Inhibitors of diacylglycerol O-acyltransferase type 1 enzyme

1. A method for treating a disorder selected from the group consisting of type 2 diabetes, obesity, elevated plasma triglycerides, metabolic syndrome, and non-alcoholic fatty liver disease, said method comprising the step of administering to a subject in need thereof a compound of formula (I),

wherein

Q is phenyl or a monocyclic heteroaryl optionally substituted with 1, 2 or 3 substituents as represented by T, wherein each T is independently alkyl, alkenyl, alkynyl, halogen, —CN, —NO 2 , —OR 1 , —OC(O)(R 2 ), —N(R w )(R 1 ), —N(R w )C(O)(R 1 ), —N(R w )—C(O)O(R 1 ), —N(R w )—C(O)N(R 1 ) 2 , —N(R w )—S(O) 2 (R 2 ), —C(O)O(R 1 ), —C(O)N(R w )(R 1 ), —C(O)R 1 , —SR 1 , —S(O)R 2 , —S(O) 2 R 2 ,—S(O) 2 N(R w )(R 1 ), —(CR g R h ) t —CN, —(CR g R h ) t —NO 2 , —(CR g R h ) t —OR 1 , —(CR g R h ) t —OC(O)(R 2 ), —(CR g R h ) t —N(R w )(R 1 ), —(CR g R h ) t —N(R w )C(O)(R 1 ), —(CR g R h ) t —N(R w )—C(O)O(R 1 ), —(CR g R h ) t —N(R w )—C(O)N(R 1 ) 2 , —(CR g R h ) t —N(R w )—S(O) 2 (R 2 ), —(CR g R h ) t —C(O)O(R 1 ), —(CR g R h ) t —C(O)N(R w )(R 1 ), —(CR g R h ) t —C(O)R 1 , —(CR g R h ) t —SR 1 , —(CR g R h ) t —S(O)R 2 , —(CR g R h ) t —S(O) 2 R 2 , —(CR g R h ) t —S(O) 2 N(R w )(R 1 ) or haloalkyl; alternatively, two of the adjacent T substituents, together with the carbon atoms to which they are attached, form a monocyclic ring selected from the group consisting of phenyl, heterocycle and heteroaryl, wherein each ring is optionally further substituted with 1, 2 or 3 substituents selected from the group consisting of oxo, alkyl, alkenyl, alkynyl, halogen, —CN, —NO 2 , —OR 1 , —OC(O)(R 2 ), —N(R w )(R 1 ), —N(R w )C(O)(R 1 ), —N(R w )—C(O)O(R 1 ), —N(R w )—C(O)N(R 1 ) 2 , —N(R w )—S(O) 2 (R 2 ), —C(O)O(R 1 ), —C(O)N(R w )(R 1 ), —C(O)R 1 , —SR 1 , —S(O)R 2 , —S(O) 2 R 2 , —S(O) 2 N(R w )(R 1 ), —(CR g R h ) t —CN, —(CR g R h) t —NO 2 , —(CR g R h ) t —OR 1 , —(CR g R h ) t —OC(O)(R 2 ), —(CR g R h ) t —N(R w )(R 1 ), —(CR g R h ) t —N(R w )C(O)(R 1 ), —(CR g R h ) t —N(R w )—C(O)O(R 1 ), —(CR g R h ) t —N(R w )—C(O)N(R 1 ) 2 , —(CR g R h ) t —N(R w )—S(O) 2 (R 2 ), —(CR g R h ) t —C(O)O(R 1 ), —(CR g R h ) t —C(O)N(R w )(R 1 ), —(CR g R h ) t —C(O)R 1 , —(CR g R h ) t —SR 1 , —(CR g R h ) t —S(O)R 2 , —(CR g R h ) t —S(O) 2 R 2 , —(CR g R h ) t —S(O) 2 N(R w )(R 1 ), and haloalkyl;

A is formula (a)

wherein

V a is N, V b is C(R 5 ), and V c is C(R 6 );

R 5 is halogen, alkyl, halogen, haloalkyl, —CN, —OR b , —SR b , —S(O) 2 R c , aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle;

R 6 is hydrogen, alkyl, halogen, haloalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle;

R 7 is hydrogen, alkyl, halogen, —CN, or haloalkyl;

r and s are independently 1 or 2;

X is X 1 , —(CR k R m ) u —X 1 , —(CR k R m ) u —C(O)—X 2 , or —C(O)—X 2 ,

X 1 at each occurrence is independently heterocycle, or heteroaryl;

X 2 at each occurrence is independently heteroaryl, heterocycle, —OR 11 , —N(R w )(R 3 ), —N(R w )—(CR n R q ) w —C(O)OR 11 , —N(R w )—(CR n R q ) w —OR 11 , or —N(R w )—(CR n R q ) w —S(O) 2 R 12 ;

R 11 , at each occurrence, is independently hydrogen, alkyl, haloalkyl, arylalkyl, or heteroarylalkyl;

R 12 , at each occurrence, is alkyl, haloalkyl, arylalkyl, or heteroarylalkyl;

wherein the cycloalkenyl, cycloalkyl, heterocycle, heteroaryl, aryl, the aryl moiety of the arylalkyl, and the heteroaryl moiety of the heteroarylalkyl as represented by X 1 , X 2 , R 5 , R 6 , R 11 and R 12 , are each optionally further substituted with 1, 2, 3, 4 or 5 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, oxo, ethylenedioxy, methylenedioxy, —CN, —NO 2 , —OR 1 , —OC(O)(R 2 ), —N(R w )(R 1 ), —N(R w )C(O)(R 1 ), —N(R w )—C(O)O(R 1 ), —N(R w )—S(O) 2 (R 2 ), —C(O)O(R 1 ), —C(O)N(R w )(R 1 ), —C(O)R 1 , —SR 1 , —S(O)R 2 , —S(O) 2 R 2 , —S(O) 2 N(R w )(R 1 ), haloalkyl, —(CR g R h ) v —CN, —(CR g R h ) v —NO 2 , —(CR g R h ) v —OR 1 , —(CR g R h ) v —OC(O)(R 2 ), —(CR g R h ) v —N(R w )(R 1 ), —(CR g R h ) v —N(R w )C(O)(R 1 ), —(CR g R h ) v —N(R w )—C(O)O(R 1 ), —(CR g R h ) v —N(R w )—S(O) 2 (R 2 ), —(CR g R h ) v —C(O)O(R 1 ), —(CR g R h ) v —C(O)N(R w )(R 1 ), —(CR g R h ) v —C(O)R 1 , —(CR g R h ) v —SR 1 , —(CR g R h ) v —S(O)R 2 , —(CR g R h ) v —S(O) 2 R 2 , —(CR g R h ) v —S(O) 2 N(R w )(R 1 ), and haloalkyl;

t, u, v and w, at each occurrence, are each independently 1, 2, 3, 4, 5, or 6;

R 3 is hydrogen, alkyl, haloalkyl, —OH, —S(O) 2 R 1 , —C(O)OR 1 , heterocycle or heteroaryl, wherein the heteroaryl is connected to the nitrogen atom through the ring carbon atom, and the heterocycle and heteroaryl are optionally further substituted with 1 or 2 substitutents selected from the group consisting of alkyl, halogen, haloalkyl, —C(O)OR 1 , —OR 1 , and —N(R w )(R 1 );

R b , R x , R y , R za , R zb , R w , R g , R h , R k , R m , R n , R q and R 1 , at each occurrence, are independently hydrogen, alkyl, or haloalkyl; and

R c and R 2 , at each occurrence, are independently alkyl or haloalkyl;

or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

2. The method of claim 1 further comprising the step of co-administering with one or more pharmaceutical agents selected from the group consisting of fenofibrate, rimonabant, sibutramine, orlistat, nicotinic acid, and a statin.

3. The method of claim 1 , wherein X is —(CR k R m ) u —C(O)—X 2 or C(O)—X 2 .

4. The method of claim 1 , wherein X is —(CR k R m ) u —C(O)—X 2 , and Q is phenyl, optionally further substituted with 1, 2, or 3 T.

5. The method of claim 1 , wherein

X is —(CR k R m ) u —C(O)—X 2 ;

Q is phenyl, optionally further substituted with 1, 2, or 3 T; and

r and s are 2.

6. The method of claim 1 , wherein the compound of formula (I) is selected from the group consisting of

Trans {4-[4-(7 amino-2-thien-2-ylpyrazolo[1,5-a]pyrimidin-6-yl)phenyl]cyclohexyl}acetic acid;

Trans {4-[4-(7-amino-2-cyclopropylpyrazolo[1,5-a]pyrimidin-6-yl)phenyl]cyclohexyl}acetic acid;

Trans (4-{4-[7-amino-2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidin-6-yl]phenyl}cyclohexyl)acetic acid;

Trans {4-[4-(7-amino-2-methylpyrazolo[1,5 -a]pyrimidin-6-yl)phenyl]cyclohexyl}acetic acid;

Trans {4-[4-(7-amino-2-hydroxypyrazolo[1,5-a]pyrimidin-6-yl)phenyl]cyclohexyl}acetic acid;

Trans 2-{4-[4-(7-aminopyrazolo[1,5-a]pyrimidin-6-yl)phenyl]cyclohexyl}-N-methylacetamide;

Trans 2-{4-[4-(7-aminopyrazolo[1,5-a]pyrimidin-6-yl)phenyl]cyclohexyl}acetamide;

Trans {4-[4-(7-aminopyrazolo[1,5-a]pyrimidin-6-yl)phenyl]cyclohexyl}acetic acid;

Trans {4-[4-(7-amino-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)phenyl]cyclohexyl}acetic acid;

Trans 3-({4-[4-(7-aminopyrazolo[1,5-a]pyrimidin-6-yl)phenyl]cyclohexyl}methyl)-1,2,4-oxadiarol-5(4H)-one; and

Trans 5-({4-[4-(7-aminopyrazolo[1,5-a]pyrimidin-6-yl)phenyl]cyclohexyl}methyl)-1,3,4-oxadiarol-2(3H)-one;

or a pharmaceutically acceptable salt thereof.