US2009264419A1PendingUtilityA1
CYCLIC MALONAMIDES AS INHIBITORS OF Abeta PROTEIN PRODUCTION
Assignee: BRISTOL MYERS SQUIBB PHARMA COPriority: Apr 3, 2000Filed: May 1, 2009Published: Oct 22, 2009
Est. expiryApr 3, 2020(expired)· nominal 20-yr term from priority
A61P 43/00C07K 5/0812A61K 31/4015A61K 31/55C07K 5/0205C07D 223/10C07D 243/24A61P 25/00C07D 223/16C07K 5/06078A61K 38/00C07K 5/06191A61P 25/28C07K 5/06139C07D 223/18C07D 243/14C07D 401/06C07D 401/12C07D 403/12A61K 31/445C07D 223/12
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Claims
Abstract
This invention relates to novel cyclic malonamides 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
exact text as granted — not AI-modified1 .- 24 . (canceled)
25 . A process for preparing a compound of Formula (I),
or a stereoisomer, or a pharmaceutically acceptable salt thereof, comprising an amide bond synthesis coupling a carboxylic acid 1 and an amine 2 including amide coupling methods comprising HATU, TBTU, BOP, EDC, CDI, and DCC-mediated couplings:
wherein the product, 3, comprises Formula (I)
wherein:
L is —NR 26 C(═O)—, —C(═O)NR 26 —, —NR 26c (═O)O—, —OC(═O)NR 26 , or —NR 26 C(═O)NR 26 —;
R 3 is (CR 7 R 7a ) n —R 4 ,
—(CR 7 R 7a ) l —S— (CR 7 R 7a ) m —R 4 ,
—(CR 7 R 7a ) l —O— (CR 7 R 7a ) m —R 4 ,
—(CR 7 R 7a ) 1 —N(R 7b )— (CR 7 R 7a ) m —R 4 ,
—(CR 7 R 7a ) l —S(═O)— (CR 7 R 7a ) m —R 4 ,
—(CR 7 R 7a ) l —S(═O) 2 —(CR 7 R 7a ) m —R 4 ,
—(CR 7 R 7a ) l —C(═O)— (CR 7 R 7a ) m —R 4 ,
—(CR 7 R 7a ) l —N(R 7b )C(═O)— (CR 7 R 7a ) m —R 4 ,
—(CR 7 R 7a ) l —C(═O)N(R 7b )— (CR 7 R 7a ) m —R 4 ,
—(CR 7 R 7a ) l —N(R 7b )S(═O) 2 —(CR 7 R 7a ) m —R 4 , or
—(CR 7 R 7a ) l —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;
l is 1, 2, or 3;
Ring C is a 3 to 8 membered carbocycle,
wherein the carbocycle is saturated or partially saturated;
optionally, the carbocycle contains a heteroatom selected from —O—, —S—, —S(═O)—, —S(═O) 2 —, and —N(R 20 )—; and
wherein the carbocycle is substituted with 0-4 R 21 ;
R 4 is H, OH, OR 14a ,
C 1 -C 8 alkyl substituted with 0-3 R 4a ,
C 2 -C 8 alkenyl substituted with 0-3 R 4a ,
C 2 -C 8 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 H, OH, F, Cl, Br, I, NR 15 R 16 , 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 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 , C 1 -C 4 alkyl, phenyl substituted with 0-5 R 7c ;
R 7a , at each occurrence, is independently selected from H, Cl, F, Br, I, CN, CF 3 , and C 1 -C 4 alkyl;
R 7b is independently selected from H and C 1 -C 4 alkyl;
R 7c , at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, CF 3 , C 1 -C 4 alkoxy, and C 1 -C 4 alkyl;
B is
R 11 is H, C 1 -C 4 alkoxy, Cl, F, Br, I, ═O, CN, NO 2 , NR 18 R 19 , C(═O)R 17 , C(═O)OR 17 , C(═O)NR 18 R 19 , S(═O) 2 NR 18 R 19 , CF 3 ;
C 1 -C 6 alkyl optionally substituted with 0-3 R 11a ;
aryl substituted with 0-3 R 11b ;
C 3 -C 10 carbocycle substituted with 0-3 R 11b ; 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 11b ;
R 11a , 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 , CF 3 , or phenyl substituted with 0-3 R 11b ;
R 11b , 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;
W is —(CR 8 R 8a ) p —;
p is 0, 1, 2, 3, or 4;
R 8 and R 8a , at each occurrence, are independently selected from
H, F, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl and C 3 -C 8 cycloalkyl;
X is a bond;
aryl substituted with 0-3 R Xb ;
C 3 -C 10 carbocycle substituted with 0-3 R Xb ; or
5 to 10 membered heterocycle substituted with 0-2 R Xb ;
R Xb , 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 halothioalkoxy;
Y is a bond or —(CR 9 R 9a ) t —V—(CR 9 R 9a ) u —;
t is 0, 1, 2, or 3;
u is 0, 1, 2, or 3;
R 9 and R 9a , at each occurrence, are independently selected from H, F, C 1 -C 6 alkyl and C 3 -C 8 cycloalkyl;
V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O) 2 —, —N(R 19 )—, C(═O)NR 19b —, —NR 19b C(═O)—, —NR 19b S(═O) 2 —, —S(═O) 2 NR 19b NR 19b S(═O)—, —S(═O)NR 19b —, —C(═O)O—, or —OC(═O)—;
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 H, phenyl substituted with 0-4 R 14b , benzyl substituted with 0-4 R 14b , C 1 -C 6 alkyl, C 2 -C 6 alkoxyalkyl, or C 3 -C 6 cycloalkyl;
R 14a is H, C 6 -C 10 aryl, benzyl, heterocycle, or C 1 -C 4 alkyl;
R 14b , 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 15 , at each occurrence, is independently selected from H, C 1 -C 6 alkyl, aryl-(C 1 -C 6 alkyl)- wherein the aryl is substituted with 0-4 R 15b , (C 1 -C 6 alkyl)-C(═O)—, and (C 1 -C 6 alkyl)-S(═O) 2 —;
R 15b , at each occurrence, is independently selected from
H, OH, Cl, F, Br, I, CN, NO 2 , 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 16 , 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 17 is H, C 1 -C 6 alkyl, C 2 -C 6 alkoxyalkyl,
aryl substituted by 0-4 R 17a , or
—CH 2 -aryl substituted by 0-4 R 17a ;
R 17a is H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, —OH, F, Cl, Br, I, CF 3 , OCF 3 , SCH 3 , S(O)CH 3 , SO 2 CH 3 , —NH 2 , —N(CH 3 ) 2 , or C 1 -C 4 haloalkyl;
R 18 , at each occurrence, is independently selected from
H, C 1 -C 6 alkyl, phenyl, benzyl, phenethyl,
(C 1 -C 6 alkyl)-C(═O)—, and (C 1 -C 6 alkyl)-S(═O) 2 —;
R 19 , at each occurrence, is independently selected from
H, OH, C 1 -C 6 alkyl, phenyl, benzyl, phenethyl,
(C 1 -C 6 alkyl)-C(═O)—, and (C 1 -C 6 alkyl)-S(═O) 2 —;
R 20 is H, C(═O)R 17 , C(═O)OR 17 , C(═O)NR 18 R 19 ,
S(═O) 2 NR 18 R 19 , S(═O) 2 R 17 ;
C 1 -C 6 alkyl optionally substituted with 0-2 R 20a ;
aryl substituted with 0-4 R 20b ;
C 3 -C 10 carbocycle substituted with 0-3 R 20b ; 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 20b ;
R 20a , at each occurrence, is independently selected from H, C 1 -C 6 alkyl, OR 14 , F, ═O, CN, NO 2 , NR 15 R 16 , CF 3 , aryl substituted with 0-4 R 20b , and heterocycle substituted with 0-4 R 20b ;
R 20b , 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 , 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 21 , at each occurrence, is independently selected from
H, C 1 -C 4 alkoxy, Cl, F, Br, I, ═O, CN, NO 2 , NR 18 R 19 , C(═O)R 17 , C(═O)OR 17 , C(═O)NR 18 R 19 , S(═O) 2 NR 18 R 19 , CF 3 ;
C 1 -C 6 alkyl optionally substituted with 0-3 R 21a ;
aryl substituted with 0-3 R 21b ;
C 3 -C 10 carbocycle substituted with 0-3 R 21b ; 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 21b ;
R 21a , 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 , CF 3 ;
phenyl substituted with 0-3 R 21b ;
C 3 -C 6 cycloalkyl substituted with 0-3 R 21b ; and
5 to 6 membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R 21b ;
R 21b , 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—;
additionally, two R 21 substituents on adjacent atoms may be combined to form a 5 to 6 membered heteroaryl fused radical, wherein said 5 to 6 membered heteroaryl fused radical comprises 1 or 2 heteroatoms selected from N, O, and S; wherein said 5 to 6 membered heteroaryl fused radical is substituted with 0-3 R 23 ;
additionally, two R 21 substituents on the same or adjacent carbon atoms may be combined to form a C 3 -C 6 carbocycle substituted with 0-3 R 23 ;
additionally, two R 21 substituents on adjacent atoms may be combined to form a benzo fused radical; wherein said benzo fused radical is substituted with 0-4 R 23 ;
R 23 , 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 26 is H;
C 1 -C 6 alkyl substituted with 0-3 R 26a ;
C 3 -C 10 carbocycle substituted with 0-3 R 26b ; or
aryl substituted with 0-3 R 26b ;
R 26a , 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 ; and
R 26b , 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.
26 . The process according to claim 25 for preparing a compound of Formula I or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:
L is —NR 26 C(═O)—, —C(═O)NR 26 —, or —OC(═O)NR 26 —; R 3 is —(CHR 7 ) n —R 4 ,
—(CHR 7 ) l —N—(CR 7 R 7a ) m —R 4 , or
—(CHR 7 ) l —O— (CR 7 R 7a ) m —R 4 ;
n is 0, 1 or 2; m is 0, 1 or 2; l is 1; Ring C is a 3 to 8 membered carbocycle substituted with 0-4 R 21 ;
optionally, the carbocycle contains a heteroatom selected from —O— and —N(R 20 )—;
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 0-2 R 4a ,
C 2 -C 6 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 H, OH, F, Cl, Br, I, NR 15 R 16 , 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 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 6 is H; R 7 , at each occurrence, is independently selected from H, OH, F, CF 3 , methyl, and ethyl; B is
R 11 is selected from
H, C 1 -C 4 alkoxy, Cl, F, Br, I, ═O, CN, NO 2 , NR 18 R 19 , C(═O)R 17 , C(═O)OR 17 , C(═O)NR 18 R 19 , S(═O) 2 NR 18 R 19 , CF 3 ;
C 1 -C 6 alkyl optionally substituted with 0-3 R 11a ;
aryl substituted with 0-3 R 11b ;
C 3 -C 10 carbocycle substituted with 0-3 R 11b ; 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 11b ;
R 11a , 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 , CF 3 ;
phenyl substituted with 0-3 R 11b ;
C 3 -C 6 cycloalkyl substituted with 0-3 R 11b ; 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 1b ;
R 11b , 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—;
W is a bond, —CH 2 —, —CH(CH 3 )—, —CH 2 CH 2 — or —CH(CH 3 )CH 2 —;
X is a bond;
phenyl substituted with 0-2 R Xb ;
C 3 -C 6 cycloalkyl substituted with 0-2 R Xb ; or
5 to 6 membered heterocycle substituted with 0-2 R Xb ;
R Xb , 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;
Y is a bond, —CH 2 —V—, —V—, or —V—CH 2 —;
V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O) 2 —, —NH—, —N(CH 3 )—, or —N(CH 2 CH 3 )—,
Z is H; C 1 -C 6 alkyl; C 2 -C 4 alkenyl; C 2 -C 4 alkynyl;
C 1 -C 3 alkyl substituted with 1-2 R 12 ;
C 2 -C 3 alkenyl substituted with 1-2 R 12 ;
C 2 -C 3 alkynyl substituted with 1-2 R 12 ;
aryl substituted with 0-4 R 12b ;
C 3 -C 6 carbocycle substituted with 0-3 R 12b ; or
5 to 10 membered heterocycle 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 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 H, phenyl, benzyl, C 1 -C 4 alkyl, or C 2 -C 4 alkoxyalkyl;
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 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 —;
R 17 is H, methyl, ethyl, propyl, butyl, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl,
phenyl substituted by 0-3 R 17a , or
—CH 2 -phenyl substituted by 0-3 R 17a ;
R 17a is H, methyl, methoxy, —OH, F, Cl, CF 3 , or OCF 3 ;
R 18 , at each occurrence, is independently selected from
H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
R 19 , at each occurrence, is independently selected from
H, methyl, and ethyl;
R 20 is H or C(═O)OR 17 ;
R 26 is H, methyl, or ethyl.
27 . The process according to claim 26 for preparing a compound of Formula I or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:
Ring C is selected from:
wherein Ring C is substituted with 0-2 R 21 ; and
Ring B is
28 . The process according to claim 27 for preparing a compound of Formula I or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:
L is —NHC(═O)—, —C(═O)NH—, or —OC(═O)NH—; R 3 is R 4 , —CH 2 OR 4 , or —CH 2 CH 2 OR 4 ; R 4 is C 1 -C 6 alkyl substituted with 0-3 R 4a ,
C 2 -C 6 alkenyl substituted with 0-1 R 4a , or
C 2 -C 6 alkynyl substituted with 0-1 R 4a ;
R 4a , at each occurrence, is independently selected from
H, OH, F, NR 15 R 16 , 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; W is a bond, —CH 2 —, —CH(CH 3 )—, —CH 2 CH 2 — or —CH(CH 3 )CH 2 —; X is a bond, phenyl, C 3 -C 6 cycloalkyl, or 5 to 6 membered heterocycle; Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O) 2 —, —NH—, —N(CH 3 )—, or —N(CH 2 CH 3 )—, Z is H; C 1 -C 6 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl,
C 1 -C 3 alkyl substituted with 1-2 R 12 ;
C 2 -C 3 alkenyl substituted with 1-2 R 12 ;
C 2 -C 3 alkynyl substituted with 1-2 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 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 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 —, ethyl-S(═O) 2 —, and propyl-S(═O) 2 —;
R 18 , at each occurrence, is independently selected from
H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
R 19 , at each occurrence, is independently selected from
H, methyl, and ethyl;
R 20 is H.
29 . A process for preparing a compound of Formula (I)
or a stereoisomer, pharmaceutically acceptable salt thereof, comprising an amide bond synthesis coupling a carboxylic acid 1 and an amine 2 including methods comprising HATU, TBTU, BOP, EDC, CDI, and DCC-mediated amide couplings,
wherein the reaction product 3 comprises Formula (I):
L is —NR 26 C(═O)—, —C(═O)NR 26 —, —NR 26 C(═O)O—, —OC(═O)NR 26 , or —NR 26 C(═O)NR 26 —;
R 3 is (CR 7 R 7a ) n —R 4 ,
—(CR 7 R 7a ) l —S—R 4 ,
—(CR 7 R 7a ) 1 —O—R 4 ;
—(CR 7 R 7a )— N (R 7b )—R 4 ,
—(CR 7 R 7a ) n —S(═O)—R 4 , or
—(CR 7 R 7a ) l —S(═O) 2 —R 4 ;
n is 0, 1 or 2;
l is 1 or 2;
R 4 is H,
C 1 -C 8 alkyl substituted with 0-3 R 4a ,
C 2 -C 8 alkenyl substituted with 0-3 R 4a ,
C 2 -C 8 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
H, OH, F, Cl, Br, I, NR 15 R 16 , 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—;
Ring C is a 3-8 membered carbocycle;
wherein said 3-8 membered carbocycle is saturated or partially unsaturated;
wherein said 3-8 membered carbocycle is substituted with 0-4 R 21 ; and
optionally, the carbocycle contains a heteroatom selected from —O— and —N(R 20 )—;
additionally, two R 21 substituents on adjacent atoms may be combined to form a benzo fused radical; wherein said benzo fused radical is substituted with 0-4 R 23 ;
additionally, two R 21 substituents on adjacent atoms may be combined to form a 5 to 6 membered heteroaryl fused radical, wherein said 5 to 6 membered heteroaryl fused radical comprises 1 or 2 heteroatoms selected from N, O, and S; wherein said 5 to 6 membered heteroaryl fused radical is substituted with 0-3 R 23 ;
additionally, two R 21 substituents on the same or adjacent carbon atoms may be combined to form a C 3 -C 6 carbocycle substituted with 0-3 R 23 ;
R 21 , at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , CF 3 , acetyl, SCH 3 , S(═O)CH 3 ,
S(═O) 2 CH 3 , NR 15 R 16 , OR 14a , C 1 -C 4 alkyl, C 2 -C 6 alkenyl,
alkynyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl,
C 1 -C 4 haloalkoxy, and C 1 -C 4 haloalkyl-S—,
C 3 -C 6 carbocycle, phenyl, and a
5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur;
R 6 is H, methyl, or ethyl;
R 7 , at each occurrence, is independently H or C 1 -C 4 alkyl;
R 7a , at each occurrence, is independently H or C 1 -C 4 alkyl;
R 7b is H or C 1 -C 4 alkyl;
Ring B is
R 11 is H, C 1 -C 4 alkoxy, Cl, F, Br, I, ═O, CN, NO 2 , NR 18 R 19 , C(═O)R 17 , C(═O)OR 17 , C(═O)NR 18 R 19 , S(═O) 2 NR 18 R 19 , CF 3 ;
C 1 -C 6 alkyl optionally substituted with 0-3 R 11a ;
aryl substituted with 0-3 R 11b ;
C 3 -C 10 carbocycle substituted with 0-3 R 11b ; 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 11b ;
R 11a , 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 , CF 3 , or phenyl substituted with 0-3 R 11b ;
R 11b , 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;
W is a bond or —(CH 2 ) p —;
p is 1 or 2;
X is a bond;
phenyl substituted with 0-2 R Xb ;
C 3 -C 6 carbocycle substituted with 0-2 R Xb ; or
5 to 6 membered heterocycle substituted with 0-2 R Xb ;
R Xb , 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 3 haloalkyl, C 1 -C 3 haloalkoxy, and C 1 -C 3 halothioalkoxy;
Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O) 2 —, —N(R 19 )—, —C(═O)NR 19b —, NR 19b C(═O)—, —NR 19b S(═O) 2 —, —S(═O) 2 NR 19b —, —NR 19b S(═O)—, —S(═O)NR 19b —, —C(═O)O—, or OC(═O)—;
Z is H;
C 1 -C 8 alkyl substituted with 0-3 R 12a ;
C 2 -C 6 alkenyl substituted with 0-3 R 12a ;
C 2 -C 6 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 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, C 1 -C 4 haloalkyl-S—, 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 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 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 —;
R 18 , at each occurrence, is independently selected from
H, C 1 -C 6 alkyl, phenyl, benzyl, phenethyl, (C 1 -C 6 alkyl)-C(═O)—, and (C 1 -C 6 alkyl)-S(═O) 2 —;
R 19 , at each occurrence, is independently selected from
H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
R 19b , at each occurrence, is independently is H or C 1 -C 4 alkyl;
R 20 is H, C 1 -C 4 alkyl, or C(═O)OR 17 ;
R 23 , 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 ; and
R 26 is H or C 1 -C 4 alkyl.
30 . The process according to claim 29 for preparing a compound of Formula (Ia):
or a stereoisomer, pharmaceutically acceptable salt, wherein:
L is —NR 26 C(═O)—, —C(═O)NR 26 —, —NR 26 C(═O)O—, —OC(═O)NR 26 , or —NR 26 C(═O)NR 26 —;
R 3 is —(CHR 7 ) n —R 4 ,
—(CHR 7 ) l —S—R 4 ,
—(CHR 7 ) l —O—R 4 ;
—(CR 7 R 7a ) l —N(R 7b )—R 4 ,
—(CR 7 R 7a ) l —S(═O)—R 4 , or
—(CR 7 R 7a ) l —S(═O) 2 —R 4 ;
n is 0, 1 or 2;
l is 1 or 2;
R 4 is H.
C 1 -C 8 alkyl substituted with 0-3 R 4a ,
C 2 -C 8 alkenyl substituted with 0-3 R 4a ,
C 2 -C 8 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
H, OH, F, Cl, Br, I, NR 15 R 16 , 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—;
Ring C is a 3-8 membered carbocycle;
wherein said 3-8 membered carbocycle is saturated or partially unsaturated;
wherein said 3-8 membered carbocycle is substituted with 0-4 R 21 ;
optionally, the carbocycle contains a heteroatom selected from —O—, and —N(R 20 )—;
additionally, two R 21 substituents on adjacent atoms may be combined to form a benzo fused radical; wherein said benzo fused radical is substituted with 0-4 R 23 ;
additionally, two R 21 substituents on the same or adjacent carbon atoms may be combined to form a C 3 -C 6 carbocycle substituted with 0-3 R 23 ;
R 21 , at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , CF 3 , acetyl, SCH 3 , S(═O)CH 3 ,
S(═O) 2 CH 3 , NR 15 R 16 , OR 14a , C 1 -C 4 alkyl, C 2 -C 6 alkenyl,
alkynyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl,
C 1 -C 4 haloalkoxy, and C 1 -C 4 haloalkyl-S—,
C 3 -C 6 carbocycle, phenyl, and a
5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur;
R 7 , at each occurrence, is independently H, methyl, or ethyl;
R 7b is H, methyl, or ethyl;
Ring B is selected from:
R 11 is H, C 1 -C 4 alkoxy, Cl, F, Br, I, ═O, CN, NO 2 , NR 18 R 19 , C(═O)R 17 , C(═O)OR 17 , C(═O)NR 18 R 19 , S(═O) 2 NR 18 R 19 , CF 3 ;
C 1 -C 6 alkyl optionally substituted with 0-3 R 11a ;
aryl substituted with 0-3 R 11b ;
C 3 -C 10 carbocycle substituted with 0-3 R 11b ; 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 11b ;
R 11a , 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 , CF 3 , or phenyl substituted with 0-3 R 11b ;
R 11b , 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;
W is a bond or —(CH 2 ) p —;
p is 1 or 2;
X is a bond;
phenyl substituted with 0-2 R Xb ;
C 3 -C 6 carbocycle substituted with 0-2 R Xb ; or
5 to 6 membered heterocycle substituted with 0-2 R Xb ;
R Xb , 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 3 haloalkyl, C 1 -C 3 haloalkoxy, and C 1 -C 3 halothioalkoxy;
Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O) 2 —, —N(R 19 )—, —C(═O)NR 19b —, NR 19b C(═O)—, —NR 19b S(═O) 2 —,
—S(═O) 2 NR 19b —, —NR 19b S(═O)—, —S(═O)NR 19b —, —C(═O)O—, or —OC(═O)—;
Z is H;
C 1 -C 8 alkyl substituted with 0-3 R 12a ;
C 2 -C 6 alkenyl substituted with 0-3 R 12a ;
C 2 -C 6 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 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, C 1 -C 4 haloalkyl-S—, 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 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 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 —;
R 18 , at each occurrence, is independently selected from
H, C 1 -C 6 alkyl, phenyl, benzyl, phenethyl,
(C 1 -C 6 alkyl)-C(═O)—, and (C 1 -C 6 alkyl)-S(═O) 2 ;
—R 19 , at each occurrence, is independently selected from
H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, phenethyl;
R 20 is H, C 1 -C 4 alkyl, or C(═O)OR 17 ;
R 23 , 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 ; and
R 26 is H or C 1 -C 4 alkyl.
31 . The process according to claim 29 for preparing a compound of Formula (Ia), a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:
L is —NHC(═O)—, —C(═O)NH—, or —OC(═O)NH—; R 3 is —R 4 , —CH 2 R 4 , —CH 2 CH 2 R 4 , —CH 2 OR 4 , or —CH 2 CH 2 OR 4 ; R 4 is 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 6 carbocycle substituted with 0-3 R 4b ,
phenyl substituted with 0-3 R 4b , or
5 to 6 membered heterocycle containing 1 to 3 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, OH, F, Cl, Br, I, NR 15 R 16 , CF 3 ,
C 3 -C 6 carbocycle substituted with 0-3 R 4b ,
phenyl substituted with 0-3 R 4b , or
5 to 6 membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 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—;
Ring C is a 3-6 membered carbocycle selected from:
wherein said 3-6 membered carbocycle is substituted with 0-1 R 21 ;
R 21 is selected from H, OH, Cl, F, CN, CF 3 , methyl, ethyl, methoxy, ethoxy, allyl, and —OCF 3 ;
R 10 is H, methyl, ethyl, phenyl, benzyl, phenethyl, 4-F-phenyl, (4-F-phenyl)CH 2 —, (4-F-phenyl)CH 2 CH 2 —, 4-Cl-phenyl, (4-Cl-phenyl)CH 2 —, (4-Cl-phenyl)CH 2 CH 2 —, 4-CH 3 -phenyl, (4-CH 3 -phenyl)CH 2 —, (4-CH 3 -phenyl)CH 2 CH 2 —, 4-CF 3 -phenyl, (4-CF 3 -phenyl)CH 2 —, or
(4-CF 3 -phenyl)CH 2 CH 2 —;
W is a bond, —CH 2 —, —CH 2 CH 2 —;
X is a bond;
phenyl substituted with 0-1 R Xb ;
C 3 -C 6 cycloalkyl substituted with 0-1 R Xb ; or
5 to 6 membered heterocycle substituted with 0-1 R Xb ;
R Xb is 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, methoxy, ethoxy, propoxy, and —OCF 3 ;
Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O) 2 —, —NH—, —N(CH 3 )—, or —N(CH 2 CH 3 )—;
Z is H;
C 1 -C 8 alkyl substituted with 0-3 R 12a ;
C 2 -C 6 alkenyl substituted with 0-3 R 12a ;
C 2 -C 6 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 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, C 1 -C 4 haloalkyl-S—,
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 sulfur, 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, 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 H, phenyl, benzyl, C 1 -C 4 alkyl, or C 2 -C 4 alkoxyalkyl;
R 15 , at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, benzyl, and phenethyl;
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 —;
R 18 , at each occurrence, is independently selected from
H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
R 19 , at each occurrence, is independently selected from
H, methyl, ethyl, propyl, and butyl;
R 20 is H or C 1 -C 4 alkyl.
32 . The process according to claim 29 for preparing a compound of Formula (Ia), a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:
L is —NHC(═O)—, —C(═O)NH—, or —OC(═O)NH—; R 3 is —R 4 , —CH 2 R 4 , —CH 2 CH 2 R 4 , —CH 2 OR 4 , or —CH 2 CH 2 OR 4 ; R 4 is C 1 -C 6 alkyl substituted with 0-3 R 4a ,
C 2 -C 6 alkenyl substituted with 0-3 R 4a , or
C 2 -C 6 alkynyl substituted with 0-3 R 4a ;
R 4a , at each occurrence, is independently selected from is H, OH, F, Cl, Br, I, NR 15 R 16 , CF 3 ,
C 3 -C 6 carbocycle substituted with 0-3 R 4b ,
phenyl substituted with 0-3 R 4b , or
5 to 6 membered heterocycle containing 1 to 3 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, 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—;
Ring C is selected from:
W is a bond or —CH 2 —;
X is a bond, phenyl, C 3 -C 6 cycloalkyl or 5 to 6 membered heterocycle;
Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O) 2 —, —NH—, —N(CH 3 )—, or —N(CH 2 CH 3 )—;
Z is H;
C 1 -C 8 alkyl substituted with 0-3 R 12a ;
C 2 -C 6 alkenyl substituted with 0-3 R 12a ;
C 2 -C 6 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 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;
phenyl substituted with 0-4 R 12b ;
C 3-6 carbocycle substituted with 0-4 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 ;
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; and
R 16 , at each occurrence, is independently selected from
H, OH, methyl, ethyl, propyl, butyl, benzyl, and phenethyl.
R 18 , at each occurrence, is independently selected from
H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
R 19 , at each occurrence, is independently selected from
H, methyl, ethyl, propyl, and butyl; and
R 20 is H, methyl, or ethyl.
33 . A process according to claim 29 for preparing a compound of Formula (Ia), a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:
L is —NHC(═O)—, —C(═O)NH—, or —OC(═O)NH—; Ring C is selected from:
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 2 CH(CH 3 ) 2 , —CH 2 (CH 3 ) 2 , —CH(CH 3 )CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —CH 2 C(CH 3 ) 3 , —CF 3 , —CH 2 CF 3 , —CH 2 CH 2 CF 3 , —CH 2 CH 2 CH 2 CF 3 , —CH(OH)CH 2 CH(CH 3 ) 2 , —CH(OH)CH(CH 3 ) 2 , —CH(NH 2 )CH 2 CH(CH 3 ) 2 , —CH 2 CH 2 OCH 3 , —CH 2 OCH 2 CH 3 , —CF 2 CH 2 CH(CH 3 ) 2 , —CH(NHCH 3 )CH 2 CH(CH 3 ) 2 , —CH(NHSO 2 CH 2 CH 2 CH 3 )CH 2 CH(CH 3 ) 2 , cyclohexyl-, cyclopentyl-, 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(OH)—, cyclohexyl-CH 2 CH 2 —, 1-NH 2 -cyclopentyl, 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-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 —, (3-F-5-Cl-phenyl)CH 2 CH 2 —, 4-piperidinyl-CH 2 CH 2 —, phenyl-CH 2 CH 2 CF 2 —, phenyl-CH 2 CH(OH)—, imidazolyl-CH 2 CH(OH)—, or phenyl-CH 2 OCH 2 —;
W is a bond or —CH 2 —;
X is a bond;
Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O) 2 —, —NH—, or —N(CH 3 )—,
Z is methyl, ethyl, i-propyl, n-propyl, n-butyl, i-butyl, s-butyl, t-butyl, allyl, 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-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, 1-benzimidazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholino, N-piperinyl, 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-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 —, (1-benzimidazolyl)CH 2 —, (cyclopropyl)CH 2 —, (cyclobutyl)CH 2 —, (cyclopentyl)CH 2 —, (cyclohexyl)CH 2 —, (morpholino)CH 2 —, (N-piperidinyl)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-F-4-Cl-phenyl)CH 2 CH 2 —, (3-F-5-Cl-phenyl)CH 2 CH 2 —, (3-Cl-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 —, (benzimidazolyl)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 —;
R 13 , at each occurrence, is independently selected from
H, F, Cl, OH, —CH 3 , —CH 2 CH 3 , —OCH 3 , or —CF 3 .
34 . A process according to claim 29 for preparing compound of Formula (Id)
or a stereoisomer, pharmaceutically acceptable salt thereof, wherein:
L is —NHC(═O)—, —C(═O)NH—, or —OC(═O)NH—;
R 3 is —(CH 2 ) n —R 4 ,
—(CH 2 ) l —S—R 4 ,
—(CH 2 ) l —O—R 4 , or
—(CH 2 ) l —N(R 7b )—R 4 ;
n is 0, 1 or 2;
l is 1 or 2;
R 4 is C 1 -C 8 alkyl substituted with 0-3 R 4a ,
C 2 -C 8 alkenyl substituted with 0-3 R 4a ,
C 2 -C 8 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
H, OH, F, Cl, Br, I, NR 15 R 16 , CF 3 ,
C 3 -C 10 carbocycle substituted with 0-3 R 4b ,
C 6 -C 10 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 7b is H, methyl, or ethyl;
Ring C is a 3-8 membered carbocycle;
wherein said 3-8 membered carbocyclic moiety is saturated or partially saturated;
wherein said 3-8 membered carbocyclic moiety is substituted with 0-3 R 21 ;
optionally, the carbocycle contains a heteroatom selected from —O— and —N(R 20 )—;
R 21 , at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , CF 3 , acetyl, SCH 3 , S(═O)CH 3 , S(═O) 2 CH 3 , NR 15 R 16 , OR 14a , C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, and C 1 -C 4 haloalkyl-S—;
R 11 , at each occurrence, is independently selected from
H, ═O, NR 18 R 19 , CF 3 ;
C 1 -C 4 alkyl optionally substituted with 0-1 R 11a ;
phenyl substituted with 0-3 R 11b ;
C 3 -C 6 carbocycle substituted with 0-3 R 11b ; and
5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said to 7 membered heterocycle is substituted with 0-3 R 11b ; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, homopiperidinyl, and tetrazolyl;
R 11a , at each occurrence, is independently selected from H, C 1 -C 4 alkyl, OR 14 , F, Cl, ═O, NR 15 R 16 , CF 3 , or phenyl substituted with 0-3 R 11b ;
R 11b , at each occurrence, is independently selected from H, OH, Cl, F, NR 15 R 16 , CF 3 , methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy;
W is a bond, —CH 2 —, —CH 2 CH 2 —;
X is a bond;
phenyl substituted with 0-2 R Xb ;
C 3 -C 6 cycloalkyl substituted with 0-2 R Xb ; or
5 to 6 membered heterocycle substituted with 0-2 R Xb ;
R Xb , 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;
Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O) 2 —,
—N(R 19 )—, —C(═O)NR 19b —, —NR 19b C(═O)—, —NR 19b S(═O) 2 —,
—S(═O) 2 NR 19b —, —NR 19b S(═O)—, —S(═O)NR 19b —, —C(═O)O—, or —OC(═O)—;
Z is H;
C 1 -C 8 alkyl substituted with 0-3 R 12a ;
C 2 -C 6 alkenyl substituted with 0-3 R 12a ;
C 2 -C 6 alkynyl substituted with 0-3 R 12a ;
C 6 -C 10 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 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, C 1 -C 4 haloalkyl-S—,
C 6 -C 10 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 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 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, alkyl)-C(═O)—, and (C 1 -C 4 alkyl)-S(═O) 2 ;
R 18 , at each occurrence, is independently selected from
H, C 1 -C 6 alkyl, phenyl, benzyl, phenethyl, alkyl)-C(═O)—, and (C 1 -C 6 alkyl)-S(═O) 2 —;
R 19 , at each occurrence, is independently selected from
H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, phenethyl; and
R 20 is H or C 1 -C 4 alkyl.
35 . A process according to claim 34 for preparing a racemic mixture of compound of Formula (Id)
or stereoisomer or pharmaceutically acceptable salt form thereof, wherein carbon 3 of lactam ring B may exist in an S or R configuration.
36 . A process according to claim 25 for preparing a compound of Formula (I) consisting of N—({N-[5-(tert-Butyl)-1-methyl-2-oxo(3H-benzo[f]1,4-diazepin-3-yl)]carbamoyl}cyclopentyl)-4-methylpentanamide,
the process comprising the following steps as illustrated in scheme 7:
wherein step 1 comprises:
adding added a 30% solution of HBr in acetic acid (16 equiv) to a stirred solution of intermediate compound 23 (1.0 equiv) in CH 2 —C 2 (0.1 M), continuing to stir the resulting mixture for 14 h.;
concentrating the reaction mixture in vacuo, and dissolving it in EtOAc and water, followed by separating and extracting the mixture with an aqueous layer made basic using 6 N NaOH and a layer of CH 2 Cl 2 ;
washing the organic extracts with brine, drying them over Na 2 SO 4 ;
filter and concentrate the extracts;
dissolving the resulting solid in CH 2 Cl 2 and adding it to a stirring solution of the acid form of intermediate compound 24 (1.2 equiv), EDC-HCl (1.5 equiv), HOBt (1.5 equiv), and DIPEA (5.0 equiv) in CH 2 Cl 2 (0.15 M);
stirring the reaction overnight, quenching it with water, washing it with 20% citric acid (3×), sat NaHCO 3 (2×), brine, drying over Na 2 SO 4 , filtering and concentrating; and
recrystallizing the crude material from EtOAc and Et 2 O to yield intermediate compound 25 (4.4 g, 95%) as a white powder which showed analytical data of 1 H NMR (500 MHz, CDCl 3 ) δ 7.71-6.98 (m, 6H), 5.87 (s, 1H), 5.29 (d, 1H), 2.38 (m, 2H), 2.21 (t, 2H) 2.01 (m, 2H), 1.52 (m, 7H), 1.23 (s, 9H), 0.88 (d, 6H); and
the step 2 comprises:
adding methyl iodide (1.5 equiv) to a suspension of 25 (1 equiv) and freshly powdered K 2 CO 3 (3.0 equiv) in DMF (0.05 M);
stirring the mixture was stirred (5 h) to the reaction was added EtOAc and water and separating the layers; washing the organic layer with 5% LiCl (2×), and brine, followed by drying over Na 2 SO 4 , filtering and concentrating; dissolving the resulting material in Et 2 O and concentrating it in vacuo providing N—(N-[5-(tert-butyl)-1-methyl-2-oxo(3H-benzo[f]1,4-diazepin-3-yl)]carbamoyl-cyclopentyl)-4-methylpentanamide (60 mg, 66%) as a white powder; having the characteristics of mp 175-178° C.; 1 H NMR (500 MHz, CDCl 3 ) δ 7.71-7.17 (m, 5H), 5.89 (s, 1 H), 5.23 (d, 1H), 3.34 (s, 3H), 2.41-2.29 (m, 3H), 2.21 (m, 2H), 2.04 (m, 3H), 1.80 (m, 4H), 1.60 (m, 1H), 1.18 (s, 9H), 0.90 (d, 6H); ESI MS m/z=455 [C 26 H 38 N 4 O 3 +H] + ; IR (KBr)=3324, 2958, 1677, 1508, 1366, 1197 cm −1 ; HPLC 96.8%, t r =15.75 min. (HPLC Conditions A).
37 . A process according to claim 25 for preparing a compound of Formula (I), stereoisomer, or pharmaceutically acceptable salt thereof, selected from:
{[N-(3-methylbutyl)carbamoyl]cyclopentyl}-N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carboxamide;
[(N-butylcarbamoyl)cyclopentyl]-N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carboxamide;
2-(3,5-difluorophenyl)-N-{[N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclohexyl}acetamide;
2-(3,5-difluorophenyl)-N—{[N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclopentyl}acetamide;
2-(3,5-difluorophenyl)-N-{[N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclopropyl}acetamide;
3-cyclopentyl-N—{[N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclohexyl}propanamide;
2-(3,5-difluorophenyl)-N-{4-[N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carbamoyl](4-piperidyl)}acetamide;
phenyl 4-[2-(3,5-difluorophenyl)acetylamino]-4-[N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]piperidinecarboxylate;
N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}{[(phenylmethoxy)carbonylamino]cyclopentyl}carboxamide;
2,2-difluoro-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]-4-phenylbutanamide;
N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]-3-(4-piperidyl)propanamide;
(2S)-2-hydroxy-4-methyl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]pentanamide;
3-cyclopropyl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]propanamide;
(2R)-2-hydroxy-3-imidazol-2-yl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]propanamide;
2-ethoxy-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]acetamide;
3-cyclopentyl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]propanamide;
(2S)-2-hydroxy-3-methyl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]butanamide;
(2S)-2-cyclohexyl-2-hydroxy-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]acetamide;
(2R)-2-cyclohexyl-2-hydroxy-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]acetamide;
(2S)-2-amino-4-methyl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]pentanamide;
[(cyclohexylcarbonylamino)cyclopentyl]-N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carboxamide;
{[N-(3-methylbutyl)carbamoyl]cyclopentyl}-N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carboxamide;
4-methyl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]pentanamide;
(2S)-2-hydroxy-4-methyl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]pentanamide;
3-methoxy-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]propanamide;
(2S)-2-hydroxy-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]-3-phenylpropanamide;
N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]-2-(phenylmethoxy)acetamide;
N-{[N-(1-butyl-5-cyclopentyl-2-oxo(3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclopentyl}-4-methylpentanamide;
N-{[N-(5-cyclopentyl-1-methyl-2-oxo(3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclopentyl}-4-methylpentanamide;
N—({N-[5-(tert-butyl)-1-methyl-2-oxo(3H-benzo[f]1,4-diazepin-3-yl)]carbamoyl}cyclopentyl)-4-methylpentanamide;
N—({N-[5-(tert-butyl)-1-butyl-2-oxo(3H-benzo[f]1,4-diazepin-3-yl)]carbamoyl}cyclopentyl)-4-methylpentanamide; and
N—({N-[5-butyl-2-oxo-1-(2-pyridylmethyl)(3H-benzo[f]1,4-diazepin-3-yl)]carbamoyl}cyclopentyl)-4-methylpentanamide.
38 . A process of preparing a pharmaceutical composition comprising combining a compound prepared by the process according to claim 25 , and a pharmaceutically acceptable carrier.
39 . A process of preparing a pharmaceutical composition comprising combining a compound prepared by the process according to claim 26 , and a pharmaceutically acceptable carrier.
40 . A process of preparing a pharmaceutical composition comprising combining a compound prepared by the process according to claim 27 , and a pharmaceutically acceptable carrier.
41 . A process of preparing a pharmaceutical composition comprising combining a compound prepared by the process according to claim 28 , and a pharmaceutically acceptable carrier.
42 . A process of preparing a pharmaceutical composition comprising combining a compound prepared by the process according to claim 29 , and a pharmaceutically acceptable carrier.
43 . A process of preparing a pharmaceutical composition comprising combining a compound prepared by the process according to claim 30 , and a pharmaceutically acceptable carrier.
44 . A process of preparing a pharmaceutical composition comprising combining a compound prepared by the process according to claim 31 , and a pharmaceutically acceptable carrier.
45 . A process of preparing a pharmaceutical composition comprising combining a compound prepared by the process according to claim 32 , and a pharmaceutically acceptable carrier.
46 . A process of preparing a pharmaceutical composition comprising combining a compound prepared by the process according to claim 33 , and a pharmaceutically acceptable carrier.
47 . A process of preparing a pharmaceutical composition comprising combining a compound prepared by the process according to claim 34 , and a pharmaceutically acceptable carrier.
48 . A process of preparing a pharmaceutical composition comprising combining a compound prepared by the process according to claim 35 , and a pharmaceutically acceptable carrier.
49 . A process of preparing a pharmaceutical composition comprising combining a compound prepared by the process according to claim 36 , and a pharmaceutically acceptable carrier.
50 . A process of preparing a pharmaceutical composition comprising combining a compound prepared by the process according to claim 37 , and a pharmaceutically acceptable carrier.Join the waitlist — get patent alerts
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