IP Library › Granted Patent US 7,304,049

Granted Patent B2

US 7,304,049 · App. 11/230,203 · Granted Dec 4, 2007

Succinoylaminobenzodiazepines as inhibitors of Aβ protein production

Assignee: Bristol-Myers Squibb Pharma Company

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Quick Facts

Patent No.: US 7,304,049
App. No.: 11/230,203
Granted: Dec 4, 2007
Kind: B2

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Abstract

This invention relates to novel lactams having the formula (I): to their pharmaceutical compositions and to their methods of use. These novel compounds inhibit the processing of amyloid precursor protein and, more specifically, inhibit the production of Aβ-peptide, thereby acting to prevent the formation of neurological deposits of amyloid protein. More particularly, the present invention relates to the treatment of neurological disorders related to β-amyloid production such as Alzheimer's disease and Down's Syndrome.

Claims (650)

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

A is O;

Q is —NR 1 R 2 ;

R 1 is independently selected from:

C 1 -C 6 alkyl substituted with 0-3 R 1a ;

C 3 -C 10 carbocycle substituted with 0-3 R 1b ;

aryl substituted with 0-3 R 1b ; and

5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R 1b ;

R 1a , at each occurrence, is independently selected from H, C 1 -C 6 alkyl Cl, F, Br, I, ═O, CN, NO 2 , NR 15 R 16 , CF 3 ;

C 3 -C 10 carbocycle substituted with 0-3 R 1b ;

aryl substituted with 0-3 R 1b ; and

5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R 1b ;

R 1b , at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 15 R 16 , CF 3 , C 1 -C 6 alkyl, C 1 -C 4 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 4 haloalkoxy;

R 2 is selected from H, C 1 - 6 alkyl, C 3 -C 10 carbocycle, C 6 -C 10 aryl, and 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur;

R 3 is —(CR 7 R 7a ) n —R 4 ,

—(CR 7 R 7a ) n —S—(CR 7 R 7a ) m —R 4 ,

—(CR 7 R 7a ) n —O—(CR 7 R 7a ) m —R 4 ,

—(CR 7 R 7a ) n —N(R 7b )—(CR 7 R 7a ) m —R 4 ,

—(CR 7 R 7a ) n —S(═O)—(CR 7 R 7a ) m —R 4 ,

—(CR 7 R 7a ) n —S(═O) 2 —(CR 7 R 7a ) m —R 4 ,

—(CR 7 R 7a ) n —C(═O)—(CR 7 R 7a ) m —R 4 ,

—(CR 7 R 7a ) n —N(R 7b )C(═O)—(CR 7 R 7a ) m —R 4 ,

—(CR 7 R 7a ) n —C(═O)N(R 7b )—(CR 7 R 7a ) m —R 4 ,

—(CR 7 R 7a ) n —N(R 7b )S(═O) 2 —(CR 7 R 7a ) m —R 4 , or

—(CR 7 R 7a ) n —S(═O) 2 N(R 7b )—(CR 7 R 7a ) m —R 4 ;

n is 0, 1, 2, or 3;

m is 0, 1, 2, or 3;

R 3a is H, OH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 2 -C 4 alkenyl or C 2 -C 4 alkenyloxy;

R 4 is H, OH, OR 14a ,

C 1 -C 6 alkyl substituted with 0-3 R 4a ,

C 2 -C 6 alkenyl substituted with 0-3 R 4a ,

C 2 -C 6 alkynyl substituted with 0-3 R 4a ,

C 3 -C 10 carbocycle substituted with 0-3 R 4b ,

aryl substituted with 0-3 R 4b , or

5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R 4b ;

R 4a , at each occurrence, is independently selected from is H, F, Cl, Br, I, CF 3 ,

C 3 -C 10 carbocycle substituted with 0-3 R 4b ,

aryl substituted with 0-3 R 4b , and

5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R 4b ;

R 4b , at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 15 R 16 , CF 3 , acetyl, SCH 3 , S(═O)CH 3 , S(═O) 2 CH 3 ,

C 1 -C 6 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl,

C 1 -C 4 haloalkoxy, and C 1 -C 4 haloalkyl-S—;

R 5 is H, OR 14 ;

C 1 -C 6 alkyl substituted with 0-3 R 5b ;

C 1 -C 6 alkoxy substituted with 0-3 R 5b ;

C 2 -C 6 alkenyl substituted with 0-3 R 5b ;

C 2 -C 6 alkynyl substituted with 0-3 R 5b ;

C 3 -C 10 carbocycle substituted with 0-3 R 5c ;

aryl substituted with 0-3 R 5c ; or

5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R 5c ;

R 5a is H, OH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 2 -C 4 alkenyl, or C 2 -C 4 alkenyloxy;

R 5b , at each occurrence, is independently selected from:

H, C 1 -C 6 alkyl, CF 3 , OR 14 , Cl, F, Br, I, ═O, CN, NO 2 , NR 15 R 16 ;

C 3 -C 10 carbocycle substituted with 0-3 R 5c ;

aryl substituted with 0-3 R 5c ; and

5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R 5c ;

R 5c , at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 15 R 16 , CF 3 , acetyl, SCH 3 , S(═O)CH 3 , S(═O) 2 CH 3 ,

C 1 -C 6 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl,

C 1 -C 4 haloalkoxy, and C 1 -C 4 haloalkyl-S—;

R 6 is H;

C 1 -C 6 alkyl substituted with 0-3 R 6a ;

C 3 -C 10 carbocycle substituted with 0-3 R 6b ; or

aryl substituted with 0-3 R 6b ;

R 6a , at each occurrence, is independently selected from H, C 1 -C 6 alkyl, OR 14 , Cl, F, Br, I, ═O, CN, NO 2 , NR 15 R 16 , aryl and CF 3 ;

R 6b , at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 15 R 16 , CF 3 , C 1 -C 6 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, and C 1 -C 4 haloalkoxy;

R 7 , at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , CF 3 , phenyl and C 1 -C 4 alkyl;

R 7a , at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , CF 3 , and C 1 -C 4 alkyl;

R 7b is selected from H and C 1 -C 4 alkyl;

Ring B is

Z is H;

C 1 -C 8 alkyl substituted with 1-3 R 12 ;

C 2 -C 4 alkenyl substituted with 1-3 R 12 ;

C 2 -C 4 alkynyl substituted with 1-3 R 12 ;

C 1 -C 8 alkyl substituted with 0-3 R 12a ;

C 2 -C 4 alkenyl substituted with 0-3 R 12a ;

C 2 -C 4 alkynyl substituted with 0-3 R 12a ;

aryl substituted with 0-4 R 12b ;

C 3 -C 10 carbocycle substituted with 0-4 R 12b ; or

5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R 12b ;

R 12 , at each occurrence, is independently selected from

aryl substituted with 0-4 R 12b ;

C 3 -C 10 carbocycle substituted with 0-4 R 12b ; and

5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R 12b ;

R 12a , at each occurrence, is independently selected from

H, OH, Cl, F, Br, I, CN, NO 2 , NR 15 R 16 , —C(═O)NR 15 R 16 , CF 3 , acetyl, SCH 3 , S(═O)CH 3 , S(═O) 2 CH 3 ,

C 1 -C 6 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl,

C 1 -C 4 haloalkoxy, and C 1 -C 4 haloalkyl-S—;

R 12b , at each occurrence, is independently selected from

H, OH, Cl, F, Br, I, CN, NO 2 , NR 15 R 16 , CF 3 , acetyl, SCH 3 , S(═O)CH 3 , S(═O) 2 CH 3 ,

C 1 -C 6 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl,

C 1 -C 4 haloalkoxy, and C 1 -C 4 haloalkyl-S—;

R 13 , at each occurrence, is independently selected from

H, OH, C 1 -C 6 alkyl, C 1 -C 4 alkoxy, Cl, F, Br, I, CN, NO 2 , NR 15 R 16 , and CF 3 ;

R 14 is, at each occurrence, H, phenyl, benzyl, C 1 -C 6 alkyl, C 2 -C 6 alkoxyalkyl, or C 3 -C 6 cycloalkyl;

R 14a is H, phenyl, benzyl, or C 1 -C 4 alkyl;

R 15 , at each occurrence, is independently selected from H, C 1 -C 6 alkyl, benzyl, phenethyl, (C 1 -C 6 alkyl)-C(═O)—, and (C 1 -C 6 alkyl)-S(═O) 2 —;

R 16 , at each occurrence, is independently selected from

H, OH, C 1 -C 6 alkyl, benzyl, phenethyl,

(C 1 -C 6 alkyl)-C(═O)—, and (C 1 -C 6 alkyl)-S(═O) 2 —; and

provided, when R 13 is H,

then Z is H;

C 4 -C 8 alkyl substituted with 1-3 R 12 ;

C 2 -C 4 alkenyl substituted with 1-3 R 12 ;

C 2 -C 4 alkynyl substituted with 1-3 R 12 ;

C 1 -C 8 alkyl substituted with 0-3 R 12a ;

C 2 -C 4 alkenyl substituted with 0-3 R 12a ; or

C 2 -C 4 alkynyl substituted with 0-3 R 12a .

2. A compound, according to claim 1 , of Formula (Ia):

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

Z is H;

C 1 -C 8 alkyl substituted with 0-3 R 12a ;

C 2 -C 4 alkenyl substituted with 0-3 R 12a ; or

C 2 -C 4 alkynyl substituted with 0-3 R 12a ;

aryl substituted with 0-4 R 12b ;

C 3 -C 6 carbocycle substituted with 0-4 R 12b ; or

5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R 12b .

3. A compound according to claim 2 of Formula (Ia) or pharmaceutically acceptable salt thereof, wherein:

R 3 is —(CR 7 R 7a ) n —R 4 ,

—(CR 7 R 7a ) n —S—(CR 7 R 7a ) m —R 4 ,

—(CR 7 R 7a ) n —O—(CR 7 R 7a ) m —R 4 , or

—(CR 7 R 7a ) n —N(R 7b )—(CR 7 R 7a ) m —R 4 ;

n is 0, 1, or 2;

m is 0, 1, or 2;

R 3a is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, allyl, or 3-buten-1-yl;

R 4 is H, OH, OR 14a ,

C 1 -C 6 alkyl substituted with 0-3 R 4a ,

C 2 -C 6 alkenyl substituted with 0-3 R 4a ,

C 2 -C 6 alkynyl substituted with 0-3 R 4a ,

C 3 -C 10 carbocycle substituted with 0-3 R 4b ,

aryl substituted with 0-3 R 4b , or

5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R 4b ;

R 4a , at each occurrence, is independently selected from is H, F, Cl, Br, I, CF 3 ,

C 3 -C 10 carbocycle substituted with 0-3 R 4b ,

aryl substituted with 0-3 R 4b , and

5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R 4b ;

R 4b , at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 15 R 16 , CF 3 , acetyl, SCH 3 , S(═O)CH 3 , S(═O) 2 CH 3 , C 1 -C 6 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, and C 1 -C 4 haloalkoxy;

R 5 is H, OR 14 ;

C 1 -C 6 alkyl substituted with 0-3 R 5b ;

C 1 -C 6 alkoxy substituted with 0-3 R 5b ;

C 2 -C 6 alkenyl substituted with 0-3 R 5b ;

C 2 -C 6 alkynyl substituted with 0-3 R 5b ;

C 3 -C 10 carbocycle substituted with 0-3 R 5c ;

aryl substituted with 0-3 R 5c ; or

5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R 5c ;

R 5a is H or C 1 -C 4 alkyl;

R 5b , at each occurrence, is independently selected from:

H, C 1 -C 6 alkyl, CF 3 , OR 14 , Cl, F, Br, I, ═O, CN, NO 2 , NR 15 R 16 ;

C 3 -C 10 carbocycle substituted with 0-3 R 5c ;

aryl substituted with 0-3 R 5c ; and

5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R 5c ;

R 5c , at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 15 R 16 , CF 3 , acetyl, SCH 3 , S(═O)CH 3 , S(═O) 2 CH 3 , C 1 -C 6 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, and C 1 -C 4 haloalkoxy;

R 6 is H, methyl, or ethyl;

R 7 , at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , CF 3 , phenyl and C 1 -C 4 alkyl;

R 7a , at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , CF 3 , and C 1 -C 4 alkyl;

R 7b is selected from H, methyl, ethyl, propyl, and butyl;

Ring B is

Z is H;

C 1 -C 6 alkyl substituted with 0-3 R 12a ;

C 2 -C 4 alkenyl substituted with 0-3 R 12a ; or

C 2 -C 4 alkynyl substituted with 0-3 R 12a ;

R 12a , at each occurrence, is independently selected from

H, OH, Cl, F, Br, I, CN, NO 2 , NR 15 R 16 , CF 3 , acetyl, SCH 3 , S(═O)CH 3 , S(═O) 2 CH 3 , C 1 -C 6 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, and C 1 -C 4 haloalkoxy;

R 13 , at each occurrence, is independently selected from

H, OH, C 1 -C 6 alkyl, C 1 -C 4 alkoxy, Cl, F, Br, I, CN, NO 2 , NR 15 R 16 , and CF 3 ;

R 14 is, at each occurrence, H, phenyl, benzyl, C 1 -C 6 alkyl, or C 2 -C 6 alkoxyalkyl;

R 14a is H, phenyl, benzyl, methyl, ethyl, propyl, or butyl;

R 15 , at each occurrence, is independently selected from H, C 1 -C 6 alkyl, benzyl, phenethyl, (C 1 -C 6 alkyl)-C(═O)—, and (C 1 -C 6 alkyl)-S(═O) 2 —; and

R 16 , at each occurrence, is independently selected from

H, OH, C 1 -C 6 alkyl, benzyl, phenethyl,

(C 1 -C 6 alkyl)-C(═O)—, and (C 1 -C 6 alkyl)-S(═O) 2 —.

4. A compound according to claim 3 of Formula (Ia) or a pharmaceutically acceptable salt thereof wherein:

R 3 is —(CHR 7 ) n —R 4 ,

—(CR 7 R 7a ) n —S—(CR 7 R 7a ) m —R 4 ,

—(CR 7 R 7a ) n —O—(CR 7 R 7a ) m —R 4 , or

—(CR 7 R 7a ) n —N(R 7b )—(CR 7 R 7a ) m —R 4 ;

n is 0 or 1;

R 3a is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, allyl, or 3-buten-1-yl;

R 4 is H, OH, OR 14a ,

C 1 -C 4 alkyl substituted with 0-2 R 4a ,

C 2 -C 4 alkenyl substituted with 0-2 R 4a ,

C 2 -C 4 alkynyl substituted with 0-1 R 4a ,

C 3 -C 6 carbocycle substituted with 0-3 R 4b ,

aryl substituted with 0-3 R 4b , or

5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R 4b ;

R 4a , at each occurrence, is independently selected from is H, F, Cl, Br, I, CF 3 ,

C 3 -C 6 carbocycle substituted with 0-3 R 4b ,

phenyl substituted with 0-3 R 4b , and

5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R 4b ;

R 4b , at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 15 R 16 , CF 3 , acetyl, SCH 3 , S(═O)CH 3 , S(═O) 2 CH 3 , C 1 -C 4 alkyl, C 1 -C 3 alkoxy, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy;

R 5 is H, OR 14 ;

C 1 -C 4 alkyl substituted with 0-3 R 5b ;

C 2 -C 4 alkenyl substituted with 0-3 R 5b ; or

C 2 -C 4 alkynyl substituted with 0-3 R 5b ;

R 5a is H, methyl, ethyl, propyl, or butyl;

R 5b , at each occurrence, is independently selected from:

H, methyl, ethyl, propyl, butyl, CF 3 , OR 14 , Cl, F, Br, I, ═O;

C 3 -C 6 carbocycle substituted with 0-3 R 5c ;

phenyl substituted with 0-3 R 5c ; and

5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R 5c ;

R 5c , at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 15 R 16 , CF 3 , acetyl, SCH 3 , S(═O)CH 3 , S(═O) 2 CH 3 , C 1 -C 4 alkyl, C 1 -C 3 alkoxy, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy;

R 6 is H;

R 7 , at each occurrence, is independently selected from H, F, CF 3 , methyl, and ethyl;

Ring B is

Z is H;

C 1 -C 4 alkyl substituted with 0-3 R 12a ;

C 2 -C 4 alkenyl substituted with 0-3 R 12a ; or

C 2 -C 4 alkynyl substituted with 0-3 R 12a ;

R 12a , at each occurrence, is independently selected from

H, OH, Cl, F, NR 15 R 16 , CF 3 , acetyl, SCH 3 , S(═O)CH 3 , S(═O) 2 CH 3 , C 1 -C 4 alkyl, C 1 -C 3 alkoxy, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy;

R 13 , at each occurrence, is independently selected from

H, OH, C 1 -C 6 alkyl, C 1 -C 4 alkoxy, Cl, F, Br, I, CN, NO 2 , NR 15 R 16 , and CF 3 ;

R 14 is, at each occurrence, H, phenyl, benzyl, C 1 -C 4 alkyl, or C 2 -C 4 alkoxyalkyl;

R 15 , at each occurrence, is independently selected from H, (C 1 -C 4 )alkyl, benzyl, phenethyl, (C 1 -C 4 alkyl)-C(═O)—, and (C 1 -C 4 alkyl)-S(═O) 2 —; and

R 16 , at each occurrence, is independently selected from

H, OH, C 1 -C 4 alkyl, benzyl, phenethyl,

(C 1 -C 4 alkyl)-C(═O)—, and (C 1 -C 4 alkyl)-S(═O) 2 —.

5. A compound of claim 4 of Formula (Ib):

or a pharmaceutically acceptable salt thereof wherein:

Ring B is

6. A compound according to claim 5 of Formula (If):

or a pharmaceutically acceptable salt thereof wherein:

R 3 is R 4 ,

R 4 is C 1 -C 4 alkyl substituted with 0-1 R 4a ,

C 2 -C 4 alkenyl substituted with 0-1 R 4a , or

C 2 -C 4 alkynyl substituted with 0-1 R 4a ;

R 4a is selected from H, F, CF 3 ,

C 3 -C 6 carbocycle substituted with 0-3 R 4b ,

phenyl substituted with 0-3 R 4b , and

5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R 4b ; wherein said 5 to 6 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;

R 4b , at each occurrence, is independently selected from H, OH, Cl, F, NR 15 R 16 , CF 3 , acetyl, SCH 3 , S(═O)CH 3 , S(═O) 2 CH 3 , methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy;

R 5 is C 1 -C 4 alkyl substituted with 0-1 R 5b ;

C 2 -C 4 alkenyl substituted with 0-1 R 5b ;

C 2 -C 4 alkynyl substituted with 0-1 R 5b ;

R 5b is selected from:

H, methyl, ethyl, propyl, butyl, CF 3 , OR 14 , ═O;

C 3 -C 6 carbocycle substituted with 0-2 R 5c ;

phenyl substituted with 0-3 R 5c ; and

5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R 5c ; wherein said 5 to 6 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;

R 5c , at each occurrence, is independently selected from H, OH, Cl, F, NR 15 R 16 , CF 3 , acetyl, SCH 3 , S(═O)CH 3 , S(═O) 2 CH 3 , methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy;

Z is H;

C 1 -C 4 alkyl substituted with 0-3 R 12a ;

C 2 -C 4 alkenyl substituted with 0-3 R 12a ; or

C 2 -C 4 alkynyl substituted with 0-3 R 12a ;

R 12a , at each occurrence, is independently selected from

H, OH, Cl, F, NR 15 R 16 , CF 3 , acetyl, SCH 3 , S(═O)CH 3 , S(═O) 2 CH 3 , methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy;

R 13 , at each occurrence, is independently selected from

H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, Cl, F, Br, CN, NR 15 R 16 , and CF 3 ;

R 14 is H, phenyl, benzyl, methyl, ethyl, propyl, or butyl;

R 15 , at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl; and

R 16 , at each occurrence, is independently selected from

H, OH, methyl, ethyl, propyl, butyl, benzyl, phenethyl, methyl-C(═O)—, ethyl-C(═O)—, methyl-S(═O) 2 —, and ethyl-S(═O) 2 .

7. A compound, according to claim 6 , or pharmaceutically acceptable salt, wherein:

R 3 is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH 2 CH 2 CH 2 CH 3 ,

—CH 2 (CH 3 ) 2 , —CH(CH 3 )CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 ,

—CH 2 CF 3 , —CH 2 CH 2 CF 3 , —CH 2 CH 2 CH 2 CF 3 ,

—CH═CH 2 , —CH 2 CH═CH 2 , —CH 2 C(CH 3 )═CH 2 ,

—CH 2 CH 2 CH═CH 2 , cis-CH 2 CH═CH(CH 3 ),

trans-CH 2 CH═CH(CH 3 );

—C≡CH, —CH 2 C≡CH, —CH 2 C≡C(CH 3 ),

cyclopropyl-CH 2 —, cyclobutyl-CH 2 —, cyclopentyl-CH 2 —,

cyclohexyl-CH 2 —, cyclopropyl-CH 2 CH 2 —,

cyclobutyl-CH 2 CH 2 —, cyclopentyl-CH 2 CH 2 —,

cyclohexyl-CH 2 CH 2 —, phenyl-CH 2 —,

(2-F-phenyl)CH 2 —, (3-F-phenyl)CH 2 —, (4-F-phenyl)CH 2 —,

(2-Cl-phenyl)CH 2 —, (3-Cl-phenyl)CH 2 —, (4-Cl-phenyl)CH 2 —,

(2,3-diF-phenyl)CH 2 —, (2,4-diF-phenyl)CH 2 —,

(2,5-diF-phenyl)CH 2 —, (2,6-diF-phenyl)CH 2 —,

(3,4-diF-phenyl)CH 2 —, (3,5-diF-phenyl)CH 2 —,

(2,3-diCl-phenyl)CH 2 —, (2,4-diCl-phenyl)CH 2 —,

(2,5-diCl-phenyl)CH 2 —, (2,6-diCl-phenyl)CH 2 —,

(3,4-diCl-phenyl)CH 2 —, (3,5-diCl-phenyl)CH 2 —,

(3-F-4-Cl-phenyl)CH 2 —, (3-F-5-Cl-phenyl)CH 2 —,

(3-Cl-4-F-phenyl)CH 2 —, phenyl-CH 2 CH 2 —,

(2-F-phenyl)CH 2 CH 2 —, (3-F-phenyl)CH 2 CH 2 —,

(4-F-phenyl)CH 2 CH 2 —, (2-Cl-phenyl)CH 2 CH 2 —,

(3-Cl-phenyl)CH 2 CH 2 —, (4-Cl-phenyl)CH 2 CH 2 —,

(2,3-diF-phenyl)CH 2 CH 2 —, (2,4-diF-phenyl)CH 2 CH 2 —,

(2,5-diF-phenyl)CH 2 CH 2 —, (2,6-diF-phenyl)CH 2 CH 2 —,

(3,4-diF-phenyl)CH 2 CH 2 —, (3,5-diF-phenyl)CH 2 CH 2 —,

(2,3-diCl-phenyl)CH 2 CH 2 —, (2,4-diCl-phenyl)CH 2 CH 2 —,

(2,5-diCl-phenyl)CH 2 CH 2 —, (2,6-diCl-phenyl)CH 2 CH 2 —,

(3,4-diCl-phenyl)CH 2 CH 2 —, (3,5-diCl-phenyl)CH 2 CH 2 —,

(3-F-4-Cl-phenyl)CH 2 CH 2 —, or (3-F-5-Cl-phenyl)CH 2 CH 2 —,

R 5 is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 ,

—CH(CH 3 )CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —CH 2 C(CH 3 ) 3 ,

—CH 2 CH 2 CH 2 CH 2 CH 3 , —CH(CH 3 )CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 )CH 2 CH 3 ,

—CH 2 CH 2 CH(CH 3 ) 2 , —CH(CH 2 CH 3 ) 2 , —CH 2 CF 3 , —CH 2 CH 2 CF 3 ,

—CH 2 CH 2 CH 2 CF 3 , —CH 2 CH 2 CH 2 CH 2 CF 3 , —CH═CH 2 , —CH 2 CH═CH 2 ,

—CH═CHCH 3 , cis-CH 2 CH═CH(CH 3 ), trans-CH 2 CH═CH(CH 3 ),

trans-CH 2 CH═CH(C 6 H 5 ), —CH 2 CH═C(CH 3 ) 2 , cis-CH 2 CH═CHCH 2 CH 3 ,

trans-CH 2 CH═CHCH 2 CH 3 , cis-CH 2 CH 2 CH═CH(CH 3 ),

trans-CH 2 CH 2 CH═CH(CH 3 ), trans-CH 2 CH═CHCH 2 (C 6 H 5 ),

—C≡CH, —CH 2 C≡CH, —CH 2 C≡C(CH 3 ), —CH 2 C≡C(C 6 H 5 )

—CH 2 CH 2 C≡CH, —CH 2 CH 2 C≡C(CH 3 ), —CH 2 CH 2 C≡C(C 6 H 5 )

cyclopropyl-CH 2 —, cyclobutyl-CH 2 —, cyclopentyl-CH 2 —,

cyclohexyl-CH 2 —, (2-CH 3 -cyclopropyl)CH 2 —,

(3-CH 3 -cyclobutyl)CH 2 —,

cyclopropyl-CH 2 CH 2 —, cyclobutyl-CH 2 CH 2 —,

cyclopentyl-CH 2 CH 2 —, cyclohexyl-CH 2 CH 2 —,

(2-CH 3 -cyclopropyl)CH 2 CH 2 —, (3-CH 3 -cyclobutyl)CH 2 CH 2 —,

phenyl-CH 2 —, (2-F-phenyl)CH 2 —, (3-F-phenyl)CH 2 —,

(4-F-phenyl)CH 2 —, furanyl-CH 2 —, thienyl-CH 2 —,

pyridyl-CH 2 —, 1-imidazolyl-CH 2 —, oxazolyl-CH 2 —,

isoxazolyl-CH 2 —,

phenyl-CH 2 CH 2 —, (2-F-phenyl)CH 2 CH 2 —, (3-F-phenyl)CH 2 CH 2 —,

(4-F-phenyl)CH 2 CH 2 —, furanyl-CH 2 CH 2 —, thienyl-CH 2 CH 2 —,

pyridyl-CH 2 CH 2 —, 1-imidazolyl-CH 2 CH 2 —, oxazolyl-CH 2 CH 2 —, or

isoxazolyl-CH 2 CH 2 —,

Z is methyl, ethyl, i-propyl, n-propyl, n-butyl, i-butyl, s-butyl, t-butyl, or allyl; and

R 13 , at each occurrence, is independently selected from H, F, Cl, OH, —CH 3 , —CH 2 CH 3 , —OCH 3 , and —CF 3 .

8. A compound according to claim 2 selected from:

(2R,3S)N1-[6,7-dihydro-5-methyl-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-allyl-butanediamide.

9. A compound of Formula (Ia)

or pharmaceutically acceptable salt thereof,

wherein:

R 3 is —(CHR 7 ) n —R 4 ,

n is 0 or 1;

R 3a is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, allyl, or 3-buten-1-yl;

R 4 is H, OH, OR 14a ,

C 1 -C 4 alkyl substituted with 0-2 R 4a ,

C 2 -C 4 alkenyl substituted with 0-2 R 4a ,

C 2 -C 4 alkynyl substituted with 0-1 R 4a ,

C 3 -C 6 carbocycle substituted with 0-3 R 4b ,

aryl substituted with 0-3 R 4b , or

5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R 4b ;

R 4a , at each occurrence, is independently selected from is H, F, Cl, Br, I, CF 3 ,

C 3 -C 6 carbocycle substituted with 0-3 R 4b ,

phenyl substituted with 0-3 R 4b , and

5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R 4b ;

R 5 is H, OR 14 ;

C 1 -C 4 alkyl substituted with 0-3 R 5b ;

C 2 -C 4 alkenyl substituted with 0-3 R 5b ; or

C 2 -C 4 alkynyl substituted with 0-3 R 5b ;

R 5a is H, methyl, ethyl, propyl, or butyl;

R 5b , at each occurrence, is independently selected from:

H, methyl, ethyl, propyl, butyl, CF 3 , OR 14 , Cl, F, Br, I, ═O;

C 3 -C 6 carbocycle substituted with 0-3 R 5c ;

phenyl substituted with 0-3 R 5c ; and

5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R 5c ;

R 6 is H;

R 7 is selected from H, F, CF 3 , methyl, and ethyl;

Ring B is

Z is C 1 -C 4 alkyl substituted with 1-3 R 12 ;

C 2 -C 4 alkenyl substituted with 1-3 R 12 ;

C 2 -C 4 alkynyl substituted with 1-3 R 12 ;

aryl substituted with 0-4 R 12b ;

C 3 -C 6 carbocycle substituted with 0-4 R 12b ; or

5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R 12b ;

R 12 , at each occurrence, is independently selected from

aryl substituted with 0-4 R 12b ;

C 3 -C 6 carbocycle substituted with 0-4 R 12b ; and

5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R 12b ;

R 12b , at each occurrence, is independently selected from

H, OH, Cl, F, NR 15 R 16 , CF 3 , acetyl, SCH 3 , S(═O)CH 3 , S(═O) 2 CH 3 , C 1 -C 4 alkyl, C 1 -C 3 alkoxy, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy;

R 13 , at each occurrence, is independently selected from

H, OH, C 1 -C 6 alkyl, C 1 -C 4 alkoxy, Cl, F, Br, I, CN, NO 2 , NR 15 R 16 , and CF 3 ;

R 14 is, at each occurrence, H, phenyl, benzyl, C 1 -C 4 alkyl, or C 2 -C 4 alkoxyalkyl;

R 14a is H, phenyl, benzyl, methyl, ethyl, propyl, or butyl;

R 15 , at each occurrence, is independently selected from H, C 1 -C 4 alkyl, benzyl, phenethyl, (C 1 -C 4 alkyl)-C(═O)—, and (C 1 -C 4 alkyl)-S(═O) 2 —;

R 16 , at each occurrence, is independently selected from

H, OH, C 1 -C 4 alkyl, benzyl, phenethyl,

(C 1 -C 4 alkyl)-C(═O)—, and (C 1 -C 4 alkyl)-S(═O) 2 —; and

provided, when R 13 is H,

then Z is butyl substituted with 1-3 R 12 ;

C 2 -C 4 alkenyl substituted with 1-3 R 12 ; or

C 2 -C 4 alkynyl substituted with 1-3 R 12 .

10. A compound of claim 9 of Formula (Ib):

or a pharmaceutically acceptable salt thereof, wherein:

Ring B is

11. A compound according to claim 10 of Formula (If):

or a pharmaceutically acceptable salt thereof wherein:

R 3 is R 4 ,

R 4 is C 1 -C 4 alkyl substituted with 0-1 R 4a ,

C 2 -C 4 alkenyl substituted with 0-1 R 4a , or

C 2 -C 4 alkynyl substituted with 0-1 R 4a ;

R 4a is selected from

H, F, CF 3 ,

C 3 -C 6 carbocycle substituted with 0-3 R 4b ,

phenyl substituted with 0-3 R 4b , and

R 5 is C 1 -C 4 alkyl substituted with 0-1 R 5b ;

C 2 -C 4 alkenyl substituted with 0-1 R 5b ; or

C 2 -C 4 alkynyl substituted with 0-1 R 5b ;

R 5b is selected from:

H, methyl, ethyl, propyl, butyl, CF 3 , OR 14 , ═O;

C 3 -C 6 carbocycle substituted with 0-2 R 5c ;

phenyl substituted with 0-3 R 5c ; and

Z is C 1 -C 3 alkyl substituted with 1-3 R 12 ;

C 2 -C 3 alkenyl substituted with 1-3 R 12 ;

C 2 -C 3 alkynyl substituted with 1-3 R 12 ;

aryl substituted with 0-4 R 12b ;

C 3 -C 6 carbocycle substituted with 0-3 R 12b ; or

5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with

0-3 R 12b , wherein said 5 to 6 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;

R 12 , at each occurrence, is independently selected from

aryl substituted with 0-4 R 12b ;

C 3 -C 6 carbocycle substituted with 0-3 R 12b ; and

5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R 12b ; wherein a 5 to 6 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;

R 12b , at each occurrence, is independently selected from

H, OH, Cl, F, NR 15 R 16 , CF 3 , acetyl, SCH 3 , S(═O)CH 3 , S(═O) 2 CH 3 , methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy;

R 13 , at each occurrence, is independently selected from

H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, Cl, F, Br, CN, NR 15 R 16 , and CF 3 ;

R 14 is H, phenyl, benzyl, methyl, ethyl, propyl, or butyl;

R 15 , at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl;

R 16 , at each occurrence, is independently selected from

H, OH, methyl, ethyl, propyl, butyl, benzyl, phenethyl, methyl-C(═O)—, ethyl-C(═O)—, methyl-S(═O) 2 —, and ethyl-S(═O) 2 —.

12. A compound according to claim 11 , or a pharmaceutically acceptable salt thereof, wherein:

R 3 is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH 2 CH 2 CH 2 CH 3 ,

—CH[[ 2]] (CH 3 ) 2 , —CH(CH 3 )CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —CH 2 CF 3 , —CH 2 CH 2 CF 3 , —CH 2 CH 2 CH 2 CF 3 ,

—CH═CH 2 , —CH 2 CH═CH 2 , —CH 2 C(CH 3 )═CH 2 ,

CH 2 CH 2 CH═CH 2 , cis-CH 2 CH═CH(CH 3 ), trans-CH 2 CH═CH(CH 3 );

—C≡CH, —CH 2 C≡CH, —CH 2 C≡C(CH 3 ),

cyclopropyl-CH 2 —, cyclobutyl-CH 2 —, cyclopentyl-CH 2 —,

cyclohexyl-CH 2 —, cyclopropyl-CH 2 CH 2 —,

cyclobutyl-CH 2 CH 2 —, cyclopentyl-CH 2 CH 2 —,

cyclohexyl-CH 2 CH 2 —, phenyl-CH 2 —,

(2-F-phenyl)CH 2 —, (3-F-phenyl)CH 2 —, (4-F-phenyl)CH 2 —,

(2-Cl-phenyl)CH 2 —, (3-Cl-phenyl)CH 2 —, (4-Cl-phenyl)CH 2 —,

(2,3-diF-phenyl)CH 2 —, (2,4-diF-phenyl)CH 2 —,

(2,5-diF-phenyl)CH 2 —, (2,6-diF-phenyl)CH 2 —,

(3,4-diF-phenyl)CH 2 —, (3,5-diF-phenyl)CH 2 —,

(2,3-diCl-phenyl)CH 2 —, (2,4-diCl-phenyl)CH 2 —,

(2,5-diCl-phenyl)CH 2 —, (2,6-diCl-phenyl)CH 2 —,

(3,4-diCl-phenyl)CH 2 —, (3,5-diCl-phenyl)CH 2 —,

(3-F-4-Cl-phenyl)CH 2 —, (3-F-5-Cl-phenyl)CH 2 —,

(3-Cl-4-F-phenyl)CH 2 —, phenyl-CH 2 CH 2 —,

(2-F-phenyl)CH 2 CH 2 —, (3-F-phenyl)CH 2 CH 2 —,

(4-F-phenyl)CH 2 CH 2 —, (2-Cl-phenyl)CH 2 CH 2 —,

(3-Cl-phenyl)CH 2 CH 2 —, (4-Cl-phenyl)CH 2 CH 2 —,

(2,3-diF-phenyl)CH 2 CH 2 —, (2,4-diF-phenyl)CH 2 CH 2 —,

(2,5-diF-phenyl)CH 2 CH 2 —, (2,6-diF-phenyl)CH 2 CH 2 —,

(3,4-diF-phenyl)CH 2 CH 2 —, (3,5-diF-phenyl)CH 2 CH 2 —,

(2,3-diCl-phenyl)CH 2 CH 2 —, (2,4-diCl-phenyl)CH 2 CH 2 —,

(2,5-diCl-phenyl)CH 2 CH 2 —, (2,6-diCl-phenyl)CH 2 CH 2 —,

(3,4-diCl-phenyl)CH 2 CH 2 —, (3,5-diCl-phenyl)CH 2 CH 2 —,

(3-F-4-Cl-phenyl)CH 2 CH 2 —, or (3-F-5-Cl-phenyl)CH 2 CH 2 —,

R 5 is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 ,

—CH(CH 3 )CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —CH 2 C(CH 3 ) 3 ,

CH 2 CH 2 CH 2 CH 2 CH 3 , —CH(CH 3 )CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 )CH 2 CH 3 ,

—CH 2 CH 2 CH(CH 3 ) 2 , —CH(CH 2 CH 3 ) 2 , —CH 2 CF 3 , —CH 2 CH 2 CF 3 ,

—CH 2 CH 2 CH 2 CF 3 , —CH 2 CH 2 CH 2 CH 2 CF 3 , —CH═CH 2 , —CH 2 CH═CH 2 ,

—CH═CHCH 3 , cis-CH 2 CH═CH(CH 3 ), trans-CH 2 CH═CH(CH 3 ),

trans-CH 2 CH═CH(C 6 H 5 ), —CH 2 CH═C(CH 3 ) 2 , cis-CH 2 CH═CHCH 2 CH 3 ,

trans-CH 2 CH═CHCH 2 CH 3 , cis-CH 2 CH 2 CH═CH(CH 3 ),

trans-CH 2 CH 2 CH═CH(CH 3 ), trans-CH 2 CH═CHCH 2 (C 6 H 5 ),

—C≡CH, —CH 2 C≡CH, —CH 2 C≡C(CH 3 ), —CH 2 C≡C(C 6 H 5 )

—CH 2 CH 2 C≡CH, —CH 2 CH 2 C≡C(CH 3 ), —CH 2 CH 2 C≡C(C 6 H 5 ),

cyclopropyl-CH 2 —, cyclobutyl-CH 2 —, cyclopentyl-CH 2 —,

cyclohexyl-CH 2 —, (2-CH 3 -cyclopropyl)CH 2 —,

(3-CH 3 -cyclobutyl)CH 2 —,

cyclopropyl-CH 2 CH 2 —, cyclobutyl-CH 2 CH 2 —,

cyclopentyl-CH 2 CH 2 —, cyclohexyl-CH 2 CH 2 —,

(2-CH 3 -cyclopropyl)CH 2 CH 2 —, (3-CH 3 -cyclobutyl)CH 2 CH 2 —,

phenyl-CH 2 —, (2-F-phenyl)CH 2 —, (3-F-phenyl)CH 2 —,

(4-F-phenyl)CH 2 —, furanyl-CH 2 —, thienyl-CH 2 —,

pyridyl-CH 2 —, 1-imidazolyl-CH 2 —, oxazolyl-CH 2 —,

isoxazolyl-CH 2 —,

phenyl-CH 2 CH 2 —, (2-F-phenyl)CH 2 CH 2 —, (3-F-phenyl)CH 2 CH 2 —,

(4-F-phenyl)CH 2 CH 2 —, furanyl-CH 2 CH 2 —, thienyl-CH 2 CH 2 —,

pyridyl-CH 2 CH 2 —, 1-imidazolyl-CH 2 CH 2 —, oxazolyl-CH 2 CH 2 —, or

isoxazolyl-CH 2 CH 2 —,

Z is phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl,

2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl,

2,4-diF-phenyl, 2,5-diF-phenyl, 2,6-diF-phenyl,

3,4-diF-phenyl, 3,5-diF-phenyl, 2,3-diCl-phenyl,

2,4-diCl-phenyl, 2,5-diCl-phenyl, 2,6-diCl-phenyl,

3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl,

3-F-5-Cl-phenyl, 3-Cl-4-F-phenyl, 2-MeO-phenyl,

3-MeO-phenyl, 4-MeO-phenyl, 2-Me-phenyl, 3-Me-phenyl,

4-Me-phenyl, 2-MeS-phenyl, 3-MeS-phenyl, 4-MeS-phenyl,

2-CF 3 O-phenyl, 3-CF 3 O-phenyl, 4-CF 3 O-phenyl, furanyl, thienyl, pyridyl, 2-Me-pyridyl, 3-Me-pyridyl,

4-Me-pyridyl, 1-imidazolyl, oxazolyl, isoxazolyl,

cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholino,

phenyl-CH 2 —, (2-F-phenyl)CH 2 —, (3-F-phenyl)CH 2 —,

(4-F-phenyl)CH 2 —, (2-Cl-phenyl)CH 2 —, (3-Cl-phenyl)CH 2 —,

(4-Cl-phenyl)CH 2 —, (2,3-diF-phenyl)CH 2 —,

(2,4-diF-phenyl)CH 2 —, (2,5-diF-phenyl)CH 2 —,

(2,6-diF-phenyl)CH 2 —, (3,4-diF-phenyl)CH 2 —,

(3,5-diF-phenyl)CH 2 —, (2,3-diCl-phenyl)CH 2 —,

(2,4-diCl-phenyl)CH 2 —, (2,5-diCl-phenyl)CH 2 —,

(2,6-diCl-phenyl)CH 2 —, (3,4-diCl-phenyl)CH 2 —,

(3,5-diCl-phenyl)CH 2 —, (3-F-4-Cl-phenyl)CH 2 —,

(3-F-5-Cl-phenyl)CH 2 —, (3-Cl-4-F-phenyl)CH 2 —,

(2-MeO-phenyl)CH 2 —, (3-MeO-phenyl)CH 2 —,

(4-MeO-phenyl)CH 2 —, (2-Me-phenyl)CH 2 —,

(3-Me-phenyl)CH 2 —, (4-Me-phenyl)CH 2 —,

(2-MeS-phenyl)CH 2 —, (3-MeS-phenyl)CH 2 —,

4-MeS-phenyl)CH 2 —, (2-CF 3 O-phenyl)CH 2 —,

(3-CF 3 O-phenyl)CH 2 —, (4-CF 3 O-phenyl)CH 2 —,

(furanyl)CH 2 —, (thienyl)CH 2 —, (pyridyl)CH 2 —,

(2-Me-pyridyl)CH 2 —, (3-Me-pyridyl)CH 2 —,

(4-Me-pyridyl)CH 2 —, (1-imidazolyl)CH 2 —,

(oxazolyl)CH 2 —, (isoxazolyl)CH 2 —,

(cyclopropyl)CH 2 —, (cyclobutyl)CH 2 —, (cyclopentyl)CH 2 —,

(cyclohexyl)CH 2 —, (morpholino)CH 2 —, (N-pipridinyl)CH 2 —,

phenyl-CH 2 CH 2 —, (phenyl) 2 CHCH 2 —, (2-F-phenyl)CH 2 CH 2 —,

(3-F-phenyl)CH 2 CH 2 —, (4-F-phenyl)CH 2 CH 2 —,

(2-Cl-phenyl)CH 2 CH 2 —, (3-Cl-phenyl)CH 2 CH 2 —,

(4-Cl-phenyl)CH 2 CH 2 —, (2,3-diF-phenyl)CH 2 CH 2 —,

(2,4-diF-phenyl)CH 2 CH 2 —, (2,5-diF-phenyl)CH 2 CH 2 —,

(2,6-diF-phenyl)CH 2 CH 2 —, (3,4-diF-phenyl)CH 2 CH 2 —,

(3,5-diF-phenyl)CH 2 CH 2 —, (2,3-diCl-phenyl)CH 2 CH 2 —,

(2,4-diCl-phenyl)CH 2 CH 2 —, (2,5-diCl-phenyl)CH 2 CH 2 —,

(2,6-diCl-phenyl)CH 2 CH 2 —, (3,4-diCl-phenyl)CH 2 CH 2 —,

(3,5-diCl-phenyl)CH 2 CH 2 —, (3-F4-Cl-phenyl)CH 2 CH 2 —,

(3-F-5-Cl-phenyl)CH 2 CH 2 —, (3-Cl-4-F-phenyl)CH 2 CH 2 —,

(2-MeO-phenyl)CH 2 CH 2 —, (3-MeO-phenyl)CH 2 CH 2 —,

(4-MeO-phenyl)CH 2 CH 2 —, (2-Me-phenyl)CH 2 CH 2 —,

(3-Me-phenyl)CH 2 CH 2 —, (4-Me-phenyl)CH 2 CH 2 —,

(2-MeS-phenyl)CH 2 CH 2 —, (3-MeS-phenyl)CH 2 CH 2 —,

(4-MeS-phenyl)CH 2 CH 2 —, (2-CF 3 O-phenyl)CH 2 CH 2 —,

(3-CF 3 O-phenyl)CH 2 CH 2 —, (4-CF 3 O-phenyl)CH 2 CH 2 —,

(furanyl)CH 2 CH 2 —, (thienyl)CH 2 CH 2 —, (pyridyl)CH 2 CH 2 —,

(2-Me-pyridyl)CH 2 CH 2 —, (3-Me-pyridyl)CH 2 CH 2 —,

(4-Me-pyridyl)CH 2 CH 2 —, (imidazolyl)CH 2 CH 2 —, (oxazolyl)CH 2 CH 2 —,

(isoxazolyl)CH 2 CH 2 , —, (cyclopropyl)CH 2 CH 2 —,

(cyclobutyl)CH 2 CH 2 —, (cyclopentyl)CH 2 CH 2 —,

(cyclohexyl)CH 2 CH 2 —, (morpholino)CH 2 CH 2 —, or

(N-piperidinyl)CH 2 CH 2 —; and

R 13 , at each occurrence, is independently selected from

H, F, Cl, OH, —CH 3 , —CH 2 CH 3 , —OCH 3 , and —CF 3 .

13. A method for the treatment of Alzheimer's Disease comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

A is O;

Q is —NR 1 R 2 ;

R 1 is OR 14 ;

R 2 is selected from H, C 1 -C 6 alkyl, C 3 -C 10 carbocycle, aryl, and 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur;

R 3 is —(CR 7 R 7a ) n —R 4 ,

—(CR 7 R 7a ) n —S—(CR 7 R 7a ) m —R 4 ,

—(CR 7 R 7a ) n —O—(CR 7 R 7a ) m —R 4 ,

—(CR 7 R 7a ) n —N(R 7b )—(CR 7 R 7a ) m —R 4 ,

—(CR 7 R 7a ) n —S(═O)—(CR 7 R 7a ) m —R 4 ,

—(CR 7 R 7a ) n —S(═O) 2 —(CR 7 R 7a ) m —R 4 ,

—(CR 7 R 7a ) n —C(═O)—(CR 7 R 7a ) m —R 4 ,

—(CR 7 R 7a ) n —N(R 7b )C(═O)—(CR 7 R 7a ) m —R 4 ,

13 (CR 7 R 7a ) n —C(═O)N(R 7b )—(CR 7 R 7a ) m —R 4 ,

—(CR 7 R 7a ) n —N(R 7b )S(═O) 2 —(CR 7 R 7a ) m —R 4 , or

—(CR 7 R 7a ) n —S(═O) 2 N(R 7b )—(CR 7 R 7a ) m —R 4 ;

n is 0, 1, 2, or 3;

m is 0, 1, 2, or 3;

R 3a is H, OH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 2 -C 4 alkenyl or C 2 -C 4 alkenyloxy;

R 4 is H, OH, OR 14a ,

C 1 -C 6 alkyl substituted with 0-3 R 4a ,

C 2 -C 6 alkenyl substituted with 0-3 R 4a ,

C 2 -C 6 alkynyl substituted with 0-3 R 4a ,

C 3 -C 10 carbocycle substituted with 0-3 R 4b ,

aryl substituted with 0-3 R 4b , or

5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R 4b ;

R 4a , at each occurrence, is independently selected from is H, F, Cl, Br, I, CF 3 ,

C 3 -C 10 carbocycle substituted with 0-3 R 4b ,

aryl substituted with 0-3 R 4b , or

5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R 4b ;

R 4b , at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 15 R 16 , CF 3 , acetyl, SCH 3 , S(═O)CH 3 , S(═O) 2 CH 3 ,

C 1 -C 6 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl,

C 1 -C 4 haloalkoxy, and C 1 -C 4 haloalkyl-S—;

R 5 is H, OR 14 ;

C 1 -C 6 alkyl substituted with 0-3 R 5b ;

C 1 -C 6 alkoxy substituted with 0-3 R 5b ;

C 2 -C 6 alkenyl substituted with 0-3 R 5b ;

C 2 -C 6 alkynyl substituted with 0-3 R 5b ;

C 3 -C 10 carbocycle substituted with 0-3 R 5c ;

aryl substituted with 0-3 R 5c ; or

5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R 5c ;

R 5a is H, OH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 2 -C 4 alkenyl, or C 2 -C 4 alkenyloxy;

R 5b , at each occurrence, is independently selected from:

H, C 1 -C 6 alkyl, CF 3 , OR 14 , Cl, F, Br, I, ═O, CN, NO 2 , NR 15 R 16 ;

C 3 -C 10 carbocycle substituted with 0-3 R 5c ;

aryl substituted with 0-3 R 5c ; and

5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R 5c ;

R 5c , at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 15 R 16 , CF 3 , acetyl, SCH 3 , S(═O)CH 3 , S(═O) 2 CH 3 ,

C 1 -C 6 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl,

C 1 -C 4 haloalkoxy, and C 1 -C 4 haloalkyl-S—;

R 6 is H;

C 1 -C 6 alkyl substituted with 0-3 R 6a ;

C 3 -C 10 carbocycle substituted with 0-3 R 6b ; or

aryl substituted with 0-3 R 6b ;

R 6a , at each occurrence, is independently selected from H, C 1 -C 6 alkyl, OR 14 , Cl, F, Br, I, ═O, CN, NO 2 , NR 15 R 16 , aryl and CF 3 ;

R 6b , at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 15 R 16 , CF 3 , C 1 -C 6 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, and C 1 -C 4 haloalkoxy;

R 7 , at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , CF 3 , phenyl and C 1 -C 4 alkyl;

R 7a , at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , CF 3 , and C 1 -C 4 alkyl;

R 7b is selected from H and C 1 -C 4 alkyl;

Ring B is

Z is H;

C 1 -C 8 alkyl substituted with 1-3 R 12 ;

C 2 -C 4 alkenyl substituted with 1-3 R 12 ;

C 2 -C 4 alkynyl substituted with 1-3 R 12 ;

C 1 -C 8 alkyl substituted with 0-3 R 12a ;

C 2 -C 4 alkenyl substituted with 0-3 R 12a ;

C 2 -C 4 alkynyl substituted with 0-3 R 12a ;

aryl substituted with 0-4 R 12b ;

C 3 -C 10 carbocycle substituted with 0-4 R 12b ; or

5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R 12b ;

R 12 , at each occurrence, is independently selected from

aryl substituted with 0-4 R 12b ;

C 3 -C 10 carbocycle substituted with 0-4 R 12b ; and

5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R 12b ;

R 12a , at each occurrence, is independently selected from

H, OH, Cl, F, Br, I, CN, NO 2 , NR 15 R 16 , —C(═O)NR 15 R 16 , CF 3 , acetyl, SCH 3 , S(═O)CH 3 , S(═O) 2 CH 3 ,

C 1 -C 6 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl,

C 1 -C 4 haloalkoxy, and C 1 -C 4 haloalkyl-S—;

R 12b , at each occurrence, is independently selected from

H, OH, Cl, F, Br, I, CN, NO 2 , NR 15 R 16 , CF 3 , acetyl, SCH 3 , S(═O)CH 3 , S(═O) 2 CH 3 ,

C 1 -C 6 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl,

C 1 -C 4 haloalkoxy, and C 1 -C 4 haloalkyl-S—;

R 13 , at each occurrence, is independently selected from

H, OH, C 1 -C 6 alkyl, C 1 -C 4 alkoxy, Cl, F, Br, I, CN, NO 2 , NR 15 R 16 , and CF 3 ;

R 14 is, at each occurrence, H, phenyl, benzyl, C 1 -C 6 alkyl, C 2 -C 6 alkoxyalkyl, or C 3 -C 6 cycloalkyl;

R 14a is H, phenyl, benzyl, or C 1 -C 4 alkyl;

R 15 , at each occurrence, is independently selected from H, C 1 -C 6 alkyl, benzyl, phenethyl, (C 1 -C 6 alkyl)-C(═O)—, and (C 1 -C 6 alkyl)-S(═O) 2 —;

R 16 , at each occurrence, is independently selected from

H, OH, C 1 -C 6 alkyl, benzyl, phenethyl,

(C 1 -C 6 alkyl)-C(═O)—, and (C 1 -C 6 alkyl)-S(═O) 2 —; and

provided, when R 13 is H,

then Z is H;

C 4 -C 8 alkyl substituted with 1-3 R 12 ;

C 2 -C 4 alkenyl substituted with 1-3 R 12 ;

C 2 -C 4 alkynyl substituted with 1-3 R 12 ;

C 1 -C 8 alkyl substituted with 0-3 R 12a ;

C 2 -C 4 alkenyl substituted with 0-3 R 12a ; or

C 2 -C 4 alkynyl substituted with 0-3 R 12a .

14. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

15. A method for the treatment of Alzheimer's Disease comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising a compound of claim 2 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

17. A pharmaceutical composition comprising a compound of claim 3 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

18. A pharmaceutical composition comprising a compound of claim 4 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

19. A pharmaceutical composition comprising a compound of claim 5 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

20. A pharmaceutical composition comprising a compound of claim 6 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

21. A pharmaceutical composition comprising a compound of claim 7 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

22. A pharmaceutical composition comprising a compound of claim 8 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

23. A pharmaceutical composition comprising a compound of claim 9 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

24. A pharmaceutical composition comprising a compound of claim 10 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

25. A pharmaceutical composition comprising a compound of claim 11 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

26. A pharmaceutical composition comprising a compound of claim 12 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

27. A method for the treatment of Alzheimer's Disease comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 2 or pharmaceutically acceptable salt thereof.

28. A method for the treatment of Alzheimer's Disease comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 3 or pharmaceutically acceptable salt thereof.

29. A method for the treatment of Alzheimer's Disease comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 4 or pharmaceutically acceptable salt thereof.

30. A method for the treatment of Alzheimer's Disease comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 5 or pharmaceutically acceptable salt thereof.

31. A method for the treatment of Alzheimer's Disease comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 6 or pharmaceutically acceptable salt thereof.

32. A method for the treatment of Alzheimer's Disease comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 7 or pharmaceutically acceptable salt thereof.

33. A method for the treatment of Alzheimer's Disease comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 9 or pharmaceutically acceptable salt thereof.

34. A method for the treatment of Alzheimer's Disease comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 10 or pharmaceutically acceptable salt thereof.

35. A method for the treatment of Alzheimer's Disease comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 11 or pharmaceutically acceptable salt thereof.

36. A method for the treatment of Alzheimer's Disease comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 12 or pharmaceutically acceptable salt thereof.

Assignments (2)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 16, 2018

From: OLSON, RICHARD E.

To: DUPONT PHARMACEUTICALS COMPANY

Reel/Frame 045544/0765 →

CHANGE OF NAME Recorded Apr 16, 2018

From: DUPONT PHARMACEUTICALS COMPANY

To: BRISTOL-MYERS SQUIBB PHARMA COMPANY

Reel/Frame 045544/0777 →

Continuity (4)

Continuation 0950578800 · Feb 17, 2000

Continuation In Part 0946993900 · Dec 24, 1999

Provisional Application 6011358800 · Dec 24, 1998

Related Publication 20060025407A1 · Feb 2, 2006