WO2013149362A1

WO2013149362A1 - 1-(dihydronaphthalenyl)pyridones as melanin-concentrating hormone receptor 1 antagonists

Info

Publication number: WO2013149362A1
Application number: PCT/CN2012/000453
Authority: WO
Inventors: Donghui Qin; Sieg CHRISTENSEN; Chengde Wu; Zhiliu Zhang; Haiyu Yu; Jiangxing YUAN
Original assignee: Glaxosmithkline Llc
Priority date: 2012-04-06
Filing date: 2012-04-06
Publication date: 2013-10-10

Abstract

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

Description

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

FIELD OF INVENTION

This invention relates to novel 1 -(dihydronaphthalenyl)pyridone thiazoles which are antagonists at 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.

I

wherein:

each R¹ is independently selected from the group consisting of hydrogen, halo, (Ci-C₃)alkyl, (C₃-C₆)cycloalkyl, hydroxyl(Ci-C₃)alkyl, (Ci-C₃)alkoxy(Ci- C₃)alkyl, (Ci-C₃)alkoxy, (Ci-C₃)haloalkyl, C(=0)0(Ci-C₃)alkyl, amino, and CN; n is 0-2;

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

II III

where in Formula (II):

Y is C, O, S, S0₂ or NR⁶;

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

s is 0-4;

r is 0-4; each R² and each R³ are independently selected from the group consisting of hydrogen, (Ci-C₆)alkyl, (C₃-C₆)cycloalkyl(Ci-C₃)alkyl, hydroxyl, halo, (Ci- C₃)alkoxy, hydroxyl(Ci-C₃)alkyl, (C₁-C₃)alkoxy(C₁-C₃)alkyl, (Ci-C₃)alkylS0₂(Ci- C₃)alkyl, -C(=0)NR⁶R⁷, -C(=0)R⁶, -S0₂R⁶, -S0₂NR⁶R⁷, oxo, -C(=0)OR⁶, -NR⁶R⁷, - NR⁶C(=0)R⁷, -NR⁶C(=0)OR⁷, -NR⁶S0₂R⁷ and (C₃-C₆)heterocycloalkyl, wherein said (C₃-C₆)heterocycloalkyl is optionally substituted with one to three times,

independently, by R⁸;

R² and R³ taken together with the carbon atom to which they are attached form a three to eight membered ring, optionally containing a heteroatom selected from the group consisting of O, N and S, which ring is optionally substituted one to three times, independently, by R⁶;

R and R are each independently selected from the group consisting of hydrogen, (Ci-C₆)alkyl, (C₃-C₆)cycloalkyl(Ci-C₃)alkyl, hydroxyl, (Ci-C₃)alkoxy, hydroxyl(Ci-C₃)alkyl, and (C₁-C₃)alkoxy(C₁-C₃)alkyl;

R⁸ is selected from the group consisting of hydrogen, (Ci-C₆)alkyl, (C₃- C₆)cycloalkyl(Ci-C₃)alkyl, hydroxyl, halo, (Ci-C₃)alkoxy, hydroxyl(Ci-C₃)alkyl, (Ci- C₃)alkoxy(Ci-C₃)alkyl, -C(=0)NR⁶R⁷, -C(=0)R⁶, -S0₂R⁶, -S0₂NR⁶R⁷, oxo, - C(=0)OR⁶, -NR⁶R⁷, -NR⁶C(=0)R⁷, -NR⁶C(=0)OR⁷, and -NR⁶S0₂R⁷;

where in Formula (III):

t is 0-4, provided that when t is 0, R⁵ is not halo;

R⁴ is selected from the group consisting of hydrogen, (Ci-C₆)alkyl, (C₃- C₆)cycloalkyl(Ci-C₃)alkyl, (Ci-C₃)alkoxyl, hydroxyl(Ci-C₃)alkyl, or (Ci- C₃)alkoxy(Ci-C₃)alkyl;

R⁵ is selected from the group consisting of hydrogen, (Ci-C₃)haloalkyl, (Ci- C₃)alkyl, NR⁶S0₂R⁷, NR⁶R⁷, NR⁶C(=0)NR⁶R⁷, -S0₂R⁶, -S0₂NR⁶R⁷, halo, hydroxyl, -C(=0)(Ci-C₃)alkyl, hydroxyl(Ci-C₃)alkyl, (Ci-C₃)alkoxy(Ci-C₃)alkyl, and (C₃- C₆)heterocycloalkyl, wherein said (C₃-C₆)heterocycloalkyl is optionally substituted with one to three times, independently, by R⁸.

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 compound of claim 1 according to Formula (IV):

IV

wherein:

Z is O, N, S0₂ or C=0;

w is 0-2;

m is 0-3;

n is 0-2; each R is independently selected from the group consisting of hydrogen,

halo, (Ci-C₃)alkyl, (C₃-C₆)cycloalkyl, hydroxyl(Ci-C₃)alkyl, (Ci-C₃)alkoxy(Ci- C₃)alkyl, (Ci-C₃)alkoxy, (Ci-C₃)haloalkyl, amino, and CN; each R⁹ is independently selected from the group consisting of hydrogen, (Ci- C₆)alkyl, (C₃-C₆)cycloalkyl(Ci-C₃)alkyl, hydroxyl, halo, (Ci-C₃)alkoxy, hydroxyl(Ci- C₃)alkyl, and (Ci-C₃)alkoxy(Ci-C₃)alkyl;

or pharmaceutically acceptable salt thereof.

The present invention also relates to compound of claim 1 according to Formula (V):

V wherein:

m is 0-3;

n is 0-2;

each R¹ is independently selected from the group consisting of hydrogen, halo, (Ci- C₃)alkyl, (C₃-C₆)cycloalkyl, hydroxyl(Ci-C₃)alkyl, (Ci-C₃)alkoxy(Ci-C₃)alkyl, (Ci- C₃)alkoxy, (Ci-C₃)haloalkyl, amino, and CN; each R⁹ is independently selected from the group consisting of hydrogen, (Ci- C₆)alkyl, (C₃-C₆)cycloalkyl(Ci-C₃)alkyl, hydroxyl, halo, (Ci-C₃)alkoxy, hydroxyl(Ci- C₃)alkyl, and (Ci-C₃)alkoxy(Ci-C₃)alkyl;

or pharmaceutically acceptable salt thereof.

The present invention also relates to compound of claim 1 according to Formula (VI):

wherein:

n is 0-2;

each R¹ is independently selected from the group consisting of hydrogen, halo, (Ci- C₃)alkyl, (C₃-C₆)cycloalkyl, hydroxyl(Ci-C₃)alkyl, (Ci-C₃)alkoxy(Ci-C₃)alkyl, (Ci-C₃)alkoxy, (Ci-C₃)haloalkyl, amino, and CN;

or a pharmaceutically acceptable salt thereof.

The present invention also relates to compound of claim 1 according to Formula

VII wherein:

Y is C, O, S0₂ or R⁶;

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

s is 0-4;

n is 0-2; each R is independently selected from the group consisting of hydrogen, halo, (Ci-C₃)alkyl, hydroxyl(Ci-C₃)alkyl, (Ci-C₃)alkoxy(Ci-C₃)alkyl, C(=0)0(Ci- C₃)alkyl and (Ci-C₃)alkoxy;

each R are independently selected from the group consisting of hydrogen, (Ci-C₆)alkyl, (C₃-C₆)cycloalkyl(Ci-C₃)alkyl, hydroxyl, halo, (Ci-C₃)alkoxy, hydroxyl(Ci-C₃)alkyl, (Ci-C₃)alkoxy(Ci-C₃)alkyl, (Ci-C₃)alkylS0₂(Ci-C₃)alkyl, - C(=0)NR⁶R⁷, -C(=0)R⁶, -S0₂R⁶, -S0₂NR⁶R⁷, oxo, -C(=0)OR⁶, -NR⁶R⁷, - NR⁶C(=0)R⁷, -NR⁶C(=0)OR⁷, -NR⁶S0₂R⁷ and (C₃-C₆)heterocycloalkyl, wherein said (C₃-C₆)heterocycloalkyl is optionally substituted with one to three times, independently, by R⁸;

R" and R' are each independently selected from the group consisting of hydrogen, (Ci-C₆)alkyl, (C₃-C₆)cycloalkyl(Ci-C₃)alkyl, hydroxyl, (Ci-C₃)alkoxy, hydroxyl(Ci-C₃)alkyl, and (Ci-C₃)alkoxy(Ci-C₃)alkyl;

or a pharmaceutically acceptable salt thereof.

The present invention also relates to compound of claim 1 according to Formula

(VIII):

VIII

is 0-2; s is 0-4;

n is 0-2;

each R¹ is independently selected from the group consisting of hydrogen,

halo, (Ci-C₃)alkyl, hydroxyl(Ci-C₃)alkyl, and (Ci-C₃)alkoxy(Ci-C₃)alkyl;

each R² are independently selected from the group consisting of hydrogen,

(Ci-C₆)alkyl, hydroxyl, halo, (C₃-C₆)cycloalkyl(Ci-C₃)alkyl, (Ci-C₃)alkoxy,

hydroxyl(Ci-C₃)alkyl, and (Ci-C₃)alkoxy(Ci-C₃)alkyl; or a pharmaceutically acceptable salt thereof.

The present invention also relates to compound of claim 1 according to Formula (IX):

IX wherein:

t is 0-4, provided that when t is 0, R⁵ is not halo;

n is 0-2;

each R¹ is independently selected from the group consisting of hydrogen,

R⁴ is selected from the group consisting of hydrogen, (Ci-C₆)alkyl, (C₃- C₆)cycloalkyl(Ci-C₃)alkyl, (Ci-C₃)alkoxy, hydroxyl(Ci-C₃)alkyl, and (Ci- C₃)alkoxy(Ci-C₃)alkyl;

R⁵ is selected from the group consisting of hydrogen, (Ci-C₃)haloalkyl, (Ci- C₃)alkyl, N R⁶S0₂R⁷, NR⁶R⁷, NR⁶C(=0)NR⁶R⁷, -S0₂R⁶, hydroxyl, halo, -C(=0)(Ci- C₃)alkyl, hydroxyl(Ci-C₃)alkyl, (Ci-C₃)alkoxy(Ci-C₃)alkyl, and (C₃- C₆)heterocycloalkyl, wherein said (C₃-C₆)heterocycloalkyl is optionally substituted with one to three times, independently, by R⁸; R⁶ and R⁷ are each independently selected from the group consisting of

hydrogen, (Ci-C₆)alkyl, (C₃-C₆)cycloalkyl(Ci-C₃)alkyl, hydroxyl, (Ci-C₃)alkoxy, hydroxyl(Ci-C₃)alkyl, and (C₁-C₃)alkoxy(C₁-C₃)alkyl;

R is selected from the group consisting of hydrogen, (Ci-C₆)alkyl, (C₃- C₆)cycloalkyl(Ci-C₃)alkyl, hydroxyl, halo, (Ci-C₃)alkoxy, hydroxyl(Ci-C₃)alkyl, (Ci- C₃)alkoxy(Ci-C₃)alkyl, -C(=0)NR⁶R⁷, -C(=0)R⁶, -S0₂R⁶, -S0₂NR⁶R⁷, oxo, - C(=0)OR⁶, -NR⁶R⁷, -NR⁶C(=0)R⁷, -NR⁶C(=0)OR⁷, and -NR⁶S0₂R⁷;

or a pharmaceutically acceptable salt thereof.

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

wherein:

t is 0-4, provided that when t is 0, R⁵ is not halo;

n is 0-2;

each R¹ is independently selected from the group consisting of hydrogen, halo, (Ci-C₃)alkyl, hydroxyl(Ci-C₃)alkyl, and (Ci-C₃)alkoxy(Ci-C₃)alkyl; R⁴ is hydrogen or (Ci-C₆)alkyl;

R⁵ is selected from the group consisting of hydrogen, (Ci-C₃)haloalkyl, (Ci- C₃)alkyl, NR⁶S0₂R⁷, NR⁶R⁷, NR⁶C(=0)NR⁶R⁷, -S0₂R⁶, -C(=0)(Ci-C₃)alkyl,

hydroxyl(Ci-C₃)alkyl, and (Ci-C₃)alkoxy(Ci-C₃)alkyl;

R" and R' are independently selected from the group consisting of hydrogen, (Ci-C₆)alkyl, (C₃-C6)cycloalkyl(Ci-C₃)alkyl, hydroxyl, (Ci-C₃)alkoxy, hydroxyl(Ci- C₃)alkyl, and (Ci-C₃)alkoxy(Ci-C₃)alkyl;

or a pharmaceutically acceptable salt thereof.

In one embodiment, this invention relates to compounds of Formula (I), (IV), (V), (VI), (VII), (VIII), or (IX), wherein n is 1 and R¹ is halo, (Ci-C₃)alkyl or hydroxyl(Ci- C₃)alkyl, or a pharmaceutically acceptable salts thereof.

In another embodiment, this invention relates to compounds of Formula (VII),

1 2 wherein n is 1 ; R is halo, (Ci-C₃)alkyl or hydroxyl(Ci-C₃)alkyl; Y is C; p is 0, 1 or 2; R is (Ci-C₃)alkyl, hydroxyl or (Ci-C₃)alkoxy; or a pharmaceutically acceptable salts thereof.

In another embodiment, this invention relates to compounds of Formula (IV), wherein n is l or 2; R¹ is halo, (Ci-C₃)alkyl or hydroxyl(Ci-C₃)alkyl; Z is O; w is 1 or 2; m is 1 ; R⁹ is hydrogen, (Ci-C₃)alkyl, hydroxyl or (Ci-C₃)alkoxy; or a pharmaceutically acceptable salts thereof.

In another embodiment, this invention relates to compounds of Formula (IX), wherein n is 1 or 2; R¹ is halo, (Ci-C₃)alkyl or hydroxyl(Ci-C₃)alkyl; t is 1 or 2; R⁴ is hydrogen or (Ci-C₃)alkyl; R⁵ is hydrogen, halo, (Ci-C₃)alkyl; -C(=0)(Ci-C₃)alkyl; hydroxyl(Ci-C₃)alkyl; or a pharmaceutically acceptable salts thereof.

Specific compounds of this invention include:

1 -[6-(4-Methyl-piperazin- 1 -ylmethyl)-3 ,4-dihydro-naphthalen-2-yl]-4-(4-methyl-thiazol-2- ylmethoxy)- 1 H-pyridin-2-one;

(S) 1 -(6- { [(2,3-Dihydroxy-propyl)-methyl-amino]-methyl} -3,4-dihydro-naphthalen-2-yl)-4- (4-methyl-thiazol-2-ylmethoxy)-lH-pyridin-2-one;

4-(4-Methyl-thiazol-2-ylmethoxy)- 1 -(6-morpholin-4-ylmethyl-3 ,4-dihydro-naphthalen-2-yl)- lH-pyridin-2-one;

(S) 1 -[6-(3-Fluoro-pyrrolidin- 1 -ylmethyl)-3 ,4-dihydro-naphthalen-2-yl]-4-(4-methyl-thiazol- 2-ylmethoxy)-lH-pyridin-2-one;

N-Methyl-N- {6-[4-(4-methyl-thiazol-2-ylmethoxy)-2-oxo-2H-pyridin- 1 -yl]-7,8-dihydro- naphthalen-2-ylmethyl}-methanesulfonamide;

l-(6- {[(2-Methoxy-ethyl)-methyl-amino]-methyl}-3,4-dihydro-naphthalen-2-yl)-4-(4- methyl-thiazol-2-ylmethoxy)- 1 H-pyridin-2-one;

1 - {6-[4-(2-Methanesulfonyl-ethyl)-piperazin-l -ylmethyl]-3 ,4-dihydro-naphthalen-2-yl} -4- (4-methyl-thiazol-2-ylmethoxy)-lH-pyridin-2-one;

l- {6-[(l ,l -Dioxo-hexahydro-116-thiopyran-4-ylamino)-methyl]-3,4-dihydro-naphthalen-2- yl} -4-(4-methyl-thiazol-2-ylmethoxy)- 1 H-pyridin-2-one;

l- {6-[(2-Fluoro-ethylamino)-methyl]-3,4-dihydro-naphthalen-2-yl} -4-(4-methyl-thiazol-2- ylmethoxy)- 1 H-pyridin-2-one;

l-[6-(3,5-Dihydroxy-piperidin-l -ylmethyl)-3,4-dihydro-naphthalen-2-yl]-4-(4-methyl- thiazol-2-ylmethoxy)-lH-pyridin-2-one;

l-(6- {[(2-Hydroxy-ethyl)-methyl-amino]-methyl}-3,4-dihydro-naphthalen-2-yl)-4-(4- methyl-thiazol-2-ylmethoxy)- 1 H-pyridin-2-one; (R)l-[6-(3-Hydroxy-pyrrolidin-l-ylmethyl)-3,4-dihydro-naphthalen-2-yl]-4-(4-methyl- thiazol-2-ylmethoxy)- 1 H-pyridin-2-one;

1 - [6-(3 ,4-Dihydroxy-piperidin- 1 -ylmethyl)-3 ,4-dihydro-naphthalen-2-yl]-4-(4-methyl- thiazol-2-ylmethoxy)- 1 H-pyridin-2-one;

(S)4-(4-Methyl hiazol-2-ylmethoxy)-l-{6-[(tetrahydro-furan-3-ylamino)-methyl]-3,4- dihydro-naphthalen-2-yl} - 1 H-pyridin-2-one;

(R)4-(4-Methyl hiazol-2-ylmethoxy)-l-{6-[(tetrahydro-furan-3-ylamino)-methyl]-3,4- dihydro-naphthalen-2-yl} - 1 H-pyridin-2-one;

l-(6-Methylaminomethyl-3,4-dihydro-naphthalen-2-yl)-4-(4-methyl-thiazol-2-ylmethoxy)- lH-pyridin-2-one;

1- (6-Dimethylaminomethyl-3,4-dihydro-naphthalen-2-yl)-4-(4-methyl-thiazol-2-ylmethoxy)- lH-pyridin-2-one;

1 -(6-Ethylaminomethyl-3 ,4-dihydro-naphthalen-2-yl)-4-(4-methyl-thiazol-2-ylmethoxy)- 1 H- pyridin-2-one;

N-Methyl-N-{6-[4-(4-methyl-thiazol-2-ylmethoxy)-2-oxo-2H-pyridin-l-yl]-7,8-dihydro- naphthalen-2-ylmethyl}-acetamide;

(S) 1 - [6-(3 -Hydroxy -pyrroli din- 1 -ylmethyl)-3 ,4-dihydro-naphthalen-2-yl]-4-(4-methyl- thiazol-2-ylmethoxy)- 1 H-pyridin-2-one;

(S)l-[6-(3 -Methoxy-pyrrolidin- 1 -ylmethyl)-3 ,4-dihydro-naphthalen-2-yl] -4-(4-methyl- thiazol-2-ylmethoxy)- 1 H-pyridin-2-one;

(R)l-[6-(3-Methoxy-pyrrolidin-l-ylmethyl)-3,4-dihydro-naphthalen-2-yl]-4-(4-methyl- thiazol-2-ylmethoxy)- 1 H-pyridin-2-one;

(S)l-[6-(2-Methyl-morpholin-4-ylmethyl)-3,4-dihydro-naphthalen-2-yl]-4-(4-methyl-thiazol-

2- ylmethoxy)- 1 H-pyridin-2-one;

(R) 1 -(6- { [Methyl-(tetrahydro-furan-3-yl)-amino]-methyl} -3 ,4-dihydro-naphthalen-2-yl)-4- (4-methyl-thiazol-2-ylmethoxy)- 1 H-pyridin-2-one;

l-[6-(4-Methoxy-piperidin-l-ylmethyl)-3,4-dihydro-naphthalen-2-yl]-4-(4-methyl-thiazol-2- ylmethoxy)- 1 H-pyridin-2-one; l-[6-(4-Hydroxy-piperidin-l-ylmethyl)-3,4-dihydro-naphthalen-2-yl]-4-(4-methyl hi ylmethoxy)- 1 H-pyridin-2-one;

1- {6-[(2,2-Difluoro-ethylamino)-methyl]-3,4^

2- ylmethoxy)- 1 H-pyridin-2-one;

l-[6-(3-Methoxy-azetidin-l-ylmethyl)-3,4-dihydro-naphthalen-2-yl]-4-(4-methyl hiazol-2- ylmethoxy)- 1 H-pyridin-2-one;

1 - {6-[(2-Hydroxy-ethylamino)-methyl]-3 ,4-dihydro-naphthalen-2-yl} -4-(4-methyl-thiazol-2- ylmethoxy)- 1 H-pyridin-2-one;

(R)4-(4-Ethyl-thiazol-2-ylmethoxy)- 1 - [6-(3 -hydroxy-pyrrolidin- 1 -ylmethyl)-3 ,4-dihydro- naphthalen-2-yl]- 1 H-pyridin-2-one;

4-(4-Ethyl-thiazol-2-ylmethoxy)- 1 -[6-(4-methyl-piperazin- 1 -ylmethyl)-3 ,4-dihydro- naphthalen-2-yl]- 1 H-pyridin-2-one;

4-(4-Ethyl-thiazol-2-ylmethoxy)- 1 -(6- { [(2-fluoro-ethyl)-methyl-amino]-methyl} -3 ,4- dihydro-naphthalen-2-yl)- 1 H-pyridin-2-one;

4-(4-Ethyl hiazol-2-ylmethoxy)-l-{6-[(2-hydroxy-ethylamino)-methyl]-3,4-dihydro- naphthalen-2-yl} - 1 H-pyridin-2-one;

4-(4-Ethyl-thiazol-2-ylmethoxy)- 1 - {6-[4-(2-methanesulfonyl-ethyl)-piperazin- 1 -ylmethyl]- 3 ,4-dihydro-naphthalen-2-yl} - 1 H-pyridin-2-one;

(R)l-{6-[4-(4-Ethyl hiazol-2-ylmethoxy)-2-oxo-2H-pyridin-l-yl]-7,8-dihydro-naphthalen-2- ylmethyl} -pyrrolidine-3-carboxylic acid;

4-(4-Ethyl-thiazol-2-ylmethoxy)- 1 -(6- { [(2-hydroxy-ethyl)-methyl-amino]-methyl} -3 ,4- dihydro-naphthalen-2-yl)- 1 H-pyridin-2-one;

4-(4-Ethyl hiazol-2-ylmethoxy)-l-{6-[(2-fluoro-ethylamino)-methyl]-3,4-dihydro- naphthalen-2-yl} - 1 H-pyridin-2-one;

l-{6-[(l ,l-Dioxo-hexahydro-116-thiopyran-4-ylamino)-methyl]-3,4-dihydro-naphthalen-2- yl} -4-(4-ethyl-thiazol-2-ylmethoxy)- 1 H-pyridin-2-one;

(S)4-(4-Ethyl hiazol-2-ylmethoxy)-l-{6-[(tetrahydro-furan-3-ylamino)-methyl]-3,4-dihydro- naphthalen-2-yl} - 1 H-pyridin-2-one;

(R)4-(4-Ethyl hiazol-2-ylmethoxy)-l-{6-[(tetrahydro-furan-3-ylamino)-methyl]-3,4- dihydro-naphthalen-2-yl} - 1 H-pyridin-2-one; 4-(4-Ethyl-thiazol-2-ylmethoxy)- 1 - { 6- [(2-methoxy-ethylamino)-methyl] -3 ,4-dihydro- naphthalen-2-yl} - 1 H-pyridin-2-one;

4-(4-Ethyl-thiazol-2-ylmethoxy)- 1 -(6- { [(2-methoxy-ethyl)-methyl-amino]-methyl} -3 ,4- dihydro-naphthalen-2-yl)- 1 H-pyridin-2-one;

1 -(6-Ethylaminomethyl-3 ,4-dihydro-naphthalen-2-yl)-4-(4-ethyl-thiazol-2-ylmethoxy)- 1 H- pyridin-2-one;

l-{6-[(Ethyl-methyl-amino)-methyl]-3,4-dihydro-naphthalen-2-yl}-4-(4-ethyl-thiazol-2- ylmethoxy)- 1 H-pyridin-2-one;

l-(6-Dimethylaminomethyl-3,4-dihydro-naphthalen-2-yl)-4-(4-ethyl-thiazol-2-ylmethoxy)- lH-pyridin-2-one;

4-(4-Ethyl-thiazol-2-ylmethoxy)- 1 -(6-methylaminomethyl-3 ,4-dihydro-naphthalen-2-yl)- 1 H- pyridin-2-one;

(S)4-(4-Ethyl-thiazol-2-ylmethoxy)- 1 -[6-(3-methoxy-pyrrolidin- 1 -ylmethyl)-3 ,4-dihydro- naphthalen-2-yl]- 1 H-pyridin-2-one;

(R)4-(4-Ethyl-thiazol-2-ylmethoxy)- 1 -(6- { [methyl-(tetrahydro-furan-3 -yl)-amino]-methyl} - 3 ,4-dihydro-naphthalen-2-yl)- 1 H-pyridin-2-one;

4-(4,5-Dimethyl-thiazol-2-ylmethoxy)-l-{6-[(2-fluoro-ethylamino)-methyl]-3,4-dihydro- naphthalen-2-yl} - 1 H-pyridin-2-one;

4-(4,5-Dimethyl-thiazol-2-ylmethoxy)-l-[6-(4-methyl-piperazin-l-ylmethyl)-3,4-dihydro- naphthalen-2-yl]- 1 H-pyridin-2-one;

4-(4,5-Dimethyl-thiazol-2-ylmethoxy)- 1 -(6-methylaminomethyl-3 ,4-dihydro-naphthalen-2- yl)-lH-pyridin-2-one;

4-(2-Methyl-thiazol-4-ylmethoxy)- 1 -(6-pyrrolidin- 1 -ylmethyl-3 ,4-dihydro-naphthalen-2-yl)- lH-pyridin-2-one;

l-{6-[(2-Fluoro-ethylamino)-methyl]-3,4-dihydro-naphthalen-2-yl}-4-(2-methyl-thiazol-4- ylmethoxy)- 1 H-pyridin-2-one;

l-[6-(4-Hydroxy-piperidin-l-ylmethyl)-3,4-dihydro-naphthalen-2-yl]-4-(2-methyl-thiazol-4- ylmethoxy)- 1 H-pyridin-2-one;

l-(6-{[(2-Methoxy-ethyl)-methyl-amino]-methyl}-3,4-dihydro-naphthalen-2-yl)-4-(2- methyl-thiazol-4-ylmethoxy)- 1 H-pyridin-2-one; (R) 1 -(6- { [Methyl-(tetrahydro-furan-3-yl)-amino]-methyl} -3 ,4-dihydro-naphthalen-2-yl)-4- (2-methyl-thiazol-4-ylmethoxy)- 1 H-pyridin-2-one;

(S) 1 -(6- { [Methyl-(tetrahydro-furan-3 -yl)-amino]-methyl} -3 ,4-dihydro-naphthalen-2-yl)-4- (2-methyl-thiazol-4-ylmethoxy)- 1 H-pyridin-2-one;

4-(4-Isopropyl-thiazol-2-ylmethoxy)- 1 -(6-methylaminomethyl-3 ,4-dihydro-naphthalen-2-yl)- lH-pyridin-2-one;

l-(6-Dimethylaminomethyl-3,4-dihydro-naphthalen-2-yl)-4-(4-isopropyl-thiazol-2- ylmethoxy)- 1 H-pyridin-2-one;

4-(2-Ethyl-thiazol-4-ylmethoxy)- 1 -(6-methylaminomethyl-3 ,4-dihydro-naphthalen-2-yl)- 1 H- pyridin-2-one;

l-(6-Dimethylaminomethyl-3,4-dihydro-naphthalen-2-yl)-4-(2-ethyl-thiazol-4-ylmethoxy)- lH-pyridin-2-one;

4-(4-Isopropyl-thiazol-2-ylmethoxy)- 1 - [6-(4-methyl-piperazin- 1 -ylmethyl)-3 ,4-dihydro- naphthalen-2-yl]- 1 H-pyridin-2-one;

l-{6-[(l ,l-Dioxo-hexahydro-116-thiopyran-4-ylamino)-methyl]-3,4-dihydro-naphthalen-2- yl} -4-(5-methyl-thiazol-2-ylmethoxy)- 1 H-pyridin-2-one;

1 -[6-(4-Methyl-piperazin- 1 -ylmethyl)-3 ,4-dihydro-naphthalen-2-yl]-4-(5-methyl-thiazol-2- ylmethoxy)- 1 H-pyridin-2-one;

l-{6-[(2-Fluoro-ethylamino)-methyl]-3,4-dihydro-naphthalen-2-yl}-4-(5-methyl-thiazol-2- ylmethoxy)- 1 H-pyridin-2-one;

l-(6-Methylaminomethyl-3,4-dihydro-naphthalen-2-yl)-4-(5-methyl-thiazol-2-ylmethoxy)- lH-pyridin-2-one;

l-(6-Dimethylaminomethyl-3,4-dihydro-naphthalen-2-yl)-4-(5-methyl-thiazol-2-ylmethoxy)- lH-pyridin-2-one;

(R)4-(5-Methyl hiazol-2-ylmethoxy)-l-{6-[(tetrahydro-furan-3-ylamino)-methyl]-3,4- dihydro-naphthalen-2-yl} - 1 H-pyridin-2-one;

4-(4-Chloro-thiazol-2-ylmethoxy)-l-[6-(4-methyl-piperazin-l-ylmethyl)-3,4-dihydro- naphthalen-2-yl]- 1 H-pyridin-2-one;

4-(4-Chloro-thiazol-2-ylmethoxy)-l-{6-[(2-fluoro-ethylamino)-methyl]-3,4-dihydro- naphthalen-2-yl} - 1 H-pyridin-2-one; 1 -[6-(4-Methyl-piperazin- 1 -ylmethyl)-3 ,4-dihydro-naphthalen-2-yl]-4-(thiazol-2- ylmethoxy)- 1 H-pyridin-2-one;

4-((5-chlorothiazol-2-yl)methoxy)- 1 -(6-((( 1 , 1 -dioxidotetrahydro-2H-thiopyran-4- yl)amino)methyl)-3 ,4-dihydronaphthalen-2-yl)pyridin-2( 1 H)-one;

2- { 1 -[6-(4-Methyl-piperazin- 1 -ylmethyl)-3 ,4-dihydro-naphthalen-2-yl]-2-oxo- 1 ,2-dihydro- pyridin-4-yloxymethyl}-thiazole-4-carboxylic acid methyl ester;

4-(4-Hydroxymethyl-thiazol-2-ylmethoxy)- 1 -[6-(4-methyl-piperazin- 1 -ylmethyl)-3 ,4- dihydro-naphthalen-2-yl]- 1 H-pyridin-2-one;

l-(6-Dimethylaminomethyl-3,4-dihydro-naphthalen-2-yl)-4-(4-methoxymethyl-thiazol-2- ylmethoxy)- 1 H-pyridin-2-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, Ν,Ν'- dibenzylethylenediamine, 2-hydroxyethylamine, 6w-(2-hydroxyethyl)amine, tri-(2- hydroxyethyl)amine, procaine, dibenzylpiperidine, dehydroabietylamine, N,7V- ^wdehydroabietylamine, 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.

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. 1 1C 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). 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 polyoxyethylene 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.

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.

The present invention also 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" represents a saturated, straight, or branched hydrocarbon moiety, 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. The term "(Ci-C6)alkyl" refers to an alkyl moiety containing from 1 to 6 carbon atoms. Exemplary alkyls include, but are not limited to methyl, ethyl, ^-propyl, isopropyl, «-butyl, isobutyl, s-butyl, i-butyl, pentyl, and hexyl.

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 preferably with 1-3 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 the radical -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, oxabicylo[2.2.1]heptyl, 1 , 1 -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, hydroxyl, 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.

Compound Preparation

Abbreviations

AcOH acetic acid

AIBN azobisisobutyronitrile

AICI₃ aluminum trichloride

aq. aqueous Ar argon gas

Br₂ bromine

CBr₄ carbon tetrabromide

CCI₄ carbon tetrachloride

CH2CI2 dichloromethane

CH₃CN acetonitrile

CH₃I methyl iodide

(CH₂0)_n paraformaldehyde

CH₃SO₃H methanesulfonic acid

cone. Concentrated

CS2CO3 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

Et₃ triethylamine

Et₂0 diethyl ether

EtOH ethanol

FeS0₄ iron(II) sulfate h hour(s)

H₂ hydrogen gas

HATU 0-(7-azabenzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

HBr hydrobromic acid

HC1 hydrochloric acid

H₂0 water

HNO₃ nitric acid

HOBt hydroxybenzotriazole

HPLC high-performance liquid chromatography

H₂SO₄ sulfuric acid

I₂ iodine

-PrMgCl isopropylmagnesium chloride

K2CO3 potassium carbonate

K₃Fe(CN)6 potassium ferricyanide

KOi-Bu potassium teri-butoxide

K₃PO₄ potassium phosphate tribasic

LCMS liquid chromatography mass spectrometry

L1AIH₄ lithium aluminum hydride

LiOH lithium hydroxide

w-CPBA weto-chloroperbenzoic acid

MeMgBr methyl magnesium bromide

MeOH methanol

Mg magnesium

MgCl₂ magnesium chloride

min minute(s)

Mn0₂ manganese dioxide

N₂ nitrogen gas

NaBH₄ sodium borohydride

NaCN sodium cyanide Na₂C0₃ sodium carbonate

NaH sodium hydride

NaHC0₃ sodium bicarbonate

NaHS0₃ sodium bisulfite

NaN₃ sodium azide

NaOH sodium hydroxide

a₂S0₄ sodium sulfate

NBS N-Bromosuccinimide

n- uLi «-butyllithium

NH₄CI ammonium chloride

NMM N-methylmorpholine

PCC pyridinium chlorochromate

PE petroleum ether

Pd/C palladium on carbon

Pd(dppf)Cl₂ [1 ,1 '-bis(diphenylphosphino)ferrocene] dichloropalladium(II)

Pd(PPh₃)₄ tetrakis(triphenylphosphine)palladium(0)

PhN0₂ nitrobenzene

POCl₃ phosphoryl chloride

PPh₃ triphenylphosphine

p-TsOR ?ara-toluene sulfonic acid

R_f retention factor

rt room temperature

R_t retention time

SOCl₂ 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. Starting materials are commercially available or are made from commercially available starting materials using methods known to those skilled in the art.

Intermediate thiazolylmethanol (3) can be prepared as illustrated in Scheme 1 via three different routes. Reaction of bromomethylketone (1) with amino-thioxo-acetic acid ethyl ester provided ethyl ester (2). Reduction of ethyl ester (2) with NaBH₄ gave thiazolylmethanol (3). Alternatively, palladium mediated carbonylation with chlorothiazole in the presence of EtOH gave ethylester (5) which could be reduced with NaBH₄ to give thiazolylmethanol (3). Finally, a thiazole could be treated with «-BuLi, followed by treatment of DMF to give aldehyde (7). Reduction of aldehyde with NaBH₄ also gave thiazolylmethanol (3). Scheme 1 : Generic Synthesis of Thiazolylmethanol (3)

Pyridine

Et₃N, 80°C

Intermediate thiazole substituted pyridone (9) can be prepared as illustrated in Scheme 2. Treatment of thiazolylmethanol (3) with methanesulfonyl chloride provided mesylate (8). Reaction of mesylate (8) with 2,4-dihydroxypyridine in the presence of K₂CO₃ gave the desired pyridone (9).

Scheme 2: Generic Synthesis of Thiazole Substituted Pyridone Intermediate (9)

DMF Intermediate iododihydronaphthalenecarbonitrile (17) can be prepared as illustrated in Scheme 3. Reaction of 2-(4-bromophenyl)acetic acid (10) with SOCl₂ provided the acid chloride (11), which was immediately treated with AICI₃ under an ethylene gas atmosphere to produce 2-bromo-6-oxo-5,6,7,8-tetrahydronaphthalene (12). Reaction of compound (12) with zinc cyanide in the presence of catalytic palladium provided the nitrile (13). Inflation of the ketone of compound (13) under standard conditions provided the triflate (14).

Compound (14) 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 (15), which was hydrolyzed using standard periodate procedures to produce the boronic acid (16). Treatment of compound (16) with NIS provided iododihydronaphthalenecarbonitrile (17).

Scheme 3: Synthesis of Intermediate Iododihydronaphthalenecarbonitrile (17)

Compounds of the invention can be prepared as illustrated in Scheme 4. Reaction of thiazole substituted pyridone intermediates (9) with intermediate (17) using standard copper- mediated coupling conditions provided 6-dihydronaphthylene-2-carbonitrile intermediates (18). Subsequent treatment of intermediates (18) with diisobutylaluminium hydride at reduced temperature provided 2-carbaldehyde intermediates (19). Reductive amination of intermediates (19) using sodium triacetoxyborohydride or an equivalent reagent, in the presence or absence of molecular sieves, with the amines encompassed within the scope of this invention or appropriately functional-group-protected version thereof, with subsequent routine deprotection and/or routine post-reductive-amination deproctection/derivitization thereof, provided Examples (20).

Scheme 4: Synthesis of Examples of Formula (I)

19 20

Alternatively, compounds of invention can be prepared as illustrated in scheme 5. Reaction of benzyl protected pyridone with Intermediate (17) using standard copper- mediated coupling conditions provided 6-dihydronaphthylene-2-carbonitrile intermediates (21). Subsequent treatment of intermediates (21) with diisobutylaluminium hydride at reduced temperature provided 2-carbaldehyde intermediates (22). Deprotection of intermediate (22) in aqueous HC1 solution to afford intermediate (23), which reacted with intermediate (8) to afford intermediate (24). Reductive amination of intermediates (24) using sodium triacetoxyborohydride or an equivalent reagent, in the presence or absence of molecular sieves, with the amines encompassed within the scope of this invention or appropriately functional-group-protected version thereof, with subsequent routine deprotection and/or routine post-reductive-amination deproctection/derivitization thereof, provided Examples (20). Scheme 5: Alternative Synthesis of Examples of Formula (I)

Alternatively, compounds of invention can be prepared as illustrated in scheme 6. Reaction of protected pyridone with intermediate (17) using standard copper-mediated coupling conditions provided 6-dihydronaphthylene-2-carbonitrile intermediates (25). Subsequent treatment of intermediates (25) with diisobutylaluminium hydride at reduced temperature provided 2-carbaldehyde (26). Deprotection of intermediate (26) using Zinc in acetic acid afforded intermediate (27), which reacted with intermediate (8) to provide intermediate (28). Intermediate (28) was hydrolyzed in sodium hydroxide to afford benzyl alcohol (29). Benzyl alcohol (29) reacted with methanesulfonyl chloride to form benzyl chloride, which was treated with the amines encompassed within the scope of this invention or appropriately functional-group-protected version thereof, to afford Examples (20). Scheme 6: Alternative Synthesis of Examples of Formula (I)

DCE 20

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. Preparation of intermediates

I. 4-Methylthiazole-2-carbaldehyde

To a solution of 4-methylthiazole (30 g, 303 mmol) in anhydrous tetrahydrofuran (500 mL) stirred under nitrogen at -78 °C was added a solution of butyllithium (121 mL, 303 mmol) dropwise. The reaction mixture was stirred at -78 °C for 2 hours. Then anhydrous N,N- dimethylformamide (47.1 mL, 605 mmol) was added dropwise to the suspension. The reaction was warmed to room temperature slowly and stirred overnight. It was quenched by saturated solution of NH₄CI (300 mL) and extracted with ethyl acetate (300 mL x 3). The organic layers were combined and dried over anhydrous Na₂S0₄ and filtered. The filtrate was concentrated to give crude 4-methylthiazole-2-carbaldehyde (33.5 g, yield 87%) as brown oil without further purification: 1H NMR (400 MHz, CDC1₃) δ 9.95 (s, 1H), 7.33 (s, 1H), 2.57 (s, 3H).

II. (4-Methylthiazol-2-yl)methanol

To a suspension of 4-methylthiazole-2-carbaldehyde (67 g, 0.527 mol) in methanol (800 mL) stirred at 0 °C was added NaBH₄ (56.7 g, 1.5 mol) portionwise. After all the NaBH₄ was added, the reaction mixture was stirred at 25 °C for 16 hours. The reaction was quenched by water (800 mL) and extracted with ethyl acetate (500 mL x 3). The organic layers were combined and dried over anhydrous Na₂S0₄ and filtered. The filtrate was concentrated and purified by flash chromatography with PE:EtOAc = 10: 1 to give (4- methylthiazol-2-yl)methanol (28 g, 217 mmol, 41 % yield) as red liquid: H NMR (400 MHz, CD₃OD) δ 7.05 (s, 1H), 4.79 (s, 2H), 2.38 (s, 3H).

III. Methanesulfonic acid 4-methyl-thiazol-2-ylmethyl ester

To a stirred solution of (4-methyl-thiazol-2-yl)-methanol (1.5 g, 11.6 mmol) and Et₃N (4.85 mL, 34.8 mmol) in DCM (50 mL) was added MsCl (2.7 mL, 34.8 mmol) in dropwise at 0°C. After the additional, the mixture was stirred for 1 hour at room temperature. The reaction mixture was quenched by water (15 mL), extracted with ethyl acetate (3 x 20 mL). The combined organic phase was dried over Na₂S0₄, filtered and concentrated in vacuum to give the crude product methanesulfonic acid 4-methyl-thiazol-2- ylmethyl ester (2.4 g, 100% yield): ^lR NMR (400 MHz, CDC1₃) δ 7.01 (s, 1H), 5.43 (s, 2H), 3.13 (s, 3H), 2.46 (s, 3H).

IV. 4-(4-Methyl-thiazol-2-ylmethox - 1 H-pyri din-

To a mixture of pyridine-2,4-diol (1.3 g, 11.6 mmoL), potassium carbonate (4 g, 29 mmoL) in dry DMF (80 mL) was added methanesulfonic acid 4-methyl-thiazol-2-ylmethyl ester (2.4 g, 11.6 mmoL). The mixture was stirred overnight at 80 °C. The mixture was filtered, and the filtrate was concentrated. The residue was purified by column chromatography to provide 4-(4-methyl-thiazol-2-ylmethoxy)- 1 H-pyridin-2-one (1.1 g, 43%): 1H NMR (400 MHz, CD₃OD) δ 7.31 (s, 1H), 7.24 (d, J = 7.6 Hz, 1H), 5.91 (d, J= 7.6 Hz, 1H), 5.85 (s, 1H), 5.32 (s, 2H), 2.33 (s, 3H); ES-LCMS m/z 223.1 (M+H).

V. 6-oxo-5,6,7, 8-Tetrahydronaphthalene-2-carbonitrile

A solution of 2-(4-bromophenyl)acetic acid (300 g, 1.4 mol) and SOCl₂ (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 AICI₃ (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 Na₂S0₄ and evaporated to yield crude 2-bromo-6-oxo-5,6,7,8- tetrahydronaphthalene (300 g, 95.5% for 2 steps) as a yellow solid, which was used immediately in the next step: ^lR NMR (400 MHz, CDC1₃) δ 7.39 (d, J = 2.4 Hz, 1H), 7.39- 7.33 (m, 1H), 7.00-6.98 (m, 1H), 3.52 (s, 2 H), 3.05-3.02 (m, 2H), 2.55-2.51 (m, 2H); EC- LCMS m/z dosen't ionized.

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 CH₂CI₂ 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%): ^lR NMR (400 MHz, CDC1₃) δ 7.54-7.51 (m, 2H), 7.26-7.23 (m, 1H), 3.64 (s, 2 H), 3.1 1 (t, J= 6.8 Hz, 2H), 2.57 (t, J= 6.8 Hz, 2H); EC-LCMS m/z 172.1 (M+H). VI. 6-Trifluoromethylsulfonyloxy- -dihydronaphthalene-2-carbonitrile

n-BuLi (2.5 M, toluene, 280 mL, 702 mmol) was added dropwise to a solution of diisopropylamine (70 g, 702 mmol) in THF (1000 mL) at -78 °C under N₂. After stirring for 30 min, a solution of 6-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (100 g, 584 mmol) in THF (800 mL) was added dropwise. After stirring for 2 h, a solution of phenyl triflimide (250 g, 702 mmol) in THF (1000 mL) was added and the reaction was maintained for an additional 2 h. at -78 °C. The reaction mixture was warmed up to room temperature and stirred overnight. The solvent was evaporated in vacuo to give a crude product which was washed with NaOH aqueous (2M, 1.5L) and extracted with DCM (300 mL x 3), the combined organic layers were dried, concentrated to give 6-cyano-3,4-dihydro-2- naphthalenyl trifluoromethanesulfonate as a brown oil (130 g, 73%): ^lH NMR (400 MHz, CDCls) δ 7.61-7.50 (m, 1H), 7.48-7.38 (m, 1H), 7.19-7.09 (m, 1H), 6.51 (s, 1H), 3.12-3.06 (m, 2H), 2.75-2.71 (m, 2H); ES-LCMS m/z 304 (M+H).

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

A solution of 6-cyano-3,4-dihydronaphthalen-2-yl trifluoromethanesulfonate (202 g,

666 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (186 g, 733 mmol), potassium acetate (196 g, 1998 mmol), PdCi₂(dppf) (19.50 g, 26.6 mmol) in 1,4-Dioxane (2400 mL) was heated to 80-85 °C under nitrogen for 12 hr. The reaction mixture was evaporated in vacuo and purified by chromatography column over silica gel to provide 6- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-7,8-dihydronaphthalene -2-carbonitrile (140 g, 74.8 % yield): 1H NMR (400 MHz, CDC1₃) δ 7.43-7.40 (m, 1H), 7.35 (s, 1H), 7.14-7.11 (m, 1 H), 2.76-2.72 (m, 2H), 2.42-2.38 (m, 2H), 1.29 (s, 12 H); ES-LCMS m/z 282 (M+H).

VIII. 7,8-Dihydronaphthalene-2-carbonitrile-6-boronic acid

To a ice-water cooled mixture of 6-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-7,8- dihydronaphthalene-2-carbonitrile (103 g, 366 mmol) and ammonium acetate (86 g, 1117 mmol) in acetone (1000 mL) and water (1000 mL) was added sodium periodate (235 g, 1099 mmol) in small portions (the reaction was highly exothermic). After the completion of addition, the reaction was stirred at room temperature overnight. The white solid was removed by filtration, and the cake was washed by acetone. The acetone was evaporated in vacuo and the crude product precipitated out as yellow solid and collected by filtration. All the impurities were removed by washing with PE to give (6-cyano-3,4-dihydronaphthalen-2- yl)boronic acid (65 g, 89 % yield): ^lR NMR (400 MHz, CD₃OD) δ 7.48-7.43 (m, 2H), 7.20- 7.18 (m, 1H), 7.05-6.95 (m, 1H), 2.73 (t, J= 8.0 Hz, 2H), 2.34 (t, J= 8.0 Hz, 2H); ES-LCMS m/z 200 (M+H).

IX. 6-Iodo-7,8-dihydronaphthalene-2-carbonitrile

A mixture of (6-cyano-3,4-dihydronaphthalen-2-yl)boronic acid (100 g, 502 mmol) and NIS (119 g, 528 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 (500 mL). The layers were separated and the aqueous layer was extracted with DCM. Combined organic layers were dried over a₂S0₄, filtered and evaporated in vacuo to a solid residue. The solid was triturated with hexanes, filtered and dried under high vacuum to give 6-iodo-7,8-dihydronaphthalene-2-carbonitrile (130 g, 92 % yield): 1H NMR (400 MHz, CDC1₃) δ 7.43-7.41 (m, 1H), 7.32 (s, 1 H), 7.12 (s, 1 H), 6.98 (d, J= 8.0 Hz, 1 H), 2.88-2.85 (m, 4 H); ES-LCMS m/z 282.0 (M+H).

X. 6-[4-{[(5-Chloro-2-pyridinyl)methyl]oxy}-2-oxo-l(2H)-pyridinyl] -7,8-dihydro-2- naphthalenecarbonitrile

A mixture of 4-{[(5-chloro-2-pyridinyl)methyl]oxy}-2(lH)-pyridinone (30 g, 126 mmol),

6-iodo-7,8-dihydro-2-naphthalenecarbonitrile (36 g, 126 mmol), N,N'-dimethyl-l ,2-ethanediamine

(4.5 g, 51 mmol), copper iodide (4.8 g, 25.4 mmol), powdered cesium carbonate (84 g, 255 mmol) and 2,6-di-tert-butyl-4-hydroxytoluene (111 g, 507 mmol) in toluene (1L) was heated under nitrogen at reflux overnight. After cooling to room temperature, the product precipitated out, and was collected by filtration. The cake was washed with toluene (100 mL x 3) and PE (300 mL x 3). Then the solid was dissolved in DCM (5 L), and filtered. The filtrate was concentrated, and pure product was obtained as grey solid (34 g, 69%): ^lR NMR (400 MHz, CDC1₃) δ ppm 8.57 (s, 1 H), 7.71 (dd, J = 8.4 Hz, 1 H), 7.50-7.42 (m, 3 H), 7.19 (d, J = 6.0 Hz, 1 H), 7.13 (d, J = 7.6 Hz, 1 H), 6.46 (s, 1 H), 6.05 (d, J = 6.4 Hz, 1 H), 5.93 (s, 1 H), 5.11 (s, 2 H), 3.05 (t, J = 8.0 Hz, 2 H), 2.76 (t, J= 8.2 Hz, 2 H); ES-LCMS m/z 390 (M+H).

XI. 6-[4- { [(5-Chloro-2-pyridinyl)methyl]oxy} -2-oxo- 1 (2H)-pyridinyl]- 7,8-dihydro-2- naphthalenecarbaldehyde

A solution of 6-[4- {[(5-chloro-2-pyridinyl)methyl]oxy}-2-oxo-l(2H)-pyridinyl]-7,8- dihydro-2-naphthalenecarbonitrile (34 g, 87 mmol) in DCM (1 L) under nitrogen was cooled with a dry ice/acetone bath. A solution of diisobutylaluminium hydride (1 M, toluene, 265 mL, 265 mmol) was added to the nitrile via addition funnel. After the completion of addition, the reaction was stirred for another 30 min at the same temperature and then quenched by dropwise addition of MeOH (70 mL). The reaction mixture was diluted with DCM (1.5 L) and washed with saturated aqueous citric acid (100 mL). The layers were separated and the aqueous phase was extracted with DCM (2 x 100 mL). The combined organic layers were dried over Na₂S0₄, filtered and evaporated in vacuo. The residue was purified by chromatography column (DCM/MeOH =100/1) over silica gel to provide 6-[4- {[(5-chloro-2- pyridinyl)methyl]oxy} -2-oxo- 1 (2H)-pyridinyl]-7,8-dihydro-2-naphthalenecarbaldehyde as a yellow solid (30 g, 87 %): 1H NMR (400 MHz, CDC1₃)□ 9.97 (s, 1 H), 8.59 (d, J= 2.0 Hz, 1 H), 7.75-7.69 (m, 3 H), 7.43 (d, J = 8.4 Hz, 1 H), 7.25-7.21 (m, 2 H), 6.53 (s, 1 H), 6.08 (dd, J = 7.6, 2.4 Hz, 1 H), 5.96 (d, J = 2.8 Hz, 1 H), 5.15 (s, 2 H), 3.13 (t, J = 8.2 Hz, 2 H), 2.81 (t, J = 8.2 Hz, 2 H); ES-LCMS m/z 393 (M+ ).

XII. 6-Iodo-7,8-dihydro-naphthalene-2-carbaldehyde

To a stirred solution of 6-iodo-7,8-dihydronaphthalene-2-carbonitrile (100 g, 356 mmol) in Dichloromethane (DCM) (1000 mL) was added DIBAL-H (889 mL, 889 mmol) at -78 °C under nitrogen for 0.5 hr. The mixture was then quenched with saturated citric aqueous (500 mL), and the solvent was then removed to give the residue which was washed by water (800 mL) and extracted with DCM (20 mL x 2). The combined organic layers were dried and concentrated to give 6-iodo-7,8-dihydronaphthalene-2-carbaldehyde (95 g, 94 % yield): 1H NMR (400 MHz, CDC1₃) δ 9.92 (s, 1 H), 7.67-7.65 (m, 1H), 7.60 (s, 1 H), 7.18 (d, J = 2.0 Hz, 1 H), 7.08 (d, J= 8.0 Hz, 1 H), 2.95-2.88 (m, 4H); ES-LCMS m/z 285.0 (M+H).

XIII. 6-[4-(4-Methyl-thiazol-2-ylmethoxy)-2-oxo-2H-pyridin-l-yl]-7,8-dihydro- naphthalene-2-carbonitrile

A mixture of 4-(4-methyl-thiazol-2-ylmethoxy)-lH-pyridin-2-one (1.05 g, 4.7 mmol), 6- iodo-7,8-dihydro-2-naphthalenecarbonitrile (1.32 g, 4.7 mmol), Ν,Ν'-dimethyl- 1 ,2-ethanediamine (218 g, 1.88 mmol), copper iodide (179 mg, 0.94 mmol), powdered cesium carbonate (3.06 g, 9.4 mmol) and 2,6-di-tert-butyl-4-hydroxytoluene (4.14 g, 18.8 mmol) in toluene (30 mL) was heated under nitrogen at reflux overnight. The reaction mixture was diluted with DCM (300 mL) and filtered. The filtrate was washed by water (100 mL), dried over a₂S0₄ and concentrated to give a crude product which was purified by chromatography column over silica gel to give 6-[4-(4- methyl-thiazol-2-ylmethoxy)-2-oxo-2H-pyridin-l-yl]-7,8-dihydro-naphthalene-2-carbonitrile (1.5 g, 84%): ^lR NMR (400 MHz, CDC1₃) δ 7.68 (m, H), 7.52 (m, 2H), 7.23 (m, 1H), 6.98 (m, 1H), 6.54 (s, 1H), 6.01 (m, 1H), 5.98 (m, 1H), 5.24 (s, 2H), 3.06 (m, 2H), 2.83 (m, 2H), 2.45 (s, 3H); ES-LCMS m/z 376.0 (M+H). XIV. 6-[4-(4-Methyl-thiazol-2-ylmethoxy)-2-oxo-2H-pyridin-l-yl]-7,8-dihydro- naphthalene-2-carbaldehyde

A solution of 6-[4-(4-Methyl-thiazol-2-ylmethoxy)-2-oxo- 2H-pyridin-l-yi]-7,8- dihydro-naphthalene-2-carbonitrile (300 mg, 0.8 mmol) in DCM (30 mL) under nitrogen was cooled to -80 °C with a dry ice/ether bath. A pre-cooled solution of diisobutylaluminium hydride (1 M, toluene, 2.4 mL, 2.4 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 (5 mL). The reaction mixture was diluted with DCM (30 mL) and washed by saturated aqueous citric acid (10 mL). The layers were separated and the aqueous phase was back- extracted with DCM (2 x 10 mL). The combined organic layers were dried over a₂S0₄, filtered and evaporated in vacuo to provide 6-[4-(4-methyl-thiazol-2-ylmethoxy)-2-oxo-2H- pyridin-l-yl]-7,8-dihydro-naphthalene-2-carbaldehyde (300 mg, 100 %): 1H NMR (400 MHz, CDCls) 9.89 (s, 0.2H), 7.13 (m, 4H), 6.87 (m, 1H), 6.43 (m, 1H), 5.97 (m, 2H), 5.23 (s, 2H), 2.98 (m, 2H), 2.64 (m, 2H), 2.46 (s, 3H);.

XV. Acetic acid 6-(4-hydroxy-2-oxo-2H-pyridin-l-yl)-7, 8-dihydro-naphthalen-2- ylmethyl ester

The mixture of 6-[4-(5-chloro-pyridin-2-ylmethoxy)-2-oxo-2H-pyridin-l-yl]-7,8- dihydro-naphthalene-2-carbaldehyde (100 g, 255 mmol) and zinc (83 g, 1273 mmol) in acetic acid (800 mL), was stirred at 140 °C for 2 hours. The mixture was filtered and the filtrated was concentrated. The mixture was purified by column chromatography on silica (DCM/ MeOH=50: 1) to give acetic acid 6-(4-hydroxy-2-oxo-2H-pyridin-l-yl)-7,8-dihydro- naphthalen-2-ylmethyl ester a yellow solid (44 g, 50% yield): 1H NMR (400MHz, CDC1₃) δ 7.10 (d, J = 7.2 Hz, 1H), 7.06-7.01 (m, 2H), 6.94-6.91 (m, 3H), 6.31 (m, 1H), 5.90 (dd, J = 7.2, 2.4 Hz, 1H), 5.68 (d, J= 2.4 Hz, 1H), 4.09 (s, 2 H), 2.89 (t, J= 8.0 Hz, 1H), 2.54 (t, J= 8.0 Hz, 1H), 1.96 (m, 3H); ES-LCMS m/z 312 (M+H).

XVI. (6-(4-((4-Methylthiazol-2-yl)methoxy)-2-oxopyridin- 1 (2H)-yl)-7,8- dihydronaphthalen-2-yl)methyl acetate

To a suspension of (6-(4-hydroxy-2-oxopyridin-l(2H)-yl)-7,8-dihydronaphthalen-2- yl) methyl acetate (1.61 g, 5.20 mmol) and (4-methylthiazol-2-yl)methyl methanesulfonate (1.4 g, 6.75 mmol) in anhydrous N,N-dimethylformamide (20 mL) was added K₂CO₃ (1.44 g, 10.41 mmol), stirred at 70 °C for 6 hours. The suspension was cooled to room temperature and filtered to give crude (6-(4-((4-methylthiazol-2-yl)methoxy)-2-oxopyridin-l(2H)-yl)- 7,8- dihydronaphthalen-2-yl)methyl acetate (2.1 g, crude) as a brown solid without further purification: 1H NMR (400 MHz, CD₃OD) δ 7.57 (d, J = 7.6 Hz, 1H), 7.24-7.14 (m, 4H), 6.58 (s, 1H), 6.26 (dd, J = 7.6, 2.8 Hz, 1H), 6.10 (d, J = 2.8 Hz, 1H), 5.41 (s, 2H), 5.09 (s, 2H), 3.08-3.05 (m, 2H), 3.03-2.66 (m, 2H), 2.46 (s, 3H), 2.10 (s, 3H); ES-LCMS m/z 423 (M+H). XVII. 1 -(6-(Hydroxymethyl)-3,4-dihydronaphthalen-2-yl)-4-((4-methylthiazol-2-yl) methoxy)pyridin-2(lH)-one

To a suspension of (6-(4-((4-methylthiazol-2-yl)methoxy)-2-oxopyridin-l(2H)-yl)- 7,8- dihydronaphthalen-2-yl)methyl acetate (2.1 g, crude) in methanol (30 mL) and water (6 mL) was added sodium hydroxide (0.31 g, 7.7 mmol), stirred at 25 °C for 3 hours. It was evaporated in vacuo to give the residue, which was purified by flash chromatography to give l-(6-(hydroxymethyl)-3,4-dihydronaphthalen-2-yl)-4-((4-methylthiazol-2- yl)methoxy)pyridin-2(lH)-one (1.25 g, yield 65% of two steps) as a yellow solid: 1H NMR (400 MHz, CDCls) δ 7.54 (d, J = 7.6 Hz, 1H), 7.22-7.16 (m, 3H), 7.11 (d, J = 8.0 Hz, 1H), 6.55 (s, 1H), 6.23 (dd, J = 7.6, 2.8 Hz, 1H), 6.07 (d, J = 2.8 Hz, 1H), 5.38 (s, 2H), 4.57 (s, 2H), 3.05-3.01 (m, 2H), 2.67-2.63 (m, 2H), 2.44 (s, 3H); ES-LCMS m/z 381 (M+H).

XVIII. 1 -(6-(Chloromethyl)-3 ,4-dihydronaphthalen-2-yl)-4-((4-methylthiazol-2- yl)methoxy)pyridin-2( lH)-one

To a solution of l-(6-(hydroxymethyl)-3,4-dihydronaphthalen-2-yl)-4-((4- methylthiazol-2-yl)methoxy)pyridin-2(lH)-one (0.40 g, 1.051 mmol) and N-ethyl-N- isopropylpropan-2-amine (0.272 g, 2.103 mmol) in DCM (20 mL) was added dropwise methanesulfonyl chloride (0.120 g, 1.051 mmol) at r.t. Then, the mixture was stirred at r.t overnight. LCMS showed that the reaction was finished. The mixture was dissolved in DCM (20 mL), washed with water (20 mLx3) and dried over a₂S0₄. The organic phase was concentrated under vacuum to give l-(6-(chloromethyl)-3,4-dihydronaphthalen-2-yl)-4- ((4-methylthiazol-2-yl)methoxy)pyridin-2(lH)-one (0.3 g, 0.752 mmol, 71.5 % yield) as a brown oil: 1H NMR (400 MHz, CDC1₃) δ 7.25-7.18 (m, 3H), 7.07-7.05 (m, 1H), 6.96 (d, J = 2.0 Hz, 1H), 6.45 (s, 1H), 6.07-6.05 (m, 2H), 5.29 (d, J= 1.6 Hz, 2H), 4.56 (s, 2H), 3.05-3.02 (m, 2H), 2.75-2.73 (m, 2H), 2.48 (s, 3H); EC-LCMS m/z 399 (M+H).

XIX. Methanesulfonic acid 4-ethyl-thiaz -2-ylmethyl ester

Step 1 : 4-Ethyl-thiazole-2-carboxylic acid ethyl ester

To a solution of 1 -bromo-butan-2-one (4 g, 26.7 mmol) in EtOH (50 mL) was added amino-thioxo-acetic acid ethyl ester (3.55 g, 26.7 mmol) and pyridine (4.21 g, 33.4 mmol) at room temperature. The mixture was heated to reflux overnight. After LCMS showed the starting material was consumed, the mixture was concentrated to give crude product, which was purified by column to give 4-ethyl-thiazole-2-carboxylic acid ethyl ester (1.6 g, 32.4%): 1H NMR (400 MHz, CD₃OD) δ 7.52-7.53 (m, 1H), 4.40-4.45 (m, 2H), 2.84-2.86 (m, 2H), 1.38-1.41 (t, J = 7.20 Hz, 2H), 1.28-1.32 (t, J = 7.60 Hz, 2H); ES-LCMS m/z 186(M+H). Step 2: (4-Ethyl-thiazol-2-yl)-methanol

To a solution of 4-isopropyl-thiazole-2-carboxylic acid ethyl ester (1.6 g, 8.65 mmol) in MeOH (20 mL) was added NaBH₄ (986 mg, 25.9 mmol) at 0 °C. Then the mixture was stirred at room temperature for 2 hours. The mixture was concentrated to give crude product which was extracted with DCM (2 x 20 mL), dried over Na₂S0₄, concentrated to give (4- ethyl-thiazol-2-yl)-methanol (1.0 g, 81%): 1H NMR (400 MHz, CD₃OD) δ 7.06 (m, 1H), 4.79-4.85 (m, 2H), 2.71-2.77 (m, 2H), 1.24-1.28 (t, J = 7.40 Hz, 2H); ES-LCMS m/z 144 (M+H).

Step 3: Methanesulfonic acid 4-ethy -thiazol-2-ylmethyl ester

To the solution of (4-isopropyl-thiazol-2-yl)-methanol (150 mg, 1.05 mmol) in DCM (15 mL) was added Et₃N (159.2 mg, 1.57 mmol) and MsCl (143 mg, 1.26 mmol) at 0 °C. After the mixture was stirred for 30 min later, the mixture was washed with citric acid and extracted with DCM (2 x 30 ml), dried over Na₂S0₄, and the organic phase was concentrated to give methanesulfonic acid 4-ethyl-thiazol-2-ylmethyl ester (0.16 g, 96.9%): ^lH NMR (400 MHz, CD3OD) δ 7.31 (m, 1H), 5.49-5.48 (d, J = 2.40 Hz, 1H), 3.19 (s, 3H), 2.85-2.78 (m, 2H), 1.35-1.27 (m, 3H); ES-LCMS m/z 222 (M+H).

XX._6-[4-(4-Ethyl-thiazol-2-ylmethoxy)-2-oxo-2H-pyridin-l-yl]-7,8-dihydro - naphthalene-2-carbaldehyde

A mixture of 6-(4-hydroxy-2-oxo-2H-pyridin-l-yl)-7,8-dihydro-naphthalene-2- carbaldehyde (267 mg, 1 mmol), methanesulfonic acid 4-ethyl-thiazol-2-ylmethyl ester (21 mg, 1 mmol) and K₂CO₃ (414 mg, 3 mmol) in DMF (15 mL) was stirred overnight at room temperature. The mixture was and extracted with DCM (2 x 20 mL), dried over a₂S0₄, and the organic phase was concentrated to give the residue, which was purified by preparative TLC to give 6-[4-(4-ethyl-thiazol-2-ylmethoxy)-2-oxo-2H-pyridin-l-yl]-7,8-dihydro- naphthalene-2-carbaldehyde (160 mg, 40.8%): ^lR NMR (400 MHz, CD₃OD) δ 9.83 (s, 1H), 7.65-7.63 (m, 1H), 7.59 (s, 1H), 7.48 (d, J = 7.60 Hz, 1H), 7.25 (d, J= 8.00 Hz, 1H), 7.14 (s, 1H), 6.59 (s, 1H), 6.16 (dd, J =7.20, 2.40 Hz, 1H), 6.00 (d, J = 2.80 Hz, 1H), 5.31 (s, 2H), 3.03 (t, J = 8.20 Hz, 2H), 2.72-2.68 (m, 2H), 2.64 (t, J = 8.20 Hz, 2H), 1.20 (t, J = 7.60 Hz, 2H); ES-LCMS m/z 393 (M+H).

XXI. (6-(4-((4-Ethylthiazol-2-yl)methoxy)-2-oxopyridin- 1 (2H)-yl)-7,8-dihy

dronaphthalen-2-yl)methyl acetate

A mixture of (6-(4-hydroxy-2-oxopyridin-l(2H)-yl)-7,8-dihydronaphthalen-2- yl)methyl acetate (4.50 g, 14.46 mmol), (4-ethylthiazol-2-yl)methylmethanesulfonate (3.2 g, 14.46 mmol) and potassium carbonate (1.998 g, 14.46 mmol) in DMF (20 mL) was heated to reflux overnight. The mixture was filtered, and the filtrate was concentrated in vacuo to give the residue which was purified by column to give (6-(4-((4-ethylthiazol-2-yl)methoxy)-2- oxopyridin-l(2H)-yl)-7,8-dihydronaphthalen-2-yl)methyl acetate (6.3 g, 59.9 % yield); ES- LCMS m/z 437 (M+H). XXII. 4-((4-Ethylthiazol-2-yl)methoxy)- 1 -(6-(hydroxymethyl)-3 ,4-dihydrona phthalen-2- yl) pyridin-2(lH)-one

A mixture of (6-(4-((4-ethylthiazol-2-yl)methoxy)-2-oxopyridin-l(2H)-yl)-7,8- dihydronaphthalen-2-yl)methyl acetate (6.3 g, 14.43 mmol) and sodium hydroxide (2.89 g, 72.2 mmol) in methanol (20 mL) and H₂0 (20 mL) was heated to reflux for 2 hours. Then the mixture was concentrated and extracted with DCM (2 x 30 mL), dried over a₂S04 and filtered. The filtrate was concentrated to give 4-((4-ethylthiazol-2-yl)methoxy)-l-(6- (hydroxymethyl)-3 ,4-dihydronaphthalen-2-yl)pyridin-2( 1 H)-one (2 g, 31.6 % yield). H NMR (400 MHz, CD₃OD) δ 7.59-7.58 (d, J= 7.60 Hz, 1H), 7.52 (s, 1H), 7.52-7.50 (m, 2H), 7.25-7.20 (m, 1H), 6.57 (s, 1H), 6.27-6.25 (dd, J= 7.60, 2.80 Hz, 1H), 6.10 (d, J= 2.80 Hz, 1H), 5.42 (s, 2H), 4.59 (s, 3H), 3.86 (s, 1H), 3.06 (t, J = 8.20 Hz, 2H), 2.84-2.80 (m, 2H), 2.67 (t, J= 8.00 Hz, 2H), 1.34-1.30 (m, 3H);

XXIII. (6-(4-((4-Ethylthiazol-2-yl)methoxy)-2-oxopyridin- 1 (2H)-yl)-7,8-dihydrona phthalen-2-yl)methyl methanesulfonat

To a mixture of 4-((4-ethylthiazol-2-yl)methoxy)-l-(6-(hydroxymethyl)-3,4- dihydrona phthalen-2-yl)pyridin-2(lH)-one (600 mg, 1.521 mmol), and Et₃N (0.32 mL, 2.28 mmol) in DCM (20 mL) was added methanesulfonyl chloride (0.130 mL, 1.673 mmol) at 0 °C. After being stirred for 30 min, the mixture was washed with citric acid and extracted with DCM (2 x 30 mL). The combined organic layers were dried over Na₂S0₄, filtered, and the filtrate was concentrated to give (6-(4-((4-ethylthiazol-2-yl)methoxy)-2-oxopyridin- l(2H)-yl)-7,8-dihydronaphthalen-2-yl)methyl methanesulfonate (650 mg, 90 % yield).

XXIV. 6-(4-Benzyloxy-2-oxo- -pyridin- 1 -yl)-7,8-dihydro-naphthalene-2- carbonitrile

The mixture of 4-benzyloxy-lH-pyridin-2-one (2.148 g, 10.67 mmol), 6-iodo-7,8- dihydro-naphthalene-2-carbonitrile (2.5 g, 8.89 mmol), N,N'-dimethyl-ethane-l,2-diamine (0.314 g, 3.56 mmol), cesium carbonate (5.80 g, 17.79 mmol) and copper(T) iodide (0.339 g, 1.779 mmol) in Ν,Ν-dimethylformamide (DMF) (50 mL) was at 25 °C under Nitrogen for 16 hours. The mixture was filtered. The filtrate was concentrated and purified by column chromatography (DCM:MeOH=50: l) to give 6-(4-benzyloxy-2-oxo-2H-pyridin-l-yl)-7,8- dihydro-naphthalene-2-carbonitrile as a yellow solid (44 g, 50% yield ): ^lH NMR (400MHz, CDC13) δ 7.48-7.33 (m, 7H), 7.26-7.14 (m, 2H), 6.48 (s, 1H), 6.6.05-6.03 (m, 1H), 5.98 (d, J = 2.4 Hz, 1H), 5.02 (s, 2H), 3.05-3.09 (m, 2H), 2.81-2.77 (m, 2H); ES-LCMS m/z 355 (M+H).

XXV. 6-(4-(Benzyloxy)-2-oxopyridin- 1 (2H)-yl)-7,8-dihydronaphthalene-2- carbaldehyde

A solution of 6-(4-(benzyloxy)-2-oxopyridin-l(2H)-yl)-7,8-dihydronaphthalene-2- carbonitrile (3 g, 8.47 mmol) in DCM (200 mL) under nitrogen was cooled to -80 °C with a dry ice/ether bath. A pre-cooled solution of diisobutylaluminium hydride (1 M, toluene, 25 mL, 25 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 (5 mL). The reaction mixture was diluted with DCM (200 mL) and washed by saturated aqueous citric acid (100 mL). The layers were separated and the aqueous phase was back-extracted with DCM (2 x 80 mL). The combined organic layers were dried over a₂S0₄, filtered and evaporated in vacuo to provide 6-(4-(benzyloxy)-2-oxopyridin-l(2H)-yl)-7,8-dihydronaphthalene-2- carbaldehyde (1.5 g, 50 %): ^lR NMR (400 MHz, CDC1₃) 9.95 (s, 1H), 7.72-7.67 (m, 2H), 7.42-7.33 (m, 5H), 7.23-7.17 (m, 2H), 6.52 (s, 1H), 6.03 (dd, J= 7.6, 2.8 Hz, 1H), 5.98 (d, J = 2.4 Hz, 1H), 5.02 (s, 2H), 3.1 1 (t, J= 8.0 Hz, 2H), 2.80 (t, J= 8.0 Hz, 2H); ES-LCMS m/z 358.0 (M+H).

XXVI. 6-(4-Hydroxy-2-oxopyridin- 1 (2H)-yl)-7,8-dihydronaphthalene-2-carbaldehyde

A solution of 6-(4-(benzyloxy)-2-oxopyridin-l(2H)-yl)-7,8-dihydronaphthalene-2- carbaldehyde (1.5 g, 4.2 mmol) in concentrated HC1 (15 mL) was stirred at 80°C for 2 hours.

After LC-MS analysis showed the starting material was disappeared, the solvent was concentrated directly to afford 6-(4-hydroxy-2-oxopyridin-l(2H)-yl)-7,8- dihydronaphthalene-2-carbaldehyde (1.1 g, 98.1%): ^lR NMR (400 MHz, CD₃OD) δ 7.93 (d, J = 7.6 Hz, 1H), 7.31-7.15 (m, 3H), 6.73 (s, 1H), 6.60 (dd, J = 7.6, 2.4 Hz, 1H), 6.31 (d, J = 2.4 Hz, 1H), 5.32 (s, 1H), 3.08 (t, J = 8.4 Hz, 2H), 2.71 (t, J = 8.4 Hz, 2H); ES-LCMS m/z 268.1 (M+H).

XXVII. Methanesulfonic acid 4,5-dimethyl-thiazol-2-ylmethyl ester

Step 1 : 4,5-Dimethyl-thiazole-2-carbaldeh de

To a stirred solution of 4,5 -Dimethyl- thiazole (2 g, 17.7 mmol) in anhydrous THF (40 mL) was added n-BuLi (2.5 M in hexane, 8.5 mL, 21.2 mmol) dropwise at -68°C over 20 min, and the resulting suspension was stirred at -78°C for another 30 min. Then DMF (2.58 g, 35.4 mmol) was added dropwise over 20 min, while the temperature was kept below -68 °C. The reaction mixture was allowed to warm to room temperature during 3 h, and quenched with 20 mL of aqueous NH₄C1 solution. The layers were separated and the aqueous phase was extracted with EA (3 x 20 mL). The combined organic layer was dried over Na₂S0₄ and concentrated in vacuo to give crude 4,5-Dimethyl-thiazole-2-carbaldehyde (2.6 g, 100% yield): 1H NMR (400 MHz, CDC13) δ 9.78 (s, 1H), 3.47 (s, 6H); ES-LCMS m/z 142.1 (M+H). Step 2: (4,5-Dimethyl-thiazol-2-yl)-methanol

To a solution of 4,5-Dimethyl-thiazole (2.6 g, 18.4 mmol) in MeOH (40 mL) was added NaBH₄ (1.4 g, 36.8 mmol) in portions while the temperature was below 40 °C, and the mixture was stirred overnight. After TLC showed the start material was disappeared, the solvent was removed in vacuo. The residue was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over Na₂S0_4j filtered and concentrated in vacuo to give the crude product, which was purified by column chromatography to give the pure product (4,5-dimethyl-thiazol-2-yl)-methanol (2 g, 77% yield): ^lR NMR (400 MHz, CDC1₃) δ 4.76 (s, 2H), 2.25-2.21 (m, 6H); ES-LCMS m/z 144.0 (M+H).

Step 3: Methanesulfonic acid 4,5-dimethyl-thiazol-2-ylmethyl ester

To a stirred solution of (4,5-dimethyl-thiazol-2-yl)-methanol (200 mg, 1.4 mmol) and Et₃N (478 mg, 4.2 mmol) in DCM (20 mL) was added MsCl (424 mL, 4.2 mmol) in dropwise at 0 °C. After the additional, the mixture was stirred for 1 hour at room temperature. The reaction mixture was quenched by water (15 mL), extracted with DCM (3 x 10 mL). The combined organic phase was dried over Na₂S0₄, filtered and concentrated in vacuum to give the crude product methanesulfonic acid 4,5-dimethyl-thiazol-2-ylmethyl eesstteerr (250 mg, 100% yield): ^lR NMR (400 MHz, CDC1₃) δ 5.21 (s, 2H), 3.67 (s, 3H), 2.88 (s, 6H).

XXVIII. Methanesulfonic acid 2-methyl-thiazol-4- lmethyl ester

Step 1 : (2-Methyl-thiazol-4-yl)-methanol

To a solution 2-methyl-thiazole-4-carboxylic acid ethyl ester (0.9 g, 5.25 mmol) in CH₃OH (40 mL) was addded NaBH₄ (1.99 g, 52.5 mmol), then the reaction mixture was stirred at room temperature. After 4 hours, LC-MS analysis showed the starting material was disappeared, the solvent was removed in vacuo. The residue was dissolved in EtOAc and washed with H₂0. The organic layer was dried and concentrated to give (2-methyl-thiazol-4- yl)-methanol (0.5 g, 74% yield): ^lR NMR (400 MHz, CD₃OD) δ 7.14 (m, 1H), 4.56 (d, J = 0.8 Hz, 2H), 2.61 (s, 3H); ES-LCMS m/z 151.9 (M+Na).

Step 2: Methanesulfonic acid 2-meth l-thiazol-4-ylmethyl ester

To a solution of (2-methyl-thiazol-4-yl)-methanol (0.15 g, 1.16 mmol) and triethylamine (0.14 g, 1.4 mmol) in DCM (20 mL) was added methanesulfonyl chloride (0.15 g, 1.28 mmol) at 0 °C. The reaction mixture was stirred at room temperature. After 2 hours, TLC analysis showed the starting material was disappeared, the mixture was washed with H₂0, the organic layer was dried and concentrated to give methanesulfonic acid 2-methyl- thiazol-4-ylmethyl ester (0.12 g, 50% yield): 1H NMR (400 MHz, CD₃OD) δ 7.49-7.48 (m, 1H), 5.20 (d, J= 0.8 Hz, 2H), 3.02 (s, 3H), 2.65 (s, 3H). XXIX. Methanesulfonic acid 4-isopropyl-thiazol-2-ylmethyl ester

Step 1 : l-Bromo-3-methyl-butan-2-one

To a solution of 3-methyl-butan-2-one (10 g, 1 16 mmol) in EtOH (120 mL) was added Br₂ (16.7 g, 104 mmol) dropwise at 0 °C. Then the mixture was stirred overnight. The reaction was quenched by aq NaHS0₃ (100 mL). The mixture was extracted by DCM (3 x 100 ml), and the organic phase was concentrated to give l-bromo-3-methyl-butan-2-one, which was not purified for next step (8 g, 41.8%): ^lR NMR (400 MHz, CDC1₃) δ 4.43 (s, 2H), 2.97-2.96 (m, 1H), 1.16-1.12 (m, 6H); ES-LCMS m/z 165 (M+H).

Step 2: 4-Isopropyl-thiazole-2-carboxylic acid ethyl ester

To a solution of l-bromo-3-methyl-butan-2-one (8 g, 48.5 mmol) in EtOH (100 mL) was added amino-thioxo-acetic acid ethyl ester (6.46 g, 48.5 mmol) and pyridine (7.67 g, 97 mmol) at room temperature. The mixture was heated to reflux overnight. After LCMS showed the starting material was consumed, the mixture was concentrated to give crude product, which was purified by column to give 4-isopropyl-thiazole-2-carboxylic acid ethyl ester (4 g, 41.4%): 1H NMR (400 MHz, CDC1₃) δ 7.16 (s, 1H), 4.46-4.41 (m, 2H), 3.17 (m, 1H), 1.36 (m, 3H), 1.30 (m, 6H); ES-LCMS m/z 200(M+H).

Step 3: (4-Isopropyl-thiazol-2-yl)-m thanol

To a solution of 4-isopropyl-thiazole-2-carboxylic acid ethyl ester (4 g, 20.07 mmol) in MeOH (100 mL) was added NaBH₄ (3.8 g, 100 mmol) at 40 °C with stirred for 24 hr. The mixture was concentrated to give crude product, which was purified by column to give (4- isopropyl-thiazol-2-yl)-methanol (0.3 g, 58.5%): ^lR NMR (400 MHz, CDC1₃) δ 6.83 (s, 1H), 4.91 (m, 2H), 3.08-3.05 (m, 1H), 1.33-1.23 (m, 6H); ES-LCMS m/z 158 (M+H).

Step 4: Methanesulfonic acid 4-isopropyl-thiazol-2-ylmethyl ester

To the solution of (4-isopropyl-thiazol-2-yl)-methanol (3 g, 19.08 mmol) in DCM (100 mL) was added Et₃N (3.86 mg, 38.2 mmol) and MsCl (3.28mg, 28.6 mmol) at 0 °C. After the mixture was stirred for 2 hours, the mixture was extracted by DCM (3 x 100 ml), and the organic phase was concentrated to give methanesulfonic acid 4-isopropyl-thiazol-2- ylmethyl ester (333 g, 100%): 1H NMR (400 MHz, CDC1₃) δ 7.00 (s, 1H), 5.50 (s, 2H), 3.13- 3.01 (m, 4H), 1.36-1.23 (m, 6H); ES-LCMS m/z 236 (M+H).

XXX. (2-Ethylthiazol-4-yl)methyl methanesulfonate

Step 1 : (2-Ethylthiazol-4-yl)methanol

To a solution of ethyl 2-ethylthiazole-4-carboxylate (1 g, 5.4 mmol) in CH₃OH

(20ml) was added NaBH₄ (2.04 g, 54 mmol) by portion. The resulting mixture was stirred at room temperature. After TLC analysis showed the starting material was disappeared. The solvent was removed in vacuo. The residue was dissolved in DCM (50 mL) and washed with H₂0. The organic layer was dried and concentrated to give (2-ethylthiazol-4-yl) methanol (0.5 g, 65%): 1H NMR (400 MHz, CD₃OD) δ 7.23-7.22 (m, 1H), 4.64 (m, 2H), 3.03-2.98 (m, 3H), 1.35 (t, J = 7.6 Hz, 2H). Step 2: (2-Ethylthiazol-4-yl)methyl methanesulfonate

To a solution of (2-ethylthiazol-4-yl)methanol (0.14g, 0.978 mmol) and Et₃N (0.136 mL, 0.978 mmol) in dichloromethane (DCM) (20 mL) was added MsCl (0.076 mL, 0.978 mmol) by drop wise. The resulting mixture was stirred at 20 °C. After TLC analysis (DCM: MeOH = 15: 1) showed the starting material disappeared, the mixture was washed with H₂0. The organic layer was dried and concentrated to give (2-ethylthiazol-4-yl)methyl methanesulfonate (0.16g, 0.651 mmol, 66.6 % yield): 1H NMR (400 MHz, CD₃OD) δ 7.59 (s, 1H), 5.28 (d, J = 0.4 Hz, 2H), 3.09-3.03 (m, 5H), 1.43-1.36 (m, 3H).

XXXI. Methanesulfonic acid 5-methyl-thiazol-2- lmethyl ester

To a stirred solution of (5-methyl-thiazol-2-yl)-methanol (150 mg, 1.16 mmol) and Et₃N (351 mg, 3.48 mmol) in anhydrous DCM (8 mL) at 0 oC was added MsCl (156 mg, 1.4 mmol). The mixture was stirred at room temperature for 0.5 hour. Water (20 mL) was added and the mixture was washed with DCM (2 x 10 mL). The combined organic DCM was washed with brine (30 mL), dried over a₂S0₄, filtered and concentrated in vacuo to give methanesulfonic acid 5-methyl-thiazol-2-ylmethyl ester (180 mg, yield 74%): ^lK NMR (400 MHz, CD₃OD) δ 7.47 (s, 1H), 5.41 (s, 2H), 3.05 (s, 3H), 2.78 (s, 3H); ES-LCMS m/z Ms dosn"t ionizate

XXXII. 2-Hydroxymethyl-thiazole-4-carboxylic acid methyl ester

Step 1 : Benzoic acid cyanomethyl ester

A mixture of benzoic acid (60 g, 492 mmol), chloro-acetonitrile (55 g, 738 mmol), triethylamine (100 g, 984 mmol) in DCM (200 mL) was stirred at room temperature for 16 hours. The mixture was poured into water (200 mL). The resulting mixture was extracted with EtOAc (200 mL x 3). The organic layer was washed with brine (100 mL), dried over anhydrous Na₂S0₄ and filtered. The organic phase was concentrated to give Benzoic acid cyanomethyl ester (55 g, 69.4%); 1H NMR (400 MHz, CD₃OD) δ 7.76 (d, J = 8.00 Hz, 2H), 7.37 (t, J= 7.2 Hz, 1H), 7.23 (t, J= 7.6 Hz, 2H), 4.8 (s, 2H); ES-LCMS m/z 162.1 (M+H).

Step 2: Benzoic acid thiocarbamoylmethyl ester

A mixture of Benzoic acid cyanomethyl ester (55 g, 0.38 mol), Diethylamine (36.5 g, 0.5 mol) in DMF (500 mL) was bubbled hydrogen sulfide at 30 °C for 2 hours. The solvent was concentrated, and the residue was poured into water (200 mL) and extracted with EtOAc (200 mL x 2). The combined organic layer was dried over a₂S0₄, filtered and concentrated to give Benzoic acid thiocarbamoylmethyl ester (58 g, 78%), which was used for next step without purification. 1H NMR (400 MHz, CD₃OD) δ 8.13 (d, J = 8.00 Hz, 2H), 7.62 (t, J = 7.2 Hz, 1H), 7.51 (t, J= 7.6 Hz, 2H), 5.07 (s, 2H); ES-LCMS m/z 196.1 (M+H).

Step 3 : 2-Benzoyloxymethyl-thiazole-4-carboxylic acid ethyl ester

A mixture Benzoic acid thiocarbamoylmethyl ester (58 g, 0.3 mol), pyridine (38 mL), 3-Bromo-2-oxo-propionic acid ethyl ester (76 g, 0.39 mol) in EtOH (500 mL) was heated to reflux under N₂ over night. The reaction mixture was concentrated and the residue was purified by column to provide 2-Benzoyloxymethyl-thiazole-4-carboxylic acid ethyl ester (22 g, 25.1%): ^lR NMR (400 MHz, CD₃OD) δ 8.44 (s, 1H), 8.09 (d, J = 8.00 Hz, 2H), 7.64 (t, J = 7.2 Hz, 1H), 7.51 (t, J = 7.6 Hz, 2H), 5.64 (s, 2H), 4.40-4.31 (m, 2H), 1.38 (t, J

3H); ES-LCMS m/z 292.1 (M+H).

Step 4: 2-Hydroxymethyl-thiazole-4-carboxylic acid methyl ester

A mixture of 2-Benzoyloxymethyl-thiazole-4-carboxylic acid ethyl ester (500 mg, 1.72 mmol), MeONa (140 mg, 2.58 mmol) in MeOH (20 mL) was stirred at room temperature for 10 hours. The solvent was concentrated and the residue was purified by column (DCM: MeOH = 30: 1) to provide 2-Hydroxymethyl-thiazole-4-carboxylic acid methyl ester (200 mg, 67%); 1H NMR (400 MHz, CD₃OD) δ 8.34 (s, 1H), 4.83 (s, 2H), 3.90 (s, 3H); ES-LCMS m/z 174.0 (M+H).

XXXIII. Methanesulfonic acid 4-chloro-thiazol-2- lmethyl ester

Step 1 : 2,4-Dichloro-thiazole

To a stirred solution of thiazolidine-2,4-dione (4 g, 26 mmol) in anhydrous MeOH (100 mL) was added POCl₃ (130 mL) and pyridine (17 mL). The mixture was heated at 120 °C for 3 hours and then cooled to room temperature. Excess POCl₃ was removed under reduced pressure. The residue was poured into ice/water, and extracted with ethyl acetate (3 x 20 mL). The combined organic layer was washed with brine (50 mL), dried over Na₂S0₄, filtered and concentrated in vacuo to give the crude product, which was purified by column chromatography to give the pure product 2,4-dichloro-thiazole (8.4 g, 26% yield): ^lH NMR (400 MHz, CDC1₃) δ 5.90 (s, 1H); ES-LCMS m/z 153.9 (M+H).

Step 2: 4-Chloro-thiazole-2-carboxylic acid methyl ester

To a solution of 2,4-dichloro-thiazole (4 g, 26 mmol) in MeOH (100 mL) was added Pd(dppf)Ci₂ (400 mg), Et₃N (5.2 mg, 52 mmol). The resulting mixture was stirred at 80°C under CO atmosphere (1.5 MPa) for 24 h, then concentrated under reduced pressure to give crude residue, which was purified by column chromatography to afforded the title compound 4-chloro-thiazole-2-carboxylic acid methyl ester as a pale yellow oil (700 mg, 15%): ^lH NMR (400 MHz, CDC1₃) δ 7.41 (s, 1H), 4.01 (s, 3H); ES-LCMS m/z 178.0 (M+H).

Step 3: (4-Chloro-thiazol-2-yl)-methanol

To a solution of 4-chloro-thiazole-2-carboxylic acid methyl ester (700 mg, 30.56 mmol) in MeOH (30 mL) was added NaBH₄ (464 mg, 11.69 mmol) in portions while the temperature was kept below 40 °C. The mixture was stirred overnight. After TLC showed the starting material disappeared, the solvent was removed in vacuo. The residue was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over Na₂S0_4j filtered and concentrated in vacuo to give the crude product, which was purified by column chromatography to give the pure product (4-chloro-thiazol-2-yl)- methanol (600 mg, 100% yield): ^lR NMR (400 MHz, CDC1₃) δ 7.02 (s, 1H), 4.88 (s, 2H); ES-LCMS m/z 150.0 (M+H).

Step 4: Methanesulfonic acid 4-chloro-thiazol-2- lmethyl ester

To a stirred solution of (4-chlorothiazol-2-yl)methanol (300 mg, 2.005 mmol) and MsCl (0.469 mL, 6.02 mmol) in dichloromethane (DCM) (50 mL) was added Et₃N (0.839 mL, 6.02 mmol), and the mixture was stirred for 0.5 hour. After the material was consumed, the mixture was washed with water (20 mL), extracted with DCM (2 x 20 mL), the organic layer was collected and concentrated to give the crude product methanesulfonic acid 4- chloro-thiazol-2-ylmethyl ester (457 mg, 100% yield): ^lR NMR (400 MHz, CDC1₃) δ 7.26- 7.15 (m, 1H), 5.42 (s, 2H), 3.69 (s, 3H); ES-LCMS m/z 227.9 (M+H). xxxrv. Methanesulfonic acid 5-chloro-thiazol-2-ylmethyl ester

To a stirred solution of (5-chloro-thiazol-2-yl)-methanol (80 mg, 0.54 mmol) and Et₃N (162 mg, 1.62 mmol) in anhydrous CH₂C1₂ (6 mL) at 0 °C was added MsCl (120 mg, 1.08 mmol). Then the mixture was stirred at rt overnight. Water (20 mL) was added to quench the reaction and extracted with DCM (3 x 10 mL). The combined organic layer was0 washed with brine (30 mL), dried over Na₂S0₄, filtered and concentrated in vacuo to give methanesulfonic acid 5-chloro-thiazol-2-ylmethyl ester (90 mg, 76%): ^lH NMR (400 MHz, CDC1₃) δ 7.61 (s, 1H), 5.39 (s, 2H), 3.09 (s, 3H); ES-LCMS m/z 228 (M+H). 5 XXXV. 6-[4-(4-Chloro-thiazol-2-ylmethoxy)-2-oxo-2H-pyridin-l-yl]-7,8-dihydro- naphthalene-2-carbaldehyde

A mixture of 6-(4-hydroxy-2-oxo-2H-pyridin-l-yl)-7,8-dihydro-naphthalene-2- carbaldehyde (50 mg, 0.19 mmoL), potassium carbonate (79 mg, 0.57 mmoL) in dry DMF0 (10 mL) was added methanesulfonic acid 4-chloro-thiazol-2-ylmethyl ester (51 mg, 0.22 mmoL), the mixture was stirred overnight at 80 °C, the mixture was filtered and the filtrate was concentrated, the residue was purified by preparative HPLC to provide 6-[4-(4-chloro- thiazol-2-ylmethoxy)-2-oxo-2H-pyridin- 1 -yl]-7,8-dihydro-naphthalene-2-carbaldehyde (20 mg, 26%): ^lR NMR (400 MHz, CDC1₃) δ 7.63 (m, 1H), 7.61 (m, 2H), 7.54 (m, 1H), 7.43 (m,5 2H), 7.41 (m, 1H), 7.38 (m, 2H), 7.34 (m, 1H); ES-LCMS m/z 399.0 (M+H). XXXVI. 6-[4-(5-Chloro-thiazol-2-ylmethoxy)-2-oxo-2H-pyridin-l-yl]-7,8-dihydro- naphthalene- 2-carbaldehyde

Methanesulfonic acid 5-chloro-thiazol-2-ylmethyl ester (100 mg, 0.44 mmol) in DMF

(5 mL) was added to a mixture of 6-(4-hydroxy-2-oxo-2H-pyridin-l-yl)-7,8-dihydro- naphthalene-2-carbaldehyde (30 mg, 0.1 1 mmol), K₂CO₃ (30 mg, 0.22 mmol) and dry DMF (10 mL). Then the mixture was stirred at 70-80 °C overnight. Solvent was concentrated in vacuo. The residue was purified by Prep.TLC to give 6-[4-(5-chloro-thiazol-2-ylmethoxy)-2- oxo-2H-pyridin-l-yl]-7,8-dihydro-naphthalene-2-carbaldehyde (20 mg, yield 46%): ^lH NMR (400 MHz, CDCI3) δ 9.89 (s, 1H), 7.63-7.62 (m, 2H), 7.54 (s, 1H), 7.19-7.15 (m, 2H), 6.46 (s, 1H), 5.93-5.91 (m, 1H), 5.90 (s, 1H), 5.16 (s, 2H), 3.08-3.03 (m, 2H), 2.75-2.71 (m, 2H); ES-LCMS m/z 398.8 (M+H). XXXVII. 4-Hydroxy- 1 -(6-(pyrrolidin- 1 -ylmethyl)-3 ,4-dihydronaphthalen-2-yl) pyridin-2(lH)- one

A mixture of 4-((5-chloropyridin-2-yl)methoxy)-l-(6-(pyrrolidin-l-ylmethyl)-3,4- dihydronaphthalen-2-yl)pyridin-2(lH)-one (300 mg, 0.67 mmol) and Zn (436 mg, 6.7 mmol) in AcOH (5 mL) was refluxed for 2 hours. The mixture was then filtered, and the filtrate was concentrated and purified by column chromatography to give 4-hydroxy- 1 -(6-(pyrrolidin- 1 - ylmethyl)-3,4-dihydronaphthalen-2-yl) pyridin-2(lH)-one (150 mg, 50% yield) as a pale yellow solid: ^lR NMR (400 MHz, CD₃OD) δ 7.45 (d, J = 7.6 Hz, 1H), 7.31-7.29 (m, 2H), 7.23 (d, J = 8.0 Hz, 1H), 6.58 (s, 1H), 6.1 1-6.08 (m, 1H), 5.80 (d, J = 2.4 Hz, 1H), 4.23 (s, 2H), 3.25-3.22 (m, 4H), 3.09-3.05 (m, 2H), 2.70-2.66 (m, 2H), 2.07-2.04 (m, 4H); ES-LCMS m/z 323.0 (M+H). XXXVIII. l ,l-Dioxo-tetrahydro-^⁶-thiopyran-4-ylamine

Dihydro-2H-thiopyran-4(3H)-one oxime

To a solution of dihydro-2H-thiopyran-4(3H)-one (9.0 g, 77.46 mmol) in ethanol (600 mL) was added NH₂OH.HCl (27.0 g, 258.22 mmol) and NaOAc (51.0 g, 619.71 mmol). The mixture was stirred overnight. The mixture was concentrated in vacuo to remove ethanol. The residue was washed by H₂0 (550 mL), and extracted into EtOAc (3 x 300 mL). The combined organic layer was dried over Na₂S0₄, and concentrated in vacuo to give dihydro- 2H-thiopyran-4(3H)-one oxime (6.8 g, 67%): 1H NMR (400 MHz, CDC1₃) δ 4.11-2.51 (m, 6H), 2.08-1.90 (m, 2H).

Step 2: Tetrahydro-2H-thiopyran-4-amine

To a solution of LiAlH₄ (9.84 g, 259 mmol) in THF (500 mL) was added dropwise a solution of dihydro-2H-thiopyran-4(3H)-one oxime (6.8 g, 51.8 mmol) in THF (100 mL).

The mixture was heated to reflux for 4 h. The mixture was quenched by 10% NaOH solution

(10 mL), filtered and the residue was washed by THF (3 x 100 mL). The organic layer was dried over Na₂S0₄, concentrated in vacuo to give tetrahydro-2H-thiopyran-4-amine (5.36 g, 75%): ^lR NMR (400 MHz, CDC1₃) 52.64-2.59 (m, 4H), 2.09-2.05 (m, 1H), 1.45-1.37 (m, 4H).

Step 3 : tert-Butyl tetrahydro-2H-thiopyran-4-ylcarbamate

oc

To a solution of tetrahydro-2H-thiopyran-4-amine (5.36 g, 45.8 mmol) in DCM (300 mL) was added Boc₂0 (11.1 g, 50.4 mmol) and Et₃N (6.0 g, 59.6 mmol). The mixture was stirred for 2 h, and washed by sat. citric acid (150 mL). The organic layer was dried over a₂S0₄, and concentrated in vacuo to give tert-butyl tetrahydro-2H-thiopyran-4-ylcarbamate (8.0 g, 81%): H NMR (400 MHz, CDC1₃) 5 2.69-2.59 (m, 4H), 2.21-2.16 (m, 2H), 1.52-1.48 (m, 4H), 1.48-1.43 (m, 9H).

Step 4: tert-Butyl (l ,l-dioxidetetrahydro-2H-thiopyran-4-yl)carbamate

To a solution of tert-butyl tetrahydro-2H-thiopyran-4-ylcarbamate (8.0 g, 36.87 mmol) in DCM (300 mL) was added 3-chlorobenzoperoxoic acid (15.91 g, 92.17 mmol). The mixture was stirred overnight, and then washed by sat. Na₂S₂0₃ (150 mL) and aq. sat. NaHC0₃ solution (150 mL). The organic layer was dried over Na₂S0₄, filtered and concentrated in vacuo to give tert-butyl (l,l-dioxidetetrahydro-2H-thiopyran-4-yl)carbamate (10.1 mg, 95%): 1H NMR (400 MHz, CDC1₃) 5 3.74-3.71 (m, 1H), 3.09-3.02 (m, 4H), 3.62- 2.96 (m, 5H), 2.25-2.01 (m, 4H), 1.52-1.48 (m, 9H).

Step 5 : 1 , 1 -D ioxo-tetrahydro- 1 λ⁶-thiopyran-4-ylamine

A mixture of tert-butyl (l,l-dioxidetetrahydro-2H-thiopyran-4-yl)carbamate (30 g, 120 mmol), DCM (80 ml) and TFA (20 mL) was stirred for 2 h. The mixture was then concentrated in vacuo to give l,l-dioxo-tetrahydro-^⁶-thiopyran-4-ylamine for next reaction without purification: ^lR NMR (400 MHz, CD₃OD) δ 3.50-3.10 (m, 5H), 2.36-2.16 (m, 4H).

XXXIX. 1 -(2-(Methylsulfonyl)ethyl)piperazine h drochloride

Step 1 : tert-Butyl 4-(2-(methylsulfonyl)ethyl)piperazine-l-carboxylate

To a solution of tert-butyl piperazine- 1 -carboxylate (1.4 g, 7.5 mmol) in EtOH (20 mL) was added methylsulfonylethene (0.53 g, 5 mmol) at room temperature. The mixture was stirred at room temperature for overnight. After TLC analysis showed the starting material was completely consumed, the mixture was concentrated to give the crude product, which was purified by column to afford the tert-butyl 4-(2-(methylsulfonyl)ethyl)piperazine-

1 -carboxylate (1.2 g, 54.5 %): 1H NMR(400 MHz, CDC1₃) δ 3.36 (t, J = 4.2Hz, 4H), 3.08 (t, J = 6.4 Hz, 2H), 2.96 (s, 3H), 2.82 (t, J = 6.4 Hz, 2H), 2.38 (t, J = 4.2Hz, 4H), 1.38-1.40(m,

9H).

Step 2: l-(2-(Methylsulfonyl)ethyl iperazine hydrochloride

A mixture of tert-butyl 4-(2-(methylsulfonyl)ethyl)piperazine-l-carboxylate (1.2 g, 4.1 mmol) in HCl/MeOH (15 mL) was stirred at 0 °C for lhour. The solvent was concentrated to give the crude product, which was used for the next step without further purification (1.15 g, 100 %): ^lR NMR (400 MHz, D₂0) δ 5.15 (t, J = 6.0 Hz, 2H), 5.07 (m, 2H), 5.03-4.92 (m, 8H), 4.56 (s, 3H).

XL. Piperidine-3,5-diol

Step 1 : l-Benzyl-4-(4-nitr -benzoyloxy)-pyrrolidine-2-carboxylic acid methyl ester

A mixture of l-benzyl-4-hydroxy-pyrrolidine-2-carboxylic acid methyl ester (17.5 g, 74.5 mmol) 4-nitro-benzoic acid (15 g, 89.4 mmol), DEAD (15.56 g, 89.4 mmol) and (23.4 g, 89.4 mmol) in THF (100 mL) was stirred overnight. The mixture was concentrated under vacuum to give the crude product which was purified by chromatography column to give 1 - benzyl-4-(4-nitro-benzoyloxy)-pyrrolidine-2-carboxylic acid methyl ester (18 g, 62.9% yield): 1H NMR (400 MHz, CD₃OD) δ 8.33-8.30 (m, 2H), 8.22-8.20 (m, 2H), 7.37-7.24 (m, 5H), 5.49-5.48 (m, 1H), 4.00-3.98 (m, 1H), 3.64 (s, 3H), 3.69-3.68 (m, 1H), 3.50-3.45 (m, 1H), 3.20-3.19 (m, 1H), 2.87-2.85 (m, 1H), 2.78-2.71 (m, 1H), 2.20-2.19 (m, 1H); ES- LCMS m/z 385 (M+H).

Step 2: l-Benzyl-4-hydroxy-pyrrolidine-2-carboxylic acid methyl ester

A mixture of l-benzyl-4-(4-nitro-benzoyloxy)-pyrrolidine-2-carboxylic acid methyl ester (18 g, 46.8 mmol) and NaOMe (4.1 g, 93.6 mmol) in MeOH (100 mL) was stirred for overnight. The mixture was concentrated under vacuum to the product which was purified by chromatography column to give 1 -benzyl-4-hydroxy-pyrrolidine-2-carboxylic acid methyl ester (5 g, 45.4% yield): ^lR NMR (400 MHz, CD₃OD) δ 7.33-7.20 (m, 5H), 4.25-4.23 (m, 1H), 3.90-3.89 (m, 1H), 3.63 (s, 3H), 3.60-3.59 (m, 1H), 3.23-3.21 (m, 1H), 2.91-2.88 (m, 1H), 2.55-2.45 (m, 2H), 1.88-1.82 (m, 1H); ES-LCMS m/z 235 (M+H).

Step 3 : l-Benzyl-5-hydroxymethyl- rrolidin-3-ol

To the solution of LAH (0.315 g, 8.5 mmol) in THF (15 mL) was added l-benzyl-4- hydroxy-pyrrolidine-2-carboxylic acid methyl ester (1.0 g, 4.25 mmol) in THF (5 mL) dropwise at 0 °C, then the mixture was stirred for 30 min. After the mixture was cooling to 0 °C, H₂0 (0.315 mL) was added to the mixture, followed by 10% NaOH solution 0.315 mL). The mixture was filtered, and the filtrate was concentrated under vacuum to give l-benzyl-5- hydroxymethyl-pyrrolidin-3-ol (0.6 g, 60% yield): ^lR NMR (400 MHz, CD₃OD) δ 7.37-7.23 (m, 5H), 4.21-4.20 (m, 1H), 4.10-4.09 (m, 1H), 3.60 (d, J= 4.40 Hz, 2H), 3.39-3.35 (m, 1H), 2.87-2.84 (m, 2H), 2.73-2.70 (m, 1H), 2.45-2.42 (m, 1H), 2.36-2.30 (m, 1H), 1.70-1.67 (m, 1H); ES-LCMS m/z 208 (M+H).

Step 4: l-Benzyl-piperidine-3,5-diol

To the solution of l-benzyl-5-hydroxymethyl-pyrrolidin-3-ol (0.6 g, 2.9 mmol) in

THF (20 mL) was added TFAA (1.06 mL, 7.24 mmol) dropwise at 0 °C, after the mixture was stirred for 1 hour later, Et₃N (0.88 g, 8.69 mmol) was added, then the mixture was heated to reflux overnight. After the mixture was cooling to 0 °C, 3.75 M NaOH solution was added and stirred for 2 hours. The mixture was washed with IN HC1 solution and extracted with EtOAc (30 mL x 2). The combined organic phase was dried over Na₂S0₄, filtered and the filtrate was concentrated under vacuum to give the crude product which was purified by column to give l-benzyl-piperidine-3,5-diol (0.55 g, 91.7% yield): 1H NMR (400 MHz, CD₃OD) δ 7.37-7.23 (m, 5H), 4.21-4.20 (m, 1H), 4.10-4.09 (m, 1H), 3.62-3.60 (m, 1H), 2.90-2.89 (m, 2H), 2.50-2.47 (m, 2H), 2.39-2.32 (m, 1H), 1.81-1.80 (m, 1H), 1.72-1.65 (m, 1H); ES-LCMS m/z 208 (M+H).

Step 5: Piperidine-3,5-diol

A mixture of l-benzyl-piperidine-3,5-diol (0.55 g, 2.66 mmol) and Pd(OH)₂ (0.1 g) in MeOH (20 mL) was stirred overnight at 45 °C under H₂ atmosphrer at 45 Psi. The mixture was filtered and the filtrate was concentrated to give piperidine-3,5-diol (250 mg, 80.6% yield): ^lR NMR (400 MHz, CD₃OD) δ 4.32-4.29 (m, 1H), 3.59-3.54 (m, 1H), 3.19-3.16 (m, 1H), 2.99-2.95 (m, 1H),2.27-2.21 (m, 2H), 2.17-2.10 (m, 1H), 1.54-1.52 (m, 1H); ES-LCMS m/z 1 18 (M+H).

XLI. 4-Methoxypiperidine, trifluoroacetic acid salt

Step 1 : teri-Butyl 4-hydroxypiperidine- 1 -carboxylate

To a suspension of piperidin-4-ol (1.0 g, 10 mmol) and Et₃N (1.67 mL, 12 mmol) in dichloromethane (20 mL) was added Boc₂0 (2.8 mL, 12 mmol), stirred at room temperature overnight. The mixture was washed with aqueous citric acid solution until pH ~ 6, and the organic layer was dried over Na₂S0₄, filtered and evaporated in vacuo to give teri-butyl 4- hydroxypiperidine-1 -carboxylate (2.0 g, yield 99%) as colorless liquid: ^lR NMR (400 MHz, CDC1₃) δ 3.86-3.81 (m, 3H), 3.05-2.98 (m, 2H), 1.86-1.82 (m, 2H), 1.47-1.43 (m, 11H).

Step 2: tert-Butyl 4-methoxypiperidine- 1 -carboxylate

A mixture of tert-butyl 4-hydroxypiperidine- 1 -carboxylate (2 g, 9.94 mmol) and KOH (1.12 g, 19.87 mmol) in dimethyl sulfoxide (8 mL) was stirred at room temperature for 1 hr, and then Mel (0.683 mL, 10.93 mmol) was added to the mixture. The reaction mixture was stirred at 25 °C for 4 hours. It was quenched by water (8 mL) and extracted with dichloromethane (8 mL x 2). The organic phase was washed with water (8 mL), dried over anhydrous Na₂S0₄, filtered and concentrated to give tert-butyl 4-methoxypiperidine- 1 - carboxylate (2.1 g, yield 98%) as colorless liquid: 1H NMR (400 MHz, CDC1₃) δ 3.82-3.71 (m, 3H), 3.34-3.32 (m, 3H), 3.10-3.01 (m, 2H), 1.85-1.80 (m, 2H), 1.50-1.47 (m, 11H); ES- LCMS m/z 238 (M+Na).

Step 3 : 4-Methoxypiperidine, Trifluoroacetic acid salt

To a suspension of tert-butyl 4-methoxypiperidine- 1 -carboxylate (0.4 g, 1.858 mmol) in dichloromethane (DCM) (5 mL) was added 2,2,2-trifluoroacetic acid (0.85 g, 7.43 mmol). The reaction mixture was stirred at 25 °C for 2 hours. The mixture was concentrated to give 4-methoxypiperidine, trifluoroacetic acid salt (0.42 g, yield 99%) as yellow oil: ^lH NMR (400 MHz, CDC1₃) δ 3.42-3.37 (m, 6H), 3.26-3.21 (m, 2H), 2.03-1.99 (m, 4H). XLII. Pyrrolidine-3-carboxylic acid

A solution of pyrrolidine-l,3-dicarboxylic acid 1 -tert-butyl ester (215 mg, 1 mmol) in TFA DCM (20% V/V=l/5, 6 mL) was stirred at room temperature for 1 hour, the solvent was concentrated to provide pyrrolidine-3-carboxylic acid (115 mg, 100%): ^lH NMR (400 MHz, CD₃OD) δ 3.55-3.54 (m, 1H), 3.43-3.39 (m, 1H), 3.31-3.30 (m, 2H), 3.30-3.28 (m, 1H), 2.32-2.23 (m, 2H) ; ES-LCMS m/z 116.1 (M+H). Examples

Example 1 : 1 -[6-(4-Methyl-piperazin- 1 -ylmethyl)-3 ,4-dihydro-naphthalen-2-yl]-4-(4- methyl- thiazol-2-ylmethoxy)- lH- ridin-2-one.

To a suspension of 6-[4-(4-methyl-thiazol-2-ylmethoxy)-2-oxo-2H-pyridin-l-yl]-7,8- dihydro-naphthalene-2-carbaldehyde (50 mg, 0.1 mmol) and (l-amino-cyclopropyl)methanol (13.3 mg, 0.15 mmol) in DCM (5 mL) was added triacetoxy sodium borohydride (83 mg, 0.39 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was treated with aqueous saturated NaHC0₃ solution (3 mL) and extracted with CH₂CI₂ (3 x 5 mL). The combined organic phase was dried over a₂S0₄, filtered and concentrated in vacuum to give crude product, which was purified by preparative HPLC to give l-[6-(4-methyl-piperazin-l-ylmethyl)-3,4-dihydro-naphthalen-2-yl]-4-(4-methyl- thiazol-2-ylmethoxy)-lH-pyridin-2-one (1 1.88 mg, 26% yield): 1H NMR (400 MHz, CD₃OD) δ 7.77 (d, J = 7.60 Hz, 1H), 7.69 (s, 1H), 7.51-7.46 (m, 2H), 7.31 (d, J = 7.60 Hz, 1H), 6.71 (s, 1H), 6.51 (d, J = 2.80 Hz, 1H), 6.27 (d, J = 2.80 Hz, 1H), 5.69 (s, 2H), 4.51 (s, 2H), 3.86-3.73 (m, 4H), 3.72-3.51 (m, 4H), 3.15-3.09 (m, 2H), 3.04 (s, 3H), 2.74 (t, J = 8.00 Hz, 2H), 2.57 (s, 3H); ES-LCMS m/z 463.1 (M+H). Example 2: l-(6-{[(2,3-Dihydroxy-propyl)-methyl-amino]-methyl}-3,4-dihydro- naphthalen -2-yl)-4-(4-methyl-thiazol-2-ylmethoxy)-lH-pyridin-2-one.

The mixture of 6-[4-(4-methyl-thiazol-2-ylmethoxy)-2-oxo-2H-pyridin-l-yl] -7,8- dihydro-naphthalene-2-carbaldehyde (80 mg, 0.21 mmol) and 3-amino-propane-l ,2-diol (20 mg, 0.22 mmol) in anhydrous DCM (8 mL) was stirred at room temperature for 16 hours. Then NaBH(OAc)₃ (134 mg, 0.63 mmol) was added. The mixture was stirred at room temperature for 3 hours. The mixture was filtered and the filtrate was concentrated and purified by preparative HPLC to give a yellow solid (55 mg, yield 58%): ^lR NMR (400 MHz, CD₃OD) δ 7.75 (d, J= 7.6 Hz, 1H), 7.67 (d, J= 0.8 Hz, 1H), 7.35 (d, J= 7.6 Hz, 1H), 7.28-7.27 (m, 1H), 6.68 (s, 1H), 6.46 (d, J = 7.6 Hz, 1H), 6.25 (d, J = 2.8 Hz, 1H), 5.67 (s, 2H), 4.23 (s, 1H), 3.95-3.93 (m, 1H), 3.58-3.57 (m, 1H), 3.54-3.52 (m, 1H), 3.10-3.08 (m, 3H), 3.02-2.96 (m, 1H), 2.73-2.71 (m, 2H), 2.57-2.56 (m, 3H); ES-LCMS m/z 468 (M+H). The mixture of l- {6-[(2,3-dihydroxy-propylamino)-methyl]-3,4-dihydro-naphthalen

-2-yl}-4-(4-methyl-thiazol-2-ylmethoxy)-lH-pyridin-2-one (55 mg, 0.12 mmol), HCHO (18 mg, 0.61 mmol), HCOOH (28 mg, 0.61 mmol), NaBH₃CN (23 mg, 0.36 mmol) and MeOH (10 mL) was stirred at room temperature for 3 hours. The mixture was filtered and the filtrate was concentrated and then purified by preparative HPLC to give a yellow solid (10.07 mg, yield 18%): 'H NMR (400 MHz, CD₃OD) 57.78 (d, J= 7.6 Hz, 1H), 7.69 (d, J = 0.8 Hz, 1H), 7.39-7.37 (m, 2H), 7.29 (d, J = 7.6 Hz, 1H), 6.71 (s, 1H), 6.51 (dd, J = 7.6, 2.0 Hz, 1H), 6.29 (d, J = 2.4 Hz, 1H), 5.71 (s, 2H), 4.40 (s, 1H), 4.11-4.01 (m, 1H), 3.59-3.50 (m, 3H), 3.19-3.09 (m, 4H), 2.93-2.85 (m, 3H), 2.75-2.73 (m, 2H), 2.57-2.56 (m, 3H); ES- LCMS m/z 468 (M+H).

Example 3: 4-((4-Methylthiazol-2-vl)methoxy)- 1 -(6-(morpholinomethyl)-3 ,4- dihydronaphthalen-2-yl)pyridin-2(lH)-one.

A mixture of l-(6-(chloromethyl)-3,4-dihydronaphthalen-2-yl)-4-((4-methylthiazol-2- yl)methoxy)pyridin-2(lH)-one (0.4 g, 1.003 mmol), morpholine (0.175 g, 2.005 mmol) and K₂C0₃ (0.277 g, 2.005 mmol) in DMF (20 mL) was stirred at r.t overnight. LCMS 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 4-((4-methylthiazol-2- yl)methoxy)- 1 -(6-(morpholinomethyl)-3 ,4-dihydronaphthalen-2-yl)pyridin-2( lH)-one hydrochloride (362.29 mg, 0.743 mmol, 74.1 % yield) as a brown oil: 1H NMR (400 MHz, CD₃OD) δ 7.65-7.63 (m, 1H), 7.40 (s, 1H), 7.25-7.22 (m, 2H), 7.15-7.13 (m, 1H), 6.60 (s, 1H), 6.36-6.33 (m, 1H), 6.16 (d, J = 2.8 Hz, 1H), 5.51 (s, 2H), 4.61 (s, 2H), 3.84 (s, 4H), 3.07-3.02 (m, 2H), 2.70-2.52 (m, 3H), 2.49 (s, 3H); EC-LCMS m/z 450 (M+H).

Example 4: (S)- 1 -(6-((3-Fluoropyrrolidin- 1 -yl)methyl)-3 ,4-dihydronaphthalen-2-yl)- 4-((4-methylthiazol-2-yl)methoxy)pyridin-2(lH)-one, hydrochloride.

To a suspension of l -(6-(hydroxymethyl)-3,4-dihydronaphthalen-2-yl)-4-((4- methylthiazol-2-yl)methoxy)pyridin-2(lH)-one (380 mg, 1 mmol) and Et₃N (0.28 mL, 2 mmol) in anhydrous dichloromethane (5 mL) was added methanesulfonyl chloride (137 mg, 1.2 mmol). The mixture was stirred at room temperature for 0.5 hr. The reaction was quenched by water (5 mL) and extracted with dichloromethane (5 mL x 2). The organic layer was combined and dried over anhydrous a₂S0₄ and filtered. The filtrate was concentrated to give crude intermediate as black liquid without further purification. To a suspension of the intermediate prepared before and (5)-3-fluoropyrrolidine, hydrochloride (251 mg, 2 mmol) in anhydrous N,N-Dimethylformamide (10 mL) was added K₂C0₃ (553 mg, 4 mmol), stirred at 70 °C for 16 hours. The suspension was cooled to room temperature and filtered. The filtrate was concentrated and purified by preparative HPLC to give (S)- 1 -(6-((3-fluoropyrrolidin- 1 -yl)methyl)-3 ,4- dihydronaphthalen-2-yl)-4-((4- methylthiazol-2-yl)methoxy)pyridin-2(lH)-one, hydrochloride (135 mg, yield 27%) as a off white solid: 1H NMR (400 MHz, CD₃OD) δ 7.85 (d, J= 7.6 Hz, 1H), 7.76 (s, 1H), 7.47-7.43 (m, 2H), 7.32 (d, J = 7.6 Hz, 1H), 6.75 (s, 1H), 6.59 (d, J = 7.2 Hz, 1H), 6.36 (s, 1H), 5.77 (s, 2H), 4.96-4.50 (s, 1H), 4.48-4.46 (m, 2H), 3.77-3.44 (m, 4H),3.16-3.12 (m, 2H), 2.77-2.74 (m, 2H), 2.56 (s, 3H), 2.55-2.22 (m, 2H); ES-LCMS m/z 452 (M+H).

Example 5: N-Methyl-N- {6-[4-(4-methyl-thiazol-2-ylmethoxy)-2-oxo-2H-pyridin- 1 - yl]-7,8-dihydro-naphthalen-2-ylmethyl}-methanesulfonamide.

A mixture of 6-[4-(5-chloro-pyridin-2-ylmethoxy)-2-oxo-2H-pyridin-l-yl]-7,8- dihydro-naphthalene-2-carbaldehyde (5 g, 12.73 mmol), methylamine hydrochloride (3.4 g, 50.9 mmol) and TEA (2.58 g, 25.46 mmol) in C1CH₂CH₂C1 (100 mL) was stirred at room temperature for 3 hours. NaBH(OAc)₃ (5.4 g, 25.46 mmol) was added and the mixture was stirred at room temperature for 16 hours, then filtered and purified by column chromatography on silica gel (DCM/MeOH=30/l) to give 4-(5-chloro-pyridin-2- ylmethoxy)-l-(6-methylaminomethyl-3,4-dihydro-naphthalen-2-yl)-lH-pyridin-2-one (2.5 g, yield 48%) as a pale yellow solid: ^lR NMR (400 MHz, CDC1₃) δ 8.54 (d, J = 2.0 Hz, 1H), 7.70 (dd, J = 8.4 Hz, 2.8 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.19-7.17 (m, 3H), 7.03 (d, J = 8.4 Hz, 1H), 6.40 (s, 1H), 6.04 (dd, J = 7.6, 2.8 Hz, 1H), 5.95 (d, J = 2.8 Hz, 1H), 5.10 (s, 2H), 3.90 (s, 2H), 2.99 (t, J = 8.0 Hz, 2H), 2.67 (t, J = 8.0 Hz, 2H), 2.47 (s, 3H); ES-LCMS m/z 408.2 (M+H). A mixture of 4-(5-chloro-pyridin-2-ylmethoxy)-l-(6-methylaminomethyl-3,4- dihydro- naphthalen-2-yl)-lH-pyridin-2-one (2.8 g, 6.86 mmol) and Zn (4.5 g, 68.6 mmol) in AcOH (50 mL) was refluxed for 2 hours, then filtered and concentrated to give 4-hydroxy-l- (6-methylaminomethyl-3,4-dihydro-naphthalen-2-yl)-lH-pyridin-2-one (2 g, yield 99%) as a pale yellow solid: 1H NMR (400 MHz, CD₃OD) δ 8.38 (d, J= 2.4 Hz, 1H), 7.70 (dd, J = 8.4, 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 282.34 (M+H). A mixture of 4-hydroxy-l-(6-methylaminomethyl-3,4-dihydro-naphthalen-2-yl) -1H- pyridin- 2-one (2 g, 7.08 mmol), (Boc)₂0 (2.32 g, 10.6 mmol) and NaOH (850 mg, 21.3 mmol) in MeOH/H₂0 (1/1, 40 mL) was stirred at room temperature for 16 hours, then filtered and purified by column chromatography on silica gel (DCM/MeOH=50/l) to give [6- (4-hydroxy-2-oxo-2H-pyridin- 1 -yl)-7,8-dihydro-naphthalen-2-ylmethyl]-methyl-carbamic acid terf-butyl ester (1 g, yield 37%) as a pale yellow solid: ^lR NMR (400 MHz, CD₃OD) δ 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 (M+H).

To a mixture of (4-methyl-thiazol-2-yl)-methanol (200 mg, 1.55 mmol) and Et₃N (313 mg, 3.10 mmol) in 20 mL of anhydrous DCM at 0 °C, was added MsCl (266 mg, 2.33 mmol) dropwise. The mixture was stirred at room temperature for 30 min. The mixture was washed with H₂0 (2 x 20 mL), dried over Na₂S0₄ and concentrated to give a brown oil. The mixture of the brown oil, [6-(4-hydroxy-2-oxo-2H-pyridin-l-yl)-7,8-dihydro- naphthalen-2-ylmethyl]-methyl-carbamicacid /er/-butyl ester (592 mg, 1.55 mmol) and K₂C0₃ (428 mg, 3.10 mmol) in 10 mL of anhydrous DMF was stirred at 60 °C for 16 hours. Then the mixture was filtered and the filtrate was purified by preparative HPLC to give a pale yellow solid (430 mg, yield 56%): 1H NMR (400 MHz, CD₃OD) δ 7.62-7.60 (m, 1H), 7.34-7.33 (m, 2H), 7.12-7.11 (m, 1H), 7.07-7.06 (m, 2H), 6.57 (s, 1H), 6.32-6.31 (m, 1H), 6.14-6.13 (d, J = 2.8 Hz, 1H), 5.46 (s, 2H), 4.40 (s, 2H), 3.03-3.01 (m, 2H), 2.68-2.66 (m, 3H), 2.47 (s, 3H), 1.48-1.41 (m, 9H); ES-LCMS m/z 494 (M+H).

The mixture of methyl- {6-[4-(4-methyl-thiazol-2-ylmethoxy)-2-oxo-2H-pyridin-l-yl] -7,8-dihydro-naphthalen-2-ylmethyl}-carbamic acid /er/-butyl ester (430 mg, 0.87 mmol) in 20 mL of 4 N HC1/EA solution, was stirred at room temperature for 2 hours. The mixture was concentrated to give a yellow solid (350.31 mg, yield 100%): 1H NMR (400 MHz, CD₃OD) δ 7.70 (d, J = 7.6 Hz, 1H), 7.58 (s, 1H), 7.32 (d, J = 7.2 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 6.66 (s, 1H), 6.41-6.40 (m, 1H), 6.21 (d, J= 2.4 Hz, 1H), 5.61 (s, 2H), 4.15 (s, 2H), 3.09 (t, J = 0.8 Hz, 2H), 2.72 (s, 3H), 2.69-2.68 (m, 2H), 2.54-2.53 (m, 3H); ES-LCMS m/z 394 (M+H).

To a mixture of l-(6-methylaminomethyl-3,4-dihydro-naphthalen-2-yl)-4-(4-methyl- thiazol-2-ylmethoxy)-lH-pyridin-2-one (30 mg, 0.08 mmol) and Et₃N (16 mg, 0.16 mmol) in 5 mL of DCM, was added MsCl (13 mg, 0.11 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated and purified by preparative HPLC to give a pale yellow solid (11.13 mg, yield 29%): 1H NMR (400 MHz, CD₃OD) δ 7.63 (d, J = 7.6 Hz, 1H), 7.38 (d, J = 0.8 Hz, 1H), 7.22-7.17 (m, 3H), 6.60 (s, 1H), 6.35-6.33 (m, 1H), 6.15 (d, J = 2.8 Hz, 1H), 5.50 (s, 2H), 4.26 (s, 2H), 3.05-3.03 (m, 2H), 2.90 (s, 3H), 2.73 (s, 3H), 2.67-2.65 (m, 2H), 2.48 (s, 3H); ES-LCMS m/z 472 (M+H).

Example 6: 1 -(6-(((2-Methoxyethyl)(methyl)amino)methyl)-3,4-dihydronaphthalen - 2-yl)-4-((5-methylthiazol-2-yl)methoxy)pyridin-2(lH)-one.

A solution of 6-[4-(5-chloro-pyridin-2-ylmethoxy)-2-oxo-2H-pyridin-l-yl]-7,8- dihydro-naphthalene-2-carbaldehyde (1 g, 2.55 mmol) and 2-methoxyethanamine (229 mg, 3.05 mmol) in DCE (20 mL) was stirred at room temperature for 4 hours, after that NaBH(OAc)₃ (1.62 g, 7.65 mmol) was added, then the mixture was stirred at room temperature for 16 hours. The mixture was filtered and the filtrate was evaporated to give 4- ((5-chloropyridin-2-yl)methoxy)- 1 -(6-((2-methoxyethylamino)methyl)-3 ,4- dihydronaphthalen-2-yl)pyridin-2(lH)-one (1.24 g, crude) as yellow oil: ES-LCMS m z 452.0 (Μ+Η).

A solution of 4-((5-chloropyridin-2-yl)methoxy)-l-(6-((2- methoxyethylamino)methyl)-3,4-dihydronaphthalen-2-yl)pyridin-2(lH)-one (1.24 g, 2.75 mmol), NaBH₃CN (518 g, 8.25 mmol) and HCHO (10 mL) in MeOH (10 mL) was stirred at room temperature for 16 hours. The mixture was filtered and the filtrate was evaporated. The crude product was purified by column chromatography on silica gel (DCM:MeOH=30: l) to give 4-((5-chloropyridin-2-yl)methoxy)- 1 -(6-(((2-methoxyethyl)(methyl)amino)methyl)- 3,4-dihydronaphthalen-2-yl)pyridin-2(lH)-one (730 mg, 57%) as yellow oil: 1H NMR (400 MHz, CDCls) δ 8.51 (d, J = 2.4 Hz, 1H), 7.65 (dd, J = 8.4, 2.4 Hz, 1H), 7.37-7.34 (m, 1H), 7.19-7.15 (m, 1H), 7.09-7.05 (m, 2H), 6.37 (s, 1H), 5.97 (dd, J = 7.6 Hz , 2.8 Hz, 1H), 5.88 (d, J = 2.8 Hz, 1H), 5.06 (s, 2H), 3.49-3.46 (m, 4H), 3.28 (s, 3H), 2.98-2.94 (m, 2H), 2.67- 2.58 (m, 4H), 2.23 (s, 3H); ES-LCMS m/z 466.2 (M+H).

A mixture of 4-((5-chloropyridin-2-yl)methoxy)-l-(6-(((2-methoxyethyl)(methyl) amino)methyl)-3,4-dihydronaphthalen-2-yl)pyridin-2(lH)-one (730 mg, 1.57 mmol) and Zn

(1 g, 15.7 mmol) in HO Ac ( 10 mL ) was refluxed for 5 hours. The reaction mixture was filtered and the filtrate was evaporated and the residue was purified by column chromatography on silica gel (DCM: MeOH = 30: 1) to give 4-hydroxy-l-(6-(((2- methoxyethyl)(methyl)amino)methyl)-3,4-dihydronaphthalen-2-yl)pyridin-2(lH)-one (300 mg, yield 88%) as a yellow solid: ES-LCMS m/z 341.1 (Μ+Η).

A mixture of 4-hydroxy-l-(6-(((2-methoxyethyl)(methyl)amino)methyl)-3,4- dihydronaphthalen-2-yl)pyridin-2(lH)-one (50 mg, 0.15 mmol), (5-methylthiazol-2- yl)methyl methanesulfonate (37 mg, 0.18 mmol) and K₂CO₃ (41 mg, 0.3 mmol) in DMF ( 1 mL ) was heated to 110 °C for 2 hours. The mixture was filtered and the filtrate was purified by preparative-HPLC to give l-(6-(((2-methoxyethyl)(methyl)amino)methyl)-3,4- dihydronaphthalen-2-yl)-4-((5-methylthiazol-2-yl)methoxy)pyridin-2(lH)-one (2.63 mg, 4%): 1Η NMR (400 MHz, CD₃OD) δ 7.56 (d, J = 7.6 Hz , 1H), 7.34-7.26 (m, 4H), 6.63 (s, 1H), 6.24-6.22 (m, 1H), 6.10 (d, J = 2.8 Hz, 1H), 5.42 (s, 2H), 4.39 (m, 1H), 4.27 (m, 1H), 3.73- 3.72 (m, 2H), 3.41-3.40 (m, 4H), 3.09-3.05 (m, 2H), 2.85 (s, 3H), 2.70-2.65 (m, 2H), 2.46- 2.45 (m, 1H), 2.45 (s, 3H); ES-LCMS m/z 452.2 (M+H).

Examples 7-30 (Table 1) were prepared by the method described above for Example 1, or routine variations thereof (unless otherwise indicated by alternative preparation), starting from 6-[4-(4-methyl-thiazol-2-ylmethoxy)-2-oxo-2H-pyridin- 1 -yl]-7,8-dihydro- naphthalene-2-carbaldehyde and the appropriate amine (A). 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.

Table 1. l-(6-((A)methyl)-3,4-dihydronaphthalen-2-yl)-4-((4-methylthiazol-2-yl) methoxy)pyridin-2( 1 H)-one

Example 31 : 4-(4-Ethyl-thiazol-2-ylmethoxy)- 1 -[6-(3 -hydroxy-pyrrolidin- 1^■ ylmethyl)-3 ,4 -dihydro-naphthalen-2-yl]-lH-pyridin-2-one.

A solution of 6-[4-(4-ethyl-thiazol-2-ylmethoxy)-2-oxo-2H-pyridin-l-yl]-7,8-dihydro -naphthalene-2-carbaldehyde (20 mg, 0.051 mmol) and pyrrolidin-3-ol (5.3 mg, 0.061 mmol) in CH₂CI₂ (5 mL) was stirred at room temperature for 2 hours. Then NaBH(OAc)₃ (32 mg, 0.153 mmol) was added to the solution and the reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with H₂0 and the aqueous phase was extracted with CH₂CI₂ (20 mL x 2). The combined organic phase was dried over a₂S0₄, filtered and concentrated in vacuo to give the residue, which was purified by preparative HPLC to give 4-(4-ethyl-thiazol-2-ylmethoxy)-l-[6-(3-hydroxy-pyrrolidin-l- ylmethyl)-3,4-dihydro-naphthalen-2-yl]-lH-pyridin-2-one (3.8 mg, 16.2%): 1H NMR (400 MHz, CD₃OD) δ 7.66 (d, J= 7.6 Hz, 1H), 7.52 (s, 1H), 7.37-7.34 (m, 2H), 7.27-7.25 (m, 1H), 6.65 (s, 1H), 6.39-6.37 (m, 1H), 6.18 (d, J= 2.4 Hz, 1H), 5.57 (s, 2H), 4.56-4.55 (m, 1H), 4.42-4.30 (m, 2H), 3.71-3.62 (m, 1H), 3.62-3.52 (m, 1H), 3.44-3.41 (m, 1H),3.08 (t, J = 8.20 Hz, 2H), 2.88-2.84 (m, 2H), 2.69 (t, J = 8.00 Hz, 2H), 2.41-2.36 (m, 1H), 2.13-2.10 (m, 1H), 2.02-1.92 (m, 1H), 1.35-1.29 (m, 3H); ES-LCMS m/z 464 (M+H). Example 32: 4-((4-Ethylthiazol-2-yl)methoxy)- 1 -(6-((4-methylpiperazin- 1 - yl)methyl)-3 ,4 -dihydronaphthalen-2-yl)pyridin-2(lH)-one, 2 hydrochloride.

A mixture of (6-(4-((4-ethylthiazol-2-yl)methoxy)-2-oxopyridin-l(2H)-yl)-7,8- dihydronaphthalen-2-yl)methyl methanesulfonate (400 mg, 0.846 mmol), 1 -methylpiperazine (170 mg, 1.693 mmol) and potassium carbonate (351 mg, 2.54 mmol) in DMF (10 mL) was heated to reflux overnight. The mixture was filtered, and the filtrate was concentrated in vacuo to give the residue which was purified by column to give 4-((4-ethylthiazol-2- yl)methoxy)- 1 -(6-((4-methylpiperazin- 1 -yl)methyl)-3 ,4-dihydronaphthalen-2-yl)pyridin- 2(lH)-one, 2 Hydrochloride (362.05 mg, 78 % yield): 1H NMR (400 MHz, CD₃OD) δ 7.72- 7.69 (m, 1H), 7.58 (s, 1H), 7.50-7.47 (m, 2H), 7.33-7.31 (m, 1H), 6.70 (s, 1H), 6.43 (dd, J= 7.6, 2.8 Hz, 1H), 6.22 (d, J = 2.4 Hz, 1H), 5.62 (s, 2H), 4.51 (s, 2H), 3.78-3.62 (m, 8H), 3.13 (t, J = 8.20 Hz, 2H), 3.04 (s, 3H), 2.94-2.90 (m, 2H), 2.74-2.72 (m, 2H), 1.31 (t, J = 7.40 Hz, 3H); ES-LCMS m/z 477 (M+H).

Example 33: 4-(4-Ethyl-thiazol-2-ylmethoxy)- 1 -(6- { [(2-fluoro-ethyl)-methyl- methyl} -3 ,4-dihydro-naphthalen-2-yl)- 1 H-pyridin-2-one.

The solution of 6-[4-(4-Ethyl-thiazol-2-ylmethoxy)-2-oxo-2H-pyridin-l-yl]-7,8- dihydro-naphthalene-2-carbaldehyde (20 mg, 0.051 mmol) and 2-fluoro-ethylamine (3.2 mg, 0.051 mmol) in DCM (4 mL) was stirred at room temperature. After 2 hours, triacetoxyborohydride (21 mg, 0.1 mmol) was added, and then the mixture was stirred at room temperature for 16 hours. After LC-MS analysis showed the starting material disappeared, the mixture was filtered and the filtrate was concentrated to give the crude product, which was purified by preparative TLC and to afford 4-(4-Ethyl-thiazol-2- ylmethoxy)-l-{6-[(2-fluoro-ethylamino)-methyl]-3,4-dihydro-naphthalen-2-yl}-lH-pyridin- 2-one (12 mg, 53.6%): ^lR NMR (400 MHz, CD₃OD) δ 7.64 (d, J = 7.60 Hz, 1H), 7.31-29 (m, 2H), 7.21-7.20 (m, 2H), 6.65 (s, 1H), 6.24 (dd, J = 8.0, 2.4 Hz, 1H), 6.09 (s, 1H), 5.39 (s, 2H), 4.80-4.75 (m, 2H), 4.70-4.69 (m, 1H), 4.60 (s, 5H), 4.20 (s, 2H), 3.10-3.01 (m, 3H), 2.69-2.67 (m, 3H); ES-LCMS m/z 391.0 (M+H)..

The solution of 4-(4-ethyl-thiazol-2-ylmethoxy)-l-{6-[(2-fluoro-ethylamino)-methyl] -3,4-dihydro-naphthalen-2-yl}-lH-pyridin-2-one (12 mg, 0.027 mmol), Formaldehyde solution (1 mL) and 2 drops of Formic acid in MeOH (5 mL), Triacetoxyborohydride (11 mg, 0.051 mmol) was stirred at room temperature for 1 hour. The mixture was concentrated, and the residue was purified by preparative HPLC and to afford 4-(4-Ethyl-thiazol-2- ylmethoxy)- 1 -(6- { [(2-fluoro-ethyl)-methyl-amino]-methyl} -3 ,4-dihydro-naphthalen-2-yl)- lH-pyridin-2-one (4.01 mg, 32.8%): ^lR NMR (400 MHz, CD₃OD) δ 7.63 (d, J = 7.6 Hz, 1H), 7.46 (s, 1H), 7.37-7.35 (m, 2H), 7.29-7.27 (m, 1H), 6.65 (s, 1H), 6.34 (dd, J = 8.0, 2.4 Hz, 1H), 6.15 (d, J = 2.4 Hz, 1H), 5.53 (s, 2H), 4.90-4.80 (m, 2H), 4.48-4.46 (m, 1H), 4.32- 4.28 (m, 1H), 3.70-3.43 (m, 2H), 3.09 (t, J = 8.0 Hz, 2H), 2.87-2.82 (m, 5H), 2.67 (t, J = 7.6 Hz, 2H), 1.33 (t, J= 7.6 Hz, 3H); ES-LCMS m/z 454.0 (M+H).

Examples 34-49 (Table 2) were prepared by the method described above for Example 31 , or routine variations thereof (unless otherwise indicated by alternative preparation), starting from [4-(4-ethyl-thiazol-2-ylmethoxy)-2-oxo-2H-pyridin- 1 -yl]-7,8-dihydro- naphthalene-2-carbaldehyde and the appropriate amine (A). 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 Intermediates section above.

Table 2. 1 -(6-((A)methyl)-3 ,4-dihydronaphthalen-2-yl)-4-((4-ethylthiazol-2- yl)methoxy)pyridin-2( 1 H)-one

Example 50: 4-(4,5-Dimethyl-thiazol-2-ylmethoxy)-l-{6-[(2-fluoro-ethylamino)- methyl]-3,4- dihydro-naphthalen-2-yl}-lH-pyridin-2-one.

To a mixture of methanesulfonic acid 4,5-dimethyl-thiazol-2-ylmethyl ester (26.5 mg, 0.12 mmoL), potassium carbonate (50 mg, 0.36 mmoL) in dry DMF (10 mL) was added (2- fluoro-ethyl)-[6-(4-hydroxy-2-oxo-2H-pyridin-l-yl)-7,8-dihydro-naphthalen-2-ylmethyl]- carbamic acid tert-butyl ester (50 mg, 0.12 mmoL). The mixture was stirred at 80 C overnight. The mixture was filtered, and the filtrate was concentrated to give the residue which was purified by preparative HPLC to give {6-[4-(4,5-dimethyl-thiazol-2-ylmethoxy)- 2-oxo-2H-pyridin- 1 -yl]-7,8-dihydro-naphthalen-2-ylmethyl} -(2-fiuoro-ethyl)-carbamic acid tert-butyl ester (30 mg, 46% yield): ^lR NMR (400 MHz, CD₃OD) δ 7.56-7.51 (m, 1H), 7.25- 7.21 (m, 1H), 7.12-7.10 (m, 1H), 6.98-6.87 (m, 1H), 6.53-6.50 (m, 1H), 6.21-6.14 (m, 1H), 6.14-6.02 (m, 1H), 5.41 (s, 1H), 5.34 (s, 1H), 4.56-4.52 (m, 1H), 4.36-4.31 (m, 1H), 4.15 (s, 1H), 3.46-3.41 (m, 1H), 2.97-2.87 (m, 2H), 2.54-2.48 (m, 2H), 2.38-2.34 (m, 5H), 1.49-1.46 (m, 1H), 1.36-1.30 (m, 3H), 1.15-1.06(m, 1H); ES-LCMS m/z 540.3 (M+H).

{6-[4-(4,5-Dimethyl-thiazol-2-ylmethoxy)-2-oxo-2H-pyridin-l-yl]-7,8-dihydro- naphthalen-2-ylmethyl}-(2-fiuoro-ethyl)-carbamic acid tert-butyl ester (30 mg, 0.056 mmoL) was dissolved in 4 N HCl/MeOH (20 mL), and the mixture was stirred for 1 hours at room temperature. The mixture was then concentrated to give 4-(4,5-dimethyl-thiazol-2- ylmethoxy)- 1 - {6-[(2-fiuoro-ethylamino)-methyl]-3,4-dihydro-naphthalen-2-yl} - lH-pyridin- 2-one (16.41 mg, 66% yield): 1H NMR (400 MHz, CD₃OD) a 7.78 (d, J= 6.4 Hz, 1H), 7.39- 7.37 (m, 2H), 7.26 (d, J = 6.8 Hz, 1H), 6.69 (s, 1H), 6.48 (s, 1H), 6.25 (d, J = 8.0 Hz, 1H), 5.75-5.70 (m, 2H), 4.83 (s, 1H), 4.72 (s, 1H), 4.26 (s, 2H), 3.21-3.19 (m, 2H), 3.15-3.04 (m, 2H), 2.71-2.69 (m, 2H), 2.59-2.45 (m, 6H); ES-LCMS m/z 440.1 (M+H).

Example 51 : 4-(4,5-Dimethyl-thiazol-2-ylmethoxy)- 1 -[6-(4-methyl-piperazin- 1 - ylmethyl)-3,4- dihydro-naphthalen-2-yl]- lH-pyridin-2-one.

To a mixture of methanesulfonic acid 4,5-dimethyl-thiazol-2-ylmethyl ester (32 mg,

0.14 mmoL), potassium carbonate (58 mg, 0.42 mmoL) in dry DMF (10 mL) was added 4- hydroxy- 1 - [6-(4-methyl-piperazin- 1 -ylmethyl)-3 ,4-dihydro-naphthalen-2-yl]- lH-pyridin-2- one (50 mg, 0.14 mmoL). The mixture was stirred overnight at 80 C. The mixture was filtered, and the filtrate was concentrated to give the residue which was purified by preparative HPLC to give 4-(4,5-dimethyl-thiazol-2-ylmethoxy)-l-[6-(4-methyl-piperazin-l- ylmethyl)-3 ,4-dihydro-naphthalen-2-yl]- lH-pyridin-2-one (4.32 mg, 6.5% yield): Η NMR (400 MHz, CD₃OD) δ 7.45 (d, J= 7.6 Hz, 1H), 7.08-7.00 (m, 3H), 6.46 (s, 1H), 6.13 (dd, J = 7.6, 2.8 Hz, 1H), 5.97 (d, J= 2.8 Hz, 1H), 5.21 (s, 2H), 3.42 (s, 2H), 2.95-2.91 (m, 2H), 2.57- 2.46 (m, 10H), 2.29 (s, 3H), 2.26 (s, 3H), 2.23 (s, 3H); ES-LCMS m/z All 2 (M+H).

Example 52 (Table 3) were prepared by the method described above for Example 50, or routine variations thereof (unless otherwise indicated by alternative preparation), starting from methanesulfonic acid 4,5-dimethyl-thiazol-2-ylmethyl ester and the appropriate (A)-[6- (4-hydroxy-2-oxo-2H-pyridin- 1 -yl)-7,8-dihydro-naphthalen-2-ylmethyl]-carbamic acid tert- butyl ester. 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.

Table 3. 1 -(6-((A)methyl)-3 ,4-dihydronaphthalen-2-yl)-4-((4,5-dimethylthiazol-2- yl)methoxy)pyridin-2( lH)-one

Example 53: 4-((2-Methylthiazol-4-yl)methoxy)- 1 -(6-(pyrrolidin- 1 -ylmethyl)-3 ,4- dihydronaphthalen-2-yl)pyridin-2( lH)-one, hydrochloride.

A solution of (2-methylthiazol-4-yl)methyl methanesulfonate (116 mg, 0.56 mmol), 4-hydroxy- 1 -(6-(pyrrolidin- 1 -ylmethyl)-3 ,4-dihydronaphthalen-2-yl)pyridin-2( lH)-one (150 mg, 0.47 mmol) and K₂C0₃ (130 mg, 0.94 mmol) in DMF (3 mL) was heated to 110 °C for 1 h. The mixture was cooled to room temperature and filtered, and the filtrate was concentrated and purified by preparative-HPLC to give 4-((2-methylthiazol-4-yl)methoxy)-l-(6- (pyrrolidin-l-ylmethyl)-3,4-dihydronaphthalen-2-yl)pyridin-2(lH)-one (27.86 mg, 14% yield): 1H NMR (400 MHz, CD₃OD) δ 7.79 (s, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.36-7.34 (m, 2H), 7.27 (d, J= 7.6 Hz, 1H), 6.64 (s, 1H), 6.31 (dd, J = 7.6, 2.8 Hz, 1H), 6.15 (d, J= 2.8 Hz, 1H), 5.26 (s, 2H), 4.34 (s, 2H), 3.51-3.49 (m, 2H), 3.11-3.07 (m, 4H), 2.85 (s, 3H), 2.72-2.68 (m, 2H), 2.22-2.19 (m, 2H) , 2.02-2.00 (m, 2H); ES-LCMS m/z 434.1 (M+H).

Example 54: 1 - {6-[(2-Fluoro-ethylamino)-methyl]-3 ,4-dihydro-naphthalen-2-yl} -4- (2-methyl -thiazol-4-ylmethoxy)- lH-pyridin-2-one.

A solution of methanesulfonic acid 2-methyl-thiazol-4-ylmethyl ester (30 mg, 0.15 mmol) and (2-fluoro-ethyl)-[6-(4-hydroxy-2-oxo-2H-pyridin- 1 -yl)-7,8-dihydro-naphthalen- 2-ylmethyl]-carbamic acid ieri-bntyl ester (50 mg, 0.12 mmol) and potassium carbonate (33 mg, 0.24 mmol) in CH3CN (3 mL) was stirred at 70 °C under N₂ overnight. The mixture was filtered, and the filtrate was purified by preparative TLC to afford (2-fluoro-ethyl)-{6-[4-(2- methyl-thiazol-4-ylmethoxy)-2-oxo-2H-pyridin- 1 -yl]-7,8-dihydro-naphthalen-2-ylmethyl} - carbamic acid teri-butyl ester (40 mg, 63% yield): 1H NMR (400 MHz, CD₃OD) δ 7.45-7.42 (m, 2H), 7.03-6.97 (m, 3H), 6.47 (m, 1H), 6.13 (dd, J = 7.6, 2.8 Hz, 1H), 5.99 (d, J = 2.4 Hz, 1H), 5.07 (s, 2H), 4.47-4.35 (m, 4H), 3.52-3.35 (m, 2H), 2.96-2.92 (m, 2H), 2.63 (s, 3H), 2.60-2.54 (m, 2H), 1.41-1.34 (m, 9H); ES-LCMS m/z 526.2 (M+H).

A solution of (2-fluoro-ethyl)-{6-[4-(2-methyl-thiazol-4-ylmethoxy)-2-oxo-2H- pyridin-1- yl]-7,8-dihydro-naphthalen-2-ylmethyl} -carbamic acid ieri-bn yl ester (40 mg, 0.076 mmol) in HCI/CH3OH (5 mL) was stirred at room temperature. After LC-MS analysis showed the starting material disappeared, the solvent was removed to give the crude product which was purified by preparative HPLC to afford l-{6-[(2-fluoro-ethylamino)-methyl]-3,4- dihydro-naphthalen-2-yl}-4-(2-methyl-thiazol-4-ylmethoxy)-lH-pyridin-2-one (7.3 mg, 23% yield): ^lR NMR (400 MHz, CD₃OD) δ 7.88 (s, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.27-7.25 (m, 2H), 7.16 (d, J= 7.6 Hz, 1H), 6.57 (s, 1H), 6.33 (dd, J= 7.6, 2.4 Hz, 1H), 6.15 (d, J= 2.4 Hz, 1H), 5.25 (s, 2H), 4.73-4.71 (m, 1H), 4.61-4.59 (m, 1H), 4.15 (s, 2H), 3.35-3.33 (m, 1H), 3.29-3.26 (m, 1H), 2.99 (t, J = 8.0 Hz, 2H), 2.84 (s, 3H), 2.60 (t, J = 8.0 Hz, 2H); ES-LCMS m/z 426.0 (M+H).

Examples 55-58 (Table 4) were prepared by the method described above for Example 53, or routine variations thereof (unless otherwise indicated by alternative preparation), starting from methanesulfonic acid 2-methyl-thiazol-4-ylmethyl ester and the appropriate 1 - (6-((A)methyl)-3 ,4-dihydronaphthalen-2-yl)-4-hydroxypyridin-2( 1 H)-one. 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. Table 4. l-(6-((A)methyl)-3,4-dihydronaphthalen-2-yl)-4-((2-methylthiazol-4- yl)methoxy)pyridin-2( 1 H)-one

Mobile phase: A: Hz, 1H), 6.41 (d, J= 2.4

Supercritical C0₂ , B:

Hz, 1H), 5.45 (s, 2H), 4.39- MeOHD0.05%DEAD

, A:B =60:40 at 4.49 (m, 1H), 4.19-4.24

80ml/min

(m, 2H), 4.11-4.16 (m,

Column Temp: 38°C

2H), 3.82-3.87 (m, 1H),

Nozzle Pressure:

lOOBar 3.72-3.73 (m, 1H), 3.1 1-

Nozzle Temp: 60°C 3.15 (m, 2H), 2.99 (s, 3H),

Evaporator Temp:

2.66-2.79 (m, 5H), 2.28-

20°C

2.56 (m, 2H)

Trimmer Temp: 25 °C

Wavelength: 220nm

Example 59: 4-(4-Isopropyl-thiazol-2-ylmethoxy)-l-(6-methylaminomethyl-3,4- dihydro-naphthalen-2-yl)- 1 H- ridin-2-one.

The mixture of (4-isopropylthiazol-2-yl)methyl methanesulfonate (500 mg, 2.125 mmol), tert-butyl((6-(4-hydroxy-2-oxopyridin- 1 (2H)-yl)-7,8-dihydronaphthalen-2- yl)methyl)(methyl)carbamate (544 mg, 1.424 mmol), potassium carbonate (587 mg, 4.25 mmol) in DMF (50 mL) was stirred at 70 °C for 8 hr. The mixture was cooled down and filtered. The filtrate was concentrated to give the residue, which was purified by HPLC to give 4-((4-isopropylthiazol-2-yl)methoxy)-l-(6-((4-methylpiperazin-l-yl)methyl)-3,4- dihydronaphthalen-2-yl)pyridin-2(lH)-one (300 mg, 27.6 %):^lR NMR(400 MHz, CDC1₃) δ ppm 7.24 (s, 1H), 7.19-7.15 (s, 3H), 6.87 (s, 1H), 6.00-5.94 (dd, J = 7.60 Hz, 2.40 Hz, 2H), 5.21 (s, 2H), 4.33-4.31 (m, 2H), 3.00-2.94 (m, 2H), 2.72 -2.64 (m, 2H), 1.51 (s, 9H), 1.41 (s, 6H), 1.21 (s, 3H); ES-LCMS m/z 522(M+H). The mixture of tert-butyl ((6-(4-((4-isopropylthiazol-2-yl)methoxy)-2-oxopyridin- 1 (2H)-yl)-7,8-dihydronaphthalen-2-yl)methyl)(methyl)carbamate(220mg, 0.422mmol) in hydrogen chloride, Methanol (solvate) (20mL) was stirred at 20 °C for 2 hr. After LC-MS analysis showed the starting material disappeared, the mixture was filtered and the filtrate was concentrated to give the crude product, which was purified by Prep-HPLC and to afford 4-(4-Isopropyl-thiazol-2-ylmethoxy)- 1 -(6-methylaminomethyl-3 ,4-dihydro- naphthalene-2- yl)-lH-pyridin-2-one (167.4mg, 82.8%): ^lR NMR (400 MHz, CD₃OD) δ 7.77-7.75 (d, J = 7.8 Hz, 1H), 7.62 (s, 1H), 7.36-7.34 (d, J= 7.8 Hz, 2H), 7.30-7.28 (d, J= 8 Hz, 1H), 6.71 (m, 1H), 6.50-6.48 (dd, J = 7.60 Hz, 2.40 Hz, 1H), 6.29-6.28 (d, J = 2.8 Hz, 1H), 4.91 (s, 1H), 3.36 (s, 1H), 3.33-3.31 (m, 3H), 2.76-2.74 (m, 5H), 1.40 (s, 3H), 1.39 (s, 3H); ES-LCMS m/z 422.1 (M+H).

Example 60: 1 -(6-Dimethylaminomethyl-3 ,4-dihydro-naphthalen-2-yl)-4-(4- isopropyl -thiazol-2-ylmethoxy)-lH- ridin-2-one.

To the mixture of 4-((4-isopropylthiazol-2-yl)methoxy)-l-(6-((methylamino)methyl)- 3,4-dihydronaphthalen-2-yl)pyridin-2(lH)-one (400 mg, 0.949 mmol) in Methanol (50 mL) was added formic acid (437 mg, 9.49 mmol), formaldehyde (285 mg, 9.49 mmol) and sodium triacetoxyborohydride (804 mg, 3.80mmol). The mixture was stirred at 20 °C for 20 hr. After LC-MS analysis showed the starting material disappeared, the mixture was filtered and the filtrate was concentrated to give the crude product, which was purified by Pre-HPLC and to afford l-(6-Dimethylaminomethyl-3,4-dihydro-naphthalen-2-yl)-4-(4-isopropyl - thiazol-2-ylmethoxy)-lH-pyridin-2-one (222.45 mg, 48.8%): 1H MR (400 MHz, CD₃OD) δ 7.69 (m, 1H), 7.52 (m, 1H), 7.38-7.36 (d, J = 7.2 Hz, 1H), 7.32-7.30 (d, J= 8.0 Hz, 2H), 6.70 (s, 1H), 6.41 (m, 1H), 6.23 (m, 1H), 5.58 (s, 2H), 4.31 (s, 2H), 3.36 (s, 1H), 3.33-3.31 (m, 2H), 2.89 (s, 6H), 2.76 -2.72 (m, 2H), 1.39-1.37 (s, 6H); ES-LCMS m/z 436.1 (M+H). Example 61 : 4-(2-Ethyl-thiazol-4-ylmethoxy)-l-(6-methylaminomethyl-3,4-dihydro- naphthalen-2-yl)-lH-pyridin-2-one.

A solution of methanesulfonic acid 2-ethyl-thiazol-4-ylmethyl ester (44 mg, 0.2 mmol), [6-(4-hydroxy-2-oxo-2H-pyridin- 1 -yl)-7,8-dihydro-naphthalen-2-ylmethyl]-methyl- carbamic acid ieri-bn yl ester (76 mg, 0.2 mmol) and potassium carbonate (64 mg, 0.4 mmol) in N,N-Dimethylformamide (DMF) (3 mL) was stirred at 20 °C overnight. The mixture was filtered. The filtrate was purified by preparative HPLC to afford {6-[4-(2-ethyl-thiazol-4- ylmethoxy)-2-oxo-2H-pyridin- 1 -yl]-7,8-dihydro- naphthalen-2-ylmethyl} -methyl-carbamic acid ieri-bntyl ester (50 mg, 50 % yield): 1H NMR (400 MHz, CD₃OD) δ 7.75-7.57 (m, 2H), 7.31-7.26 (m, 2H), 7.13-7.05 (m, 1H), 6.63-6.59 (m, 1H), 6.35-6.32 (m, 1H), 6.29-6.13 (m, 1H), 5.26 (s, 2H), 4.40-4.15 (m, 2H), 3.17-3.11 (m, 4H), 2.83 (s, 2H), 2.69-2.67 (m, 3H), 1.45-1.40 (m, 9H); ES-LCMS m/z 508.0 (M+H).

A solution of {6-[4-(2-ethyl-thiazol-4-ylmethoxy)-2-oxo-2H-pyridin-l-yl]-7,8- dihydro- naphthalen-2-ylmethyl} -methyl-carbamic acid iert-bn yl ester (50 mg, 0.098 mmol) in HC1 (5 mL, 165 mmol) was stirred at 25 °C. After 0.5 hr, TLC analysis showed the starting material was disappeared. The solvent was removed to give 4-(2-ethyl-thiazol-4- ylmethoxy)-l-(6-methylaminomethyl-3,4-dihydro-naphthalen-2-yl)-lH-pyridin-2-one (31.76 mg, 0.072 mmol, 72.6 % yield): 1H NMR (400 MHz, CD₃OD) δ 7.85 (s, 1H), 7.59 (d, J= 7.6 Hz, 1H), 7.22-7.20 (m, 2H), 7.15 (d, J = 7.6 Hz, 1H), 6.56 (s, 1H), 6.29 (dd, J = 7.6, 2.4 Hz, 1H), 6.12 (d, J = 2.4 Hz, 1H), 5.23 (s, 2H), 4.05 (s, 2H), 3.16-3.12 (m, 2H), 2.98 (t, J = 8.2 Hz, 2H), 2.61-2.60 (m, 5H), 1.36 (t, J= 7.6 Hz, 3H); ES-LCMS m/z 408.2 (M+H).

Example 62: l-(6-((Dimethylamino)methyl)-3,4-dihydronaphthalen-2-yl)-4-((2- ethylthiazol-4- yl)methoxy)pyridin-2( lH)-one.

To a solution of 4-((2-ethylthiazol-4-yl)methoxy)-l-(6-((methylamino)methyl)-3,4- dihydronaphthalen-2-yl)pyridin-2(lH)-one, hydrochloride (400 mg, 0.901 mmol) in methanol (10 mL) was added formaldehyde (0.671 mL, 9.01 mmol) and formic acid (0.364 mL, 9.01 mmol). The resulting mixture was stirred at 20 °C. After 1 hour, NaCNBH₄ (113 mg, 1.802 mmol) was added. After LC-MS analysis showed the starting material disappeared, the solvent was removed in vacuo to give the crude product, which was purified by preparative HPLC to afford l-(6-((dimethylamino)methyl)-3,4-dihydronaphthalen-2-yl)- 4-((2-ethylthiazol-4-yl)methoxy)pyridin-2(lH)-one (344.9mg, 0.752 mmol, 84 % yield): ^lR NMR (400 MHz, CD₃OD) δ 7.98 (s, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.31-7.29 (m, 2H), 7.33 (d, J= 7.6 Hz, 1H), 6.65 (s, 1H), 6.43 (dd, J= 7.6, 2.8 Hz, 1H), 6.24 (d, J= 2.8 Hz, 1H), 5.33 (s, 2H), 4.23 (s, 2H), 3.25-3.23 (m, 2H), 3.05 (t, J = 8.2 Hz, 2H), 2.80 (s, 6H), 2.69-2.65 (m, 2H), 1.43 (t, J= 7.6 Hz, 3H); ES-LCMS m/z 422.2 (M+H).

Example 63 (Table 5) were prepared by the method described above for Example 59, or routine variations thereof (unless otherwise indicated by alternative preparation), starting from (4-isopropylthiazol-2-yl)methyl methanesulfonate and the appropriate l-(6- ((A)methyl)-3,4-dihydronaphthalen-2-yl)-4-hydroxypyridin-2(lH)-one. 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.

Table5. 4-((4-isopropylthiazol-2-yl)methoxy)- 1 -(7-((A)methyl)- 1 ,2- dihydronaphthalen-3-yl)pyridin-2(lH)-one

Example 64: l-{6-[(l,l-Dioxo-hexahydro-^⁶-thiopyran-4-ylamino)-methyl]-3,4- dihydro- naphthalen-2-yl} -4-(5-methyl-thiazol-2-ylmethoxy)- lH-pyridin-2-one.

To a solution of (l,l-dioxo-hexahydro-116-thiopyran-4-yl)-[6-(4-hydroxy-2-oxo-2H- pyridin-l-yl)-7,8-dihydro-naphthalen-2-ylmethyl]-carbamic acid ieri-bn yl ester (50 mg, 0.1 mmol) in anhydrous DMF (6 mL) was added methanesulfonic acid 5-methyl-thiazol-2- ylmethyl ester (180 mg, 0.87 mmol) and K₂CO₃ (27 mg, 0.2 mmol). Then the resultant mixture was heated to 60-70 °C overnight. Solvent was removed in vacuo to give (1 ,1- dioxo- hexahydro-^⁶-thiopyran-4-yl)-{6-[4-(5-methyl-thiazol-2-ylmethoxy)-2-oxo-2H- pyridin-l-yl]-7,8-dihydro-naphthalen-2-ylmethyl}-carbamic acid teri-butyl ester (55 mg, crude). Then the crude residue was dissolved in TFA/CH₂CI₂ (5 mL) and stirred at room temperature for 30 minutes. Solvent was removed in vacuo to give the crude product which was purified by HPLC to get l-{6-[(l ,l-dioxo-hexahydro-^⁶-thiopyran-4-ylamino)-methyl]- 3,4- dihydro- naphthalen-2-yl}-4-(5-methyl-thiazol-2-ylmethoxy)-lH-pyridin-2-one (10.97 mg, 22%): ¹HNMR (400 MHz, CD₃OD) δ 7.70 (d, J= 0.8 Hz, IH), 7.65-7.63 (d, J= 8.4 Hz, IH), 7.36-7.34 (d, J = 7.8 Hz, IH), 7.26-7.24 (d, J = 7.8 Hz, IH), 6.69 (s, IH), 6.64 (s, IH), 6.36-6.33 (dd, J = 7.6, 2.8 Hz, IH), 6.16-6.15 (d, J=2.4 Hz, IH,), 5.49 (s, 2H), 4.25 (s, 2H), 3.56-3.52 (m, IH), 3.31-3.28 (m, 2H), 3.19-3.16 (m, 2H), 3.10-3.06 (m, 2H,), 2.68-2.60 (m, 2H), 2.58-2.49 (m, 5H), 2.28-2.19 (m, 2H); ES-LCMS m/z 512 (M+H). Example 65: 1 -[6-(4-Methyl-piperazin- 1 -ylmethyl)-3 ,4-dihydro-naphthalen-2-yl]-4-

(5-methyl-thiazol-2-ylmethoxy)-lH-pyridin-2-one.

To a solution of l-[6-(4-methyl-piperazin-l-ylmethyl)-3,4-dihydro-naphthalen-2-yl]- 4-(5-methyl-thiazol-2-ylmethoxy)-lH-pyridin-2-one (30 mg, 0.085) in anhydrous DMF (6 mL) was added methanesulfonic acid 5-methyl-thiazol-2-ylmethyl ester (180 mg, 0.87 mmol) and K₂CO3 (23 mg, 0.17 mmol). Then the resultant mixture was heated to 60-70 °C overnight. Solvent was removed in vacuo to give l-[6-(4-methyl-piperazin-l-ylmethyl)-3,4- dihydro-naphthalen-2-yl]-4-(5-methyl-thiazol-2-ylmethoxy)- lH-pyridin-2-one which was purified by preparative TLC (4.43 mg, 11%): ¾ MR (400 MHz, CD₃OD) δ 7.82 (d, J=1.2Hz, IH), 7.72-7.70 (d, J= 7.6Hz, IH), 7.49-7.45 (m, 2H), 7.32-7.30 (d, J= 7.6Hz, IH), 6.69 (s, IH), 6.44-6.41 (dd, J =7.6Hz, J =2.8Hz IH,), 6.22-6.21 (d, J= 2.8Hz, IH), 5.58 (s, 1H), 4.50 (s, 2H), 3.93-3.71 (m, 4H), 3.63-3.56 (m, 4H), 3.13-3.09 (m, 2H), 3.02 (s, 3H), 2.73 (m, 2H,), 2.58 (s, 3H); ES-LCMS m/z 463 (M+H).

Examples 66-69 (Table 6) were prepared by the method described above for Example 64, or routine variations thereof (unless otherwise indicated by alternative preparation), starting from methanesulfonic acid 5-methyl-thiazol-2-ylmethyl ester and the appropriate 1- (6-((A)methyl)-3,4-dihydronaphthalen-2-yl)-4-((5-methylthiazol-2-yl)methoxy)pyridin- 2(lH)-one. 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.

Table 6. 4-((5-methylthiazol-2-yl)methoxy)-l-(7-((A)methyl)-l ,2-dihydronaphthalen- 3-yl)pyridin-2(lH)-one

Example 70: 4-(4-Chloro-thiazol-2-ylmethoxy)- 1 -[6-(4-methyl-piperazin- 1 -ylmethyl) -3, 4-dihydro-naphthalen-2-yl]-lH-pyridin-2-one.

To a suspension of 6-[4-(4-chloro-thiazol-2-ylmethoxy)-2-oxo-2H-pyridin-l-yl]-7,8- dihydro-naphthalene-2-carbaldehyde (20 mg, 0.05 mmol) and 1 -methyl-piperazine (10 mg, 0.1 mmol) in DCM (10 mL) was added Et₃N (15 mg, 0.15 mmol) and triacetoxy sodium borohydride (32 mg, 0.15 mmol), the resulting mixture was stirred at room temperature overnight. The reaction mixture was treated with 5 mL of aqueous saturated NaHC0₃ solution and extracted with CH₂CI₂ (10 mL). The organic layer was dried over a₂S0₄, filtered and concentrated in vacuum to give the crude product, which was purified by preparative HPLC to give 4-(4-chloro-thiazol-2-ylmethoxy)-l-[6-(4-methyl-piperazin -1- ylmethyl)-3 ,4-dihydro-naphthalen-2-yl]- lH-pyridin-2-one (5.08 mg, 21% yield): Η NMR (400 MHz, CD₃OD) δ 7.56 (d, J = 7.6 Hz, 1H), 7.52 (s, 1H), 7.39 (d, J = 9.2 Hz, 2H), 7.27 (d, J= 7.6 Hz, 1H), 6.63 (s, 1H), 6.28 (dd, J= 7.6, 2.4 Hz, 1H), 6.10 (d, J= 2.4 Hz, 1H), 5.42 (s, 2H), 4.39 (s, 2H), 3.84-3.43 (m, 8H), 3.08 (t, J= 8.0 Hz, 2H), 2.99 (s, 3H), 2.68 (t, J= 8.0 Hz, 2H); ES-LCMS m/z 483.1 (M+H). Example 71 : 4-(4-Chloro-thiazol-2-ylmethoxy)-l-{6-[(2-fluoro-ethylamino)-methyl]-

3, 4-dihydro-naphthalen-2-yl}-lH-pyridin-2-one.

To a mixture of (2-fluoro-ethyl)-[6-(4-hydroxy-2-oxo-2H-pyridin-l-yl)-7,8-dihydro- naphthalen-2-ylmethyl]-carbamic acid teri-butyl ester (50 mg, 0.12 mmoL), potassium carbonate (50 mg, 0.36 mmoL) in dry DMF (10 mL) was added methanesulfonic acid 4- chloro-thiazol-2-ylmethyl ester (33 mg, 0.14 mmoL). The mixture was stirred overnight at 80 °C. The mixture was then filtered, and the filtrate was concentrated to provide {6-[4-(4- chloro-thiazol-2-ylmethoxy)-2-oxo-2H-pyridin- 1 -yl]-7,8-dihydro-naphthalen-2-ylmethyl} - (2-fluoro-ethyl)-carbamic acid tert- butyl ester (65 mg, 100% yield), which was used for the next step without purification. ^lR NMR (400 MHz, CDC1₃) δ 7.95 (s, 1H), 7.10 (d, J = 4.0 Hz, 1H), 7.02-6.97 (m, 3H), 6.38 (s, 1H), 5.97 (dd, J = 7.6, 2.4 Hz, 1H), 5.90 (d, J = 2.4 Hz, 1H), 5.20 (s, 2H), 4.87-4.46 (m, 4H), 3.47-3.38 (m, 2H), 2.98-2.89 (m, 2H), 2.71-2.64 (m, 2H), 1.42 (s, 9H); ES-LCMS m/z 546.1 (M+H).

- I l l - {6-[4-(4-Chloro-thiazol-2-ylmethoxy)-2-oxo-2H-pyridin-l-yl]-7,8-dihydro- naphthalen-2-ylmethyl}-(2-fluoro-ethyl)-carbamic acid iert-bn yl ester (65.4 mg, 0.12 mmol) was dissolved in 4 N HCl/MeOH (30 mL), and the mixture was stirred for lh at room temperature. The reaction mixture was concentrated in vacuum, and then purified by preparative HPLC to give 4-(4-chloro-thiazol-2-ylmethoxy)-l- {6-[(2-fluoro- ethylamino)- methyl]-3,4-dihydro- naphthalen-2-yl}-lH-pyridin-2-one (24.17 mg, 45% yield): 1H NMR (400 MHz, CD₃OD) δ 7.62 (d, J = 7.6 Hz, 1H), 7.53 (s, 1H), 7.33 (d, J = 6.8 Hz, 1H), 7.26 (d, J= 8.4 Hz, 1H), 6.64 (s, 1H), 6.34 (dd, J= 7.6, 2.8 Hz, 1H), 6.15 (d, J= 2.8 Hz, 1H), 5.44 (s, 2H), 4.80 (t, J = 4.8 Hz, 1H), 4.69 (t, J = 8.4 Hz, 1H), 4.23 (s, 2H), 3.43-3.38 (m, 1H), 3.36-3.29 (m, 1H), 3.08 (t, J = 8.0 Hz, 2H), 2.69 (t, J = 8.0 Hz, 2H); ES-LCMS m/z 446.1 (M+H).

Example 72: 1 -[6-(4-Methyl-piperazin- 1 -ylmethyl)-3, 4-dihydro-naphthalen-2-yl]-4- (thiazol-2-ylmethoxy)-lH-pyridin-2-one.

To a solution of thiazol-2-yl-methanol (49 mg, 0.43 mmol) and Et₃N (85 mg, 084 mmol) in 10 mL of anhydrous DCM at 0 °C was added MsCl (64 mg, 056 mmol) dropwise. The mixture was stirred at room temperature for 1 hour. The mixture was partitioned between DCM (10 mL) and H₂0 (10 mL). The organic layer was separated, washed with H₂0 (2 x 50 mL), dried over Na₂S0₄, and filtered. The filtrate was concentrated to give brown oil. The mixture of the brown oil, 4-hydroxy-l-[6-(4-methyl-piperazin-l-ylmethyl)- 3,4-dihydro -naphthalen-2-yl]-lH-pyridine-2-one (100 mg, 0.28 mmol) and K₂C0₃ (117 mg, 0.84 mmol) in 10 mL of anhydrous DMF was stirred at 110 °C for 16 hours. Then The mixture was filtered, and the filtrate was purified by preparative HPLC to give l-[6-(4- Methyl-piperazin- 1 -ylmethyl)-3 , 4-dihydro-naphthalen-2-yl]-4- (thiazol-2-ylmethoxy)- 1H- pyridin-2-one as a yellow solid (13.09 mg, 7% yield): 1H NMR (400 MHz, CD₃OD) δ 7.84 (d, J = 3.2 Hz, 1H), 7.69 (d, J = 3.6 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.37-7.30 (m, 2H), 7.20 (d, J = 7.6 Hz, 1H), 6.58 (s, 1H), 6.29-6.28 (m, 1H), 6.10 (d, J = 2.4 Hz, 1H), 5.45 (s, 2H), 4.39 (s, 2H), 3.90-3.52 (m, 8H), 3.03-2.99 (m, 2H), 2.93 (s, 3H), 2.64-2.61 (m, 2H); ES- LCMS m/z 449 (M+H). Example 73 : 4-(5-Chloro-thiazol-2-ylmethoxy)- l-{6-[(l,l -dioxo-hexahydro- 1 λ⁶- thiopyran-4-ylamino)-methyl]- -dihydro-naphthalen-2-yl}-lH-pyridin-2-one

A mixture of 6-[4-(5-chloro-thiazol-2-ylmethoxy)-2-oxo-2H-pyridin-l-yl]-7,8- dihydro-naphthalene-2-carbaldehyde (20 mg, 0.05 mmol) and l ,l-dioxo-hexahydro-^⁶- thiopyran- 4-ylamine (40 mg, 0.27 mmol) was dissolved in dry CH2CI2 (6 mL). The mixture was stirred at rt for 2.5 hours, NaBH(OAc)₃ (1 13 mg, 0.54 mmol) was then added. Then the mixture was stirred at rt overnight. Water (20 mL) was added and the mixture was washed with DCM (2 x 10 mL). The combined organic DCM was washed with brine (30 mL), dried over a₂S0₄, filtered and concentrated in vacuo to give 4-(5-chloro-thiazol-2-ylmethoxy)-l- {6- [( 1 , 1 - dioxo-hexahydro- 1 λ⁶-thiopyran-4-ylamino)-methyl]-3 ,4-dihydro-naphthalen-2-yl} - lH-pyridin-2-one (4.95 mg, yield 19%): ^lR NMR (400 MHz, CD₃OD) δ 7.72 (s, 1H), 7.60 (d, J= 7.6 Hz, 1H), 7.35 (d, J= 6.8 Hz, 2H), 7.27 (d, J = 8.4 Hz, 1H), 6.64 (s, 1H), 6.31 (dd, J = 7.6, 2.4 Hz, 1H), 6.14 (d, J= 2.8 Hz, 1H), 5.41 (s, 2H), 4.26 (s, 2H), 3.61-3.52 (m, 1H), 3.36- 3.35 (m, 2H) 3.22-3.11 (m, 2H), 3.09-3.07 (m, 2H), 2.72-2.68 (m, 2H), 2.66-2.57 (m, 2H), 2.26-2.10 (m, 2H); ES-LCMS m/z 533.1 (M+H).

Example 74: 2- { 1 -[6-(4-Methyl-piperazin- 1 -ylmethyl)-3 , 4-dihydro-naphthalen-2-yl] -2-oxo- 1 , 2-dihydro-pyridin-4-yloxymethyl} -thiazole-4-carboxylic acid methyl ester.

A mixture of 2-hydroxymethyl-thiazole-4-carboxylic acid methyl ester (50 mg, 0.288 mmol), triethylamine (29 mg, 0.29 mmol), methanesulfonyl chloride (33 mg, 0.29 mmol) in DCM (5 mL) was stirred at room temperature for 30 minutes. The mixture was washed with H₂0 (3 mL), and the organic phase was dried over anhydrous a₂S0₄ and filtered, The filtrate was concentrated, and the residue was added into the mixture of 4-hydroxy-l-[6-(4- methyl- piperazin-l-ylmethyl)-3,4-dihydro-naphthalen-2-yl]-lH-pyridin-2-one (93 mg, 0.27 mmol), potassium carbonate (75 mg, 0.54 mmol) in DMF (5 mL). The mixture was stirred at room temperature for 48 hours. The solvent was concentrated, and the residue uas purified by preparative-HPLC to provide 2-{l-[6-(4-methyl-piperazin-l-ylmethyl)-3,4-dihydro- naphthalen-2-yl]-2-oxo- 1 ,2-dihydro-pyridin-4-yloxymethyl} -thiazole-4-carboxylic acid methyl ester (20 mg, 14.6% yield): ^lR NMR (400 MHz, CD₃OD) δ 8.50 (s, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.48-7.45 (m, 2H), 7.30 (d, J = 7.6 Hz, 1H), 6.69 (s, 1H), 6.43 (dd, J = 7.6, 2.8 Hz, 1H), 6.23 (d, J = 2.4 Hz, 1H), 5.53 (s, 2H), 4.49 (s, 2H), 3.93 (s, 3H), 3.92-3.50 (m, 8H), 3.1 1 (t, J= 8.4 Hz, 2H), 3.02 (s, 3H), 2.71 (t, J= 8.0 Hz, 2H); ES-LCMS m/z 507.2 (M+H).

Example 75: 4-(4-Hydroxymethyl-thiazol-2-ylmethoxy)- 1 -[6-(4-methyl-piperazin- 1 - ylmethyl)-3, 4-dihydro-naphthalen-2-yl]- lH-pyridin-2-one.

A mixture of 2- {l-[6-(4-methyl-piperazin-l-ylmethyl)-3, 4-dihydro-naphthalen-2-yl] -2-oxo- 1 , 2-dihydro-pyridin-4-yloxymethyl} -thiazole-4-carboxylic acid methyl ester (20 mg, 0.04 mmol), DIBAL-H (0.2 mL, 0.2 mmol) in DCM (3 mL) was stirred at -78 °C for 1 hour. The solvent was concentrated, the residue was purified by preparative HPLC to afford 4-(4- hydroxymethyl-thiazol-2-ylmethoxy)-l-[6-(4-methyl-piperazin -l-ylmethyl)-3,4-dihydro- naphthalen-2-yl]-lH-pyridin-2-one (1.45 mg, 7.6% yield): ^lR NMR (400 MHz, CD₃OD) δ 7.59 (d, J = 7.6 Hz, 1H), 7.52 (s, 1H), 7.43 (d, J = 10.4 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 6.65 (s, 1H), 6.32-6.30 (m, 1H), 6.14 (d, J = 2.8 Hz, 1H), 5.46 (s, 2H), 4.71 (s, 2H), 4.45 (s, 2H), 3.85-3.40 (m, 8H), 3.12-3.08 (m, 2H), 3.01 (s, 3H), 2.70 (t, J = 8.0 Hz, 2H); ES-LCMS w/z 479.1 (M+H).

Example 76: l-(6-Dimethylaminomethyl-3, 4-dihydro-naphthalen-2-yl)-4-(4-methoxy methyl-thiazol-2-ylmethoxy)- lH-pyridin-2-one.

A solution of 2-methanesulfonyloxymethyl-thiazole-4-carboxylic acid methyl ester (0.17 g, 0.66 mmol) and [6-(4-hydroxy-2-oxo-2H-pyridin-l-yl)-7, 8-dihydro- naphthalen-2- ylmethylj-methyl-carbamic acid iert-bn yl ester (210 mg, 0.55 mmol) and K₂C0₃ (0.15 g, 1.1 mmol) in DMF (4 mL) was stirred at room temperature overnight. The mixture was concentrated in vacuo. The residue was dissolved in EtOAc and washed with H₂0. The organic layer was dried and concentrated to give the crude product, which was purified by preparative TLC to afford 2-(l-{6-[(teri-butoxy carbonyl-methyl-amino)-methyl]-3,4- dihydro-naphthalen-2-yl} -2-oxo- 1 ,2-dihydro-pyridin-4-yloxymethyl)-thiazole-4-carboxylic acid methyl ester (0.3 g, 100% yield): ^lR NMR (400 MHz, CD₃OD) δ 8.42 (s, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.99 (d, J = 7.2 Hz, 1H), 6.50 (s, 1H), 6.21 (dd, J = 7.6, 2.8 Hz, 1H), 6.03 (d, J= 2.8 Hz, 1H), 5.41 (s, 2H), 4.33 (s, 2H), 3.86 (s, 3H), 2.96 (t, J = 8.4 Hz, 2H), 2.76 (s, 3H), 2.59 (t, J = 8.4 Hz, 2H), 1.40 (m, 9H); ES-LCMS m/z 538.1 (M+H). To a solution of 2-(l-{6-[(teri-butoxycarbonyl-methyl-amino)-methyl]-3, 4-dihydro- naphthalen-2-yl} -2-oxo- 1 , 2-dihydro-pyridin-4-yloxymethyl)-thiazole-4-carboxylic acid methyl ester (0.3 g, 0.55 mmol) in CH₃OH (10 mL) was added NaBH₄ (0.21 g, 5.6 mmol). The resulting mixture was stirred at 60 °C. After TLC analysis showed the starting material disappeared, the mixture was concentrated in vacuo. The residue was dissolved in DCM and washed with H₂0. The organic layer was dried and concentrated to give {6-[4-(4- hydroxymethyl-thiazol-2-ylmethoxy)-2-oxo-2H-pyridin - 1 -yl]-7,8-dihydro-naphthalen-2- ylmethyl}-methyl-carbamic acid tert-butyl ester (0.25 g, 89% yield): 1H NMR (400 MHz, CD3OD) δ 7.46 (d, J = 7.6 Hz, 1H), 7.39 (s, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.96 (d, J = 7.2 Hz, 2H), 6.46 (s, 1H), 6.15 (dd, J = 7.6, 2.8 Hz, 1H), 6.00 (d, J = 2.8 Hz, 1H), 5.33 (s, 2H), 4.61 (d, J = 0.8 Hz, 2H), 4.30 (s, 2H), 2.93 (t, J = 8.0 Hz, 2H), 2.73 (s, 3H), 2.56 (t, J = 8.0 Hz, 2H), 1.37 (d, J= 14.8 Hz, 9H); ES-LCMS m/z 510.2 (M+H).

To a solution of {6-[4-(4-hydroxymethyl-thiazol-2-ylmethoxy)-2-oxo-2H-pyridin-l - yl]-7,8-dihydro-naphthalen-2-ylmethyl}-methyl-carbamic acid tert-butyl ester (0.25 g, 0.49 mmol) in THF (10 mL) was added NaH (40 mg, 1 mmol). The reaction was stirred at room temperature for 30 minutes, before Mel (104 mg, 0.74 mmol) was added. The resulting mixture was stirred at room temperature overnight. After TLC analysis showed the starting material disappeared, the mixture was concentrated in vacuo. The residue was dissolved in EtOAc and washed with H₂0. The organic layer was dried and concentrated to give the crude product, which was purified by preparative TLC to afford {6-[4-(4-methoxymethyl- thiazol-2-ylmethoxy)-2-oxo-2H-pyridin- 1 -yl]-7, 8- dihydro-naphthalen-2-ylmethyl} -methyl- carbamic acid tert-butyl ester (70 mg, 26% yield): 1H NMR (400 MHz, CD₃OD) δ 7.52 (d, J = 10.0 Hz, 1H), 7.10-7.00 (m, 3H), 6.52 (s, 1H), 6.21 (dd, J = 10.4, 4.0 Hz, 1H), 6.05 (d, J = 4.0 Hz, 1H), 5.39 (s, 2H), 4.52 (s, 2H), 4.36 (s, 2H), 3.37 (s, 3H), 2.99 (t, J = 10.8 Hz, 2H), 2.79 (s, 3H), 2.62 (t, J= 10.8 Hz, 2H), 1.43 (s, 9H); ES-LCMS m/z 524.0 (M+H).

A solution of {6-[4-(4-methoxymethyl-thiazol-2-ylmethoxy)-2-oxo-2H-pyridin-l-yl] -7, 8- ihydro-naphthalen-2-ylmethyl}-methyl-carbamic acid tert-butyl ester (70 mg, 0.13 mmol) in 4 NHCI CH3OH (15 mL) was stirred at room temperature. After LC-MS analysis showed the starting material disappeared, the mixture was concentrated in vacuo to give 4- (4-methoxymethyl-thiazol-2-ylmethoxy)- 1 -(6-methyl aminomethyl-3 ,4-dihydro-naphthalen- 2-yl)-lH-pyridin-2-one (55 mg, 100% yield): ^lR NMR (400 MHz, CD₃OD) δ 7.58 (d, J = 7.6 Hz, 1H), 7.53 (s, 1H), 7.19 (d, J = 6.8 Hz, 2H), 7.14 (d, J = 8.4 Hz, 1H), 6.55 (s, 1H), 6.32 (dd, J = 7.6, 2.8 Hz, 1H), 6.12 (d, J = 2.4 Hz, 1H), 5.40 (s, 2H), 4.45 (d, J = 0.8 Hz, 2H), 4.03 (s, 2H), 3.30 (s, 3H), 2.97 (t, J = 8.0 Hz, 2H), 2.59-2.56 (m, 5H); ES-LCMS m/z 424.2 (M+H).

A solution of 4-(4-methoxymethyl-thiazol-2-ylmethoxy)-l-(6-methylaminomethyl - 3,4-dihydro-naphthalen-2-yl)-lH-pyridin-2-one (55 mg, 0.13 mmol), HCHO (0.1 g, 1.3 mmol) and HCOOH (60 mg, 1.3 mmol) in CH₃OH was stirred at room temperature. After 2 hours, NaBH(OAc)₃ (55 mg, 0.26 mmol) was added. The mixture was stirred at room temperature overnight. After LC-MS analysis showed the starting material disappeared, the mixture was concentrated in vacuo. The residue was dissolved in DCM and washed with H₂0. The organic layer was dried and concentrated to give the crude product, which was purified by preparative HPLC to afford l-(6-dimethylaminomethyl-3,4-dihydro-naphthalen- 2-yl)-4-(4-methoxy methyl-thiazol-2-ylmethoxy)-lH-pyridin-2-one (54 mg, 95% yield): 1H NMR (400 MHz, CD₃OD) δ 7.54 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 0.4 Hz, 1H), 7.22 (d, J = 7.2 Hz, 2H), 7.16 (d, J = 8.0 Hz, 1H), 6.55 (s, 1H), 6.26 (dd, J = 7.8, 2.0 Hz, 1H), 6.08 (d, J = 2.4 Hz, 1H), 5.37 (s, 2H), 4.45 (d, J = 0.8 Hz, 2H), 4.17 (s, 2H), 3.30 (s, 3H), 2.98 (t, J = 8.0 Hz, 2H), 2.74 (s, 6H), 2.59 (t, J= 7.2 Hz, 2H); ES-LCMS m/z 438.2 (M+H).

Assay

A: MCHR1 pIC^ 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 μΕ DMEM/F12, 10% FBS, 2 mM 1-glutamine. Compounds to be profiled were prepared by making a stock solution at 3xl0^"3M in 100% DMSO. The stock solutions were serially diluted 1 :4 in 100% DMSO using JANUS (PerkinElmer) liquid handling instrument to allow for an 11 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 μϊ_^ of loading buffer (Calcium 4 Kit, Molecular Dynamics corporation). Following 50 min incubation at 37°C, 10 μΐ. 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 μΕ of MCH challenge concentration at 4XECso. Data was collected over 4 minutes and subjected to a nonlinear regression analysis curve fitting program to generate pIC₅oS.

B: MCHR1 pIC^ 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 μΕ of media without serum to reduce background signal noise. Compounds were prepared by making a stock solution at 3xl0^"3M. 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 μΕ) were pipetted into the assay plate using JANUS. Following incubation for 45 minutes at 37°C, 10 μΕ of 6xEC₈o 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 15μΕ 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.

Results

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 MCHRl receptor with pICsoS >5.5. Examplar compounds with specific biological activities tested according to assays described herein are listed in Table 7 with pICsoS ranged from 6 to 8.7.

Table 7

Claims

Claims:

1. A compound according to Formula (I):

wherein:

each R¹ is independently selected from the group consisting of hydrogen, halo, (Ci-

C₃)alkyl, (C₃-C₆)cycloalkyl, hydroxyl(Ci-C₃)alkyl, (Ci-C₃)alkoxy(Ci-C₃)alkyl, (Ci- C₃)alkoxy, (Ci-C₃)haloalkyl, C(=0)0(Ci-C₃)alkyl, amino, and CN;

n is 0-2;

A is selected from the rou consistin of Formula II and Formula (III),

II III where in Formula (II):

Y is C, O, S, S0₂ or R⁶;

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

s is 0-4;

r is 0-4; each R² and each R³ are independently selected from the group consisting of hydrogen, (Ci-C₆)alkyl, (C₃-C₆)cycloalkyl(Ci-C₃)alkyl, hydroxyl, halo, (Ci- C₃)alkoxy, hydroxyl(Ci-C₃)alkyl, (C₁-C₃)alkoxy(C₁-C₃)alkyl, (Ci-C₃)alkylS0₂(Ci- C₃)alkyl, -C(=0)NR⁶R⁷, -C(=0)R⁶, -S0₂R⁶, -S0₂NR⁶R⁷, oxo, -C(=0)OR⁶, -NR⁶R⁷, - NR⁶C(=0)R⁷, -NR⁶C(=0)OR⁷, -NR⁶S0₂R⁷ and (C₃-C₆)heterocycloalkyl, wherein said (C₃-C₆)heterocycloalkyl is optionally substituted with one to three times, independently, by R⁸;

where in Formula (III):

t is 0-4, provided that when t is 0, R⁵ is not halo;

R⁵ is selected from the group consisting of hydrogen, (Ci-C₃)haloalkyl, (Ci- C₃)alkyl, NR⁶S0₂R⁷, NR⁶R⁷, NR⁶C(=0)NR⁶R⁷, -S0₂R⁶, -S0₂NR⁶R⁷, halo, hydroxyl, -C(=0)(Ci-C₃)alkyl, hydroxyl(Ci-C₃)alkyl, (Ci-C₃)alkoxy(Ci-C₃)alkyl, and (C₃- C₆)heterocycloalkyl, wherein said (C₃-C₆)heterocycloalkyl is optionally substituted with one to three times, independently, by R⁸;

or a pharmaceutically acceptable salt thereof. The compound of claim 1 according to Formula (IV):

IV

wherein:

Z is O, N, S0₂ or C=0;

w is 0-2;

m is 0-3;

n is 0-2;

each R¹ is independently selected from the group consisting of hydrogen, halo, (Ci-C₃)alkyl, (C₃-C₆)cycloalkyl, hydroxyl(Ci-C₃)alkyl, (Ci-C₃)alkoxy(Ci- C₃)alkyl, (Ci-C₃)alkoxy, (Ci-C₃)haloalkyl, amino, and CN; each R⁹ is independently selected from the group consisting of hydrogen, (Ci- C₆)alkyl, (C₃-C6)cycloalkyl(Ci-C₃)alkyl, hydroxyl, halo, (Ci-C₃)alkoxy, hydroxyl(Ci- C₃)alkyl, and (Ci-C₃)alkoxy(Ci-C₃)alkyl;

or pharmaceutically acceptable salt thereof.

The compound of claim 2 according to Formula (V):

V wherein:

m is 0-3;

n is 0-2;

each R¹ is independently selected from the group consisting of hydrogen, halo, (Ci- C₃)alkyl, (C₃-C₆)cycloalkyl, hydroxyl(Ci-C₃)alkyl, (Ci-C₃)alkoxy(Ci-C₃)alkyl, (C_r

C₃)alkoxy, (Ci-C₃)haloalkyl, amino, and CN; each R⁹ is independently selected from the group consisting of hydrogen, (Ci- C₆)alkyl, (C₃-C6)cycloalkyl(Ci-C₃)alkyl, hydroxyl, halo, (Ci-C₃)alkoxy, hydroxyl(Ci C₃)alkyl, and (Ci-C₃)alkoxy(Ci-C₃)alkyl;

or pharmaceutically acceptable salt thereof.

The compound of claim 3 according to Formula (VI):

(R¹

VI wherein:

n is 0-2;

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 4 according to Formula (VI), wherein: n is 0-2; each

R¹ is independently selected from the group consisting of hydrogen, halo, (Ci- C₃)alkyl, hydroxyl(Ci-C₃)alkyl, (Ci-C₃)alkoxy(Ci-C₃)alkyl, and (Ci- C4)alkoxy; or a pharmaceutically acceptable salt thereof. The compound of claim 1 according to Formula (VII):

VII wherein:

Y is C, O, S0₂ or R⁶;

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

s is 0-4;

n is 0-2;

each R¹ is independently selected from the group consisting of hydrogen, halo, (Ci-C₃)alkyl, hydroxyl(Ci-C₃)alkyl, (Ci-C₃)alkoxy(Ci-C₃)alkyl, C(=0)0(Ci- C₃)alkyl and (Ci-C₃)alkoxy;

R⁶ and R⁷ are each independently selected from the group consisting of hydrogen, (Ci-C₆)alkyl, (C₃-C₆)cycloalkyl(Ci-C₃)alkyl, hydroxyl, (Ci-C₃)alkoxy, hydroxyl(Ci-C₃)alkyl, and (Ci-C₃)alkoxy(Ci-C₃)alkyl; R⁸ is selected from the group consisting of hydrogen, (Ci-C₆)alkyl, (C₃- C₆)cycloalkyl(Ci-C₃)alkyl, hydroxyl, halo, (Ci-C₃)alkoxy, hydroxyl(Ci-C₃)alkyl, (Ci- C₃)alkoxy(Ci-C₃)alkyl, -C(=0)NR⁶R⁷, -C(=0)R⁶, -S0₂R⁶, -S0₂NR⁶R⁷, oxo, - C(=0)OR⁶, -NR⁶R⁷, -NR⁶C(=0)R⁷, -NR⁶C(=0)OR⁷, and -NR⁶S0₂R⁷;

or a pharmaceutically acceptable salt thereof.

The compound of claim 6 according to Formula (VIII):

VIII wherein:

p is 0-2;

s is 0-4;

n is 0-2;

each R¹ is independently selected from the group consisting of hydrogen, halo, (Ci-C₃)alkyl, hydroxyl(Ci-C₃)alkyl, and (Ci-C₃)alkoxy(Ci-C₃)alkyl;

each R² are independently selected from the group consisting of hydrogen, (Ci-C₆)alkyl, hydroxyl, halo, (C₃-C₆)cycloalkyl(Ci-C₃)alkyl, (Ci-C₃)alkoxy, hydroxyl(Ci-C₃)alkyl, and (Ci-C₃)alkoxy(Ci-C₃)alkyl; or a pharmaceutically acceptable salt thereof. The compound of claim 1 according to Formula (IX):

IX wherein:

t is 0-4, provided that when t is 0, R⁵ is not halo;

n is 0-2;

R⁵ is selected from the group consisting of hydrogen, (Ci-C₃)haloalkyl, (Ci- C₃)alkyl, N R⁶S0₂R⁷, NR⁶R⁷, NR⁶C(=0)NR⁶R⁷, -S0₂R⁶, hydroxyl, halo, -C(=0)(Ci C₃)alkyl, hydroxyl(Ci-C₃)alkyl, (Ci-C₃)alkoxy(Ci-C₃)alkyl, and (C₃- C₆)heterocycloalkyl, wherein said (C₃-C₆)heterocycloalkyl is optionally substituted with one to three times, independently, by R ;

R⁶ and R⁷ are each independently selected from the group consisting of hydrogen, (Ci-C₆)alkyl, (C₃-C₆)cycloalkyl(Ci-C₃)alkyl, hydroxyl, (Ci-C₃)alkoxy, hydroxyl(Ci-C₃)alkyl, and (Ci-C₃)alkoxy(Ci-C₃)alkyl;

R is selected from the group consisting of hydrogen, (Ci-C₆)alkyl, (C₃- C₆)cycloalkyl(Ci-C₃)alkyl, hydroxyl, halo, (Ci-C₃)alkoxy, hydroxyl(Ci-C₃)alkyl, (C C₃)alkoxy(Ci-C₃)alkyl, -C(=0)NR⁶R⁷, -C(=0)R⁶, -S0₂R⁶, -S0₂NR⁶R⁷, oxo, - C(=0)OR⁶, -NR⁶R⁷, -NR⁶C(=0)R⁷, -NR⁶C(=0)OR⁷, and -NR⁶S0₂R⁷;

or a pharmaceutically acceptable salt thereof.

The compound of claim 8 according to Formula (IX): wherein:

t is 0-4, provided that when t is 0, R⁵ is not halo;

n is 0-2;

R⁴ is hydrogen or (Ci-C6)alkyl;

R⁵ is selected from the group consisting of hydrogen, halo(Ci-C₃)alkyl, (Ci- C₃)alkyl, NR⁶S0₂R⁷, NR⁶R⁷, NR⁶C(=0)NR⁶R⁷, -S0₂R⁶, -C(=0) (Ci-C₃)alkyl, hydroxyl(Ci-C₃)alkyl, and (Ci-C₃)alkoxy(Ci-C₃)alkyl;

R and R are independently selected from the group consisting of hydrogen,

(Ci-C₆)alkyl, (C₃-C₆)cycloalkyl(Ci-C₃)alkyl, hydroxyl, (Ci-C₃)alkoxy, hydroxyl(Ci- C₃)alkyl, and (Ci-C₃)alkoxy(Ci-C₃)alkyl;

or a pharmaceutically acceptable salt thereof. 10. A pharmaceutically composition comprising the compound or salt according to any one of claims 1 to 9 and a pharmaceutically acceptable carrier.

11. A method of treating obesity comprising administering to a human in need thereof an effective amount of a compound according to any one of claims 1 to 9.

12. A method of treating obesity in a mammal in need thereof, which comprises: administering to such mammal a therapeutically effective amount of

a) a compound of Formula (I), as described in claim 1 or a pharmaceutically acceptable salt thereof; and b) at least one anti-obesity agent.