l-(DIHYDRONAPHTHALENYL)PYRIDONES AS MELANIN-CONCENTRATING HORMONE RECEPTOR 1 ANTAGONISTS

FIELD OF INVENTION

This invention relates to novel 1 -(dihydronaphthalenyl)pyridones which are antagonists of the melanin-concentrating hormone receptor 1 (MCHR1), to pharmaceutical compositions containing them, to processes for their preparation, and to their use in therapy for the treatment of obesity and diabetes.

BACKGROUND OF THE INVENTION

Obesity is a medical condition that is reaching epidemic proportions among humans in a number of countries throughout the world. It is a condition that is also associated with or induces other diseases or conditions that disrupt life activities and lifestyles. Obesity is recognized as a serious risk factor for other diseases and conditions such as diabetes, hypertension, and arteriosclerosis. It is also known that increased body weight due to obesity can place a burden on joints, such as knee joints, causing arthritis, pain, and stiffness.

Because overeating and obesity have become such a problem in the general population, many individuals are now interested in losing weight, reducing weight, and maintaining a healthy body weight and desirable lifestyle.

It is known that melanin-concentrating hormone originates in the hypothalamus and has orexigenic action (see Nature, Vol. 396, p. 670 (1998), for example). There is an ongoing need for the development of a melanin-concentrating hormone antagonist useful in the treatment of obesity and other associated or related diseases and conditions.

Accordingly, we have now found a novel group of l-(dihydronaphthalenyl)pyridones that exhibit a useful profile of activity as antagonists of the melanin-concentrating hormone receptor 1 (MCHR1). SUMMARY OF THE INVENTION

The present invention relates to compounds according to Formula (I), and pharmaceutically acceptable salts thereof.

wherein:

each R ⁵ is independently selected from hydrogen, halo, (Ci-C3)alkyl and (d- C3)haloalkyl;

X is C or ;

Y is C or ;

n is 0-2;

A is selected from the group consisting of Formula (II) and Formula (III),

II III where in Formula (II):

Z is C, O, S, S0 ₂ or NR ⁶ ;

p is 0-2, provided that when p is 0, Z is C;

s is 0-4;

r is 0-4;

R 2" and R 3 are each independently selected from hydrogen, (Ci-C ₆ )alkyl, (Ci- C3)haloalkyl, (C3-C6)cycloalkyl(Ci-C3)alkyl, hydroxyl, halo, (Ci-C3)alkoxy, hydroxyl(Ci-C ₃ )alkyl, -(Ci-C ₃ )alkyl(Ci-C ₃ )alkoxy, -(Ci-C ₃ )alkylNR ⁶ R ⁷ , -(Ci- C ₃ )alkyl( R ⁶ R ⁷ )C(=0)R ⁷ , -(Ci-C ₃ )alkylNR ⁶ S0 ₂ R ⁷ , -(Ci-C ₃ )alkylS0 ₂ (Ci-C ₃ )alkyl, - (Ci-C ₃ )alkylS0 ₂ NR ⁶ R ⁷ , -(Ci-C3)alkylC(=0)(C ₃ - C ₆ )heterocycloalkyl, -C(=0)NR ⁶ R ⁷ , -C(=0)R ⁶ , -S0 ₂ R ⁶ , -S0 ₂ NR ⁶ R ⁷ , oxo, -C(=0)OR ⁶ , -NR ⁶ R ⁷ , -NR ⁶ C(=0)OR ⁷ , - NR ⁶ S0 ₂ R ⁷ , aryl, heteroaryl, -(Ci-C ₃ )alkylheteroaryl and (C ₃ -C ₆ )heterocycloalkyl, wherein said (C ₃ -Ce)heterocycloalkyl, aryl and heteroaryl are optionally substituted with one to three times, independently, by R ;

R 2 and R 3 taken together with the carbon atom to which they are attached form a three to ten membered ring, optionally containing one or more heteroatoms selected from O, N and S, which said ring can be aromatic or non-aromatic and is optionally substituted one to three times, independently, by R ⁸ ; said three to ten membered ring together with the ring to which it is attached to form a fused, spiral or a bridged ring system;

where in Formula (III):

t is 0-4, provided that when t is 0, R ¹ is not halo;

R ⁴ is selected from hydrogen, (Ci-C ₆ )alkyl, -(Ci-C ₃ )alkyl(C ₃ -C ₆ )cycloalkyl, (Ci-C ₃ )alkoxy, hydroxyl(Ci-C ₆ )alkyl, and -(Ci-C ₃ )alkyl(Ci-C ₃ )alkoxy;

R ¹ is selected from hydrogen, (Ci-C ₆ )alkyl, (Ci-C ₃ )haloalkyl, (C ₃ - C ₆ )cycloalkyl, -NR ⁶ S0 ₂ R ⁷ , -NR ⁶ R ⁷ , -(Ci-C ₃ )alkylNR ⁶ R ⁷ , -NR ⁶ C(=0)NR ⁶ R ⁷ , -(Ci- C ₃ )alkylNR ⁶ C(=0)NR ⁶ R ⁷ , -S0 ₂ R ⁶ , -S0 ₂ NR ⁶ R ⁷ , halo, hydroxyl, -C(=0)(Ci-C ₃ )alkyl, - (Ci-C ₃ )alkylNR ⁶ S0 ₂ R ⁷ , -(Ci-C ₃ )alkylNR ⁶ S0 ₂ NR ⁶ R ⁷ , hydroxyl(Ci-C ₅ )alkyl, -(d- C ₃ )alkyl(Ci-C ₃ )alkoxy, -(Ci-C ₃ )alkylC(=0)(C ₃ -C ₆ )heterocycloalkyl, -(Ci- C ₃ )alkylC(=0)NR ⁶ R ⁷ , heteroaryl, -(Ci-C ₃ )alkyl(C ₃ -C ₆ )heterocycloalkyl and (C ₃ - Cio)heterocycloalkyl, wherein said (C ₃ -Cio)heterocycloalkyl, (C ₃ -C ₆ )cycloalkyl and heteroaryl are optionally substituted with one to three times, independently, by R ⁸ ;

R ⁶ and R ⁷ are each independently selected from hydrogen, (Ci-C ₆ )alkyl, (Ci- C ₃ )haloalkyl, (C ₃ -C ₆ )cycloalkyl, -(Ci-C ₃ )alkyl(C ₃ -C ₆ )cycloalkyl, hydroxyl, (d- C ₃ )alkoxy, hydroxyl(Ci-C ₃ )alkyl, -(Ci-C ₃ )alkylC(=0)NH(Ci-C ₃ )alkyl, (Ci- C ₃ )haloalkyl, oxo, (C ₃ -C ₆ )heterocycloalkyl, -C(=0)(Ci-C ₃ )haloalkyl and -(Ci- C ₃ )alkyl(Ci-C ₃ )alkoxy;

R ⁸ is selected from hydrogen, (Ci-C ₆ )alkyl, -(Ci-C ₃ )alkyl(C ₃ -C ₆ )cycloalkyl, hydroxyl, halo, (Ci-C ₃ )alkoxy, hydroxyl(Ci-C ₃ )alkyl, -(Ci-C ₃ )alkyl(Ci-C ₃ )alkoxy, - C(=0)NR ⁶ R ⁷ , -C(=0)R ⁶ , -S0 ₂ R ⁶ , -S0 ₂ NR ⁶ R ⁷ , oxo, -C(=0)OR ⁶ , -NR ⁶ R ⁷ , - NR ⁶ C(=0)R ⁷ , -NR ⁶ C(=0)OR ⁷ , and -NR ⁶ S0 ₂ R ⁷ . There is also provided a pharmaceutical composition comprising a compound of Formula (I) or pharmaceutically acceptable salt thereof.

Further, there is provided a pharmaceutical composition comprising a compound of Formula (I) or salt thereof and one or more excipients.

There is still further provided a method of treatment comprising the administering to a mammal, particularly a human, a pharmaceutical composition comprising a compound of Formula (I) or pharmaceutically acceptable salt thereof and at least one excipient, wherein said treatment is for obesity, diabetes, depression, or anxiety.

Additionally, there is provided a compound of Formula (I) or pharmaceutically acceptable salt thereof for use as an active therapeutic substance (in therapy).

And, there is also provided a compound of Formula (I) or pharmaceutically acceptable salt thereof for use in the treatment of obesity, diabetes, depression, or anxiety in a mammal, especially a human.

A process for preparing a compound of Formula (I) or pharmaceutically acceptable salt thereof is also provided.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds of Formula (I) as shown above.

The present invention also relates to compounds according to Formula (IV):

IV

wherein:

each R ⁵ is independently selected from hydrogen, halo, (Ci-C3)alkyl and (d-

C ₃ )haloalkyl;

X is C or ; Y is C or ;

n is 0-2;

Z is C, O, S, S0 ₂ or NR ⁶ ;

p is 0-2, provided that when p is 0, Z is C;

s is 0-4;

r is 0-4;

R ² and R ³ are each independently selected from hydrogen, (Ci-C ₆ )alkyl, (Ci- C ₃ )haloalkyl, (C ₃ -C ₆ )cycloalkyl(Ci-C ₃ )alkyl, hydroxyl, halo, (Ci-C ₃ )alkoxy, hydroxyl(Ci-C ₃ )alkyl, -(Ci-C ₃ )alkyl(Ci-C ₃ )alkoxy, -(Ci-C ₃ )alkylNR ⁶ R ⁷ , -(Ci- C ₃ )alkyl( R ⁶ R ⁷ )C(=0)R ⁷ , -(Ci-C ₃ )alkylNR ⁶ S0 ₂ R ⁷ , -(Ci-C ₃ )alkylS0 ₂ (Ci-C ₃ )alkyl, - (Ci-C ₃ )alkylS0 ₂ NR ⁶ R ⁷ , -(Ci-C3)alkylC(=0)NR ⁶ R ⁷ , -(Ci-C3)alkylC(=0)(C3- C ₆ )heterocycloalkyl, -C(=0)NR ⁶ R ⁷ , -C(=0)R ⁶ , -S0 ₂ R ⁶ , -S0 ₂ NR ⁶ R ⁷ , oxo, -C(=0)OR ⁶ , -NR ⁶ R ⁷ , -NR ⁶ C(=0)R ⁷ , -NR ⁶ C(=0)OR ⁷ , - NR ⁶ S0 ₂ R ⁷ , aryl, heteroaryl, -(Ci-C ₃ )alkylheteroaryl and (C ₃ -C ₆ )heterocycloalkyl, wherein said (C ₃ -Ce)heterocycloalkyl, aryl and heteroaryl are optionally substituted with one to three times, independently, by R ⁸ ;

R 2 and R 3 taken together with the carbon atom to which they are attached form a three to ten membered ring, optionally containing one or more heteroatoms selected from O, N and S, which said ring can be aromatic or non-aromatic and is optionally substituted one to three times, independently, by R ⁸ ; said three to ten membered ring together with the ring to which it is attached to form a fused, spiral or a bridged ring system;

R ⁶ and R ⁷ are each independently selected from hydrogen, (Ci-C ₆ )alkyl, (Ci- C ₃ )haloalkyl, (C ₃ -C ₆ )cycloalkyl, -(Ci-C ₃ )alkyl(C ₃ -C ₆ )cycloalkyl, hydroxyl, (d- C ₃ )alkoxy, hydroxyl(Ci-C ₃ )alkyl, -(Ci-C ₃ )alkylC(=0)NH(Ci-C ₃ )alkyl, (Ci- C ₃ )haloalkyl, oxo, (C ₃ -C ₆ )heterocycloalkyl, -C(=0)(Ci-C ₃ )haloalkyl and -(Ci- C ₃ )alkyl(Ci-C ₃ )alkoxy;

R is selected from hydrogen, (Ci-C ₆ )alkyl, -(Ci-C ₃ )alkyl(C ₃ -C ₆ )cycloalkyl, hydroxyl, halo, (Ci-C ₃ )alkoxy, hydroxyl(Ci-C ₃ )alkyl, -(Ci-C ₃ )alkyl(Ci-C ₃ )alkoxy, - C(=0)NR ⁶ R ⁷ , -C(=0)R ⁶ , -S0 ₂ R ⁶ , -S0 ₂ NR ⁶ R ⁷ , oxo, -C(=0)OR ⁶ , -NR ⁶ R ⁷ , - NR ⁶ C(=0)R ⁷ , -NR ⁶ C(=0)OR ⁷ , and -NR ⁶ S0 ₂ R ⁷ ; or a pharmaceutically acceptable salt thereof.

The present invention also relates to compounds according to Formula (V):

V

wherein:

each R ⁵ is independently selected from hydrogen, halo, (Ci-C3)alkyl and (d- C ₃ )haloalkyl;

X is C or ;

Y is C or ;

n is 0-2;

s is 0-2;

r is 0-2;

R 2" and R 3 are each independently selected from hydrogen, (Ci-C ₆ )alkyl, hydroxyl, halo, (Ci-C ₃ )alkoxy, hydroxyl(Ci-C ₃ )alkyl, -(Ci-C ₃ )alkyl(Ci-C ₃ )alkoxy, - (Ci-C ₃ )alkylNR ⁶ R ⁷ , -(Ci-C ₃ )alkyl(NR ⁶ R ⁷ )C(=0)R ⁷ , -(Ci-C ₃ )alkylNR ⁶ S0 ₂ R ⁷ , -S0 ₂ R ⁶ , -NR ⁶ R ⁷ , -NR ⁶ C(=0)R ⁷ , -NR ⁶ (C C ₃ )alkylC(=0)NR ⁶ R ⁷ , -NR ⁶ S0 ₂ R ⁷ , and (C ₃ - C ₆ )heterocycloalkyl, wherein said (C ₃ -C ₆ )heterocycloalkyl is optionally substituted with one to three times, independently, by R ⁸ ;

R ² and R ³ taken together with the carbon atom to which they are attached form a three to ten membered ring, optionally containing one or more heteroatoms selected from O, N and S, which said ring can be aromatic or non-aromatic and is optionally substituted one to three times, independently, by R ; said three to ten membered ring together with the ring to which it is attached to form a fused, spiral or a bridged ring system;

R ⁶ and R ⁷ are each independently selected from hydrogen, (Ci-C ₆ )alkyl, (Ci- C ₃ )haloalkyl, (C ₃ -C ₆ )cycloalkyl, -(Ci-C ₃ )alkyl(C ₃ -C ₆ )cycloalkyl, hydroxyl, (d- C ₃ )alkoxy, hydroxyl(Ci-C ₃ )alkyl, -(Ci-C ₃ )alkylC(=0)NH(Ci-C ₃ )alkyl, (Ci- C ₃ )haloalkyl, oxo, (C ₃ -C ₆ )heterocycloalkyl, -C(=0)(Ci-C ₃ )haloalkyl and -(Ci- C ₃ )alkyl(Ci-C ₃ )alkoxy;

R is selected from hydrogen, (Ci-C ₆ )alkyl, -(Ci-C ₃ )alkyl(C ₃ -C ₆ )cycloalkyl, hydroxyl, halo, (Ci-C ₃ )alkoxy, hydroxyl(Ci-C ₃ )alkyl, -(Ci-C ₃ )alkyl(Ci-C ₃ )alkoxy, - C(=0)NR ⁶ R ⁷ , -C(=0)R ⁶ , -S0 ₂ R ⁶ , -S0 ₂ NR ⁶ R ⁷ , oxo, -C(=0)OR ⁶ , -NR ⁶ R ⁷ , - NR ⁶ C(=0)R ⁷ , -NR ⁶ C(=0)OR ⁷ , and -NR ⁶ S0 ₂ R ⁷ ;

or a pharmaceutically acceptable salt thereof.

The present invention also relates to compounds according to Formula (VI):

VI

wherein:

each R ⁵ is independently selected from hydrogen, halo, (Ci-C ₃ )alkyl and (d- C ₃ )haloalkyl;

X is C or ;

Y is C or ;

n is 0-2;

s is 0-2;

r is 0-2;

R 2 and R 3 are each independently selected from hydrogen, (Ci-C ₆ )alkyl, (Ci- C ₃ )haloalkyl, hydroxyl, halo, (C C ₃ )alkoxy, hydroxyl(Ci-C ₃ )alkyl, -C(=0)NR ⁶ R ⁷ , - S0 ₂ R ⁶ , -C(=0)OR ⁶ , -NR ⁶ R ⁷ , and (C ₃ -C ₆ )heterocycloalkyl, wherein said (C ₃ - C ₆ )heterocycloalkyl is optionally substituted with one to three times, independently, by R ⁸ ;

R and R taken together with the carbon atom to which they are attached form a three to ten membered ring, optionally containing one or more heteroatoms selected from O, N and S, which said ring can be aromatic or non-aromatic and is optionally substituted one to three times, independently, by R ; said three to ten membered ring together with the ring to which it is attached to form a fused, spiral or a bridged ring system; R ⁶ and R ⁷ are each independently selected from hydrogen, (Ci-C ₆ )alkyl, (Ci- C ₃ )haloalkyl, (C ₃ -C ₆ )cycloalkyl, -(Ci-C ₃ )alkyl(C ₃ -C ₆ )cycloalkyl, hydroxyl, (d- C ₃ )alkoxy, hydroxyl(Ci-C ₃ )alkyl, -(Ci-C ₃ )alkylC(=0)NH(Ci-C ₃ )alkyl, (Ci- C ₃ )haloalkyl, oxo, (C ₃ -C ₆ )heterocycloalkyl, -C(=0)(Ci-C ₃ )haloalkyl and -(Ci- C ₃ )alkyl(Ci-C ₃ )alkoxy;

R ⁸ is selected from hydrogen, (Ci-C ₆ )alkyl, -(Ci-C ₃ )alkyl(C ₃ -C6)cycloalkyl, hydroxyl, halo, (Ci-C ₃ )alkoxy, hydroxyl(Ci-C ₃ )alkyl, -(Ci-C ₃ )alkyl(Ci-C ₃ )alkoxy, - C(=0)NR ⁶ R ⁷ , -C(=0)R ⁶ , -S0 ₂ R ⁶ , -S0 ₂ NR ⁶ R ⁷ , oxo, -C(=0)OR ⁶ , -NR ⁶ R ⁷ , - NR ⁶ C(=0)R ⁷ , -NR ⁶ C(=0)OR ⁷ , and -NR ⁶ S0 ₂ R ⁷ ;

or a pharmaceutically acceptable salt thereof.

The present invention also relates to compounds according to Formula (VII):

VII

wherein:

each R ⁵ is independently selected from hydrogen, halo, (Ci-C ₃ )alkyl and (d- C ₃ )haloalkyl;

X is C or ;

Y is C or ;

n is 0-2;

s is 0-2;

r is 0-2;

R 2 and R 3 are each independently selected from hydrogen, (Ci-C ₆ )alkyl, (Ci- C ₃ )haloalkyl, hydroxyl, halo, (Ci-C ₃ )alkoxy, hydroxyl(Ci-C ₃ )alkyl, -(Ci-C ₃ )alkyl(Ci- C ₃ )alkoxy, -(Ci-C ₃ )alkylS0 ₂ NR ⁶ R ⁷ , -(Ci-C ₃ )alkylC(=0)(C ₃ -C ₆ )heterocycloalkyl, - C(=0)NR ⁶ R ⁷ , -C(=0)R ⁶ , oxo, -NR ⁶ R ⁷ , aryl, heteroaryl, and (C ₃ -C ₆ )heterocycloalkyl, wherein said (C ₃ -Ce)heterocycloalkyl, aryl and heteroaryl are optionally substituted with one to three times, independently, by R ⁸ ;

R ² and R ³ taken together with the carbon atom to which they are attached form a three to ten membered ring, optionally containing one or more heteroatoms selected from O, N and S, which said ring can be aromatic or non-aromatic and is optionally substituted one to three times, independently, by R ; said three to ten membered ring together with the ring to which it is attached to form a fused, spiral or a bridged ring system;

R ⁶ and R ⁷ are each independently selected from hydrogen, (Ci-C ₆ )alkyl, (Ci- C ₃ )haloalkyl, (C ₃ -C ₆ )cycloalkyl, -(Ci-C ₃ )alkyl(C ₃ -C ₆ )cycloalkyl, hydroxyl, (d- C ₃ )alkoxy, hydroxyl(Ci-C ₃ )alkyl, -(Ci-C ₃ )alkylC(=0)NH(Ci-C ₃ )alkyl, (Ci- C ₃ )haloalkyl, oxo, (C ₃ -C ₆ )heterocycloalkyl, -C(=0)(Ci-C ₃ )haloalkyl and -(Ci- C ₃ )alkyl(Ci-C ₃ )alkoxy;

R is selected from hydrogen, (Ci-C ₆ )alkyl, -(Ci-C ₃ )alkyl(C ₃ -C ₆ )cycloalkyl, hydroxyl, halo, (Ci-C ₃ )alkoxy, hydroxyl(Ci-C ₃ )alkyl, -(Ci-C ₃ )alkyl(Ci-C ₃ )alkoxy, - C(=0)NR ⁶ R ⁷ , -C(=0)R ⁶ , -S0 ₂ R ⁶ , -S0 ₂ NR ⁶ R ⁷ , oxo, -C(=0)OR ⁶ , -NR ⁶ R ⁷ , - NR ⁶ C(=0)R ⁷ , -NR ⁶ C(=0)OR ⁷ , and -NR ⁶ S0 ₂ R ⁷ ;

or a pharmaceutically acceptable salt thereof.

The present invention also relates to compounds according to Formula (VIII):

VIII

wherein:

each R ⁵ is independently selected from hydrogen, halo, (Ci-C ₃ )alkyl and (d- C ₃ )haloalkyl;

X is C or ;

Y is C or ;

Z is C or O;

p is 0-2, provided that when p is 0, Z is C;

n is 0-2;

R ⁹ is (C ₂ -C ₆ )heterocycloalkyl, wherein said (C ₂ -Ce)heterocycloalkyl is optionally substituted with one to three times, independently, by R ¹⁰ , and said (C ₂ - C ₆ )heterocycloalkyl taken together with the ring to which it is attached form a spiral ring system; R is selected from hydrogen, (Ci-C ₆ )alkyl, halo and oxo;

or a pharmaceutically acceptable salt thereof.

The present invention also relates to compounds according to Formula (IX):

IX

wherein:

each R ⁵ is independently selected from hydrogen, halo, (Ci-C3)alkyl and (d- C ₃ )haloalkyl;

X is C or ;

Y is C or ;

n is 0-2;

t is 0-4, provided that when t is 0, R ¹ is not halo;

R ⁴ is selected from hydrogen, (Ci-C ₆ )alkyl, -(Ci-C ₃ )alkyl(C ₃ -C ₆ )cycloalkyl, (Ci-C ₃ )alkoxy, hydroxyl(Ci-C ₆ )alkyl, and -(Ci-C ₃ )alkyl(Ci-C ₃ )alkoxy;

R ¹ is selected from hydrogen, (Ci-C ₆ )alkyl, (Ci-C ₃ )haloalkyl, (C ₃ - C ₆ )cycloalkyl, -NR ⁶ S0 ₂ R ⁷ , -NR ⁶ R ⁷ , -(Ci-C ₃ )alkylNR ⁶ R ⁷ , -NR ⁶ C(=0)NR ⁶ R ⁷ , -(Ci- C ₃ )alkylNR ⁶ C(=0)NR ⁶ R ⁷ , -S0 ₂ R ⁶ , -S0 ₂ NR ⁶ R ⁷ , halo, hydroxyl, -C(=0)(Ci-C ₃ )alkyl, - (Ci-C ₃ )alkylNR ⁶ S0 ₂ R ⁷ , -(Ci-C ₃ )alkylNR ⁶ S0 ₂ NR ⁶ R ⁷ , hydroxyl(Ci-C ₅ )alkyl, -(d- C ₃ )alkyl(Ci-C ₃ )alkoxy, -(Ci-C ₃ )alkyl C(=0)(C ₃ -C ₆ )heterocycloalkyl, -(Ci- C ₃ )alkylC(=0)NR ⁶ R ⁷ , heteroaryl, -(Ci-C ₃ )alkyl(C ₃ -C ₆ )heterocycloalkyl and (C ₃ - Cio)heterocycloalkyl, wherein said (C ₃ -Cio)heterocycloalkyl, (C ₃ -C ₆ )cycloalkyl and heteroaryl are optionally substituted with one to three times, independently, by R ⁸ ;

R ⁶ and R ⁷ are each independently selected from hydrogen, (Ci-C ₆ )alkyl, (Ci- C ₃ )haloalkyl, (C ₃ -C ₆ )cycloalkyl, -(Ci-C ₃ )alkyl(C ₃ -C ₆ )cycloalkyl, hydroxyl, (d- C ₃ )alkoxy, hydroxyl(Ci-C ₃ )alkyl, -(Ci-C ₃ )alkylC(=0)NH(Ci-C ₃ )alkyl, (Ci- C ₃ )haloalkyl, oxo, (C ₃ -C ₆ )heterocycloalkyl, -C(=0)(Ci-C ₃ )haloalkyl and -(Ci- C ₃ )alkyl(Ci-C ₃ )alkoxy;

R ⁸ is selected from hydrogen, (Ci-C ₆ )alkyl, -(Ci-C ₃ )alkyl (C ₃ -C ₆ )cycloalkyl, hydroxyl, halo, (Ci-C ₃ )alkoxy, hydroxyl(Ci-C ₃ )alkyl, -(Ci-C ₃ )alkyl(Ci-C ₃ )alkoxy, - C(=0)NR ⁶ R ⁷ , -C(=0)R ⁶ , -S0 ₂ R ⁶ , -S0 ₂ NR ⁶ R ⁷ , oxo, -C(=0)OR ⁶ , -NR ⁶ R ⁷ , - NR ⁶ C(=0)R ⁷ , -NR ⁶ C(=0)OR ⁷ , and -NR ⁶ S0 ₂ R ⁷ ;

or a pharmaceutically acceptable salt thereof.

The resent invention also relates to compounds according to Formula (X):

X

wherein:

each R ⁵ is independently selected from hydrogen, halo, (Ci-C3)alkyl and (d- C ₃ )haloalkyl;

X is C or ;

Y is C or ;

Z is C, O, S0 ₂ , or ;

n is 0-2;

w is 0-2;

k is 0-3;

t is 0-2;

R ⁴ is selected from hydrogen, (Ci-C ₆ )alkyl, (Ci-C ₃ )alkyl(C ₃ -C ₆ )cycloalkyl,

(Ci-C ₃ )alkoxy, hydroxyl(Ci-C ₆ )alkyl, or (Ci-C ₃ )alkyl(Ci-C ₃ )alkoxy;

each R ¹¹ is independently selected from hydrogen, (Ci-C ₆ )alkyl, (Ci- C ₃ )alkyl(C ₃ -C ₆ )cycloalkyl, hydroxyl, halo, (Ci-C ₃ )alkoxy, hydroxyl(Ci-C ₃ )alkyl, (Ci- C ₃ )alkyl(Ci-C ₃ )alkoxy, -C(=0)NR ⁶ R ⁷ , -C(=0)R ⁶ , -S0 ₂ R ⁶ , -S0 ₂ NR ⁶ R ⁷ , oxo, - C(=0)OR ⁶ , -NR ⁶ R ⁷ , -NR ⁶ C(=0)R ⁷ , -NR ⁶ C(=0)OR ⁷ , and -NR ⁶ S0 ₂ R ⁷ ;

or a pharmaceutically acceptable salt thereof.

In one embodiment, this invention relates to compounds of Formula (I), (IV), (V), (VI), (VII), (VIII), (IX) or (X), wherein n is 1; X is N; Y is C; R ⁵ is CI; or a pharmaceutically acceptable salts thereof.

In another embodiment, this invention relates to compounds of Formula (IX), wherein R ¹ is selected from hydrogen, (Ci-C ₃ )haloalkyl, -NR ⁶ S0 ₂ R ⁷ , -NR ⁶ R ⁷ , -(d- C ₃ )alkylNR ⁶ R ⁷ , -NR ⁶ C(=0)NR ⁶ R ⁷ , -(C C ₃ )alkylNR ⁶ C(=0)NR ⁶ R ⁷ , -S0 ₂ R ⁶ , halo, hydroxy, -C(=0)(Ci-C ₃ )alkyl, -(Ci-C ₃ )alkylNR ⁶ S0 ₂ R ⁷ , -(Ci-C ₃ )alkylNR ⁶ S0 ₂ NR ⁶ R ⁷ , hydroxyl(Ci-C ₅ )alkyl, -(Ci-C ₃ )alkyl(Ci-C ₃ )alkoxy, and

R ⁶ and R ⁷ are each independently selected from hydrogen, (Ci-C ₆ )alkyl, (C ₃ - C ₆ )cycloalkyl, -(Ci-C ₃ )alkyl(C ₃ -C ₆ )cycloalkyl, hydroxyl, (Ci-C ₃ )alkoxy, hydroxyl(Ci- C ₃ )alkyl, -(Ci-C ₃ )alkylC(=0)NH(Ci-C ₃ )alkyl, (Ci-C ₃ )haloalkyl, (C ₃ - C ₆ )heterocycloalkyl, -C(=0)(Ci-C ₃ )haloalkyl and -(Ci-C ₃ )alkyl(Ci-C ₃ )alkoxy;

or a pharmaceutically acceptable salt thereof.

In another embodiment, this invention relates to compounds of Formula (VIII), wherein Z is S0 ₂ ; p is 2; R ⁹ is hydrogen; or a pharmaceutically acceptable salts thereof.

In another embodiment, this invention relates to compounds of Formula (IX), wherein R ⁴ is methyl; R ¹ is methyl; t is 0; or a pharmaceutically acceptable salts thereof.

Specific compounds of this invention include:

4-(benzyloxy)- 1 -(6- { [(3R)-3-hydroxypyrrolidin- 1 -yl]methyl} -3,4-dihydronaphthalen-2- yl)pyridin-2(lH)-one;

4-(benzyloxy)- 1 -[6-(piperidin- 1 -ylmethyl)-3,4-dihydronaphthalen-2-yl]pyridin-2(l H)-one; 4-(benzyloxy)- 1 -[6-(pyrrolidin- 1 -ylmethyl)-3,4-dihydronaphthalen-2-yl]pyridin-2(l H)-one; 4-(benzyloxy)-l-[6-(morpholin-4-ylmethyl)-3,4-dihydronaphtha len-2-yl]pyridin-2(lH)-one; 4-[(4-chlorobenzyl)oxy]-l-{6-[(dimethylamino)methyl]-3,4-dih ydronaphthalen-2-yl}pyridin- 2(lH)-one;

4-[(4-chlorobenzyl)oxy] - 1 -[6-( { [2-(propan-2-ylamino)ethyl] amino} methyl)-3,4- dihydronaphthalen-2-yl]pyridin-2(lH)-one;

4-[(4-chlorobenzyl)oxy]- 1 - {6-[(4-hydroxypiperidin- 1 -yl)methyl]-3,4-dihydronaphthalen-2- yl}pyridin-2(lH)-one;

N-(2- { [(6- {4- [(4-chlorobenzyl)oxy]-2-oxopyridin- 1 (2H)-yl} -7,8-dihydronaphthalen-2- yl)methyl]amino}ethyl)propane-2-sulfonamide;

l-(2- {[(6-{4-[(4-chlorobenzyl)oxy]-2-oxopyridin-l(2H)-yl}-7,8-dih ydronaphthalen-2- yl)methyl] amino } ethyl)urea;

4-[(4-chlorobenzyl)oxy]- 1-(6- {[(1 ,3-dihydroxypropan-2-yl)amino]methyl} -3,4- dihydronaphthalen-2-yl)pyridin-2( 1 H)-one; 4-[(4-chlorobenzyl)oxy]- 1 - {6-[( {2-[4-(methylsulfonyl)piperazin- 1 -yl]ethyl} amino)methyl]- 3 ,4-dihydronaphthalen-2-yl} pyridin-2( 1 H)-one;

4-[(4-chlorobenzyl)oxy]-l-[6-({[(2S)-2-hydroxypropyl]amino}m ethyl)-3,4- dihydronaphthalen-2-yl]pyridin-2(lH)-one;

4-[(4-chlorobenzyl)oxy]- 1 -[6-( {(3R)-3-[ethyl(methyl)amino]pyrrolidin- 1 -yl} methyl)-3 ,4- dihydronaphthalen-2-yl]pyridin-2(lH)-one;

4-[(4-chlorobenzyl)oxy]- 1 -(6- {[(3R)-3-hydroxypiperidin- 1 -yl]methyl} -3,4- dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(4-chlorobenzyl)oxy]- 1 -(6- {[4-(morpholin-4-yl)piperidin- 1 -yl]methyl} -3,4- dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

l-(2- {[(6-{4-[(4-chlorobenzyl)oxy]-2-oxopyridin-l(2H)-yl}-7,8-dih ydronaphthalen-2- yl)methyl] (methyl)amino } ethyl)urea;

1- [6-({[2-(4-acetylpiperazin-l-yl)ethyl]amino}methyl)-3,4-dihy dronaphthalen-2-yl]-4-[(4- chlorobenzyl)oxy]pyridin-2(lH)-one;

4-[(4-chlorobenzyl)oxy]- 1 -[6-( {[ 1 -(methylsulfonyl)piperidin-4-yl] amino} methyl)-3,4- dihydronaphthalen-2-yl]pyridin-2(lH)-one;

4-[(4-chlorobenzyl)oxy]- 1 - {6-[(4-methylpiperazin- 1 -yl)methyl]-3,4-dihydronaphthalen-2- yl}pyridin-2(lH)-one;

4-[(4-chlorobenzyl)oxy]- 1 - {6-[(4-hydroxy-4-methylpiperidin- 1 -yl)methyl]-3,4- dihydronaphthalen-2-yl} pyridin-2( 1 H)-one;

4-[(4-chlorobenzyl)oxy]- 1 -(6- {[(3S)-3-hydroxypyrrolidin- 1 -yl]methyl} -3,4- dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(4-chlorobenzyl)oxy]- 1 -[6-( { [2-(cyclohexylamino)ethyl] amino} methyl)-3,4- dihydronaphthalen-2-yl]pyridin-2(lH)-one;

4-[(4-chlorobenzyl)oxy]- 1 -(6- { [4-(methylamino)piperidin- 1 -yl]methyl} -3 ,4- dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(4-chlorobenzyl)oxy]-l-[6-(2,9-diazaspiro[5.5]undec-9-ylm ethyl)-3,4-dihydronaphthalen-

2- yl]pyridin-2(lH)-one;

4-[(4-chlorobenzyl)oxy]-l-[6-(2,7-diazaspiro[4.4]non-2-ylmet hyl)-3,4-dihydronaphthalen-2- yl]pyridin-2(lH)-one; 4-[(4-chlorobenzyl)oxy]-l-{6-[(3aR,7aR)-octahydro-2H-pyrrolo [3,4-c]pyridin-2-ylmethyl]- 3 ,4-dihydronaphthalen-2-yl} pyridin-2( 1 H)-one;

4-[(4-chlorobenzyl)oxy]-l-[6-(2,7-diazaspiro[4.5]dec-7-ylmet hyl)-3,4-dihydronaphthalen-2- yl]pyridin-2(lH)-one;

4-[(4-chlorobenzyl)oxy]-l-{6-[(3aR,6aS)-hexahydropyrrolo[3,4 -c]pyrrol-2(lH)-ylmethyl]- 3 ,4-dihydronaphthalen-2-yl} pyridin-2( 1 H)-one;

l-{6-[(l-amino-3-azabicyclo[3.1.0]hex-3-yl)methyl]-3,4-di hydronaphthalen-2-yl}-4-[(4- chlorobenzyl)oxy]pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-[6-(pyrrolidin-l-ylmethy l)-3,4-dihydronaphthalen-2- yl]pyridin-2(lH)-one;

4- [(5-chloropyridin-2-yl)methoxy] - 1 - { 6- [( 1 S ,4S)-2 ,5-diazabicyclo [2.2.1 ]hept-2-ylmethyl] - 3 ,4-dihydronaphthalen-2-yl} pyridin-2( 1 H)-one;

1 -(6- {[(2-aminoethyl)(methyl)amino]methyl} -3,4-dihydronaphthalen-2-yl)-4-[(5- chloropyridin-2-yl)methoxy]pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -[6-( {methyl[2-(pyrrolidin- 1 -yl)ethyl] amino } methyl)-

3 ,4-dihydronaphthalen-2-yl]pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-[6-({methyl[(3S)-morphol in-3- ylmethyl] amino } methyl)-3,4-dihydronaphthalen-2-yl]pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-(6-{[(3S,4S)-3-(dimethyl amino)-4-hydroxypyrrolidin-l- yl]methyl}-3,4-dihydronaphthalen-2-yl)pyridin-2(lH)-one;

N-[(6-{4-[(5-chloropyridin-2-yl)methoxy]-2-oxopyridin-l(2H)- yl}-7,8-dihydronaphthalen-2- yl)methyl]-N-methylmethanesulfonamide;

4-[(5-chloropyridin-2-yl)methoxy]-l- {6-[(dimethylamino)methyl]-3,4-dihydronaphthalen-2- yl}pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -[6-(piperidin- 1 -ylmethyl)-3,4-dihydronaphthalen-2- yl]pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -(6- { [(3R)-3-hydroxypyrrolidin- 1 -yl]methyl} -3 ,4- dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l- {6-[(ethylamino)methyl]-3,4-dihydronaphthalen-2- yl}pyridin-2(lH)-one; 4-[(5-chloropyridin-2-yl)methoxy]-l- {6-[(4-methylpiperazin-l-yl)methyl]-3,4- dihydronaphthalen-2-yl} pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 - {6-[( {2-[(2-methoxyethyl)amino]ethyl} amino)methyl]- 3 ,4-dihydronaphthalen-2-yl} pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l- {6-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(lH)- ylmethyl]-3,4-dihydronaphthalen-2-yl}pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -(6- { [4-(methylamino)piperidin- 1 -yl]methyl} -3,4- dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

N-(2-{[(6- {4-[(5-chloropyridin-2-yl)methoxy]-2-oxopyridin-l(2H)-yl}-7, 8- dihydronaphthalen-2-yl)methyl](methyl)amino}ethyl)methanesul fonamide;

4-[(5-chloropyridin-2-yl)methoxy]-l- {6-[(3aR,7aR)-octahydro-2H-pyrrolo[3,4-c]pyridin-2- ylmethyl]-3,4-dihydronaphthalen-2-yl}pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-[6-(2,7-diazaspiro[4.4]n on-2-ylmethyl)-3,4- dihydronaphthalen-2-yl]pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -(6- { [(3S)-3-methoxypyrrolidin- 1 -yl]methyl} -3,4- dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -(6- { [(3R)-3-ethoxypyrrolidin- 1 -yl]methyl} -3 ,4- dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-(6-{[(3S)-3-(hydroxymeth yl)piperidin-l-yl]methyl}-3,4- dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-[6-({[(3S)-l-methylpiper idin-3-yl]amino}methyl)-3,4- dihydronaphthalen-2-yl]pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -[6-( {(3R)-3-[ethyl(methyl)amino]pyrrolidin- 1 - yl}methyl)-3,4-dihydronaphthalen-2-yl]pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-[6-(morpholin-4-ylmethyl )-3,4-dihydronaphthalen-2- yl]pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-[6-(2,8-diazaspiro[4.5]d ec-2-ylmethyl)-3,4- dihydronaphthalen-2-yl]pyridin-2(lH)-one;

l-(6-{[(lR,5S)-l-amino-3-azabicyclo[3.1.0]hex-3-yl]methyl }-3,4-dihydronaphthalen-2-yl)-4- [(5-chloropyridin-2-yl)methoxy]pyridin-2(lH)-one; 4-[(5-chloropyridin-2-yl)methoxy]-l-(6-{[(lR,4R)-5-methyl-2, 5-diazabicyclo[2.2.1]hept-2- yl]methyl}-3,4-dihydronaphthalen-2-yl)pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l -(6- {[methyl

3 ,4-dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

N- {l-[(6-{4-[(5-chloropyridin-2-yl)methoxy]-2-oxopyridin-l(2H) -yl}-7,8- dihydronaphthalen-2-yl)methyl]pyrrolidin-3-yl}-N-methylmetha nesulfonamide;

4-[(5-chloropyridin-2-yl)methoxy]-l-[6-(2,7-diazaspiro[4. 5]dec-2-ylmethyl)-3,4- dihydronaphthalen-2-yl]pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-(6-{[(2R)-2-(hydroxymeth yl)thiomorpholin-4- yl]methyl}-3,4-dihydronaphthalen-2-yl)pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l- {6-[(methylamino)methyl]-3,4-dihydronaphthalen-2- yl}pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -(6- { [(3R)-3-(dimethylamino)pyrrolidin- 1 -yl]methyl} - 3 ,4-dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -(6- { [(3S)-3-(dimethylamino)pyrrolidin- 1 -yl]methyl} - 3 ,4-dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 - {6-[(3-methoxyazetidin- 1 -yl)methyl]-3,4- dihydronaphthalen-2-yl} pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-[6-({[2-(dimethylamino)e thyl]amino}methyl)-3,4- dihydronaphthalen-2-yl]pyridin-2(lH)-one;

l-[6-(azetidin-l-ylmethyl)-3,4-dihydronaphthalen-2-yl]-4- [(5-chloropyridin-2- yl)methoxy]pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 - {6-[(pyridin-2-ylamino)methyl]-3,4-dihydronaphthalen- 2 -yl } pyr idin-2 ( 1 H) -one;

4-[(5-chloropyridin-2-yl)methoxy]-l-(6-{[(lR,5S)-6-(methylam ino)-3-azabicyclo[3.1.0]hex-

3-yl]methyl}-3,4-dihydronaphthalen-2-yl)pyridin-2(lH)-one ;

N- {l-[(6-{4-[(5-chloropyridin-2-yl)methoxy]-2-oxopyridin-l(2H) -yl}-7,8- dihydronaphthalen-2-yl)methyl]pyrrolidin-3-yl}-N-methylaceta mide;

N- {l-[(6-{4-[(5-chloropyridin-2-yl)methoxy]-2-oxopyridin-l(2H) -yl}-7,8- dihydronaphthalen-2-yl)methyl]pyrrolidin-3-yl}-N-methylaceta mide; N2- { 1 -[(6- {4- [(5-chloropyridin-2-yl)methoxy]-2-oxopyridin- 1 (2H)-yl} -7,8- dihydronaphthalen-2-yl)methyl]pyrrolidin-3-yl}-N,N2-dimethyl glycinamide;

4-[(5-chloropyridin-2-yl)methoxy]-l-[6-(piperazin-l-ylmet hyl)-3,4-dihydronaphthalen-2- yl]pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l- {6-[(4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridin-6- ylmethyl]-3,4-dihydronaphthalen-2-yl}pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-[6-({[2-(tetrahydro-2 H-pyran-4- ylamino)ethyl]amino}methyl)-3,4-dihydronaphthalen-2-yl]pyrid in-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -[6-( {(3R)-3-[(2-methoxyethyl)amino]pyrrolidin- 1 - yl}methyl)-3,4-dihydronaphthalen-2-yl]pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l- {6-[(4-hydroxypiperidin-l-yl)methyl]-3,4- dihydronaphthalen-2-yl} pyridin-2( 1 H)-one;

l-(2-{[(6-{4-[(5-chloropyridin-2-yl)methoxy]-2-oxopyridin -l(2H)-yl}-7,8- dihydronaphthalen-2-yl)methyl]amino}ethyl)urea;

N-(2-{[(6- {4-[(5-chloropyridin-2-yl)methoxy]-2-oxopyridin-l(2H)-yl}-7, 8- dihydronaphthalen-2-yl)methyl] amino} ethyl)sulfuric diamide;

4-[(5-chloropyridin-2-yl)methoxy]-l-{6-[({2-[(3R)-3-hydroxyp yrrolidin-l- yl]ethyl}amino)methyl]-3,4-dihydronaphthalen-2-yl}pyridin-2( lH)-one;

1 - {6-[(3-amino-3-methylazetidin- 1 -yl)methyl]-3,4-dihydronaphthalen-2-yl} -4-[(5- chloropyridin-2-yl)methoxy]pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-(6-{[(3R)-3-hydroxypiper idin-l-yl]methyl}-3,4- dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

1 -[6-( {3- [ 1 -amino-2-oxo-2-(pyrrolidin- 1 -yl)ethyl]pyrrolidin- 1 -yl} methyl)-3 ,4- dihydronaphthalen-2-yl]-4-[(5-chloropyridin-2-yl)methoxy]pyr idin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-[6-({[l-(methylsulfon yl)piperidin-4-yl]amino}methyl)- 3 ,4-dihydronaphthalen-2-yl]pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -[6-( {3-[(methylamino)methyl]pyrrolidin- 1 -yl}methyl)- 3 ,4-dihydronaphthalen-2-yl]pyridin-2( 1 H)-one;

l-(6-{[3-azabicyclo[3.1.0]hex-6-yl(methyl)amino]methyl}-3 ,4-dihydronaphthalen-2-yl)-4- [(5-chloropyridin-2-yl)methoxy]pyridin-2(lH)-one; (3S)-l-[(6-{4-[(5-chloropyridin-2-yl)methoxy]-2-oxopyridin-l (2H)-yl}-7,8- dihydronaphthalen-2-yl)methyl]pyrrolidine-3-carboxamide;

(3R)-l-[(6-{4-[(5-chloropyridin-2-yl)methoxy]-2-oxopyridi n-l(2H)-yl}-7,8- dihydronaphthalen-2-yl)methyl]pyrrolidine-3-carboxamide;

4-[(5-chloropyridin-2-yl)methoxy]-l-(6-{[(3S)-3-hydroxypyrro lidin-l-yl]methyl}-3,4- dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

2- {[(6- {4-[(5-chloropyridin-2-yl)methoxy]-2-oxopyridin- 1 (2H)-yl} -7,8-dihydronaphthalen-2- yl)methyl](methyl)amino}-N-methylethanesulfonamide;

4-[(5-chloropyridin-2-yl)methoxy]-l-[6-(2,9-diazaspiro[5.5]u ndec-9-ylmethyl)-3,4- dihydronaphthalen-2-yl]pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -(6- { [(2-methoxyethyl)(methyl)amino]methyl} -3,4- dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-[6-(2,7-diazaspiro[4.5]d ec-7-ylmethyl)-3,4- dihydronaphthalen-2-yl]pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-[6-(l-oxa-4,8-diazaspiro [5.5]undec-4-ylmethyl)-3,4- dihydronaphthalen-2-yl]pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-[6-(l-oxa-4,8-diazaspiro [5.5]undec-8-ylmethyl)-3,4- dihydronaphthalen-2-yl]pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-[6-(2,8-diazaspiro[5.5]u ndec-2-ylmethyl)-3,4- dihydronaphthalen-2-yl]pyridin-2(lH)-one;

8-[(6-{4-[(5-chloropyridin-2-yl)methoxy]-2-oxopyridin-l(2H)- yl}-7,8-dihydronaphthalen-2- yl)methyl]-2,8-diazaspiro[4.5]decane-l ,3-dione;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -(6- { [(3S)-3,4-dimethylpiperazin- 1 -yl]methyl} -3,4- dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -(6- { [(4aR,7aR)- 1 -methyloctahydro-6H-pyrrolo[3,4- b]pyridin-6-yl]methyl}-3,4-dihydronaphthalen-2-yl)pyridin-2( lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -[6-( {(2S)-2-[(dimethylamino)methyl]pyrrolidin- 1 - yl}methyl)-3,4-dihydronaphthalen-2-yl]pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -(6- { [4-(morpholin-4-yl)piperidin- 1 -yl]methyl} -3 ,4- dihydronaphthalen-2-yl)pyridin-2( 1 H)-one; 4-[(5-chloropyridin-2-yl)methoxy]-l-{6-[(5-fluoro-l ,2-dihydro- H-spiro[indole-3,4'- piperidin]-r-yl)methyl]-3,4-dihydronaphthalen-2-yl}pyridin-2 (lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-[6-(2,7-diazaspiro[3. 5]non-7-ylmethyl)-3,4- dihydronaphthalen-2-yl]pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-[6-(2,7-diazaspiro[3.5]n on-2-ylmethyl)-3,4- dihydronaphthalen-2-yl]pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 - {6-[( {2-[4-(methylsulfonyl)piperazin- 1 - yl]ethyl}amino)methyl]-3,4-dihydronaphthalen-2-yl}pyridin-2( lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l- {6-[(4-hydroxy-4-methylpiperidin-l-yl)methyl]-3,4- dihydronaphthalen-2-yl} pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-(6-{[4-(l ,3-thiazol-2-yl)piperazin-l-yl]methyl}-3,4- dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 - {6-[(4-phenylpiperazin- 1 -yl)methyl]-3,4- dihydronaphthalen-2-yl} pyridin-2( 1 H)-one;

1- {6-[(4-acetylpiperazin-l-yl)methyl]-3,4-dihydronaphthalen-2- yl}-4-[(5-chloropyridin-2- yl)methoxy]pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-(6-{[4-(2-hydroxyethyl)p iperazin-l-yl]methyl}-3,4- dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -(6- { [(3S)-3-methoxy-4-methylpiperazin- 1 -yljmethyl} - 3 ,4-dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -(6- { [(3S)-3-(hydroxymethyl)pyrrolidin- 1 -yljmethyl} - 3 ,4-dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

2- {4-[(6- {4-[(5-chloropyridin-2-yl)methoxy]-2-oxopyridin-l(2H)-yl}-7, 8-dihydronaphthalen- 2-yl)methyl]piperazin- 1 -yl} -N,N-dimethylacetamide;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -(6- { [4-(hydroxymethyl)piperidin- 1 -yljmethyl} -3,4- dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -(6- { [(2S)-2-(hydroxymethyl)pyrrolidin- 1 -yljmethyl} - 3 ,4-dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-(6-{[(l-methylpiperidin- 4-yl)amino]methyl}-3,4- dihydronaphthalen-2-yl)pyridin-2( 1 H)-one; 4-[(5-chloropyridin-2-yl)methoxy]- 1 -[6-( { [3-(morpholin-4-yl)propyl]amino} methyl)-3,4- dihydronaphthalen-2-yl]pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -(6- {[4-(tetrahydro-2H-pyran-4-yl)piperazin- 1 - yl]methyl}-3,4-dihydronaphthalen-2-yl)pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -(6- { [(tetrahydro-2H-pyran-4-ylmethyl)amino]methyl} - 3 ,4-dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

l-{6-[(4-aminopiperidin-l-yl)methyl]-3,4-dihydronaphthale n-2-yl}-4-[(5-chloropyridin-2- yl)methoxy]pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -(6- { [4-(2,2,2-trifluoroethyl)piperazin- 1 -yljmethyl} -3,4- dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -(6- { [(2R)-2-(hydroxymethyl)pyrrolidin- 1 -yljmethyl} - 3 ,4-dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(6-{4-[(5-chloropyridin-2-yl)methoxy]-2-oxopyridin-l(2H)- yl}-7,8-dihydronaphthalen-2- yl)methyl]piperazine- 1 -carboxamide;

4-[(5-chloropyridin-2-yl)methoxy]-l-[6-(l-oxa-4,9-diazaspiro [5.5]undec-9-ylmethyl)-3,4- dihydronaphthalen-2-yl]pyridin-2(lH)-one;

9-[(6-{4-[(5-chloropyridin-2-yl)methoxy]-2-oxopyridin-l(2H)- yl}-7,8-dihydronaphthalen-2- yl)methyl]-l-oxa-4,9-diazaspiro[5.5]undecan-3-one;

1 -(6- { [(3R)-3-(aminomethyl)pyrrolidin- 1 -yljmethyl} -3,4-dihydronaphthalen-2-yl)-4-[(5- chloropyridin-2-yl)methoxy]pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-[6-(6,7-dihydrothieno[3, 2-c]pyridin-5(4H)-ylmethyl)- 3 ,4-dihydronaphthalen-2-yl]pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l- {6-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6- ylmethyl]-3,4-dihydronaphthalen-2-yl}pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -[6-( {(3R)-3-[(methylamino)methyl]pyrrolidin- 1 - yl}methyl)-3,4-dihydronaphthalen-2-yl]pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -(6- { [( 1 , 1 -dioxidotetrahydro-2H-thiopyran-4- yl)amino]methyl} -3 ,4-dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

7-[(6-{4-[(5-chloropyridin-2-yl)methoxy]-2-oxopyridin-l(2H)- yl}-7,8-dihydronaphthalen-2- yl)methyl]-2,7-diazaspiro[4.5]decan-l-one; 2- {[(6- {4-[(5-chloropyridin-2-yl)methoxy]-2-oxopyridin- 1 (2H)-yl} -7,8-dihydronaphthalen-2- yl)methyl]amino}-N,N-dimethylethanesulfonamide;

N-( {(3 S)- 1 - [(6- {4- [(5-chloropyridin-2-yl)methoxy]-2-oxopyridin- 1 (2H)-yl} -7,8- dihydronaphthalen-2-yl)methyl]pyrrolidin-3-yl}methyl)-2,2,2- trifluoro-N-methylacetamide;

N-({(3R)-l-[(6-{4-[(5-chloropyridin-2-yl)methoxy]-2-oxopy ridin-l(2H)-yl}-7,8- dihydronaphthalen-2-yl)methyl]pyrrolidin-3-yl}methyl)-2,2,2- trifluoroacetamide;

l-[6-(l ,3'-bipyrrolidin-r-ylmethyl)-3,4-dihydronaphthalen-2-yl]-4-[ (5-chloropyridin-2- yl)methoxy]pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-(6-{[4-(pyrimidin-2-yl)p iperazin-l-yl]methyl}-3,4- dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -(6- { [4-(cyclopropylcarbonyl)piperazin- 1 -yl]methyl} - 3 ,4-dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -(6- { [4-(thiophen-2-ylmethyl)piperazin- 1 -yl]methyl} - 3 ,4-dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

N- {(3R)- 1 -[(6- {4-[(5-chloropyridin-2-yl)methoxy]-2-oxopyridin- 1 (2H)-yl} -7,8- dihydronaphthalen-2-yl)methyl]piperidin-3-yl}acetamide;

4-[(5-chloropyridin-2-yl)methoxy]-l-[6-({[(3S)-l-(methyls ulfonyl)piperidin-3- yl]amino } methyl)-3,4-dihydronaphthalen-2-yl]pyridin-2( 1 H)-one;

7-[(6-{4-[(5-chloropyridin-2-yl)methoxy]-2-oxopyridin-l(2H)- yl}-7,8-dihydronaphthalen-2- yl)methyl]-2,7-diazaspiro[4.5]decane-l ,3-dione;

4-[(5-chloropyridin-2-yl)methoxy]-l-[6-({[(2S)-l-hydroxyprop an-2- yl](methyl)amino}methyl)-3,4-dihydronaphthalen-2-yl]pyridin- 2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-[6-(3,4-dihydroquinoxali n-l(2H)-ylmethyl)-3,4- dihydronaphthalen-2-yl]pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l- {6-[(9aS)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)- ylmethyl]-3,4-dihydronaphthalen-2-yl}pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-[6-({methyl[2-(piperidin -l-yl)ethyl]amino}methyl)-3,4- dihydronaphthalen-2-yl]pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-(6-{[(2R,6S)-2,6-dimethy lmoφholin-4-yl]methyl}-3,4- dihydronaphthalen-2-yl)pyridin-2( 1 H)-one; 4-[(5-chloropyridin-2-yl)methoxy]- 1 -(6- { [(2R)-2-(hydroxymethyl)piperidin- 1 -yl]methyl} - 3 ,4-dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-[6-({(3R)-3-[(2,2-difluo roethyl)amino]pyrrolidin-l- yl}methyl)-3,4-dihydronaphthalen-2-yl]pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l- {6-[(4,4-difluoropiperidin-l-yl)methyl]-3,4- dihydronaphthalen-2-yl} pyridin-2( 1 H)-one;

1 -(6- { [(2S)-2-(aminomethyl)pyrrolidin- 1 -yl]methyl} -3,4-dihydronaphthalen-2-yl)-4-[(5- chloropyridin-2-yl)methoxy]pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 - {6-[(pyridin-3-ylamino)methyl]-3,4-dihydronaphthalen-

2 -yl } pyr idin-2 ( 1 H) -one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -(6- { [(4aR,7aS)-4-methyloctahydro- 1 H- cyclopenta[b]pyrazin- 1 -yljmethyl} -3 ,4-dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -[6-( {(3S)-3-[(dimethylamino)methyl]pyrrolidin- 1 - yl} methyl)-3 ,4-dihydronaphthalen-2-yl]pyridin-2( 1 H)-one;

1 -(6- { [(3S)-3-(aminomethyl)pyrrolidin- 1 -yljmethyl} -3,4-dihydronaphthalen-2-yl)-4-[(5- chloropyridin-2-yl)methoxy]pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-[6-({(3S)-3-[(2,2-difluo roethyl)amino]pyrrolidin-l- yl}methyl)-3,4-dihydronaphthalen-2-yl]pyridin-2(lH)-one;

1- (6-{[(3-aminocyclobutyl)amino]methyl}-3,4-dihydronaphthalen- 2-yl)-4-[(5-chloropyridin-

2- yl)methoxy]pyridin-2(lH)-one;

N-({(3R)-l-[(6-{4-[(5-chloropyridin-2-yl)methoxy]-2-oxopyrid in-l(2H)-yl}-7,8- dihydronaphthalen-2-yl)methyl]pyrrolidin-3-yl}methyl)methane sulfonamide;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -(6- { [(3R)-3-(methoxymethyl)pyrrolidin- 1 -yljmethyl} - 3 ,4-dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-(6-{[(2S)-2-methylmorpho lin-4-yl]methyl}-3,4- dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 - {6-[(4-methoxypiperidin- 1 -yl)methyl]-3,4- dihydronaphthalen-2-yl} pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -(6- { [(3S)-3-fluoropyrrolidin- 1 -yl]methyl} -3,4- dihydronaphthalen-2-yl)pyridin-2( 1 H)-one; 4-[(5-chloropyridin-2-yl)methoxy]-l- {6-[(tetrahydro-2H-pyran-4-ylamino)methyl]-3,4- dihydronaphthalen-2-yl} pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -[6-( { [(2R)-morpholin-2-ylmethyl]amino} methyl)-3,4- dihydronaphthalen-2-yl]pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -(6- { [(3R)-3-fluoropyrrolidin- 1 -yl]methyl} -3 ,4- dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-[6-({[(3S)-morpholin-3-y lmethyl]amino}methyl)-3,4- dihydronaphthalen-2-yl]pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -(6- { [(2R)-2-(hydroxymethyl)morpholin-4-yl]methyl} - 3 ,4-dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-[6-({4-[(2-methoxyethyl) amino]piperidin-l-yl}methyl)- 3 ,4-dihydronaphthalen-2-yl]pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 - [6-( { [2-( 1 , 1 -dioxidoisothiazolidin-2- yl)ethyl]amino}methyl)-3,4-dihydronaphthalen-2-yl]pyridin-2( lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-[6-({4-[2-(morpholin- 4-yl)-2-oxoethyl]piperazin-l- yl}methyl)-3,4-dihydronaphthalen-2-yl]pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1-(6- {[(1 -methylazetidin-3-yl)amino]methyl} -3,4- dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

1 -(6- { [(3S)-3-aminopiperidin- 1 -yl]methyl} -3,4-dihydronaphthalen-2-yl)-4-[(5-chloropyridin- 2-yl)methoxy]pyridin-2(lH)-one;

4-[(6-{4-[(5-chloropyridin-2-yl)methoxy]-2-oxopyridin-l(2H)- yl}-7,8-dihydronaphthalen-2- yl)methyl]piperazin-2-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -(6- { [4-(pyrazin-2-yl)piperazin- 1 -yl]methyl} -3,4- dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

l-[6-({[2-(azetidin-3-yl)ethyl]amino}methyl)-3,4-dihydron aphthalen-2-yl]-4-[(5- chloropyridin-2-yl)methoxy]pyridin-2(lH)-one;

l-(6- {[4-(azetidin-3-yl)piperazin-l-yl]methyl}-3,4-dihydronaphtha len-2-yl)-4-[(5- chloropyridin-2-yl)methoxy]pyridin-2(lH)-one;

1 -(6- { [(2R)-2-(aminomethyl)pyrrolidin- 1 -yl]methyl} -3,4-dihydronaphthalen-2-yl)-4-[(5- chloropyridin-2-yl)methoxy]pyridin-2(lH)-one; 4-[(5-chloropyridin-2-yl)methoxy]- 1 -(6- { [(3-hydroxypropyl)(methyl)amino]methyl} -3,4- dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-[6-({[(4S)-2-methyl-l ,2-oxazinan-4-yl]amino}methyl)- 3 ,4-dihydronaphthalen-2-yl]pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-[6-({[(2R)-pyrrolidin-2- ylmethyl]amino}methyl)-3,4- dihydronaphthalen-2-yl]pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l- {6-[(l,l-dioxidothiomorpholin-4-yl)methyl]-3,4- dihydronaphthalen-2-yl} pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -[6-( { [2-(morpholin-4-yl)-2-oxoethyl]amino} methyl)- 3 ,4-dihydronaphthalen-2-yl]pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l- {6-[(cyclopentylamino)methyl]-3,4-dihydronaphthalen- 2 -yl } pyr idin-2 ( 1 H) -one;

4-[(5-chloropyridin-2-yl)methoxy]-l-[6-({[(5S)-2-methyl-l ,2-oxazinan-5-yl]amino}methyl)- 3 ,4-dihydronaphthalen-2-yl]pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 - {6- [(4-fluoropiperidin- 1 -yl)methyl]-3 ,4- dihydronaphthalen-2-yl} pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -(6- { [(3S)-3-(methoxymethyl)pyrrolidin- 1 -yl]methyl} - 3 ,4-dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-(6-{[(3S,5S)-3,5-dimethy lmorpholin-4-yl]methyl}-3,4- dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-[6-(2,6-diazaspiro[3.3]h ept-2-ylmethyl)-3,4- dihydronaphthalen-2-yl]pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -(6- { [(2R,4S)-4-hydroxy-2-(hydroxymethyl)pyrrolidin- 1 - yl]methyl}-3,4-dihydronaphthalen-2-yl)pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-(6-{[4-(pyridazin-3-yl)p iperazin-l-yl]methyl}-3,4- dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

(3'R)- 1 '- [(6- {4- [(5 -chloropyridin-2-yl)methoxy] -2-oxopyridin- 1 (2H)-yl} -7,8- dihydronaphthalen-2-yl)methyl]- 1 ,3'-bipyrrolidin-2-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -[6-( { [(3R)- 1 -(methylsulfonyl)pyrrolidin-3- yl]amino } methyl)-3,4-dihydronaphthalen-2-yl]pyridin-2( 1 H)-one; N2-[(6-{4-[(5-chloropyridin-2-yl)methoxy]-2-oxopyridin-l(2H) -yl}-7,8-dihydronaphthalen- 2-yl)methyl]-N-(l,l-dioxidotetrahydro-2H-thiopyran-4-yl)glyc inamide;

4-[(5-chloropyridin-2-yl)methoxy]-l-[6-({[(2S)-l-(cyclohe xylamino)propan-2- yl]amino } methyl)-3,4-dihydronaphthalen-2-yl]pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -[6-( {[(2S)- 1 -(tetrahydro-2H-pyran-4-ylamino)propan-2- yl]amino } methyl)-3,4-dihydronaphthalen-2-yl]pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -(6- { [( 1 , 1 -dioxidotetrahydro-2H-thiopyran-4- yl)(methyl)amino]methyl} -3 ,4-dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -(6- { [4-(4-fluorophenyl)piperazin- 1 -yl]methyl} -3,4- dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -(6- { [(6-methoxypyridin-3-yl)amino]methyl} -3,4- dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -[6-( { [(1 S,2R)-2-hydroxycyclopentyl]amino} methyl)- 3 ,4-dihydronaphthalen-2-yl]pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-(6-{[(lR,4S,6R)-6-hydrox y-2-azabicyclo[2.2.1]hept-2- yl]methyl}-3,4-dihydronaphthalen-2-yl)pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-(6-{[(lR,4S,6S)-6-hydrox y-2-azabicyclo[2.2.1]hept-2- yl]methyl}-3,4-dihydronaphthalen-2-yl)pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-(6-{[(lR,4R,5S)-5-hydrox y-2-azabicyclo[2.2.1]hept-2- yl]methyl}-3,4-dihydronaphthalen-2-yl)pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-(6-{[(lR,4R,5R)-5-hydrox y-2-azabicyclo[2.2.1]hept-2- yl]methyl}-3,4-dihydronaphthalen-2-yl)pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-[6-(l ,8-diazaspiro[5.5]undec-l-ylmethyl)-3,4- dihydronaphthalen-2-yl]pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-(6-{[(3R,4S)-3,4-dihydro xypyrrolidin-l-yl]methyl}-3,4- dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -[6-( { [(5R)-2-methyl- 1 ,2-oxazinan-5-yl]amino} methyl)- 3 ,4-dihydronaphthalen-2-yl]pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l- {6-[(cyclobutylamino)methyl]-3,4-dihydronaphthalen-2- yl}pyridin-2(lH)-one; (2R)-4-[(6-{4-[(5-chloropyridin-2-yl)methoxy]-2-oxopyridin-l (2H)-yl}-7,8- dihydronaphthalen-2-yl)methyl]-N,N-dimethylpiperazine-2-carb oxamide;

2-{4-[(6- {4-[(5-chloropyridin-2-yl)methoxy]-2-oxopyridin-l(2H)-yl}-7, 8-dihydronaphthalen- 2-yl)methyl]piperazin- 1 -yl} -N,N-dimethylethanesulfonamide;

4-[(5-chloropyridin-2-yl)methoxy]-l-(6-{[(2-{[(2R)-2- hydroxypropyl]amino}ethyl)amino]methyl}-3,4-dihydronaphthale n-2-yl)pyridin-2(lH)-one; N2-[(6-{4-[(5-chloropyridin-2-yl)methoxy]-2-oxopyridin-l(2H) -yl}-7,8-dihydronaphthalen- 2 -yl)methyl] -N ,N- dimethy lglycinamide;

4-[(5-chloropyridin-2-yl)methoxy]-l-[6-(2,3-dihydro-4H-l,4-b enzoxazin-4-ylmethyl)-3,4- dihydronaphthalen-2-yl]pyridin-2(lH)-one;

(8aR)-2-[(6-{4-[(5-chloropyridin-2-yl)methoxy]-2-oxopyridin- l(2H)-yl}-7,8- dihydronaphthalen-2-yl)methyl]hexahydropyrrolo [ 1 ,2-a]pyrazine- 1 ,4-dione;

N-(cis-4- { [(6- {4- [(5-chloropyridin-2-yl)methoxy]-2-oxopyridin- 1 (2H)-yl} -7,8- dihydronaphthalen-2-yl)methyl]amino}cyclohexyl)acetamide;

(3*S)- 1 *- [(6- {4- [(5-chloropyridin-2-yl)methoxy]-2-oxopyridin- 1 (2H)-yl} -7,8- dihydronaphthalen-2-yl)methyl]- 1 ,3'-bipyrrolidin-2-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-[6-({4-[(3S)-tetrahydrof uran-3-yl]piperazin-l- yl}methyl)-3,4-dihydronaphthalen-2-yl]pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -[6-( {4-[(3R)-tetrahydrofuran-3-yl]piperazin- 1 - yl}methyl)-3,4-dihydronaphthalen-2-yl]pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 - {6-[( { [ 1 -(methylsulfonyl)piperidin-4- yl]methyl}amino)methyl]-3,4-dihydronaphthalen-2-yl}pyridin-2 (lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -(6- {[(3R)-3-(methoxymethyl)piperazin- 1 -yl]methyl} - 3 ,4-dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

1 -(6- { [4-(aminomethyl)piperidin- 1 -yl]methyl} -3,4-dihydronaphthalen-2-yl)-4-[(5- chloropyridin-2-yl)methoxy]pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -[6-( { [ 1 -(hydroxymethyl)cyclopropyl] amino } methyl)- 3 ,4-dihydronaphthalen-2-yl]pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 - {6-[( {2-[(2,2-difluoroethyl)amino]ethyl} amino)methyl]- 3 ,4-dihydronaphthalen-2-yl} pyridin-2( 1 H)-one; 4-[(5-chloropyridin-2-yl)methoxy]- 1 -[6-( { [(2R)-3-hydroxy-3-methylbutan-2- yl](methyl)amino}methyl)-3,4-dihydronaphthalen-2-yl]pyridin- 2(lH)-one;

(5r,8r)-8 - {[(6- {4-[(5-chloropyridin-2-yl)methoxy]-2-oxopyridin- 1 (2H)-yl} -7,8- dihy dronaphthalen-2 -yl)methy 1] amino } - 1 - azaspiro [4.5 ] decan-2 -one ;

l-{6-[(6-amino-3-azabicyclo[3.1.0]hex-3-yl)methyl]-3,4-di hydronaphthalen-2-yl}-4-[(5- chloropyridin-2-yl)methoxy]pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -(6- { [4-(fluoromethyl)piperidin- 1 -yl]methyl} -3,4- dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-(6-{[(trans-4-hydroxycyc lohexyl)amino]methyl}-3,4- dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -[6-( { [(4-hydroxy- 1 ,1 -dioxidotetrahydro-2H-thiopyran-

4-yl)methyl]amino}methyl)-3,4-dihydronaphthalen-2-yl]pyri din-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -[6-( {[( 1 , 1 -dioxidotetrahydro-2H-thiopyran-4- yl)methyl]amino}methyl)-3,4-dihydronaphthalen-2-yl]pyridin-2 (lH)-one;

N- {l-[(6-{4-[(5-chloropyridin-2-yl)methoxy]-2-oxopyridin-l(2H) -yl}-7,8- dihydronaphthalen-2-yl)methyl]piperidin-3-yl}-N-ethylacetami de;

N- {l-[(6-{4-[(5-chloropyridin-2-yl)methoxy]-2-oxopyridin-l(2H) -yl}-7,8- dihydronaphthalen-2-yl)methyl]piperidin-3-yl}-N-ethylacetami de;

4-[(5-chloropyridin-2-yl)methoxy]-l-[6-({[(3R)-2-oxotetrahyd rofuran-3-yl]amino}methyl)- 3 ,4-dihydronaphthalen-2-yl]pyridin-2( 1 H)-one;

(3R)-l-[(6-{4-[(5-chloropyridin-2-yl)methoxy]-2-oxopyridin-l (2H)-yl}-7,8- dihydronaphthalen-2-yl)methyl]-N-methylpiperidine-3-carboxam ide;

4-[(5-chloropyridin-2-yl)methoxy]-l- {6-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6- ylmethyl]-3,4-dihydronaphthalen-2-yl}pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-(6-{[(l ,l-dioxidotetrahydrothiophen-3- yl)(methyl)amino]methyl} -3 ,4-dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -(6- { [(3S)-tetrahydrofuran-3-ylamino]methyl} -3,4- dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-(6-{[(3R)-tetrahydrofura n-3-ylamino]methyl}-3,4- dihydronaphthalen-2-yl)pyridin-2( 1 H)-one; 4-[(5-chloropyridin-2-yl)methoxy]- 1 -(6- { [methyl(tetrahydrofuran-3-yl)amino]methyl} -3,4- dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -(6- { [methyl(tetrahydrofuran-3-yl)amino]methyl} -3,4- dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

N- {3-[(6-{4-[(5-chloropyridin-2-yl)methoxy]-2-oxopyridin-l(2H) -yl}-7,8- dihydronaphthalen-2-yl)methyl]-3-azabicyclo[3.1.0]hex-6-yl}m ethanesulfonamide;

4-[(5-chloropyridin-2-yl)methoxy]-l- {6-[(oxetan-3-ylamino)methyl]-3,4-dihydronaphthalen- 2 -yl } pyr idin-2 ( 1 H) -one;

9-[(6-{4-[(5-chloropyridin-2-yl)methoxy]-2-oxopyridin-l(2H)- yl}-7,8-dihydronaphthalen-2- yl)methyl]-3,9-diazaspiro[5.5]undecane-2,4-dione;

4-[(5-chloropyridin-2-yl)methoxy]-l-(6-{[methyl(piperidin-4- yl)amino]methyl}-3,4- dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l- {6-[(3aR,7aR)-octahydro-6H-pyrrolo[2,3-c]pyridin-6- ylmethyl]-3,4-dihydronaphthalen-2-yl}pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -(6- { [(3R)-3-(methylsulfonyl)piperidin- 1 -yl]methyl} - 3 ,4-dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -(6- { [(3R)-3-(methylsulfonyl)pyrrolidin- 1 -yl]methyl} - 3 ,4-dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l- {6-[(4aR,8aS)-hexahydro[l,4]dioxino[2,3-c]pyridin- 6(5H)-ylmethyl]-3,4-dihydronaphthalen-2-yl}pyridin-2(lH)-one ;

4-[(5-chloropyridin-2-yl)methoxy]-l-(6-{[(3R,4S)-3,4-dimetho xypiperidin-l-yl]methyl}-3,4- dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-{6-[(8aR)-hexahydropyrro lo[l ,2-a]pyrazin-2(lH)- ylmethyl]-3,4-dihydronaphthalen-2-yl}pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-[6-({[(2S)-tetrahydrofur an-2-ylmethyl]amino}methyl)- 3 ,4-dihydronaphthalen-2-yl]pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -(6- { [( 1 , 1 -dioxido-3 ,4-dihydro-2H-thiochromen-4- yl)amino]methyl} -3 ,4-dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

l-[(6-{4-[(5-chloropyridin-2-yl)methoxy]-2-oxopyridin-l(2 H)-yl}-7,8-dihydronaphthalen-2- yl)methyl]piperidine-4-carboxylic acid; 4-[(5-chloropyridin-2-yl)methoxy]-l-(6-{[(l ,l-dioxidotetrahydrothiophen-3- yl)amino]methyl} -3 ,4-dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-(6-{[(l ,l-dioxidotetrahydrothiophen-3- yl)amino]methyl} -3 ,4-dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-{6-[(3aR,6aS)-tetrahydro -lH-furo[3,4-c]pyrrol-5(3H)- ylmethyl]-3,4-dihydronaphthalen-2-yl}pyridin-2(lH)-one;

4-[(5-chloropyridin-2-yl)methoxy]- 1 -(6- { [(tetrahydrofuran-3-ylmethyl)amino]methyl} -3,4- dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

4-[(5-chloropyridin-2-yl)methoxy]-l-{6-[(3aR,6aR)-hexahydro- 5H-furo[2,3-c]pyrrol-5- ylmethyl]-3,4-dihydronaphthalen-2-yl}pyridin-2(lH)-one;

1 -(6- {[(1 ,1 -dioxidotetrahydro-2H-thiopyran-4-yl)amino]methyl} -3 ,4-dihydronaphthalen-2- yl)-4-{[5-(trifluoromethyl)pyridin-2-yl]methoxy}pyridin-2(lH )-one;

1 - {6-[(methylamino)methyl]-3,4-dihydronaphthalen-2-yl} -4- {[5-(trifluoromethyl)pyridin-2- yl]methoxy}pyridin-2(lH)-one;

1 - {6-[(dimethylamino)methyl]-3,4-dihydronaphthalen-2-yl} -4- { [5-(trifluoromethyl)pyridin-2- yl]methoxy}pyridin-2(lH)-one;

l-[6-(moφholin-4-ylmethyl)-3,4-dihydro

yl]methoxy}pyridin-2(lH)-one;

l-[6-({4-[2-(methylsulfonyl)ethyl]piperazin-l-yl}methyl)- 3,4-dihydronaphthalen-2-yl]-4-{[5-

(trifluoromethyl)pyridin-2-yl]methoxy}pyridin-2(lH)-one;

1 -(6- { [(2-fluoroethyl)amino]methyl} -3 ,4-dihydronaphthalen-2-yl)-4- { [5-

(trifluoromethyl)pyridin-2-yl]methoxy}pyridin-2(lH)-one;

4-[(6-chloropyridazin-3-yl)methoxy]-l-{6-[(tetrahydrofuran-3 -ylamino)methyl]-3,4- dihydronaphthalen-2-yl}pyridin-2(lH)-one; and

4-[(6-chloropyridazin-3-yl)methoxy]-l-{6-[(tetrahydrofuran-3 -ylamino)methyl]-3,4- dihydronaphthalen-2-yl} pyridin-2( 1 H)-one;

or a pharmaceutically acceptable salt thereof.

Typically, but not absolutely, the salts of the present invention are pharmaceutically acceptable salts. Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention. Salts of the disclosed compounds containing a basic amine or other basic functional group may be prepared by any suitable method known in the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid, such as glucuronic acid or galacturonic acid, alpha-hydroxy acid, such as citric acid or tartaric acid, amino acid, such as aspartic acid or glutamic acid, aromatic acid, such as benzoic acid or cinnamic acid, sulfonic acid, such as p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid or the like. Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates succinates, suberates, sebacates, fumarates, maleates, butyne-l,4-dioates, hexyne-l ,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, phenylacetates, phenylpropionates, phenylbutrates, citrates, lactates, γ- hydroxybutyrates, glycolates, tartrates mandelates, and sulfonates, such as xylenesulfonates, methanesulfonates, propanesulfonates, naphthalene- 1 -sulfonates and naphthalene-2-sulfonates.

Salts of the disclosed compounds containing a carboxylic acid or other acidic functional group can be prepared by reacting with a suitable base. Such a pharmaceutically acceptable salt may be made with a base which affords a pharmaceutically acceptable cation, which includes alkali metal salts (especially sodium and potassium), alkaline earth metal salts (especially calcium and magnesium), aluminum salts and ammonium salts, as well as salts made from physiologically acceptable organic bases such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, NJV- dibenzylethylenediamine, 2-hydroxyethylamine, &zs-(2-hydroxyethyl)amine, tri-(2- hydroxyethyl)amine, procaine, dibenzylpiperidine, dehydroabietylamine, NJV- todehydroabietylamine, glucamine, N-methylglucamine, collidine, quinine, quinoline, and basic amino acid such as lysine and arginine. Other salts, which are not pharmaceutically acceptable, may be useful in the preparation of compounds of this invention and these should be considered to form a further aspect of the invention. These salts, such as oxalic or trifluoroacetate, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable salts.

As used herein, the term "a compound of Formula (I)" or "the compound of Formula (I)" refers to one or more compounds according to Formula (I). The compound of Formula (I) may exist in solid or liquid form. In the solid state, it may exist in crystalline or

noncrystalline form, or as a mixture thereof. The skilled artisan will appreciate that pharmaceutically acceptable solvates may be formed for crystalline compounds wherein solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates may involve non-aqueous solvents such as, but not limited to, ethanol, isopropanol, DMSO, acetic acid, ethanolamine, or ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice. Solvates wherein water is the solvent incorporated into the crystalline lattice are typically referred to as "hydrates." Hydrates include

stoichiometric hydrates as well as compositions containing variable amounts of water. The invention includes all such solvates.

The skilled artisan will further appreciate that certain compounds of the invention that exist in crystalline form, including the various solvates thereof, may exhibit polymorphism (i.e. the capacity to occur in different crystalline structures). These different crystalline forms are typically known as "polymorphs." The invention includes all such polymorphs.

Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. The skilled artisan will appreciate that different polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.

The compound of Formula (I) or a salt thereof may exist in stereoisomeric forms (e.g., it contains one or more asymmetric carbon atoms). The individual stereoisomers

(enantiomers and diastereomers) and mixtures of these are included within the scope of the present invention. Likewise, it is understood that a compound or salt of Formula (I) may exist in tautomeric forms other than that shown in the formula and these are also included within the scope of the present invention. It is to be understood that the present invention includes all combinations and subsets of the particular groups defined hereinabove. The scope of the present invention includes mixtures of stereoisomers as well as purified enantiomers or enantiomerically/diastereomerically enriched mixtures. It is to be understood that the present invention includes all combinations and subsets of the particular groups defined hereinabove.

The subject invention also includes isotopically-labelled compounds, which are identical to those recited in formula (I) and following, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, iodine, and chlorine, such as 2H, 3H, 11C, 13C, 14C, 15N, 170, 180, 31P, 32P, 35S, 18F, 36C1, 1231 and 1251.

Compounds of the present invention and pharmaceutically acceptable salts of said compounds that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present invention. Isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as 3H, 14C are

incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. 11 C and 18F isotopes are particularly useful in PET (positron emission tomography), and 1251 isotopes are particularly useful in SPECT (single photon emission computerized tomography), all useful in brain imaging. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of formula I and following of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.

The invention further provides a pharmaceutical composition (also referred to as pharmaceutical formulation) comprising a compound of Formula (I) or pharmaceutically acceptable salt, thereof and one or more excipients (also referred to as carriers and/or diluents in the pharmaceutical arts). The excipients are acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof (i.e., the patient).

In accordance with another aspect of the invention there is provided a process for the preparation of a pharmaceutical composition comprising mixing (or admixing) a compound of Formula (I) or salt thereof with at least one excipient.

Pharmaceutical compositions may be in unit dose form containing a predetermined amount of active ingredient per unit dose. Such a unit may contain a therapeutically effective dose of the compound of Formula (I) or salt thereof or a fraction of a therapeutically effective dose such that multiple unit dosage forms might be administered at a given time to achieve the desired therapeutically effective dose. Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical compositions may be prepared by any of the methods well-known in the pharmacy art.

Pharmaceutical compositions may be adapted for administration by any appropriate route, for example, by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) routes. Such compositions may be prepared by any method known in the art of pharmacy, for example, by bringing into association the active ingredient with the excipient(s).

When adapted for oral administration, pharmaceutical compositions may be in discrete units such as tablets or capsules; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; oil-in-water liquid emulsions or water-in-oil liquid emulsions. The compound or salt thereof of the invention or the pharmaceutical composition of the invention may also be incorporated into a candy, a wafer, and/or tongue tape formulation for administration as a "quick-dissolve" medicine.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Powders or granules are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing, and coloring agents can also be present.

Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin or non-gelatinous sheaths. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, solid polyethylene glycol can be added to the powder mixture before the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate, or sodium carbonate can also be added to improve the availability of the medicine when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars, such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, sodium alginate,

carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum, and the like.

Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets. A powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, and aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt, and/or an absorption agent such as bentonite, kaolin, or dicalcium phosphate. The powder mixture can be granulated by wetting a binder such as syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials and forcing through a screen. As an alternative to granulating, the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc, or mineral oil. The lubricated mixture is then compressed into tablets. The compound or salt of the present invention can also be combined with a free-flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps. A clear opaque protective coating consisting of a sealing coat of shellac, a coating of sugar, or polymeric material, and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different dosages.

Oral fluids such as solutions, syrups, and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of active ingredient. Syrups can be prepared by dissolving the compound or salt thereof of the invention in a suitably flavoured aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound or salt of the invention in a nontoxic vehicle. Solubilizers and emulsifiers, such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additives such as peppermint oil, natural sweeteners, saccharin, or other artificial sweeteners, and the like, can also be added.

Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release as, for example, by coating or embedding particulate material in polymers, wax, or the like.

In the present invention, tablets and capsules are preferred for delivery of the pharmaceutical composition.

The present invention provides a method of treatment in a mammal, especially a human, suffering from obesity, diabetes, hypertension, depression, anxiety, drug addiction, substance addiction, or a combination thereof. Such treatment comprises the step of administering a therapeutically effective amount of a compound of Formula (I) or salt thereof to said mammal, particularly a human. Treatment can also comprise the step of administering a therapeutically effective amount of a pharmaceutical composition containing a compound of Formula (I) or salt thereof to said mammal, particularly a human.

While it is possible that, for use in therapy, a therapeutically effective amount of a compound of Formula (I) or salt thereof may be administered as the raw chemical, it is typically presented as the active ingredient of a pharmaceutical composition or formulation.

The precise therapeutically effective amount of a compound or salt thereof of the invention will depend on a number of factors, including, but not limited to, the age and weight of the subject (patient) being treated, the precise disorder requiring treatment and its severity, the nature of the pharmaceutical formulation/composition, and route of administration, and will ultimately be at the discretion of the attending physician or veterinarian. Typically, a compound of Formula (I) or salt thereof will be given for the treatment in the range of about 0.1 to 100 mg/kg body weight of recipient (patient, mammal) per day and more usually in the range of 0.1 to 10 mg/kg body weight per day. Acceptable daily dosages may be from about 1 to about 1000 mg/day, and preferably from about 1 to about 100 mg/day. This amount may be given in a single dose per day or in a number (such as two, three, four, five, or more) of sub-doses per day such that the total daily dose is the same. An effective amount of a salt thereof may be determined as a proportion of the effective amount of the compound of Formula (I) per se. Similar dosages should be appropriate for treatment (including prophylaxis) of the other conditions referred herein for treatment. In general, determination of appropriate dosing can be readily arrived at by one skilled in medicine or the pharmacy art.

Additionally, the present invention comprises a compound of Formula (I) or salt thereof or a pharmaceutical composition thereof with at least one other anti-obesity drug and at least one anti-diabetes drug. Such anti-obesity drugs can include, for example, Metformin (or glucophage), CB1 receptor antagonists, GLP-1 agonists, opioid antagonists, and neurotransmitter reuptake inhibitors. When a compound of the invention is employed in combination with another anti-obesity drug or anti-diabetes drug, it is to be appreciated by those skilled in the art that the dose of each compound or drug of the combination may differ from that when the drug or compound is used alone. Appropriate doses will be readily appreciated and determined by those skilled in the art. The appropriate dose of the compound of Formula (I) or salt thereof and the other therapeutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect, and are with the expertise and discretion of the attending doctor or clinician.

DEFINITIONS

Terms are used within their accepted meanings. The following definitions are meant to clarify, but not limit, the terms defined.

As used herein, the term "alkyl" (or "alkylene") refers to a straight or branched chain alkyl, preferably having from one to twelve carbon atoms, which may be unsubstituted or substituted, saturated or unsaturated with multiple degrees of substitution included within the present invention. Suitable substituents are selected from the group consisting of halogen, and hydroxyl. Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, t-butyl, isopentyl, n-pentyl, and the like, as well as substituted versions thereof.

As used herein, the term "haloalkyl" refers to an alkyl group, defined hereinabove, substituted with one or more halo substituents.

As used herein, the term "hydroxylalkyl" refers to an alkyl group, defined

hereinabove, substituted with one or more hydroxyl substituents.

As used herein, the term "cycloalkyl" refers to an unsubstituted or substituted mono- or polycyclic non-aromatic saturated ring, which optionally includes an alkylene linker through which the cycloalkyl may be attached. Exemplary "cycloalkyl" groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, as well as unsubstituted and substituted versions thereof.

As used herein, the term "alkoxy" refers to the group -OR ^a , where R ^a is alkyl or cycloalkyl as defined above.

The terms "halogen" and "halo" represent chloro, fluoro, bromo, or iodo substituents.

"Hydroxy" or "hydroxyl" is intended to mean -OH.

"Heterocycloalkyl" represents a group or moiety comprising a non-aromatic, monovalent monocyclic or bicyclic radical, which is saturated or partially unsaturated, containing 3 to 10 ring atoms, which includes 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, including N-oxides, sulfur oxides, and dioxides. Illustrative examples of heterocycloalkyls useful in the present invention include, but are not limited to, azetidinyl, pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl, tetrahydrofuranyl, dihydrofuranyl, 1,3-dioxolanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dihydropyranyl, 1 ,3-dioxanyl, 1 ,4-dioxanyl, 1 ,3-oxathiolanyl, 1 ,3-oxathianyl, 1 ,3-dithianyl, hexahydro-lH-l ,4-diazepinyl,

azabicylo[3.2.1]octyl, azabicylo[3.3.1]nonyl, azabicylo[4.3.0]nonyl, azabicyclo[3.1.0]hexyl, oxabicylo[2.2.1]heptyl, l,l-dioxidotetrahydro-2H-thiopyranyl and 1,5,9-triazacyclododecyl.

As used herein, the term "aryl", unless otherwise defined, is meant aromatic, hydrocarbon, ring system. The ring system may be monocyclic or fused polycyclic (e.g., bicyclic, tricyclic, etc.), substituted or unsubstituted. In various embodiments, the monocyclic aryl ring is C5-C10, or C5-C7, or C5-C6, where these carbon numbers refer to the number of carbon atoms that form the ring system. A C6 ring system, i.e. a phenyl ring, is a suitable aryl group. In various embodiments, the polycyclic ring is a bicyclic aryl group, where suitable bicyclic aryl groups are C8-C12, or C9-C10. A naphthyl ring, which has 10 carbon atoms, is a suitable polycyclic aryl group. Suitable substituents for aryl are described in the definition of "optionally substituted".

As used herein, the term "heteroaryl", unless otherwise defined, is meant an aromatic ring system containing carbon(s) and at least one heteroatom. Heteroaryl may be monocyclic or polycyclic, substituted or unsubstituted. A monocyclic heteroaryl group may have 1 to 4 heteroatoms in the ring, while a polycyclic heteroaryl may contain 1 to 10 hetero atoms. A polycyclic heteroaryl ring may contain fused, spiro or bridged ring junctions, for example, bicyclic heteroaryl is a polycyclic heteroaryl. Bicyclic heteroaryl rings may contain from 8 to 12 member atoms. Monocyclic heteroaryl rings may contain from 5 to 8 member atoms (carbons and heteroatoms). Exemplary heteroaryl groups include but are not limited to:

benzofuran, benzothiophene, furan, imidazole, indole, isothiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinoline, quinazoline, quinoxaline, thiazole, and thiophene. Suitable substituents for heteroaryl are described in the definition of "optionally substituted".

As used herein, the term "cyano" refers to the group -CN.

As used herein, the term "acetyl" refers to the group -C(0)R ^b , where R ^b is alkyl, cycloalkyl, or heterocyclyl, as each is defined herein.

As used herein, the term "optionally" means that the subsequently described event(s) may or may not occur, and includes both event(s) that occur and event(s) that do not occur.

As used herein, unless otherwise defined, the phrase "optionally substituted" or variations thereof denote an optional substitution, including multiple degrees of substitution, with one or more substitutent group. The phrase should not be interpreted as duplicative of the substitutions herein described and depicted. Exemplary optional substituent groups include acyl, alkyl, alkylsulfonyl, alkoxy, alkoxycarbonyl, cyano, halogen, haloalkyl, hydro xyl, oxo, and nitro.

As used herein, the term "treatment" includes prophylaxis and refers to alleviating the specified condition, eliminating or reducing one or more symptoms of the condition, slowing or eliminating the progression of the condition, and preventing or delaying the reoccurrence of the condition in a previously afflicted or diagnosed patient or subject. Prophylaxis (or prevention or delay of disease onset) is typically accomplished by administering a drug in the same or similar manner as one would to a patient with the developed disease or condition.

As used herein, the term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought, for instance, by a researcher or clinician.

The term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function. For use in therapy, therapeutically effective amounts of a compound of Formula (I), as well as salts thereof, may be administered as the raw chemical. Additionally, the active ingredient may be presented as a pharmaceutical composition. COMPOUNDS PREPARATION

Abbreviations

AcOH acetic acid

AIBN azobisisobutyronitrile

AICI3 aluminum trichloride

aq. aqueous

Ar argon gas

Br ₂ bromine

CBr ₄ carbon tetrabromide

CCI4 carbon tetrachloride

CH ₂ C1 ₂ dichloromethane

CH ₃ CN acetonitrile

C¾I methyl iodide

(CH ₂ 0) _n paraformaldehyde

CH3SO3H methanesulfonic acid

cone. Concentrated

Cs ₂ C0 ₃ cesium carbonate

CuBr copper(I) bromide

CuCN copper(I) cyanide

Cul copper(I) iodide

(COCl) ₂ oxalyl chloride

DCM dichloromethane

DCE 1 ,2-dichloroethane

DEAD Diethyl Azodicarboxylate

DIPEA N,N-diisopropylethylamine

DMAP 4-(dimethylamino)pyridine

DME 1 ,2-dimethoxyethane

DMF N,N-dimethylformamide

DMSO dimethylsulfoxide

EA ethyl acetate

EtOAc ethyl acetate

EDC N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride

Et ₃ N triethylamine

Et ₂ 0 diethyl ether

EtOH ethanol

FeS0 ₄ iron(II) sulfate

h hour(s)

H ₂ hydrogen gas

HATU 0-(7-azabenzotriazol- 1 -y\)-N,N,N',N '-tetramethyluronium

hexafluoropho sphate

HBr hydrobromic acid

HC1 hydrochloric acid

H ₂ 0 water HNO ₃ nitric acid

HOBt hydroxybenzotriazole

HPLC high-performance liquid chromatography

H ₂ SO ₄ sulfuric acid

I ₂ iodine

z ^' -PrMgCl isopropylmagnesium chloride

K ₂ CO ₃ potassium carbonate

K ₃ Fe(CN) ₆ potassium ferricyanide

KOi-Bu potassium ieri-butoxide

K ₃ PO ₄ potassium phosphate tribasic

LCMS liquid chromatography mass spectrometry

L1AIH ₄ lithium aluminum hydride

LiOH lithium hydroxide

m-CPBA meto-chloroperbenzoic acid

MeMgBr methyl magnesium bromide

MeOH methanol

Mg magnesium

MgCl ₂ magnesium chloride

min minute(s)

Mn0 ₂ manganese dioxide

N ₂ nitrogen gas

aBH ₄ sodium borohydride

NaCN sodium cyanide

Na ₂ C0 ₃ sodium carbonate

NaH sodium hydride

NaHC0 ₃ sodium bicarbonate

NaHS0 ₃ sodium bisulfite

NaN ₃ sodium azide

NaOH sodium hydroxide

Na ₂ SC>4 sodium sulfate

NBS N-Bromosuccinimide

«-BuLi «-butyllithium

NH ₄ CI ammonium chloride

NMM N-methylmorpholine

PCC pyridinium chlorochromate

PE petroleum ether

Pd/C palladium on carbon

Pd(dppf)Cl ₂ [1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(II)

Pd(PPh ₃ )4 tetrakis(triphenylphosphine)palladium(0)

PhN0 ₂ nitrobenzene

POCl ₃ phosphoryl chloride

PPh ₃ triphenylphosphine

p-TsOH para-toluene sulfonic acid

Rf retention factor

rt room temperature Rt retention time

SOCI2 thionyl chloride

TFA trifluoroacetic acid

TFAA trifluoroacetic anhydride

THF tetrahydrofuran

TLC thin layer chromatography

^® T3P 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide

Zn zinc powder

Generic Synthesis Schemes

The compounds of this invention may be made by a variety of methods, including well-known standard synthetic methods. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the working examples. The skilled artisan will appreciate that if a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions. The protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound. In all of the schemes described below, protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of synthetic chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Green and P.G.M. Wuts, (1991) Protecting Groups in Organic Synthesis, John Wiley & Sons, incorporated by reference with regard to protecting groups). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of processes as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of the present invention.

The synthesis of the compounds of the general formula (I) and pharmaceutically acceptable derivatives and salts thereof may be accomplished as outlined below in Schemes 1 - 6 by those skilled in the art. In the following description, the groups are as defined above for compounds of formula (I) unless otherwise indicated. Starting materials are commercially available or are made from commercially available starting materials using methods known to those skilled in the art. Pyridone intermediates of the invention can be prepared as illustrated in Scheme 1. Briefly, alkoxyformylation of substituted arylbromides (A) followed by reduction provided hydroxymethylaryl intermediates (B). Reaction of intermediates (B) with 4-nitropyridine- 1 - oxide in the presence of sodium metal provided substituted hydroxymethyl ether

intermediates (C). Alternatively, reaction of intermediates (B) with 4-nitropyridine- 1 -oxide in the presence of benzyltriethylammonium chloride and a base provided substituted hydroxymethyl ether intermediates (C). Treatment of intermediates (C) with trifluoroacetic anhydride (TFAA) or acetic anhydride (Ac ₂ 0), either neat or in a suitable solvent, such as THF, provided the desired pyridone intermediates (D).

Scheme 1 : Generic Synthesis of Pyridone Intermediates

Alternatively, pyridone intermediates of the invention can be prepared as illustrated in Scheme 2. Thus, reaction of hydroxymethylaryl intermediates (B) with a brominating agent (e.g., perbromomethane in the presence of triphenylphosphine) in a suitable solvent, such as DCM, provided bromomethylpyridine intermediates (E). Reaction of bromomethylpyridine intermediates (E) with pyridine-2,4-diol in the presence of a base (e.g., potassium carbonate) in a suitable solvent, such as DMF, at reduced temperature provided the desired pyridone intermediates (D). Scheme 2: Alternative Generic Synthesis of Pyridone Intermediates

Compound (P) of the invention can be prepared as illustrated in Scheme 3. Reaction of 2-(4-bromophenyl)acetic acid (F) with SOCl ₂ provided the acid chloride (G), which was immediately treated with A1C1 ₃ under an ethylene gas atmosphere to produce 2-bromo-6-oxo- 5,6,7, 8-tetrahydronaphthalene (H). Reaction of H with zinc cyanide in the presence of catalytic palladium provided the nitrile (K). Triflation of the ketone of (K) under standard conditions provided the triflate (L). Compound (L) was reacted with 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi-l ,3,2-dioxaborolane using standard palladium catalytic conditions to produce the boronate ester (M), which was hydrolyzed using standard periodate procedures to produce the boronic acid (N). Treatment of compound (N) with S provided compound (P).

Scheme 3:

Alternatively, compound (P) of the invention can be prepared as illustrated in Scheme 4. Thus, compound (K) was reacted with hydrazine hydrate under standard conditions to produce the hydrazone (I). Reaction of compound (I) with iodine under standard conditions provided compound (P).

Scheme 4:

Compounds of the invention can be prepared as illustrated in Scheme 5. Reaction of substituted pyridone intermediates (D) with compound (P) using standard copper-mediated coupling conditions provided 6-dihydronaphthylene-2-carbonitrile intermediates (J).

Alternatively, intermediates (J) were prepared by copper-mediated coupling of pyridone intermediates (D) with compound (N) (Scheme 6). Subsequent treatment of intermediates (J) with diisobutylaluminium hydride at reduced temperature provided 2-carbaldehyde intermediates (K). Reductive amination of intermediates (K) using reducing agents such as sodium triacetoxyborohydride, in the presence or absence of molecular sieves, with the amines encompassed within the scope of this invention provided examples of Formula I. The requisite amines (and appropriately functional-group-protected versions thereof) utilized herein were purchased if available commercially, were synthesized as described in the literature or by routine modifications thereof known by those skilled in the art, or were synthesized by alternative procedures known by those skilled in the art.

Scheme 5: Synthesis of Examples

deprotection/derivitization

if necessary)

Scheme 6: Alternative Synthesis of Intermediates (J)

Compounds of Formula (I) can be converted to another compounds of Formula (I) using chemical transformations known to those skilled in the art. For example, compound of Formula (I) with suitable protecting groups can be deprotected to provide another compound of Formula (I) which can be further functionalized (eg, reductive amination, sulfonylation, alkylation) to another compound of Formula (I). Alternatively, compound of Formula (I) with suitable functional groups such as primary or secondary amines can undergo further chemical transformations such as reductive amination, sulfonylation and alkylation to provide another compound of Formula (I).

Preparation of Intermediates

I. methyl 5-chloro-2-pyridinecarboxylate

To a solution of 2-bromo-5-chloropyridine (30.0 g, 155.9 mmol) in MeOH (280 mL) was added Pd(OAc) ₂ (3.5 g, 10.8 mmol), dppf (17.3 g, 37.96 mmol), Et ₃ N (42.0 mL, 312 mmol).

The resulting mixture was stirred at 50°C under a CO atmosphere (15 psi) for 24 h, then concentrated under reduced pressure to give crude residue. This residue was partitioned between EtOAc (3 X 500 mL) and water (300 mL). The combined organic layers were dried (Na ₂ SC>4) and evaporated. Flash chromatography of the residue over silica gel, by using 10: 1 petroleum ether/EtOAc, afforded the title compound as a pale yellow solid (25 g, 93% yield): 1H NMR (400 MHz, CDC1 ₃ ) δ ppm 8.60 (d, J = 1.60 Hz, 1H), 8.01 (d, J= 8.40 Ηζ,ΙΗ), 7.75 (dd, J = 8.40, 2.40 Hz, 1H), 3.92 (s, 3H).

II. (5-chloro-2-pyridinyl)methanol

To a cooled (0°C) solution of methyl 5-chloro-2-pyridinecarboxylate (43 g, 251 mmol) in methanol (400 mL) was added NaB¾ (28.7 g, 754 mmol) in small portions over approximately 30 min. After addition, the reaction mixture was stirred at room temperature for 2 h, at which time TLC analysis showed the completion of the reaction. The reaction mixture was then concentrated under reduced pressure, and the residue was adjusted to pH 1 by adding IN HC1. The resulting solution was extracted with EtOAc (3 X 300 mL). The combined organic layers were dried (Na ₂ SC>4) and evaporated. Flash chromatography of the residue over silica gel using 10: 1 petroleum ether/EtOAc as eluent provided the title compound (36 g, 99% yield): ^! H NMR (400 MHz, CDC1 ₃ ) δ ppm 8.44 (d, J = 1.60 Hz, 1H), 7.62 (dd, J = 8.40, 2.40 Hz, 1H), 7.25 (d, J = 8.40 Hz, 1H), 4.69 (s, 2 H), 3.83

(s, 1Η).

III. methyl 5-trifluoromethyl-pyridine-2-carboxylate

A mixture of 2-bromo-5-trifluoromethyl-pyridine (10 g, 44.25 mmol), TEA (17.9 g, 177 mmol) and Pd(dppf)Cl ₂ (3.24 g, 4.42 mmol) was stirred at 80°C under an average pressure of 1.5 MPa with CO gas. The reaction mixture was filtered and the filtrate was concentrated.

The residue was extracted between EA (100 mL) and H ₂ 0 (100 mL). The EA layer was washed with saturated aqueous NaHC0 ₃ (2 X 100 mL), brine (1 X 100 mL), dried,

concentrated and purified by column chromatography on silica gel to give the title compound as a white solid (6 g, 66% yield): 1H NMR (400 MHz, CDC1 ₃ ) δ ppm 8.97-8.98 (m, 1H),

8.23-8.25 (m, 1H), 8.07-8.09 (m, 1H), 4.03 (s, 3H); ES-LCMS m/z 206 ( +H) ⁺ .

IV. (5-trifluoromethyl-2-pyridinyl)methanol

To a solution of methyl 5-trifluoromethyl-pyridine-2-carboxylate (2 g, 9.75 mmol) in MeOH (30 mL) at 0°C was added NaB¾ (738 mg, 19.5 mmol) portionwise. The mixture was stirred at room temperature for 2 h and concentrated. The residue was diluted with water (30 mL), acidified to pH~5 (IN HC1), extracted with EA (3 X 50 mL), dried, concentrated and purified by column chromatography on silica gel to give the title compound as a colorless oil (1.6 g, 93% yield): 1H NMR (400 MHz, CDC1 ₃ ) δ ppm 8.82 (s, 1H), 7.90-7.92 (m, 1H), 7.40-7.42 (m, 1H), 4.82-4.83 (m, 2H), 3.44-3.46 (m, 1H); ES-LCMS m/z 178 ( +H) ⁺ .

V. 2-(methansulfonyloxymethyl)-5-trifluoromethylpyridine

To a solution of (5-trifluoromethyl-2-pyridinyl)methanol (330 mg, 1.86 mmol) and TEA

(246 mg, 2.42 mmol) in DCM (10 mL) at 0°C was added MsCl (235 mg, 2.05 mmol)

dropwise. The mixture was stirred at 0°C for 30 min, followed by room temperature for 2 h, then quenched with water (30 mL), and extracted with DCM (3 X 30 mL). The DCM

layer was washed with brine (1 X 30 mL), dried and concentrated to give the title

compound as a yellow oil (450 mg, 10% yield): ^! H NMR (400 MHz, CDC1 ₃ ) δ ppm 8.80

(d, J = 0.8 Hz, 1H), 7.94 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 5.32 (s, 2H), 3.07 (s, 3H); ES-LCMS m/z 255.9 ( +H) ⁺ .

VI. 4- {[(5-chloro-2-pyridinyl)methyl]oxy}pyridine-l-oxide

Sodium (7.5 g, 326 mmol) was added to a solution of (5-chloro-2-pyridinyl)methanol (36 g, 252 mmol) in THF (400 mL). After addition, the mixture was stirred at reflux for 16 h and then cooled to room temperature. To this mixture, a solution of 4-nitropyridine N-oxide (1 1.7 g, 84 mmol) in THF (100 mL) was added and the resulting mixture was stirred at room

temperature for another 4 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. Et ₂ 0 was added and a precipitate was formed. The precipitate was

collected by filtration and washed with Et ₂ 0 (3 X). This solid was dissolved in CH ₂ C1 ₂ and filtered. The filtrate was dried (Na ₂ SC>4) and evaporated to give the title compound (9.7 g, 49% yield): 1H NMR (400 MHz, CDC1 ₃ ) δ ppm 8.54 (d, J= 0.80 Hz, 1H), 8.09 (m, 2H), 7.71 (dd, J = 8.40, 2.40 Hz, 2H), 7.39 (dd, J= 8.40, 0.40 Hz, 1H), 6.87 (m, 2H), 5.17 (s, 2H).

An alternative procedure was used for a larger-scale synthesis of the title compound. Thus, a stirred mixture of (5-chloro-2-pyridinyl)methanol (15.36 g, 107 mmol) and 4-nitropyridine 1-oxide (14.99 g, 107 mmol) in DCM (250 ml) cooled in an ice/water bath was charged with

benzyltriethylammonium chloride (0.682 g, 3.00 mmol), and 9M NaOH (140 mL) was added dropwise via addition funnel. The mixture was stirred for 2.5 hours at room temperature with periodic checking by HPLC. The reaction mixture became a dark solution over this time period with easier stirring. LC/MS indicated that the reaction was complete. Water (300 mL) was added to the reaction and it quickly became an oily suspension. The reaction mixture was diluted with DCM and the organic layer was separated. The aqueous layer was extracted 3 more times with DCM, and the combined organic layers were washed with brine and dried over sodium sulfate. Concentration yielded a bright yellow solid, which was collected, washed with ether, and dried overnight (22.37 g, 88% yield): ES-LCMS m/z 237 ( +H) ⁺ .

VII. 4- {[(5-chloro-2-pyridinyl)methyl]oxy}-2(lH)-pyridinone

TFAA (9.7 g, 46.6 mmol) was added dropwise to a stirred and cooled (0 °C) solution of 4- {[(5- chloro-2-pyridinyl)methyl]oxy}pyridine-l -oxide (1.1 g, 4.7 mmol) and Et ₃ N (1.4 g, 14.0 mmol) in THF (15 mL). The reaction mixture was stirred at room temperature for 16 h, at which time TLC analysis showed almost completion of the reaction. The reaction mixture was diluted with water, and then extracted with CH ₂ CI ₂ (3 X). The combined organic layers were washed with water, 1 N NaOH, brine, dried and concentrated in vacuo. The residue solid was triturated with ether to give the title compound (850 mg, 77% yield): 'lINMR (400 MHz, DMSO-i/ ₆ ) δ ppm 1 1.1 1 (s, 1H), 8.61 (s, 1H), 7.96 (d, J= 6.00 Hz, 1H), 7.52 (d, J = 8.40 Hz, 1 H), 7.23 (d, J = 7.60 Hz, 1H), 5.92 (d, J = 4.80 Hz, 1H), 5.73 (s, 1H), 5.10 (s, 2H); ES-LCMS m/z 237 (M+ ) ⁺ .

An alternative procedure was used for a larger-scale synthesis of the title compound. Thus, 4- {[(5-chloro-2-pyridinyl)methyl]oxy}pyridine-l-oxide (25 g, 106 mmol) and triethylamine

(44.2 mL, 317 mmol) were allowed to stir in 300 mL of THF while cooling in an ice bath.

Trifluoroacetic anhydride (224 mL, 1585 mmol) was added dropwise via addition funnel. The reaction mixture was allowed to stir an additional 15 min at ice bath temperature, and then warmed to room temperature. The reaction was allowed to stir overnight at room temperature. The next morning, LC/MS indicated that the reaction was complete. The reaction was poured over ice, and the resulting solution was extracted with DCM (4 X 100 mL). The organic layers were combined, washed with water, I NaOH, saturated brine solution, dried over sodium sulfate, and concentrated. The resulting solid was purified via chromatography using a gradient of (0-100% EtOAC/hexanes over a 30 minute run), to provide the title compound as a white solid (15 g, 60% yield).

A second alternative procedure was used on a similar scale. Thus, a solution of 4-{[(5-chloro- 2-pyridinyl)methyl]oxy}pyridine-l -oxide (21g, 90 mmol) in anhydrous Ac ₂ 0 (210 mL) was heated at reflux for 2 h. The mixture was concentrated under reduced pressure. The residue was dissolved in 5: 1 EtOAc/MeOH (400 mL), and the mixture was refluxed for another 2 h.

The solvent was removed, and the residue was dissolved in EtOAc (200 mL). The mixture was left standing overnight. The mixture was filtered, and the filter cake was washed with

EtOAc to give the title compound as a black solid (15 g, 75% yield).

In a third alternative procedure, a mixture of (5-chloropyridin-2-yl)methanol (16 g, 1 11.44 mmol) and triphenylphosphine (35.1 g, 133.7 mmol) in dry dichloromethane (300 mL) was cooled to 0°C. Then perbromomethane (48.04 g, 144.9 mmoL) was added in portions over 30 minutes at 0°C and, after addition, the mixture was stirred at room temperature for 3 hours. The solvent was concentrated and the residue was washed with petroleum ether (2 X 250 mL). The combined petroleum ether phase was concentrated to provide 2-(bromomethyl)-5-chloropyridine as a red oil (23 g, 99% yield), which was immediately added dropwise to a mixture of pyridine-2,4-diol (12.4 g, 111.4 mmoL) and potassium carbonate (38.5 g,279 mmoL) in dry DMF (500 mL) at 0°C. After addition, the mixture was stirred at room temperature for 72 h, the mixture was filtered. The filtrate was concentrated and the residue was recrystallized from ethyl acetate ( 100 mL) to provide a crude brown solid. This solid was washed with 10% aqueous sodium carbonate (5 mL), water (5 mL), and cooled acetone (50 mL) to provide The title compound as a yellow solid (1 1 g, 41.7% yield). VIII. 4- {[(4-chlorophenyl)methyl]oxy} -2(lH)-pyridinone

To a suspension of pyridine-2,4-diol (13.52 g, 0.12 mol) and K ₂ CO ₃ (33.63 g, 0.24 mol) in DMF (100 mL) was added dropwise l-(bromomethyl)-4-chlorobenzene (25 g, 0.12 mol) in DMF (100 mL) at 0°C. After the addition was completed, the reaction was stirred at 0°C for 1 h, and then 16 h at room temperature. The mixture was filtered and the filtrate was poured into ice water, with a precipitate forming. The precipitate was collected by filtration and washed with H ₂ 0 (50 mL). This solid was washed with EtOAc (30 mL) to give the title compound as a white solid (8.4 g, 30% yield): ^! H NMR (400 MHz, CDC1 ₃ ) δ ppm 7.25-7.31 (m, 4H), 7.15-7.20 (m, 1H), 5.95-5.97 (m, 1H), 5.86-5.95 (m, 1H), 4.92 (s, 2H); ES-LCMS m/z 236 (M+H) ⁺ .

IX. 4- {[(5-trifluoromethyl-2-pyridinyl)methyl]oxy}-2(lH)-pyridinon e

A mixture of pyridine-2,4-diol (27.8 g, 250 mmol), K ₂ C0 ₃ (76.7 g, 556 mmol) and 2- (methansulfonyloxymethyl)-5-trifluoromethylpyridine (71 g, 278 mmol) in DMF (500 mL) was stirred at 80°C for 6 h. Then H ₂ 0 (200mL) was added to the mixture. The mixture was filtered and the solid was washed with H ₂ 0 and EtOAc to provide the title compound as a pale brown solid (43 g, 63.6% yield): 1H NMR (400 MHz, CDC1 ₃ ) δ ppm 8.86 (s, 1 H), 8.15 (dd, J = 6.0 and 2. 0 Hz, 1 H), 7.73 (d, J = 8.0 Hz, 1 H), 7.36 (d, J = 7.2 Hz, 1 H), 6.21 (dd, J = 4.8 and 2. 4 Hz, 1 H), 5.94 (d, J= 2. 4 Hz, 1 H), 5.27 (s, 2 H); ES-LCMS m/z 271.0 ( +H) ⁺ .

X. -5,6,7, 8-tetrahydronaphthalene-2-carbonitrile

A solution of 2-(4-bromophenyl)acetic acid (300 g, 1.4 mol) and SOCl ₂ (500 mL) in DCM (500 mL) was stirred at room temperature overnight. The reaction was evaporated to yield crude 2-(4-bromophenyl)acetyl chloride (350 g), which was immediately used in the next step.

To a mixture of A1C1 ₃ (400 g, 3 mol) in DCM (2 L) in an ice bath was added dropwise 2-(4- bromophenyl)acetyl chloride (350 g) and, at the same time, ethylene gas was introduced. After 30 min, the addition was complete, and the reaction mixture was stirred in an ice bath for another 30 min. The mixture was poured into ice/water, the separated organic layer was dried over a ₂ S04 and evaporated to yield crude 2-bromo-6-oxo-5,6,7,8- tetrahydronaphthalene (300 g, 95.5% yield for 2 steps) as a yellow solid, which was used immediatel in the next step.

2-Bromo-6-oxo-5,6,7,8-tetrahydronaphthalene (300 g, 1.74 mol), tetrakis

(triphenylphosphine)palladium (100.4 g, 0.087mol) and zinc cyanide (607.7 g, 5.24 mol) were combined under nitrogen in DMF (2 L) and heated at 140°C overnight. The reaction mixture was cooled to ambient temperature, was filtered and evaporated in vacuo. The residue was redissoloved in CH ₂ C1 ₂ and filtered. The organic layer was evaporated in vacuo. The residue was purified by column chromatography to give the title compound as a yellow solid (150 g, 32% yield): 1H NMR (400 MHz, CDC1 ₃ ) δ ppm 7.49-7.47 (m, 2H), 7.19-7.16 (m, 1H), 3.57 (s, 2H), 3.04 (t, J= 6.8 Hz, 2H), 2.51 (t, J= 6.8 Hz, 2H); EC-LCMS m/z 172 (M+ ) ⁺ .

XI. 6-trifluoromethylsulfonyloxy-7,8-dihydronaphthalene-2-carbon itrile

«-BuLi (2.5 M, toluene, 140 mL,351 mmol) was added dropwise to a solution of

diisopropylamine (35 g, 351 mmol) in THF (600 mL) at -70°C under N ₂ . After stirring for 30 min, a solution of 6-oxo-5,6,7, 8-tetrahydronaphthalene-2-carbonitrile (50 g, 292 mmol) in THF (400 mL) was added dropwise. After stirring for 2 h, a solution of phenyl triflimide (125 g, 351 mmol) in THF (500 mL) was added and the reaction was maintained for an additional 2 h at -70°C. The reaction mixture was warmed to room temperature and stirred overnight. The solvent was evaporated in vacuo to give a crude product, which was purified by chromatography over silica gel to give the title compound as a yellow oil (75 g, 85% yield): 1H NMR (400 MHz, CDC1 ₃ ) δ ppm 7.27 (d, J= 8.0 Hz, 1H), 6.95 (d, J= 8.0 Hz, 1H), 6.30 (s, 1 H), 2.88 (t, J= 8.4 Hz, 2H), 2.51 (t, J= 8.4 Hz, 2H); ES-LCMS m/z 304 (M+ ) ⁺ .

XII. 6-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-7,8-dihydronaphthalene-2- carbonitrile

A solution of 6-trifluoromethylsulfonyloxy-7,8-dihydronaphthalene-2-carbon itrile (42 g, 139 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-l,3,2-dioxaborolane (53 g, 208 mmol),

Pd(dppf)Ci ₂ (1.2 g, 1.46 mmol), and potassium acetate (27 g, 277 mmol) in anhydrous THF ( 1000 mL) was heated under nitrogen at reflux overnight. The reaction mixture was evaporated in vacuo and the residue was purified by chromatography over silica gel to provide the title compound as a yellow solid (36 g, 92% yield): 1H NMR (400 MHz, CDC1 ₃ ) δ ppm 7.45-7.37 (m, 2H), 7.32 (s, 1 H), 7.14 (s, 1H), 2.76 (t, J= 8.2 Hz, 2H), 2.40 (t, J= 8.2 Hz, 2H), 1.29 (s, 12H); ES-LCMS m/z 282 ( +H) ⁺ .

XIII. 7,8-dihydronaphthalene-2-carbonitrile-6-boronic acid A mixture of 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-7,8-dihydron aphthalene-2- carbonitrile (36 g, 128 mmol), NaIC>4 (82 g, 384 mmol) and ammonium acetate (30 g, 384 mmol) in acetone (464 mL) and H ₂ 0 (358 mL) was stirred at room temperature overnight.

The acetone was evaporated in vacuo and the residual solid was filtered. The solid was dissolved in a mixture of ethyl acetate and water and transferred to a separatory funnel. After separating the layers, the aqueous layer was back-extracted with ethyl acetate and the

combined organic layers were washed with brine, dried over Na ₂ SC>4, filtered and evaporated in vacuo to provide the title compound as a pale yellow solid (22 g, 86% yield): ^! H NMR

(400 MHz, CDCls) δ ppm 7.40 (s, 1H), 7.32 (s, 1H), 7.44 (s, 1H), 7.08 (d, J= 3.2 Hz, 1H), 2.84 (s, 2H), 2.53 (s, 2H); ES-LCMS m/z 200 ( +H) ⁺ .

XIV. 6-iodo-7,8-dihydronaphthalene-2-carbonitrile

A mixture of 7,8-dihydronaphthalene-2-carbonitrile-6-boronic acid (20 g, 100 mmol) and N- iodosuccinimide (25 g, 111 mmol) in acetonitrile (1L) was stirred at ambient temperature under nitrogen overnight. The reaction mixture was evaporated in vacuo and the residue was partitioned between DCM and IN NaOH. The layers were separated and the aqueous layer was back-extract aqueous with DCM. The combined organic layers were dried over Na ₂ SC>4, filtered and evaporated in vacuo to a solid residue. The solid was triturated with hexanes, filtered and dried under high vacuum to provide the title compound as a tan solid (19 g, 67% yield): 1H NMR (400 MHz, CDC1 ₃ ) δ ppm 7.56 (d, J= 8.8 Hz, 1H), 7.28 (s, 1H), 7.07 (s, 1H), 6.94 (d, J= 7.6 Hz, 1H), 2.86-2.77 (m, 4H); ES-LCMS m/z 282 ( +H) ⁺ .

In an alternative procedure, a solution of 6-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (50 g, 0.292 mol), ΝΗ ₂ ΝΗ ₂ ·Η ₂ 0 (87 g, 1.75 mol), Et ₃ N (236 g, 2.37 mol) and anhydrous EtOH (500 mL) was heated to reflux for 2 h. When TLC analysis showed completion of the reaction, the reaction mixture was concentrated under reduced pressure to give 6-hydrazono-5,6,7,8- tetrahydronaphthalene-2-carbonitrile (50 g), which was used immediately in the next step. To a mixture of 6-hydrazono-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (50 g) in ether (1 L) at 0°C was added the solution of I ₂ (222 g, 0.876 mol) and 1 ,1 ,3,3-tetramethylguanidine (302 g, 2.63 mol) in ether (500 mL) dropwise. After addition, the reaction mixture was stirred at room temperature overnight, with TLC analysis showing completion of the reaction. The reaction mixture was washed with 0.5 N HC1 (3 X 100 mL), 10% aq. NaS ₂ 0 ₃ (3 X 100 mL), saturated aqueous NaHC0 ₃ (2 X 100 mL) and brine (150 mL). The organic layer was dried over anhydrous a ₂ S04 and evaporated, and the residue was purified by chromatography over silica gel to give the title compound as a yellow solid (41 g, 50% yield for the 2 steps).

XV. 6-[4- {[(5-chloro-2-pyridinyl)methyl]oxy}-2-oxo-l(2H)-pyridinyl]-7 ,8- dihydronaphthalene-2-carbonitrile

A mixture of 4- {[(5-chloro-2-pyridinyl)methyl]oxy}-2(lH)-pyridinone (10 g, 42 mmol), 6- iodo-7,8-dihydronaphthalene-2-carbonitrile (12 g, 42 mmol), N,N'-dimethyl- l ,2- ethanediamine (1.5 g, 17 mmol), copper iodide (1.6 g, 8.454 mmol), powdered cesium carbonate (28 g, 85 mmol) and 2,6-di-tert-butyl-4-hydroxytoluene (37 g, 169 mmol) in toluene (400 mL) was heated under nitrogen at reflux overnight. The reaction mixture was diluted with DCM (300 mL) and filtered. The filtrate was washed with water (100 mL), dried over a ₂ S0 ₄ and concentrated. The crude product was purified by chromatography over silica gel to give the title compound as a cream- colored solid (13 g, 81% yield): 1H NMR (400 MHz, CDC1 ₃ ) δ ppm 8.57 (s, 1H), 7.71 (dd, J = 8.4 Hz, 1H), 7.50-7.42 (m, 3H), 7.19 (d, J = 6.0 Hz, 1H), 7.13 (d, J= 7.6 Hz, 1H), 6.46 (s, 1H), 6.05 (d, J = 6.4 Hz, 1H), 5.93 (s, 1H), 5.1 1 (s, 2H), 3.05 (t, J = 8.0 Hz, 2H), 2.76 (t, J= 8.2 Hz, 2H); ES-LCMS m/z 390 ( +H) ⁺ .

6-[4- { [(5-chloro-2-pyridinyl)methyl]oxy } -2-oxo- 1 (2H)-pyridinyi]-7,8- dihydronaphthalene-2-carbaldehyde

A solution of 6-[4- {[(5-chloro-2-pyridinyl)methyl]oxy}-2-oxo-l (2H)-pyridinyl]-7,8- dihydronaphthalene-2-carbonitrile (25.03 g, 64.2 mmol) in DCM (1.4 L) under nitrogen was cooled to -80°C with a dry ice/ether bath. A pre-cooled solution of diisobutylaluminium hydride in DCM (1 M, 193 mL, 193 mmol) at -80°C was added to the nitrile via canula. The reaction was stirred at -80°C for 30 min, and then quenched by dropwise addition of MeOH (10 mL). The reaction mixture was added with vigorous stirring to saturated aqueous citric acid, and the mixture was allowed to warm to ambient temperature with stirring. The mixture was transferred to a separatory funnel, the layers were separated and the aqueous phase was back-extracted with DCM. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was triturated with diethyl ether, filtered and dried at ~35°C under vacuum to provide the title compound as a yellow solid (23.56 g, 93% yield): ^! H NMR (400 MHz, CDC1 ₃ ) δ ppm 9.94 (s, 1 H), 8.57 (d, J= 2.2 Hz, 1 H), 7.72 (dd, J = 8.4, 2.4 Hz, 1 H), 7.68-7.66 (m, 2 H), 7.42 (d, J = 8.3 Hz, 1 H), 7.22- 7.19 (m, 2 H), 6.51 (s, 1 H), 6.08 (dd, J = 7.7, 2.7 Hz, 1 H), 6.01 (d, J = 2.6 Hz, 1 H), 5.14 (s, 2 H), 3.10 (t, J= 8.1 Hz, 2 H), 2.78 (t, J = 8.1 Hz, 2 H); ES-LCMS m/z 393 (M+ ) ⁺ .

In an alternative procedure conduced on a similar scale, a solution of 6-[4- {[(5-chloro-2- pyridinyl)methyl]oxy} -2-oxo- l(2H)-pyridinyl]-7,8-dihydronaphthalene-2-carbonitrile (15 g, 38.5 mmol) in DCM (840 mL) under nitrogen was cooled to -78°C with a dry ice/ether bath. A solution of diisobutylaluminium hydride (1 M, toluene, 1 16 mL, 1 16 mmol) was added dropwise. The reaction was stirred at -78°C until the reaction was complete, then quenched by dropwise addition of MeOH (12 mL). The mixture was added with vigorous stirring to a saturated aqueous citric acid solution (1500 mL), and this mixture was allowed to warm to room temperature. The layers were separated and the aqueous phase was back-extracted with DCM (3 X 400 mL). The combined organic layers were dried over Na ₂ SC>4 and condensed to give the title compound as a light yellow solid (13 g, 86% yield). 6-[4-{[(phenyl)methyi]oxy} -2-oxo- l(2H)-pyri dinyl]-7,8-dihy dronaphthalene-2- carbonitrile

A mixture of commercially-available 4-{[(phenyl)methyl]oxy}-2(iH)-pyridinone (944 mg, 4.69 mmol), 7,8-dihydronaphthalene-2-carbonitrile-6-boronic acid (1400 mg, 7.04 mmol) and dihydroxy-bis[(N,N,N',N'-tetramethylethylenediamine)copper(I I)]chloride (Cu-TMEDA catalyst, 654 mg, 1.41 mmol) in DCM (50 mL) was stirred under dry air overnight. The reaction mixture was filtered, evaporated in vacuo and purified on flash grade silica gel eluting with 25-100% EtOAc in hexanes to provide the title compound as a tan solid (615 mg, 37% yield): ^! H NMR (400 MHz, DMSO-i/ ₆ ) δ ppm 7.64-7.62 (m, 2H), 7.52 (d, J= 7.6 Hz, 1H), 7.42-7.30 (m, 6H), 6.65 (s, 1H), 6.05 (dd, J= 7.7, 2.7 Hz, 1H), 5.89 (d, J= 2.8 Hz, 1H), 5.08 (s, 2H), 2.94 (t, J= 8.1 Hz, 2H), 2.59 (t, J= 8.2 Hz, 2H); ES-LCMS m/z 355 ( +H) ⁺ .

6-[4-{[(phenyl)methyl]oxy} -2-oxo- l(2H)-pyri dinyl]-7,8-dihydronaphthalene-2- carbaldehyde

A solution of 6-[4-{[(phenyl)methyl]oxy}-2-oxo-l(2H)-pyridinyl]-7,8-dihydr onaphthalene-2- carbonitrile (200 mg, 0.564 mmol) in DCM (10 mL) was cooled to -35°C with a dry ice/isopropanol bath. A solution of diisobutylaluminium hydride in DCM (1.0 M, 1.69 mL, 1.69 mmol) was added via syringe and the reaction was stirred for ~20 min. The reaction mixture was quenched with IN NaHSC>4 and stirred for ~1 h. The organic layer was dried over anhydrous MgSC>4, filtered and evaporated in vacuo to provide the title compound as a tan solid (170 mg, 84% yield): ^! H NMR (400 MHz, DMSO-i/ ₆ ) δ ppm 9.91 (s, 1H), 7.73-7.68 (m, 2H), 7.53 (d, J= 7.7 Hz, 1H), 7.43-7.31 (m, 6H), 6.67 (s, 1H), 6.06 (dd, J= 7.7, 2.7 Hz, 1H), 5.90 (d, J = 2.7 Hz, 1H), 5.09 (s, 2H), 2.99 (t, J= 8.3 Hz, 2H), 2.61 (t, J = 8.1 Hz, 2H); ES-LCMS m/z 358 (M+ ) ⁺ .

XIX. 6-[4- {[(4-chlorophenyl)methyl]oxy} -2-oxo- 1 (2H)-pyridinyl]-7,8- dihydronaphthalene-2-carbonitrile

A degassed mixture of 4- {[(4-chlorophenyl)methyl]oxy}-2(iH)-pyridinone (1 g, 4.24 mmol), 6-iodo-7,8-dihydro-2-naphthalenecarbonitrile (1.08 g, 3.84 mmol), N,N'-dimethyl-l ,2- ethanediamine (0.2 mL), copper iodide (220 mg, 1.16 mmol), powdered cesium carbonate (2.5 g, 7.72 mmol) and 2,6-di-tert-butyl-4-hydroxytoluene (1.7 g, 7.72 mmol) in toluene (100 mL) was heated under nitrogen at reflux for 10 hours. The reaction mixture was combined with Celite, diluted with DCM and filtered through a pad of Celite. The filter cake was then re-slurried in DCM with vigorous agitation and then filtered again. The combined filtrates were evaporated in vacuo and then partitioned between DCM and 10% concentrated ΝΗ ₄ ΟΗ. The layers were separated and the aqueous layer was back-extracted with DCM. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was triturated with Et ₂ 0, filtered and dried under high vacuum to provide the title compound as a yellow solid (495 mg, 33% yield): ^! H NMR (400 MHz, CDCI ₃ ) δ ppm 7.26-7.37 (m, 7H), 7.00-7.13 (m, 1H), 6.41 -6.43 (m, 1H), 5.94-5.96 (m, 1H), 5.87 (s, 1H), 3.00 (m, 2H), 2.72 (m, 2H); ES-LCMS m/z 389 ( +H) ⁺ .

6-[4- {[(4-chlorophenyl)methyl]oxy} -2-oxo-l(2H)-pyridinyl]-7,8- dihydronaphthalene-2-carbaldehyde

A solution of 6-[4- {[(4-chlorophenyl)methyl]oxy} -2-oxo-l(2H)-pyridinyl]-7,8- dihydronaphthalene-2-carbonitrile (5.97 g, 15.35 mmol) in DCM (100 mL) under nitrogen was cooled to -80°C with a dry ice/ether bath. A pre-cooled solution of diisobutylaluminium hydride (1 m, 46 mL, 46 mmol) at -80°C was added to the nitrile via canula. The reaction was stirred at -80°C for 30 min and then quenched by dropwise addition of MeOH (10 mL). The reaction mixture was added with vigorous stirring to saturated aqueous citric acid (50 mL) and the mixture was allowed to warm to ambient temperature with stirring. The mixture was transferred to a separatory funnel, the layers were separated and the aqueous phase was back- extracted with DCM (100 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was triturated with DCM, filtered and dried at ~35°C under vacuum to provide the title compound as a yellow solid (2.3 g, 39% yield): ^! H NMR (400 MHz, CDC1 ₃ ) δ ppm 9.89 (s, 1H), 7.59-7.63 (m, 1H), 7.28-7.33 (m, 5H), 7.04-7.19 (m, 2H), 6.37-6.45 (m, 1H), 5.87-5.96 (m, 2H), 4.88-4.97 (m, 2H), 2.97- 3.07 (m, 2H), 2.65-2.75 (m, 2H); ES-LCMS m/z 392 (M+ ) ⁺ .

XXI. 6-[4- { [(5-trifluoromethyl-2-pyridinyl)methyl]oxy} -2-oxo- 1 (2H)-pyridinyl]-7,8- dihydronaphthalene-2-carbonitrile

A mixture of 4- {[(5-trifluoromethyl-2-pyridinyl)methyl]oxy}-2(lH)-pyridinon e (0.5 g, 1.85 mmol), 6-iodo-7,8-dihydronaphthalene-2-carbonitrile (0.52 g, 1.85 mmol), Cul (0.07 g, 0.37 mmol), Cs ₂ C0 ₃ (1.21 g, 3.70 mmol) and N,N'-EDA (0.07 g, 0.74 mmol) in DMF (5 mL) was stirred at room temperature overnight. LC-MS showed that the reaction was finished. The reaction was mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by preparative HPLC to give the title compound as a yellow solid (0.8 g, 100% yield): 1H MR (400 MHz CDC1 ₃ ) δ ρριη 8.88 (s, 1H), 8.01 -7.97 (m, 1H), 7.61 -7.59 (m, 1H), 7.48-7.43 (m, 2H), 7.24-7.21 (m, 1H), 7.15-7.13 (m, 1H), 6.48 (s, 1H), 6.10 (dd, J = 2.4 Hz, 5.2 Hz, 1H), 5.94 (d, J = 2.4 Hz, 1H), 5.22 (s, 2H), 3.08-3.04 (m, 2H), 2.88-2.76 (m, 2H); LC-MS m/z 424 ( +H) ⁺ .

XXII. 6-[4- {[(5-trifluoromethyl-2-pyridinyl)methyl]oxy} -2-oxo-l (2H)-pyridinyl]-7,8- dihydronaphthalene-2- carbaldehyde

To a solution of 6-[4- {[(5-trifluoromethyl-2-pyridinyl)methyl]oxy}-2-oxo- l(2H)-pyridinyl]- 7,8-dihydronaphthalene-2-carbonitrile (0.83 g, 1.96 mmol) in dry DCM (10 mL) was added DIBAl-H (1M in toluene, 5.89 mL) at -78°C. Then, the reaction mixture was stirred at -78°C for 2 h. LC-MS showed that the reaction was finished. The reaction was quenched by addition of MeOH (10 mL). The reaction mixture was concentrated under vacuum. The residue was dissolved in DCM (30 mL) and the organic phase was washed with aqueous citric acid (10 mL), aqueous NaHC0 ₃ (10 mL) and H ₂ 0 (10 mL). The organic phase was was dried over Na ₂ SC>4 and concentrated under vacuum to give the title compound as a yellow solid

(500 mg, 59.88% yield): 1H NMR (400 MHz CDC1 ₃ ) δ ppm 9.89 (s, 1H), 8.80 (d, J = 6.4 Hz, 1H), 7.93-7.91 (m, 1H), 7.62 (d, J = 6.0 Hz, 1H), 7.55-7.53 (m, 1H), 7.42-7.38 (m, 1H), 7.18- 7.15 (m, 1H), 7.12-7.05 (m, 1H), 6.47-6.38 (m, 1H), 6.05-6.00 (m, 1H), 5.89-5.87 (m, 1H), 5.23 (s, 1H), 5.17 (s, 2H), 3.08-3.00 (m, 2H), 2.76-2.65 (m, 2H); LC-MS m/z 427 (M+ ) ⁺ .

XXIII. 1 - {2-[(methylamino)methyl]-7,8-dihydronaphthalen-6-yl} -4 {hydroxy} -2(1 H)- pyridinone

A mixture of l - {2-[(methylamino)methyl]-7,8-dihydronaphthalen-6-yl} -4- {[(5-chloro-2- pyridinyl)methyl]oxy}-2(iH)-pyridinone (2.8 g, 6.86 mmol) and Zn (4.5 g, 68.6 mmol) in AcOH (50 mL) was refluxed for 2 h, then filtered and concentrated to give the title compound as a pale yellow solid (2 g, 99% yield): 1H NMR (400 MHz, MeOH-d ₄ ) δ ppm 8.38 (d, J = 2.4 Hz, 1H), 7.70 (dd, J= 8.4 Hz, 2.8 Hz, 1H), 7.46 (d, J = 7.6 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 5.82 (d, J = 2.4 Hz, 1H), 4.12 (s, 2H), 3.05 (t, J = 8.0 Hz, 2H), 2.66 (t, J = 8.0 Hz, 2H), 2.49 (s, 3H); ES-LCMS m/z 282.3 ( +H) ⁺ .

1 - {2-[(methyl{ [(tertiarybutyl)oxy]carbonyl} amino)methyi]-7,8- dihydronaphthalen-6-yl} -4- {hydroxy} -2(iH)-pyridinone

A mixture of 1 - {2-[(methylamino)methyl]-7,8-dihydronaphthalen-6-yl} -4 {hydroxy} -2(1 H)- pyridinone (2 g, 7.08 mmol), (Boc) ₂ 0 (2.32 g, 10.6 mmol) and NaOH (850 mg, 21.3 mmol) in MeOH/H ₂ 0 (1/1 , 40 mL) was stirred at room temperature for 16 h, then filtered and purified by column chromatography on silica gel (DCM/MeOH, 50: 1) to give the title compound as a pale yellow solid (1 g, 37% yield): 1H NMR (400 MHz, MeOH-d ₄ ) δ ppm 7.47 (d, J = 7.6 Hz, 1H), 7.12-7.03 (m, 3H), 6.53 (s, 1H), 6.10 (dd, J = 7.6 Hz, 2.4 Hz, 1H), 5.82 (d, J = 2.4 Hz, 1H), 4.39 (s, 2H), 3.02 (t, J = 8.0 Hz, 2H), 2.82 (s, 3H), 2.64 (t, J = 8.0 Hz, 2H); ES-LCMS m/z 383.2 ( +H) ⁺ . l - {2-[(methyl{[(tertiarybutyl)oxy]carbonyl}amino)methyl]-7,8-d ihydronaphthalen- 6-yl} -4- { [(5-trifluoromethyl-2-pyridinyl)methyl]oxy} -2(iH)-pyridinone

A mixture of 2-(methansulfonyloxymethyl)-5-trifiuoromethylpyridine (66.73 mg, 0.26 mmol), l - {2-[(methyl{[(tertiarybutyl)oxy]carbonyl}amino)methyl]-7,8-d ihydronaphthalen-6-yl} -4- {hydroxy} -2(iH)-pyridinone (100 mg, 0.26 mmol) and K ₂ C0 ₃ (71.76 mg, 0.52 mmol) in DMF (20 mL) was refluxed overnight. LC-MS showed that the reaction was finished. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by preparative HPLC to give the title compound as a yellow solid (50 mg, 35.6% yield): 'H NMR (400 MHz MeOH-d ₄ ) δ ρριη 8.89 (s, 1H), 8.20-8.18 (m, 1H), 7.80-7.78 (m, 1H), 7.57-7.55 (m, 1H), 7.14-7.12 (m, 1H), 7.08-7.03 (m, 2H), 6.55 (s, 1H), 6.31-6.29 (m, 1H), 6.02 (d, J = 2.8 Hz, 1H), 5.33 (s, 2H), 4.40 (s, 2H), 3.08-2.98 (m, 2H), 2.84-2.79 (m, 3H), 2.70-2.60 (m, 2H), 1.50-1.40 (m, 9H); LC-MS m/z 542 ( +H) ⁺ .

XXVI. 1 - {2-[(morpholin-4-yl)methyl]-7,8-dihydronaphthalen-6-yl} -4- {hydroxy} -2(1 H)- pyridinone

A solution of l- {2-[(morpholin-4-yl)methyl]-7,8-dihydronaphthalen-6-yl}-4- {[(5-chloro-2- pyridinyl)methyl]oxy}-2(iH)-pyridinone (2 g, 4.3 mmol) and Zn (2.8 g, 43 mmol) in HOAc (20 mL) was stirred at reflux. After 2 h, the mixture was filtered, and the filtrate was concentrated to give the crude product, which was purified by preparative HPLC to afford the title compound (1.0 g, 69% yield): ^! H NMR (400 MHz, MeOH-d ₄ ) δ ppm 7.37 (d, J = 7.6 Hz, 1H), 7.23-7.21 (m, 2H), 7.15 (d, J = 8.0 Hz, 1H), 6.49 (s, 1H), 6.00 (dd, J = 7.4, 2.6 Hz, 1H), 5.72 (d, J = 2.4 Hz, 1H), 4.21 (s, 2H), 3.94-3.91 (m, 2H), 3.64-3.57 (m, 2H), 3.28-3.25 (m, 2H), 3.1 1-3.05 (m, 2H), 2.96 (t, J = 8.2 Hz, 2H), 2.57 (t, J = 8.2 Hz, 2H); ES-LCMS m/z 339.2 ( +H) ⁺ .

Examples Example 1 : 4-(benzyloxy)- 1 -(6- { [(3R)-3-hydroxypyrrolidin- 1 -yl]methyl} -3,4-dihydronaphthalen- 2-yl)pyridin-2(lH)-one

A mixture of 6-[4- {[(phenyl)methyl]oxy}-2-oxo-l(2H)-pyridinyl]-7,8-dihydronaph thalene-2- carbaldehyde (25 mg, 0.070 mmol), sodium triacetoxyborohydride (30 mg, 0.14 mmol) and (3i?)-3-pyrrolidinol (12 mg, 0.14 mmol) were combined in DCM and stirred at ambient temperature overnight. The filtrate was washed with 5% w/v aq. Na ₂ C0 ₃ and the layers were separated. The organic phase was back-extracted twice with DCM and the combined organic layers were dried over anhydrous Na ₂ SC>4, filtered, evaporated in vacuo and triturated with Et ₂ 0. The resulting slurry was filtered and the product was dried under high vacuum to provide the title compound as an off-white solid (22 mg, 73% yield): 1H NMR (400 MHz,

MeOH-d ₄ ) δ ppm 7.50 (d, J= 7.5 Hz, 1H), 7.43-7.30 (m, 5H), 7.17-7.13 (m, 2H), 7.09 (d, J = 7.7 Hz, 1H), 6.53 (s, 1H), 6.20 (dd, J= 7.7, 2.6 Hz, 1H), 6.01 (d, J= 2.6 Hz, 1H), 5.11 (s, 2H), 4.32 (m, 1H), 3.60 (m, 2H), 3.01 (t, J= 8.3 Hz, 2H), 2.79 (m, 1H), 2.71 (m, 1H), 2.63 (t, J= 8.1 Hz, 2H), 2.54 (m, 1H), 2.46 (m, 1H), 2.12 (m, 1H), 1.69 (m, 1H); ES-LCMS m/z 429 (M+H) ⁺ .

Examples 2-4 (Table 1) were prepared using procedures analogous to those described in

Example 1 using starting materials such as 6-[4-{[(phenyl)methyl]oxy}-2-oxo-l(2H)- pyridinyl]-7,8-dihydronaphthalene-2-carbaldehyde and the appropriate amines. The requisite amines utilized herein were purchased if available commercially, were synthesized as

described in the literature or by routine modifications thereof, or were synthesized as detailed in the Intermediates section above. As is appreciated by those skilled in the art, these

analogous examples may involve variations in general reaction conditions. Table 1.

Example 5 : 4-[(4-chlorobenzyl)oxy]-l - {6-[(dimethylamino)methyl]-3,4-dihydronaphthalen- 2-yl}pyridin-2(lH)-one trifluoroacetate

A mixture of 6-[4- {[(4-chlorophenyl)methyl]oxy}-2-oxo-l(2H)-pyridinyl]-7,8- dihydronaphthalene-2-carbaldehyde (200 mg, 0.51 mmol) and dimethylamine (62 mmol) were combined in DCM and stirred at ambient temperature for 2 h. Then sodium triacetoxyborohydride (324 mg, 1.53 mmol) was added to the mixture and stirred overnight. The reaction mixture was diluted with DCM and combined with anhydrous Na ₂ S0 ₄ and Celite and then filtered. The filtrate was evaporated in vacuo and purified by preparative HPLC to provide the title compound (27.74 mg, 14% yield): ^! H NMR (400 MHz, MeOH-d ₄ ) δ ppm 7.27-7.53 (m, 8H), 6.62 (m, 1H), 6.22-6.25 (m, 1H), 6.02-6.03 (m, 1H), 5.12 (s, 2H), 4.27 (s, 2H), 3.06-3.08 (m, 2H), 2.85 (s, 6H), 2.67-2.69 (m, 2H); ES-LCMS m/z 421 (M+H) ⁺ .

Example 6: 4- [(4-chlorobenzyl)oxy] - 1 - [6-( { [2-(propan-2-ylamino)ethyl] amino } methyl)-3 ,4- dihydronaphthalen-2-yl]pyridin-2( 1 H)-one dihydrochloride

To a solution of 2-[isopropyl{[tertiarybutyloxy]carbonyl}amino]ethylamine (70 mg, 0.35 mmol) in DCM (2 mL) was added 6-[4-{[(4-chlorophenyl)methyl]oxy}-2-oxo-l(2H)- pyridinyl]-7,8-dihydronaphthalene-2-carbaldehyde (136 mg, 0.35 mmol). The reaction mixture was stirred at room temperature overnight. Then sodium triacetoxyborohydride (0.183 g, 0.87 mmol) was added to the mixture, which was stirred for 16 h. The mixture was filtered, and the filtrate was concentrated and purified by HPLC to afford l-{2-[{2- [isopropyl(tertiarybutyloxycarbonyl)amino]ethylamino}methyl] -7,8-dihydronaphthalen-6- yl}-4-{[(4-chlorophenyl)methyl]oxy}-2(iH)-pyridinone (0.03 g, 15 % yield): 1H NMR (400 MHz, MeOH-d ₄ ) δ ppm 8.52-8.53 (d, J= 2.0 Hz, 1H), 7.66-7.69 (m, 1H), 7.36-7.38 (d, J = 8.0 Hz, 1H), 7.19-7.20 (m, 1H), 7.13-7.15 (m, 2H), 7.01-7.03 (d, J= 8.0 Hz, 1H), 6.39 (s, 1H), 6.04-6.09 (m, 2H), 5.09 (s, 2H), 3.90-4.06 (m, 3H), 3.31-3.34 (m, 2H), 3.09 (s, 2H), 2.93-2.95 (m, 2H), 2.64-2.68 (m, 2H), 1.38 (s, 9H), 0.98-0.99 (d, J= 7.2 Hz, 6H); ES-LCMS m/z 579 (M+H) ⁺ .

A solution of l-{2-[{2-[isopropyl(tertiarybutyloxycarbonyl)amino]ethylamin o}methyl]-7,8- dihydronaphthalen-6-yl}-4-{[(4-chlorophenyl)methyl]oxy}-2(iH )-pyridinone (30 mg, 0.05 mmol) in HCl-Et ₂ 0 (3 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated to afford the title compound (16.04 mg, 59% yield): 1H NMR (400 MHz, MeOH-d ₄ ) δ ρριη 8.73-8.74 (d, J= 2.0 Hz, 1H), 8.14-8.16 (m, 1H), 7.72-7.77 (m, 2H), 7.40- 7.43 (m, 2H), 7.25-7.27 (m, 1H), 6.67 (s, 1H), 6.48-6.51 (m, 1H), 6.22-6.23 (m, 1H), 5.36 (s, 2H), 4.28 (s, 2H), 3.44-3.46 (m, 5H), 3.07-3.1 1 (m, 2H), 2.68-2.72 (m, 2H), 1.36-1.37 (d, J = 12 Hz, 6H); ES-LCMS m/z 478 (M+H) ⁺ .

Examples 7-21 (Table 2) were prepared using procedures analogous to those described in Example 5 using starting materials such as 6-[4-{[(4-chlorophenyl)methyl]oxy}-2-oxo-l(2H)- pyridinyl]-7,8-dihydronaphthalene-2-carbaldehyde and the appropriate amines. The requisite amines utilized herein were purchased if available commercially, were synthesized as described in the literature or by routine modifications thereof, or were synthesized as detailed in the Intermediates section above. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions.

Table 2.

yl)pyridin-2(l H)-one 6.24 (dd, J= 2.4,d 7.6 Hz,

trifluoroacetate 1H), 6.04-6.03 (d, .7= 2.4

Hz, 1H), 4.57-4.29 (m,

3H), 3.70-3.45 (m, 2H),

3.11 -3.03 (t, .7= 8.2 Hz,

2H), 2.73-2.68 (t, .7= 8.2

Hz, 2H), 2.42-2.03 (m, 2H)

Examples 22-29 (Table 3) were prepared using procedures analogous to those described in Example 6 using starting materials such as 6-[4- {[(4-chlorophenyl)methyl]oxy}-2-oxo-l(2H)- pyridinyl]-7,8-dihydronaphthalene-2-carbaldehyde and the appropriate amines. The requisite amines utilized herein were purchased if available commercially, were synthesized as described in the literature or by routine modifications thereof, or were synthesized as detailed in the Intermediates section above. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions.

Table 3.

Example 30: 4-[(5-chloropyridin-2-yl)methoxy]- 1 -[6-(pyrrolidin- 1 -ylmethyl)-3,4- dihydronaphthalen-2-yl]pyridin-2 lH)-one bis(trifluoroacetate)

A mixture of 6-[4-{[(5-chloro-2-pyridinyl)methyl]oxy}-2-oxo-l(2H)-pyridin yl]-7,8- dihydronaphthalene-2-carbaldehyde (30 mg, 0.076 mmol), sodium triacetoxyborohydride (32 mg, 0.15 mmol) and pyrrolidine (13 uL, 0.15 mmol) were combined in DCM (2 mL) and stirred at ambient temperature overnight. The reaction was diluted with DCM and washed with 5% w/v aqueous K ₂ CO ₃ . After separating the layers, the aqueous phase was back- extracted with DCM. The combined organic layers were dried over anhydrous Na ₂ S0 ₄ , filtered and evaporated in vacuo. The residue was triturated with ether, filtered and the product was dried under high vacuum to provide the title compound as a white solid (25 mg, 69% yield): ^! H NMR (400 MHz, MeOH-c ) δ ppm 8.55 (d, J= 2.4 Hz, 1H), 7.89 (dd, J= 8.4,

2.5 Hz, 1H), 7.55 (d, J= 8.4 Hz, 1H), 7.51 (d, J= 7.6 Hz, 1H), 7.16-7.12 (m, 2H), 7.08 (d, J =

7.6 Hz, 1H), 6.53 (s, 1H), 6.23 (dd, J= 7.6, 2.7 Hz, 1H), 5.99 (d, J= 2.6 Hz, 1H), 5.19 (s, 2H), 3.59 (s, 2H), 3.00 (t, J= 8.3 Hz, 2H), 2.62 (t, J= 8.2 Hz, 2H), 2.53 (m, 4H), 1.79 (m, 4H); ES-LCMS m/z 448 (M+H) ⁺ .

In an alternative procedure, a mixture of 6-[4-{[(5-chloro-2-pyridinyl)methyl]oxy}-2-oxo- l(2H)-pyridinyl]-7,8-dihydronaphthalene-2-carbaldehyde (40 mg, 0.10 mmol) and pyrrolidine (7.11 mg, 0.10 mmol) in CH ₂ CI ₂ (5 mL) was stirred at room temperature for 2 h. Then, 4A molecule sieves (0.1 g) were added, and the mixture was stirred for a further 2 hours. Sodium triacetoxyborohydride (42.39 mg, 0.20 mmol) was added, and the mixture was stirred at room temperature overnight. After LC-MS showed that the reaction was complete, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound as an off-white solid (25 mg, 55.9% yield).

Example 31 : 4- [(5 -chloropyridin-2-yl)methoxy] - l- {6-[(l S ,4S)-2 ,5-diazabicyclo [2.2.1 ]hept- 2-ylmethyl]-3,4-dihydronaphthalen-2- l}pyridin-2(lH)-one tris(trifluoroacetate)

To a suspension of 6-[4- {[(5-chloro-2-pyridinyl)methyl]oxy}-2-oxo-l(2H)-pyridinyl]-7 ,8- dihydronaphthalene-2-carbaldehyde (40 mg, 0.1 mmol) and (lS,4S)-2-

{[(tertiarybutyl)oxy]carbonyl}-2,5-diazabicyclo[2.2.1]hep tane (29.74 mg, 0.15 mmol) in DCE (5 mL) was added sodium triacetoxyborohydride (63.6 mg, 0.3 mmol), and the resulting mixture was stirred at room temperature overnight. The reaction mixture was treated with 5 mL of aqueous saturated NaHC0 ₃ solution, was extracted with DCM (10 mL), was dried over a ₂ S04, was filtered and concentrated in vacuo to give crude l-{2-[{(15',45 -2- {[(tertiarybutyl)oxy]carbonyl}-2,5-diazabicyclo[2.2.1]heptan -5-yl}methyl]-7,8- dihydronaphthalen-6-yl} -4- { [(5-chloro-2-pyridinyl)methyl]oxy} -2(iH)-pyridinone (40 mg, 75% yield); ES-LCMS m/z 575 (M+H) ⁺ .

1 - {2-[ {(lS,4S)-2- {[(tertiarybutyl)oxy]carbonyl}-2,5-diazabicyclo[2.2. l]heptan-5-yl}methyl]- 7,8-dihydronaphthalen-6-yl} -4- { [(5-chloro-2-pyridinyl)methyl]oxy} -2(iH)-pyridinone (40 mg, 0.07 mmol) was dissolved in 20% TFA DCM solution (30 mL), and the mixture was stirred at 0°C for 1 h. After TLC showed the starting material was consumed, the solvent was removed in vacuo to give the crude product, which was purified by preparative HPLC to afford the title compound (34.2 mg, 100% yield): 1H NMR (400 MHz, MeOH-d δ ppm 8.57 (d, J= 2.4 Hz, 1H), 7.92 (dd, J= 8.2, 2.6 Hz, 1H), 7.56 (m, 2H), 7.37 (d, J= 8.4 Hz, 2H), 7.24 (d, J= 7.6 Hz, 1H), 6.61 (s, 1H), 6.27 (dd, J= 7.6, 2.8 Hz, 1H), 6.02 (s, 1H), 5.26 (s, 2H), 4.60 (s, 1H), 4.52-4.59 (m, 2H), 4.37 (d, J= 12.8 Hz, 1H), 3.86 (d, J= 5.6 Hz, 1H), 3.67 (m, 1H), 3.54 (m, 2H), 3.09 (m, 2 H), 2.65 (m, 3H), 2.27 (d, J= 12.8 Hz, 1H); ES-LCMS m/z 475 (M+H) ⁺ .

Example 32: l-(6-{[(2-aminoethyl)(methyl)amino]methyl}-3,4-dihydronaphth alen-2-yl)-4- [(5-chloropyridin-2-yl)methoxy]pyridin-2(lH)-one tris(trifluoroacetate)

A solution of 6-[4-{[(5-chloro-2-pyridinyl)methyl]oxy}-2-oxo-l(2H)-pyridin yl]-7,8- dihydronaphthalene-2-carbaldehyde (60 mg, 0.153 mmol) and 2,2,2-trifiuoro-N-(2- (methylamino)ethyl)acetamide (51.9 mg, 0.305 mmol) in DCM (5 mL) was stirred at room temperature for 2 h. Then sodium triacetoxyborohydride (97.1 mg, 0.458 mmol) was added to the solution and the reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with H ₂ 0 (20 mL) and the aqueous phase was extracted with DCM (2 X 20 mL). The combined organic phase was dried over a ₂ S0 ₄ and concentrated in vacuo to give the residue, which was purified by preparative TLC to give l-{2-[{methyl(2- trifluoroacetamidoethyl)amino}methyl]-7,8-dihydronaphthalen- 6-yl}-4- {[(5-chloro-2- pyridinyl)methyl]oxy}-2(;H)-pyridinone (50 mg, 60% yield): 1H NMR (400 MHz, CD ₃ OD) δ ppm 8.58 (d, J= 2.00 Hz, 1H), 7.91 (dd, J= 8.40, 2.40 Hz, 1H), 7.53-7.59 (m, 2H), 7.08-7.16 (m, 3H), 6.55 (s, 1H), 6.26 (dd, J= 7.60, 2.80 Hz, 1H), 6.02 (d, J= 2.40 Hz, 1H), 5.21 (s, 2H), 3.55 (s, 2H), 3.42 (t, J= 6.60 Hz, 2H), 3.02 (t, J= 8.20 Hz, 2H), 2.65 (t, J= 8.20 Hz, 2H), 2.71 (t, J= 6.60 Hz, 2H), 2.28 (s, 3H); ES-LCMS m/z 547 (M+H) ⁺ . l-{2-[{Methyl(2 rifluoroacetamidoethyl)amino}methyl]-7,8-dihydronaphthalen-6 -yl}-4- {[(5-chloro-2-pyridinyl)methyl]oxy}-2(iH)-pyridinone (50 mg, 0.091 mmol) was dissolved in concentrated ΝΗ ₃ /Η ₂ Ο (3 mL) and MeOH (0.5 mL), then the mixture was stirred overnight. The mixture was concentrated and the aqueous phase was extracted with DCM (2 X 20 mL). The combined organic phase was dried over Na ₂ S0 ₄ and concentrated in vacuo to give the residue, which was purified by preparative HPLC to provide the title compound (30.27 mg, 73.4% yield): ^! H NMR (400 MHz, CD ₃ OD) δ ppm 8.58 (d, J= 2.40 Hz, 1H), 7.93 (dd, J = 8.40, 2.40 Hz, 1H), 7.53-7.59 (m, 2H), 7.34 (d, J= 9.20 Hz, 2H), 7.26 (d, J= 8.00 Hz, 1H), 6.62 (s, 1H), 6.28 (dd, J= 7.20, 2.40 Hz, 1H), 6.03 (d, J= 2.40 Hz, 1H), 5.22 (s, 2H), 4.31 (s, 2H), 3.38 (m, 4H), 3.07 (t, J= 8.20 Hz, 2H), 2.82 (s, 3H), 2.68 (t, J= 8.00 Hz, 2H); ES- LCMS m/z 451 (M+H) ⁺ .

Example 33: 4-[(5-chloropyridin-2-yl)methoxy]-l-[6-({methyl[2-(pyrrolidi n-l- yl)ethyl]amino}methyl)-3,4-dih dronaphthalen-2-yl]pyridin-2(lH)-one tris(trifluoroacetate)

To a mixture of l-{2-[{(2-[pyrrolidin-l-yl]ethyl)amino}methyl]-7,8-dihydrona phthalen-6- yl}-4-{[(5-chloro-2-pyridinyl)methyl]oxy}-2(iH)-pyridinone (75 mg, 0.15 mmol), formaldehyde (62 mg, 0.76 mmol, 37% in H ₂ 0) and formic acid (42 mg, 0.92 mmol) in MeOH (10 mL) was added sodium cyanoborohydride (24 mg, 0.38 mmol). The mixture was stirred at room temperature for 3 h. The mixture was concentrated and purified by preparative HPLC to provide the title compound as a yellow oil (43.2 mg, 56% yield): ^! H NMR (400 MHz, CD ₃ OD) δ ppm 8.58 (dd, J= 2.4 Hz, 0.4 Hz, 1H), 7.91 (dd, J= 8.4 Hz, 2.4 Hz, 1H), 7.58 (dd, J= 8.4 Hz, 0.4 Hz, 1H), 7.54 (d, J= 7.6 Hz, 1H), 7.36 (d, J= 7.6 Hz, 2H), 7.28 (d, J = 7.6 Hz, 1H), 6.62 (s, 1H), 6.28 (dd, J= 7.6 Hz, 2.8 Hz, 1H), 6.03 (d, J= 2.8 Hz, 1H), 5.22 (s, 2H), 4.34 (s, 2H), 3.68-3.76 (m, 2H), 3.52-3.59 (m, 2H), 3.32-3.47 (m, 4H), 3.03-3.11 (m, 2H), 2.83 (s, 3H), 2.65-2.69 (m, 2H), 2.11 (d, J= 2.8 Hz, 4H); ES-LCMS m/z 505 (M+H) ⁺ . Example 34: 4-[(5-chloropyridin-2-yl)methoxy]-l-[6-({methyl[(3S)-morphol in-3- ylmethyl]amino}methyl)-3,4- ihydronaphthalen-2-yl]pyridin-2(lH)-one tris(trifluoroacetate)

A mixture of 6-[4-{[(5-chloro-2-pyridinyl)methyl]oxy}-2-oxo-l(2H)-pyridin yl]-7,8- dihydronaphthalene-2-carbaldehyde (50 mg, 0.13 mmol) and (35)-3-aminomethyl-4- {[(tertiarybutyl)oxy]carbonyl}morpholine (54 mg, 0.19 mmol) in DCM (2 mL) was stirred at room temperature for 4 h. Then sodium triacetoxyborohydride (42 mg, 0.25 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was washed with water (5 mL) and the organic layer was dried over anhydrous Na ₂ S0 ₄ , filtered and evaporated in vacuo to give l-{2-[{(35)-[{(4-{[(tertiarybutyl)oxy]carbonyl}morpholin-3- yl)methyl}amino]}methyl]-7,8-dihydronaphthalen-6-yl}-4- {[(5-chloro-2- pyridinyl)methyl]oxy}-2(;H)-pyridinone (50 mg, 64.8% yield): 1H NMR (400 MHz, CD ₃ OD) 8 ppm 8.51 (d, J= 2.0 Hz, 1H), 7.65 (d, J= 8. 4 Hz, 1H), 7.35 (d, J= 8.0 Hz, 1H), 7.20 (m, 1H), 7.11 (m, 2H), 7.06 (m, 1H), 6.37 (d, J= 8.0 Hz, 1H), 5.98 (d, J= 7.6 Hz, 1H), 5.90 (d, J= 2.8 Hz, 1H), 5.23 (s, 2H), 2.97-2.95 (m, 3H), 2.68-2.64 (m, 3H), 2.38-2.33 (m, 9H), 1.45-1.36 (m, 9H); ES-LCMS m/z 594 (M+H) ⁺ .

A mixture of l-{2-[{(35)-[{(4-{[(tertiarybutyl)oxy]carbonyl}morpholin-3- yl)methyl}amino]}methyl]-7,8-dihydronaphthalen-6-yl}-4- {[(5-chloro-2- pyridinyl)methyl]oxy}-2(iH)-pyridinone (50 mg, 0.08 mmol), formaldehyde (12.6 mg, 0.4 mmol), formic acid (19.4 mg, 0.4 mmol) and sodium cyanoborohydride (34 mg, 0.16 mmol) in MeOH (1 mL) was stirred at room temperature for 2 h. The solvent was evaporated under reduced pressure and the crude product (55 mg, 100%) was dissolved in DCM (4 mL). TFA (1 mL) was added at 0°C and the mixture was stirred at room temperature for 3 h. The solvent was evaporated under reduced pressure to give the residue, which was purified by preparative HPLC to provide the title compound (11.3 mg, 24.8% yield): ^! H NMR (400 MHz, CD ₃ OD) δ ppm 8.57 (d, J= 2.0 Hz, 1H), 7.92 (dd, J= 8.2, 2.4 Hz, 1H), 7.58 (d, J= 8.2 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.34-7.30 (m, 2H), 7.22 (d, J= 7.6 Hz, 1H), 6.60 (s, 1H), 6.28 (dd, J = 7.6, 2.8 Hz, 1H), 6.03 (d, J = 2.8 Hz, 1H), 5.22 (s, 2H), 4.22-4.03 (m, 3H), 4.03-3.74 (m, 4H), 3.58-3.5 (m, 1H), 3.28-3.24 (m, 2H), 3.07-3.04 (m, 3H), 2.72-2.66 (m, 5H); ES- LCMS m/z 507 (M+H) ⁺ .

Example 35: 4-[(5-chloropyridin-2-yl)methoxy]-l -(6- {[(3S,4S)-3-(dimethylamino)-4- hydroxypyrrolidin-l-yl]methyl} -3,4-dihydronaphthalen-2-yl)pyridin-2(lH)-one

trihydrochloride

A mixture of 6-[4- {[(5-chloro-2-pyridinyl)methyl]oxy}-2-oxo-l(2H)-pyridinyl]-7 ,8- dihydronaphthalene-2-carbaldehyde (39 mg, 0.4 mmol) and (35,45)-3-hydroxy-4- {[methyl[(benzyl)oxy]carbonyl]amino}pyrrolidine (100 mg, 0.4 mmol) in DCM (5 mL) was stirred at room temperature overnight. Sodium triacetoxyborohydride (84 mg, 0.4 mmol) was added to the mixture and it was stirred for another 2 h. The reaction was filtered, the filtrate was concentrated and purified by TLC (DCM/MeOH, 10: 1) to provide crude 1 - {2-[ {(35,45)- 3-hydroxy-4- {[methyl[(benzyl)oxy]carbonyl]amino}pyrrolidin-l-yl}methyl]- 7,8- dihydronaphthalen-6-yl} -4- { [(5-chloro-2-pyridinyl)methyl]oxy} -2(iH)-pyridinone (64 mg, 100% yield).

A mixture of l - {2-[ {(35,45)-3-hydroxy-4- {[methyl[(benzyl)oxy]carbonyl]amino}pyrrolidin- 1 -yl}methyl]-7,8-dihydronaphthalen-6-yl} -4- { [(5-chloro-2-pyridinyl)methyl]oxy} -2(1 H)- pyridinone (64 mg,0.1 mmol) in TMSI-CH ₃ CN (1 N, 1 mL, 5 mL) was stirred at room temperature for 1 h. The mixture was washed with PE (5 mL), and the residue was purified by preparative HPLC to provide l- {2-[ {(35,45)-3-hydroxy-4- {methylamino}pyrrolidin-l- yl}methyl]-7,8-dihydronaphthalen-6-yl}-4- {[(5-chloro-2-pyridinyl)methyl]oxy} -2(iH)- pyridinone (24.95 mg, 51% yield): ^! H NMR (400 MHz, CD ₃ OD) δ ppm 8.59 (s, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.61 -7.59 (m, 2H), 7.35 (m, 2H), 7.19 (d, J = 7.6 deHz, 1H), 6.57 (s, 1H), 6.32 (d, J= 12 Hz, 1H), 6.06 (s, 1H), 5.22 (s, 2H), 4.64 (s, 1H), 4.44 (s, 2H), 3.98-3.22 (m, 5H), 3.01 (t, J= 8.4 Hz, 2H), 2.74 (s, 3H), 2.62 (t, J= 8.4 Hz, 2H); ES-LCMS m/z 493 (M+H) ⁺ .

To a mixture of l-{2-[{(35',45 -3-hydroxy-4-{methylamino}pyrrolidin-l-yl}methyl]-7,8- dihydronaphthalen-6-yl} -4- { [(5-chloro-2-pyridinyl)methyi]oxy} -2(7H)-pyridinone (20 mg, 0.04 mmol), HCHO (37% aqueous, 16.6 mg, 0.205 mmol) and HCOOH (9.4 mg, 0.205 mmol) in MeOH (5 mL) was added sodium cyanoborohydride (5 mg, 0.082 mmol). The mixture was filtered, the filtrate was concentrated and purified by preparative HPLC to provide the title compound (21 mg, 100% yield): ^! H NMR (400 MHz, CD ₃ OD) δ ppm 8.70 (s, 1H), 8.12-8.09 (m, 1H), 7.73-7.68 (m, 2H), 7.43-7.41 (m, 2H), 7.27 (d, J= 7.6 Hz, 1H), 6.67 (s, 1H), 6.46-6.44 (m, 1H), 6.18 (d, J= 2.4 Hz, 1H), 5.34 (s, 2H), 4.49 (s, 2H), 4.02-3.75 (m, 4H), 3.46-3.37 (m, 1H), 3.10-3.01 (m, 9H), 2.70 (t, J= 8.0 Hz, 2H); ES-LCMS m/z 507 (M+H) ⁺ .

Example 36: N-[(6-{4-[(5-chloropyridin-2-yl)methoxy]-2-oxopyridin-l(2H)- yl}-7,8- dihydronaphthalen-2-yl)methyl]-N-methylmethanesulfonamide trifluoroacetate

To a solution of 4-[(5-chloropyridin-2-yl)methoxy]-l-{6-[(methylamino)methyl] -3,4- dihydronaphthalen-2-yl}pyridin-2(lH)-one (20 mg, 0.05 mmol) and triethylamine (7 mg, 0.07 mmol) in DCM (3 mL) was added methanesulfonyl chloride (7 mg, 0.06 mmol) at 0°C, then the reaction mixture was stirred at room temperature. After 2 h, the solvent was removed, the crude product was purified by preparative HPLC to afford the title compound (2.27 mg, 9.4% yield): 1H NMR (400 MHz, CD ₃ OD) δ ppm 8.50 (d, J= 2.0 Hz, 1H), 7.84 (dd, J= 8.4, 2.4 Hz, 1H), 7.52-7.47 (m, 2H), 7.14-7.07 (m, 3H), 6.50 (s, 1H), 6.20 (dd, J= 7.8, 2.6 Hz, 1H), 5.95 (d, J= 2.4 Hz, 1H), 5.15 (s, 2H), 4.19 (s, 2H), 2.97 (t, J

(s, 3H), 2.59 (t, J= 6.4 Hz, 2H); ES-LCMS m/z 486 (M+H) ⁺

Examples 37-255 (Table 4) were prepared using procedures analogous to those described in Examples 30-36 using starting materials such as 6-[4-{[(5-chloro-2-pyridinyl)methyl]oxy}-2- oxo-l(2H)-pyridinyl]-7,8-dihydronaphthalene-2-carbaldehyde and the appropriate amines. The requisite amines utilized herein were purchased if available commercially, were synthesized as described in the literature or by routine modifications thereof, or were synthesized as detailed in the Intermediates section above. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions.

Table 4.

- Ill -

a Chiral, undetermined absolute configuration. Chiral separation: Chiralcel OD-H 150x4.6 mm, 5 urn; 40% IPA (0.05% DEA)/C0 ₂ , 2.35 mL/min; λ: 220.

b Chiral separation: Chiralpak AD-H 100x4.6 mm, 5 urn; 45% IPA (0.05% DEA)/C0 ₂ , 4.5 mL/min; λ: 220.

c Chiral, undetermined absolute configuration. Chiral separation: Chiralcel OJ-H 250x4.6 mm, 5 urn; 5-40% IPA (0.05% DEA)/C0 ₂ , 2.35 mL/min; λ: 220.

Example 256: 1 -(6- { [( 1 , 1 -dioxidotetrahydro-2H-thiopyran-4-yl)amino]methyl} -3,4- dihydronaphthalen-2-yl)-4-{[5-(trifluoromethyl)pyridin-2-yl] methoxy}pyridin-2(lH)-one dihydrochloride

A mixture of 6-[4- {[(5-trifluoromethyl-2-pyridinyl)methyl]oxy}-2-oxo-l (2H)-pyridinyl]-7,8- dihydronaphthalene-2- carbaldehyde (0.5 g, 1.17 mmol), tetrahydro-l ,l-dioxido-2H- thiopyran-4-ylamine (0.26 g, 1.404 mmol) and Et ₃ N (0.24 g, 2.34 mmol) in dry DCM (10 mL) was stirred at room temperature overnight. Then, to the reaction mixture was added NaHB(OAc) ₃ (0.50 g, 2.34 mmol), the mixture was stirred at room temperature overnight. LC-MS showed that the reaction was finished. The reaction mixture was dissolved in DCM (30 mL). The organic phase was washed with H ₂ 0 (3 X 10 mL). The organic phase was dried over a ₂ S0 ₄ and concentrated under vacuum. The residue was purified by preparative HPLC to give the title compound as a white solid (140 mg, 21.4% yield): ^! H NMR (400 MHz, MeOH-d ₄ ) δ ρριη 8.90 (s, 1H), 8.21 -8.18 (m, 1H), 7.78-7.76 (m, 1H), 7.58-7.56 (m, 1H), 7.33-7.32 (m, 2H), 7.26-7.24 (m, 1H), 6.62 (s, 1H), 6.32 (dd, J = 2.8 Hz, 4.8 Hz, 1H), 6.04 (d, J = 2.4 Hz, 1H), 5.34 (s, 2H), 4.24 (s, 2H), 3.57-3.48 (m, 2H), 3.32-3.30 (m, 1H), 3.20-3.16 (m, 2H), 3.09-3.05 (m, 2H), 2.71-2.64 (m, 2H), 3.59-3.51 (m, 2H), 2.30-2.13 (m, 2H); LC-MS m/z 560 ( +H) ⁺ .

Example 257: 1 - {6-[(methylamino)methyl]-3,4-dihydronaphthalen-2-yl} -4- {[5- (trifluoromethyl)pyridin-2-yl]methoxy}pyridin-2(lH)-one dihydro chloride

A solution of l - {2-[(methyl{[(tertiarybutyl)oxy]carbonyl}amino)methyl]-7,8- dihydronaphthalen-6-yl} -4- { [(5-trifluoromethyl-2-pyridinyl)methyl]oxy} -2(iH)-pyridinone (50 mg, 92.38 mmol) in HCl/MeOH (10 mL) was stirred at room temperature for 3 h. LC-MS showed that the reaction was finished. The mixture was concentrated under vacuum and the residue was purified by preparative HPLC to give the title compound as a yellow solid (12 mg, 29.46% yield): 1H NMR (400 MHz, MeOH-d ₄ ) δ ppm 8.91 (s, 1H), 8.21 (dd, J= 2.0 Hz, 6.4 Hz, 1H), 7.80-7.78 (m, 1H), 7.63-7.61 (m, 1H), 7.30-7.29 (m, 2H), 7.25-7.23 (m, 1H), 6.63 (s, 1H), 6.38-6.36 (m, 1H), 6.09 (d, J = 1.6 Hz, 1H), 5.36 (s, 2H), 4.14 (s, 2H), 3.09-3.05 (m, 2H), 2.70-2.66 (m, 5H); LC-MS m/z 442 ( +H) ⁺ .

Example 258: 1 - {6-[(dimethylamino)methyl]-3,4-dihydronaphthalen-2-yl} -4- {[5- (trifluoromethyl)pyridin-2- l]methoxy}pyridin-2(lH)-one

A mixture of l - {2-[(methylamino)methyl]-7,8-dihydronaphthalen-6-yl}-4- {[(5- trifluoromethyl-2-pyridinyl)methyl]oxy}-2(iH)-pyridinone (30 mg, 0.068 mmol) in 30% formaldehyde (1 mL) and MeOH (lmL) was stirred for 6 h, then the mixture was concentrated and purified by preparative HPLC to give the title compound as a yellow solid (18.26 mg, 55% yield): ^! H NMR (400 MHz, MeOH-dO δ ppm 8.82-8.81 (m, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.23-7.17 (m, 3H), 7.03 (d, J = 8.0 Hz, 1H), 6.40 (s, 1H), 6.02 (dd, J = 7.6, 2.8 Hz, 1H), 5.87 (d, J = 2.4 Hz, 1H), 5.16 (s, 2H), 3.80 (s, 2H), 3.01- 2.97 (m, 2H), 2.69-2.65 (m, 2H), 2.51 (s, 6H); ES-LCMS m z 456 (M+ ) ⁺ .

Example 259: 1 -[6-(morpholin-4-ylmethyl)-3,4-dihydronaphthalen-2-yl]-4- { [5- (trifluoromethyl)pyridin-2-yl methoxy}pyridin-2(lH)-one dihydrochloride

A solution of 2-(methansulfonyloxymethyl)-5-trifluoromethylpyridine (77 mg, 0.3 mmol), 1- {2-[(morpholin-4-yl)methyl]-7,8-dihydronaphthalen-6-yl} -4- {hydroxy} -2(iH)-pyridinone (101 mg, 0.3 mmol) and K ₂ CO ₃ (276 mg, 0.6 mmol) in DMF (3 mL) was stirred at room temperature. After LC-MS analysis showed the starting material was consumed, the mixture was filtered, and the filtrate was purified by preparative HPLC to afford the title compound (53.9 mg, 36% yield): ^! H NMR (400 MHz, MeOH-d ₄ ) δ ppm 8.84 (s, 1H), 8.16 (dd, J = 8.0, 2.0 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.29-7.27 (m, 2H), 7.19 (d, J = 7.6 Hz, 1H), 6.58 (s, 1H), 6.35 (dd, J = 7.6, 2.8 Hz, 1H), 6.06 (d, J = 2.4 Hz, 1H), 5.31 (s, 2H), 4.24 (s, 2H), 3.97-3.93 (m, 2H), 3.69-3.63 (m, 2H), 3.30-3.27 (m, 2H), 3.15-3.08 (m, 2H), 3.00 (t, J = 8.0 Hz, 2H), 2.61 (t, J = 8.0 Hz, 2H); ES-LCMS m/z 498.0 (M+ ) ⁺ .

Examples 260 and 261 (Table 5) were prepared using procedures analogous to those described in Example 256 using starting materials such as 6-[4- {[(5-trifluoromethyl-2- pyridinyl)methyl]oxy} -2-oxo- 1 (2H)-pyridinyl]-7,8-dihydronaphthalene-2- carbaldehyde and the appropriate amines. The requisite amines utilized herein were purchased if available commercially, were synthesized as described in the literature or by routine modifications thereof, or were synthesized as detailed in the Intermediates section above. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions.

Table 5.

Example 262 and 263: 4-[(6-chloropyridazin-3-yl)methoxy]-l - {6-[(tetrahydrofuran-3- ylamino)methyl]-3,4-dihydronaphthalen-2-yl}pyridin-2(lH)-one hydrochloride (peak 1 , single unknown stereochemistry) and 4-[(6-chloropyridazin-3-yl)methoxy]-l- {6- [(tetrahydrofuran-3-ylamino)methyl]-3,4-dihydronaphthalen-2- yl}pyridin-2(lH)-one hydrochloride (peak 2, single unknown stereochemistry)

A mixture of 3-chloro-6-methyl-pyridazine (4 g, 31.2 mmol) in CHCI ₃ (80 mL) was added l ,3,5-trichloro-[l ,3,5]triazinane-2,4,6-trione (2.47 g, 10.4 mmol) at room temperature. The mixture was refluxed till the reaction was over. The mixture was concentrated to give the residue, which was purified by column to give 3-chloro-6-chloromethyl-pyridazine (2.5 g, 49.3% yield). 1H NMR(400 MHz, CDC1 ₃ ) δ ppm 7.69 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 4.86 (s, 2H), ES-LCMS m/z 163 (M+ ) ⁺ .

A mixture of (6-(4-hydroxy-2-oxopyridin-l(2H)-yl)-7,8-dihydronaphthalen-2 -yl)methyl acetate (2 g, 6.42 mmol), 3-chloro-6-(chloromethyl)pyridazine (1.047 g, 6.42 mmol) and potassium carbonate (0.888 g, 6.42 mmol) in Ν,Ν-dimethylformamide (DMF) (40 mL) was heated to 80 °C for 6 hr, then the mixture was filtered and concentrated to give the residue which was purified by a flash column to give (6-(4-((6-chloropyridazin-3-yl) methoxy)-2- oxopyridin- l(2H)-yl)-7,8-dihydronaphthalen-2-yl)methyl acetate (2.4 g, 4.93 mmol, 77% yield): 1H NMR (400 MHz, CDC1 ₃ ) δ ppm 7.65 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.25-7.23 (m, 1H), 7.17-7.16 (m, 2H), 7.06 (dd, J = 4.8, 3.2 Hz, 1H), 6.45 (s, 1H), 6.04-5.98 (m, 2H), 5.37 (s, 2H), 5.06 (s, 2H),3.04 (t, J = 8.4 Hz, 2H), 2.73 (t, J = 8.4 Hz, 2H), 2.1 1 (s, 3H); ES-LCMS m/z 438 ( +H) ⁺ . a mixture of (6-(4-((6-chloropyridazin-3-yl)methoxy)-2-oxopyridin-l(2H)-y l)-7,8- dihydronaphthalen-2-yl)methyl acetate (2.4 g, 5.48 mmol) and sodium hydroxide (0.438 g, 10.96 mmol) in tetrahydrofuran (20 mL) and water (20.00 mL) was stirred at room temperature for 8 hr, then solvent was removed and washed by water (200 mL) and extracted with DCM (20 mL x 2), the combined organic layers were dried, concentrated to give 4-((6- chloropyridazin-3-yl)methoxy)- 1 -(6-(hydroxymethyl)- 3,4-dihydronaphthalen-2-yl)pyridin- 2(lH)-one (1.1 g, 2.501 mmol, 45.6 % yield): 1H NMR (400 MHz, CDC1 ₃ ) δ ppm 7.66 (d, J = 8.8 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.26-7.25 (m, 1H), 7.17 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 7.2 Hz, 1H), 6.46 (s, 1H), 6.06-6.00 (m, 2H), 5.37 (s, 2H), 4.68 (s, 2H), 3.04 (t, J = 8.4 Hz, 2H), 2.73 (t, J = 8.4 Hz, 2H); ES-LCMS m/z 396 ( +H) ⁺ .

To a stirred solution of 4-((6-chloropyridazin-3-yl)methoxy)-l -(6-(hydroxymethyl)- 3,4- dihydronaphthalen-2-yl)pyridin-2(lH)-one (500 mg, 1.263 mmol) and triethylamine (0.528 mL, 3.79 mmol) in dichloromethane (DCM) (20 mL) was added dropwise MsCl (0.1 18 mL, 1.516 mmol) at room temperature and stirred for 0.5 hr, solvent was removed and the residue was washed with water and extracted with DCM (20 mL x2). The combined organic layers were dried to give (6-(4-((6-chloropyridazin-3-yl)methoxy)-2-oxopyridin-l (2H)-yl)-7,8- dihydronaphthalen-2-yl)methyl methanesulfonate (550 mg, 92%yield): ^! H NMR (400 MHz, CDCI ₃ ) δ ppm 7.66 (d, J = 8.8 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.26-7.20 (m, 3H), 7.09- 7.05 (m, 1H), 6.46 (s, 1H), 6.47-6.45 (m, 1H), 6.09-6.07 (m, 2H), 5.38 (s, 2H), 5.20 (s, 2H), 3.04 (t, J= 4.4 Hz, 2H), 2.73 (t, J = 4.8 Hz, 2H), 1.90 (s, 3H).

A mixture of (6-(4-((6-chloropyridazin-3-yl)methoxy)-2-oxopyridin-l (2H)-yl)-7,8- dihydronaphthalen-2-yl)methyl methanesulfonate (350 mg, 0.739 mmol), tetrahydrofuran-3- amine (77 mg, 0.886 mmol) and K ₂ CO ₃ (306 mg, 2.216 mmol) in N, N-dimethylformamide (DMF) (15 mL) was stirred at 80 °C for 6 hr, then solvent was removed to give the residue which was purified by prep HPLC and chiral prep HPLC to give 4-[(6-chloropyridazin-3- yl)methoxy]-l - {6-[(tetrahydrofuran-3-ylamino)methyl]-3,4-dihydronaphthalen -2-yl}pyridin- 2(lH)-one hydrochloride as a yellow solid (peak 1 , 65 mg, 1 1.2% yield): 1H NMR (400 MHz, CD ₃ OD) δ ppm 8.05 (d, J = 7.2 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.93 (d, J = 8.8 Hz, 1H), 7.41-7.38 (m, 2H), 7.30-7.28 (m, 1H), 6.89-6.87 (m, 1H), 6.80 (s, 1H), 6.63 (d, J = 2.4 Hz, 1H), 5.64 (s, 2H), 4.23-4.21 (m, 2H), 4.06-3.95 (m, 3H), 3.86-3.82 (m, 1H), 3.75-3.72 (m, 1H), 3.1 1 -3.09 (m, 2H), 2.76-2.68 (m, 2H), 2.43-2.41 (m, 1H), 2.15-2.10 (m, 1H); ES- LCMS m/z 465 (M+H), and 4-[(6-chloropyridazin-3-yl)methoxy]-l - {6-[(tetrahydrofuran-3- ylamino)methyl]-3,4-dihydronaphthalen-2-yl}pyridin-2(lH)-one hydrochloride as a yellow solid (peak 2, 49.3 mg, 8.5% yield): 1H NMR (400 MHz, CD ₃ OD) δ ppm 7.98-7.93 (m, 3H), 7.41-7.38 (m, 2H), 7.30-7.28 (m, 1H), 6.85-6.79 (m, 2H), 6.61 -6.60 (m, 1H), 5.64 (s, 2H), 4.23-4.22 (m, 2H), 4.05-4.00 (m, 3H), 3.87-3.83 (m, 1H), 3.73-3.71 (m, 1H), 3.13-3.09 (m, 2H), 2.73-2.67 (m, 2H), 2.41-2.39 (m, 1H), 2.12-2.10 (m, 1H); ES-LCMS m/z 465 ( +H) ⁺ .

Chiral HPLC method

Instrument: Thar 80

Column: AS 250mm*20mm, 20um

Mobile phase: A: Supercritical C0 ₂ , B: MeOH, A: B =55:45 at 80mL/min

Column Temp: 38°C

Nozzle Pressure: lOOBar

Nozzle Temp: 60°C

Evaporator Temp: 20°C

Trimmer Temp: 25°C

Wavelength: 220nm

Assays and activities

A: MCHR1 pIC ₅₀ Determination FLIPR™ Assay (U20S cells): Frozen U20S cells were rapidly thawed in a 37°C water bath 24 hours prior to assay. The cells were counted, diluted to appropriate concentration, and mixed with 0.53% v/v of human MCHR1 and 0.13% v/v Gqi5 BacMam virus stocks for transduction of the receptor. 50 uL of this cell suspension was plated utilizing a Combi Multidrop (Thermo) at a concentration of 15,000 cells/well in a black 384-well clear bottom plate (Greiner) in DMEM/F12 media containing 10% FBS and stored at 37°C overnight. Compounds to be profiled were prepared by making a stock solution at 3xl0 ^"3 M in 100% DMSO. The stock solutions were serially diluted 1 :4 in 100% DMSO using a Beckman Biomek FX as 1 1 point curves in singlicate. In a polypropylene 384-well plate, 2 uL of the compound dilution was pipetted using a BiomekFX. The compound plate was diluted by adding 40 uL of load buffer to the plate and gently shaken. At the time of the assay, the media was removed from the cell plate by aspiration, followed by the addition of 20 uL of load buffer (Calcium Plus Kit, MDC) using a Matrix wellmate. Following a one hour incubation at 37°C, 10 uL of compound was added to the plates via the FL1PR™ instrument. The plates were incubated at 37°C for 30 minutes along with an MCH peptide agonist challenge plate. On the FL1PR™, a basal response was collected over 10 seconds followed by the addition of 10 uL of MCH challenge made at the 4XECso concentration in load buffer. Data was collected over 4 minutes and subjected to a nonlinear regression analysis curve fitting program to generate MCHR1 plCsoS.

B: MCHR1 pIC ₅₀ Determination FLIPR™ Assay (HEK293 cells): HEK293 cells stably transfected with hMCHRl were propagated as adherent cultures at 37°C in a humidified incubator. Cells were split 1 :8 at 90% confluency two times per week. New cell stocks were recovered from storage every two months. Cells were plated in black 384-well plates

(Greiner) 24 hours prior to assay at 15,000 cells/well in 50 uL DMEM/F12, 10% FBS, 2 mM 1-glutamine. Compounds to be profiled were prepared by making a stock solution at 3xl0 ^"3 M in 100% DMSO. The stock solutions were serially diluted 1 :4 in 100% DMSO using JANUS (PerkinElmer) liquid handling instrument to allow for an 1 1 point curve in singlicate. At the time of the assay, the media was removed from the cell plate by aspiration, followed by the addition of 20 uL of loading buffer (Calcium 4 Kit, Molecular Dynamics corporation).

Following 50 min incubation at 37°C, 10 uL of compound was added to the plates via the FLIPR™ instrument (Molecular Dynamics corporation). The plates were incubated at room temperature for 15 minutes along with an MCH peptide agonist challenge plate. On the FLIPR™, a basal response was collected over 10 seconds followed by the addition of 10 uL of MCH challenge concentration at 4XECso. Data was collected over 4 minutes and subjected to a nonlinear regression analysis curve fitting program to generate pICsoS. C: MCHR1 lCso Determination Reporter Gene Assay (Luciferase Assay): The assay consists of stable CHO cell line expressing hMCHRl and the inducible reporter Gal-4/Elk-l-luc plated at ten thousand cells/well in DMEM/F12, 5% FBS, 2 mM I-glutamine in black 384-well assay plates. The day after plating, the media was removed by aspiration sixteen hours prior to assay, followed by the addition of 50 uL of media without serum to reduce background signal noise. Compounds were prepared by making a stock solution at 3xl0 ^~3 M. The stock solutions were serially diluted 1 :4 in 100% DMSO using a Beckman Biomek FX as 11 point curves in singlicate. On the day of the assay, compounds (0.5 uL) were pipetted into the assay plate using a BeckmanFX.

Following incubation for 45 minutes at 37°C, a 4XECso concentration of MCH (MCH

Rl) or thrombin (host) was added to the plate allowing for appropriate controls. The plates were then incubated under the same conditions for five hours. Under subdued light conditions, the compound/assay solution was removed by aspiration from the plates, followed by the addition of 20 uL of a 1 : 1 solution containing SteadyGlo™ and

Dulbecco's Phosphate Buffered Saline with 1 mM CaCI ₂ and 1 mM MgCI ₂ . Plates were sealed with self-adhesive clear plate seals and wiped with a static free dryer sheet to reduce false counts due to static charge. The amount of luciferase generated was quantified in a Viewlux (Perkin Elmer) with a 2 second per well count time.

D: MCHR1 pICso Determination Reporter Gene Assay: The assay consists of stable CHO cell line expressing hMCHRl and the inducible reporter Gal-4/Elk- 1 -luc plated at ten thousand cells/well in DMEM/F12, 5% FBS, 2 mM 1-glutamine in black 384-well assay plates. The day after plating, the media was removed by aspiration seventeen hours prior to assay, followed by the addition of 50 uL of media without serum to reduce background signal noise.

Compounds were prepared by making a stock solution at 3x10 ^" M. The stock solutions is serially diluted 1 :4 in 100% DMSO using the JANUS liquid handling instrument (Perkin Elmer) to allow for an 11 point curves in singlicate. On the day of the assay, compounds (0.5 uL) were pipetted into the assay plate using JANUS. Following incubation for 45 minutes at 37°C, 10 uL of 6xEC ₈ o concentration (6x50nM) of MCH was added to the plate allowing for appropriate controls. The plates were then incubated under the same conditions for five hours. Under subdued light conditions, the compound/assay solution was removed by aspiration from the plates, followed by the addition of 15μί per well SteadyGlo™ reagent using a Multidrop. Plates were then sealed with self-adhesive clear plate seals and wiped with a static free dryer sheet to reduce false counts due to static charge and placed on the shaker for 8 min in dark. The amount of luciferase generated was quantified in a TopCount (PerkinElmer Packard) at 19.8°C in SPC (single photon counting) mode with a 5 second count/well and subjected to a nonlinear regression analysis curve fitting program to generate pICsoS.

Although specific embodiments of the present invention are herein illustrated and described in detail, the invention is not limited thereto. The above-detailed descriptions are provided as exemplary of the present invention and should not be construed as constituting any limitation of the invention. Modifications will be obvious to those skilled in the art, and all modifications that do not depart from the spirit of the invention are intended to be included with the scope of the appended claims.

Exemplified compounds of the present invention were tested at one or more of the assays described above and were found to be functional antagonists of MCH at the MCHR1 receptor with pICsoS >6. Examplar compounds with specific biological activities tested according to assays described herein are listed in Table 6 with p!C ₅ oS ranged from 7.3 to 9.5.

Table 6.

A:MCH 1 C:MCHR1

B:MCHR1 D:MCHR1

Example # USOS FLIPR Luciferase

FLIPR pICso Reporter pIC ₅₀ pICso Reporter pIC ₅₀

Example 1 8 8.8

Example 5 7.6 9.5

Example 6 8 8.3

Example 30 9

Example 31 7.5 8.6

Example 32 7.5 8.3

Example 33 7.6 8.6

Example 34 7.4 8.2

Example 35 7.4 8.2

Example 36 7.7 9.2

Example 96 7.7 9.5

Example 214 7.5 8.6 Example 215 7.5 8.6

Example 234 7.4 9

Example 235 7.4 9

Example 256 7.5 8.7

Example 257 7.6 8.1

Example 258 7.3 8.1

Example 259 7.5 7.9

Example 262 7.6 7.8

Example 263 7.7 8