| US 7,498,324 B2 | ||
| Substituted lactams as inhibitors of Aβ protein production | ||
| Qi Han, Hockessin, Del. (US); Hong Liu, Glen Mills, Pa. (US); Richard E. Olson, Wilmington, Del. (US); and Michael G. Yang, Wilmington, Del. (US) | ||
| Assigned to Bristol-Myers Squibb Pharma Company, Princeton, N.J. (US) | ||
| Filed on Apr. 19, 2007, as Appl. No. 11/788,708. | ||
| Application 11/348091 is a division of application No. 11/005573, filed on Dec. 06, 2004, granted, now 7,276,495. | ||
| Application 11/788708 is a continuation of application No. 11/655637, filed on Jan. 19, 2007, granted, now 7,390,802. | ||
| Application 11/655637 is a continuation of application No. 11/348091, filed on Feb. 06, 2006, abandoned. | ||
| Application 11/005573 is a continuation of application No. 10/685031, filed on Oct. 14, 2003, granted, now 6,900,199. | ||
| Application 10/685031 is a continuation of application No. 09/832455, filed on Apr. 11, 2001, granted, now 6,632,812. | ||
| Claims priority of provisional application 60/196549, filed on Apr. 11, 2000. | ||
| Prior Publication US 2008/0221087 A1, Sep. 11, 2008 | ||
| Int. Cl. C07D 243/12 (2006.01); A61K 31/55 (2006.01) | ||
| U.S. Cl. 514—221 [540/509] | 39 Claims |
1. A process for preparing a compound of Formula (I)
![]() ![]() Q′ is Q
Q is —(CR7R7a)m—R4,
—(CR7R7a)n—S—R4,
—(CR7R7a)n—O—R4,
—(CR7R7a)m—N(R7b)—R4,
—(CR7R7a)n—S(═O)—R4,
—(CR7R7a)n—S(═O)2—R4, or
—(CR7R7a)n—C(═O)—R4;
provided when n is 0, then R4 is not H;
m is 1, 2, or 3;
n is 0, 1, or 2;
R4 is H,
C1-C8 alkyl substituted with 0-3 R4a,
C2-C8 alkenyl substituted with 0-3 R4a,
C2-C8 alkynyl substituted with 0-3 R4a,
C3-C10 carbocycle substituted with 0-3 R4b,
aryl substituted with 0-3 R4b, 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 R4b;
R4a, at each occurrence, is independently selected from is H, Cl, F, Br, I, CN, NO2, NR15R16, CF3, OR14a, OR22, SR22, C(═O)OR22, NR21R22, S(═O)R22, S(═O)2R22,
C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
C1-C4 haloalkoxy, C1-C4 haloalkyl-S—,
C3-C10 carbocycle substituted with 0-3 R4b,
aryl substituted with 0-3 R4b, 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 R4b;
R4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
R5 is H;
C1-C6 alkyl substituted with 0-3 R5b;
C2-C6 alkenyl substituted with 0-3 R5b;
C2-C6 alkynyl substituted with 0-3 R5b;
C3-C10 carbocycle substituted with 0-3 R5c;
aryl substituted with 0-3 R5c; 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 R5c;
R5b, at each occurrence, is independently selected from:
H, C1-C6 alkyl, CF3, Cl, F, Br, I, ═O, CN, NO2, NR15R16;
C3-C10 carbocycle substituted with 0-3 R5c;
aryl substituted with 0-3 R5c; 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 R5c;
R5c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and
C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
R6 is H;
C1-C6 alkyl substituted with 0-3 R6a;
C3-C10 carbocycle substituted with 0-3 R6b; or
aryl substituted with 0-3 R6b;
R6a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, aryl or CF3;
R6b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
R7, at each occurrence, is independently H or C1-C4 alkyl;
R7a, at each occurrence, is independently H or C1-C4 alkyl;
R7b is H or C1-C4 alkyl;
Ring B is
![]() R11, at each occurrence, is independently selected from
H, C1-C4 alkoxy, Cl, F, Br, I, ═O, CN, NO2, NR18R19, C(═O)R17, C(═O)OR17, C(═O)NR18R19, S(═O)2NR18R19, CF3;
C1-C6 alkyl optionally substituted with 0-3 R11a;
aryl substituted with 0-3 R11b;
C3-C10 carbocycle substituted with 0-3 R11b; 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 R11b;
R11a, at each occurrence, is independently selected from
H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, CF3;
phenyl substituted with 0-3 R11b;
C3-C6 cycloalkyl substituted with 0-3 R11b; 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 R11b;
R11b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
W is a bond or —(CR8R8a)p—;
p is 0, 1, 2, 3, or 4;
R8 and R8a, at each occurrence, are independently selected from H, F, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl and C3-C8 cycloalkyl;
X is a bond;
aryl substituted with 0-3 RXb;
C3-C10 carbocycle substituted with 0-3 RXb; or
5 to 10 membered heterocycle substituted with 0-2 RXb;
RXb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 halothioalkoxy;
Y is a bond or —(CR9R9a)t—V—(CR9R9a)u—;
t is 0, 1, or 2;
u is 0, 1, or 2;
R9 and R9a, at each occurrence, are independently selected from H, F, C1-C6 alkyl or C3-C8 cycloalkyl;
V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —N(R19)—, —C(═O)NR19b—, —NR19bC(═O)—, —NR19bS(═O)2—, —S(═O)2NR19b—, —NR19bS(═O)—, —S(═O)NR19b—, —C(═O)O—, or —OC(═O)—;
Z is H;
C1-C8 alkyl substituted with 0-3 R12a;
C2-C6 alkenyl substituted with 0-3 R12a;
C2-C6 alkynyl substituted with 0-3 R12a;
aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; 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 R12b;
R12a, at each occurrence, is independently selected from
H, OH, Cl, F, Br, I, CN, NO2, NR15R16, —C(═O)NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
C1-C4 haloalkoxy, C1-C4 haloalkyl-S—,
aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; 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 R12b;
R12b, at each occurrence, is independently selected from
H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, aryl, C3-C6 cycloalkyl,
C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
R13, at each occurrence, is independently selected from
H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3;
R14 is H, phenyl, benzyl, C1-C6 alkyl, C2-C6 alkoxyalkyl, or C3-C6 cycloalkyl;
R14a is H, phenyl, benzyl, or C1-C4 alkyl;
R15, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, (C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
R16, at each occurrence, is independently selected from
H, OH, C1-C6 alkyl, benzyl, phenethyl,
(C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
alternatively, R15 and R16, together with the nitrogen to which they are attached, may combine to form a 4-7 membered ring wherein said 4-7 membered
ring optionally contains an additional heteroatom selected from O or NH;
R17 is H, C1-C6 alkyl, C2-C6 alkoxyalkyl,
aryl substituted by 0-4 R17a, or
—CH2-aryl substituted by 0-4 R17a;
R17a is H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, —OH, F, Cl, Br, I, CF3, OCF3, SCH3, S(O)CH3, SO2CH3, —NH2, —N(CH3)2, or C1-C4 haloalkyl;
R18, at each occurrence, is independently selected from
H, C1-C6 alkyl, phenyl, benzyl, phenethyl,
(C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
R19, at each occurrence, is independently selected from
H, OH, C1-C6 alkyl, phenyl, benzyl, phenethyl,
(C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
R19b, at each occurrence, is independently is H or C1-C4 alkyl;
R21 is H, phenyl, benzyl, or C1-C4 alkyl; and
R22 is C1-C4 alkyl, C2-C4 alkenyl, or C3-C4 alkynyl.
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