and formulae used throughout this disclosure that are R enantiomers. Further, some
embodiments of the present invention pertain to compounds of Formula (I) and formulae used
throughout this disclosure that are S enantiomers. When more than one chiral center is present, for
example two chiral centers then, some embodiments of the present invention include compounds that
are RS or SR enantiomers. In further embodiments, compounds of the present invention are RR or SS
enantiomers. It is understood that compounds of Formula (I) and formulae used throughout this
disclosure are intended to represent all individual enantiomers and mixtures thereof, unless stated or
shown otherwise.
Compounds of the invention can also include tautomeric forms, such as keto-enol tautomers,
and the like. Tautomeric forms can be in equilibrium or sterically locked into one form by
appropriate substitution. It is understood that the various tautomeric forms are within the scope of the
compounds of the present invention.
Compounds of the invention can also include all isotopes of atoms occurring in the
intermediates and/or final compounds. Isotopes include those atoms having the same atomic number
but different mass numbers. For example, isotopes of hydrogen include deuterium and tritium.

In some embodiments, heteroaryl refers to 5-member heteroaryl groups. In some

embodiments, heteroaryl refers to heteroatom containing aromatic rings selected from the group
consisting of the following formulae:

wherein the 5-member 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-yl or imiadazol-5-yl group).
In some embodiments, heteroaryl refers to 6-member heteroatom containing aromatic rings
selected from the group consisting of the following formulae:

wherein the heteroaryl group is bonded at any ring carbon.
In some embodiments, Ai and A2 are both -CH2- and each optionally substituted with one or
more substituents (i.e., 1 or 2 substituents for A] and 1 or 2 substituents for A2) selected independently
from the group consisting of Q.6 alkyl, C1-6 alkoxy, and carboxy.
Some embodiments of the present invention pertain to compounds wherein A] and A2 are
both -CH2-, forming a four-member ring, and each A] and A2 is optionally substituted with 1 or 2
methyl groups.
In some embodiments, Ai and A2 are both -CH2- and can be represented by Formula (lb) as
illustrated below:

1
wherein each variable in Formula (lb) has the same meaning as described herein, supra and infra.
In some embodiments, A] is -CH2- and A2 is -CH2CH2-, and each optionally substituted with
one or more substituents (i.e., 1 or 2 substituents for Ai and 1,2, 3, or 4 substituents for A2) selected
independently from the group consisting of C\.e alkyl, C\.(, alkoxy, and carboxy.
Some embodiments of the present invention pertain to compounds wherein A] is -CH2- and
A2 is -CH2CH2-, forming a five-member ring, and Ai is optionally substituted with 1 or 2 methyl
groups and A2 is optionally substituted with 1,2, 3 or 4 methyl groups.
In some embodiments, Ai is -CH2- and A2 is -CH2CH2- and can be represented by Formula (Id)
as illustrated below:

wherein each variable in Formula (Id) has the same meaning as described herein, supra and infra.
In some embodiments, Ai and A2 are both -CH2CH2-, and each optionally substituted with
one or more substituents (i.e., 1, 2, 3, or 4 substituents for Ai and 1, 2, 3, or 4 substituents for A2)
selected independently from.the group consisting of C1-6 alkyl, C]r6 alkoxy, and carboxy.
Some embodiments of the present invention pertain to compounds wherein A] and A2 are
both -CH2CH2-, forming a six-member ring, and each Ai and A2 is optionally substituted with 1, 2, 3
or 4 methyl groups.
In some embodiments, Ai and A2 are both -CH2CH2- and can be represented by Formula (If)
as illustrated below:

wherein each variable in Formula (If) has the same meaning as described herein, supra and infra.
In some embodiments, Ai is -CH2CH2-and A2 is -CH2CH2CH2-, and each optionally
substituted with one or more substituents (i.e., 1, 2, 3, or 4 substituents for A] and 1, 2, 3, 4, 5, or 6
substituents for A2) selected independently from the group consisting of Ci_6 alkyl, Ci_6 alkoxy, and
carboxy.

Some embodiments of the present invention pertain to compounds wherein Ai is
-CH2CH2-and A2 is -CH2CH2CH2-, forming a seven-member ring, and each A] and A2 is optionally
substituted with 1,2, 3 or 4 methyl groups.
In some embodiments, Aj is -CH2CH2-and A2 is -CH2CH2CH2- and can be represented by
Formula (Ih) as illustrated below:

wherein each variable in Formula (Ih) has the same meaning as described herein, supra and infra.
In some embodiments, A] and A2 are both -CH2CH2CH2-, and each optionally substituted
with one or more substituents (i.e., 1, 2, 3, 4, 5, or 6 substituents for Aj and 1, 2, 3, 4, 5, or 6
substituents for A2) selected independently from the group consisting of Ci_6 alkyl, C\.e alkoxy, and
carboxy.
Some embodiments of the present invention pertain to compounds wherein Aj and A2 are
both -CH2CH2CH2-, forming an eight-member ring, and each Ai and A2 is optionally substituted with
1,2,3 or 4 methyl groups.
In some embodiments, Ai and A2 are both -CH2CH2CH2- and can be represented by Formula
(Ij) as illustrated below:

wherein each variable in Formula (Ij) has the same meaning as described herein, supra and infra.
Some embodiments of the present invention pertain to compounds wherein Ai is -CH2- and
A2 is -CRCK2-', or Ai is -CH2CH2- and A2 is =CH-; and each A] and A2 is optionally substituted with
1, 2, 3 or 4 methyl groups as permitted.
In some embodiments, A] is -CH2- and A2 is =CHCH2-; or Ai is -CH2CH2- and A2 is
=CH-, and can be represented by Formulae (Ik) and (Im), respectively, as illustrated below:


wherein each variable in Formulae (Ik) and (Im) has the same meaning as described herein, supra and
infra.
Some embodiments of the present invention pertain to compounds wherein Ai is
-CH2CH2- and A2 is =CHCH2-, and A, is optionally substituted with 1, 2, 3 or 4 methyl groups and A2
is optionally substituted with 1, 2 or 3 methyl groups.
In some embodiments, A] is -CH2CH2- and A2 is =CHCH2- and can be represented by
Formula (Io) as illustrated below:

wherein each variable in Formula (Io) has the same meaning as described herein, supra and infra.
Some embodiments of the present invention pertain to compounds wherein Aj is
-CH2CH2- and A2 is =CHCH2CH2-; or A, is -CH2CH2CH2- and A2 is =CHCH2-; and each A, and A2 is
optionally substituted with 1, 2, 3 or 4 methyl groups.
In some embodiments, Aj is -CH2CH2- and A2 is =CHCH2CH2-; or A] is -CH2CH2CH2- and A2
is =CHCH2-; and can be represented by Formulae (Iq) and (Is), respectively, as illustrated below:

wherein each variable in Formulae (Iq) and (Is) has the same meaning as described herein, supra and
infra.
Some embodiments of the present invention pertain to compounds wherein A] is
-CH2CH2CH2- and A2 is =CHCH2CH2-, and each Aj and A2 is optionally substituted with 1, 2, 3 or 4
methyl groups.
In some embodiments, A] is -CH2CH2CH2- and A2 is =CHCH2CH2- and can be represented
by Formula (Iu) as illustrated below:

wherein each variable in Formula (Iu) has the same meaning as described herein, supra and infra.

Some embodiments of the present invention pertain to compounds wherein , — - is a single
bond.
In some embodiments, compounds of the present invention can be represented by Formula
(Iw) as illustrated below:

wherein each variable in Formula (Iw) has the same meaning as described herein, supra and infra.
Some embodiments of the present invention pertain to compounds wherein — is a double
bond. It is understood that when is a double bond then E is C (i.e., carbon atom) and E is not N
(i.e., a nitrogen atom).
Some embodiments of the present invention pertain to compounds wherein K is absent.
In some embodiments, compounds of the present invention can be represented by Formula
(Iy) as illustrated below:

wherein each variable in Formula (Iy) has the same meaning as described herein, supra and infra.
In some embodiments, K is C3.6 cycloalkylene optionally substituted with one or more
substituents selected independently from the group consisting of C).6 alkyl" C1-6 alkoxy, carboxy,
cyano, and halogen.
Some embodiments of the present invention pertain to compounds wherein K is C3.6
cycloalkylene.
In some embodiments, K is selected from the group consisting of cyclopropylene,
cyclobutylene, cyclopentylene, and cyclohexylene.
In some embodiments, K is cyclobutylene.
In some embodiments, K is cyclopropylene.
In some embodiments, compounds of the present invention can be represented by Formula
(Ha) as illustrated below:

wherein each variable in Formula (Ila) has the same meaning as described herein, supra and infra.

Some embodiments of the present invention pertain to compounds wherein K is C1.3 alkylene
group each optionally substituted with one or more substituents selected independently from the group
consisting of Ci.g alkyl, C^ alkoxy, carboxy, cyano, and halogen.
Some embodiments of the present invention pertain to compounds wherein K is Q.3 alkylene
optionally substituted with 1,2, 3, or 4 substituents selected independently from the group consisting
of C1-6 alkyl, Ci_6 alkoxy, carboxy, cyano, and halogen.
Some embodiments of the present invention pertain to compounds wherein K is
-CH2CH2- optionally substituted with 1, 2, 3, or 4 substituents selected independently from the group
consisting of Ci_6 alkyl, C1-6 alkoxy, carboxy, cyano, and halogen.
Some embodiments of the present invention pertain to compounds wherein K is -CH2-
optionally substituted with 1 or 2 substituents selected independently from the group consisting of Ci_6
alkyl, C1-6 alkoxy, carboxy, cyano, and halogen.
In some embodiments, K is -CH2-.
In some embodiments, compounds of the present invention can be represented by Formula
(lie) as illustrated below:

wherein each variable in Formula (He) has the same meaning as described herein, supra and infra.
Some embodiments of the present invention pertain to compounds wherein V is absent.
In some embodiments, compounds of the present invention can be represented by Formula
(He) as illustrated below:

wherein each variable in Formula (He) has the same meaning as described herein, supra and infra.
In some embodiments, V is Q.3 heteroalkylene optionally substituted with one or more
substituents selected independently from the group consisting of C1.3 alkyl, C1-6 alkoxy, carboxy,
cyano,. C1.3 haloalkyl, and halogen.
Some embodiments of the present invention pertain to compounds wherein V is Q.3
heteroalkylene optionally substituted with 1, 2, 3, or 4 substituents selected independently from the
group consisting of C].3 alkyl, C1-6 alkoxy, carboxy, cyano, Ci_3 haloalkyl, and halogen.
Some embodiments of the present invention pertain to compounds wherein V is

-OCH2CH2- optionally substituted with 1 or 2 substituents selected independently from the group
consisting of C].3 alkyl, C\.6 alkoxy, carboxy, cyano, Cx.-$ haloalkyl, and halogen.
In some embodiments, V is -OCH2CH2- and can be represented by Formula (Ilg) as
illustrated below:

wherein each variable in Formula (Ilg) has the same meaning as described herein, supra and infra.
In some embodiments, V is Q.3 alkylene optionally substituted with one or more substituents
selected independently from the group consisting of C1.3 alkyl, C1-6 alkoxy, carboxy, cyano, Q.3
haloalkyl, and halogen.
Some embodiments of the present invention pertain to compounds wherein V is C]_3 alkylene
optionally substituted with 1, 2, 3, or 4 substituents selected independently from the group consisting
of C1.3 alkyl, C1-6 alkoxy, carboxy, cyano, C1.3 haloalkyl, and halogen.
Some embodiments of the present invention pertain to compounds wherein V is -CH2-
optionally substituted with 1 or 2 substituents selected independently from the group consisting of Q.3
alkyl, C1-6 alkoxy, carboxy, cyano, Cj.3 haloalkyl, and halogen.
In some embodiments, V is -CH2- and can be represented by Formula (Ili) as illustrated
below:

wherein each variable in Formula (IB) has the same meaning as described herein, supra and infra.
Some embodiments of the present invention pertain to compounds wherein Ch is NR4.
In some embodiments, Qi is NIL) and can be represented by Formula (Ilk) as illustrated
below:

wherein each variable in Formula (Ilk) has the same meaning as described herein, supra and infra.

Some embodiments of the present invention pertain to compounds wherein R4 is H, or Ci_6
alkyl.
Some embodiments of the present invention pertain to compounds wherein R4 is H.
Some embodiments of the present invention pertain to compounds wherein R4 is C3.7
cycloalkyl. In some embodiments, R4 is cyclopropyl.
Some embodiments of the present invention pertain to compounds wherein R4 is C1.3-
alkylene-C3.7-cycloalkyl In some embodiments, R4 is cyclopropylmethyl (i.e., CC3H5CH2-).
Some embodiments of the present invention pertain to compounds wherein Qi is O.
In some embodiments, Qi is O and can be represented by Formula (Urn) as illustrated below:

wherein each variable in Formula (Urn) has the same meaning as described herein, supra and infra.
In some embodiments, Q\ is S.
In some embodiments, Qi is S(O), also represented as -S(=O)-.
In some embodiments, Qi is S(O)2, also represented as -S(=O)2-.
Some embodiments of the present invention pertain to compounds wherein Q2 is absent.
In some embodiments, Q2 is absent and can be represented by Formula (IIo) as illustrated
below:

wherein each variable in Formula (IIo) has the same meaning as described herein, supra and infra.
Some embodiments of the present invention pertain to compounds wherein Q2 is NR5.
In some embodiments, Q2 is NR5 and can be represented by Formula (Ilq) as illustrated
below:

wherein each variable in Formula (Ilq) has the same meaning as described herein, supra and infra.
Some embodiments of the present invention pertain to compounds wherein R5 is H, Q.6 alkyl,
C3.7 cycloalkyl, or C3.7-cycloalkyl-Ci.3-alkylene.

Some embodiments of the present invention pertain to compounds wherein R5 is H.
Some embodiments of the present invention pertain to compounds wherein Q2 is O.
In some embodiments, Ch is O and can be represented by Formula (lis) as illustrated below:

wherein each variable in Formula (lis) has the same meaning as described herein, supra and infra.
In some embodiments, W is N.
In some embodiments, W is CH.
In some embodiments, X is N.
In some embodiments, X is CRs.
In some embodiments, Y is N.
In some embodiments, Y is CR7.
In some embodiments, Z is N.
In some embodiments, Z is CRg.
Some embodiments of the present invention pertain to compounds wherein W is CH; X is N
or N-oxide; Y is CR7; and Z is N or N-oxide.
In some embodiments, W is CH; X is N; Y is CR7; and Z is N; and can be represented by
Formula (llu) as illustrated below:

wherein each variable in Formula (llu) has the same meaning as described herein, supra and infra.
Some embodiments of the present invention pertain to compounds wherein W is CH; X is N
or N-oxide; Y is CR7; and Z is CRs.
In some embodiments, W is CH; X is N; Y is CR7; and Z is CRS; and can be represented by
Formula (IIw) as illustrated below:

wherein each variable in Formula (IIw) has the same meaning as described herein, supra and infra.

Some embodiments of the present invention pertain to compounds wherein W is CH; X is
CR5; Y is CR7; and Z is N or N-oxide.
In some embodiments, W is CH; X is CR$; Y is CR7; and Z is N; and can be represented by
Formula (Ily) as illustrated below:

wherein each variable in Formula (Ily) has the same meaning as described herein, supra and infra.
Some embodiments of the present invention pertain to compounds wherein W is N or N-
oxide; X is CRg; Y is CR7; and Z is CR8.
In some embodiments, W is N; X is CR^; Y is CR7; and Z is CRs; and can be represented by
Formula (Ilia) as illustrated below:

wherein each variable in Formula (Ilia) has the same meaning as described herein, supra and infra.
Some embodiments of the present invention pertain to compounds wherein W is CH; X is
CFU;. Y is N or .N-oxide; and Z is CRg.
In some embodiments, W is CH; X is CR$; Y is N; and Z is CRS; and can be represented by
Formula (IIIc) as illustrated below:

wherein each variable in Formula (IIIc) has the same meaning as described herein, supra and infra.
Some embodiments of the present invention pertain to compounds wherein R from the group consisting of H, Q.6 alkyl, and halogen.
Some embodiments of the present invention pertain to compounds wherein R5 is H.
Some embodiments of the present invention pertain to compounds wherein R7 is selected
from the group consisting of H, C1-6 alkyl, and halogen.
Some embodiments of the present invention pertain to compounds wherein R7 is H.

Some embodiments of the present invention can be represented by Formula (Illi) as
illustrated below:

wherein each variable in Formula (Illi) has the same meaning as described herein, supra and infra.
Some embodiments of the present invention pertain to compounds wherein R2 is selected
from the group consisting of CN6 alkyl, aryl, aryloxy, heteroaryl, and heteroaryloxy; wherein R2 is
optionally substituted with 1, 2, 3, 4, or 5 substituents selected independently from the group
consisting of C1-6 alkoxy, Ci_6 alkyl, C1-6 alkylamino, amino, di-C1-6-alkylamino, C1-6 alkoxycarbonyl,
carboxy, halogen, and heteroaryl, and wherein Ci_6 alkyl is further optionally substituted with 1, 2, or
3 substituents selected independently from the group consisting of C\^ alkylamino, di-C1-6-
alkylamino, C3^ cycloalkyl, and halogen.
Some embodiments of the present invention pertain to compounds wherein R2 is C1-6 alkyl
optionally substituted C\.6 alkoxycarbonyl, or carboxy.
Some embodiments of the present invention pertain to compounds wherein R2 is
ethoxycarbonylmethyl (i.e., -CH2C02Et), or carboxymethyl (i.e., -CH2C02H).
Some embodiments of the present invention pertain to compounds wherein R2 is aryl
optionally substituted with 1, 2, or 3 substituents selected from the group consisting of Ci_6 alkoxy,
and C1-6 alkyl.
Some embodiments of the present invention pertain to compounds wherein R2 is 4-isopropyl-
phenyl, 4-isobutyl-phenyl, or 4-isopropoxy-phenyl.
Some embodiments of the present invention pertain to compounds wherein R2 is aryloxy
optionally substituted with 1,2, 3,4, or 5 halogens.
Some embodiments of the present invention pertain to compounds wherein R2 is 3-fluoro-
phenoxy
In some embodiments R2 is a 5-member heteroaryl, for example but not limited to those
shown in TABLE 3,-eptionally substituted with 1 to 4 substituents selected from the group consisting
of C1-6 acyl, Cj-6 acyloxy, C2.6 alkenyl, C1-6 alkoxy, Q-e alkyl, C1-6 alkylamino, Ci_6 alkylcarboxamide,
C2.6 alkynyl, C).6 alkylsulfonamide, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6
alkylthiocarboxamide, C1-6 alkylthioureyl, C1-6 alkylureyl, amino, aryl, di-C1-6-alkyIamino, carbo-C1-6-
alkoxy, carboxamide, carboxy, cyano, C3.6 cycloalkyl, di-C1-6-aIkylcarboxamide, di-C1-6-
alkylsulfonamide, di-C1-6-alkylthiocarboxamido, C1-6 haloalkoxy, C1-6 haloalkyl, halogen, C1-6

haloalkylsulfinyl, C]_6 haloalkylsulfonyl, C1-6 haloalkylthio, heterocyclic, heteroaryl, hydroxyl,
hydroxylamino, nitro, and thiol.
In some embodiments, E is N, D is CHR2, and R2 is a 5-member heteroaryl, for example but
not limited to those shown in TABLE 3, optionally substituted with 1 to 4 substituents selected from
the group consisting of Ch6 acyl, C1-6 acyloxy, C2-6 alkenyl, Ci_6 alkoxy, Ci„6 alkyl, Cj_6 alkylamino,
C1-6 alkylcarboxamide, C2.6 alkynyl, C^ alkylsulfonamide, C1-6 alkylsulfinyl, C^ alkylsulfonyl, C1-6
alkylthio, C^ alkylthiocarboxamide, C1-6 alkylthioureyl, C1-6 alkylureyl, amino, aryl, di-C1-6-
alkylamino, carbo-Ci_6-alkoxy, carboxamide, carboxy, cyano, C3.6 cycloalkyl, di-Q-e-
alkylcarboxamide, di-C1-6-alkylsulfonamide, di-C1-6-alkylthiocarboxamido, C]_6 haloalkoxy, C1-6
haloalkyl, halogen, C1-6 haloalkylsulfinyl, C^ haloalkylsulfonyl, Cj_6 haloalkylthio, heterocyclic,
heteroaryl, hydroxyl, hydroxylamino, nitro, and thiol.
Some embodiments of the present invention pertain to compounds wherein R2 is heteroaryl
optionally substituted with 1,2, or 3 substituents selected independently from the group consisting of
C1-6 alkyl, and heteroaryl, and wherein C1-6 alkyl is further optionally substituted with 1, or 2
substituents selected independently from the group consisting of C1-6 alkylamino, di-C1-6-alkylamino,
and C3.6 cycloalkyl.
Some embodiments of the present invention pertain to compounds wherein R2 is 3-isopropyl-
[l,2,4]oxadiazol-5-yl, 3-isobutyl-[l,2,4]oxadiazol-5-yI, 3-dimethylaminomethyl-[l,2,4]oxadiazol-5-
yl, 3-cycIopropylmethyl-[l,2,4]oxadiazol-5-yl, or 3-pyridin-2-yl-[l,2,4]oxadiazol-5-yl.
Some embodiments of the present invention pertain to compounds wherein R2 is
heteroaryloxy optionally substituted with 1, 2, or 3 substituents selected independently from Cj. alkoxy. .
Some embodiments of the present invention pertain to compounds wherein R2 is 5-
isopropoxy-pyridin-2-yloxy.
Some embodiments of the present invention pertain to compounds wherein R2 is aryl,
arylcarbonyl, C1-6 alkoxycarbonyl, C3_7-cycloalkoxycarbonyl, heteroaryl, and heteroarylcarbonyl;
wherein each R2 is optionally substituted with one or more substituents selected independently from
the group consisting of C,.6 acyl, Cx.6 acyloxy, C2.6 alkenyl, C}.6 alkoxy, C1-6 alkyl, Cu alkylamino,
C1-6 alkylcarboxamide, C2.6 alkynyl, C1-6 alkylsulfonamide, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6
alkylthio, C1-6 alkylthiocarboxamide, C^ alkylthioureyl, C1-6 alkylureyl, amino, aryl, di-C1-6-
alkylamino, carbo-Ci^-alkoxy, carboxamide, carboxy, cyano, C3.6 cycloalkyl, di-C1-6-
alkylcarboxamide, di-C1-6-alkylsulfonamide, di-C1-6-alkylthiocarboxamido, C1-6 haloalkoxy, C]^
haloalkyl, halogen, C« haloalkylsulfinyl, C,.6 haloalkylsulfonyl, CU6 haloalkylthio, heterocyclic,
heteroaryl, hydroxyl, hydroxylamino, nitro, and thiol.
Some embodiments of the present invention pertain to compounds wherein R2 is aryl,
arylcarbonyl, C1-6 alkoxycarbonyl, C3.7-cycloalkoxycarbonyl, heteroaryl, and heteroarylcarbonyl;
wherein each R2 is optionally substituted with one or more substituents selected independently from

the group consisting of Q.6 acyl, Q.6 alkoxy, Q.6 alkyl, C1-6 alkylamino, Q.6 alkylcarboxamide, Q.6
alkylsulfonyl, di-Q_6-alkylamino, carboxamide, carboxy, cyano, Q_6 haloalkoxy, Q.6 haloalkyl,
halogen, Q.6 haloalkylsulfonyl, heterocyclic, and hydroxyl.
Some embodiments of the present invention pertain to compounds wherein R2 is selected
from the group consisting of H, C1-6 alkyl, aryl, arylcarbonyl, Q.6 alkoxycarbonyl, Q.7-
cycloalkoxycarbonyl, heteroaryl, heteroaryl-Q.3-alkylene, heteroarylcarbonyl, and heteroaryloxy,
wherein each R2 is optionally substituted with 1, 2,3, or 4 substituents selected independently from
the group consisting of Q_6 alkoxy, Q.6 alkyl, Q.6 alkoxycarbonyl, carboxy, C3.6 cycloalkyl, and
halogen.
Some embodiments of the present invention pertain to compounds wherein R2 is C1-6
alkoxycarbonyl, Q_6 alkoxycarbonyl substituted by Q.6 cycloalkyl, or C3.7-cycloalkoxycarbonyl.
Some embodiments of the present invention pertain to compounds wherein R2 is tert-
butoxycarbonyl, isobutoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
cyclopropylmethoxycarbonyl, 3-methyl-butoxycarbonyl, cyclobutoxycarbonyl, or 1-ethyl-
propoxycarbonyl.
Some embodiments of the present invention pertain to compounds wherein R2 is
heteroarylcarbonyl optionally substituted with 1, 2, 3, or 4 substituents selected independently from
the group consisting of Q.6 alkoxy, C1-6 alkyl, and halogen.
Some embodiments of the present invention pertain to compounds wherein R2 is selected
from the group consisting of 5-butyl-pyridine-2-carbonyl, 6-chloro-pyridine-2-carbonyl, 6-bromo-
pyridine-2-carbonyl, 6-methyl-pyridine-2-carbonyl, 6-fluoro-pyridine-2-carbonyl, pyridine-2-
carbonyl, 5-bromo-pyridine-3-carbonyl, 5-methyl-pyridine-3-carbonyl, and 5,6-dichloro-pyridine-3-
carbonyl.
Some embodiments of the present invention pertain to compounds wherein R2 is heteroaryl
optionally substituted with 1, 2,3, or 4 substituents selected independently from the group consisting
of Q.6 alkoxy, Q.6 alkyl, and halogen.
Some embodiments of the present invention pertain to compounds wherein R2 is 5-fluoro-
pyridin-2-yl, 5-isopropoxy-pyridin-2-yl, or 3-isopropyl-[l,2,4]oxadiazol-5-yl.
Some embodiments of the present invention pertain to compounds wherein R2 is heteroaryl-
Cu-alkylene optionally substituted with 1, 2, or 3 substituents selected independently from C1-6 alkyl.
Some embodiments of the present invention pertain to compounds wherein R2 is 3-isopropyl-
[l,2,4]oxadiazol-5-ylmethyl, or2-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-ethyl.
Some embodiments of the present invention pertain to compounds wherein R2 is Cue alkyl
optionally substituted with a Q.6 alkoxycarbonyl or carboxy group.
Some embodiments of the present invention pertain to compounds wherein R2 is
ethoxycarbonylmethyl (-CH2C02Et), carboxymethyl (-CH2C02H), 2-ethoxycarbonyl-ethyl (-
CH2CH2C02Et), or 2-carboxy-ethyl (-CH2CH2C02H).

Some embodiments of the present invention pertain to compounds wherein R2 is aryl
optionally substituted with 1, 2, or 3, C,.6 alkoxy groups.
Some embodiments of the present invention pertain to compounds wherein R2 is 4-
isopropoxy-pheny 1.
Some embodiments of the present invention pertain to compounds wherein Ar is aryl or
heteroaryl optionally substituted with R9, Rio, Rn, R12, and R]3.
Some embodiments of the present invention pertain to compounds wherein Ar is phenyl
optionally substituted with R9., Rw, R11, R12, and R13.
Some embodiments of the present invention pertain to compounds wherein Ar is selected
from the group consisting of pyridinyl, 4,5,6,7-tetrahydro-2H-indazolyl, quinolinyl, benzothiazolyl,
thienyl, lH-pyrazolo[3,4-b]pyridinyl, thiazolyl, 5-oxo-4,5-dihydro-lH-pyrazolyl, isoxazolyl, and
[l,3,4]thiadiazolyl, or an N-oxide thereof.
Some embodiments of the present invention pertain to compounds wherein Ar is selected
from the group consisting of pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, 4,5,6,7-tetrahydro-2H-
indazol-3-yl, quinolin-6-yl, benzothiazol-6-yl, thien-2-yl, thien-3-yl, lH-pyrazolo[3,4-b]pyridin-3-yl,
thiazol-2-yl, 5-oxo-4,5-dihydro-lH-pyrazol-3-yl, isoxazol-4-yl, and [l,3,4]thiadiazol-2-yL or anN-
oxide thereof.
Some embodiments of the present invention can be represented by Formula (Illk) as
illustrated below:

wherein each variable in Formula (Illk) has the same meaning as described, herein, supra and infra.
Some embodiments of the present invention can be represented by Formula (Him) as
illustrated below:

wherein each variable in Formula (Him) has the same meaning as described herein, supra and infra.
Some embodiments of the present invention can be represented by Formula (IIIo) as
illustrated below:


wherein each variable in Formula (IIIo) has the same meaning as described herein, supra and infra.
Some embodiments of the present invention pertain to compounds wherein R9 is C^ acyl, Cj.
6 acylsulfonamide, CU6 alkoxy, C1-6 alkyl, C1-6 alkylamino, C1-6 alkylcarboxamide, C2.6 alkynyl, C1-6
alkylsulfonamide, C1-6 alkylsulfinyl, C\.6 alkylsulfonyl, C1-6 alkylthio, amino, aryl, arylsulfonyl, di-C].
6-alkylamino, carbamimidoyl, Ci_6 alkoxycarbonyl, carboxamide, carboxy, cyano, C3.6 cycloalkoxy,
C3.6 cycloalkyl, di-C1-6-alkylsulfonamide, guanidine, C1-6 haloalkoxy, C1-6 haloalkyl, halogen, Ci_6
haloalkylsulfonyl, heteroaryl, heteroarylcarbonyl, heteroarylsulfonyl, heterocyclic,
heterocyclicsulfonyl, hydroxyl, sulfonamide, and thiol; wherein Q.6 alkoxy, C1-6 alkyl, Q.6
alkylamino, amino, aryl, carbamimidoyl, heterocyclic, are optionally substituted with 1, 2, 3 or 4
substituents selected independently from the group consisting of C1-6 alkoxy, C1-6 alkyl, C2.6 alkynyl,
Ci_6 alkylsulfonamide, C1-6 alkylsulfonyl, amino, aryl, C3.6 cycloalkyl, di-C1-6-alkylamino, halogen,
heteroaryl, heterocyclic, and hydroxyl.
Some embodiments of the present invention pertain to compounds wherein R9 is C1-6 alkyl
optionally substituted with C1-6 acylsulfonamide. In some embodiments, R9 is:
acetylsulfamoyl-methyl [i.e. -CH2S(=O)2NHC(==0)CH3],
propionylsulfamoyl-methyl [i.e. -CH2S(=O)2NHC(=O)CH2CH3],
2-acetylsulfamoyl-ethyl [i.e. -CH2CH2S(=O)2NHC(=O)CH3], or
2-propionylsulfamoyl-ethyl [i.e. -CH2CH2S(=O)2NHC(=O)CH2CH3].
Some embodiments of the present invention pertain to compounds wherein Rio, Rn, R]2, and
R13 are independently selected from the group consisting of C1-6 alkoxy, CU6 alkyl, C1-6 alkylamino,
carboxy, cyano, halogen, C1-6 haloalkoxy, C1-6 haloalkylsulfonyl, and hydroxyl; or two adjacent R!0,
Rn, Rn, and R]3 groups together with the atoms to which they are bonded form a 5 or 6 member
cycloalkyl or 5 or 6 member heterocyclic group wherein said 5 or 6 member group is optionally
substituted with halogen or oxo.
Some embodiments of the present invention pertain to compounds wherein R9 is C1-6 acyl, C],
6 acylsulfonamide, C1-6 alkoxy, CU6 alkyl, C1-6 alkylamino, Ci_6 alkylcarboxamide, C1-6
alkylsulfonamide, C\.6 alkylsulfinyl, C1-6 alkylsulfonyl, Q.6 alkylthio, amino, di-C1-6-alkyIamino,
carbamimidoyl, C1-6 alkoxycarbonyl, carboxy, cyano, C3.6 cycloalkoxy, di-C1-6-alkylsulfonamide,
guanidine, halogen, C1-6 haloalkylsulfonyl, heteroaryl, heteroarylcarbonyl, heterocyclicsulfonyl,
hydroxyl, sulfonamide, and thiol; wherein C1-6 alkoxy, C1-6 alkyl, C1-6 alkylamino, amino, and

carbamimidoyl, are optionally substituted with 1, 2, 3 or 4 substituents selected independently from
the group consisting of C1-6 alkoxy, Ci_6 alkyl, Q.6 alkynyl, Q.6 alkylsulfonyl, amino, aryl, Q.6
cycloalkyl, heteroaryl, heterocyclic, and hydroxyl.
Some embodiments of the present invention pertain to compounds wherein R9 is Q.6 acyl, Q.
6 acylsulfonamide, Q.6 alkoxy, Q_6 alkyl, Q.6 alkylamino, Q.6 alkylcarboxamide, C1-6
alkylsulfonamide, C1-6 alkylsulfonyl, Q.6 alkylthio, amino, carbamimidoyl, Q.6 alkoxycarbonyl,
carboxy, cyano, di-Q.6-alkylsulfonamide, halogen, Q.6 haloalkylsulfonyl, heteroaryl,
heteroarylcarbonyl, heterocyclicsulfonyl, hydroxyl, and sulfonamide;wherein Q.6 alkyl, Q.6
alkylamino, and carbamimidoyl, are optionally substituted with 1, 2, 3 or 4 substituents selected
independently from the group consisting of C1-6 alkyl, Q.6 alkylsulfonyl, amino, heteroaryl,
heterocyclic, and hydroxyl.
Some embodiments of the present invention pertain to compounds wherein R9 is selected
from the group consisting of methanesulfonyl (CH3S02-), 2-methanesulfonyl-ethyl (CH3S02CH2CH2-
), acetylsulfamoyl [MeC(=O)NHS(=O)2-], propionylsulfamoyl [EtC(=O)NHS(=O)2-], ethylsulfanyl
(CH3CH2S-), isopropylsulfanyl [(CH3)2CHS-], ethylsulfamoyl (CH3CH2NHSOr), methylsulfamoyl
(CH3NHS02-), dimethylsulfamoyl [(CH3)2NS02-], rnethylsulfamoylmethyl [CH3NHS02CH2-],
sulfamoyl (H2NS02-), [l,2,4]triazol-1-yl, [l,2,4]triazol-1-ylmethyl, 2-[l,2,4]triazol-1-yl-ethyl,
methoxy (CH3O-), 2-oxo-oxazoIidin-4-ylmethyl, l,l-dioxo-lX6-thiomorpholin-4-ylmethyl, pyrazol-1-
yl, trifluoromethanesulfonyl (CF3S02-), morpholine-4-sulfonyl, pyridine-2-carbonyl, F, Cl, cyano, Br,
carboxy, butyryl [CH3CH2CH2C(=0>], propoxycarbonyl [CH3CH2CH2OC(=O)-], hydroxy,
propylcarbamoyl [CH3CH2NHC(=O)-], 7/-hydroxycarbamimidoyl [NH2C(=NOH)-], carbamimidoyl
[NH2C(=NH)-],-7V-ethylcarbamimidoyl [CH3CH2NHC(=NH)-], and 2-amino-ethylamino
[NH2CH2CH2NH-].
Some embodiments of the present invention pertain to compounds wherein R]0, Rn, Rn, and
R]3 are independently selected from the group consisting of Q.6 alkoxy, Q_6 alkyl, carboxy, and
halogen; or two adjacent R]0, Rn, Rn, and R13 groups together with the atoms to which they are
bonded form a 5 member heterocyclic group and is optionally substituted with halogen.
Some embodiments of the present invention pertain to compounds wherein R10, Rn, Rn, and
R]3 are independently selected from the group consisting of F, methoxy (CH3O-), methyl, ethyl, and
carboxy.
Some embocRrnents of the present invention pertain to compounds wherein R9 is selected
from the group consisting of Q.6 acylsulfonamide, C1-6 alkoxy, Q.6 alkyl, C1-6 alkylamino, C«
alkylcarboxamide, C2.6 alkynyl, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, Q.6 alkylthio, amino, di-Q.6-
alkylamino, carbamimidoyl, cyano, Q.6 cycloalkoxy, guanidine, Q_6 haloalkoxy, and halogen;
wherein Q.6 alkoxy, Q.6 alkyl, Q.6 alkylamino, and amino, are optionally substituted with 1, 2, 3 or 4
substituents selected independently from the group consisting of Q.6 alkoxy, Q.6 alkyl, C2.6 alkynyl,
Q.6 alkylsulfonyl, aryl, C3.6 cycloalkyl, di-Q.6-alkylamino, heteroaryl, and heterocyclic.

Some embodiments of the present invention pertain to compounds wherein R9 is selected
from the group consisting of C1-6 acylsulfonamide, C1-6 alkoxy, C1-6 alkyl, C1-6 alkylamino, C1-6
Jkylcarboxamide, C1-6 alkynyl, C1-6 alkylsulfonyl, C1-6 alkylthio, di-C1-6-aIkylamino, cyano, C1-6
haloalkoxy, and halogen; wherein C1-6 alkoxy, C1-6 alkylamino, and amino, are optionally substituted
with 1,2, 3 or 4 substituents selected independently from the group consisting of C1-6 alkoxy, d.6
alkyl, di-d.6-alkylamino, and heterocyclic.
Some embodiments of the present invention pertain to compounds wherein R9 is selected
from the group consisting of methanesulfonyl (CH3S02-), cyano, F, Gl, Br, I, methyl, methoxy
(CH3O-), ethylamino (CH3CH2NH-), ethylsulfanyl (CH3CH2S-), isopropylsulfanyl [(CH3)2CHS-],
hydroxy, isopropoxy [(CH3)2CHO-], propoxy (CH3CH2CH20-), dimethylamino [(CH3)2N-],
propylamine (CH3CH2CH2NH-), isopropylamino [(CH3)2CHNH-], acetylamino [CH3C(=O)NH-],
piperidin-1-yl, trifluoromethoxy (CF30-), oxazol-5-yl, ethynyl (Hd=d), 3-methyl-butylamino
[(CH3)2CHCH2CH2NH-], 2-morpholin-4-yl-ethylamino, acetylsulfamoyl [MeC(=O)NHS(=O)2-],
propionylsulfamoyl [EtC(=O)NHS(=O)2-], tetrahydro-furan-2-ylmethoxy, morpholin-4-yl, 4-methyl-
piperazin-1-yl, butylamino, 2-pyrrolidin-1-yl-ethoxy, 2-dimethylamino-ethoxy, 2-morpholin-4-yl-
ethoxy, morpholin-4-ylamino, 2-methoxy-ethylamino, and tetrahydro-furan-2-ylmethyl-amino.
Some embodiments of the present invention pertain to compounds wherein R]0, Rn, Rn, and
R]3are independently selected from the group consisting of C1-6 alkoxy, C1-6 alkyl, cyano, halogen, d-
6 haloalkoxy, and hydroxyl; or two adjacent Rio, Rn, R]2, and R]3 groups together with the atoms to
which they are bonded form a 5 or 6 member cycloalkyl or 5 or 6 member heterocyclic group wherein
said 5 or 6 member group is optionally substituted with oxo.
Some embodiments of the present invention pertain to compounds wherein Rj0, Rn, R12, and
R]3are independently selected from the group consisting of F, CI, Br, I, hydroxyl, methoxy (CH3O-),
cyano, methyl, and trifluoromethoxy.
Some embodiments of the present invention pertain to compounds wherein R9 is selected
from the group consisting of C1-6 acyl, C1-6 acylsulfonamide, d.6 alkoxy, C1-6 alkyl, C1-6 alkylamino,
d.6 alkylcarboxamide, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, d.6 alkylthio, amino, di-d.6-alkylamino,
carbamimidoyl, carboxy, cyano, C1-6 cycloalkoxy, guanidine, C1-6 haloalkyl, and halogen; wherein d-
6 alkoxy, C1-6 alkyl, d.6 alkylamino, and amino are optionally substituted with 1, 2, 3 or 4 substituents
selected independently from the group consisting of C1-6 alkoxy, C1-6 alkyl, C1-6 alkynyl, C1-6
alkylsulfonyl, aryl, C^.e cycloalkyl, heteroaryl, and heterocyclic.
Some embodiments of the present invention pertain to compounds wherein R9 is selected
from the group consisting of d.6 acYh d.6 acylsulfonamide, C1-6 alkoxy, d.6 alkyl, d.6
alkylcarboxamide, d.6 alkylsulfonyl, carboxy, C1-6 haloalkyl, and halogen.
Some embodiments of the present invention pertain to compounds wherein R9 is selected
from the group consisting of methanesulfonyl (CH3S02-), methoxy (CH30-), carboxy,

acetylsulfamoyl [MeC(=O)NHS(=O)2-J, propionylsulfamoyl [EtC(=O)NHS(=O)r], acetylamino
[CH3C(=O)NH-], F, Cl, Br, methyl, and trifluoromethyl.
Some embodiments of the present invention pertain to compounds wherein R10, Rn, R12, and
R!3are independently selected from the group consisting of C1-6 alkoxy, C1-6 alkyl, and halogen.
Some embodiments of the present invention pertain to compounds wherein R]0, Rn, R12, and
Ri3are independently selected from the group consisting of methoxy (CH30-), methyl, F, Cl, and Br.
Some embodiments of the present invention pertain to compounds wherein R9 is selected
from the group consisting of Ci_6 acylsulfonamide, C1-6 alkoxy, Q.6 alkyl, Ci_6 alkylamino, C1-6
alkylcarboxamide, C1-6 alkylsulfmyl, Cue alkylsulfonyl, Q.6 alkylthio, amino, aryl, arylsulfonyl, di-
Ci_6-alkylamino, carbamimidoyl, carboxamide, cyano, C3.6 cycloalkoxy, guanidine, C]_6 haloalkyl,
halogen, heteroaryl, and heterocyclic; wherein C1-6 alkoxy, C1-6 alkyl, C1-6 alkylamino, amino, and
aryl, are optionally substituted with 1,2, 3 or 4 substituents selected independently from the group
consisting of C,.6 alkoxy, C,.6 alkyl, C2-6 alkynyl, C,.6 alkylsulfonyl, aryl, C3.6 cycloalkyl, halogen,
heteroaryl, and heterocyclic. »
Some embodiments of the present invention pertain to compounds wherein R9 is selected
from the group consisting of C1-6 acylsulfonamide, C1-6 alkoxy, C1-6 alkyl, C« alkylamino, Ch6
alkylcarboxamide, C1-6 alkylthio, aryl, arylsulfonyl, carboxamide, cyano, C3.6 cycloalkoxy, Cj^
haloalkyl, halogen, heteroaryl, and heterocyclic; wherein aryl, is optionally substituted with 1,2, 3 or
4 substituents selected independently from the group consisting of C^ alkyl, and halogen.
Some embodiments of the present invention pertain to compounds wherein Rg is selected
from the group consisting of cyano, F, Cl, Br, acetylamino [CH3C(=O)NH-], methoxy (CH3O-),
methyl, propoxy (CH3CH2CH20-), propylamino (CH3CH2CH2NH-), isopropylamino [(CH3)2CHNH-],
phenyl, f-butyl, 4-methylphenyl, ethyl, methylsulfanyl (CH3S-), morpholin-4-yl, benzenesulfonyl,
trifluoromethyl (CF3-), cyclopropyl, carbamoyl [H2NC(O)-], 3,4-difluorophenyl, 4-chlorophenyl, 1-
methyI-pyrrolidin-2-yl, acetylsulfamoyl [MeC(=O)NHS(=O)2-], propionylsulfamoyl
[EtC(=O)NHS(=O)2-], and pyridine-2-yl.
Some embodiments of the present invention pertain to compounds wherein Rio, Rn, Rn, and
RJ3are independently selected from the group consisting of C1-6 alkoxy, C\.6 alkyl, and halogen.
Some embodiments of the present invention pertain to compounds wherein R)0, Rn, R12, and
Ri3are independently methyl, F or Cl.
Some embodiments of the present invention pertain to compounds wherein Ar is phenyl and
two adjacent R]0, Rn, Ri2, and R!3 groups together with the carbons they are bonded form a 5, 6 or 7
member cycloalkyl, 5, 6 or 7 member cycloalkenyl, or 5, 6 or 7 member heterocyclic group wherein
the 5, 6 or 7 member group is optionally substituted with halogen or oxo.
In some embodiments, Ar is phenyl and together with two adjacent RI0 and Rn groups form a
5, 6 or 7 member cycloalkyl as represented in TABLE 5:


wherein "a" is 1, 2 or 3 to give a 5, 6 or 7 member cycloalkyl that is 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 carbons (i.e., the non aromatic ring carbons) in TABLE
5 are replaced by 1, 2 or 3 heteroatoms selected from, but not limited to, O, S, and N, wherein N is
substituted with H or C1-6 alkyl, thus forming a 5, 6 or 7 member heterocyclic group.
In some embodiments, the two adjacent groups form a 5 member heterocyclic group with the
phenyl group.
In some embodiments, the 5 member heterocyclic group with the phenyl group together is a
2,3-dihydro-benzofuran-5-yl or benzo[l,3]dioxol-5-yl group.
In some embodiments, the two adjacent groups form a 6 member heterocyclic group with the
phenyl group. In some embodiments, the 6 member heterocyclic group with the phenyl group
together is a2,3-dihydro-benzo[l,4]dioxin-6-yl or 2,3-dihydro-benzo[l,4]dioxin-2-yl group.
In some embodiments, the two adjacent groups form a 7 member heterocyclic group with the
phenyl group. In some embodiments, the 7 member heterocyclic group with the phenyl group
together is a3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-yl group.
Some embodiments of the present invention include compounds illustrated in TABLES A and
B shown below.











































Some embodiments of the present invention pertain to compounds wherein R8 is selected
from the group consisting of H, CM; alkyl, and halogen.
Some embodiments of the present invention pertain to compounds wherein Rg is H.
In some embodiments, X is CH.
In some embodiments, Y is CH.
In some embodiments, Z is CH.
Some embodiments of the present invention pertain to compounds wherein W and Y are both
CH, and X and Z are both N.
In some embodiments, W and Y are both CH, and X and Z are both N; and can be represented
by Formula (Hie) as illustrated below:

wherein each variable in Formula (Hie) has the same meaning as described herein, supra and infra.
Some embodiments of the present invention pertain to compounds wherein E is N.
Some embodiments of the present invention pertain to compounds wherein E is C (i.e., a
carbon atom).
Some embodiments of the present invention pertain to compounds wherein E is CR3.
Some embodiments of the present invention pertain to compounds wherein E is CH.
Some embodiments of the present invention pertain to compounds wherein D is CRiR2.
Some embodiments of the present invention pertain to compounds wherein D is NR2.
Some embodiments of the present invention pertain to compounds wherein E is N and D is
CRiR2. In some embodiments, Rj is H.
Some embodiments of the present invention can be represented by Formula (Illg) as
illustrated below:

wherein each variable in Formula (Illg) has the same meaning as described herein, supra and infra.
Some embodiments of the present invention pertain to compounds wherein E is CR3 and D is
NR2.






















































Additionally, compounds of Formula (I), such as those illustrated in Tables A and B,
encompass all pharmaceutical^ acceptable salts, solvates, particularly hydrates, thereof.
In some embodiments, a compound of the present invention is 4-[6-(2-fluoro-4-
methanesulfonyl-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester.
In some embodiments, a compound of the present invention is not 4-[6-(2-fluoro-4-
methanesulfonyl-phenoxy)-pyrirnidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester.
General Synthetic Methods
The de novo biosynthesis of pyrimidine nucleotides provides essential precursors for multiple
growth-related events in higher eukaryotes. Assembled from ATP, bicarbonate and glutamine, the
uracil and cytosine nucleotides are fuel for the synthesis of KNA, DNA, phospholipids, UDP sugars
and glycogen. Over_the past 2 decades considerable progress has been made in elucidating the
mechanisms by which cellular pyrimidines are modulated to meet the needs of the cell. These studies
point to increasing evidence for cooperation between key cell signaling pathways and basic elements
of cellular metabolism, and suggest that these events have the potential to determine distinct cellular
fates, including growth, differentiation and death.
As a result of their profound biological significance in higher eukaryotes and utilization of the
pyrimidine core in a number of marketed drugs (Scheme 1) and other medicinally relevant

compounds, pyrimidines and pyridines play pivotal roles as chemotypes in drug discovery campaigns.
As a direct consequence of this there is a wealth of scientific literature describing synthetic
construction, as well as chemical modification and elaboration of these classes of heterocyles.

The novel substituted pyrimidines and pyridines of the current invention can prepared
according to a variety of synthetic manipulations, all of which would be familiar to one skilled in the
art of synthetic organic chemistry. Certain methods for the preparation of compounds of the present
invention include, but are not limited to, those described in Schemes 2-10 set forth in this section of
the specification.
Common dichloro-substituted intermediate 8, used as a starting point for the synthesis of
compounds of the present invention can be prepared as depicted in Scheme 2. This is accomplished
in two steps from a di-C^-alkylmalonate, one particularly useful di-C1-6-alkylmalonate is diethyl
malonate 5. Cyclization to the 4,6-dihydroxypyrimidine 7 is achieved by reacting 5 with
formamidine in the presence of an alkali metal alkoxide, by mixing the malonate and all or part of the
formamidine with the alkoxide or with the alkoxide and the rest of the formamide. Alternative
reagents such as dimethylmalonate, sodium methoxide, formamide, in low molecular weight alcoholic
solvents, including methanol, ethanol, 2-propanol and the like, may be utilized in the synthesis by
heating at a temperature range between about 80 to about 100°C for about 30 mins to about 90 mins
followed by a mineral acid work up. Preparation of dihydroxypyrimidines can also be achieved using
microorganisms such as Rhodococcus (see for reference WO97008152 Al).
Chlorination of the 4 and 6 ring positions to produce intermediate 8 maybe carried out by
reacting 7 with a chlorinating reagent, such as, phosgene, POCl3 (for reference see A. Gomtsyan et al.,
J. Med. Chem. 2002, 45, 3639-3648), thionyl chloride, oxalyl chloride and by mixtures of the above
reagents including PC13 / POCl3 at elevated reaction temperatures.


Conventional thermal aromatic substitution reactions of amines and alcohols with halogenated
pyrimidines have been well documented (see for example A. G. Arvanitis et al., J. Medicinal
Chemistry, 1999, 42, 805-818 and references therein). Nucleophilic aromatic (SNAr) substitution
reactions of electron deficient halogenated pyrimidines are usually rapid and high yielding. However,
in certain cases, such as electron rich or neutral halogenated heterocycles, successful substitution is
afforded by prolonged heating. To facilitate rapid entry into many of the compounds of the invention
microwave synthesis was utilized (Schemes 3 and 4). The Smith synthesizer from Personal
Chemistry is a commercially available focussed field heating instrument that provides safer and more
uniform conditions for performing the base catalysed substitution reactions depicted in Schemes 3a,
3b and 3c. Bases employed for such conversions (whereby Q2 = N) include tertiary amines such as
triethylamine, Hunig's base (i.e. diisopropyl-ethylamine), N-methylmorpholine and the like.
Alternatively, one skilled in the art can employ alkali metal hydrides, alkali metal carbonates (such as,
Li2CC>3, Na2C03, K2C03 and the like), an alkali metal hydrogencarbonate (such as, LiHC03,
NaHC03, KHC03 and the like). Wherein Q2 = N, inert lower alkyl alcoholic solvent can be emplyed
(such as, MeOH, EtOH, i-PrOH, n-BuOH and the like) or wherein Q2 = O, an ethereal solvent such as
tetrahydrofuran, 1,4-dioxane, and the like can be used. Reaction times to access typical intermediates
such as, 9,10, and 11, can range from about 300 s to about 3000 s and when conventional thermal
methods are employed (wherein Q2 = O) about 20 mins to about 120 mins.


Methods for conversion of intermediate monosubstituted pyrimidines and pyridines 9,10 and
11 are illustrated in Scheme 4. Examples wherein Ch = N (Schemes 4a, 4b, 4c) were obtained using
palladium catalysed aminations. This synthetic strategy has emerged as a powerful tool for synthesis
of substituted aryl and heteroaryl anilines- in recent times (for reference see S.-L. Buchwald., Top.
CUIT. Chem., 2002, 219, 131 and references therein). Reaction of a suitably substituted amine (such
as, Intermediate 16) in the presence of a palladium or alternative transition metal catalyst selected
from but not limited to Pd2(dba)3, Pd(OAc)2, Cul, Cu(OTf)2, Ni(COD)2, Ni(acac)2 in a suitable
anhydrous solvent (such as, THF, 1,4-dioxane, and the like) with as strong alkali metal alkoxide base
(such as, NaO'Bu, KO'Bu and the like). A suitable ligand employed in this step can be selected from
BINAP, P(o-tolyl)3, tBu3P, DPPF, P[NCBu)CH2CH3]3N and the like when the catalyst is a palladium
derived complex.
Alternatively, for "Ullman-type" aryl aminations catalysed by copper derived complexes the
base employed mayEe selected from an alkali metal carbonate in an aprotic polar solvent (such as
N,7V-dimethylacetamide, DMF, DMSO, and the like) with L-proline, N-methylglycine or
diethylsalicyclamide as the ligand (for reference see D. Ma, Organic Lett., 2003, 5, 14, 2453 - 2455).


Compounds of general formula 12 to 15 may also be obtained by reversing the order of the
reaction steps (i.e. introduction of Q] followed by Q2), wherein the initial step comprises of
introduction of either Intermediate 16 or 17 by using base in 'PrOH followed by addition of 4N HC1 in
dioxane.
As illustrated in Scheme 5, a similar transition metal catalysed couplings were utilized to
obtain molecules of general formula 21a and 21b (Scheme 5a) wherein the "Ar" substituent (Hal =
Br, I) of intermediate 20 is modified to give analogs with alkyl amino substituents (i.e., NRaRb,
wherein Ra and Rt, are each independently H, C1-6 alkyl or a substituted Cj_6 alkyl, or Ra and Rb
together with the nitrogen form a heterocyclic ring, as described herein). Alternatively, the linker
atom can be oxygen by utilizing the Cul catalysed method for aromatic C-0 formation described by
Buchwald (see for reference S. L. Buchwald; Organic Lett., 2002, 4, 6, 973-976) by utilizing, for
example, 10 mol% Cul, 20 mol% 1,10-phenanthroline, 2 equivalents of Cs2C03, at 110 °C for 18 h
(Scheme 5b), with an "Ar" iodo substitution in the substrate. One particular embodiment is when the
Hal group on "Ar" is substituted at the para position of a phenyl ring.


A particular substitution for compounds 12,13, 14, and 15 is wherein D = NCOORc wherein
R prepared directly from intermediates depicted in Schemes 3 and 4 when D = NH. In certain reactions,
use of a suitable nitrogen protecting group (such as, 'Boc, Cbz, Moz, Alloc, Fmoc and the like) may
be necessary during further chemical modification of the core. Deprotection maybe achieved using
standard reagents familiar to one skilled in the art (these might include TFA, mineral acid, Palladium /
hydrogen gas and the like in an alcoholic or ethereal solvent system chosen from methanol, ethanol,
tert-butanol, THF, 1,4-dioxane, and the like). On occasion wherein the target molecule contains 2
protecting groups, an orthogonal protection strategy may be adopted. The deprotected secondary
amine (D = NH) can subsequently be modified accordingly.
Schemes 6 and 7 illustrate such chemistries wherein generation of a carbamate, urea or amide
can be executed using an appropriate reaction in the presence of a base, for example, a tertiary amine
base such as TEA, DIEA and the like, in an inert solvent system.
As illustrated in Scheme 6, urethane 19 can be obtained by a urethane reaction using RcOCO-
halide (wherein Ra is as described supra, and halide is chloro, bromo, or iodo, particularly useful is
chloro) in an inert solvent with or without a base. Suitable bases include an alkali metal carbonate
(such as, sodium carbonate, potassium carbonate, and the like), an alkali metal hydrogencarbonate
(such as, sodium hydrogencarbonate, potassium hydrogencarbonate, and the like), an alkali hydroxide
(such as, sodium hydroxide, potassium hydroxide, and the like), a tertiary amine (such as, N,N-
diisopropylethylamine, triethylamine, A^-methylmorpholine, and the like), or an aromatic amine (such
as, pyridine, imidazole, poly-(4-vinylpyridine), and the like). The inert solvent includes lower
halocarbon solvents (such as, dichloromethane, dichloroethane, chloroform, and the like), ethereal
solvents (such as, tetrahydrofuran, dioxane, and the like), aromatic solvents (such as, benzene,

toluene, and the like), or polar solvents (such as, AyV-dimethylformamide, dimethyl sulfoxide, and the
like). Reaction temperature ranges from about -20°C to 120°C, preferably about 0°C to 100°C.

As shown in Scheme 7a, the amine intermediate obtained from acidic deprotection of 22 can
be functionalized to amides represented by species 23. Carbamate 22 is first reacted with 4N HC1 in
dioxane or alternatively TFA in dichloromethane and further reacted with a carboxylic acid (RdCC^H,
wherein as used in Scheme 7a, R^ is Ar, or a C1-6-alkylene-Ar; Ar can be substituted or unsubstituted
and has the same meaning as described herein) with a dehydrating condensing agent in an inert
solvent with or without a base to provide the amide 23 of the present invention. The dehydrating
condensing agent includes dicyclohexylcarbodiimide (DCC), 1,3-diisopropylcarbodiimide (DIC), 1-
ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDOHC1), bromo-tris-pyrrolidino-
phosphonium hexafluorophosphate (PyBroP), benzotriazoloyloxytris(dimethylamino)-phosphonium
hexafluorophosphate (BOP), 0-(7-azabenzo triazol-1-yl)-l,l,3,3-tetramethyluronium
hexafluorophosphate (HATU), or l-cyclohexyl-3-methylpolystyrene-carbodiimide. The base includes
a tertiary amine (such as, AW-diisopropylethylamine, triethylamine, and the like). The inert solvent
includes lower halocarbon solvents (such as, dichloromethane, dichloroethane, chloroform, and the
like), ethereal solvents (such as, tetrahydrofuran, dioxane, and the like), nitrile solvents (such as,
acetonitrile, and the like), amide solvents (A^V-dimethylformarnide, Af,iV-dimethylacetamide, and the
like) and mixtures thereof. Optionally, 1-hydroxybenzotriazole (HOBT), HOBT-6-
carboxaamidomethyl polystyrene, or l-hydroxy-7-azabenzotriazole (HOAT) can be used as a reactant
agent. Reaction temperature ranges from about -20 °C to 50 °C, preferably about 0 °C to 40 °C.


Alternatively, amides 23 of the present invention can be obtained by an amidation reaction
using an acid halide (such as, R^COCl) and a base in an inert solvent (Scheme 7a). The base includes
an alkali metal carbonate (such as, sodium carbonate, potassium carbonate, and the like), an alkali
metal hydrogencarbonate (such as, sodium hydrogencarbonate, potassium hydrogencarbonate, and the
like), an alkali hydroxide (such as, sodium hydroxide or potassium hydroxide, and like), a tertiary
amine (such as, TV^V-diisopropylethylamine, triethylamine, JV-methylmorpholine, and the like), or an
aromatic amine (such as, pyridine, imidazole, poly-(4-vinylpyridine), and the like). The inert solvent
includes lower halocarbon solvents (such as, dichloromethane, dichloroethane, chloroform, and the
like), ethereal solvents (such as, tetrahydrofuran, dioxane, and the like), amide solvents (such as, Nfl-
dimerhylacetamide, AfyV-dimethylformamide, and the like), aromatic solvents (benzene, toluene,
pyridine, and the like) and mixtures thereof. Reaction temperature ranges from about -20 °C to 50 °C,
preferably about 0 °C to 40 °C.
Also illustrated in Scheme 7, amide 23 can be reacted with a reducing agent in an inert
solvent to provide the amine 24 of the present invention. The reducing agent includes alkali metal
aluminum hydrides (such as, lithium aluminum hydride, and the like), alkali metal borohydrides (such
as, lithium borohydride, and the like), alkali metal trialkoxyaluminum hydrides (such as, lithium tri-
fert-butoxyaluminum hydride, and the like), dialkylaluminum hydrides (such as, di-isobutylaluminum
hydride, and the like), borane, dialkylboranes (such as, di-isoamyl borane, and the like), alkali metal
trialkylboron hydrides (such as, lithium triethylboron hydride, and the like). The inert solvent
includes ethereal solvents (such as, tetrahydrofuran, dioxane, and the like), aromatic solvents (such as,
toluene, and the like) and mixtures thereof. Reaction temperature ranges from about -78 °C to 200 °C,

si-ph as, about 50 °C to 120 °C.
Alternatively, the amine 24 of the present invention can be obtained by a reductive amination
reaction using the acid deprotected secondary amine intermediate with an aldehyde (RgCHO) and a
reducing agent in an inert solvent with or without an acid. The reducing agent includes sodium
triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, borane-pyridine complex, and
the like. The inert solvent includes lower alkyl alcohol solvents (such as, methanol, ethanol, and the
like), lower halocarbon solvents (such as, dichloromethane, dichloroethane, chloroform, and the like),
ethereal solvents (such as, tetrahydrofuran, dioxane, and the like), aromatic solvents (such as,
benzene, toluene, and the like) and mixtures thereof. The acid includes an inorganic acid (such as,
hydrochloric acid, sulfuric acid, and the like) or an organic acid (such as, acetic acid, and the like).
Reaction temperature ranges from about -20 °C to 120 °C, preferably about 0 °C to 100 °C. In
addition, this reaction can optionally be carried out under microwave conditions.
In an alternative manner, the intermediate amine product of acid deprotection of 22 can be
alkylated directly with an alkylating agent, such as Re-halide (wherein R6 is substituted or
unsubstituted Q.6 alkyl, or substituted or unsubstituted C1-6 alkyl-Ar, and halide is chloro, bromo and
iodo), in the presence of a base and in an inert solvent to provide amine 24. The base includes an
alkali metal carbonate (such as, sodium carbonate, potassium carbonate, and the like), an alkali metal
hydride (such as, sodium hydride, potassium hydride, and the like), alkali metal alkoxide (such as,
potassium tert-butoxide, sodium te/Y-butoxide, and the like); alkyl lithiums (such as, tert-butyl
lithium, n-butyl lithium and the like). The inert solvents include, ethereal solvents (such as,
tetrahydrofuran, dioxane), aromatic solvents (such as, benzene, toluene, and the like), amide solvents
(such as, A^V'-dimethylforrnamide, andthe like) and mixtures thereof. Reaction temperature ranges
from about -20 °C to 120 °C, preferably about 0 °C to 100 °C.
Also shown in Scheme 7 is the preparation of additional compounds of the invention via
alkylating the nitrogen of ureas represented by 23 with an alkyl-halide (wherein halide is chloro,
bromo and iodo) in the presence of a base in an inert solvent to provide di-substituted urea. The base
includes an alkali metal hydride (such as, sodium hydride, potassium hydride, and the like), alkali
metal alkoxide (such as, potassium tert-butoxide, sodium ter^-butoxide, and the like); alkyl lithiums
(such as, tart-butyl lithium, 72-butyl lithium and the like). The inert solvents include, ethereal solvents
(such as, tetrahydrofuran, dioxane), aromatic solvents (such as, benzene, toluene, and the like), amide
solvents (such as, A^-dimethylformamide, and the like) and mixtures thereof. Reaction temperature
ranges from about -20 °C to 120 °C, preferably about 0 °C to 100 °C.
In addition, as illustrated in Scheme 8a, urea 25a can be obtained from deprotecting common
intermediate 18 and allowing the amine (i.e., D = NH) to react with a variety isocyanates (RaNCO,
wherein Ra has the same meaning as described herein) in an inert solvent with or without a base.
Suitable bases include an alkali metal carbonate (such as, sodium carbonate, potassium carbonate, and
the like), an alkali metal hydrogencarbonate (such as, sodium hydrogencarbonate, potassium

hydrogencarbonate, and the like), an alkali hydroxide (such as, sodium hydroxide, potassium
hydroxide, and the like), a tertiary amine (such as, 7V,JV-diisopropylethylarnine, triethylamine, N-
methylmorpholine, and the like), or an aromatic amine (such as, pyridine, imidazole, and the like).
The inert solvent includes lower halocarbon solvents (such as, dichloromethane, dichloroethane,
chloroform, and the like), ethereal solvents (such as, tetrahydrofuran, dioxane, and the like), aromatic
solvents (such as, benzene, toluene, and the like), or polar solvents (such as, iV^-dimethylformamide,
dimethyl sulfoxide, and the like). Reaction temperature ranges from about -20 °C to 120 °C,
preferably about 0 °C to 100 °C.

Further, as illustrated in Scheme 8b, thiourea 25b can be obtained from deprotecting common
intermediate 18 and allowing the amine (i.e., D = NH) to react with a variety thioisocyanates (RaNCS,
wherein Ra has the same meaning as described herein) in an inert solvent with or without a base.
Suitable bases include an alkali metal carbonate (such as, sodium carbonate, potassium carbonate, and
the like), an alkali metal hydrogencarbonate (such as, sodium hydrogencarbonate, potassium
hydrogencarbonate, and the like), an alkali hydroxide (such as, sodium hydroxide, potassium
hydroxide, and the like), a tertiary amine (such as, N,N-diisopropylethylamine, triethylamine, N-
methylmorpholine, and the like), or an aromatic amine (such as, pyridine, imidazole, and the like).
The inert solvent includes lower halocarbon solvents (such as, dichloromethane, dichloroethane,
chloroform, and the like), ethereal solvents (such as, tetrahydrofuran, dioxane, and the like), aromatic
solvents (such as, benzene, toluene, and the like), or polar solvents (such as, AyV-dimethylformamide,
dimethyl sulfoxide, and the like). Reaction temperature ranges from about -20 °C to 120 °C,
preferably about 0 °C to 100 °C.
Scheme 9 illustrates the synthesis of ara-alkyl sulfones (27) which are used as aryl building

blocjks in Scheme 4 of the present invention, wherein Rio, Rn, R12, and RI3 have the same meaning as
i
described herein. The common methods for preparing these sulfones include the oxidation of sulfides
or the sulfonylation of arenes using aryl sulfonyl halides or aryl sulfonic acids in th presence of a
strong acid catalyst (see for general reference: the Organic Chemistry of Sulfur; Oae S., Ed.; Plenum
Press: New York, 1977). Optimal conversion to the optionally 2,5-disubstituted arene 27 was
achieved thermally wherein Hal is preferably iodo using 5 mol % (CuOTf)2'PhH and 10 mol % N,N'-
dimethylethylenediamine in DMSO by the method of Wang et al (see for reference Wang Z.; Baskin
J. M., Org. Lett., 2002, 4, 25, 4423-4425). In some embodiments, Rio and R]3 are each independently
H, halogen, or C1-6 alkyl; Rn and Kn are both H; Hal = Br, I; and Ql = OH, or NH2.

Alternative standard organic synthetic methods may be used to introduce alternate
substituents in to the Ar component. In one example wherein the linker atom is Qi = N, the
manipulation maybe carried out by protecting the aniline amino functionality using standard FmocCl
and CbzCl protection deprotection steps familiar to one skilled in the art (Scheme 10, wherein R]o,
Rn, Rn, and R!3 have the same meaning as described herein) and subsequently using the deprotected
aniline in subsequent steps such as those depicted in Scheme 4. Nitrile 29, maybe alternatively
transformed in to amidine A84, A90 or- A103 (see Table A) by using hydroxylamine HC1 followed by
reduction using zinc / acetic acid. In some embodiments of the invention Rio is halogen, and Ri3 is H
or halogen.

Synthesis of the 3,5-oxadiazolo variant is depicted in Schemell. Zinc(II)chloride catalysed

coupling of amidoxime 34 with 4-hydroxypiperidine, CNBr derived 36 yielded building block 37
after acidic workup, which was subsequently utilized in reaction sequences depicted as illustrated in
Scheme 3.

Protecting groups may be required for various functionality or functionalities during the
synthesis of some of the compounds of the invention. Accordingly, representative protecting groups
that are suitable for a wide variety of synthetic transformations are disclosed in Greene and Wuts,
Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York, 1999, the
disclosure of which is incorporated herein by reference in its entirety.
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 (I). 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 AND METHODS OF TREATMENT
In addition to the foregoing beneficial uses for compounds of the present invention disclosed
herein, compounds of the invention are useful in the 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 (3-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 risk of inducing hypoglycemia. For these
reasons, there has been intense interest in the development of pharmaceuticals that function in a

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 (3-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 channel, 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, P-cell GPCRs, including RUP3, would also stimulate the release of endogenous insulin
and consequently promote normoglycemia in Type II diabetes.
It is also established that increased cAMP, for example as a result of GLP1 stimulation,
promotes p-cell proliferation, inhibits P-cell death and thus improves islet mass. This positive effect
on P-cell mass is expected to be beneficial in both Type U diabetes, where insufficient insulin is
produced, and Type I diabetes, where P-cells are destroyed by an inappropriate autoimmune response.
Some P-cell GPCRs, including RUP3, are also present in the hypothalamus where they
modulate hunger, satiety, decrease food intake, controlling or decreasing weight and energy
expenditure. Hence, given their function within the hypothalamic circuitry, agonists or inverse
agonists of these receptors mitigate hunger, promote satiety and therefore modulate weight.
It 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, insulin 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 expected that effective treatment of the diabetic
condition will in turn be of benefit to such interconnected disease states.
In some embodiments of the present invention the metabolic-related disorder is
hyperlipidemia, type 1 diabetes, type 2 diabetes mellitus, idiopathic type 1 diabetes (Type lb), latent
autoimmune diabetes in adults (LADA), early-onset type 2 diabetes (EOD), youth-onset atypical
diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes,
gestational diabetes, coronary heart disease, ischemic stroke, restenosis after angioplasty, peripheral
vascular disease, intermittent claudication, myocardial infarction (e.g. necrosis and apoptosis),
dyslipidemia, post-prandial lipemia, conditions of impaired glucose tolerance (IGT), conditions of
impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, obesity, osteoporosis,
hypertension, congestive heart failure, left ventricular hypertrophy, peripheral arterial disease, diabetic
retinopathy, macular degeneration, cataract, diabetic nephropathy, glomerulosclerosis, chronic renal
failure, diabetic neuropathy, metabolic syndrome, syndrome X, premenstrual syndrome, coronary

herfrt disease, angina pectoris, thrombosis, atherosclerosis, myocardial infarction, transient ischemic
attacks, stroke, vascular restenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia,
hypertrygliceridemia, insulin resistance, impaired glucose metabolism, conditions of impaired glucose
tolerance, conditions of impaired fasting plasma glucose, obesity, erectile dysfunction, skin and
connective tissue disorders, foot ulcerations and ulcerative colitis, endothelial dysfunction and
impaired vascular compliance.
One aspect of the present invention pertains to methods for treatment of a metabolic-related
disorder in an individual comprising administering to the individual in need of such treatment a
therapeutically effective amount of a compound as described herein or a pharmaceutical composition
thereof. In some embodiments the metabolic-related disorder is type I diabetes, type II diabetes,
inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia,
hypertriglyceridemia, hypercholesterolemia, dyslipidemia or syndrome X. In some embodiments the
metabolic-related disorder is type II diabetes. In some embodiments the metabolic-related disorder is
hyperglycemia. In some embodiments the metabolic-related disorder is hyperlipidemia. In some
embodiments the metabolic-related disorder is hypertriglyceridemia. In some embodiments the
metabolic-related disorder is type I diabetes. In some embodiments the metabolic-related disorder is
dyslipidemia. In some embodiments the metabolic-related disorder is syndrome X. In some
embodiments the individual is a mammal. In some embodiments the mammal is a human.
One aspect of the present invention pertains to methods of decreasing food intake of an
individual comprising administering to the individual in need thereof a therapeutically effective
amount of a compound of the present invention or pharmaceutical composition thereof. In some
embodiments the individual is a mammal. In some embodiments the mammal is a human.
One aspect of the present invention pertains to methods of inducing satiety in an individual
comprising administering to the individual in need of such treatment a therapeutically effective
amount of a compound of the present invention or pharmaceutical composition thereof. In some
embodiments the individual is a mammal. In some embodiments the mammal is a human.
One aspect of the present invention pertains to methods of controlling or decreasing weight
gain of an individual comprising administering to the individual in need of such treatment a
therapeutically effective amount of a compound of the present invention or pharmaceutical
composition thereof. In some embodiments the individual is a mammal. In some embodiments the
mammal is a humarrr
Some embodiments of the present invention pertain to methods wherein 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 methods of modulating a RTJP3 receptor in an
individual comprising contacting the receptor with a compound according to any one of claims 1 to

127'. In some embodiments, the compound is an agonist. In some embodiments, the compound is an
inverse agonist. In some embodiments, the compound is an antagonist. In some embodiments, the
modulation of the RUP3 receptor is treatment of a metabolic-related disorder and complications
thereof. In some embodiments, the metabolic-related disorder is type I diabetes, type II diabetes,
inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia,
hypertriglyceridemia, hypercholesterolemia, dyslipidemia or syndrome X. In some embodiments, the
metabolic-related disorder is type II diabetes. In some embodiments, the metabolic-related disorder is
hyperglycemia. In some embodiments, the metabolic-related disorder is hyperlipidemia. In some
embodiments, the metabolic-related disorder is hypertriglyceridemia. In some embodiments, the
metabolic-related disorder is type I diabetes. In some embodiments, the metabolic-related disorder is
dyslipidemia. In some embodiments, the metabolic-related disorder is 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 reduces food intake 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. 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.
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 induces-satiety in theindividual. 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. 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.
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. 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 use of a compound as described herein, for
production of a medicament for use in treatment of a metabolic-related disorder. In some
embodiments, the metabolic-related disorder is type II diabetes, inadequate glucose tolerance, insulin

resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia
or syndrome X.
One aspect of the present invention pertains to use of a compound as described herein, for
production of a medicament for use in decreasing food intake of an individual. In some embodiments,
the individual is a mammal. In some embodiments, the mammal is a human. In some embodiments,
the human 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 use of a compound as described herein, for
production of a medicament for use of inducing satiety in an 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. 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 use of a compound as described herein, 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 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, as described herein, for use in a
method of treatment of the human or animal body by therapy.
One aspect of the present invention pertains to a compound, as described herein, for use in a
method of treatment of a metabolic-related disorder of the human or animal body by therapy.
PHARMACEUTICAL COMPOSITIONS AND SALTS
A further aspect of the present invention pertains to pharmaceutical compositions comprising
one or more compotrrrds of Formula (I) or any formula disclosed herein, and one or more
pharmaceutically acceptable carriers. Some embodiments of the present invention pertain to
pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically
acceptable carrier.
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.

Formulations may be prepared by any suitable method, typically by uniformly mixing the
active compound(s) with liquids or finely divided solid carriers, or both, in the required proportions,
and then, if necessary, forming the resulting mixture into a desired shape.
Conventional excipients, such as binding agents, fillers, acceptable wetting agents, tabletting
lubricants, and disintegrants may be used in tablets and capsules for oral administration. Liquid
preparations for oral administration may be in the form of solutions, emulsions, aqueous or oily
suspensions, and syrups. Alternatively, the oral preparations may be in the form of dry powder that
can be reconstituted with water or another suitable liquid vehicle before use. Additional additives
such as suspending or emulsifying agents, non-aqueous vehicles (including edible oils), preservatives,
and flavorings and colorants may be added to the liquid preparations. Parenteral dosage forms may be
prepared by dissolving the compound of the invention in a suitable liquid vehicle and filter sterilizing
the solution before filling and sealing an appropriate vial or ampoule. These are just a few examples
of the many appropriate methods well known in the art for preparing dosage forms.
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 known in the art; for example, see Remington, The Science and
Practice of Pharmacy, 20th Edition, 2000, Lippincott Williams & Wilkins, (Editors: Gennaro, A. R.,
et al.).
While it is possible that, for use in the 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 thereof and/or prophylactic ingredients. The carrier(s) must be
"acceptable" in the sense of being compatible with the other ingredients of the formulation and not
overly deleterious to the recipient thereof.
Pharmaceutical formulations include those suitable for oral, rectal, nasal, topical (including
buccal and sub-lingual), vaginal or parenteral (including intramuscular, sub-cutaneous and
intravenous) administration or in a form suitable for administration by inhalation, insufflation or by a
transdermal patch. Transdermal patches dispense a drug at a controlled rate by presenting the drug for
absorption in an efficient manner with a minimum of degradation of the drug. Typically, transdermal
patches comprise an impermeable backing layer, a single pressure sensitive adhesive and a removable
protective layer with a release liner. One of ordinary skill in the art will understand and appreciate the
techniques appropriate for manufacturing a desired efficacious transdermal patch based upon the
needs of the artisan.

The compounds of the invention, together with a conventional adjuvant, carrier, or diluent,
may thus be placed into the form of pharmaceutical formulations and unit 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 administration, 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.
Compounds of the present invention, including pharmaceutically acceptable salts and solvates
thereof, can be used as active ingredients in pharmaceutical compositions, specifically as RUP3
receptor modulators. By the term "active ingredient" is defined in the context of a "pharmaceutical
composition" and shall mean a component of a pharmaceutical composition that provides the primary
pharmacological effect, as opposed to an "inactive ingredient" which would generally be recognized
as providing no pharmaceutical benefit.
The dose when using the compounds of the present invention 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 present invention. Representative doses of the present invention
include, but not limited to, about 0.001 mg to about 5000 mg, about 0.001 to about 2500 mg, about
0.001 to about 1000 mg, 0.001 to about 500 mg, 0.001 mg to about 250 mg, about 0.001 mg to 100
mg, about 0.001 mg to about 50 mg, and about 0.001 mg to about 25 mg. Multiple doses may be
administered during the day, especially when relatively large amounts are deemed to be needed, for
example 2, 3 or 4, doses. Depending on the individual and as deemed appropriate from the patient's
physician or care-giver it may be necessary to deviate upward or downward from the doses described
herein.

The amount of active ingredient, 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 rodent
diabetes model as described in Example 5, infra (as well as other animal models known in the art,
such as those 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 in the
respective 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, but not limited to, the type, age, weight, sex, diet andmedical
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 (I) 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 therefore 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 pharmaceutical^
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,

flouring 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 melting 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 diluent or
solvent, for example, as a solution in 1,3-butanediol. 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 formulations suitable for oral use can be prepared by dissolving or suspending 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 dispersing 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, shortly before
use, to liquid form preparations for oral administration. Such liquid forms include solutions,
suspensions, and emulsions. 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 (I) 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 (I) 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 (I) in water,
water/alcohol mixtures or suitable saline solutions can be employed using customary additives, for
example benzyl alcohol or other suitable preservatives, absorption enhancers for increasing the
bioavailability, solubilizers, dispersants and others, and, if appropriate, customary propellants, for
example include carbon dioxide, CFC's, such as, dichlorodifiuoromethane, 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 respiratory 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 hydroxypropylmethyl 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 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 itself, 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 compounds according to the invention may optionally exist as pharmaceutically
acceptable salts including pharmaceutically acceptable acid addition salts prepared from
pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Representative
acids include, but are-Hot limited to, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,
ethenesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic,
hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, oxalic,
pamoic, pantothenic, phosphoric, succinic, sulfiric, tartaric, oxalic, p-toluenesulfonic and the like,
such as those pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2
(1977); incorporated herein by reference in its entirety.

The acid addition salts may be obtained as the direct product of compound synthesis. In the
alternative, the free base may be dissolved in a suitable solvent containing the appropriate acid, and
the salt isolated by evaporating the solvent or otherwise separating the salt and solvent. The
compounds of this invention may form solvates with standard low molecular weight solvents using
methods known to the skilled artisan.
In addition, compounds according to the invention may optionally exist as pharmaceutically
acceptable basic addition salts. For example, these salts can be prepared in situ during the final
isolation and purification of the compounds of the invention, or separately by reacting an acidic
moiety, such as a carboxylic acid, with a suitable base such as the hydroxide, carbonate or bicarbonate
of a pharmaceutically acceptable metal cation or with ammonia, or an organic primary, secondary or
tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, cations based on the
alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, aluminum
salts and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations,
including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine,
dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Other representative organic
amines useful for the formation of base addition salts include diethylamine, ethylenediamine,
ethanolamine, diethanolamine, piperazine and the like.
Compounds of the present invention can be converted to "pro-drugs." The term "pro-drugs"
refers to compounds that have been modified with specific chemical groups known in the art and
when administered into an individual these groups undergo biotransformation to give the parent
compound. Pro-drugs can thus be viewed as compounds of the invention containing one or more
specialized non-toxic protective groups used in a transient manner to alter or to eliminate a property -
of the compound. In one general aspect, the "pro-drug" approach is utilized to facilitate oral
absorption. 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 in their entirety.
Some embodiments of the present invention include a method of producing a pharmaceutical
composition for "combination-therapy" comprising admixing at least one compound according to any
of the compound embodiments disclosed herein, together with at least one known pharmaceutical
agent as described rTSrein and a pharmaceutically acceptable carrier.
In some embodiments the pharmaceutical agents is selected from the group consisting of:
sulfonylureas, meglitinides, biguanides, a-glucosidase inhibitors, peroxisome proliferators-activated
receptor-y (i.e., PPAR-y) agonists, insulin, insulin analogues, HMG-CoA reductase inhibitors,
cholesterol-lowering drugs (for example, fibrates that include: fenofibrate, bezafibrate, gemfibrozil,
clofibrate and the like; bile acid sequestrants which include: cholestyramine, colestipol and the like;

and niacin), antiplatelet agents (for example, aspirin and adenosine diphosphate receptor antagonists
that include: clopidogrel, ticlopidine and the like), angiotensin-converting enzyme inhibitors,
mgiotensin II receptor antagonists and adiponectin.
It is noted that when the RUP3 receptor modulators are utilized as active ingredients in a
pharmaceutical composition, these are not intended for use only in humans, but in other non-human
mammals as well. Indeed, recent advances in the area of animal health-care mandate that
consideration be given for the use of active agents, such as RUP3 receptor modulators, for the
treatment of obesity in domestic animals (e.g., cats and dogs), and RUP3 receptor modulators in other
domestic animals where no disease or disorder is evident (e.g., food-oriented animals such as cows,
chickens, fish, etc.). Those of ordinary skill in the art are readily credited with understanding the
utility of such compounds in such settings.
COMBINATION THERAPY
In the context of the present invention, a compound of Formula (I) or pharmaceutical
composition thereof can be utilized for modulating the activity of RUP3 receptor mediated diseases,
conditions and/or disorders as described herein. Examples of modulating the activity of RUP3
receptor mediated diseases include the treatment of metabolic related disorders. Metabolic related
disorders includes, but not limited to, hyperlipidemia, type 1 diabetes, type 2 diabetes mellitus, and
conditions associated therewith, such as, but not limited to coronary heart disease, ischemic stroke,
restenosis after angioplasty, peripheral vascular disease, intermittent claudication, myocardial
infarction (e.g. necrosis and apoptosis), dyslipidemia, post-prandial lipemia, conditions of impaired
glucose tolerance (IGT), conditions of-impaired fasting plasma glucose, metabolic acidosis, ketosis,
arthritis, obesity, osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy,
peripheral arterial disease, diabetic retinopathy, macular degeneration, cataract, diabetic nephropathy,
glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X,
premenstrual syndrome, coronary heart disease, angina pectoris, thrombosis, atherosclerosis,
myocardial infarction, transient ischemic attacks, stroke, vascular restenosis, hyperglycemia,
hyperinsulinemia, hyperlipidemia, hypertrygliceridemia, insulin resistance, impaired glucose
metabolism, conditions of impaired glucose tolerance, conditions of impaired fasting plasma glucose,
obesity, erectile dysfunction, skin and connective tissue disorders, foot ulcerations and ulcerative
colitis, endothelial dysfunction and impaired vascular compliance. In some embodiments, metabolic
related disorders include type I diabetes, type II diabetes, inadequate glucose tolerance, insulin
resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia
and syndrome X. Other examples of modulating the activity of RUP3 receptor mediated diseases
include the treatment of obesity and/or overweight by decreasing food intake, inducing satiation (i.e.,
the feeling of fullness), controlling weight gain, decreasing body weight and/or affecting metabolism
such that the recipient loses weight and/or maintains weight.

While the compounds of the invention can be administered as the sole active pharmaceutical
agent (i.e., mono-therapy), they can also be used in combination with other pharmaceutical agents
(i.e., combination-therapy) for the treatment of the diseases/conditions/disorders described herein.
Therefore, another aspect of the present invention includes methods of prophylaxis and/or treatment
of a metabolic related disorder or a weight related disorder, such as obesity, comprising administering
to an individual in need of prophylaxis and/or treatment a therapeutically effective amount of a
compound of the present invention, for example Formula (I), in combination with one or more
additional pharmaceutical agent as described herein.
Suitable pharmaceutical agents that can be used in combination with the compounds of the
present invention include anti-obesity agents such as apolipoprotein-B secretion/microsomal
triglyceride transfer protein (apo-B/MTP) inhibitors, MCR-4 agonists, cholescystokinin-A (CCK-A)
agonists, serotoninand norepinephrine reuptake inhibitors (for example, sibutramine),
sympathomimetic agents, (33 adrenergic receptor agonists, dopamine agonists (for example,
bromocriptine), melanocyte-stimulating hormone receptor analogs, cannabinoid 1 receptor antagonists
[for example, SR141716: N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-lH-
pyrazole-3-carboxamide], melanin concentrating hormone antagonists, leptons (the OB protein),
leptin analogues, leptin receptor agonists, galanin antagonists, lipase inhibitors (such as
tetrahydrolipstatin, i.e., Orlistat), anorectic agents (such as a bombesin agonist), Neuropeptide-Y
antagonists, thyromimetic agents, dehydroepiandrosterone or an analogue thereof, glucocorticoid
receptor agonists or antagonists, orexin receptor antagonists, urocortin binding protein antagonists,
glucagon-like peptide-1 receptor agonists, ciliary neutrotrophic factors (such as Axokine™ available
from" Regeneron Pharmaceuticals, Inc., Tarrytowh,TSIY and Procter & Gamble Company, Cincinnati,
OH), human agouti-related proteins (AGRP), ghrelin receptor antagonists, histamine 3 receptor
antagonists or reverse agonists, neuromedin U receptor agonists, noradrenergic anorectic agents (for
example, phentermine, mazindol and the like) and appetite suppressants (for example, bupropion).
Other anti-obesity agents, including the agents set forth infra, are well known, or will be
readily apparent in light of the instant disclosure, to one of ordinary skill in the art.
In some embodiments, the anti-obesity agents are selected from the group consisting of
orlistat, sibutramine, bromocriptine, ephedrine, leptin, and pseudoephedrine. In a further
embodiment, compounds of the present invention and combination therapies are administered in
conjunction with exercise and/or a sensible diet.
It will be understood that the scope of combination-therapy of the compounds of the present
invention with other anti-obesity agents, anorectic agents, appetite suppressant and related agents is
not limited to those listed above, but includes in principle any combination with any pharmaceutical
agent or pharmaceutical composition useful for the treatment of overweight and obese individuals.

Other suitable pharmaceutical agents, in addition to anti-obesity agents, that can be used in
combination with the compounds of the present invention include agents useful in the treatment of
metabolic related disorders and/or concomitant diseases thereof. For example, but not limited to,
congestive heart failure, type I diabetes, type II diabetes, inadequate glucose tolerance, insulin
resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia,
syndrome X, retinopathy, nephropathy and neuropathy. Treatment of one or more of the diseases
cited herein include the use of one or more pharmaceutical agents known in the art belonging to the
classes of drugs referred to, but not limited to, the following: sulfonylureas, meglitinides, biguanides,
a-glucosidase inhibitors, peroxisome proliferators-activated receptor-y (i.e., PPAR-y) agonists,
insulin, insulin analogues, HMG-CoA reductase inhibitors, cholesterol-lowering drugs (for example,
fibrates that include: fenofibrate, bezafibrate, gemfibrozil, clofibrate and the like; bile acid
sequestrants which include: cholestyramine, colestipol and the like; and niacin), antiplatelet agents
(for example, aspirin and adenosine diphosphate receptor antagonists that include: clopidogrel,
ticlopidine and the like), angiotensin-converting enzyme inhibitors, angiotensin II receptor
antagonists, adiponectin and the like. In accordance to one aspect of the present invention, a
compound of the present can be used in combination with a pharmaceutical agent or agents belonging
to one or more of the classes of drugs cited herein.
It will be understood that the scope of combination-therapy of the compounds of the present
invention with other pharmaceutical agents is not limited to those listed herein, supra or infra, but
includes in principle any combination with any pharmaceutical agent or pharmaceutical composition
useful for the treatment of diseases, conditions or disorders that are linked to metabolic related
disorders."
Some embodiments of the present invention include methods of treatment of a disease,
disorder, condition or complication thereof as described herein, comprising administering to an
individual in need of such treatment a therapeutically effective amount or dose of a compound of the
present invention in combination with at least one pharmaceutical agent selected from the group
consisting of: sulfonylureas, meglitinides, biguanides, a-glucosidase inhibitors, peroxisome
proliferators-activated receptor-y (i.e., PPAR-y) agonists, insulin, insulin analogues, HMG-CoA
reductase inhibitors, cholesterol-lowering drugs (for example, fibrates that include: fenofibrate,
bezafibrate, gemfibrozil, clofibrate and the like; bile acid sequestrants which include: cholestyramine,
colestipol and the like; and niacin), antiplatelet agents (for example, aspirin and adenosine
diphosphate receptor antagonists that include: clopidogrel, ticlopidine and the like), angiotensin-
converting enzyme inhibitors, angiotensin II receptor antagonists and adiponectin. In some
embodiments, methods of the present invention include compounds of the present invention and the
pharmaceutical agents are administered separately. In further embodiments, compounds of the
present invention and the pharmaceutical agents are administered together.

Suitable pharmaceutical agents that can be used in conjunction with compounds of the present
invention include sulfonylureas. The sulfonylureas (SU) are drugs which promote secretion of insulin
from pancreatic (3 cells by transmitting signals of insulin secretion via SU receptors in the cell
membranes. Examples of the sulfonylureas include glyburide , glipizide, glimepiride and other
sulfonylureas known in the art.
Suitable pharmaceutical agents that can be used in conjunction with compounds of the present
invention include the meglitinides. The meglitinides are benzoic acid derivatives represent a novel
class of insulin secretagogues. These agents target postprandial hyperglycemia and show comparable
efficacy to sulfonylureas in reducing HbAlc. Examples of meglitinides include repaglinide,
nateglinide and other meglitinides known in the art.
Suitable pharmaceutical agents that can be used in conjunction with compounds of the present
invention include the biguanides. The biguanides represent 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
biguanides include phenformin, metformin, buformin, and biguanides known in the art.
Suitable pharmaceutical agents that can be used in conjunction with compounds of the present
invention include the a-glucosidase inhibitors. The a-glucosidase inhibitors competitively inhibit
digestive enzymes such as cc-amylase, maltase, a-dextfinase, sucrase, etc. in the pancreas and or small
intestine. The reversible inhibition by a-glucosidase inhibitors retard, diminish or otherwise reduce
blood glucose levels by delaying the digestion of starch and sugars. Examples of a-glucosidase
inhibitors include acarbose, N-(l,3-dihydroxy-2-propyl)valiolamine (generic name; voglibose),
miglitol, and a-glucosidase inhibitors known in the art.
Suitable pharmaceutical agents that can be used in conjunction with compounds of the present
invention include the peroxisome proliferators-activated receptor-y (i.e., PPAR-y) agonists. The
peroxisome proliferators-activated receptor-y agonists represent a class of compounds that activates
the nuclear receptor PPAR-y and therefore regulate the transcription of insulin-responsive genes
involved in the control of glucose production, transport and utilization. Agents in the class also
facilitate the regulation of fatty acid metabolism. Examples of PPAR-y agonists include rosiglitazone,
pioglitazone, tesaglitazar, netoglitazone, GW-409544, GW-501516 and PPAR-y agonists known in
the art. —
Suitable pharmaceutical agents that can be used in conjunction with compounds of the present
invention include the HMG-CoA reductase inhibitors. The HMG-CoA reductase inhibitors are agents
also referred to as Statin compounds that 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. The statins lower serum LDL concentrations by
upregulating the activity of LDL receptors and are responsible for clearing LDL from the blood.

Some representative examples the statin compounds include rosuvastatin, pravastatin and its sodium
salt, simvastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin, rosuvastatin, pitavastatin, BMS's
"superstatin", and HMG-CoA reductase inhibitors known in the art.
Suitable pharmaceutical agents that can be used in conjunction with compounds of the present
invention include the Fibrates. 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.
Suitable pharmaceutical agents that can be used in conjunction with compounds of the present
invention include the angiotensin converting enzyme (ACE) inhibitors. The angiotensin converting
enzyme 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.
Suitable pharmaceutical agents that can be used in conjunction with compounds of the present
invention include the angiotensin II receptor antagonists. Angiotensin II receptor antagonists target
the angiotensin II receptor subtype 1 (i.e., ATI) and demonstrate a beneficial effect on hypertension.
Examples of angiotensin II receptor antagonists include losartan (and the potassium salt form), and
angiotensin II receptor-antagonists known in the art. -
Suitable pharmaceutical agents that can be used in conjunction with compounds of the present
invention include the squalene synthesis inhibitors. 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)-a-[Bis[2,2-dimethyl-1-oxopropoxy)methoxy] phosphinyI]-3-
phenoxybenzenebutanesulfonic acid, mono potassium salt (BMS-188494) and squalene synthesis
inhibitors known in the art.
Suitable pharmaceutical agents that can be used in conjunction with compounds of the present
invention include, but not limited to, amylin agonists (for example, pramlintide), insulin
secretogogues (for example, GLP-1 agonists; exendin-4; insulinotropin (NN2211); dipeptyl peptidase
inhibitors (for example, NVP-DPP-728), acyl CoA cholesterol acetyltransferase inhibitors (for
example, Ezetimibe, eflucimibe, and like compounds), cholesterol absorption inhibitors (for example,
ezetimibe, pamaqueside and like compounds), cholesterol ester transfer protein inhibitors (for
example, CP-529414, JTT-705, CETi-1, and like compounds), microsomal triglyceride transfer
protein inhibitors (for example, implitapide, and like compounds), cholesterol modulators (for
example, NO-1886, and like compounds), bile acid modulators (for example, GT103-279 and like

compounds), insulin signalling pathway modulators, like inhibitors of protein tyrosine phosphatases
(PTPases), non-small mol. mimetic compds. and inhibitors of glutamine-fructose-6-phosphate
amidotransferase (GFAT), compds. influencing a dysregulated hepatic glucose prodn., like inhibitors
of glucose-6-phosphatase (G6Pase), inhibitors of fructose-1,6-bisphosphatase (F-l,6-BPase),
inhibitors of glycogen phosphorylase (GP), glucagon receptor antagonists and inhibitors of
phosphoenolpyruvate carboxykinase (PEPCK), pyruvate dehydrogenase kinase (PDHK) inhibitors,
insulin sensitivity enhancers, insulin secretion enhancers, inhibitors of gastric emptying, cc2-adrenergic
antagonists, and retinoid X receptor (RXR) agonists.
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 (I) are administered as a combination therapy 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 UTILITIES
Another object of the present invention relates to radio-labeled compounds of Formula (I) that
would be useful not only in radio-imaging but also in assays, both in vitro and in vivo, for localizing
and quantitating the RUP3 receptor in tissue samples, including human, and for identifying RUP3
receptor ligands by inhibition binding of a radio-labeled compound. It is a further object of this
invention to develop novel RUP3 receptor assays of which comprise such radio-labeled compounds.
The present invention embraces isotopically-labeled compounds of Formula (I) and any
subgenera herein, such as but not limited to, Formula (la) through Formula (IIIo). An "isotopically"
or "radio-labeled" compounds are those which are identical to compounds disclosed herein, but for
the fact that one or more atoms are replaced or substituted by an atom having an atomic mass or mass
number different from the atomic mass or mass number typically found in nature (i.e., naturally
occurring). Suitable radionuclides that may be incorporated in compounds of the present invention
include but are not limited to 2H (also written as D for deuterium), 3H (also written as T for tritium),
"C, I3C, ,4C, ,3N, 15N, ,50, nO, ,80,18F, 35S, 36C1, S2Br, 75Br, 76Br, 77Br, 123I, 124I, I25I and 131I. The
radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific
application of that radio-labeled compound. For example, for in vitro RUP3 receptor labeling and
competition assays, compounds that incorporate 3H, !4C, 82Br, 125I, I311,35S or will generally be most
useful. For radio-imaging applications UC, ,8F, 1251,123L 124I, 13IL 75Br, 76Br or 77Br will generally be
most useful.

It is understood that a "radio-labeled " or "labeled compound" is a compound of Formula (I)
that has incorporated at least one radionuclide; in some embodiments the radionuclide is selected from
the group consisting of 3H, 14C, 1251,35S and ^Br.
Certain isotopically-labeled compounds of the present invention are useful in compound and/or
substrate tissue distribution assays. In some embodiments the radionuclide 3H and/or 14C isotopes are
useful in these studies. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may
afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo
half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
Isotopically labeled compounds of the present invention can generally be prepared by following
procedures analogous to those disclosed in the Schemes supra and Examples infra, by substituting an
isotopically labeled reagent for a non-isotopically labeled reagent. Other synthetic methods that are
useful are discussed infra. 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 radio-isotopes into organic compounds are applicable to
compounds of the invention and are well known in the art. These synthetic methods, for example,
incorporating activity levels of tritium into target molecules, are as follows:
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 [3H] - 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 [3H ] - 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 [3H] - This procedure is usually employed to prepare
O-methyl orN-methyl (3H) products by treating appropriate precursors with high specific activity
methyl iodide (3H). This method in general allows for higher specific activity, such as for example,
about 70-90 Ci/mmoT
Synthetic methods for incorporating activity levels of 125I 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 125I labeled compound
using NaI_5I. A represented procedure was reported by Zhu, D.-G. and co-workers in J. Org. Chem.
2002, 67, 943-948.

B. Ortho 125Iodination of phenols - This procedure allows for the incorporation of ]25I at the
ortho position of a phenol as reported by Collier, T. L. and co-workers in J. Labeled Compd
Radiopharm. 1999, 42, S264-S266.
C. Aryl and heteroaryl bromide exchange with I25I - 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(Ph3P)4] or through an aryl or
heteroaryl lithium, in the presence of a tri-alkyltinhalide or hexaalkylditin [e.g., (CH3)3SnSn(CH3)3].
A represented procedure was reported by Bas, M.-D. and co-workers in J. Labeled Compd
Radiopharm. 2001, 44, S280-S282.
A radio-labeled RTJP3 receptor compound of Formula (I) 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 "radio-labeled compound of
Formula (I)" to the RUP3 receptor. Accordingly, the ability of a test compound to compete with the
"radio-labeled compound of Formula (I)" for the binding to the RUP3 receptor directly correlates to
its binding affinity.
The labeled compounds of the present invention bind to the RUP3 receptor. In one
embodiment the labeled compound has an IC50 less than about 500 pJM, in another embodiment the
labeled compound has an IC50 less than about 100 uM, in yet another embodiment the labeled
compound has an IC50 less than about 10 p.M, in yet another embodiment the labeled compound has
an IC50 less than about 1 p.M, and in still yet another embodiment the labeled inhibitor has an IC50 less
than about 0.1 uM.
Other uses of the disclosed receptors and methods will become apparent to those in the art
based upon, inter alia, a review of this disclosure.
As will be recognized, the steps of the methods of the present invention need not be
performed any particular number of times or in any particular sequence. Additional objects,
advantages, and novel features of this invention will become apparent to those skilled in the art upon
examination of the following examples thereof, which are intended to be illustrative and not intended
to be limiting.
_ 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 125I
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-23 83
6) IBMX- Sigma 1-7018
7) Hepes - 1M solution in distilled water - Gibco #15630080
8) MgC12 - Sigma M-1028- 1M Solution
9) NaCl - Sigma - S6546 - 5M Solution
10) Bradford Protein Assay Kit - Biorad # 5000001
11) Proclin 300- Sigma #4-8126
Binding Buffer - filter through 45- micron Nalgene filter and keep in refrigerator. All buffers and
membranes should be kept cold (in ice bucket) while performing assay.
20 mM Hepes, pH7.4
lmMMgC12
lOOmMNaCl
2X Regeneration Buffer (make-in binding buffer):
20 mM 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 ml)
0.2 mM ATP (22.04 mg/200 ml)
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 columns 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
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)
IC50S or EC50S are done in triplicate. One Flashplate can therefore be set up to handle 3
compounds, (i.e., 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 in 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) In column 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 I25I 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 125I + 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.
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 rsalers 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, IC50 EC50 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 pmole/well (for 15 ug/well protein), and for
CMV are between 2 to 3 pmole/well (for 15 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 IC50 or EC50 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%.
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 I25I-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 125I-cAMP. Bound 125I-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-T15 cells
It is known that stimulation of cAMP in HIT-T15 cells causes an increase in insulin secretion
when the glucose concentration in the culture media is changed from 3mM to 15 mM. Thus, RUP3
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. RTJP3 is an endogenously expressed GPCR in the insulin-producing cells of rat

islets. Thus, RUP3 Hgands 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 (T£Q) 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 urn mesh sterile cell strainers in wells of a 6-well plate with 5 ml of low
(60 mg/dl) glucose Krebs-Ringers Buffer (KRB) assay medium.
C. Incubate 30 minutes (1 hour if overnight step skipped) at 37°C and 5% C02. 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. Move strainers to final wells with-low-glucose assay-medium (Low-2). Incubate and. .
collect supernatants as before.
H. Keeping cold, centrifuge supernatants at 1800 rpm 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 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:
ZC47: 5'-CATTGCCGGGCTGTGGTTAGTGTC-3' (forward primer), (SEQ ID NO:3);
ZC48: 5'-GGCATAGATGAGTGGGTTGAGCAG-3' (reverse primer), (SEQ ID NO:4);
and the human multiple tissue cDNA panels (MTC, 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 (J.1 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 |il) 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 IB).
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 32P-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 ID).
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'-CATGGGCCCTGCACCTTCTTTG-3' (SEQ ID NO:5);
rRUP3 reverse: 5'-GCTCCGGATGGCTGATGATAGTGA-3' (SEQ IDNO:6).
PCR was performed using Platinum PCR SuperMix (Life Technologies, Inc.; manufacture
instructions were followed) in a 50 \x\ 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 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 RGPERTRESAYHTVTISHPELDG (SEQ ID NO: 7) 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 cross linking 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
though 4). In this assay,' "the~GST-RUP3 fusion protein wasreadily 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 p 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 a) 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 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 c and d), but
not in glucagons producing cells (panels e and f). These data demonstrated that RUP3 is expressed in

P cells but not in p 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
RTJP3 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 insulin-producing cells of the pancreas, these
cells exhibit an 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 Tu6 cells that express high levels of RUP3. Tu6 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 present in the culture media. As shown in Figure 3C, Tu6 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
In vivo effects of RUP3 agonists on glucose homeostasis in mice.
A. Oral Glucose tolerance test (oGTT)
Male C57bl/6J mice at approximately 8 weeks of age were fasted for 18 hours and randomly
grouped (n=5) to receive a RUP3 agonist (either Compound B3 or B124) at 1, 3 or 10 mg/Kg.
Compounds were delivered orally via a gavage needle (p.o., volume 10 mL/Kg). At time 0, levels of
blood glucose were assessed using a glucometer (Elite XL, Bayer), and mice were administered either
vehicle (20% hydroxypropyl-beta-cyclodextrin) or test compound. Thirty minutes after
administration of test compound, levels of blood glucose were again assessed, and mice were
administered dextrose orally at a dose of 3 g/Kg. Blood glucose measurements were then taken 20
min, 40 min, 60 min and 120 min after this time. Table 6 shows the mean percentage inhibition of

glucose excursion for each dose of test compound, averaged across the five animals in each treatment
group. These results demonstrated that the RUP3 agonists, Compounds B3, and B124, lowered blood
glucose in a dose-dependent manner in mice after challenged with glucose.

Example 6
Generation of Tu6/ RUP3 Stable Lines
To produce Tu6 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 pLNCX2 (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 supernatant was obtained by collecting media from the resultant stables
according to the manufacturer's directions. Tu6 cells, in a 10 cm dish, were then infected with
retrovirus by incubating in a solution of 1 ml viral supernatant/ 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 neornycin-resistance gene
cassette present in the pLNCX2 vector, thus indicating the successful integration of retrovirus into the
Tu6 genome. The expression of RUP3 in the Tu6/RUP3 G418-resistant colonies was confirmed by
Northern blot.
Example 7
Insulin secretion, Tu6 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 8
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
radiolabeled ligand to the RUP3 receptor. Absent the use of known ligands for the RUP3 receptor
and radiolabels thereof, compounds of Formula (I) can be labelled with a radioisotope and used in an
assay for evaluating the affinity of a test compound to the RUP3 receptor.
A radiolabeled RUP3 compound of Formula (I) 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 "radiolabeled compound of
Formula (I)" to the RUP3 receptor. Accordingly, the ability to compete with the "radio-labelled
compound of Formula (I)" or Radiolabeled 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 MgCl2,100 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 HC1 (pH 7.4), lOmM MgCl2, and ImM EDTA; 5-50ug protein) is added
to 96-well polyproylene microtiter plates followed by addition of lOOul of assay buffer and 50ul of
Radiolabeled RUP3 Ligand. For nonspecific binding, 50 ul of assay buffer is added instead of

ItiOul and an additional 50ul of lOuM cold RUP3 is added before 50ul of Radiolabeled 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 a Brandell 96-well plate harvester followed by washing with cold 50 mM Tris HC1, 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 lOOul of assay
buffer, lOOul of appropriately diluted test compound is added to appropriate wells followed by
addition of 50 ul of Radiolabelled RUP3 Ligand.
C. CALCULATIONS
The test compounds are initially assayed at 1 and 0.1 JJM 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., IC50). 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 (BD) minus non-specific binding (NSB).
IC50 is determined from an inhibition response curve, logit-log plot of % B/B0 vs concentration of test
compound.
Kj is calculated by the Cheng and Prustoff transformation:
•Ki = IC5o/(l + [L]/KD)
where [L] is the concentration of a Radio-RUP3 Ligand used in the assay and KD is the
dissociation constant of a Radio-RUP3 Ligand "determined independently under the same binding
conditions.
CHEMISTRY EXAMPLES
SYNTHESES OF COMPOUNDS OF THE PRESENT INVENTION
The compounds of the invention and their synthesis are further illustrated by the following
examples. The following examples are provided to further define the invention without, however,
limiting the invention to the particulas of these examples. The compounds described herein, supra
and infra, are namedTaccording to the CS Chem Draw Ultra Version 7.0.1. In certain instances
common names are used and it is understood that these common names would be recognized by those
skilled in the art.
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 Inverse) 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, q = quartet, m = multiplet,
br = broad. Microwave irradiations were carried out using the Emyrs Synthesizer (Personal
Chemistry). Thin-layer chromatography (TLC) was performed on silica gel 60 F254 (Merck),
preparatory thin-layer chromatography (prep TLC) was preformed on PK6F silica gel 60 A 1 mm
plates (Whatman), and column 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 filtrations.
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.
Example 9:
Example 9.1: Preparation of 4-({[6-(2-FIuoro-4-methanesuIfonyl-phenyIamino)-pyrimidin-4-
yl]-methyl-amino}-methyl)-piperidine-1-carboxyIic acid tert-butyl ester, also referred to herein
as Compound A4.
- Step 1: Preparation of 4-{[(6-chloro-pyrimidin-4-yI)-methyI-amino]-metb.yI}-piperidine-
1-carboxylic acid tert-butyl ester.
A mixture of 4, 6-dichloropyrimidine (194 mg, 1.31 mmol), 4-methylaminomethyl-
piperidine-1-carboxylic acid tert-butyl ester (300 mg, 1.31 mmol) and diisopropylethyl amine (0.45
mL, 2.62 mmol) in isopropyl alcohol (2 mL) was heated under microwave irradiation for 5 min at
100°C. The crude mixture was concentrated in vacuo and purified by HPLC to provide 4-{[(6-chloro-
pyrimidin-4-yl)-methyl-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester as an oil (240
mg, 54%). XHNMR (CDC13, 400 MHz) 5 0.90-0.92 (m, 2H), 1.13-1.25 (m, 2H), 1.45 (s, 9H), 1.58-
1.61 (m, 2H), 1.86-2.04 (m, 1H), 2.64-2.70 (m, 2H), 3.05 (s, 3H), 4.11-4.12 (m, 2H), 6.38 (s, 1H),
8.35 (s, 1H). Exacrffiass calculated for C16H25C1N402 340.2, found 341.0 (Mlt).
Step 2: Preparation of 4-({[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-
yl]-methyl-amino}-methyI)-piperidine-1-carboxylic acid tert-butyl ester (Compound A4).
A mixture of4-{[(6-chloro-pyrimidin-4-yl)-methyl-amino]-methyl}-piperidine-1-carboxylic
acid tert-butyl ester (240 mg, 0.71 mmol), 2-fluoro-4-methanesulfonylaniline (113 mg, 0.60 mmol),
palladium acetate (1.4 mg, 0.006 mmol), di-f-butyl-biphenylphosphine (2 mg, 0.0066 mmol) and
sodium t-butoxide (144 mg, 1.5 mmol) in dioxane (2 ml) was heated under microwave irradiation at

120°C for 2 hours. The crude mixture was purified by HPLC to provide compound A4 as a solid.
'HNMR(CDC13,400 MHz) d 1.18-1.21 (m, 2H), 1.45 (s, 9H), 1.55-1.58 (m, 2H), 1.81-1.88 (m, 1H),
2.68 (t, 2H), 3.00 (s, 3H), 3.10 (s, 3H), 3.60-3.66 (m, 2H), 4.10-4.13 (m, 2H), 5.36 (d, 1H), 7.61-7.63
(m, 1H), 7.80 (d, 2H), 8.22 (s, 1H). Exact mass calculated for C23H32FN5O4S 493.2, found 494.5
(Mtf).
Using essentially the same methodology and procedures as described in the Reaction
Scheme(s) and Examples herein, the following compounds were prepared from the appropriate
materials.
Example 9.2: (2-fluoro-4-methanesulfonyI-phenyl)-{6-[4-(3-fluoro-phenoxy)-piperidin-1-yl]-
pyrimidin-4-yI}-amine (Compound A8).
Compound A8 was obtained as tan solid (48mg, 52%). 'H NMR 400MHz CDC13 5 (ppm):
8.25(s, 1H); 7.80(d,2H); 7.60(t, 1H); 6.71-6.69(m,3H); 6.63(d,lH); 5.52(s,lH); 4.64(m,lH); 3.95(m,
2H); 3.83(m, 2H); 3.10(s, 3H); 2.04-1.98(m, 4H). Exact mass calculated for C22H22F2N4O3 S 460.1,
LCMS (ESI) m/z 461.1(M+H+, 100%).
Example 9.3: 4-({[6-(4-Cyano-2-fluoro-phenyIamino)-pyrimidin-4-yl]-methyI-amino}-methyl)-
piperidine-1-carboxylic acid tert-butyl ester (Compound A14).
Compound A14 was obtained as white solid(13mg, 20%). JH NMR 400MHz CDC13 8 (ppm):
8.19(s, 1H); 7.53-7.50(m,3H); 5.35(s, 1H); 4.13 (m,2H); 3.66(m,2H)- 2.99(s, 3H); 2.71-2.65 (m, 2H);
-1.88(sb, 1H);-1.57-1.55(m,2H);-l:46(s,9H);l.24-1,18(m,2H). Exact mass calculated for-C23H29 •
FN602 440.2, found LCMS (ESI) m/z 441.2^+1^, 100%).
Example 9.4: 4-[({6-[4-(2-MethanesulfonyI-ethyI)-phenylamino]-pyrimidin-4-yI}-metb.yl-
amino)-methyI]-piperidine-1-carboxylic acid tert-butyl ester (Compound A15).
Compound A15 was obtained as yellow solid (5mg, 7%). 'H NMR 400MHz CDC13 5 (ppm):
8.1 l(s, 1H); 7.30-7.21 (m,4H); 5.62(s, 1H); 4.12 (m,2H); 3.62(m,2H); 3.31-3.28 (m, 2H); 3.20-3.16
(m,2H); 2.95(s, 3H); 2.90 (s,3H); 2.70-2.64 (m, 2H); 1.87(sb, 1H); 1.56-1.54(m, 2H); 1.47(s, 9H);
1.20-1.17(m,2H). Exact mass calculated for C25H37 N5O4 S 503.3, LCMS (ESI) m/z 504.3(M+jr,
100%). -
Example 9.5: 4-({[6-(4-EthyIsulfanyI-phenyIamino)-pyrimidin-4-yI]-methyI-amino}-methyl)-
piperidine-1-carboxylic acid tert-butyl ester (Compound A16).
Compound A16 was obtained as yellow solid (9mg, 13%). Exact mass calculated for C24H35
N5O2 S 457.2, LCMS (ESI) m/z 458.3(M+H+,,100%).

Example 9.6: 4-({[6-(4-IsopropylsuIfanyl-phenyIamino)-pyrimidin-4-yl]-methyl-amino}-
methyl)-piperidine-1-carboxyIic acid tert-butyl ester (Compound A17).
Compound A17 was obtained as yellow solid (18mg, 25%). Exact mass calculated for C25H37
N502 S 471.3, LCMS (ESI) m/z 472.4(M+H*, 100%).
Example 9.7: 4-({[6-(4-EthylsulfamoyI-phenylamino)-pyrimidin-4-yI]-methyl-amino}-methyI)-
piperidine-1-carboxylic acid tert-butyl ester (Compound A18)
Compound A18 was obtained as white solid (4mg, 5%). !HNMR 400MHz CDC13 8 (ppm):
8.17(s, 1H); 7.91(d,2H); 7.46 (d,2H); 5.80(s, 1H); 4.13 (sb,2H); 3.65(sb,2H); 3.07-3.01(m, 2H);
2.99(s,3H); 2.69-2.64 (m,2H); 1.88(sb, 1H); 1.58-1.55(m,2H); 1.45(s,9H); 1.30-1.21(m,2H);
1.14(t,3H). Exact mass calculated for C24H36N604 S 504.2, LCMS (ESI) m/z 505.4(M+Hf, 100%).
Example 9.8: 4-({MethyI-[6-(4-methylsuIfamoyI-phenylamino)-pyrimidin-4-yI]-amino}-
methyI)-piperidine-1-carboxylic acid tert-butyl ester (Compound A19).
Compound A19 was obtained as white solid (3mg, 4%). ]H NMR 400MHz CDCI3 5 (ppm):
8.17(s, 1H); 7.90(d,2H); 7.47 (d,2H); 5.82(s, 1H); 4.12 (sb,2H); 3.65(sb,2H); 3.16 (s, 3H);
2.99(s,3H); 2.68-2.62 (m,2H); 1.89(sb, 1H); 1.62-1.55(m, 2H); 1.45(s, 9H); 1.30-1.18(m,2H).Exact
mass calculated for C23H34 N604 S 490.2, LCMS (ESI) m/z 491.4(M+lf, 100%).
Example 9.9: 4-({[6-(4-DimethyIsulfamoyl-phenylamino)-pyrimidin-4-yl]-methyI-amino}-
methyl)-piperidine-1-carboxylic acid tert-butyl ester (Compound A20).
- Compound A20 was obtained as white solid (25mg, 33%).- 'HNMR-400MHz CDC13 6
(ppm): 8.19(s, 1H); 7.84 (d,2H); 7.49 (d,2H); 5.78(s, 1H); 4.14 (sb,2H); 3.67(sb,2H); 3.02 (s, 3H);
2.75(s,6H); 2.73-2.66 (m,2H); 1.89(sb, 1H); 1.59-1.56(m,2H); 1.43(s,9H); 1.22-1.18(m,2H). Exact
mass calculated for C24H36N604 S 504.2, LCMS (ESI) m/z 505.4(M+H+, 100%).
Example 9.10: 4-({Methyl-[6-(4-methylsulfamoylmethyI-phenylamino)-pyrimidin-4-yl]-amino}-
methyl)-piperidine-1-carboxylic acid tert-butyl ester (Compound A21).
Compound A21 was obtained as yellow solid (7mg, 9%). Exact mass calculated for
C24H36N604 S 504.2, LCMS (ESI) m/z 505.3(M+Hf, 100%).
Example 9.11: 4-({Methyl-[6-(4-sulfamoyl-phenylamino)-pyrimidin-4-yI]-amino}-methyl)-
piperidine-1-carboxylic acid tert-butyl ester (Compound A22).
Compound A22 was obtained as white solid (4mg, 6%). Exact mass calculated for
C22H32N604 S 476.2, LCMS (ESI) m/z 477.2(M+H+, 100%).

Example 9.12: 4-({Methyl-[6-(4-[l,2,4]triazoI-1-yl-phenylamino)-pyrimidiii-4-yI]-amino}-
methyI)-piperidine-1-carboxyIic acid tert-butyl ester (Compound A23).
Compound A23 was obtained as white solid (12mg, 17%). Exact mass calculated for
C24H32N802 464.3, LCMS (ESI) m/z465.4(M+H1', 100%).
Example 9.13: 4-({Methyl-[6-(4-[l,2,4]triazol-1-ylmethyI-phenylamino)-pyrimidin-4-yl]-amino}-
metbyl)-piperidine-1-carboxylic acid tert-butyl ester (Compound A24).
Compound A24 was obtained as yellow solid (3mg, 4 %). Exact mass calculated for
C25H34N802 478.3, LCMS (ESI) m/z 479.1(M+H+, 100%).
Example 9.14: 4-[(MethyI-{6-[4-(2-[l,2,4]triazol-1-yl-ethyl)-phenylamino]-pyrimidin-4-yl}-
amino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (Compound A25).
Compound A25 was obtained as white solid (6mg, 8 %). Exact mass calculated for
C26H36N802 492.3, LCMS (ESI) m/z493.4(M+H*, 100%).
Example 9.16: 4-({[6-(Benzo[l,3]dioxol-5-ylamino)-pyrimidin-4-yl]-methyl-amino}-methyI)-
piperidine-1-carboxylic acid tert-butyl ester (Compound A26).
Compound A26 was obtained as tan solid (1 lmg, 17 %). Exact mass calculated for
C23H3iN504 441.2, found LCMS (ESI) m/z 442.3(M+H+, 100%).
Example 9.17: 4-({[6-(6-MethanesuIfonyl-pyridin-3-ylamino)-pyrimidin-4-yI]-methyl-amino}-
methyI)-piperidine-1-carboxylic acid tert-butyl ester (Compound A27).
Compound A27 was obtained as off-white solid (3mg, 4 %). Exact mass calculated for
C22H32N604 S 476.2, found LCMS (ESI) m/z 477.4(M+tf, 100%).
Example 9.18: 4-({[6-(3,5-Dimethoxy-phenylamino)-pyrimidin-4-yI]-methyl-amino}-methyI)-
piperidine-1-carboxylic acid tert-butyl ester (Compound A28).
Compound A28 was obtained as yellow solid (13mg, 19 %). Exact mass calculated for
C24H35N504 457.3, found LCMS (ESI) m/z 458.3(M+H+, 100%).
Example 9.19: 4-[(MethyI-{6-[4-(2-oxo-oxazoIidin-4-ylmethyl)-phenylamino]-pyrimidin-4-yI}-
amino)-methyI]-piperidine-1-carboxylic acid tert-butyl ester (Compound A29).
Compound A29 was obtained as yellow solid (30mg, 40 %). Exact mass calculated for
C26H36N604 496.3, found LCMS (ESI) m/z497.5(M+Hf, 100%).
Example 9.20: 4-[({6-[4-(l,l-Dioxo-lX6-thiomorpholin-4-ylmethyI)-phenylamino]-pyrimidin-4-
yl}-methyI-amino)-methyl]-piperidine-1-carboxyIic acid tert-butyl ester (Compound A30).

Compound A30 was obtained as white solid (12mg, 15 %). Exact mass calculated for
C27H40N6CX, S 544.3, found LCMS (ESI) m/z 545.4(M+H+, 100%).
Example 9.21: 4-({Metbyl-[6-(4-pyraz»I-1-yI-phenylamino)-pyrimidin-4-yI]-amino}-methyl)-
piperidine-1-carboxylic acid tert-butyl ester (Compound A31).
Compound A31 was obtained as white solid (6mg, 9 %). Exact mass calculated for
C25H33N702 463.3, found LCMS (ESI) m/z 464.3(M+Hf, 100%).
Example 9.22: 4-({[6-(2,2-Difluoro-benzo[l,3]dioxoI-5-ylamino)-pyrimidin-4-yl]-methyl-amino}-
methyl)-piperidine-1-carboxyIic acid tert-butyl ester (Compound A32).
Compound A32 was obtained as white solid (3mg, 4 %). Exact mass calculated for C23H29
F2N5O4 477.2, found LCMS (ESI) m/z 478.3(M+H+, 100%).
Example 9.23: 4-({MethyI-[6-(4-trifluoromethanesulfonyI-phenylamino)-pyrimidin-4-yl]-
amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester (Compound A33).
Compound A33 was obtained as white solid (13mg, 16 %). Exact mass calculated for C23H30
F3N5O4S 529.2, found LCMS (ESI) m/z 530.2(M+IT\ 100%).
Example 9.24: 4-[(Methyl-{6-[4-(morphoIine-4-sulfonyl)-phenylamino]-pyrimidin-4-yl}-amino)-
methyl]-piperidine-1-carboxylic acid tert-butyl ester (Compound A34).
Compound A34 was obtained as white solid (13mg, 16 %). Exact mass calculated for C26H38
NfiOjS 546:3, found LCMS (ESI) m/z 547.3(M+H+, 100%). -
Example 9.25: 4-[(MethyI-{6-[2-(pyridine-2-carbonyl)-phenylamino]-pyrimidin-4-yl}-amino)-
methyl]-piperidine-1-carboxylic acid tert-butyl ester (Compound A35).
Compound A35 was obtained as brown solid (0.4mg, 0.5 %). Exact mass calculated for
C28H34N603 502.3, found LCMS (ESI) m/z 503.5(M+Ff, 100%).
Example 9.26: 4-({[6-(2-FIuoro-5-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-methyl-
ammo}-methyl)-piperidine-1-carboxyIic acid tert-butyl ester (Compound A36).
Compound 3E36 was obtained as a solid (11 mg, 15 %). Exact mass calculated for
C25H32FN5O4S 493.2, found 494.3 (M+H*).
Example 9.27: 4-({[6-(3,4-Difluoro-phenylamino)-pyrimidin-4-yl)-methyl-amino}-methyI)-
piperidine-1-carboxylic acid tert-butyl ester (Compound A39).
Compound A39 was obtained as a solid (6 mg, 9%). Exact mass calculated for C22H29F2N5O2
433.2, found 434.3 (M+H4).

Example 9.28: 4-({[6-(2,6-Difluoro-phenylamino)-pyrimidin-4-yl]-methyI-ammo}-methyI)-
piperidine-1-carboxylic acid tert-butyl ester (Compound A40).
Compound A40 was obtained as a solid (28 mg, 43%). Exact mass calculated for
C22H29F2N502 433.2, found 434.3 (M+H4).
Example 9.29: 4-({[6-(2,5-Difluoro-phenyIamino)-pyrimidin-4-yI]-methyl-amino}-methyI)-
piperidine-1-carboxylic acid tert-butyl ester (Compound A41).
Compound A41 was obtained as a solid (22 mg, 34%). Exact mass calculated for
C22H29F2N502 433.2, found 434.0 (M+H*).
Example 9.30: 4-({[6-(2,3-Difluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyI)-
piperidine-1-carboxylic acid tert-butyl ester (Compound A42).
Compound A42 was obtained as a solid (10 mg, 15%). Exact mass calculated for
C22H29F2N502 433.2, found 434.2(M+H+).
Example 9.31: 4-({Methyl-[6-(2,3,5-trifluoro-phenyIamino)-pyrimidin-4-yI]-amino}-methyl)-
piperidine-1-carboxylic acid tert-butyl ester (Compound A43).
Compound A43 was obtained as a solid (4 mg, 6%). Exact mass calculated for C22H28F3N502
451.2, found 452.2 (M+H4).
-Example 9.32: 4-({[6-(2-FIuoro-phenylamino)-pyrimidin-4-yl]-methyI-amino}-methyl)-
piperidine-1-carboxylic acid tert-butyl ester (Compound A44).
Compound A44 was obtained as a solid (11 mg, 18%). Exact mass calculated for
C22H3oFN502 415.2, found 416.3 (M+H4). •
Example 9.33: 4-({[6-(2-Fluoro-4-methyl-phenylamino)-pyrimidin-4-yI]-methyI-amino}-
methyI)-piperidine-1-carboxylic acid tert-butyl ester (Compound A45).
Compound A45 was obtained as a solid (7 mg, 11%). Exact mass calculated for C23H32FN502
429.2, found 430.1 (M+H4).
Example 9.34: 4-({[6-(3-Chloro-2-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyI)-
piperidine-1-carboxylic acid tert-butyl ester (Compound A46).
Compound A46 was obtained as a solid (19 mg, 28%). Exact mass calculated for
C22H29FC1N502 449.2, found 450.4 (M+H4).

Example 9.35: 4-({[6-(2,4-Difluoro-phenyIamino)-pyrimidin-4-yI]-methyl-amino}-methyl)-
piperidine-1-carboxylic acid tert-butyl ester (Compound A47).
Compound A47 was obtained as a solid (26 mg, 40%). Exact mass calculated for
C22H29F2N502 433.2, found 434.4 (M+H*").
Example 9.36: 4-[(Methyl-{6-[2-(l-oxy-pyridin-3-yl)-ethyIamino]-pyrimidin-4-yl}-amino)-
methyl]-piperidine-1-carboxylic acid tert-butyl ester (Compound A48).
Compound A48 was obtained as a solid (6 mg, 9%). Exact mass calculated for C23H34N6O3
442.2, found 443.3 (M+H*).
Example 9.37: 4-({[6-(4-Cyano-2-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyI)-
piperidine-1-carboxylic acid isobutyl ester (Compound-A51).
Compound A51 was obtained as a trifluoroacetic acid salt (37 mg, 9%). 'HNMR (CDC13, 400
MHz) 5 0.94 (d, 6H), 1.21-1.25 (m, 2H), 1.57-1.60 (m, 2H), 1.89-1.96 (m, 2H), 2.72-2.74 (m, 2H),
3.00 (s, 3H), 3.55-3.60 (m, 2H), 3.86 (d, 2H), 4.10-4.18 (m, 2H), 5.37 (d, 1H), 7.51-7.53 (m, 3H),
8.20 (s, 1H), 11.8 (s, 1H). Exact mass calculated for C23H29FN602 440.2, found 441.3 (M+H*).
Example 9.38: 4-({[6-(4-Ethylsulfamoyl-2-fluoro-phenylamino)-pyrimidin-4-yI]-methyI-amino}-
methyI)-piperidine-1-carboxy!ic acid tert-butyl ester (Compound A58).
Compound A58 was obtained as white solid (6mg, 8 %). Exact mass calculated for C24H35 F
N604S 522.2, found LCMS (ESI) m/z 523.4(M+Ff, 100%).
Example 9.39: 4-({[6-(2-FIuoro-4-isopropylsulfamoyl-phenylamino)-pyrimidin-4-yl]-methyl-
amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester (Compound A59).
Compound A59 was obtained as white solid (7mg, 9 %). Exact mass calculated for C25H37 F
N604S 536.3, found LCMS (ESI) m/z 537.4(M+Ff, 100%).
Example 9.40: 4-({[6-(4-Cyano-2,5-difluoro-phenyIamino)-pyrimidin-4-yI]-methyl-amino}-
methyl)-piperidine~l-carboxylic acid tert-butyl ester (Compound A60).
Compound A60 was obtained as white solid (4mg, 6 %). Exact mass calculated for C23H2g F2
N602 458.2, found CCMS (ESI) m/z 459.3(M+H+, 100%).
Example 9.41: 4-({[6-(4-Bromo-2,5-difluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-
methyl)-piperidine-1-carboxylic acid tert-butyl ester (Compound A61).
Compound A61 was obtained as yellow solid (25mg, 32 %). Exact mass calculated for
C22H2sBrF2N502 511.1, found LCMS (ESI) m/z 512.2(M+Ff, 100%).

Example 9.42: 4-({[6-(5-Carboxy-2-fluoro-phenyIamino)-pyrimidin-4-yI]-methyI-amino}-
methyI)-piperidine-1-carboxylic acid tert-butyl ester (Compound A62).
Compound A62 was obtained as brown solid (2mg, 3 %). Exact mass calculated for
C23H30FN5O4 459.2, found LCMS (ESI) m/z 460.3(M+HT, 100%).
Example 9.43: 4-({[6-(6-Methoxy-pyridin-3-yIamino)-pyrimidin-4-yl]-methyI-amino}-methyI)-
piperidine-1-carboxylic acid tert-butyl ester (Compound A63).
Compound A63 was obtained as brown solid (1 lmg, 17 %). Exact mass calculated for
C22H32N603 428.3, found LCMS (ESI) m/z 429.2(M+H", 100%).
Example 9.44: 4-({[6-(2,6-Dimethoxy-pyridin-3-yIamino)-pyrimidin-4-yI]-methyI-amino}-
methyl)-piperidine-1-carboxyIic acid tert-butyl ester (Compound A64).
Compound A64 was obtained as brown solid (8mg, 12 %). Exact mass calculated for
C23H34N604 458.3, found LCMS (ESI) m/z 459.3(M+H+, 100%).
Example 9.45: 6-{6-[(l-tert-Butoxycarbonyl-piperidin-4-ylmethyI)-methyl-amino]-pyrimidin-4-
ylamino}-nicotinic acid (Compound A65).
Compound A65 was obtained as tan solid (2mg, 3 %). Exact mass calculated for C22H30N6O4
442.2, found LCMS (ESI) m/z 443.4(M+lf, 100%).
Example 9.46: 4-({[6-(6-AcetyIamino-pyridin-3-ylamino)-pyrimidin-4-yl]-methyI-amino}-
methyl)-piperidine-1-carboxylic acid tert-butyl ester (Compound A66). -
Compound A66 was obtained as yellow solid (3mg, 4 %). Exact mass calculated for
C23H33N7O3 455.3, found LCMS (ESI) m/z 456.2(M+jf, 100%).
Example 9.47: 4-({[6-(5-Fluoro-pyridin-2-ylamino)-pyrimidin-4-yI]-methyI-amino}-methyI)-
piperidine-1-carboxylic acid tert-butyl ester (Compound A67).
Compound A67 was obtained as yellow solid (19mg, 31%). Exact mass calculated for C21H29
FN602 416.2, found LCMS (ESI) m/z 417.3(M+Hf, 100%).
Example 9.48: 4-({[6-(4-Cyano-2-ethyl-phenylamino)-pyrimidin-4-yI]-methyI-amino}-methyl)-
piperidine-1-carboxylic acid tert-butyl ester (Compound A68).
Compound A68 was obtained as white solid (8mg, 12%). Exact mass calculated for C25H34
N602 450.3, found LCMS (ESI) m/z 451.3(M+Hf, 100%).
Example 9.49: 4-({[6-(4-Butyryl-phenyIamino)-pyrimidin-4-yI]-methyl-amino}-methyI)-
piperidine-1-carboxylic acid tert-butyl ester (Compound A69).

Compound A69 was obtained as yellow solid (9mg, 13%). Exact mass calculated for C26H37
N5O3 467.3, found LCMS (ESI) m/z 468.5(M+H+, 100%).
Example 9.50: 4-({[6-(5-Bromo-3-methyl-pyridin-2-yIamino)-pyrimidin-4-yl]-methyl-amino}-
methyl)-piperidine-1-carboxylic acid tert-butyl ester (Compound A70).
Compound A70 was obtained as yellow solid (4mg, 5%). Exact mass calculated for C22H31
BrN602 490.2, found LCMS (ESI) m/z491.3(M+Ff, 100%).
Example 9.51: 4-({[6-(3-Bromo-5-methyl-pyridin-2-ylamino)-pyrimidin-4-yl]-methyl-amino}-
methyl)-piperidine-1-carboxylic acid tert-butyl ester (Compound A71).
Compound A71 was obtained as yellow solid (17mg, 23%). Exact mass calculated for C22H31
BrN602490.2, found LCMS (ESI) m/z 491.3(M+H+, 100%).
Example 9.52: 4-({Methyl-[6-(5-trifluoromethyI-pyridin-2-yIamino)-pyrimidin-4-yl]-amino}-
methyl)-piperidine-1-carboxylic acid tert-butyl ester (Compound A72).
Compound A72 was obtained as yellow solid (2mg, 3%). Exact mass calculated for
C22H29F3N602 466.2, found LCMS (ESI) m/z 467.3(M+Hf, 100%).
Example 9.53: 4-({[6-(4-Bromo-2-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-
piperidine-1-carboxylic acid tert-butyl ester (Compound A73).
Compound A73 was obtained as cream solid (9mg, 12%). Exact mass calculated for C22H29
BrFN502 493.2, found LCMS (ESI)m/z 496.4(M+FT\ 100%). • ■■
Example 9.54: 4-({[6-(3-Carboxy-4-fiuoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-
methyl)-piperidine-1-carboxylic acid tert-butyl ester (Compound A74).
Compound A74 was obtained as cream solid (lmg, 1%). Exact mass calculated for C23H30
FN5O4 459.2, found LCMS (ESI) m/z 460.4(M+H+, 100%).
Example 9.55: 4-({[6-(4-Ethoxycarbonyl-2-fluoro-phenyIamino)-pyrimidin-4-yI]-methyl-
amino}-methyl)-piperidine-1-carboxyIic acid isobutyl ester (Compound A75).
and
Example 9.56: 4-({[6-(4-Carboxy-2-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-
methyI)-piperidine-1-carboxylic acid isobutyl ester (Compound A76).
Step 1: Preparation of (4-cyano-2-fluoro-phenyl)-carbamic acid 9i?-fluoren-9-ylmethyl
ester.
A mixture of 2.05 g (15.06 mmol) 4-amino-3-fluorobenzonitrile and 2 g (23.8 mmol) sodium
bicarbonate in 30 mL acetonitrile was cooled in an ice-bath and 4.4 g (17.0 mmol) FMOC-C1 were

added. Mixture was allowed to warm to room temperature. After 16 h, mixture was concentrated and
extracted with 1M HC1 and ethyl acetate. Combined organic phases were dried over magnesium
sulfate, filtered, and concentrated. Crystallization out of ethyl acetate/hexane gave (4-cyano-2-fluoro-
phenyl)-carbamic acid 9#-fluoren-9-yImethyl ester as a white solid (2.68 g, 50%).1HNMR (CDC13,
400 MHz) d 4.21-4.24 (t, 1H), 4.50-4.54 (d, 2H), 6.99 (s br, 1H), 7.19-7.32 (m, 6H), 7.48-7.58 (m,
2H), 7.67-7.74 (m, 2H), 8.16 (s br, 1H). Exact mass calculated for C22H15FN2Q2 358.11, found 358.9
(MH4).
Step 2: Preparation of 4-amino-3-fluoro-benzoic acid ethyl ester.
HC1 was bubbled slowly through a solution of 1.6 g (4.46 mmol) (4-cyano-2-fluoro-phenyl)-
carbamic acid 9#-fiuoren-9-ylmethyl ester in 300 mL EtOH. After 5 h solution was concentrated.
Residue was dissolved in 100 mL THF and 100 mL 6 M HC1 in water. After stirring for 4 h at 50°C,
mixture was concentrated. Residue was treated with 2M NHEt2 in MeOH. After 3h, mixture was
concentrated, and residue was purified by HPLC to give 4-amino-3-fluoro-benzoic acid ethyl ester as
a white solid (TFA salt, 0.696 g, 42%). 'HNMR (MeOD, 400 MHz) 8. 1.20-1.25 (t, 3H), 4.13-4.22 (q,
2H), 6.66-6.71 (m, 1H), 7.42-7.50 (m, 2H). Exact mass calculated for C9Hi0FNO2 183.07, found
184.0(MIf).
Step 3: Preparation of Compound A75 and Compound A76.
Compound A75 was prepared in a similar manner as described above as a TFA salt, 13.2 mg,
11% (tan solid), and Compound A76 was also obtained as a TFA salt, 24.4 mg, 21% (tan solid).
Compound A75: 'HNMR (MeOD, 400 MHz) 5 0.79-0.84 (d, 6H), 1.10-1.19 (m, 2H), 1.28-
1.32 (t, 3H), 1.56-1.59 (m, 2H), 1.79-1.94 (m, 2H), 2.62-2.81 (m, 2H), 3.03 (s, 3H), 3.38-3.51 (m,
2H), 3.74-3.-76 (d, 2H), 4.04-4.07(d br, 2H),-4.26-4;32 (m,-2H), 5.91 (s, 1H), 7.67-7.83 (m, 3H), 8;-l8
(s, 1H); Exact mass calculated for C25H34FN5O4 487.26, found 488.2 (MH4).
Compound A76: 'HNMR (MeOD, 400 MHz) 8 0.89-0.91 (d, 6H), 1.05-1.20 (m, 2H), 1.55-
1.58 (m, 2H), 1.78-1.95 (m, 2H), 2.60-2.80 (m, 2H), 3.14 (s, 3H), 3.41-3.51 (m, 2H), 3.72-3.74 (d,
2H), 4.01-4.06 (d br, 2H), 5.89 (s, 1H), 7.62-7.66 (m, 1H), 7.76-7.84 (m, 2H), 8.18 (s, 1H); Exact
mass calculated for C23H30FN5O4 459.23, found 460.3 (MPf).
Example 9.57: 4-({[6-(4-Cyano-2-fluoro-phenyIamino)-pyrimidin-4-yI]-methyl-amino}-methyl)-
piperidine-1-carboxylic acid isopropyl ester (Compound A77).
Compound A77 was obtained as a solid (20 mg, 48%). 'HNMR (CDC13, 400 MHz) 8 1.19-
1.24 (m, 8H), 1.61-1.64 (m, 2H), 1.90-1.96 (m, 1H), 2.68-2.74 (m, 2H), 3.01-3.04 (m, 3H), 3.45-3.55
(m, 2H), 4.10-4.30 (m, 2H), 4.89-4.92 (m, 1H), 5.73 (s, 1H), 7.36-7.45 (m, 2H), 8.34 (s, 1H), 8.50 (t,
1H). Exact mass calculated for C22H27FN602 426.2, found 427.2 (MH4).
Example 9.58: 4-({[6-(4-Cyano-2-fluoro-phenylamino)-pyrimidin-4-yI]-methyl-amino}-methyI)-
piperidine-1-carboxylic acid butyl ester (Compound A78).

Compound A78 was obtained as a trifluoroacetic acid salt (30 mg, 68%). 'HNMR (CDCI3,
400 MHz) 5 0.94 (t, 3H), 1.20-1.26 (m, 2H), 1.33-1.43 (m, 2H), 1.58-1.63 (m, 4H), 1.90-1.96 (m, 1H),
2.62-2.78 (m, 2H), 3.00 (s, 3H), 3.66-3.68 (m, 2H), 4.06-4.30 (m, 4H), 5.37 (s, 1H), 7.48-7.58 (m,
3H), 8.20 (s, 1H), 11.9 (s, 1H). Exact mass calculated for C23H29FN602 440.2, found 441.4 (M+H4).
Example 9.59: 4-({[6-(4-Cyano-2-fluoro-phenylamino)-pyrimidin-4-yl]-methyI-amino}-methyl)-
piperidine-1-carboxylic acid cyclopropylmethyl ester (Compound A79).
Compound A79 was obtained as a solid (26 mg, 45%). Exact mass calculated for
C23H27FN602 438.2, found 439.3 (M+lf).
Example 9.60: {4-[6-(2-Fluoro-4-methanesuIfonyl-phenylamino)-pyrimidin-4-yl]-piperazin-1-
yl}-acetic acid ethyl ester (Compound A80).
Step 1: Preparation of [4-(6-chIoro-pyrimidin-4-yl)-piperazin-1-yl]-acetic acid ethyl
ester.
A mixture of 4,6-dichloropyrimidine (1 g, 6.75 mmol), l-(ethoxycarbonylmethyl) piperazine
(1.16 g, 6.75 mmol) and diisopropyl ethyl amine in isopropyl alcohol (8 mL) was heated under
microwave irradiation at 100°C for 2 minutes. The crude was purified by flash chromatography
(hexane : ethyl acetate = 1:2) to give [4-(6-chloro-pyrimidin-4-yl)-piperazin-1-yl]-acetic acid ethyl
ester as an oil (1.80 g, 93%). 1HNMR (CDC13,400 MHz) 8 1.29 (t, 3H), 2.69 (s, 4H), 3.29 (s, 2H),
3.72 (s, 4H), 4.20 (q, 2H), 6.50 (s, 1H), 8.37 (s, 1H). Exact mass calculated for C12H,7C1N402 284.2,
found 258.0 (M+H4).
Step 2:~Preparationof {4^[6-(2-FIuoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-
yl]-piperazin-1-yl}-acetic acid ethyl ester (Compound A80).
Compound A80 was prepared in a similar manner as described above as a solid (290 mg,
62%). 1HNMR (CDCI3, 400 MHz) 5 1.42 (t, 3H), 2.90-2.93 (m, 4H), 3.06-3.07 (m, 3H), 3.46 (s, 2H),
3.80-3.90 (m, 4H), 4.40 (q, 2H), 5.88 (s, 1H), 7.70-7.78 (m, 2H), 8.46 (s, 1H), 8.61-8.65 (t, 1H), 9.83
(s, 1H). Exact mass calculated for Q9H24FN5O4S 437.2, found 438.2 (M+H4).
Example 9.61: (2-FIuoro-4-methanesulfonyl-phenyl)-{6-[4-(3-isopropyI-[l,2,4]oxadiazol-5-
ylmethyl)-piperazin-1-yl]-pyrimidin-4-yl}-amine (Compound A81).
Compound A81 was obtained as a solid (30 mg, 14%). Exact mass calculated for
C21H26FN703S 475.2, found 476.2 (M+H*).
Example 9.62: 4-({[6-(2,5-Difluoro-4-hydroxy-phenyIamino)-pyrimidin-4-yl]-methyl-amino}-
methyI)-piperidine-1-carboxylic acid isobutyl ester (Compound A82).
Compound A82 (TFA salt, 77.9 mg, 44%) was obtained as a tanned solid. 'HNMR (DMSO,
400 MHz) 5 0.84-0.86 (d, 6H), 1.01-1.15 (m, 2H), 1.54-.1.57 (m, 2H), 1.80-1.99 (m, 2H), 2.65-2.85

(m,.2H), 3.06 (s, 3H), 3.40-3.52 (m, 2H), 3.76-3.81 (d, 2H), 3.92-4.01 (m, 3H), 5.72 (s br, 1H), 6.90-
6.98 (m, 1H), 7.41-7.45 (s, 1H), 8.31 (s, 1H), 9.73 (s br 1H), 10.50 (s br, 1H). Exact mass calculated
for C22H29F2N503 449.2, found 450.3 (MH*).
Example 9.63: 4-({[6-(4-EthyIcarbamoyl-2-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-
amino}-methyl)-piperidine-1-carboxylic acid isobutyl ester (Compound A83).
A mixture of compound A76 (TFA salt, 35.2 mg, mmol) in 1 mL 2M ethyl amine was stirred at room temperature. After 10 min, the solution was
continued to be stirred in microwave at 180°C. After 1 hour, mixture was purified by HPLC to give
compound A83 as a white solid (TFA salt, 9.5 mg, 26%). 1HNMR (MeOD, 400 MHz) 5 0.81-0.83 (d,
6H), 1.05-1.16 (m, 5H), 1.53-1.61 (m, 2H), 1.79-1.99 (m, 2H), 2.62-2.80 (m, 2H), 3.07 (s, 3H), 3.30-
3.35 (q, 2H), 3.42-3.55 (m, 2H), 3.74-3.76 (d, 2H), 4.03-4.07 (d br, 2H), 5.82 (s br, 1H), 7.54-7.68 (m,
3H), 8.17 (s,lH). Exact mass calculated for C25H35FN603 486.28, found 487.3 (MH*).
Example 9.64: 4-[({6-[2-Fluoro-4-(N-hydroxycarbamimidoyI)-phenylamino]-pyrimidin-4-yl}-
methyl-amino)-methyI]-piperidine-1-carboxylic acid isobutyl ester (Compound A84).
A mixture of4-({[6-(4-cyano-2-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-
methyl)-piperidine-1-carboxylic acid isobutyl ester (Compound A51, 33.5 mg, 0.060 mmol),
hydroxylamine hydrochloride (430 mg, 6.19 mmol), and potassium carbonate (870 mg, 6.29 mmol) in
1 mL EtOH and 0.5 mL H20 was stirred for 20 min at 80°C. Mixture was purified by HPLC to give
Compound A84 as a white solid (TFA salt, 32.2 mg, 91%). 'HNMR (MeOD, 400 MHz) 8 0.83-0.86
(d, 6H), 1.10-1-17 (m,-2H),l.57-1.60 (m,-2H), 1.88-1.99 (m,2H), 2:63-.2.80 (m, 2H), 3.03 (s, 3H),
3.40-3.45 (m, 2H), 3.74-3.76 (d, 2H), 4.04-4.07 (d br, 2H), 6.03 (s, 1H), 7.45-7.54 (m, 2H), 8.14-8.19
(m, 2H). Exact mass calculated for C23H32FN703 473.26, found 474.5 (MH4).
Example 9.65: 4-({[6-(4-Carbamimidoyl-2-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-
amino}-methyl)-piperidine-1-carboxylic acid isobutyl ester (Compound A90).
To a solution of Compound A84 (TFA salt, 22.6 mg, 0.0385 mmol) in 1 mL acetic acid, zinc
powder (50 mg, 0.76 mmol) was added. After stirring the mixture for 10 min, Zn was filtered off;
filtrate was concentrated, and purified by HPLC to give Compound A90 as a white solid (8.4 mg,
38%). 'HNMR (MeOD, 400 MHz) 8 0.80-8.83 (d, 6H), 1.05-1.17 (m, 2H), 1.55-1.61 (m, 2H), 1.80-
2.01 (m, 2H), 2.61-2.81 (m, 2H), 3.07 (s, 3H), 3.40-3.47 (m, 2H), 3.69-3.71 (d, 2H), 4.04-4.07 (d br,
2H), 6.05 (s, 1H), 7.54-7.67 (m, 2H), 8.07-8.12 (m, 1H), 8.22 (s, 1H). Exact mass calculated for
C23H32FN702 457.26, found 458.3 (MH4).
Example 9.66: 4-({[6-(2,5-Difluoro-4-methanesulfonyI-phenylamino)-pyrimidin-4-yl]-methyl-
amino}-methyI)-piperidine-1-carboxylic acid tert-butyl ester (Compound A86).

Compound A86 was obtained as a solid (57 mg, 37%). Exact mass calculated for
C23H31F2N5O4S5H.2, found 512.3 (M+H4).
Example 9.67: N-(2-FIuoro-4-methanesulfonyl-phenyl)-N'-(5'-fluoro-3,4,5,6-tetrahydro-2H-
[l4lbipyridinyI-4-ylmethyl)-N'-methyl-pyrimidine^,6-diamine (Compound A89).
Compound A89 was obtained as a solid (3 mg, 6%). Exact mass calculated for
C23H26F2N602S 488.2, found 489.2 (M+H4).
Example 9.68: 4-[6-(2-Fluoro-4-methanesulfonyI-phenylamino)-pyrimidin-4-ylamino]-
piperidine-1-carboxylic acid tert-butyl ester (Compound A92).
Compound A92 was obtained as a solid (18 mg, 13%). Exact mass calculated for
C2,H28FN504S 465.2, found 466.3 (M+H4).
Example 9.69: Ar-(2-Fluoro-4-methanesulfonyl-phenyl)-N'-[l-(3-isopropyl-[l,2,4]oxadiazol-5-
yImethyl)-piperidin-4-ylmethyl]-N'-methyl-pyrimidine-4,6-diamine (Compound A93).
Compound A93 was obtained as a solid (45 mg, 38%). Exact mass calculated for
C24H32FN703S 517.2, found 518.4 (M+H1).
Example 9.70: 4-({[6-(4-Cyano-2,5-difluoro-phenyIamino)-pyrimidin-4-yl]-ethyI-amino}-
methyl)-piperidine-1-carboxylic acid isopropyl ester (Compound A97).
A mixture of4-[6-(ethyl-piperidin-4-ylmethyl-amino)-pyrimidin-4-ylamino]-2,5-difluoro-
- benzonitrile (HGl-salt, 1.8712 g, 4.57-mmol); Iriethylamine (1.91 mL, 13.71 mmol), and isopropyl
chloroformate (1M in toluene, 9.14 mL, 9.14 mmol) in 100 mL CH3CN was stirred at room
temperature for 30 min. Mixture was purified by HPLC to give Compound A97 as a white solid
(TFA salt, 600 mg, 23%). 'HNMR (MeOD-d4, 400 MHz) 8 1.13-1.21 (d br, 11H), 1.59-1.67 (d, 2H),
1.96 (s br, 1H), 2.7 (s br, 2H), 3.4 (s br, 2H), 3.51-3.61 (d br, 2H), 4.05-4.15 (d, 2H), 4.75-4.83 (m,
1H), 6.26 (s, 1H), 7.61-7.67 (m, 1H), 8.04-8.11 (m, 1H), 8.33 (s, 1H). Exact mass calculated for
C23H28F2N602 458.22, found 459.5 (MH4).
Example 9.71: 4-({[6-(2,5-Difluoro-4-methoxy-phenylamino)-pyrimidin-4-yl]-ethyl-amino}-
methyl)-piperidineTl-carboxylic acid tert-butyl ester (Compound A99).
A mixture of 4-( {[6-(2,5-difluoro-4-hydroxy-phenylamino)-pyrimidin-4-yl]-ethyl-amino} -
methyl)-piperidine-1-carboxylic acid tert-butyl ester (61.9 mg, 0.134 mmol), diisopropyl ethylamine
(33 \i\, 0.189 mmol), and (trimethylsilyl)diazomethane (2M in Et20, 94 jj.1, 0.188 mmol) in 0.5 mL
CH3CN/MeOH 9:1 was stirred at room temperature for 15 h. Mixture was purified by HPLC to give
Compound A99 as a white solid (TFA salt, 24.3 mg, 31%). 'HNMR (MeOD, 400 MHz) 8 1.02-1.12
(m, 5H), 1.36 (s, 9H), 1.50-1.60 (m, 2H), 1.81-1.90 (m, 1H), 2.59-2.70 (m, 2H), 3.33-3.52 (m, 4H),

3.82 (s, 3H), 3.98-4.05 (d br, 2H), 5.64 (s, 1H), 6.78-6.80 (m, 1H), 7.05-7.20 (m, 1H), 8.09 (s, IH).
Exact mass calculated for C24H33F2N5O3 477.26, found 478.1 (MB4).
Example 9.72: 4-({[6-(2,5-Difluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-ethyl-
amino}-methyI)-piperidine-1-carboxyIic acid tert-butyl ester (Compound A100).
Compound A100 was obtained as an off-white powder (32.5 mg, 22 %). Exact mass
calculated for C24H33F2N504S 525.2, found LCMS (ESI) m/z 526.5 (M+Ff'89%).
Example 9.73: 4-({Ethyl-[6-(2,4,5-trifluoro-phenylamino)-pyrimidin-4-yI]-amino}-methyl)-
piperidine-1-carboxylic acid tert-butyl ester (Compound A101).
Compound A101 was obtained as an off-white powder (16.3 mg, 13%). Exact mass
calculated for C23H3oF3N502 465.2, found LCMS (ESI) m/z 466.4 (M+Ff-100%).
Example 9.74: 4-({[6-(4-Bromo-2,5-difluoro-phenylamino)-pyrimidin-4-yI]-ethyl-amino}-
methyl)-piperidine-1-carboxylic acid tert-butyl ester (Compound A104).
Compound A104 was obtained as a white powder (20.1 mg, 14%). Exact mass calculated for
C23H3oBrF2N502 525.2, found LCMS (ESI) m/z 528.5 (M+Ff'74%).
Example 9.75: {l-[6-(2-Fluoro-4-methanesulfonyI-phenyIamino)-pyrimidin-4-yl]-piperidin-4-
yl}-acetic acid methyl ester (Compound A106).
Compound A106 was obtained as a solid (62 mg, 30%). Exact mass calculated for
-C^HisFN^S 422.1; found 423.1 (M+Ff).
Example 9.76: 3-{4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yI]-piperazin-1-
yl}-propionic acid ethyl ester (Compound A107).
Compound A107 was obtained as a solid (50 mg, 23%). Exact mass calculated for
C2oH26FN504S 451.2, found 452.1 (M+Ff).
Example 9.77: (2-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(4-isobutyl-phenyl)-piperidin-1-yI]-
pyrimidin-4-yI}-amine (Compound A108).
Compound A40S was obtained as a solid (35 mg, 15%). Exact mass calculated for
C26H3iFN402S 482.2, found 483.4 (M+Ff).
Example 9.78: (2-FIuoro-4-methanesulfonyl-phenyl)-{6-[4-(4-isopropyl-phenyl)-piperidin-1-ylJ-
pyrimidin-4-yl}-amine (Compound A109).
Compound A109 was obtained as a solid (44 mg, 19%). Exact mass calculated for
C25H29FN402S 468.2, found 469.4 (M+Ff).

Example 9.79: (2-Fluoro-4-methanesulfonyl-phenyl)-(6-{4-[2-(3-isopropyl-[l,2,4]oxadiazol-5-
yI)-ethyl]-piperazin-1-yl}-pyrimidin-4-yl)-amine (Compound A116).
Compound A116 was obtained as a solid (160 mg, 100%). Exact mass calculated for
C22H28FN703S 489.2, found 490.2 (M+H4).
Example 9.80: (2-Fluoro-4-methanesuIfonyl-phenyl)-{6-[4-(5-isopropoxy-pyridin-2-yloxy)-
piperidin-1-yl]-pyrimidin-4-yl}-amine (Compound A117).
Compound A117 was obtained as a solid (180 mg, 70%). 1HNMR (CDC13, 400 MHz) 8 1.36
(d, 6H), 1.95-2.08 (m, 4H), 3.07 (s, 3H), 4.50 (sept, 1H), 5.22 (s, 1H), 5.53 (s, 1H), 6.86-6.88 (m, 1H),
7.46-7.48 (m, 1H), 7.59-7.63 (m, 1H), 7.80-7.82 (m, 2H), 7.88 (s, 1H), 8.27 (s, 1H), 11.6 (s, 1H).
Exact mass calculated for C24H28FN504S 501.2, found 502.2 (M+H4).
Example 9.81: 4-({[6-(2-Fluoro-4-methanesuIfonyl-phenyIamino)-pyrimidin-4-yI]-isopropyl-
amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester (Compound A122).
Compound A122 was obtained as a solid (33 mg, 32%). Exact mass calculated for
C25H36FN504S 521.2, found 522.5 (MH4).
Example 9.82: 4-({[6-(4-Methanesulfonyl-phenyIamino)-pyrimidin-4-yI]-methyl-amino}-
methyl)-piperidine-1-carboxylic acid tert-butyl ester (Compound A5).
(6-Chloro-pyrimidin-4-yl)-(4-methanesulfonyl-phenyl)-amine (57mg, 0.2mmol), 4-
"methylaminomethyl-piperidme-1-carboxylic acid tert-butyl ester (0.2mmole,1.0eq) and K2C03 -
(0.4mmol, 2eq) were dissolved in DMF (3mL) and then stirred at 120°C for 24 hours. The crude was
purified through HPLC provided Compound A5 as white solid (48mg, 51%). !H NMR 400MHz
CDC13 6 (ppm): 9.79(sb, NH); 8.30(s,lH); 7.84(d, 2H); 7.80 (d,2H); 5.95(s,lH); 3.94(m, 2H); 3.42(m,
2H); 3.15 (s, 3H); 3.03(s, 3H); 2.61(m, 2H); 1.95-1.87(m,lH); 1.57-1.54(m,2H); 1.39(s, 9H); 1.15-
1.03(m, 2H). Exact mass calculated for C^JfeNsC^ S 475.2, LCMS (ESI) m/z 476.2(M+H+, 100%).
Using essentially the same methodology and procedures as described in the Reaction
Scheme(s) and Examples herein, the following compounds are prepared from the appropriate
materials:
Example 9.83: 4-{[6-(2-Fluoro-4-methanesuIfonyl-phenylamino)-pyrimidin-4-yl]-methyl-
amino}-piperidine-1-carboxylic acid tert-butyl ester (Compound A3).
Compound A3 was obtained as a solid (6 mg, 20%). Exact mass calculated for CZ1H30FN5O4S
479.2, found 480.4 (M+H4).

Example 9.84: 4-({MethyI-[6-(2-pyridin-4-yl-ethylamino)-pyriraidin-4-yI]-amino}-methyI)-
piperidine-1-carboxylic acid tert-butyl ester (Compound A9).
Compound A9 was obtained as yellow solid (7mg, 8%). Exact mass calculated for C23H34
N602 426.3, LCMS (ESI) m/z 427.2(M+HI", 100%).
Example 9.85: 4-({Methyl-[6-(2-pyridin-3-yl-ethylamino)-pyrimidin-4-yl]-amino}-methyl)-
piperidine-1-carboxylic acid tert-butyl ester (Compound A10).
Compound A10 was obtained as yellow solid (13mg, 15%). Exact mass calculated for C23H34
N602 426.3, LCMS (ESI) m/z 427.3(M+HT, 100%).
Example 9.86: 4-[(Methyl-{6-[(pyridin-3-ylmethyl)-amino]-pyrimidin-4-yl}-amino)-methyI]-
piperidine-1-carboxylic acid tert-butyl ester (Compound All).
Compound All was obtained as yellow solid (5mg, 6%). Exact mass calculated for C22H32
N602 412.3, LCMS (ESI) m/z 413.4(M+H+, 100%).
Example 9.87: 4-[(MethyI-{6-[2-(l-oxy-pyridin-3-yl)-ethylamino]-pyrimidin-4-yI}-amino)-
methyl]-piperidine-1-carboxylic acid isobutyl ester (Compound A49).
Compound A49 was obtained as a solid (24 mg, 55%). Exact mass calculated for
C27H39FN604S 562.2, found 563.5 (M+H4).
Example 9.88: 4-[({6-[2-(2-Fluoro-phenoxy)-ethyIamino]-pyrimidin-4-yl}-methyI-amino)-
methyl]-piperidine-1-carboxylic acid tert-butyl ester (Compound A52); -
Compound A52 was obtained as a solid (1 mg, 2%). Exact mass calculated for C24H34FN5O3
459.2, found 460.3 (M+H4).
Example 9.89: 4-({[6-(2-Fluoro-phenoxy)-pyrimidin-4-yI]-methyl-amino}-methyI)-piperidine-1-
carboxylic acid tert-butyl ester (Compound A53).
Compound A53 was obtained as a solid (12 mg, 20%). Exact mass calculated for
C22H29FN4O3 416.2, found 417.4 (M+H4).
Example 9.90: 4-({T5-(2,5-Difluoro-phenoxy)-pyrimidin-4-yl]-methyl-amino}-methyl)-
piperidine-1-carboxylic acid tert-butyl ester (Compound A54).
Compound A54 was obtained as a solid (6 mg, 9%). Exact mass calculated for C22H28F2N4O3
434.2, found 435.2 (M+H4).
Example 9.91: 4-[({6-[2-(2-ChIoro-phenoxy)-ethylamino]-pyrimidin-4-yI}-methyl-amino)-
methyl]-piperidine-1-carboxyIic acid tert-butyl ester (Compound A55).

Compound A55 was obtained as a solid (5 mg, 9%). Exact mass calculated for C24H34CIN5O3
475.2, found 476.3 (M+lT).
Example 9.92: 4-({[6-(2-Chloro-phenoxy)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-
carboxylic acid tert-butyl ester (Compound A56).
Compound A56 was obtained as a solid (16 mg, 25%). Exact mass calculated for
C22H29C1N403 432.2, found 433.2 (M+H4).
Example 9.93: 4-[({6-[2-(4-FIuoro-phenoxy)-propylamino]-pyrimidin-4-yI}-methyI-amino)-
methyl]-piperidine-1-carboxylic acid tert-butyl ester (Compound A57).
Compound A57 was obtained as a solid (12 mg, 17%). Exact mass calculated for
C^HseFNsOs 473.2, found 474.4 (M+H*).
Example 10:
Example 10.1: Preparation of 4-[6-(2-FIuoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-
yloxy]-piperidine-1-carboxylic acid tert-butyl ester, also referred to herein as Compound Bl.
Step 1: Preparation of 4-(6-chloro-pyrimidin-4-yIoxy)-piperidine-1-carboxyIic acid tert-
butyl ester.
4-Hydroxy-piperidine-1-carboxylic acid tert-butyl ester (46mmol, 1.3eq) andNaH (92mmole,
2eq, 60% in mineral oil) were dissolved in THF (30ml) under N2 and stirred at 60°C for 40 minutes
■ then 4,'6-dichloropyrimidine (5.237g, 35;4mmole) was added into the solution-dropwise. The •
reaction mixture was stirred at room temp for another 20minutes. The reaction was quenched with
water, extracted with ethyl acetate, and concentrated in vacuo, and purified by flash column (Hexane :
Ethyl Acetate= 2:1, Rf=0.48) to provide 4-(6-chloro-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid
tert-butyl ester as a yellow oil (3.236 g, 29 %). Exact mass calculated for C^HboClNsOs 313.1,
found 314.2 (MH1).
Step 2: Preparation of 2-fluoro-4-(methanesulfonyl)aniIine.
To a solution of 2-fluoro-4-iodoaniline (206.8 g, 872.3 mmol) in DMSO (1.1 L), was added
by the sequential addition of copper (IT) trifluoromethanesulfonate-benzene complex (30.74 g, 61.1
mmol), sodium metHanesulfinate (106.9 g, 1.047 mol), and N,W-dimethylethylenediamine (13.2 mL,
122 mmol). The reaction vessel was then placed in a preheated oil bath at 120 °C and stirred
overnight. After cooling to room temperature, the reaction was diluted with water and extracted
repeatedly with EtOAc. The combined organic extract was rinsed with brine (5X), dried over MgS04,
and the solvent was removed. The resulting purple solid was rinsed with diisopropyl ether, then dried
to constant weight in a vacuum oven at room temperature overnight to furnish a dull purple solid

1 £ 1.5 g, 92% yield: 'H NMR (DMSO-rf6) 5 7.48 (d, 1 H, J = 11.2 Hz), 7.41 (d, 1 H, J = 8.5 Hz), 6.87
(t, 1 H, J = 8.6 Hz), 6.19 (s, 2 H), 3.10 (s, 3 H); MS m/z 190.3 (M4).
Step 3: Preparation of 4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-
yloxy]-piperidine-1-carboxyIic acid tert-butyl ester (Compound Bl).
A mixture of 4-(6-chloro-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid tert-butyl ester
(3.23 g, 10.3 mmol), 2-fluoro-4-methanesulfonylaniline (1.95 g, 10.3 mmol), palladium acetate (115
mg, 0.515 mmol), ditbutyl-biphenylphosphine (184 mg, 0.618 mmol) and sodium t-butoxide (2.47 g,
25.75 mmol) in dioxane (20 ml) was heated to reflux for 2 hours under nitrogen gas. The crude
mixture was quenched with water, extracted with ethyl acetate and concentrated in vacuo. The crude
was purified by flash column (hexanes: ethyl acetate = 1:1) to provide Compound Bl as a solid (1.69
g, 35%). 1HNMR (CDC13, 400 MHz) 5 1.44 (s, 9H), 1.63-1.80 (m, 2H), 1.97-2.06 (m, 2H), 3.07 (s,
3H), 3.25-3.31 (m, 2H), 3.70-3.78 (m, 2H), 5.27-5.33 (m, 1H), 6.18 (s, 1H), 7.52-7.57 (m, 1H), 7.70-
7.77 (m, 2H), 8.51 (s, 1H). Exact mass calculated for C^IH^FKAS 466.2, found 467.2 (MIT1).
Using essentially the same methodology and procedures as described in the Reaction
Scheme(s) and Examples herein, the following compounds were prepared from the appropriate
materials.
Example 10.2: (2-Fluoro-4-methanesulfonyI-phenyl)- {6- [l-(3-isopropyl- [1,2,4] oxadiazol-5-
yImethyl)-piperidm-4-yIoxy]-pyrimidin-4-yI}-amine (Compound B2).
Compound B2 was obtained as a solid (253 mg, 93%). Exact mass calculated for
C22H27FN604S 490.2,-found 491.2 (M+rf).
Example 10.3: 4-[6-(2,5-Difluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yIoxy]-
piperidine-1-carboxylic acid tert-butyl ester (Compound B13).
Compound B13 was obtained as a yellow powder (2.3 mg, 2 %). Exact mass calculated for
C2iH26F2N405S 484.2, found LCMS (ESI) m/z 485.2 (M+H+- 86%).
Example 10.4: 4-[6-(2,4,5-Trifluoro-phenylamino)-pyrimidin-4-yIoxy]-piperidine-1-carboxyIic
acid tert-butyl ester (Compound B14).
Compound"Bl4 was obtained as a yellow powder (6 mg, 7%). Exact mass calculated for
C20H23F3N4O3 424.2, found LCMS (ESI) m/z 425.3 (M+ET'99%).
Example 10.5: 4-[6-(4-Bromo-2,5-difluoro-phenylamino)-pyrimidin-4-yIoxy]-piperidine-1-
carboxylic acid tert-butyl ester (Compound B15).
Compound B15 was obtained as a yellow powder (1 mg, 1%). Exact mass calculated for
C2oH23BrF2N403 484.1, found LCMS (ESI) m/z 501.5 (M+H^'78%).

Example 10.6: 4-[6-(6-Chloro-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxyIic
acid tert-butyl ester (Compound B20).
Compound B20 was obtained as a tan powder (10.3 mg, 10%). Exact mass calculated for
C,9H24C1N503 405.2, found LCMS (ESI) m/z 406.2 (M+HM00%).
Example 10.7: 4-[6-(4-EthyIsulfanyl-phenyIamino)-pyrimidin-4-yIoxy]-piperidine-1-
carboxylic acid tert-butyl ester (Compound B27).
Compound B27 was obtained as a white powder (1 mg, 1%). Exact mass calculated for
C^HbFWjS 430.2, found LCMS (ESI) m/z 431.2 (M+^76%).
Example 10.8: 4-[6-(4-IsopropylsulfanyI-phenylamino)-pyrimidin-4-yloxyJ-piperidine-1-
carboxylic acid tert-butyl ester (Compound B28).
Compound B28 was obtained as an oil (1.4 mg, 2%). Exact mass calculated for
C23H3IFN403S 484.1, found LCMS (ESI) m/z 445.6 (M+H^'80%).
Example 10.9: 4-[6-(5-Chloro-3-methyl-pyridin-2-ylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid tert-butyl ester (Compound B30).
Compound B30 was obtained as an off-white powder (9 mg, 10%). Exact mass calculated for
CzoHteClNsOs 419.2, found LCMS (ESI) m/z 420.6 (M+HT'80%).
Example 10.10: 4-[6-(6-Acetylamino-4-methyI-pyridin-3-yIamino)-pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid tert-butyl ester (Compound B31).
Compound B31 was obtained as a brown powder (2.3 mg, 2%). Exact mass calculated for
C22H3oN604 442.2, found LCMS (ESI) m/z 443 (M+lT'41%).
Example 10.11: 4-[6-(5-Fluoro-4-methyl-pyridin-2-yIamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid tert-butyl ester (Compound B32).
Compound B32 was obtained as a peach powder (15.4 mg, 20%). Exact mass calculated for
C20H26FN5O3 403.2, found LCMS (ESI) m/z 404.3 (M+H4"'99%).
Example 10.12: 4-[6-(6-Methoxy-5-methyI-pyridin-3-yIamino)-pyrimidin-4-yloxy]-piperidine-
1-carboxylic acid tert-butyl ester (Compound B33).
Compound B33 was obtained as an off-white powder (10.7 mg, 10%). Exact mass calculated
for C2iH29N504 415.2, found LCMS (ESI) m/z 416.3 (M+H+,92%).

Example 10.13: 4-[6-(6-Methoxy-2-methyl-pyridin-3-ylamino)-pyrimidin-4-yIoxy]-piperidine-
1-carboxylic acid tert-butyl ester (Compound B34).
Compound B34 was obtained as an off-white powder (2 mg, 2%). Exact mass calculated for
C2,H29N504 415.2, found LCMS (ESI) m/z 416.3 (M+lf'94%).
Example 10.14: 4-[6-(6-FIuoro-5-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid tert-butyl ester (Compound B35).
Compound B35 was obtained as a tan powder (12.7 mg, 20%). Exact mass calculated for
C20H26FN5O3 403.2, found LCMS (ESI) m/z 404.3 (M+lT'92%).
Example 10.15: 4-[6-(2-Chloro-6-methyl-pyridin-3-ylamino)-pyrimidin-4-yIoxy]-piperidine-1-
carboxylic acid tert-butyl ester (Compound B36).
Compound B36 was obtained as a yellow powder (11.5 mg, 10%). Exact mass calculated for
C2oH26ClN503 419.2, found LCMS (ESI) m/z 420.5 (M+H^'99%).
Example 10.16: 4-[6-(4-Methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic
acid tert-butyl ester (Compound B37).
Compound B37 was obtained as an off-white powder (8.2 mg, 10%). Exact mass calculated
for C20H27N5O3 385.2, found LCMS (ESI) m/z 386.2 (M+lf'97%).
Example 10.17: 4-[6-(2-Methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic
acid tert-butyl ester (Compound B38).
Compound B38 was obtained as an off-white powder (7 mg, 10%). Exact mass calculated for
C2oH27N503 385.2, found LCMS (ESI) m/z 386.2 (M+lf'99%).
Example 10.18: 4-[6-(6-Chloro-2-methyI-pyridin-3-yIamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid tert-butyl ester (Compound B39).
Compound B39 was obtained as a yellow powder (3.7 mg, 4%). Exact mass calculated for
C2oH26ClN503 419.2, found LCMS (ESI) m/z 420.5 (M+tf'95%).
Example 10.19: 4^-(6-Fluoro-pyridin-3-yIamino)-pyrimidin-4-yloxy]-piperidine-1-carboxyIic
acid tert-butyl ester (Compound B40).
Compound B40 was obtained as a tan powder (13.8 mg, 20%). Exact mass calculated for
C]9H24FN503 389.2, found LCMS (ESI) m/z 390.2 (M+H^P/o).
Example 10.20: 4-[6-(2-ChIoro-4-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid tert-butyl ester (Compound B41).

Compound B41 was obtained as an off-white powder (7.8 mg, 10%). Exact mass calculated
for C2oH26ClN503 419.2, found LCMS (ESI) m/z 420.5 (U+Yt'99%).
Example 10.21: 4-[6-(6-Methoxy-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid tert-butyl ester (Compound B42).
Compound B42 was obtained as a gold powder (17.4 mg, 20%). Exact mass calculated for
C20H27N5O4 401.2, found LCMS (ESI) m/z 402.2 (M+rf'99%).
Example 10.22: 4-[6-(5-FIuoro-pyridin-2-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic
acid tert-butyl ester (Compound B43).
Compound B43 was obtained as a peach powder (16.2 mg, 20%). Exact mass calculated for
C9H24FN5O3 389.2, found LCMS (ESI) m/z 390.4 (M+rf-96%).
Example 10.23: 4-[6-(2-Fluoro-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic
acid tert-butyl ester (Compound B44).
Compound B44 was obtained as a brown powder (9.6 mg, 10%). Exact mass calculated for
C,9H24FN503 389.2, found LCMS (ESI) m/z 390.1 (M+tf'99%).
Example 10.24: 4-[6-(6-Chloro-5-methyl-pyridin-3-ylamino)-pyrimidin-4-yIoxy]-piperidine-1-
carboxylic acid tert-butyl ester (Compound B45).
Compound B45 was obtained as a gold powder (13.3 mg, 20%). Exact mass calculated for
C20H26CIN5O3 419.2, found LCMS (ESI) m/z 420:6 (M+If-100%): -
Example 10.25: 4-[6-(2-Methyl-pyridin-4-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic
acid tert-butyl ester (Compound B46).
Compound B46 was obtained as an off-white powder (13.1 mg, 20%). Exact mass calculated
for C20H27N5O3 385.2, found LCMS (ESI) m/z 386.1 0^+^88%).
Example 10.26: 4-[6-(2-Methoxy-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid tert-butyl ester (Compound B47).
Compound TJ47 was obtained as a beige powder (14.1 mg, 20%). Exact mass calculated for
C20H27N5O4 401.2, found LCMS (ESI) m/z 402.1 (M+Hf'99%).
Example 10.27: 4-[6-(2,5-Difluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxyIic
acid tert-butyl ester (Compound B48).
Compound B48 was obtained as a light brown powder (16 mg, 20%). Exact mass calculated
for C20H24F2N4O3 406.2, found LCMS (ESI) m/z 407.3 (M+H+'99%).

Example 10.28: 4-[6-(4-Chloro-2-fluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid tert-butyl ester (Compound B49).
Compound B49 was obtained as an ivory powder (18.3 mg, 20%). Exact mass calculated for
C2oH24ClFN403 422.2, found LCMS (ESI) m/z 423.1 (M+tf'99%).
Example 10.29: 4-[6-(2,5-Difluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic
acid isopropyl ester (Compound B50).
Compound B50 was obtained as a yellow solid (282.4 mg, 18 %). Exact mass calculated for
C9H22F2N4O3 392.2, found LCMS (ESI) m/z 393.5 (M+ET'98%).
Example 10.30: 4-[6-(6-Methoxy-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester (Compound B51).
Compound B51 was obtained as a yellow powder (7.1 mg, 10 %). Exact mass calculated for
C,9H25N504 387.2, found LCMS (ESI) m/z 388.2 (M+Ff'93%).
Example 10.31: 4-[6-(4-Cyano-3-methoxy-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester (Compound B52).
Compound B52 was obtained as a yellow powder (6.3 mg, 7%). Exact mass calculated for
C2iH25Ns04 411.2, found LCMS (ESI) m/z 412.1 ^+1^80%).
Example 10.32: 4-[6-(3-Fluoro-4-hydroxy-phenylamino)-pyrimidin-4-yIoxy]-piperidine-1-
carboxylic acid isopropyl ester (Compound B53).
Compound B53 was obtained as an off-white powder (1.5 mg, 2%). Exact mass calculated
for Ci9H23FN404 390.2, found LCMS (ESI) m/z 391.2 (M+Jf'98%).
Example 10.33: 4-[6-(6-Ethoxy-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic
acid isopropyl ester (Compound BS4).
Compound B54 was obtained as an off-white powder (3.1 mg, 4%). Exact mass calculated
for C2oH27N504 401.2, found LCMS (ESI) m/z 402.3 ^+1^96%).
Example 10.34: 4-[6-(2,5-Difluoro-4-isopropoxy-phenylamino)-pyrimidin-4-yloxy]-piperidine-
l-carboxylic acid isopropyl ester (Compound B55).
Compound B54 was obtained as a brown powder (18.9 mg, 20%). Exact mass calculated for
C22H28F2N404 450.2, found LCMS (ESI) m/z 451.3 (M+lf'87%).

Example 10.35: (2-FIuoro-4-methanesulfonyl-phenyl)-[6-(5'-isopropoxy-3,4,5,6-tetrahydro-2H-
[l,2']bipyridinyl-4-yloxy)-pyrimidin-4-yl]-amine (Compound B56).
Compound B56 was obtained as a solid (18 mg, 25%). Exact mass calculated for
C34H28FN5O4S 501.2, found 502.3 (M+tf).
Example 10.36: 4-[6-(2,5-Difluoro-4-propoxy-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester (Compound B61).
Step 1: Preparation of (2,5-difluoro-4-hydroxy-phenyl)-carbamic acid benzyl ester.
A mixture of 4-ammo-2,5-difluorophenol (2.1 g, 14.5 mmol) and sodium bicarbonate (1.33 g,
15.9 mmol) in 20 mL acetonitrile were cooled in an ice-bath. Benzylcarbonate was added (2.3 ml,
15.9 mmol) and mixture was allowed to warm to room temperature. After 3h, mixture was
concentrated and residue was extracted with CH2C12 and 1M HC1 solution. The resulting organic
phase was extracted with 2M NaOH. The H20 layer was acidified with concentrated HC1 and
extracted with CH2C12. The organic phase was dried over MgS04, filtered, and concentrated to give
(2,5-difluoro-4-hydroxy-phenyl)-carbamic acid benzyl ester as a reddish solid (3.84 g, 95%). !HNMR
(CDC13,400 MHz) 8 5.16 (s, 1H), 5.30 (s, 2H), 6.73-6.79 (m, 2H), 7.33-7.42 (m, 5H), 7.92 (s br, 1H).
Exact mass calculated for C14HnF2N03 279.07, found 280.0 (MH*).
Step 2: Preparation of (2,5-difhioro-4-propoxy-phenyI)-carbamic acid benzyl ester.
A mixture of (2,5-difluoro-4-hydroxy-phenyl)-carbamic acid benzyl ester (743 mg, 2.66
mmol), potassium carbonate (703 mg, 5.72 mmol), and 1-iodopropane (556 JJ.1, 5.72 mmol) were
stirred at 60°C for 16 hours. Mixture was concentrated and residue was extracted with CH2C12 and 1M
NaOH solution. Organic phases were dried over MgS04, filtred and concentrated to give (2,5-
difluoro-4-propoxy-phenyl)-carbamic acid benzyl ester as a reddish compound (846 mg, 99%).
'HNMR (CDCI3, 400 MHz) 5 1.19-1.23 (t, 3H), 1.95-2.04 (tq, 2H), 4.08-4.11 (t, 2H), 5.38 (s, 2H),
6.87-6.92 (m, 2H), 7.51-7.59 (m, 5H), 8.05 (s br, 1H). Exact mass calculated for Ci7H17F2N03 321.12,
found 322.1 (MET"), 643.7 (2MH+).
Step 3: Preparation of 2,5-difluoro-4-propoxy-phenyIamine.
To a solution of (2,5-difluoro-4-propoxy-phenyl)-carbamic acid benzyl ester (2.50 g, 7.81
mmol) in 100 mL methanol 10% palladium on carbon (50% water) was added and hydrogen was
bubbled through the mixture for 1 min. Mixture was stirred under a hydrogen atmosphere (balloon) at
room temperature. After 4 hours, Pd/C was filter off and washed with MeOH. 5 mL 4M HC1 in
dioxane were added to the filtrate, and it was concentrated to give 2,5-difluoro-4-propoxy-
phenylamine as a reddish solid (1.65g, 94%). Exact mass calculated for C9HnF2NO 187.08, found
188.2 (MH*).
Step 4: Preparation of 4-[6-(2,5-Difluoro-4-propoxy-phenylamino)-pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid isopropyl ester (Compound B61).

** Compound B61 was prepared in a similar manner as described herein using 4-(6-chloro-
pyrimidin-4-y]oxy)-piperidine-1-carboxylic acid isopropyl ester and 2,5-difluoro-4-propoxy-
Dhenylamine to give a tan solid (TFA salt, 280 mg, 30%). ]HNMR (MeOD, 400 MHz) 5 0.83-.0.88 (t,
3H), 1.00-.1.04 (d, 6H), 1.45-1.66 (m, 4H), 1.75-1.80 (m, 2H), 8.09-3.20 (m, 2H), 3.51-3.57 (m, 2H),
3.78-3.81 (t, 2H), 4.62-4.70 (m, 1H), 4.95-5.00 (m, 1H), 5.78 (s, 1H), 6.78-6.83 (m, 1H), 7.26-7.31
(m, 1H), 8.06 (s, 1H). Exact mass calculated for C22H28F7N4O4 450.21, found 451.3 (MFf).
Example 10.37: 4-[6-(2-Methyl-6-propylamino-pyridin-3-ylamino)-pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid isopropyl ester (Compound B66).
Compound B66 was obtained as a solid (15 mg, 16%). Exact mass calculated for C22H32N6O3
428.2, found 429.3 (M+lf).
Example 10.38: 4-[6-(2-Methyl-pyridin-3-ylamino)-pyrimidin-4-yIoxy]-piperidine-1-carboxyIic
acid isopropyl ester (Compound B67).
Compound B67 was obtained as a solid. Exact mass calculated for C19H25N5O337I.2, found
372.2 (M+H+).
Example 10.39: 4-[6-(6-Isopropylamino-2-methyl-pyridin-3-ylamino)-pyrhnidin-4-yloxy]-
piperidine-1-carboxylic acid isopropyl ester (Compound B68).
Compound B68 was obtained as a solid (7 mg, 10%). Exact mass calculated for C22H32N6O3
428.2, found 429.3 (M+lT).
Example 10.40: 4-[6-(2-MethyI-6-propoxy-pyridin-3-yIamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester (Compound B69).
Compound B69 was obtained as a solid (40 mg, 55%). Exact mass calculated for C21H31N5O4
429.2, found 430.2 (M+lT).
Example 10.41: 4-[6-(2-Fluoro-4-iodo-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester (Compound B71).
Compound B71 was obtained as a brown powder (216.2 mg, 43%). Exact mass calculated for
C19H22FIN4O3 500.l7?bund LCMS (ESI) m/z 501.1 (M+Ff'90%).
Example 10.42: 4-{6-[Methyl-(2-methyl-4,5,6,7-tetrahydro-2H-indazol-3-yl)-amino]-pyrimidin-
4-yIoxy}-piperidine-1-carboxyIic acid isopropyl ester (Compound B72).
Compound B72 was obtained as a white powder (0.5 mg, 1%). Exact mass calculated for
C22H32N603 428.3, found LCMS (ESI) m/z 429.3 (M+lT'58%).

Example 10.43: 4-[6-(2-Methyl-2H-pyrazol-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester (Compound B73).
Compound B73 was obtained as an off-white powder (0.4 mg, 1%). Exact mass calculated
for C17H24N6O3 360.2, found LCMS (ESI) m/z 360.9 (M+tf'100%).
Example 10.44: 4-[6-(2-Phenyl-2H-pyrazol-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester (Compound B74).
Compound B74 was obtained as an off-white powder (6.5 mg, 20%). Exact mass calculated
for C22H26N6O3 422.2, found LCMS (ESI) m/z 423.1 (M+Hf'100%).
Example 10.45: 4-[6-(5-tert-Butyl-lH-pyrazoI-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester (Compound B75).
Compound B75 was obtained as a yellow powder (1.9 mg, 5%). Exact mass calculated for
C20H30N6O3 402.2, found LCMS (ESI) m/z 403.1 (M+lf'92%).
Example 10.46: 4-[6-(5-p-Tolyl-lH-pyrazol-3-ylamino)-pyrimidin-4-yIoxy]-piperidine-1-
carboxylic acid isopropyl ester (Compound B76).
Compound B76 was obtained as an off-white powder (2.8 mg, 6%). Exact mass calculated
for C23H28N603 436.2, found LCMS (ESI) m/z 437.3 (M+Hf,97%).
Example 10.47: 4-[6-(6-Methoxy-5-methyI-pyridin-3-yIamino)-pyrimidin-4-yloxy]-piperidine-
1-carboxylic acid isopropyl ester (Compound B77).
Compound B77 was obtained as a white powder (4 mg, 10%). Exact mass calculated for
C20H27N5O4 401.2, found LCMS (ESI) m/z 402.1 (M+HM00%).
Example 10.48: 4- [6-(4-MethyI-pyridin-3-ylamino)-pyrimidin-4-yloxy] -piperidine-1-carboxylic
acid isopropyl ester (Compound B78).
Compound B78 was obtained as an off-white powder (1.2 mg, 3%). Exact mass calculated
for CI9H25N503 371.2, found LCMS (ESI) m/z 372.3 (M+lf'79%).
Example 10.49: 4-[6"-(4-Acetylamino-3-methyI-phenyIamino)-pyrimidin-4-yloxyl-piperidine-1-
carboxylic acid isopropyl ester (Compound B79).
Compound B79 was obtained as an off-white powder (1.2 mg, 3%). Exact mass calculated
for C22H29N5O4 427.2, found LCMS (ESI) m/z 428.1 (M+ETf'98%).
Example 10.50: 4-[6-(3-Chloro-4-fluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester (Compound B80).

Compound B80 was obtained as an off-white powder (7.2 mg, 20%). Exact mass calculated
for CI9H22C1FN403 408.1, found LCMS (ESI) m/z 409.3 (M+Jf-96%).
Example 10.51: 4-[6-(3,5-Dimethoxy-phenyIamino)-pyrimidin-4-yloxy]-piperidine-1-carboxyIic
acid isopropyl ester (Compound B81).
Compound B81 was obtained as a white powder (1.5 mg, 4%). Exact mass calculated for
C2,H28N405 416.2, found LCMS (ESI) m/z 417.4 (M+H+'100%).
Example 10.52: 4-[6-(6-Ethyl-pyridin-2-yIamino)-pyrimidin-4-yIoxy]-piperidine-1-carboxylic
acid isopropyl ester (Compound B82).
Compound B82 was obtained as an off-white powder (3.7 mg, 10%). Exact mass calculated
for C20H27NjO3 385.2, found LCMS (ESI) m/z 386.1 (M+H^'78%).
Example 10.53: 4-[6-(5-Methyl-pyridin-2-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic
acid isopropyl ester (Compound B83).
Compound B83 was obtained as an off-white powder (4.9 mg, 10%). Exact mass calculated
for Ci9H25N503 371.2, found LCMS (ESI) m/z 372.3 (M+KT'88%).
Example 10.54: 4-[6-(2-MethyI-quinolin-6-yJamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester (Compound B84).
Compound B84 was obtained as a yellow powder (2.6 mg, 10%). Exact mass calculated for
C23H27N5O3-42L2, found LCMS (ESI) m/z-422.1 (M+HM00%).
Example 10.55: 4-[6-(2-MethyIsuIfanyl-benzothiazoI-6-yIamino)-pyrimidin-4-yIoxy]-
piperidine-1-carboxylic acid isopropyl ester (Compound B85).
Compound B85 was obtained as a white powder (0.4 mg, 1%). Exact mass calculated for
C2IH25N503S2 459.1, found LCMS (ESI) m/z 460.3 (M+H+*85%).
Example 10.56: 4-[6-(6-Morpholin-4-yl-pyridin-3-yIamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester (Compound B86).
Compound B86 was obtained as a purple powder (3 mg, 7%). Exact mass calculated for
C22H3oN604 442.2, found LCMS (ESI) m/z 443.4 (M+H+'99%).
Example 10.57: 4-[6-(4-BenzenesuIfonyI-thiophen-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester (Compound B87).
Compound B87 was obtained as an off-white powder (3.9 mg, 8%). Exact mass calculated
for C23H26N405S2 502.1, found LCMS (ESI) m/z 503.3 (M+H+,98%).

Example 10.58: 4-[6-(4-Piperidin-1-yl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester (Compound B88).
Compound B88 was obtained as a purple powder (1 mg, 2%). Exact mass calculated for
C24H33N5O3 439.3, found LCMS (ESI) m/z 440.4 (M+HMCKP/o).
Example 10.59: 4-[6-(3-Trifluoromethoxy-phenyIamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester (Compound B89).
Compound B89 was obtained as a beige powder (6.3 mg, 10%). Exact mass calculated for
C2oH23F3N404 440.2, found LCMS (ESI) m/z 441.2 (M+Jf'80%).
Example 10.60: 4-[6-(5-Oxo-5,6,7,8-tetrahydro-naphthalen-2-yIamino)-pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid isopropyl ester (Compound B90).
Compound B90 was obtained as a yellow powder (0.5 mg, 1%). Exact mass calculated for
C23H28N404 424.2, found LCMS (ESI) m/z 425.1 (M+Ff'89%).
Example 10.61: 4-[6-(6-Methyl-lH-pyrazolo[3,4-b]pyridin-3-ylamino)-pyrimidin-4-yIoxy]-
piperidine-1-carboxylic acid isopropyl ester (Compound B91).
Compound B91 was obtained as a yellow powder (0.5 mg, 1%). Exact mass calculated for
C20H25N7O3 411.2, found LCMS (ESI) m/z 412.3 (M+tf-78%).
" Example 10.62:" 4-[6-(5-Cyano-pyridin-2-ylamino)-pyrimidin-4-yIoxy]-piperidine-1-carboxylic
acid isopropyl ester (Compound B92).
Compound B92 was obtained as a white powder (1.3 mg, 3%). Exact mass calculated for
Ci9H22N603 382.2, found LCMS (ESI) m/z 383.3 (M+H+>88%).
Example 10.63: 4-[6-(4-Bromo-2,5-difluoro-phenylamino)-pyrimidin-4-yIoxy]-piperidine-1-
carboxylic acid isopropyl ester (Compound B93).
Compound B93 was obtained as a tan solid (TFA salt, 286.5 mg, 29%). 1HNMR (CDC13,400
MHz) 8 1.22-125 (d, 7H), 1.66-1.76 (m, 2H), 1.92-2.01 (m, 2H), 3.27-3.35 (m, 2H), 3.74-3.83 (m,
2H), 4.88-4.95 (m, IH), 5.25-5.32 (m, 1H), 6.0 (s, 1H), 7.3-7.35 (m, 1H), 7.955-8.01 (m, 1H), 8.4 (s,
1H). Exact mass calculated for Ci9H2iBrF2N403 470.08, found 471.0 (MFf).
Example 10.64: 4-[6-(4-Trifluoromethyl-pyridin-2-ylamino)-pyrimidin-4-yIoxy]-piperidine-1-
carboxylic acid isopropyl ester (Compound B94).
Compound B94 was obtained as a white powder (2.3 mg, 5%). Exact mass calculated for
Ci9H22F3N503 425.2, found LCMS (ESI) m/z 426 (M+¥?75%).

Example 10.65: 4-[6-(5-MethyI-lH-pyrazoI-3-yIamino)-pyrimidin-4-yIoxy]-piperidine-1-
carboxylic acid isopropyl ester (Compound B95).
Compound B95 was obtained as a white powder (0.4mg, 1%). Exact mass calculated for
CnH24N603 360.2, found LCMS (ESI) m/z 360.9 (M+lf'84%).
Example 10.66: 4-[6-(5-CyclopropyI-lH-pyrazol-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester (Compound B96).
Compound B96 was obtained as a brown powder (1.7 mg, 4%). Exact mass calculated for
C,9H26N603 386.2, found LCMS (ESI) m/z 387.3 (M+tf'66%).
Example 10.67: 4-[6-(2,6-Dimethyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester (Compound B97).
Compound B97 was obtained as a solid (28 mg, 36%). Exact mass calculated for C20H27N5O3
385.2, found 386.3 (M+H4).
Example 10.68: 4-[6-(4-Cyano-2-methyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester (Compound B98).
Compound B98 was obtained as a solid (20 mg, 25%). Exact mass calculated for C21H25N5O3
395.2, found 396.1 (M+H4).
Example 10:69: 4-[6-(4-Methoxy-2-methyl-phenylamino)-pyrimidin-4-yIoxy]-piperidine-1- --• -
carboxylic acid isopropyl ester (Compound B99).
Compound B99 was obtained as a solid (24 mg, 30%). Exact mass calculated for C21H28N4O4
400.2, found 401.4 (M+H*).
Example 10.70: 4-[6-(2,4-Dimethoxy-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxyIic
acid isopropyl ester (Compound B100).
Compound B100 was obtained as a solid (20 mg, 24%). Exact mass calculated for
C2IHMN Example 10.71: 4-[6-(5-Carbamoyl-pyridin-2-yIamino)-pyrimidin-4-yIoxy]-piperidine-1-
carboxylic acid isopropyl ester (Compound B102).
Compound B102 was obtained as an off-white powder (2.9 mg, 5%). Exact mass calculated
for C,9H24N604 400.2, found LCMS (ESI) m/z 401.3 (M+HT'68%).

Example 10.72: 4-{6-[4-(3,4-Difluoro-phenyI)-thiazoI-2-ylamino]-pyrimidin-4-yIoxy}-
piperidine-1-carboxylic acid isopropyl ester (Compound B103).
Compound B103 was obtained as a pale yellow powder (4.9 mg, 7%). Exact mass calculated
for C22H23F2N5O3S 475.2, found LCMS (ESI) m/z 476.2 (M+Lf'66%).
Example 10.73: 4-[6-(5-Oxo-1-phenyl-4,5-dihydro-lH-pyrazol-3-yIamino)-pyrimidin-4-yIoxy]-
piperidine-1-carboxylic acid isopropyl ester (Compound B104).
Compound B104 was obtained as a pale yellow powder (0.5 mg, 0.8%). Exact mass
calculated for C22H26N6C>4 438.2, found LCMS (ESI) m/z 439.4 (M+H^'98%).
Example 10.74: 4-[6-(3-Oxazol-5-yl-phenylamino)-pyrimidin-4-yIoxy]-piperidine-1-carboxylic
acid isopropyl ester_(Compound B105).
Compound B105 was obtained as a pale yellow powder (5.4 mg, 9%). Exact mass calculated
for C22H25N5O4 423.2, found LCMS (ESI) m/z 424.3 (M+H"'100%).
Example 10.75: 4-[6-(5-Trifluoromethyl-pyridin-2-yIamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester (Compound B106).
Compound B106 was obtained as an off-white powder (4.8 mg, 7%). Exact mass calculated
for C19H22F3N503 425.2, found LCMS (ESI) m/z 426.4 (M+FT'44%).
Example 10.76: 4-[6-(4-Chloro-2-trifluoromethoxy-phenylamino)-pyrimidin-4-yIoxy]-
piperidine-1-carboxylic acid isopropyl ester (Compound B107). "
Compound B107 was obtained as a brown powder (32.6 mg, 46%). Exact mass calculated for
C20H22CIF3N4O4 474.1, found LCMS (ESI) m/z 475.3 (M+lT'93%).
Example 10.77: 4-{6-[(5-Pyridin-2-yl-thiophen-2-ylmethyl)-amino]-pyrimidin-4-yloxy}-
piperidine-1-carboxylic acid isopropyl ester (Compound B108).
Compound B108 was obtained as an off-white powder (1.6 mg, 2%). Exact mass calculated
for C23H27N503S 453.2, found LCMS (ESI) m/z 451.4 (M+lf-71%).
Example 10.78: 4^6-[5-(4-ChIoro-phenyl)-2H-pyrazoI-3-ylamino]-pyrimidin-4-yIoxy}-
piperidine-1-carboxylic acid isopropyl ester (Compound B109).
Compound B109 was obtained as a brown powder (1.1 mg, 2%). Exact mass calculated for
C22H25C1N603 456.2, found LCMS (ESI) m/z 457.1 (M+l07%).
Example 10.79: 4-[6-(l-Oxo-indan-5-yIamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid
isopropyl ester (Compound B110).

-* Compound B110 was obtained as a brown powder (3.6 mg, 6%). Exact mass calculated for
C22H26N4O4 410.2, found LCMS (ESI) m/z 411.0 (M+Hf' 42%).
Example 10.80: 4-{6-[5-(l-Methyl-pyrroIidin-2-yI)-pyridin-2-yIamino]-pyrimidin-4-yIoxy}-
piperidine-1-carboxylic acid isopropyl ester (Compound Bill).
Compound Bill was obtained as an off-white powder (0.6 mg, 0.9%). Exact mass calculated
for C23H32N6O3.440.3, found LCMS (ESI) m/z 440.4 (M+H*1100%).
Example 10.81: 4-[6-(6-Methoxy-2-methyl-pyridin-3-yIamino)-pyrimidin-4-yIoxy]-piperidine-
1-carboxylic acid isopropyl ester (Compound B112).
Compound B112 was obtained as a yellow powder (3.4 mg, 6%). Exact mass calculated for
C20H27N5O4 401.2, found LCMS (ESI) m/z 402.1 (M+LT'99%).
Example 10.82: 4-[6-(5-Bromo-3-methyI-pyridin-2-yIamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester (Compound B113).
Compound B113 was obtained as a white powder (6.6 mg, 10%). Exact mass calculated for
CipH^BrNsOa 449.1, found LCMS (ESI) m/z 452.2 (M+H"'94%).
Example 10.83: 4-[6-(2-Chloro-6-methyI-pyridin-3-ylamino)-pyrimidin-4-yIoxy]-piperidine-1-
carboxylic acid isopropyl ester (Compound B114).
Compound B114 was obtained as a beige powder (7.9 mg, 13%). Exact mass calculated for
- -Q9H24CIN5O3 405.2,'found LCMS (ESI) m/z 406.2 (M+Ht'98%).
Example 10.84: 4-[6-(2-Ethynyl-pbenyIamino)-pyrimidin-4-yloxy]-piperidine-1-carboxyIic acid
isopropyl ester (Compound B115).
Compound B115 was obtained as a brown powder (2.3 mg, 4%). Exact mass calculated for
C2,H24N403 380.2, found LCMS (ESI) m/z 381.2 (M+H"'56%).
Example 10.85: 4-[6-(4-Bromo-2-trifluoromethoxy-phenylamino)-pyrimidin-4-yIoxy]-
piperidine-1-carboxylic acid isopropyl ester (Compound B116).
Compound BH6 was obtained as a beige powder (16.6 mg, 21%). Exact mass calculated for
C20H22BrF3N4O4. 518.1, found LCMS (ESI) m/z 519.2 (M+tf;91%).
Example 10.86: 4-[6-(3-Iodo-4-methyI-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester (Compound B117).
Compound B117 was obtained as an off-white powder (0.7 mg, 0.8%). Exact mass calculated
for C2oH25lN403 496.1, found LCMS (ESI) m/z 497.3 (M+Hf,98%).

Example 10.87: 4-[6-(2-Fluoro-5-methyI-phenyIamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester (Compound B118).
Compound B118 was obtained as an off-white powder (10.6 mg, 18%). Exact mass
calculated for C20H25FN4O3 388.2, found LCMS (ESI) m/z 389.4 (M+H4' 95%).
Example 10.88: 4-{6-[5-(4-Methoxy-phenyI)-[l,3,4]thiadiazoI-2-ylamino]-pyrimidin-4-yIoxy}-
piperidine-1-carboxylic acid isopropyl ester (Compound B119). '
Compound B119 was obtained as an off-white powder (2.5 mg, 4%). Exact mass calculated
for C22H26N6O4S.470.2, found LCMS (ESI) m/z 473.3 (M+H*- 52%).
Example 10.89: 4-[6-(3,5-Dimethyl-isoxazol-4-ylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester (Compound B120).
Compound B120 was obtained as a white powder (3.1 mg, 6%). Exact mass calculated for
C18H25N5O4.375.2, found LCMS (ESI) m/z 376.1 (M+rf-100%).
Example 10.90: 4-[2-(2,5-Difluoro-4-propoxy-phenylamino)-pyridin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester (Compound B121).
Compound B121 was obtained as a solid. 'HNMR (CDC13,400 MHz) 5 8.02 (d, 1H), 7.72
(m, 1H), 6.76 (m, 1H), 6.34 (m, 1H), 6.28 (bs, 1H), 4.90 (m, 1H), 4.50 (m, 1H), 3.93 (t, 2H), 3.66 (m,
. 2H), 3.39 (m, 2H), 1.87 (m, 2H), 1,80 (m, 2H), 1,75 (m,2H), 1.23 (d, 6H),L02 (t, 3H),.LRMS....
calculated for C23H29F2N3O4: 449.21. Found: 450.5 (M+H)+.
Example 10.91: (2,5-Difluoro-4-propoxy-pbenyl)-{6-[l-(5-isopropyl-[l,2,4]oxadiazoI-3-yl)-
piperidin-4-yIoxy]-pyrimidin-4-yl}-amine (Compound B133).
Compound B133 was obtained as a tan solid (HC1 salt, 65.9 mg, 18%).JHNMR (MeOD, 400
MHz) 5 0.84-0.88 (t, 3H), 1.05-1.07 (d, 6H), 1.60-1.76 (m, 4H), 1.92-2.01 (m, 2H), 2.63-2.68 (m,
1H), 3.42-3.47 (m, 2H), 3.61-3.65 (m, 2H), 3.83-3.86 (t, 2H), 5.03-5.08 (m, 1H), 6.08 (s, 1H), 6.92-
6.97 (m, 1H), 7.16-7.21 (m, 1H), 8.32 (s, 1H). Exact mass calculated for Q-sHzgFzNfiOs 474.22, found
475.4 (MET). ~
Example 10.92: 4-[6-(2,5-Difluoro-4-propyIamino-phenylamino)-pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid isopropyl ester (Compound B122).
A mixture of 4-[6-(4-bromo-2,5-difluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-l -
carboxylic acid isopropyl ester (TFA salt, 51.2 mg, 0.087 mmol), copper iodide (17.6 mg, 0.092
mmol), potassium carbonate (37.3 mg, 0.269 mmol), propyl amine (57.4 |j,l, 0.698 mmol), and L-

proline (21.2 mg, 0.184 mmol) in 1.5 mL DMSO was heated in microwave for 9 hours at 80 °C. The
mixture was purified by HPLC to give compound B122 as tan solid (TFA salt, 13 mg, 26%). 'HNMR
(MeOD-d4, 400 MHz) 8 0.85-0.91 (m, 3H), 1.09-1.14 (d, 6H), 1.51-1.60 (m, 2H), 1.61-1.71 (m, 2H),
1.85-1.95 (m, 2H), 3.02-3.08 (m, 2H), 3.25-3.35 (in, 2H), 3.55-3.65 (m, 2H), 4.70-4.80 (m, 1H), 5.04-
5.12 (m, 1H), 6.14 (s, 1H), 6.63-6.71 (m, 1H), 7.16-7.24 (m, 1H), 8.36 (s, 1H). Exact mass calculated
for C22H29F2N503 449.22, found 450.3 (MH*).
Example 10.93: 4-[6-(2,5-Difluoro-4-morphoIin-4-yl-phenylaminb)-pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid isopropyl ester (Compound B123).
Compound B123 was obtained as tan solid (TFA salt, 9.8 mg, 12%). 'HNMR (MeOD-d4, 400
MHz) 5 1.00-1.05 (d, 6H), 1.53-1.63 (m, 2H), 1.76-1.87 (m, 2H), 2.88-2.94 (m, 4H), 3.17-3.27 (m,
2H), 3.46-3.55 (m, 2H), 3.59-3.65 (m, 4H), 4.6-4.7 (m, 1H), 4.93-5.00 (m, 1H), 6.1 (s, 1H), 6.75-6.83
(m, 1H), 7.15-7.23 (m, 1H), 8.30 (s, 1H). Exact mass calculated for C23H29F2N504 477.22, found
478.4 (MH").
Example 10.94: 4-(6-{2,5-Difluoro-4-[(tetrahydro-furan-2-ylmethyl)-amino]-phenylamino}-
pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (Compound B136).
Compound B136 was obtained as a white solid (HC1 salt, 48.8 mg, 22%). 'HNMR (MeOD,
400 MHz) 5 1.05-1.10 (d, 6H), 1.49-1.70 (m, 3H), 1.78-1.98 (m, 5H), 3.02-.3.11 (m, 1H), 3.22-3.31
(m, 2H), 3.54-3.69 (m, 4H), 3.71-3.78 (m, 1H), 3.92-3.98 (m, 1H), 4.64-4.70 (s, 1H), 5.03-5.11 (m,
1H), 6.07 (s, 1H), 6.64-6.69 (m, 1H), 7.04-7.09 (m, 1H), 8.32 (s, 1H). Exact mass calculated for
C2-4H31F2N504 491.23, found"492.4-(MFf); "
Example 10.95: 4-{6-[2,5-Difluoro-4-(2-methoxy-ethylamino)-phenyIamino]-pyrimidin-4-
yloxy}-piperidine-1-carboxylic acid isopropyl ester (Compound B135).
Compound B135 was obtained as a white solid (HC1 salt, 44.5 mg, 21%). 'HNMR (MeOD,
400 MHz) 8 1.14-1.16 (d, 6H), 1.63-1.72 (m, 2H), 1.88-1.98 (m, 2H), 3.26-3.38 (m, 7H), 3.47-3.51
(m, 2H), 3.60-3.68 (m, 2H), 4.64-4.70 (s, 1H), 5.10-5.06 (m, 1H), 6.13 (s, 1H), 6.68-6.73 (m, 1H),
7.13-7.17 (m, 1H), 8.44 (s, 1H). Exact mass calculated for C22H29F2N504 465.22, found 466.4 (MH1).
Example 10.96: 4-[6-(4-Butylamino-2,5-difluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-
l-carboxylic acid isopropyl ester (Compound B137).
Compound B137 was obtained as a white solid (HC1 salt, 70.1 mg, 33%). 'HNMR (MeOD,
400 MHz) 8 1.10-1.14 (t, 3H), 1.38-1.40 (d, 6H), 1.54-1.62 (m, 2H), 1.75-1.83 (m, 2H), 1.91-1.95 (m,
2H), 2.14-2.18 (m, 2H), 3.34-3.37 (m, 2H), 3.5-3.61 (m, 2H), 3.85-3.91 (m, 2H), 4.64-4.70 (s, 1H),

5.32-5.38 (m, 1H), 6.39 (s, 1H), 6.90-6.95 (m, 1H), 7.43-7.48 (s, 1H), 8.62 (s, 1H). Exact mass
calculated for CzsHs^NjCU 463.24, found 464.5 (Mrf).
Example 10.97: 4-{6-[2,5-Difluoro-4-(3-methyI-burylamino)-phenylamino]-pyrimidin-4-yIoxy}-
piperidine-1-carboxylic acid isopropyl ester (Compound B138).
Compound B138 was obtained as a white solid (HC1 salt, 100 mg, 45%). 'HNMR (MeOD,
400 MHz) 5 0.77-0.78 (d, 6H), 1.04-. 106 (d, 6H), 1.34-1.40 (m, 2H), 1.48-1.81 (m, 3H), 1.79-1.88 (m,
2H), 3.02-3.10 (m, 2H), 3.18-3.25 (m, 2H), 3.50-3.57 (m, 2H), 4.64-4.70 (m, 1H), 4.95-5.02 (m, 1H),
6.08 (s, 1H), 6.61-6.66 (m, 1H), 7.14-7.18 (m, 1H), 8.29 (s, 1H). Exact mass calculated for
C24H33F2N503 477.26, found 478.5 (Mit).
Example 10.98: 4-{6-[2,5-Difluoro-4-(tetrahydro-furan-2-yImethoxy)-phenyIamino]-pyrimidin-
4-yloxy}-piperidine-1-carboxylic acid isopropyl ester (Compound B145).
Compound B145 was obtained as a solid (4 mg, 4%). Exact mass calculated for
C24H30F2N4O5 492.2, found 493.6 (MET).
The following compounds were prepared using the general method as described in
Example 10.1.
Example 10.99: 4-[6-(3-Fluoro-4-methyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid tert-butyl ester (Compound B16).
Compound B16 was obtained as yellow solid (16mg, 27 %). Exact mass calculated for
C2iH27FN403 402.2,'found LCMS (ESI) rn/z 403.2(M+pf, 100%).
Example 10.100: 4- [6-(3-Hyd roxy-4-methoxy-phenylamino)-pyrimidin-4-yIoxy] -piperidine-1-
carboxylic acid tert-butyl ester (Compound B17).
Compound B17 was obtained as yellow solid (1 lmg, 18 %). Exact mass calculated for
C2,H2gN405 416.2, found LCMS (ESI) m/z 417.1(M+H+, 100%).
Example 10.101: 4-[6-(6-Cyano-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid tert-butyl ester (Compound B18).
Compound B18 was obtained as yellow solid (7mg, 12 %). Exact mass calculated for
C2oH24N603 396.2, found LCMS (ESI) m/z 397.1(M+H+, 100%).
Example 10.102: 4-[6-(3-Chloro-4-cyano-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid tert-butyl ester (Compound B19).
Compound B19 was obtained as yellow solid (19mg, 30 %). Exact mass calculated for
C21H24CIN5O3 429.2, found LCMS (ESI) m/z 430.2(M+H+, 100%).

Example 10.103: 4-[6-(3-Fluoro-4-methoxy-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid tert-butyl ester (Compound B21).
Compound B21 was obtained as brown solid (12mg, 19 %). Exact mass calculated for C21H27
FN4O4 418.2, found LCMS (ESI) m/z 419.4(M+FT\ 100%).
Example 10.104: 4-[6-(3,4-Dimethoxy-pbenylamino)-pyrimidin-4-yIoxy]-piperidine-1-
carboxylic acid tert-butyl ester (Compound B22).
Compound B22 was obtained as brown solid (9mg, 14 %). Exact mass calculated for C22H30
N4O5 430.2, found LCMS (ESI) m/z 431.3(M+Ff", 100%).
Example 10.105: 4-[6-(2,3-Dihydro-benzo[l,4]dioxin-6-yIamino)-pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid tert-butyl ester (Compound B23).
Compound B23 was obtained as brown solid (7mg, 11 %). Exact mass calculated for C22H28
N4O5 428.2, found LCMS (ESI) m/z 429.3(M+FT\ 100%).
Example 10.106: 4-[6-(4-Cyano-2,5-difluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester (Compound B24).
2,5-Difluoro-4-[6-(piperidin-4-yloxy)-pyrimidin-4-ylammo]-benzonitrile (1.793g, 4.6mmol)
and TEA (18.4 mmole, 4eq) were dissolved in THF (lOmL) and then isopropyl chloroformate
(5.98mmole, 1.3eq) was added into the solution. The reaction mixture was stirred at room temp for 2
hours. The crude waspurified through flash column (Hexane: Ethyl Acetate=l:l)provided -
Compound B24 as a white solid( 400 mg, 21 %). !H NMR 400MHz CDC13 5(ppm): 9.86 (s,NH);
8.65 (dd, 1H); 8.55 (s,lH); 7.97 (dd,lH); 6.55 (s,lH); 5.21 (m, 1H); 4.78 (sep,lH); 3.75-3.70 (m,2H);
3.22-3.20 (m, 2H); 1.99-1.94 (m,2H); 1.59-1.55 (m,2H); 1.19 (d, 6H). Exact mass calculated for
C20H21F2N5O3 417.2, found LCMS (ESI) m/z 418.2(M+Ff, 100%).
Example 10.107: 4-[6-(4-Ethoxy-2,5-difluoro-phenyIamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester (Compound B26).
Compound B26 was obtained as tan solid (17mg, 20 %). Exact mass calculated for
C21H26F2N404 436.27found LCMS (ESI) m/z 437.3(M+FT\ 100%).
Example 10.108: (2-Fluoro-4-methanesuIfonyI-phenyl)-{6-[l-(3-isopropyI-[l,2,4]oxadiazoI-5-
yl)-piperidin-4-yloxy]-pyrimidin-4-yI}-amine (Compound B57).
Step 1: Preparation of isopropyl amidoxime.
A solution of isobutyronitrile (276 g, 4.0 mol) in EtOH (2.0 L) was combined with
hydroxylamine (50% aqueous solution, 1.1 L, 16 mol), and refluxed for 5 h. The solvent was then

removed in vacuo, and the residual water was azeotropically removed with toluene. The residue was
then taken up in CH2C12, dried over MgS04, and the solvent was removed to afford a white solid (402
g, 98% yield). ]H NMR (CDC13) 6 7.94 (br s, 1 H), 4.55 (br s, 2 H), 2.47 (m, 1 H), 1.20 (d, 6 H, J=
7.1 Hz).
Step 2: Preparation of l-cyano-4-hydroxypiperidine.
A 5-liter, 3-neck flask was equipped with mechanical stirring, a reflux condenser, and a
powder addition funnel. Sodium bicarbonate (840 g, 10 mmol) was added via the powder funnel
while stirring, then water (ca. 300-400 mL) was gradually added while vigorously stirring to form a
thick, uniform slurry. The flask was then place.d in an ice bath, and a solution of 4-hydroxypiperidine
(506 g, 5.00 mol) in CH2C12 (1.0 L) was added, and the contents were vigorously mixed while
cooling. A solution of cyanogen bromide (640 g, 6.0 mol) in CH2C12 (600 mL) was added in a
dropwise fashion over 2 h, and stirring was continued for an additional 30 min. The ice bath was
removed, and the mechanical stirrer was replaced by a magnetic stirrer, and the reaction mixture was
stirred for 16 h. The flask was once again placed under mechanical stirring, and sodium carbonate
(100 g) was added in order to ensure complete neutralization. MgS04 (500 g) was added, and
vigorous stirring was continued for 15 min. The resulting suspension was filtered, rinsing with
CH2C12 (2.0 L). A light amber, viscous oil was obtained upon solvent removal (574 g, 91% yield).
'HNMR (CDC13) 8 3.80 (m, 1 H), 3.39 (m, 2 H), 3.05 (m, 2 H), 1.87 (m, 2 H), 1.70 (br s, 1 H), 1.62
(m, 2 H); MS m/z 212.1 (Ivf).
Step 3: 4-Hydroxy-1-(3-isopropyI-l,2,4-oxadiazol-5-yI)piperidine
In a variation of the method described by Yarovenko et al. in Bull. Acad. Sci. USSR, Div.
Chem.Sci. 1991, 40, 1924; ZnCl2 (1 N in ether, 120 mE," "120 mmol) was added in a, dropwise fashion
over 15 min to a magnetically stirred solution of step 1 (12.2 g, 120 mmol) and step 2 (12.6 g, 100
mmol) in ethyl acetate (500 mL). Precipitate formed immediately upon addition, and at a point the
stirring bar became immobilized in the matrix, requiring the reaction to be manually shaken for the
remainder of addition. After standing for 15 min, the supernatant was decanted and filtered, and the
residue was rinsed twice with ether, furnishing a hard white precipitate which was collected by
filtration. The precipitate was identified via LC/MS as the intermediate O-amidinoamidoxime (m/z
229). This material was taken up in cone. HC1 (50 mL), diluted to 4 N with EtOH (100 mL), and
refluxed for 1 h. Upon cooling, a white precipitate was removed by filtration, then the filtrate was
reduced to 50 mL and diluted with 100 mL water. Solid Na2CC>3 was added until the mixture was
basic, CH2C12 was added, and the resulting mixture was filtered, rinsing with CH2C12. The organic
extract was separated, dried over MgS04, and the solvent was removed to afford a viscous, amber oil
(15.0 g, 71% yield): 'HNMR (CDC13) 8 3.95 (m, 3 H), 3.37 (m, 2 H), 2.88 (m, 1 H), 2.34 (br s, 1 H),
1.93 (m, 2 H), 1.63 (m, 2 H), 1.28 (d, 6 H, J= 7.1 Hz); MS m/z 212.3 (M").

Step 4: Preparation of (2-Fluoro-4-methanesulfonyl-phenyI)-{6-[l-(3-isopropyI-
[l,2,4]oxadiazol-5-yI)-piperidin-4-yloxy]-pyrimidin-4-yl}-amine (Compound B57).
Compound B57 was prepared in a similar manner as described above as a brown oil (230mg,
20 %). 'HNMR400MHz CDC13 5 (ppm): 9.64(s, NH); 8.49-8.45(m, 2H); 7.80(d,lH); 7.71(d,lH);
6.41(s,lH); S.25(m,lH); 3.82-3.78(m,2H); 3.50-3.44(m,2H); 3.23 (s, 3H); 2.07-2.04(m, 2H); 1.75-
1.73(m,2H); 1.18(d, 6H). Exact mass calculated for C2iH25FN604S 476.2, found LCMS (ESI) m/z
477.2(M+tr, 100%).
Example 10.109: 4-[6-(4-Cyano-2-fluoro-phenyIamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester (Compound B58).
Compound B58 was obtained as yellow solid (34mg, 57 %). !H NMR 400MHz CDC13
8(ppm): 8.46(s, 1H); 7.62-7.53(m, 3H); 5.96(s,lH); 5.38(m,lH); 4.92(sep,lH); 3.81-3.78(db,2H);
3.35-3.29(m,2H); 1.97(sb,2H); 1.73 (mb, 2H); 1.26(d, 6H). Exact mass calculated for QjoHbFNsOj
399.2, found LCMS (ESI) m/z 400.2(M+H+, 100%).
Example 10.110: 4-[6-(Pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid
isopropyl ester (Compound B59).
Compound B59 was obtained as yellow solid (34mg, 46 %). !H NMR 400MHz CDC13 5
(ppm): 9.22(s,lH); 8.79(d,lH); 8.54(s, 1H); 8.49(d, 1H); 7.86-7.83(m,lH); 6.41(s,lH); 5.30(m,lH);
4.93(sep,lH); 3.81-3.76(m,2H); 3.41-3.34(m,2H); 2.02-1.98(sb,2H); 1.80-1.76 (sb, 2H); 1.26(d, 6H).
Exact mass calculated for C18H23N503 357.2, found LCMS (ESI) m/z 358.201+11^, 100%).
Example 10.111: 4-[6-(Pyridin-4-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid
isopropyl ester (Compound B60).
Compound B60 was obtained as yellow solid (21mg, 30 %). 'HNMR 400MHz CDC13 8
(ppm): 8.56(s, 1H); 8.36(d, 2H); 8.27(d,2H); 6.57(s,lH); 5.30(m,lH); 4.93(sep,lH); 3.81-3.77(m,2H);
3.38-3.32(m,2H); 1.97(sb,2H); 1.77-1.73 (sb, 2H); 1.25(d, 6H). Exact mass calculated for
CigBbNjCb 357.2, found LCMS (ESI) m/z 358.2(M+H+, 100%).
Example 10.112: 4-[6-(2,5-Difluoro-phenoxy)-pyrimidin-4-yIoxy]-piperidine-1-carboxylic acid
isopropyl ester (Compound B142).
Compound B142 was obtained as a solid. JH NMR 400MHz CDC13 8(ppm): 8.49(s,lH);
7.20-7.15 (m, 1H); 7.01-6.96(m, 2H); 6.22(s,lH); 5.33-5.31 (m,lH); 4.93(sep,lH); 3.80-3.74(m, 2H);
3.44-3.38(m, 2H); 2.03-1.98(m,2H); 1.82-1.77(m,2H); 1.27(d,6H). Exact mass calculated:
C,9H2,F2N304 393.2, found LCMS (ESI) m/z 394.2(M+H+, 100%)

Example 10.113: Preparation of 4-[6-(2-fluoro-4-methanesulfonyl-phenylamino)-pyridin-2-
yIoxy]-piperidine-1-carboxylic acid tert-butyl ester (Compound B146).
A suspension of 4-(6-bromo-pyridin-2-yIoxy)-piperidine-1-carboxylic acid tert-butyl ester
(2.93 g, 8.23 mmol) and 2-fluoro-4-methanesulfonyl-phenylamine (1.87 g, 9.87 mmol) in anhydrous
toluene (82 mL) was degassed by bubbling nitrogen gas through the suspension for 15 min.
Tris(dibenzylideneacetone)dipalladium(O) (Pd2dba3) (754 mg, 0.82 mmol), 1,3-
bis(diphenylphosphino)propane (dppp) (678 mg, 1.65 mmol), and NaOtBu (1.11 g, 11.5 mmol) were
added, the reaction vessel was purged with nitrogen gas, and the reaction mixture was heated at 70C
under a nitrogen atmosphere for 9h. The reaction mixture was diluted with ether (83 mL), washed
with brine 3 times (3 x 83 mL),then the solids in the organic and aqueous layers were filtered and
washed with ether 3 times. The organic extracts and washes were combined, dried with MgS04, and
the solvent was evaporated in vacuo to give a solid which was purified by flash chromatography using
hexanes-EtOAc (50:50, v/v) to afford 4-[6-(2-fluoro-4-methanesulfonyl-phenylamino)-pyridin-2-
yloxy]-piperidine-1-carboxylic acid tert-butyl ester (Compound B146) as a pale yellow solid (3.47 g,
91%). 'H NMR (CDC13, 400 MHz) 8 8.53 (m, 1H), 7.66 (m, 2H), 7.53 (m, 1H), 6.83 (bs, 1H), 6.42 (d,
1H), 6.36 (d, 1H), 5.13 (m, 1H), 3.80 (m, 2H), 3.31 (m, 2H), 3.07 (s, 3H), 2.01 (m, 2H), 1.78 (m, 2H),
1.48 (s, 9H). LRMS calculated for C^BbFNaOsS: 465.17. Found: 466.2 (M+H)+.
Example 10.114: Preparation of 4-[2-(2-Fluoro-4-methanesuIfqnyl-phenyIamino)-pyridin-4-
yloxy]-piperidine-1-carboxy!ic acid isopropyl ester (Compound B151).
Compound B151 was prepared from 4-(2-chloro-pyridin-4-yloxy)-piperidine-1-carboxylic
acid isopropyl ester and~2-flu6r6-4-methanesulfonyl-ph'enylamine using the'general method as " ~
described in Example 10.1, step 3. !H NMR (CDC13,400 MHz) 5 8.59 (m, 1H), 8.14 (d, 1H), 7.66
(m, 2H), 6.84 (bs, 1H), 6.5 (m, 1H), 6.33 (s, 1H), 4.91 (m, 1H), 4.56 (m, 1H), 3.69 (m, 2H), 3.42 (m,
2H), 1.93 (m, 2H), 1.78 (m, 2H), 1.24 (d, 6H). LRMS calculated for C2iH26FN305S: 451.16. Found:
452.3 (M+H)+.
Example 10.115: Preparation of 4-[4-(2-FIuoro-4-methanesulfonyl-phenyIamino)-pyridin-2-
y!oxy]-piperidine-1-carboxylic acid isopropyl ester (Compound B149)
A mixture of 4-(4-chloro-pyridin-2-yloxy)-piperidine-1-carboxylic acid isopropyl ester (82
mg, 0.274 mmol), palladium acetate (8.3 mg, 0.037 mmol), 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-
phospha-bicyclo[3,3,3]undecane (26.3 (J.1, 0.077 mmol), 2-fluoro-4-methanesulfonyl-phenylamine
(77.8 mg, 0.41 mmol), sodium tert-butoxide (53 mg, 0.55 mmol), and 4 ml dioxane was heated in
microwave for 2 hours at 120°C. Mixture was purified by HPLC to give 4-[4-(2-fluoro-4-
methanesulfonyl-phenylamino)-pyridin-2-yloxy]-piperidine-1-carboxylic acid isopropyl ester as a
tanned solid (TFA salt, 88 mg, 57%). !HNMR (MeOD, 400 MHz) 8 1.27-1.28 (d, 6H), 1.82-1.86 (m,

2H), 2.03-2.08 (m, 2H), 3.22 (s, 3H), 3.42-3.50 (m, 2H), 3.71 -3.78 (m, 2H), 4.98-5.01 (m, 1H), 6.65
(s, 1H), 6.87-6.89 (m, 1H), 7.75 (m, 1H), 7.89-7.99 (m, 3H). C2iH26FN305S 451.16, found 452.3 (MFf).
Example 10.116: Preparation of 4-[5-(2-Fluoro-4-metl anesuIfonyI-phenyIamino)-pyridin-
3-yloxy]-piperidine-1-carboxyIic acid tert-bufyl ester (Comp ^und B147)
Sodium j-butoxide (17 mg, 0.180 mmol), BINAP (96 m. i, 0.154 mmol), Pd2(dba)3 (75 mg,
0.0824 mmol), 4-(5-bromo-pyridin-3-yloxy)-piperidine-1-carbo::ylic acid tert-butyl ester (46 mg,
0.0129 mmol), and 2-fluoro-4-methanesulfonyl-phenylamine (2? mg, 0.155 mmol) were suspended in
toluene (5 mL), and this mixture was heated at 70 C under a nitrogen atmosphere for 18 h. The
solvent was evaporated in vacuo to give an oil which was dissolved in DMSO (1 mL), and this crude
product was purified by mass-triggered preparative LCMS to give 4-[5-(2-fiuoro-4-methanesuIfonyl-
phenylamino)-pyridin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester as an oil (4 mg). Mass
calcd. for C22H28FN3O5S: 465.17. Found 466.4 (M+H)+, 410.3 (M-56+H)+.
Example 10.117: Preparation of 4-[6-(2-Methyl-4-propylamino-phenylamino)-pyrimidin-
4-yloxy]-piperidine-1-carboxyIic acid isopropyl ester (Compound B124).
Step 1: Preparation of 4-[6-(4-iodo-2-methyl-phenylamino)-pyrimidin-4-yIoxy]-
piperidine-1-carboxylic acid isopropyl ester.
A mixture of 4-(6-chloro-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester
(687 mg, 2.29 mmol), 2-methyl-4-iodoaniline ( 533 mg, 2.29 mmol), and sodium tert-butoxide (220
mg, 2.29 mmol) in 20 mL dioxane were heated under-microwave irradiation for 90 minutes at 80°C. -
Mixture was purified by HPLC to give 4-[6-(4-iodo-2-methyl-phenylamino)-pyrimidin-4-yIoxy]-
piperidine-1-carboxylic acid isopropyl ester as a white solid (TFA salt, 188 mg, 13%). 'HNMR
(MeOD, 400 MHz) 8 1.01-1.03 (d, 6H), 1.45-1.52 (m, 2H), 1.73-1.80 (m, 2H), 1.99 (s, 3H), 3.10-3.18
(m, 2H), 3.47-3.53 (m, 1H), 4.94-4.97 (m, 1H), 5.70 (s, 1H), 6.88-6.90 (d, 1H), 7.37-7.39 (d, 1H),
7.49 (s, 1H), 8.06 (s, 1H). Exact mass calculated for Q20H25IN4O3 496.10, found 496.34 (MH4).
Step 2: Preparation of 4-[6-(2-MethyI-4-propyIamino-phenyIamino)-pyrimidin-4-
yloxy]-piperidine-1-carboxylic acid isopropyl ester (Compound B124).
Compound B124 was prepared using a similar procedure as described herein as a white solid
(TFA salt, 120 mg, 74%). !HNMR (MeOD, 400 MHz) 5 0.86-0.90 (t, 3H), 1.07-1.09 (d, 6H), 1.50-
1.60 (m, 4H), 1.80-1.87 (m, 2H), 2.11 (s, 3H), 3.09-3.20 (m, 4H), 3.55-3.62 (m, 2H), 4.67-4.74 (m,
1H), 5.03-5.06 (m, 1H), 5.79 (s, 1H), 6.92-6.94 (d, 1H), 6.99 (s, 1H), 7.27-7.29 (d, 1H), 8.09 (s, 1H).
Exact mass calculated for C23H33N5O3 427.26, found 428.2 (MEf).

Example 10.117: Preparation of 4-[6-(2-FIuoro-4-methanesuIfonyl-phenyIamino)-
pyrimidin-4-yIoxy]-piperidine-1-carboxyIic acid isopropyl ester (Compound B3).
(2-Fluoro-4-methanesulfonyl-phenyl)-[6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine (697mg,
1.3mmol) and TEA (5.2 mmole, 4eq) were dissolved in DMF (10 mL) and then isopropyl
chloroformate (1.69mmole, 1.3eq) was added into the solution. The reaction mixture was stirred at
Room Temp for 1 hours. The crude was purified through HPLC provided Compound B3 as a yellow
solid (476 mg, 81 %). 'HNMR 400MHZ CDC13 8 (ppm): 8.45 (s, 1H); 8.02 (t,lH); 7.80-7.76 (m,2H);
6.06 (s,lH); 5.35 (m, 1H); 4.92 (sep,lH); 3.79 (sb,2H); 3.35-3.28 (m, 2H); 3.09 (s,3H); 1.97-2.01 (m,
2H); 1.73-1.74 (m, 2H); 1.25 (d, 6F£). Exact mass calculated for CjoHasFN^S 452.2, found LCMS
(ESI) m/z 453.2(MH+, 100%).
Example 10.118: Preparation of 4-[6-(2-Methyl-pyridin-3-yloxy)-pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid tert-butyl ester (Compound B157).
A solution of 4-(6-chloro-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid tert-butyl ester
(1.57 g, 5.0 mmol) and 2-methyl-pyridin-3-ol (654 mg, 6.0 mmol) in anhydrous DMF (10 mL)
containing K2C03 (1.38 g, 10 mmol) was heated at 150°C for 1.5 h. The reaction mixture was cooled
to ambient temperature, filtered over Celite, and the solvent was removed from the filtrate under high
vacuum. The residue was dissolved in ethyl acetate, rinsed with water and brine, and the organic
extract was dried over MgSCv The solution was concentrated to dryness and the residue was
dissolved in diethyl ether, filtered over Celite, and the filtrate was treated with IN HCl/ether (5 mL).
The resulting precipitate was collected by filtration to afford the title compound as a white solid (1.83
g;'87%yield): MS m/z 387.3,331.4; >H NMR (DMSO-ds) 8 8.59 (d,'l H, 1 = 5.3"Hz), 8.46 (s, 1" H),
8.08 (d, 1 H, J = 8.0 Hz), 7.69 (t, 1 H, J = 8.1 Hz), 6.63 (s, 1 H), 5.26 (m, 1 H), 3.71 (m, 2 H), 3.18 (m,
2 H), 2.45 (s, 3 H), 1.97 (m, 2 H), 1.59 (m, 2 H), 1.41 (s, 9 H).
Example 10.119: Preparation of 4-[6-(6-Bromo-2-methyI-pyridin-3-yloxy)-pyrimidin-4-yIoxy]-
piperidine-1-carboxylic acid isopropyl ester (Compound B156).
A solution of 4-(6-chloro-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester
(3.0 g, 10 mmol) and 6-bromo-2-methyl-pyridin-3-ol (2.25 g, 12 mmol) in anhydrous DMF (20 mL)
containing K2C03 (2.76 g, 20 mmol) was heated at 125°C for 4h. Upon cooling to ambient
temperature, the reaction mixture was filtered over Celite, and the solvent was removed from the
filtrate under high vacuum. The residue was dissolved in ethyl acetate, and the resulting solution was
rinsed twice with IN NaOH, and subsequently rinsed with water and brine. The organic extract was
dried over MgS04, the solution was concentrated to dryness, and the residue was dissolved in diethyl
ether. The addition of IN HCl/ether (10 mL) resulted in the formation of a small amount of dark
precipitate, which was removed by filtration. The solvent was removed from the filtrate to give a
colorless oil (loss of HC1 upon solvent removal rendered the free base), which gradually formed the

titie compound as a white solid upon standing (3.91 g, 87% yield): MS rn/z 451.4,453.4; ]H NMR
(DMSO-d6) 5 8.44 (s, 1 H), 7.61 (d, 1 H, J = 8.5 Hz), 7.56 (d, 1 H, J = 8.5 Hz), 6.56 (s, 1 H), 5.27 (m,
1 H), 4.78 (m, 1 H), 4.03 (m, 2 H), 3.23 (m, 2 H), 2.27 (s, 3 H), 1.95 (m, 2 H), 1.59 (m, 2 H), 1.18 (d,
6 H, J = 6.3 Hz).
Example 10.120: Preparation of 4-(6-{6-[(2,2-Dimethyl-[l,3]dioxolan-4-ylmethyl)-amino]-2-
methyI-pyridin-3-yIoxy}-pyrimidin-4-yIoxy)-piperidine-1-carboxyIic acid isopropyl ester
(Compound B154).
A mixture of 4- [6-(6-bromo-2-methyl-pyridin-3 -yloxy)-pyrimidin-4-yloxy] -piperidine-1 -
carboxylic acid isopropyl ester (1.13 g, 2.5 mmol), 4-(aminomethyl)-2,2-dimethyl-l,3-dioxolane (393
mg, 3.0 mmol), 2-(di-t-butylphosphino)biphenyl (75 mg, 0.25 mmol),
tris(dibenzylideneacetone)dipalladium (115 mg, 0.125 mmol), and sodium t-butoxide (480 mg, 5.0
mmol) in anhydrous toluene (10 mL) in a sealed vial was heated at 150°C for 2h. After cooling, the
reaction mixture was rinsed twice with water, and then the organic extract was filtered over Celite,
rinsing with a small amount of ethyl acetate. The filtrate was then directly subjected to flash
chromatography (25-30% ethyl acetate/hexane). The title compound was obtained as an amber gum
obtained upon solvent removal (505 mg, 40% yield): MS m/z 462.3 (due to loss of protective group
upon ionization); !HNMR (DMSO-d6) 5 8.42 (s, 1 H), 7.16 (d, 1 H, J = 8.8 Hz), 6.62 (t, 1 H, J = 5.9
Hz), 6.40 (d, 1 H, J = 8.8 Hz), 6.25 (s, 1 H), 5.24 (m, 1 H), 4.77 (m, 1 H), 4.23 (m, 1 H), 4.01 (m, 1
H), 3.69 (m, 3 H), 3.37 (m, 2 H), 3.22 (m, 1 H), 2.07 (s, 3 H), 1.96 (m, 2 H), 1.57 (m, 2 H), 1.36 (s, 3
H), 1.27 (s, 3 H), 1.17 (d, 6 H, J = 6.2 Hz).
Example 10.121: Preparation of 4-{6-[6-(2,3-Dihydroxy-propyIamino)-2-methyl-pyridin-3-
yIoxy]-pyrimidin-4-yIoxy}-piperidine-1-carboxyIic acid isopropyl ester (Compound B153).
A solution of 4-(6-{6-[(2,2-dimethyl-[l,3]dioxolan-4-ylmethyl)-amino]-2-methyl-pyridin-3-
yloxy}-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (Compound 154,480 mg,
0.96 mmol) in THF was treated with 6 mL cone. HC1 and stirred for 2h. The solvent was removed,
and the residue was dissolved in CH2CI2, to which was added diethyl ether, at which point a
precipitate formed. This material was collected by filtration, yielding a hygroscopic solid which
rapidly formed a sticky gum. The filter cake was then dissolved in CH2CI2, and the resulting solution
was washed with 2KTNa2C03 and dried over MgS04. The solvent was removed to furnish an amber
gum (238 mg, 54% yield): MS m/z 462.6; 'H NMR (DMSO-d6) 5 8.42 (s, 1 H), 7.17 (d, 1 H, J = 8.8
Hz), 6.47 (t, 1 H, J = 5.7 Hz), 6.42 (d, 1 H, J = 8.8 Hz), 6.26 (s, 1 H), 5.24 (m, 1 H), 4.96 (d, 1 H, J =
4.8 Hz), 4.77 (m, 1 H), 4.68 (t, 1 H, J = 5.9 Hz), 3.68 (m, 2 H), 3.61 (m, 1 H), 3.35 (m, 3 H), 3.19 (m,
3 H), 2.06 (s, 3 H), 1.95 (m, 2 H), 1.57 (m, 2 H), 1.17 (d, 6 H, J = 6.3 Hz).

Example 11: Protocol for RUP3 Dose Responses in Melanophores
Melanophores are maintained in culture as reported by Potenza, M. N. and Lerner, M. R., in
Pigment Cell Research, Vol. 5, 372-378,1992 and transfected with the RUP3 expression vector
(pCMV) using electroporation. Following electroporation, the transfected cells are plated into 96 well
plates for the assay. The cells are then allowed to grow for 48 hours in order to both recover from the
electroporation procedure and attain maximal receptor expression levels.
On the assay day, the growth medium on the cells is replaced with serum-free buffer
containing 10nM melatonin. The melatonin acts via an endogenous Gi-coupled GPCR in the
melanophores to lower intracellular cAMP levels. In response to lowered cAMP levels, the
melanophores translocate their pigment to the center of the cell. The net effect of this is a significant
decrease in the absorbance reading of the cell monolayer in the well, measured at 600-650nM.
After a 1-hour incubation in melatonin, the cells become completely pigment-aggregated. At
this point a baseline absorbance reading is collected. Serial dilutions of test compounds are then added
to the plate and compounds that stimulate RUP3 produce increases in intracellular cAMP levels. In
response to these increased cAMP levels, the melanophores translocate their pigment back into the
cell periphery. After one hour, stimulated cells are fully pigment-dispersed. The cell monolayer in the
dispersed state absorbs much more light in the 600-650nm range. The measured increase in
absorbance compared to the baseline reading allows one to quantitate the degree of receptor
stimulation and plot a dose-response curve.
The compounds in the above examples were screened using the melanophore dispersion
assay, as described above. Representative compounds of the present invention and their
-corresponding EC50-values are shown in Table 6 below. -Certain other compounds illustrated in the
Examples showed EC50 activities in the melanophore dispersion assay of less than about 10 µM.

Each of the embodiments of the present invention may in the alternative be limited to relate to
those compounds that demonstrate about 100 fold or greater binding to RUP3 compared to the
corticotrophin-releasing factor-1 (CRF-1) receptor; a recent review of CRF-1 compounds can be
found in Expert Opin. Ther. Patents 2002,12(11), 1619-1630, incorporated herein by reference in its
entirety.

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.

We Claim:
1. A compound selected from compounds of Formula (I) and pharmaceutically acceptable
salts, solvates, hydrates and N-oxides thereof:

wherein:
A1 and A2 are both --CH2CH2-, and each A1 and A2 is optionally substituted with
1, 2, 3 or 4 methyl groups;
D is CR1R2 or NR2, wherein R1 is selected from H, C1-6 alkyl, C1-6 alkoxy,
halogen and hydroxyl;
E is N or CR3, wherein R3 is H or C1-6 alkyl;
— is a single bond;
K is absent, C3-6 cycloalkylene, or C1-3 alkylene group each optionally substituted
with one or more substituents selected independently from C1-6 alkyl, C1-6 alkoxy,
carboxy, cyano, and halogen;
Q1 is NR4, O, S, S(O), or S(O)2, wherein R4 is H, C1-6 acyl, C1-6 alkyl, C2-6
alkenyl. C2-6 alkynyl, C3-7 cycloalkyl. or C3-7-cycloalkyl-C1-3-alkylene, wherein said C1-6
alkyl is optionally substituted with one or more substituents selected independently from
C1-6 acyl, C1-6 acyloxy, C2-6 alkenyl, C1-6 alkoxy, C1-6 alkyl, C1-6 alkylamino, C1-6
alkylcarboxamide, C2-6 alkynyl, C1-6 alkylsulfonamide, C1-6 alkylsulfinyl, C1-6
alkylsulfonyl, C1-6 alkylthio, C1-6 alkylthiocarboxamide, C1-6 alkylthioureyl, C1-6
alkylureyl, amino, di-C1-6-alkylamino, C1-6 alkoxycarbonyl, carboxamide, carboxy,
cyano, C3-6 cycloalkyl, di-C1-6-alkylcarboxamide, di-C1-6-alkylsulfonamide, di-C1-6-
alkylthiocarboxamido, C1-6 haloalkoxy, C1-6 haloalkyl, halogen, C1-6 haloalkylsulfinyl,
C1-6 haloalkylsulfonyl, C1-6 haloalkylthio, hydroxyl, hydroxylamino and nitro;
Q2 is NR5 or O, wherein R5 is H, C1-6 acyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl,
C3-7 cycloalkyl, or C3-7-cycloalkyl-C1-3-alkylene, wherein said C1-6 alkyl is optionally
substituted with one or more substituents selected independently from C1-6 acyl, C1-6

acyloxy, C2-6 alkenyl, C1-6 alkoxy, C1-6 alkyl, C1-6 alkylamino, C1-6 alkylcarboxamide, C2-
6 alkynyl, C1-6 alkylsulfonamide, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6
alkylthiocarboxamide, C1-6 alkylthioureyl, C1-6 alkylureyl, amino, di-C1-6-alkylamino, C1-
6 alkoxycarbonyl, carboxamide, carboxy, cyano, C3-6 cycloalkyl, di-C1-6-
alkylcarboxamide, di-C1-6-alkylsulfonamide, di-C1-6-alkylthiocarboxamido, C1-6
haloalkoxy, C1-6 haloalkyl, halogen, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6
haloalkylthio, hydroxyl, hydroxylamino and nitro;
W is CH;
X is N or CR6;
Y is N or CR7;
Z is N;
V is absent, C1-3 heteroalkylene, or C1-3 alkylene wherein each are optionally
substituted with one or more substituents selected independently from C1-3 alkyl. C1-6
alkoxy, carboxy, cyano, C1-3 haloalkyl, and halogen;
R6, R7, and R8 are each independently selected from H, C1-6 acyl, C1-6 acyloxy, C2-
6 alkenyl, C1-6 alkoxy, C1-6 alkyl, C1-6 alkylamino, C1-6 alkylcarboxamide, C2-6 alkynyl,
C1-6 alkylsulfonamide, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6
alkylthiocarboxamide, C1-6 alkylthioureyl, C1-6 alkylureyl, amino, di-C1-6-alkylamino, C1-.
6 alkoxycarbonyl, carboxamide, carboxy, cyano, C3-6 cycloalkyl, di-C1-6-
alkylcarboxamide, di-C1-6-alkylsulfonamide, di-C1-6-alkylthiocarboxamido, C1-6
haloalkoxy, C1-6 haloalkyl, halogen, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6
haloalkylthio, hydroxyl, hydroxylamino and nitro. wherein said C2-6 alkenyl, C1-6 alkyl.
C2-6 alkynyl and C3-6 cycloalkyl are each optionally substituted with one or more
substituents independently selected from C1-6 acyl, C1-6 acyloxy, C2-6 alkenyl, C1-6
alkoxy. C1-6 alkyl. C1-6 alkylamino. C1-6 alkylcarboxamide, C2-6 alkynyl. C1-6
alkylsulfonamide. C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6
alkylthiocarboxamide, C1-6 alkylthioureyl, C1-6 alkylureyl, amino, di-C1-6-alkylamino, C1-
6 alkoxycarbonyl, carboxamide, carboxy, cyano, C3-6 cycloalkyl, di-C1-6-
alkylcarboxamide, di-C1-6-alkylsulfonamide, di-C1-6-alkylthiocarboxamido, C1-6
haloalkoxy, C1-6 haloalkyl, halogen, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6
haloalkylthio, hydroxyl, hydroxylamino and nitro;

Ar is phenyl, naphthyl, pyridyl, benzofuranyl, pyrazinyl, pyridazinyl, pyrimidinyl,
triazinyl, quinoline, benzoxazole, benzothiazole. 1H-benzimidazole, isoquinoline,
quinazoline, quinoxaline, pyrrole or indole, optionally substituted with R9, Rl0, Rn, R12,
and R13;
R9 is selected from C1-6 acyl, C1-6 acylsulfonamide, C1-6 acyloxy, C2-6 alkenyl, C1-6
alkoxy, C1-6 alkyl, C1-6 alkylamino, C1-6 alkylcarboxamide, C2-6 alkynyl, C1-6
alkylsulfonamide, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkyllhio, C1-6
alkyhhiocarboxamide, C1-6 alkylthioureyl, C1-6 alkylureyl, amino, aryl, arylcarbonyl,
arylsulfonyl, di-C1-6-alkylamino, carbamimidoyl, C1-6 alkoxycarbonyl, carboxamide.
carboxy, cyano, C3-6 cycloalkyl, di-C1-6-alkylcarboxamide, di-C1-6-alkylsulfonamide, di-
C1-6-alkylthiocarboxamido, guanidine, C1-6 haloalkoxy, C1-6 haloalkyl, halogen. C1-6,
haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6 haloalkylthio, heterocyclic,
heterocyclicsulfonyl, heteroaryl, hydroxyl, hydroxylamino, nitro, C3-6 oxo-cycloalkyl,
phenoxy, sulfonamide, sulfonic acid and thiol; and wherein each R9 is optionally
substituted with one or more substituents selected independently from C1-6 acyl. C1-6
acylsulfonamide, C1-6 acyloxy, C2-6 alkenyl, C1-6 alkoxy, C1-6 alkyl, C1-6 alkylamino, C1-6
alkylcarboxamide, C2-6 alkynyl, C1-6 alkylsulfonamide, C1-6 alkylsulfinyl, C1-6
alkylsulfonyl, C1-6 alkylthio, C1-6 alkylthiocarboxamide, C1-6 alkylthioureyl, C1-6
alkylureyl, amino, aryl, arylcarbonyl, arylsulfonyl, di-C1-6-alkylamino, C1-6
alkoxycarbonyl, carboxamide, carboxy, cyano, C3-6 cycloalkyl, di-C1-6-alkylcarboxamide,
di-C1-6-alkylsulfonamide, di-C1-6-alkylthiocarboxamido, C1-6 haloalkoxy, C1-6 haloalkyl,
halogen, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6 haloalkylthio, heteroaryl,
heteroarylcarbonyl, heteroarylsulfonyl, heterocyclic, hydroxyl, hydroxylamino, and nitro;
R10, R11, R12, and R13 are independently selected from C1-6 acyl, C1-6 acyloxy, C2-6
alkenyl, C1-6 alkoxy, C1-6 alkyl, C1-6 alkylamino, C1-6 alkylcarboxamide. C2-6 alkynyl, C1-6
alkylsulfonamide, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6
alkylthiocarboxamide. C1-6 alkylthioureyl. C1-6 alkylureyl. amino. di-C1-6-alkylamino, C1-
6 alkoxycarbonyl. carboxamide, carboxy, cyano, C3-6 cycloalkyl, di-C1-6-
alkylcarboxamide, di-C1-6-alkylsulfonamide, di-C1-6-alkylthiocarboxamido, C1-6
haloalkoxy, C1-6 haloalkyl, halogen, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6
haloalkylthio, hydroxyl, hydroxylamino, nitro, and thiol; or two adjacent Rio, Rn, R12,


and R13 groups together with the atoms to which they are bonded form a 5, 6 or 7 member
cycloalkyl, 5, 6 or 7 member cycloalkenyl, or 5, 6 or 7 member heterocyclic group
wherein the 5. 6 or 7 member group is optionally substituted with halogen or oxo; and
cither:
R2 is aryl, arylcarbonyl, C1-6 alkoxycarbonyl, C3-7-cycloalkoxycarbonyl,
heteroaryl, or heteroarylcarbonyl; wherein each R2 is optionally substituted with one or
more substituents selected independently from the group consisting of C1-6 acyl, C1-6
acyloxy, C2-6 alkenyl, C1-6 alkoxy, C1-6 alkyl, C1-6 alkylamino, C1-6 alkylcarboxamide, C2-
6 alkynyl, C1-6 alkylsulfonamide, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6
alkylthiocarboxamide, C1-6 alkylthioureyl, C1-6 alkylureyl, amino, aryl, di-C1-6-
alkylamino, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-6 cycloalkyl, di-C1-6-
alkylcarboxamide, di-C1-6-alkylsulfonamide, di-C1-6-alkylthiocarboxamido, C1-6
haloalkoxy, C1-6 haloalkyl, halogen, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6
haloalkylthio, heterocyclic, heteroaryl, hydroxyl, hydroxylamino, nitro, and thiol;
or:
R2 is C1-6 alkoxycarbonyl, C1-6 alkoxycarbonyl substituted by C3-6 cycloalkyl. C3-
7-cycloalkoxycarbonyl, or heteroaryl-C1-3-alkylene optionally substituted with 1, 2, or 3
C1-6 alkyl;
provided that the compound is not 4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-
pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester.
2. A compound according to claim 1, wherein K is absent.
3. A compound according to claim 1, wherein K is -CH2-.
4. A compound according to any one of claims 1 to 3, wherein V is absent.
5. A compound according to any one of claims 1 to 4, wherein Q1 is O.
6. A compound according to any one of claims 1 to 4. wherein Q1 is NH.

7. A compound according to any one of claims 1 to 6, wherein Q2 is O.
8. A compound according to any one of claims 1 to 6, wherein Q2 is NR5.
9. A compound according to claim 8 wherein R5 is H or C1-6 alkyl.
10. A compound according to any one of claims 1 to 9 wherein:
W is CH;
X is N;
Y is CR7, wherein R7 is H, C1-6 alkyl, or halogen; and
Z is N.
11. A compound according to any one of claims 1 to 10, wherein E is CH and D is NR2.
12. A compound according to any one of claims 1 to 11, wherein R2 is aryl, arylcarbonyl,
C1-6 alkoxycarbonyl, C3-7-cycloalkoxycarbonyl, heteroaryl, or heteroarylcarbonyl; each
optionally substituted with one or more substituents selected independently from C1-6 acyl,
C1-6 acyloxy, C2-6 alkenyl, C1-6 alkoxy, C1-6 alkyl, C1-6 alkylamino. C1-6 alkylcarboxamide,
C2-6, alkynyl, C1-6 alkylsulfonamide, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6
alkylthiocarboxamide, C1-6 alkylthioureyl, C1-6 alkylureyl, amino, aryl, di-C1-6-alkylamino.
carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-6 cycloalkyl, di-C1-6-alkylcarboxamide,
di-C1-6-alkylsulfonamide, di-C1-6-alkylthiocarboxamido, C1-6 haloalkoxy, C1-6 haloalkyl,
lalogen, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6 haloalkylthio, heterocyclic,
leteroaryl, hydroxyl, hydroxylamino, nitro, and thiol.
13. A compound according to any one of claims 1 to 11, wherein R2 is C1-6 alkoxycarbonyl,
C1-6 alkoxycarbonyl substituted by C3-6 cycloalkyl, C3-7-cycloalkoxycarbonyl, or heteroaryl-
C1-3-alkylene optionally substituted with 1, 2, or 3 C1-6 alkyl.
14. A compound according to any one of claims 1 to 13, wherein Ar is phenyl optionally
substituted with R9, R10, R11, R12 and R13;

R9 is selected from methanesulfonyl, 2-methanesulfonyl-ethyl, acetylsulfamoyl,
propionylsulfamoyl, ethylsulfanyl, isopropylsulfanyl, ethylsulfamoyl, methylsulfamoyl,
dimethylsulfamoyl, methylsulfamoylmethyl, sulfamoyl, [1,2,4]triazol-1-yl, [1
,2,4]triazol-
1-ylmethyl, 2-[1,2,4]triazol-1 -yl-ethyl, methoxy, 2-oxo-oxazolidin-4-ylmethyl, 1,1-
dioxo-1λ6-thiomorpholin-4-ylmethyl, pyrazol-1 -yl, trifluoromethanesulfonyl,
morpholine-4-sulfonyl. pyridine-2-carbonyl, F, Cl, cyano, Br, carboxy, butyryl,
propoxycarbonyl, hydroxy, propylcarbamoyl, N-hydroxycarbamimidoyl, carbamimidoyl,
N-ethylcarbamimidoyl, and 2-amino-ethylamino; and
R10, R11, R12, and R13 are independently selected from F, methoxy, methyl, ethyl,
and carboxy.
15. A compound according to any one of claims 1 to 13, wherein Ar is phenyl optionally
substituted with R9, R10, R11, R12, and R13;
R9 is selected from methanesulfonyl, cyano, F, Cl, Br, I, methyl, methoxy,
ethylamino, ethylsulfanyl, isopropylsulfanyl, hydroxy, isopropoxy, propoxy,
dimethylamino, propylamino, isopropylamino, acetylamino, piperidin-1-yl.
trifluoromethoxy. oxazol-5-yl, ethynyl, 3-methyl-butylamino, 2-morpholin-4-yl-
ethylamino, acetylsulfamoyl, propionylsulfamoyl, tetrahydro-furan-2-ylmethoxy,
morpholin-4-yl, 4-methyl-piperazin-1-yl, butylamino, 2-pyrrolidin-1-yl-ethoxy, 2-
dimethylamino-ethoxy, 2-morpholin-4-yl-ethoxy, morpholin-4-ylamino, 2-methoxy-
ethylamino, and tetrahydro-furan-2-ylmethyl-amino; and
R10, R11, R12, and R13 are independently selected from F, Cl, Br, I, hydroxyl,
methoxy, cyano, methyl, and trifluoromethoxy.
16. A compound according to any one of claims 1 to 13, wherein Ar is selected from pyridin-
2-yl, pyridin-3-yl, pyridin-4-yl, quinolin-6-yl, and benzothiazol-6-yl, each optionally
substituted with R9, R10, R11, R12, and R13;
R9 is selected from methanesulfonyl, methoxy, carboxy, acetylsulfamoyl,
propionylsulfamoyl, acetylamino, F, Cl, Br, methyl, and trifluoromethyl; and
R10, R11 R12, and R13 are independently selected from methoxy, methyl, F, Cl, and
Br.

17. A compound according to any one of claims 1 to 13, wherein Ar is selected from
pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, quinolin-6-yl, and benzothiazol-6-yl,
optionally substituted with R9, R10, R11, R12, and R13;
R9 is selected from cyano, F, Cl, Br, acetylamino, methoxy, methyl, propoxy,
propylamino, isopropylamino, phenyl, t-butyl, 4-methylphenyl, ethyl, methylsulfanyl,
morpholin-4-yl, benzenesulfonyl, trifluoromethyl, cyclopropyl, carbamoyl, 3,4-
difluorophenyl, 4-chlorophenyl, 1-methyl-pyrrolidin-2-yl, acetylsulfamoyl,
propionylsulfamoyl, and pyridine-2-yl; and
R10, R11, R12, and R13 are independently methyl, F or Cl.
18. A compound according to claim 1, selected from compounds having Formula (IIIi) and
pharmaceutically acceptable salts, solvates, hydrates and N-oxides thereof:

wherein:
K is absent or a C1-3 alkylene group;
Q1 is NH or O;
Q2 is NR5 or O, wherein R5 is H or C1-6 alkyl:
W is CH, X is N, Y is CH, and Z is N;
V is absent;
Ar is selected from pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, quinolin-6-yl, and
benzothiazol-6-yl, each optionally substituted with R9, R10, R11, R12, and R13;
R9 is C1-6 acyl, C1-6 acylsulfonamide, C1-6 alkoxy, C1-6 alkyl, C1-6 alkylamino, C1-6
alkylcarboxamide, C2-6 alkynyl, C1-6 alkylsulfonamide, C1-6 alkylsulfinyl, C1-6
alkylsulfonyl, C1-6 alkylthio, amino, aryl, arylsulfonyl, di-C1-6-alkylamino,
carbamimidoyl, C1-6 alkoxycarbonyl, carboxamide, carboxy, cyano, C3-6 cycloalkoxy, C3-
6 cycloalkyl, di-C1-6-alkylsulfonamide, guanidine, C1-6 haloalkoxy, C1-6 haloalkyl,

halogen, C1-6 haloalkylsulfonyl, heteroaryl, heteroarylcarbonyl, heteroarylsulfonyl,
heterocyclic, heterocyclicsulfonyl, hydroxyl, sulfonamide, or thiol; wherein C1-6 alkoxy,
C1-6 alkyl, C1-6 alkylamino, amino, aryl, carbamimidoyl, heterocyclic, are optionally
substituted with 1, 2, 3 or 4 substituents selected independently from C1-6 alkoxy, C1-6
alkyl, C2-6 alkynyl, C1-6 alkylsulfonamide, C1-6 alkylsulfonyl, amino, aryl, C3-6 cycloalkyl,
di-C1-6-alkylamino, halogen, heteroaryl, heterocyclic, and hydroxyl;
R10, R11, R12, and R13 are independently selected from C1-6 alkoxy, C1-6 alkyl, C1-6
alkylamino, carboxy, cyano, halogen, C1-6 haloalkoxy, C1-6 haloalkylsulfonyl, and
hydroxyl; or two adjacent R10, R11, R12, and R13 groups together with the atoms to which
they are bonded form a 5 or 6 member cycloalkyl or 5 or 6 member heterocyclic group,
wherein said 5 or 6 member group is optionally substituted with halogen or oxo; and
R2 is tert-butoxycarbonyl, isobutoxycarbonyl. isopropoxycarbonyl,
butoxycarbonyl, cyclopropylmethoxycarbonyl, 3-methyl-butoxycarbonyl, or 3-isopropyl-
[ 1,2,4]oxadiazol-5-yl.
A compound according to claim 1, wherein said compound is selected from the
following compounds and pharmaceutically acceptable salts, solvates, hydrates and N-
oxides thereof:
(A3) 4-{[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-methyl-
amino}-piperidine-1-carboxylic acid tert-butyl ester;
(A4) 4-({[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-methyl-
amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester;
(A5) 4-({[6-(4-Methanesulfonyl-phenylamino)-pyrimidin-4-yl]-methyl-amino}-
methyl)-piperidine-1-carboxylic acid tert-butyl ester;
(A6) 4-({[6-(2,5-Difluoro-benzylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-
piperidine-1-carboxylic acid tert-butyl ester;
(A7) 4-[({6-f(Benzo[1,3]dioxol-5-ylmethyl)-amino]-pyrimidin-4-yl}-methyl-
amino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester;
(A9) 4-({Methyl-[6-(2-pyridin-4-yl-ethylamino)-pyrimidin-4-yl]-amino}-methyl)-
piperidine-1 -carboxylic acid tert-butyl ester;

(A10) 4-({Methyl-[6-(2-pyridin-3-yl-ethylamino)-pyrimidin-4-yl]-amino}-
methyl)-piperidine-1-carboxylic acid tert-butyl ester;
(A11) 4-[(Methyl-{6-[(pyridin-3-ylmethyl)-amino]-pyrimidin-4-yl}-amino)-
methyl]-piperidine-1-carboxylic acid tert-butyl ester;
(A12) 4-[({6-[(2-Fluoro-4-methanesulfonyl-phenyl)-methyl-amino]-pyrimidin-4-
yl}-methyl-amino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester;
(A13) 4-({ [6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-methyl-
amino}-methyl)-piperidine-1-carboxylic acid isobutyl ester;
(A 14) 4-({[6-(4-Cyano-2-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino} -
methyl)-piperidine-1-carboxylic acid tert-butyl ester;
(A15) 4-[({6-[4-(2-Methanesulfonyl-ethyl)-phenylamino]-pyrimidin-4-yl}-
methyl-amino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester;
(A16) 4-({[6-(4-Ethylsulfanyl-phenylamino)-pyrimidin-4-yl]-methyl-amino}-
methyl)-piperidine-1-carboxylic acid tert-butyl ester;
(A17) 4-({[6-(4-Isopropylsulfanyl-phenylamino)-pyrimidin-4-yl)-methyl-amino}-
methyl)-piperidine-1-carboxylic acid tert-butyl ester;
(A18) 4-({[6-(4-Ethylsulfamoyl-phenylamino)-pyrimidin-4-yl]-methyl-amino}-
methyl)-piperidine-1-carboxylic acid tert-butyl ester;
(A19) 4-({Methyl-[6-(4-methylsulfamoyl-phenylamino)-pyrimidin-4-yl]-amino} -
methyl)-piperidine-1-carboxylic acid tert-butyl ester;
(A20) 4-({[6-(4-Dimethylsulfamoyl-phenylamino)-pyrimidin-4-yl]-methyl-
amino }-methyl)-piperidine-1-carboxylic acid tert-butyl ester;
(A21) 4-({Methyl-[6-(4-methylsulfamoylmethyl-phenylamino)-pyrimidin-4-yl]-
amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester;
(A22) 4-({Methyl-[6-(4-sulfamoyl-phenylamino)-pyrimidin-4-yl]-amino}-
methyl)-piperidine-1-carboxylic acid tert-butyl ester;
(A23) 4-({Methyl-[6-(4-1,1,2,4]triazol-1 -yl-phenylamino)-pyrimidin-4-yl]-
amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester;
(A24) 4-({Methyl-[6-(4-[1,2,4]triazol-1-ylmethyl-phenylamino)-pyrimidin-4-yl]-
amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester;

(A25)4-[(Methyl-{6-[4-(2-[1,2,4]triazol-1-yl-ethyl)-phenylamino]-pyrimidin-4-
yl}-arnino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester;
(A26) 4-({[6-(Benzo[1,3]dioxol-5-ylamino)-pyrimidin-4-yl]-methyl-amino}-
methyl)-piperidine-1-carboxylic acid tert-butyl ester;(A27) 4-({[6-(6-Methanesulfonyl-
pyridin-3-ylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylic acid
tert-butyl ester;
(A28)4-({[6-(3,5-Dimethoxy-phenylamino)-pyrimidin-4-yl]-methyl-amino}-
methyl)-piperidine-1 -carboxylic acid tert-butyl ester;
(A29) 4-[(Methyl-{6-[4-(2-oxo-oxazolidin-4-ylmethyl)-phenylamino]-pyrimidin-
4-yl}-amino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester;
(A30) 4-[({6-[4-(1,1-Dioxo-1λ6-thiomorpholin-4-ylmethyl)-phenylamino)-
pyrimidin-4-yl}-methyl-amino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester;
(A31) 4-({Methyl-[6-(4-pyrazol-1 -yl-phenylamino)-pyrimidin-4-yl]-amino}-
methyl )-piperidine-l -carboxylic acid tert-butyl ester;
(A32) 4-({[6-(2,2-Difluoro-benzo[1,3]dioxol-5-ylamino)-pyrimidin-4-yl]-methyl-
amino}-methyl)-piperidinc-1-carboxylic acid tert-butyl ester;
(A33) 4-({Methyl-[6-(4-trifluoromethanesulfonyl-phenylamino)-pyrimidin-4-yl]-
amino }-methyl)-piperidine-1-carboxylic acid tert-butyl ester;
(A34) 4-[(Methyl-{6-[4-(morpholine-4-sulfonyl)-phenylamino]-pyrimidin-4-yl}-
amino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester;
(A35) 4-[(Methyl-{6-[2-(pyridine-2-carbonyl)-phenylamino]-pyrimidin-4-yl} -
amino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester;
(A36) 4-( {[6-(2-Fluoro-5-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-methyl-
amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester;
(A39) 4-({[6-(3,4-Difluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-
methyl)-piperidine-1-carboxylic acid tert-butyl ester;
(A40) 4-({[6-(2,6-Difluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-
methyl)-piperidine-1-carboxylic acid tert-butyl ester;
(A41) 4-({[6-(2,5-Difluoro-phenylamino)-pyrimidin-4-yl]-methyl-arnino}-
methyl)-piperidine-1-carboxylic acid tert-butyl ester;


(A42) 4-({[6-(2,3-Difluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-
methyl)-piperidine-1-carboxylic acid tert-butyl ester;
(A43) 4-({Methyl-[6-(2,3,5-trifluoro-phenylamino)-pyrimidin-4-yl]-amino}-
mcthyl)-piperidine-1-carboxylic acid tert-butyl ester;
(A44) 4-({[6-(2-Fluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-
piperidine-1-carboxylic acid tert-butyl ester;
(A45) 4-({[6-(2-Fluoro-4-methyl-phenylarnino)-pyrimidin-4-yl]-methyl-arnino}-
methyl)-piperidine-1-carboxylic acid tert-butyl ester;
(A46) 4-({[6-(3-Chloro-2-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-
methyl)-piperidine-1-carboxylic acid tert-butyl ester;
(A47) 4-({[6-(2,4-Difluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-
methyl)-piperidine-1-carboxylic acid tert-butyl ester;
(A48) 4-[(Methyl-{6-[2-(l-oxy-pyridin-3-yl)-ethylamino]-pyrimidin-4-yl}-
amino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester;
(A49) 4-[(Methyl-{6-[2-(1-oxy-pyridin-3-yl)-ethylamino]-pyrimidin-4-yl}-
amino)-methyl]-piperidine-1-carboxylic acid isobutyl ester;
(A50) 4-({[6-(2,5-Difluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-
methyl)-piperidine-1-carboxylic acid isobutyl ester;
(A51) 4-({[6-(4-Cyano-2-fluoro-phenylamino)-pyrimidin-4 -yl]-methy 1-amino}-
methyl)-piperidine-1-carboxylic acid isobutyl ester;
(A52)4-[({6-[2-(2-Fluoro-phenoxy)-ethylamino]-pyrimidin-4-yl}-methyl-
amino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester;
(A53) 4-({[6-(2-Fluoro-phenoxy)-pyrimidin-4-yl]-methyl-amino}-methyl)-
piperidine-1-carboxylic acid tert-butyl ester;
(A54) 4-({[6-(2,5-Difluoro-phenoxy)-pyrimidin-4-yl]-methyl-amino}-methyl)-
piperidine-1-carboxylic acid tert-butyl ester;
(A55) 4-[({6-[2-(2-Chloro-phenoxy)-ethylamino]-pyrimidin-4-yl}-methyl-
amino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester;
(A56) 4-({[6-(2-Chloro-phenoxy)-pyrimidin-4-yl]-methyl-amino}-methyl)-
pipcridine-1-carboxylic acid tert-butyl ester:


(A57)4-[({6-[2-(4-Fluoro-phenoxy)-propylamino]-pyrimidin-4-yl}-methyl-
amino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester;
(A58) 4-({[6-(4-Ethylsulfamoyl-2-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-
amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester;
(A59) 4-({[6-(2-Fluoro-4-isopropylsulfamoyl-phenylamino)-pyrimidin-4-yl]-
methyl-amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester;
(A60) 4-({[6-(4-Cyano-2,5-dinuoro-phenylamino)-pyrimidin-4-yl]-methyl-
amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester;
(A61) 4-( {[6-(4-Bromo-2,5-difluoro-phenylamino)-pyrimidin-4-yl]-methyl-
amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester;
(A62) 4-({[6-(5-Carboxy-2-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-
methyl)-piperidine-1-carboxylic acid tert-butyl ester;
(A63) 4-({[6-(6-Methoxy-pyridin-3-ylamino)-pyrimidin-4-yl]-methyl-amino}-
methyl)-piperidine-1-carboxylic acid tert-butyl ester;
(A64) 4-({[6-(2,6-Dimethoxy-pyridin-3-ylamino)-pyrimidin-4-yl]-methyl-
amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester;
(A65) 6-{6-[(1-tert-Butoxycarbonyl-piperidin-4-ylmethyl)-methyl-amino]-
pyrimidin-4-ylamino}-nicotinic acid;
(A66) 4-({[6-(6-Acetylamino-pyridin-3-ylamino)-pyrimidin-4-yl]-methyl-
amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester;
(A67) 4-({[6-(5-Fluoro-pyridin-2-ylamino)-pyrimidin-4-yl]-methyl-amino}-
methyl)-piperidine-1-carboxylic acid tert-butyl ester;
(A68)4-({[6-(4-Cyano-2-ethyl-phenylamino)-pyrimidin-4-yl]-methyl-amino}-
methyl)-piperidine-1-carboxylic acid tert-butyl ester;
(A69) 4-({[6-(4-Butyryl-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-
piperidine-1-carboxylic acid tert-butyl ester;
(A70) 4-({[6-(5-Bromo-3-methyl-pyridin-2-ylamino)-pyrimidin-4-yl]-methyl-
amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester;
(A71) 4-({f6-(3-Bromo-5-methyl-pyridin-2-ylamino)-pyrimidin-4-yl]-methyl-
aminoJ-methyl)-piperidine-1-carboxylic acid tert-butyl ester;


(A72) 4-({Methyl-[6-(5-trifluoromethyl-pyridin-2-ylamino)-pyrimidin-4-yl]-
amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester;
(A73)4-({[6-(4-Bromo-2-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-
methyl)-piperidine-1-carboxylic acid tert-butyl ester;
(A74)4-({[6-(3-Carboxy-4-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-
methyl)-piperidine-1-carboxylic acid tert-butyl ester;
(A75) 4-({[6-(4-Ethoxycarbonyl-2-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-
amino}-methyl)-piperidine-1-carboxylic acid isobutyl ester;
(A76) 4-({[6-(4-Carboxy-2-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-
methyl)-piperidine-1-carboxylic acid isobutyl ester;
(A77) 4-({[6-(4-Cyano-2-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-
methyl)-piperidine-1-carboxylic acid isopropyl ester;
(A78)4-({[6-(4-Cyano-2-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-
methyl)-piperidine-1-carboxylic acid butyl ester;
(A79)4-({[6-(4-Cyano-2-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-
methyl)-piperidine-1-carboxylic acid cyclopropylmethyl ester;
(A82)4-({[6-(2,5-Difluoro-4-hydroxy-phenylamino)-pyrimidin-4-yl]-methyl-
amino}-methyl)-piperidine-1-carboxylic acid isobutyl ester;
(A83) 4-({[6-(4-Ethylcarbamoyl-2-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-
amino}-methyl)-piperidine-1-carboxylic acid isobutyl ester;
(A84) 4-[({6-f2-Fluoro-4-(N-hydroxycarbamimidoyl)-phenylamino]-pyrimidin-4-
yl}-methyl-amino)-methyl]-piperidine-1-carboxylic acid isobutyl ester;
(A85) 4-({[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-methyl-
amino}-methyl)-piperidine-1-carboxylic acid 3-methyl-butyl ester;
(A86) 4-( {[6-(2,5-Difluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-
methyl-amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester;
(A87) 4-( {[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-methyl-
amino}-methyl)-piperidine-1-carboxylic acid isopropyl ester;
(A88) (5-Butyl-pyridin-2-yl)-[4-({[6-(2-fluoro-4-methanesulfonyl-phenylamino)-
pyrimidin-4-yl]-methyl-amino}-methyl)-piperidin-1-yl]-methanone;


(A89)N-(2-Fluoro-4-methanesulfonyl-phenyl)-N'-(5'-fluoro-3,4,5,6-tetrahydro-
2H-[1,2']bipyridinyl-4-ylmethyl)-N'-methyl-pyrimidine-4,6-diamine;
(A90) 4-( {[6-(4-Carbarnimidoyl-2-fluoro-phenylamino)-pyrirnidin-4-yl]-methyl-
amino}-methyl)-piperidine-1-carboxylic acid isobutyl ester;
(A91)4-({[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-methyl-
amino}-methyl)-piperidine-1-carboxylic acid cyclobutyl ester;
(A92) 4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-ylamino]-
piperidine-1-carboxylic acid tert-butyl ester;
(A94) 4-({(6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-methyl-
amino}-methyl)-piperidine-1-carboxylic acid 1-ethyl-propyl ester;
(A95) 4-({Ethyl-[6-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-
amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester;
(A96) 4-({Ethyl-[6-(2-fluoro-4-mcthanesulfonyl-phenylamino)-pyrimidin-4-yl]-
amino}-methyl)-piperidine-1-carboxylic acid isopropyl ester;
(A97) 4-({[6-(4-Cyano-2,5-difluoro-phenylamino)-pyrimidin-4-yl]-ethyl-amino}-
methyl)-piperidine-1-carboxylic acid isopropyl ester;
(A98)4-({[6-(4-Amino-2,5-difluoro-phenoxy)-pyrimidin-4-yl]-ethyl-amino}-
methyl)-piperidine-1-carboxylic acid tert-butyl ester;
(A99) 4-({[6-(2,5-Difluoro-4-methoxy-phenylamino)-pyrimidin-4-yl]-ethyl-
amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester;
(A100) 4-({[6-(2,5-Difluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-
cthyl-amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester;
(A101) 4-({Ethyl-[6-(2,4,5-trifluoro-phenylamino)-pyrimidin-4-yl]-amino}-
methyl)-piperidine-1-carboxylic acid tert-butyl ester;
(A103) 4-[(Ethyl-{6-[4-(N-ethylcarbamimidoyl)-2,5-difluoro-phenylamino]-
pyrimidin-4-yl}-amino)-methyl]-piperidine-1-carboxylic acid isopropyl ester;
(A 104) 4-({[6-(4-Bromo-2,5-difluoro-phenylamino)-pyrimidin-4-yl]-ethyl-
amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester;
(A105)4-[({6-[5-(2-Amino-ethylamino)-4-cyano-2-fluoro-phenylamino]-
pyrimidin-4-yl}-ethyl-amino)-methyl]-piperidine-1-carboxylic acid isopropyl ester;


(A120)4-{[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-ylamino]-
methyl}-piperidine-1-carboxylic acid tert-butyl ester;
(A121) 4- {[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-ylamino]-
methyl}-piperidine-1-carboxylic acid isopropyl ester;
(A122) 4-({[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-
isopropyl-amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester; and
(A123) 4-({[4-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyridin-2-yl]-methyl-
amino}-methyl)-piperidine-1-carboxylic acid isobutyl ester.
A compound according to claim 1, wherein said compound is selected from the
following compounds and pharmaceutically acceptable salts, solvates, hydrates and N-
oxides thereof:
(B1) 4-[6-(2-Fluoro-4-methanesulfonyl-phenylarnino)-pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid tert-butyl ester;
(B3) 4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid isopropyl ester;
(B4) (6-Chloro-pyridin-2-yl)-{4-[6-(2-fluoro-4-methanesulfonyl-phenylamino)-
pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
(B5) (6-Bromo-pyridin-2-yl)-{4-[6-(2-fluoro-4-methanesulfonyl-phenylamino)-
pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
(B6) {4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-
piperidin-1-yl}-(6-methyl-pyridin-2-yl)-methanone;
(B7) {4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-
piperidin-1-yl} -(6-fluoro-pyridin-2-yl)-methanone;
(B8) {4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-
piperidin-1 -yl} -pyridin-2-yl-methanone;
(B9) (5-Bromo-pyridin-3-yl)-{4-[6-(2-fluoro-4-methanesulfonyl-phenylamino)-
pyrimidin-4-yloxy]-piperidin-1-yl} -methanone;
(B10) {4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-
piperidin-1 -yl} -(5-methyl-pyridin-3-yl)-methanone;


(B11) (5,6-Dichloro-pyridin-3-yl)-{4-[6-(2-fluoro-4-methanesulfonyl-
phenylamino)-pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
(B12) 4-[6-(4-Cyano-2,5-difluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid tert-butyl ester;
(B13)4-[6-(2,5-Difluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid tert-butyl ester;
(B14)4-[6-(2,4,5-Trifluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid tert-butyl ester;
(B15) 4-[6-(4-Bromo-2,5-difluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-
1 -carboxylic acid tert-butyl ester;
(B16) 4-[6-(3-Fluoro-4-methyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid tert-butyl ester;
(B17) 4-[6-(3-Hydroxy-4-methoxy-phenylamino)-pyrimidin-4-yloxy]-piperidine-
1 -carboxylic acid tert-butyl ester ;
(B18) 4-[6-(6-Cyano-pyridin-3-ylamino)-pyrimidin-4-yloxy)-piperidine-1-
carboxylic acid tert-butyl ester;
(B19) 4-[6-(3-Chloro-4-cyano-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid tert-butyl ester;
(B20) 4-[6-(6-Chloro-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid tert-butyl ester;
(B21)4-[6-(3-Fluoro-4-methoxy-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid tert-butyl ester;
(B22) 4-[6-(3,4-Dimethoxy-phenylamino)-pyrimidin-4-yloxy]-piperidine-1 -
carboxylic acid tert-butyl ester;
(B23) 4-[6-(2,3-Dihydro-benzo[1,4]dioxin-6-ylamino)-pyrimidin-4-yloxy]-
pipcridine-1-carboxylic acid tert-butyl ester;
(B24) 4-[6-(4-Cyano-2,5-difluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester;
(B25) 4-[6-(4-Cyano-5-ethylamino-2-fluoro-phenylamino)-pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid tert-butyl ester;

(B26) 4-[6-(4-Ethoxy-2,5-difluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-
1-carboxylic acid isopropyl ester;
(B27) 4-[6-(4-Ethylsulfanyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid tert-butyl ester;
(B28) 4-[6-(4-Isopropylsulfanyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid tert-butyl ester;
(B29) (5-Butyl-pyridin-2-yl)-{4-[6-(2-fluoro-4-methanesulfonyl-phenylamino)-
pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;
(B30) 4-[6-(5-Chloro-3-methyl-pyridin-2-ylamino)-pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid tert-butyl ester;
(B31) 4-[6-(6-Acetylamino-4-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid tert-butyl ester;
(B32) 4-[6-(5-Fluoro-4-methyl-pyridin-2-ylamino)-pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid tert-butyl ester;
(B33) 4-[6-(6-Methoxy-5-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid tert-butyl ester;
(B34) 4-[6-(6-Methoxy-2-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid tert-butyl ester;
(B35) 4-[6-(6-Fluoro-5-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid tert-butyl ester;
(B36) 4-[6-(2-Chloro-6-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid tert-butyl ester;
(B37) 4-[6-(4-Methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid tert-butyl ester;
(B38) 4-[6-(2-Methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid tert-butyl ester;
(B39) 4-[6-(6-Chloro-2-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid tert-butyl ester;
(B40) 4-[6-(6-Fluoro-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid tert-butyl ester;


(B41) 4-[6-(2-Chloro-4-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid tert-butyl ester;
(B42) 4-[6-(6-Methoxy-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1 -
carboxylic acid tert-butyl ester;
(B43) 4-[6-(5-Fiuoro-pyridin-2-ylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid tert-butyl ester;
(B44) 4-l6-(2-Fluoro-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid tert-butyl ester;
(B45) 4-[6-(6-Chloro-5-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid tert-butyl ester;
(B46) 4-[6-(2-Methyl-pyridin-4-ylamino)-pyrimidin-4-yloxy]-piperidine-1 -
carboxylic acid tert-butyl ester;
(B47)4-[6-(2-Methoxy-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid tert-butyl ester;
(B48) 4-[6-(2,5-Difluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1 -
carboxylic acid tert-butyl ester;
(B49) 4-[6-(4-Chloro-2-fluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1 -
carboxylic acid tert-butyl ester;
(B50) 4-[6-(2,5-Difluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester;
(B51) 4-[6-(6-Methoxy-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1 -
carboxylic acid isopropyl ester;
(B52) 4-[6-(4-Cyano-3-methoxy-phenylamino)-pyrimidin-4-yloxy]-piperidine-1 -
carboxylic acid isopropyl ester;
(B53)4-[6-(3 -Fluoro-4-hydroxy-phenylamino)-pyrimidin-4-yloxy] -piperidine-1 -
carboxylic acid isopropyl ester;
(B54)4-[6-(6-Ethoxy-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester;
(B55) 4-[6-(2,5-Difluoro-4-isopropoxy-phenylamino)-pyrimidin-4-yloxy)-
piperidine-1-carboxylic acid isopropyl ester:


(B56) (2-Fluoro-4-methanesulfonyl-phenyl)-[6-(5'-isopropoxy-3,4,5,6-tetrahydro-
2H-[1,2']bipyridinyl-4-yloxy)-pyrimidin-4-yl]-amine;
(B57) (2-Fluoro-4-methanesulfonyl-phenyl)- {6-[ 1 -(3-isopropyl-[1,2,4]oxadiazol-
5-yl)-piperidin-4-yloxy]-pyrimidin-4-yl} -amine;
(B58) 4-[6-(4-Cyano-2-fluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1 -
carboxylic acid isopropyl ester;
(B59) 4-[6-(Pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1 -carboxylic acid
isopropyl ester;
(B60) 4-[6-(Pyridin-4-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid
isopropyl ester;
(B61) 4-[6-(2,5-Difluoro-4-propoxy-phenylamino)-pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid isopropyl ester;
(B62) 4- [6-(4-Ethylamino-2-fluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-
1 -carboxylic acid isopropyl ester;
(B63) 4-[6-(4-Dimethylamino-2-fluoro-phenylamino)-pyrimidin-4-yloxy]-
piperidine-1 -carboxylic acid isopropyl ester;
(B64) 4-[6-(2-Fluoro-4-propylamino-phenylamino)-pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid isopropyl ester;
(B65) 4-[6-(2-Fluoro-4-isopropylamino-phenylamino)-pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid isopropyl ester;
(B66) 4-[6-(2-Methyl-6-propylamino-pyridin-3-ylamino)-pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid isopropyl ester;
(B67) 4-[6-(2-Methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester;
(B68) 4-[6-(6-Isopropylamino-2-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid isopropyl ester;
(B69) 4-[6-(2-Methyl-6-propoxy-pyridin-3-ylamino)-pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid isopropyl ester;
(B70) 4-[6-(4-Iodo-2-methyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1 -
carboxylic acid isopropyl ester;


(B71) 4-[6-(2-Fluoro-4-iodo-phenylamino)-pyrimidin-4-yloxy]-piperidine-1 -
carboxylic acid isopropyl ester;
(B77) 4-[6-(6-Methoxy-5-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid isopropyl ester;
(B78)4-[6-(4-Methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester;
(B79) 4-[6-(4-Acetylamino-3-methyl-phenylamino)-pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid isopropyl ester;
(B80) 4-[6-(3-Chloro-4-fluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester;
(B81) 4-[6-(3,5-Dimethoxy-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester;
(B82) 4-[6-(6-Ethyl-pyridin-2-ylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester;
(B83) 4-[6-(5-Methyl-pyridin-2-ylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester;
(B84) 4-[6-(2-Methyl-quinolin-6-ylamino)-pyrimidin-4-yloxy]-piperidine-1 -
carboxylic acid isopropyl ester;
(B85) 4-[6-(2-Methylsulfanyl-benzothiazol-6-ylamino)-pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid isopropyl ester;
(B86) 4-[6-(6-Morpholin-4-yl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-
1-carboxylic acid isopropyl ester;
(B88) 4-[6-(4-Piperidin-1-yl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester;
(B89) 4-[6-(3-Trifluoromethoxy-phenylamino)-pyrimidin-4-yloxy]-piperidine-1 -
carboxylic acid isopropyl ester;
(B90) 4-[6-(5-Oxo-5,6,7,8-tetrahydro-naphthalen-2-ylamino)-pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid isopropyl ester;
(B92) 4-[6-(5-Cyano-pyridin-2-ylamino)-pyrimidin-4-yloxy]-piperidine-1 -
carboxylic acid isopropyl ester;


(B93) 4-[6-(4-Bromo-2,5-difluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-
1-carboxylic acid isopropyl ester;
(B94) 4-[6-(4-Trifluoromethyl-pyridin-2-ylamino)-pyrimidin-4-yloxy]-piperidine-
1 -carboxylic acid isopropyl ester;
(B97)4-[6-(2,6-Dimethyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-
. carboxylic acid isopropyl ester;
(B98) 4-[6-(4-Cyano-2-methyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1 -
carboxylic acid isopropyl ester;
(B99) 4-[6-(4-Methoxy-2-methyl-phenylamino)-pyrimidin-4-yloxy)-piperidinc-1-
carboxylic acid isopropyl ester;
(B100) 4-[6-(2,4-Dimethoxy-phenylamino)-pyrimidin-4-yloxyl-piperidine-1-
carboxylic acid isopropyl ester;
(B101) 4-{6-[Acetyl-(2-fluoro-4-methanesulfonyl-phenyl)-amino]-pyrimidin-4-
yloxy}-piperidine-1-carboxylic acid isopropyl ester;
(B102) 4-[6-(5-Carbamoyl-pyridin-2-ylamino)-pyrimidin-4-yloxy]-piperidine-1 -
carboxylic acid isopropyl ester;
(B105) 4-[6-(3-Oxazol-5-yl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester;
(B106) 4-[6-(5-Trifluoromethyl-pyridin-2-ylamino)-pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid isopropyl ester;
(B107) 4-[6-(4-Chloro-2-trifluoromethoxy-phenylamino)-pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid isopropyl ester;
(B110) 4-[6-( 1 -Oxo-indan-5-ylamino)-pyrimidin-4-yloxy]-piperidine-1 -
carboxylic acid isopropyl ester;
(B111) 4-{6-[5-(1-Methyl-pyrrolidin-2-yl)-pyridin-2-ylamino]-pyrimidin-4-
yloxy}-piperidine-1-carboxylic acid isopropyl ester;
(B112) 4-[6-(6-Methoxy-2-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxyJ-
piperidine-1-carboxylic acid isopropyl ester;
(B113) 4-[6-(5-Bromo-3-methyl-pyridin-2-ylamino)-pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid isopropyl ester;


(B114) 4-[6-(2-Chloro-6-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid isopropyl ester;
(B115) 4-[6-(2-Ethynyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester;
(B116) 4-[6-(4-Bromo-2-trifluoromethoxy-phenylamino)-pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid isopropyl ester;
(B117)4-[6-(3-Iodo-4-methyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester;
(B118) 4-[6-(2-Fluoro-5-methyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1 -
carboxylic acid isopropyl ester;
(B122) 4-[6-(2,5-Difluoro-4-propylamino-phenylamino)-pyrimidin-4-yloxy]-
pipcridine-1-carboxylic acid isopropyl ester;
(B123) 4-f6-(2,5-Difluoro-4-morpholin-4-yl-phenylamino)-pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid isopropyl ester;
(B124) 4-[6-(2-Methyl-4-propylamino-phenylamino)-pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid isopropyl ester;
(B125) 4-{6-[2,5-Difluoro-4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-
4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;
(B126) 4-{6-[2,5-Difluoro-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-pyrimidin-
4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;
(B127) 4-{6-[4-(2-Dimethylamino-ethoxy)-2,5-difluoro-phenylamino]-pyrimidin-
4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;
(B128)4-{6-[2,5-Difluoro-4-(2-morpholin-4-yl-ethoxy)-phenylamino]-pyrimidin-
4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;
(B129) 4-[6-(2,4-Difluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester;
(B130) 4-[6-(2,4,5-Trifluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester;
(B131) 4-[6-(4-Methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1 -
carboxylic acid isopropyl ester;


(B132) 4-{6-[Acetyl-(4-methanesulfonyl-phenyl)-amino|-pyrimidin-4-yloxy}-
piperidine-1-carboxylic acid isopropyl ester;
(B133) (2,5-Difluoro-4-propoxy-phenyl)-{6-[1-(5-isopropyl-[1,2,4]oxadiazol-3-
yl)-piperidin-4-yloxy]-pyrimidin-4-yl}-amine;
(B134) 4-{6-[2,5-Difluoro-4-(morpholin-4-ylamino)-phenylamino]-pyrimidin-4-
yloxy}-piperidine-1-carboxylic acid isopropyl ester;
(B135) 4-{6-[2,5-Difluoro-4-(2-methoxy-ethylamino)-phenylamino]-pyrimidin-4-
yloxy}-piperidine-1-carboxylic acid isopropyl ester;
(B136) 4-(6-{2,5-Difluoro-4-[(tetrahydro-furan-2-ylmethyl)-amino]-
phenylamino}-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester;
(B137) 4-[6-(4-Butylamino-2,5-difluoro-phenylamino)-pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid isopropyl ester;
(B138) 4-{6-[2,5-Difluoro-4-(3-methyl-butylamino)-phenylamino]-pyrimidin-4-
yloxy}-piperidine-1-carboxylic acid isopropyl ester;
(B139) 4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-2-methyl-pyrimidin-4-
yloxy]-piperidine-1-carboxylic acid isopropyl ester;
(B140) 4-{6-[2,5-Difiuoro-4-(2-morpholin-4-yl-ethylamino)-phenylarnino]-
pyrimidin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;
(B141) 4-{6-[2-(2,5-Difluoro-phenoxy)-ethylamino]-pyrimidin-4-yloxy}-
piperidine-1-carboxylic acid isopropyl ester;
(B142)4-[6-(2,5-Difluoro-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylic
acid isopropyl ester;
(B143) 4-[6-(4-Bromo-2-fluoro-phenoxy)-pyrimidin-4-yloxy]-piperidine-1 -
carboxylic acid isopropyl ester;
(B144)4-[6-(2-Fluoro-4-morpholin-4-yl-phenoxy)-pyrimidin-4-yloxy]-
piperidine-1-carboxylic acid isopropyl ester;
(B145) 4-{6-[2,5-Difluoro-4-(tetrahydro-furan-2-ylmethoxy)-phenylamino]-
pyrimidin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester;
(B149) 4-[4-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyridin-2-yloxy]-
piperidine-1-carboxylic acid isopropyl ester; and


(B150)4-[4-(2,5-Difluoro-4-propoxy-phenylamino)-pyridin-2-yloxy]-piperidine-
1 -carboxylic acid isopropyl ester.
21. A compound according to claim 1, wherein said compound is selected from the
following compounds and pharmaceutically acceptable salts, solvates, hydrates and N-
oxidcs thereof:
(B153) 4-{6-[6-(2,3-Dihydroxy-propylamino)-2-methyl-pyridin-3-yloxy]-
pyrimidin-4-yloxy}-piperidine-1 -carboxylic acid isopropyl ester;
(B155)4-[6-(2-Methyl-pyridin-3-yloxy)-pyrimidin-4-yloxy]-piperidine-1-
carboxylic acid isopropyl ester;
(B156) 4-[6-(6-Bromo-2-methyl-pyridin-3-yloxy)-pyrimidin-4-yloxy]-piperidine-
1 -carboxylic acid isopropyl ester; and
(B157) 4-[6-(2-Methyl-pyridin-3-yloxy)-pyrimidin-4-yloxy]-piperidine-1 -
carboxylic acid tert-butyl ester.
22. A compound selected from compounds of Formula (I) and pharmaceutically acceptable
salts, solvates, hydrates and N-oxides thereof:

wherein:
A1 and A2 are independently C1-3 alkylene optionally substituted with one or more
substituents selected independently from C1-6 alkyl, C1-6 alkoxy, and carboxy;
D is CR1R2, wherein R1 is selected from H, C1-6 alkyl, C1-6 alkoxy, halogen and
hydroxyl;
E is N, C or CR3, wherein R3 is H or C1-6 alkyl;
is a single bond when E is N or CR3, or a double bond when E is C;

K is absent, C3-6 cycloalkylene, or C 1-3 alkylene group each optionally substituted
with one or more substituents selected independently from C1-6 alkyl, C1-6 alkoxy,
carboxy, cyano, and halogen;
Q1 is NH;
Q2 is absent;
W is CH;
X is N or CR6;
Y is N or CR7;
X is N;
V is absent, C1-3 heteroalkylene, or C1-3 alkylene wherein each are optionally
substituted with one or more substituents selected independently from C1-3 alkyl, C1-6
alkoxy, carboxy, cyano, C1-3 haloalkyl, and halogen;
R6, R7, and R8 are each independently selected from H, C1-6 acyl, C1-6 acyloxy, C2-
6 alkenyl, C1-6 alkoxy, C1-6 alkyl, C1-6 alkylamino, C1-6 alkylcarboxamide, C2-6 alkynyl,
C1-6 alkylsulfonamide, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6
alkylthiocarboxamide, C1-6 alkylthioureyl, C1-6 alkylureyl, amino, di-C1-6-alkylamino, C1-
6 alkoxycarbonyl, carboxamide, carboxy, cyano. C3-6 cycloalkyl, di-C1-6-
alkylcarboxamide, di-C 1-6-alkylsulfonamide, di-C1-6-alkylthiocarboxamido, C1-6
haloalkoxy, C1-6 haloalkyl, halogen, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6
haloalkylthio. hydroxyl, hydroxylamino and nitro, wherein said C2-6 alkenyl, C1-6 alkyl.
C2-6 alkynyl and C3-6 cycloalkyl are each optionally substituted with one or more
substituents independently selected from C1-6 acyl. C1-6 acyloxy, C2-6 alkenyl, C1-6
alkoxy, C1-6 alkyl, C1-6 alkylamino, C1-6 alkylcarboxamide, C2-6 alkynyl, C1-6
alkylsulfonamide, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6
alkylthiocarboxamide, C1-6 alkylthioureyl, C1-6 alkylureyl, amino, di-C1-6-alkylamino, C1-
6 alkoxycarbonyl, carboxamide, carboxy, cyano, C3-6 cycloalkyl, di-C1-6-
alkylcarboxamide, di-C1-6-alkylsulfonamide, di-C1-6-alkylthiocarboxamido, C1-6
haloalkoxy, C1-6 haloalkyl, halogen, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6
haloalkylthio, hydroxyl, hydroxylamino and nitro;
Ar is phenyl, naphthyl, pyridyl, benzofuranyl, pyrazinyl, pyridazinyl, pyrimidinyl.
triazinyl, quinoline, benzoxazole, benzothiazole, 1H-benzimidazole, isoquinoline.

quinazoline, quinoxaline, pyrrole or indole optionally substituted with R9, R10, R11, R12,
and R13;
R9 is selected from C1-6 acyl, C1-6 acylsulfonamide, C1-6 acyloxy, C2-6 alkenyl, C1-6
alkoxy, C1-6 alkyl, C1-6 alkylamino, C1-6 alkylcarboxamide, C2-6 alkynyl, C1-6
alkylsulfonamide, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6
alkylthiocarboxamide, C1-6 alkylthioureyl, C1-6 alkylureyl, amino, aryl, arylcarbonyl.
arylsulfonyl, di-C1-6-alkylamino, carbamimidoyl, C1-6 alkoxycarbonyl, carboxamide,
carboxy, cyano, C3-6 cycloalkyl, di-C1-6-alkylcarboxamide, di-C1-6-alkylsulfonamide, di-
C1-6-alkylthiocarboxamido, guanidine, C1-6 haloalkoxy, C1-6 haloalkyl, halogen, C1-6
haloalkylsulfinyl. C1-6 haloalkylsulfonyl, C1-6 haloalkylthio, heterocyclic,
hetcrocyclicsullbnyl, heteroaryl, hydroxyl, hydroxylamino, nitro. C3-6 oxo-cycloalkyl,
phenoxy, sulfonamide, sulfonic acid and thiol; and wherein each R9 is optionally
substituted with one or more substituents selected independently from C1-6 acyl, C1-6
acylsulfonamide, C1-6 acyloxy, C2-6 alkenyl, C1-6 alkoxy, C1-6 alkyl, C1-6 alkylamino, C1-6
alkylcarboxamide, C2-6 alkynyl, C1-6 alkylsulfonamide, C1-6 alkylsulfinyl, C1-6
alkylsulfonyl, C1-6 alkylthio, C1-6 alkylthiocarboxamide, C1-6 alkylthioureyl, C1-6
alkylureyl, amino, aryl, arylcarbonyl, arylsulfonyl, di-C1-6-alkylamino, C1-6
alkoxycarbonyl, carboxamide, carboxy, cyano, C3-6 cycloalkyl, di-C1-6-alkylcarboxamide,
di-C1-6-alkylsulfonamide, di-C1-6-alkylthiocarboxamido, C1-6 haloalkoxy, C1-6 haloalkyl,
halogen. C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6 haloalkylthio, heteroaryl,
heteroarylcarbonyl, heteroarylsulfonyl, heterocyclic, hydroxyl, hydroxylamino, and nitro;
R10, R11, R12- and R13 are independently selected from C1-6 acyl. C1-6 acyloxy, C2-6
alkenyl, C1-6 alkoxy. C1-6 alkyl, C1-6 alkylamino, C1-6 alkylcarboxamide. C2-6 alkynyl. C1-6
alkylsulfonamide, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6
alkylthiocarboxamide, C1-6 alkylthioureyl, C1-6 alkylureyl, amino, di-C1-6-alkylamino, C1-.
6 alkoxycarbonyl, carboxamide, carboxy, cyano, C3-6 cycloalkyl, di-C1-6-
alkylcarboxamide, di-C1-6-alkylsulfonamide, di-C1-6-alkylthiocarboxamido, C1-6
haloalkoxy, C1-6 haloalkyl, halogen, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6
haloalkylthio, hydroxyl, hydroxylamino, nitro, and thiol; or two adjacent R10, R11, R12,
and R13 groups together with the atoms to which they are bonded form a 5, 6 or 7 member

cycloalkyl, 5, 6 or 7 member cycloalkenyl, or 5, 6 or 7 member heterocyclic group
wherein the 5, 6 or 7 member group is optionally substituted with halogen or oxo; and
R2 is selected from: C1-6 alkyl, aryl, aryloxy, heteroaryl, and heteroaryloxy;
wherein R2 is optionally substituted with 1, 2, 3, 4, or 5 substituents selected
independently from: C1-6 alkoxy, C1-6 alkyl, C1-6 alkylamino, amino, di-C1-6-alkylamino,
C1-6 alkoxycarbonyl, carboxy, halogen, and heteroaryl, and wherein C1-6 alkyl is further
optionally substituted with 1, 2, or 3 substituents selected independently from C1-6
alkylamino, di-C1-6-alkylamino, C3-6 cycloalkyl, and halogen.
23. A compound according to claim 22. wherein K is absent.
24. A compound according to claim 22 or 23, wherein V is absent.
25. A compound according to any one of claims 22 to 24, wherein E is N and D is CHR2.
26. A compound according to any one of claims 22 to 25, wherein A1 and A2 are both -
CH2CH2-, and each A1 and A2 is optionally substituted with 1, 2, 3 or 4 methyl groups.
27. A compound according to any one of claims 22 to 26, wherein:
W is CH;
X is N;
Y is CR7, wherein R7 is H, C1-6 alkyl, or halogen; and
Z is N.
28. A compound according to claim 22, wherein said compound is selected from the
following compounds and pharmaceutically acceptable salts, solvates, hydrates and N-
oxides thereof:
(A2) {6-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-pyrimidin-4-yl}-
(4-methanesulfonyl-phenyl)-amine;
(A8) (2-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(3-fluoro-phenoxy)-piperidin-1-
yl]-pyrimidin-4-yl} -amine;

(A102) (2-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(3-isopropyl-
[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-pyrimidin-4-yl}-amine;
(A108) (2-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(4-isobutyl-phenyl)-
piperidin-1-yl]-pyrimidin-4-yl} -amine;
(A109) (2-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(4-isopropyl-phenyl)-
piperidin-1-yl]-pyrimidin-4-yl}-amine;
(A110) {6-[4-(3-Cyclopropylmethyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-
pyrimidin-4-yl}-(2-fluoro-4-methanesulfonyl-phenyl)-amine;
(A111) (2-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(3-isobutyl-[1,2,4]oxadiazol-
5-yl)-piperidin-1 -yl]-pyrimidin-4-yl} -amine;
(Al 13) (2-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(4-isopropoxy-phenyl)-
piperidin-1 -yl]-pyrimidin-4-yl} -amine;
(Al 15) {6-[4-(3-Dimethylaminomethyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-
pyrimidin-4-yl}-(2-fluoro-4-methanesulfonyl-phenyl)-amine;
(Al 17) (2-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(5-isopropoxy-pyridin-2-
yloxy)-piperidin-1-yl]-pyrimidin-4-yl}-amine; and
(A118) (2-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(3-pyridin-3-yl-
[ 1,2,4]oxadiazol-5-yl)-piperidin-1 -yl]-pyrimidin-4-yl} -amine.
29. A pharmaceutical composition comprising at least one compound according to any one of
claims 1 to 28, and a pharmaceutically acceptable carrier.
30. A method of producing a pharmaceutical composition comprising admixing at least one
compound according to any one of claims 1 to 28 and a pharmaceutically acceptable carrier.
31. A compound according to any one of claims 1 to 28 for use in a method of treatment of the
human or animal body by therapy.
32. A compound according to any one of claims 1 to 28 or 4-[6-(2-fluoro-4-methanesulfonyl-
phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester, for use in a

method of prophylaxis of treatment of a metabolic-related disorder of the human or animal
body by therapy.
33. A compound according to any one of claims 1 to 28 for use in a method of treatment of type I
diabetes, type II diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia,
hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia or syndrome X.


The present invention relates to certain substituted aryl
and heteroaryl derivative of Formula (I) that are modulators of metabolism,
especially of the activity of a GPCR, referred to herein as RUP3.
Accordingly, compounds of the present invention are useful in the treatment
of metabolic-related disorders and complications thereof, such as,
diabetes and obesity.

Documents:

03206-kolnp-2006 abstract.pdf

03206-kolnp-2006 assignment.pdf

03206-kolnp-2006 claims.pdf

03206-kolnp-2006 correspondence others.pdf

03206-kolnp-2006 description(complete).pdf

03206-kolnp-2006 drawings.pdf

03206-kolnp-2006 form-1.pdf

03206-kolnp-2006 form-3.pdf

03206-kolnp-2006 form-5.pdf

03206-kolnp-2006 international publication.pdf

03206-kolnp-2006 international search authority report.pdf

03206-kolnp-2006 pct other document.pdf

03206-kolnp-2006 priority document.pdf

03206-kolnp-2006-assignment-1.1.pdf

3206-KOLNP-2006-ABSTRACT 1.1.pdf

3206-KOLNP-2006-AMANDED CLAIMS.pdf

3206-KOLNP-2006-CORRESPONDENCE.pdf

3206-KOLNP-2006-CORRESPONDENCE1.1.pdf

3206-KOLNP-2006-DESCRIPTION (COMPLETE) 1.1.pdf

3206-KOLNP-2006-DRAWINGS 1.1.pdf

3206-KOLNP-2006-EXAMINATION REPORT.pdf

3206-KOLNP-2006-FORM 1 1.1.pdf

3206-KOLNP-2006-FORM 13.1.pdf

3206-KOLNP-2006-FORM 13.pdf

3206-KOLNP-2006-FORM 18.1.pdf

3206-kolnp-2006-form 18.pdf

3206-KOLNP-2006-FORM 3 1.1.pdf

3206-KOLNP-2006-FORM 3.pdf

3206-KOLNP-2006-FORM 5 1.1.pdf

3206-KOLNP-2006-FORM 5.pdf

3206-KOLNP-2006-GPA.pdf

3206-KOLNP-2006-GRANTED-ABSTRACT.pdf

3206-KOLNP-2006-GRANTED-CLAIMS.pdf

3206-KOLNP-2006-GRANTED-DESCRIPTION (COMPLETE).pdf

3206-KOLNP-2006-GRANTED-DRAWINGS.pdf

3206-KOLNP-2006-GRANTED-FORM 1.pdf

3206-KOLNP-2006-GRANTED-SPECIFICATION.pdf

3206-KOLNP-2006-OTHERS.pdf

3206-KOLNP-2006-PA.pdf

3206-KOLNP-2006-REPLY TO EXAMINATION REPORT.pdf

3206-KOLNP-2006-REPLY TO EXAMINATION REPORT1.1.pdf

abstract-03206-kolnp-2006.jpg


Patent Number 249747
Indian Patent Application Number 3206/KOLNP/2006
PG Journal Number 45/2011
Publication Date 11-Nov-2011
Grant Date 08-Nov-2011
Date of Filing 02-Nov-2006
Name of Patentee ARENA PHARMACEUTICALS, INC.
Applicant Address 6166, NANCY RIDGE DRIVE, SAN DIEGO, CA 92121-3223, UNITED STATES OF AMERICA
Inventors:
# Inventor's Name Inventor's Address
1 JONES, ROBERT, M. 10937 CORTE LUZ DEL SOL, SAN DIEGO, CA 92130, UNITED STATES OF AMERICA
2 XIONG, YIFENG 5036 PEARLMAN WAY ,SAN DIEGO, CA 92130, UNITED STATES OF AMERICA
3 SHIN, YOUNG-JUN 11051 ICE SKATE PLACE ,SAN DIEGO, CA 92126, UNITED STATES OF AMERICA
4 REN, ALBERT S. 4266 CORTE DE SAUSALITO ,SAN DIEGO CA 92130, UNITED STATES OF AMERICA
5 LEHMANN, JUERG 9840 LA TORTOLA COURT, SAN DIEGO CA 92129, UNITED STATES OF AMERICA
6 FIORAVANTI, BEATRIZ 60 WEST STONE LOOP, NO.327,TUCSON, AR 85704, UNITED STATES OF AMERICA
7 BRUCE, MARC, A. 662 CORTE RAQUEL, SAN MARCOS, CA 92069, UNITED STATES OF AMERICA
8 CHOI, JIN SUN KAROLINE 9926 SCRIPPS WESTVIEW WAY, NO.251, SAN DIEGO, CA 92131, UNITED STATES OF AMERICA
9 SEMPLE, GRAEME 15920 CAMINO CODORNIZ ,SAN DIEGO, CA 92127, UNITED STATES OF AMERICA
PCT International Classification Number C07D 239/48
PCT International Application Number PCT/US2005/019318
PCT International Filing date 2005-06-02
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/577,354 2004-06-04 U.S.A.