AU7479700A - Hydroxyalkanoyl aminolactams and related structures as inhibitors of a beta protein production - Google Patents

Hydroxyalkanoyl aminolactams and related structures as inhibitors of a beta protein production Download PDF

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Publication number
AU7479700A
AU7479700A AU74797/00A AU7479700A AU7479700A AU 7479700 A AU7479700 A AU 7479700A AU 74797/00 A AU74797/00 A AU 74797/00A AU 7479700 A AU7479700 A AU 7479700A AU 7479700 A AU7479700 A AU 7479700A
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Prior art keywords
phenyl
substituted
methyl
alkyl
amino
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AU783914B2 (en
Inventor
Hong Liu
Richard Eric Olson
Lorin Andrew Thompson Iii
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Bristol Myers Squibb Pharma Co
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DuPont Merck Pharmaceutical Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
    • C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
    • C07D243/24—Oxygen atoms

Description

WO 01/19797 PCT/USOO/24967 TITLE HYDROXYALKANOYLAMINOLACTAMS AND RELATED STRUCTURES AS INHIBITORS OF AS PROTEIN PRODUCTION 5 FIELD OF THE INVENTION This invention relates to novel lactams having drug and bio-affecting properties, their pharmaceutical compositions and methods of use. These novel compounds inhibit the processing of amyloid precursor protein and, 10 more specifically, inhibit the production of Ap-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 $-amyloid production such as 15 Alzheimer's disease and Down's Syndrome. BACKGROUND OF THE INVENTION Alzheimer's disease (AD) is a degenerative brain disorder characterized clinically by progressive loss of 20 memory, temporal and local orientation, cognition, reasoning, judgment and emotionally stability. AD is a common cause of progressive dementia in humans and is one of the major causes of death in the United States. AD has been observed in all races and ethnic groups worldwide, and 25 is a major present and future health problem. No treatment that effectively prevents AD or reverses the clinical symptoms and underlying pathophysiology is currently available (for review, Dennis J. Selkoe; Cell Biology of the amyloid (beta)-protein precursor and the mechanism of 30 Alzheimer's disease, Annu Rev Cell Biol, 1994, 10: 373 403). Histopathological examination of brain tissue derived upon autopsy or from neurosurgical specimens in effected individuals revealed the occurrence of amyloid plaques and 35 neurofibrillar tangles in the cerebral cortex of such patients. Similar alterations were observed in patients with Trisomy 21 (Down's syndrome), and hereditary cerebral WO 01/19797 PCT/USOO/24967 hemorrhage with amyloidosis of the Dutch-type. Neurofibrillar tangles are nonmembrane-bound bundles of abnormal proteinaceous filaments and biochemical and immunochemical studies led to the conclusion that their 5 principle protein subunit is an altered phosphorylated form of the tau protein (reviewed in Selkoe, 1994). Biochemical and immunological studies revealed that the dominant proteinaceous component of the amyloid plaque is an approximately 4.2 kilodalton (kD) protein of about 39 10 to 43 amino acids. This protein was designated AS, amyloid peptide, and sometimes $/A4; referred to herein as AS. In addition to its deposition in amyloid plaques, A$ is also found in the walls of meningeal and parenchymal arterioles, small arteries, capillaries, and sometimes, 15 venules. AP was first purified and a partial amino acid reported in 1984 (Glenner and Wong, Biochem. Biophys. Res. Commun. 120: 885-890). The isolation and sequence data for the first 28 amino acids are described in U.S. Pat. No 4,666,829. 20 Compelling evidence accumulated during the last decade revealed that A$ is an internal polypeptide derived from a type 1 integral membrane protein, termed P amyloid precursor protein (APP). P APP is normally produced by many cells both in vivo and in cultured cells, derived from 25 various animals and humans. A$ is derived from cleavage of $ APP by as yet unknown enzyme (protease) system(s), collectively termed secretases. The existence of at least four proteolytic activities has been postulated. They include P secretase(s), 30 generating the N-terminus of A$, a secretase(s) cleaving around the 16/17 peptide bond in AS, and y secretases, generating C-terminal AP fragments ending at position 38, 39, 40, 42, and 43 or generating C-terminal extended precursors which are subsequently truncated to the above 35 polypeptides. -2- WO 01/19797 PCT/USOO/24967 Several lines of evidence suggest that abnormal accumulation of A$ plays a key role in the pathogenesis of AD. Firstly, A$ is the major protein found in amyloid plaques. Secondly, A3 is neurotoxic and may be causally 5 related to neuronal death observed in AD patients. Thirdly, missense DNA mutations at position 717 in the 770 isoform of P APP can be found in effected members but not unaffected members of several families with a genetically determined (familiar) form of AD. In addition, several 10 other 1 APP mutations have been described in familiar forms of AD. Fourthly, similar neuropathological changes have been observed in transgenic animals overexpressing mutant forms of human $ APP. Fifthly, individuals with Down's syndrome have an increased gene dosage of $ APP and develop 15 early-onset AD. Taken together, these observations strongly suggest that A$ depositions may be causally related to the AD. It is hypothesized that inhibiting the production of AS will prevent and reduce neurological degeneration, by 20 controlling the formation of amyloid plaques, reducing neurotoxicity and, generally, mediating the pathology associated with AD production. One method of treatment methods would therefore be based on drugs that inhibit the formation of A$ in vivo. 25 Methods of treatment could target the formation of A$ through the enzymes involved in the proteolytic processing of $ amyloid precursor protein. Compounds that inhibit or ysecretase activity, either directly or indirectly, could control the production of A$. Advantageously, 30 compounds that specifically target y secretases, could control the production of AD. Such inhibition of $ or ysecretases could thereby reduce production of AD, which, thereby, could reduce or prevent the neurological disorders associated with Approtein. -3- WO 01/19797 PCT/USOO/24967 SUMMARY OF THE INVENTION One object of the present invention is to provide novel compounds which are useful as inhibitors of the 5 production of AP protein or pharmaceutically acceptable salts or prodrugs thereof. It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically 10 effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt form or prodrug form thereof. It is another object of the present invention to provide a method for treating degenerative neurological 15 disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt form or prodrug form thereof. 20 These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that compounds of Formula (I): R5 R 5 a R O R N W-X-Y-Z
R
2 'B 25
OR
3 0 (I) or pharmaceutically acceptable salt form or prodrug forms thereof, wherein Q, R 2 , R 3 , R 5 , R 5 a, R 6 , B, W, X, Y, and Z are defined below, are effective inhibitors of the 30 production of AP. DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS Thus, in a first embodiment, the present invention provides a novel compound of Formula (I): -4- WO 01/19797 PCT/USOO/24967
R
5
R
5 a R 6 R N W-X-Y-Z
OR
3 0 (I) 5 or a pharmaceutically acceptable salt form or prodrug thereof, wherein: Q is Q 1 , (Ci-C 3 alkyl)-O-Q 1 , 10 (Ci-C 3 alkyl)-S-Q 1 , (Ci-C 3 alkyl)-S(=O)-Ql, (Ci-C 3 alkyl)-S(=0) 2
-Q
1 , or (Ci-C 3 alkyl)-N(R 20 )-Q1; 15 Q 1 is Ci-C 8 alkyl substituted with 0-3 Ria;
C
2
-C
8 alkenyl substituted with 0-3 Ria;
C
2
-C
8 alkynyl substituted with 0-3 Ria;
C
3 -C1O cycloalkyl substituted with 0-3 Rib;
C
3 -Cio carbocycle substituted with 0-3 Rib; 20 C 6
-C
10 aryl substituted with 0-3 Rib; 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 Rib; 25 Ria, at each occurrence, is independently selected from H, Ci-C 6 alkyl, OR1 4 , Cl, F, Br, I, NR 1 5
R
1 6 , CF 3 ; C3-C1O carbocycle substituted with 0-3 Rib;
C
6 -Cio aryl substituted with 0-3 Rib; and 30 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and -5- WO 01/19797 PCT/USOO/24967 sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 Rib; Rib, at each occurrence, is independently selected from H, 5 OH, Cl, F, Br, I, CN, NO 2 , NR 1 5
R
1 6 , CF 3 , acetyl, SCH 3 ,
S(=O)CH
3 , S(=0) 2
CH
3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, Ci-C 4 haloalkyl-S-, and (Ci-C 6 alkyl)-O-C(=O)-; 10 R 2 is H, methyl, ethyl, propyl, or butyl;
R
3 is H, Ci-C 6 alkyl, -C(=O) (Ci-C 6 alkyl), -C(=S) (Ci-C 6 alkyl), or -C(=0)NR21R22. 15 alternatively, R 2 and OR 3 are combined to form C=O or C=N-OH;
R
5 is H, OR 14 ; Ci-C 6 alkyl substituted with 0-3 R 5 b; 20 Ci-C 6 alkoxy substituted with 0-3 R5b;
C
2
-C
6 alkenyl substituted with 0-3 R5b;
C
2
-C
6 alkynyl substituted with 0-3 R 5 b;
C
3
-C
10 cycloalkyl substituted with 0-3 R 5 c;
C
3
-C
10 carbocycle substituted with 0-3 R 5 c; 25 C 6
-C
10 aryl substituted with 0-3 R 5 c; 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 0-3R 5 c; 30
R
5 a is H, Ci-C 4 alkyl, or C 2
-C
4 alkenyl; alternatively, R 5 and R 5 a may be combined to form a 3-7 membered cycloalkyl ring substituted with 0-3 R 5 c; 35 optionally the cycloalkyl ring formed by combining R 5 -6- WO 01/19797 PCT/USOO/24967 and R 5 a may be benzo fused, wherein the benzo fused ring may be substituted with 0-3 R 5 c;
R
5 b, at each occurrence, is independently selected from: 5 H, Ci-C 6 alkyl, CF 3 , OR 1 4 , Cl, F, Br, I, =0, CN, NO 2 ,
NR
1 5
R
1 6 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2 CH3, C 2
-C
6 alkenyl, C 2
-C
6 alkynyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, Ci-C 4 haloalkyl-S-,
C
3
-C
1 o cycloalkyl substituted with 0-3 R 5 c; 10 C 3
-C
10 carbocycle substituted with 0-3 R 5 c;
C
6 -Cio aryl substituted with 0-3 R 5 c; and 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered 15 heterocycle is substituted with 0-3 R 5 c;
R
5 c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR1 5
R
1 6 , CF 3 , acetyl, SCH 3 ,
S(=O)CH
3 , S(=0) 2
CH
3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 20 haloalkyl, Ci-C 4 haloalkoxy, and Ci-C 4 haloalkyl-S-;
R
6 is H or Ci-C 6 alkyl; W is -(CR8R8a)p_; 25 p is 0, 1, 2, 3, or 4;
R
8 and R 8 a, at each occurrence, are independently selected from H, F, Ci-C 4 alkyl, C 2
-C
4 alkenyl, C 2
-C
4 alkynyl 30 and C 3
-C
8 cycloalkyl; X is a bond;
C
6
-C
10 aryl substituted with 0-3 RXb;
C
3
-C
10 cycloalkyl substituted with 0-3 Rxb; 35 C 3
-C
1 O carbocycle substituted with 0-3 RXb; or 5 to 10 membered heterocycle substituted with 0-2 Rxb; -7- WO 01/19797 PCT/USOO/24967 RXb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 1 5 R1 6 , CF 3 , acetyl, SCH 3 ,
S(=O)CH
3 , S(=0) 2
CH
3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, C1-C 4 haloalkoxy, and Ci-C 4 haloalkyl-S-; 5 Y is a bond or -(CR 9
R
9 a)t-V-(CR 9
R
9 a)u-; t is 0, 1, 2, or 3; 10 u is 0, 1, 2, or 3;
R
9 and R 9 a, at each occurrence, are independently selected from H, F, Ci-C 6 alkyl or C 3
-C
8 cycloalkyl; 15 V is a bond, -C(=O)-, -0-, -S-, -S(=O)-, -S(=0) 2 -, -N(R19)-, -C(=0)NR19b-, -NR19bC(=0)-, -NR19bS (=0)2-, -S(=0) 2 NR1 9 b-, -C(=O)O-, or -OC(=O)-; Z is H; 20 Ci-C 8 alkyl substituted with 0-2 R1 2 ;
C
2
-C
4 alkenyl substituted with 0-2 R1 2 ;
C
2
-C
4 alkynyl substituted with 0-2 R1 2 ;
C
6 -C1 0 aryl substituted with 0-4 R12b;
C
3
-C
1 0 carbocycle substituted with 0-4 R12b; or 25 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 R1 2 b; 30 Ring B is a 6, 7, or 8 membered lactam, wherein the lactam is saturated, partially saturated or unsaturated; wherein each additional lactam carbon is substituted with 0-2 R1l; and, -8- WO 01/19797 PCT/USOO/24967 optionally, the lactam contains a heteroatom selected from -N=, -NH-, -N(R1 0 )-, -0-, -S-, -S(=O)-, and -S(=0)2-; 5 additionally, two R 11 substituents on adjacent atoms may be combined to form C 3
-C
6 carbocycle fused radical, a benzo fused radical, or a 5 to 6 membered heteroaryl fused radical, wherein said 5 to 6 membered heteroaryl fused radical 10 comprises 1-2 heteroatoms selected from N, 0, and S; wherein said benzo fused radical or 5 to 6 membered heteroaryl fused radical is substituted with 0-3 R1 3 ;
R
1 0 is H, C(=0)R1 7 , C(=O)OR 1 7 , C(=O)NR1 8 R1 9 , S(=0) 2
NR
1 8
R
1 9 , 15 S(=0)2Rl7;
C
1
-C
6 alkyl substituted with 0-2 R10a;
C
6
-C
10 aryl substituted with 0-4 R10b;
C
3 -Cio carbocycle substituted with 0-3 R10b; or 5 to 10 membered heterocycle containing 1 to 4 20 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is optionally substituted with 0-3 R10b; 25 R 10 a, at each occurrence, is independently selected from H, Ci-C 6 alkyl, OR 1 4 , Cl, F, Br, I, =0, CN, NO 2 , NR 1 5
R
1 6 ,
CF
3 ; aryl substituted with 0-4 R10b;
C
3
-C
10 carbocycle substituted with 0-3 R10b; or 30 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is optionally substituted with 0-3 R10b; 35 -9- WO 01/19797 PCT/USOO/24967 R10b, at each occurrence, is independently selected from H, OH, Ci-C 6 alkyl, Ci-C 4 alkoxy, Cl, F, Br, I, CN, NO 2 ,
NR
1 5
R
1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2
CH
3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, 5 and Ci-C 4 haloalkyl-S-;
R
11 , at each occurrence, is independently selected from H, Ci-C 4 alkoxy, Cl, F, Br, I, =0, CN, NO 2 , NR1 8
R
1 9 ,
C(=O)R
1 7 , C(=O)OR 17 , C(=O)NR1 8 R1 9 , S(=0) 2 NR1 8 R1 9 , 10
CF
3 ; Ci-C 6 alkyl substituted with 0-1 R11a;
C
6
-C
10 aryl substituted with 0-3 R11b;
C
3
-C
1 o carbocycle substituted with 0-3 R11b; or 5 to 10 membered heterocycle containing 1 to 4 15 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R11b;
R
11 a, at each occurrence, is independently selected from H, 20 Ci-C 6 alkyl, OR 1 4 , Cl, F, Br, I, =0, CN, NO 2 , NR 1 5
R
1 6 ,
CF
3 ; phenyl substituted with 0-3 Riib;
C
3
-C
10 carbocycle substituted with 0-3 R11b; or 5 to 10 membered heterocycle containing 1 to 4 25 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R11b; R11b, at each occurrence, is independently selected from H, 30 OH, Cl, F, Br, I, CN, NO 2 , NR 1 5
R
1 6 , CF 3 , acetyl, SCH 3 ,
S(=O)CH
3 , S(=0) 2
CH
3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Cu-C 4 haloalkoxy, and Ci-C 4 haloalkyl-S-;
R
12 at each occurrence, is independently selected from H, 35 OH, Cl, F, Br, I, CN, NO 2 , NR 1 5
R
1 6 , -C(=O)NR 1 5 R1 6 , CF 3 , -10- WO 01/19797 PCT/USOO/24967 acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2
CH
3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, and Ci-C 4 haloalkyl-S-;
C
6
-C
1 0 aryl substituted with 0-4 R12b; 5 C 3
-C
10 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 R1 2 b; 10 R1 2 b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 1 5
R
1 6 , CF 3 , acetyl, SCH 3 ,
S(=O)CH
3 , S(=0) 2
CH
3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, and Ci-C 4 haloalkyl-S-; 15
R
13 , at each occurrence, is independently selected from H, OH, Ci-C 6 alkyl, Ci-C 4 alkoxy, Cl, F, Br, I, CN, NO 2 ,
NR
1 5
R
1 6 , and CF 3 ; 20 R 14 , at each occurrence, is independently selected from H, phenyl, benzyl, Ci-C 6 alkyl, and C 2
-C
6 alkoxyalkyl;
R
14 a is H, phenyl, benzyl, or Ci-C 6 alkyl; 25 R 15 , at each occurrence, is independently selected from H, Ci-C 6 alkyl, phenyl, benzyl, phenethyl, (C1-C 6 alkyl) C(=O)-, (Ci-C 6 alkyl)-O-C(=O)- and (Ci-C 6 alkyl) S(=0)2-; 30 R1 6 , at each occurrence, is independently selected from H, OH, Ci-C 6 alkyl, phenyl, benzyl, phenethyl, (Ci-C 6 alkyl)-C(=O)-, (Ci-C 6 alkyl)-O-C(=O)- and (Ci-C 6 alkyl)-S(=0)2-; -11- WO 01/19797 PCT/USOO/24967 alternatively, -NR 15
R
16 may be a heterocyclic ring selected from the group piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, homopiperidinyl, piperazinyl, and N-methylpiperizinyl; 5 R1 7 is H, Ci-C 6 alkyl, or C 2
-C
6 alkoxyalkyl, aryl substituted by 0-4 R 1 7 a, or aryl-CH 2 - wherein said aryl is substituted by by 0-4 R1 7 a; 10
R
1 7 a 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 , S(=0) 2
CH
3 , -NH 2 , -N(CH 3
)
2 , or Ci-C 4 haloalkyl; 15
R
18 , at each occurrence, is independently selected from H, Ci-C 6 alkyl, phenyl, benzyl, phenethyl, (Ci-C 6 alkyl) C(=O)- and (Ci-C 6 alkyl)-S(=0) 2 -; 20 alternatively, -NR 1 7 R1 8 may be a heterocyclic ring selected from the group piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, homopiperidinyl, piperazinyl, and N-methylpiperizinyl; 25 R 19 , at each occurrence, is independently selected from H, OH, Ci-C 6 alkyl, phenyl, benzyl, phenethyl, (Ci-C 6 alkyl)-C(=O)- and (Ci-C 6 alkyl)-S(=0) 2 -; Ri9b, at each occurrence, is independently selected from H 30 and Ci-C 6 alkyl;
R
20 is H, OH, Ci-C 4 alkyl, phenyl, benzyl, or phenethyl;
R
21 , at each occurrence, is independently selected from H, 35 Ci-C 6 alkyl, phenyl, benzyl, and phenethyl; and -12- WO 01/19797 PCT/USOO/24967
R
22 , at each occurrence, is independently selected from H, Ci-C 6 alkyl, phenyl, benzyl, and phenethyl. [2] In a preferred embodiment the present invention 5 provides a compound of Formula (I) wherein: Q is Q1, (Ci-C 3 alkyl)-O-Q 1 , (Ci-C 3 alkyl)-S-Ql, 10 (Ci-C 3 alkyl)-S(=O)-Ql, (Ci-C 3 alkyl)-S(=0) 2
-Q
1 , or (Ci-C 3 alkyl) -N(R 2 0 ) -Q 1 ;
Q
1 is Ci-C 6 alkyl substituted with 0-3 Ria; 15 C 2
-C
6 alkenyl substituted with 0-3 Ria;
C
2
-C
6 alkynyl substituted with 0-3 Ria;
C
3
-C
10 cycloalkyl substituted with 0-3 Rib;
C
3
-C
10 carbocycle substituted with 0-3 Rib;
C
6
-C
10 aryl substituted with 0-3 Rib; or 20 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 Rib; 25 Rla, at each occurrence, is independently selected from H, Ci-C 6 alkyl, OR 14 , Cl, F, Br, I, NR 1 5
R
1 6 , CF 3 ;
C
3 -C1O carbocycle substituted with 0-3 Rib;
C
6
-C
1 0 aryl substituted with 0-3 Rib; and 5 to 10 membered heterocycle containing 1 to 4 30 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 Rib; -13- WO 01/19797 PCT/USOO/24967 Rib, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 1 5 R1 6 , CF 3 , acetyl, SCH 3 ,
S(=O)CH
3 , S(=0) 2
CH
3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, Ci-C 4 haloalkyl-S-, and 5 (Ci-C 6 alkyl)-O-C(=O)-;
R
2 is H, methyl, ethyl, propyl, or butyl;
R
3 is H, Ci-C 4 alkyl, -C(=O) (Ci-C 4 alkyl), -C(=S) (Ci-C 4 10 alkyl), or -C(=O)NR 2 1
R
2 2 ;
R
5 is H, OR1 4 ; Ci-C 6 alkyl substituted with 0-3 R5b; C1-C 6 alkoxy substituted with 0-3 R5b; 15 C 2
-C
6 alkenyl substituted with 0-3 R5b;
C
2
-C
6 alkynyl substituted with 0-3 R 5 b;
C
3
-C
10 cycloalkyl substituted with 0-3 R 5 c;
C
3 -Cio carbocycle substituted with 0-3 R 5 C;
C
6
-C
1 0 aryl substituted with 0-3 R 5 c; or 20 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 0-3R 5 c; 25 R 5 a is H, Ci-C 4 alkyl, or C 2
-C
4 alkenyl; alternatively, R 5 and R 5 a may be combined to form a 3-7 membered cycloalkyl ring substituted with 0-3 R 5 c; 30 R5b, at each occurrence, is independently selected from: H, Ci-C 6 alkyl, CF 3 , OR 1 4 , Cl, F, Br, I, =0, CN, NO 2 ,
NR
1 5
R
1 6 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2
CH
3 , C 2
-C
6 alkenyl, C 2
-C
6 alkynyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, C 1
-C
4 haloalkoxy, and 35 Ci-C 4 haloalkyl-S-,
C
3 -C1O cycloalkyl substituted with 0-3 R 5 c.
C
3
-C
1 o carbocycle substituted with 0-3 R 5 c; -14- WO 01/19797 PCT/USOO/24967
C
6 -Cio aryl substituted with 0-3 R 5 c; and 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered 5 heterocycle is substituted with 0-3 R 5 c;
R
5 c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 1 5 R1 6 , CF 3 , acetyl, SCH 3 ,
S(=O)CH
3 , S(=0) 2
CH
3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 10 haloalkyl, Ci-C 4 haloalkoxy, and Ci-C 4 haloalkyl-S-;
R
6 is H, methyl, or ethyl; W is -(CR8R 8 a)p_; 15 p is 0, 1, or 2;
R
8 and R 8 a, at each occurrence, are independently selected from H, F, methyl, and ethyl; 20 X is a bond; phenyl substituted with 0-3 RXb;
C
3
-C
6 cycloalkyl substituted with 0-3 RXb; or 5 to 6 membered heterocycle substituted with 0-2 RXb; 25 RXb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 1 5
R
1 6 , CF 3 , acetyl, SCH 3 ,
S(=O)CH
3 , S(=0) 2
CH
3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, and Ci-C 4 haloalkyl-S-; 30 Y is a bond or -(CR 9
R
9 a)t-V-(CR 9
R
9 a)u~; t is 0, 1, or 2; 35 u is 0, 1, or 2; -15- WO 01/19797 PCT/USOO/24967
R
9 and R 9 a, at each occurrence, are independently selected from H, F, methyl, and ethyl; V is a bond, -C(=0)-, -0-, -S-, -S(=O)-, -S(=0) 2 -, 5 -N(R1 9 )-, -C(=0)NH-, -NHC(=O)-, -NHS(=0) 2 -, or -S(=0) 2 NH-; Z is H, halo; Ci-C 4 alkyl substituted with 0-2 R1 2 ; 10 C 2
-C
4 alkenyl substituted with 0-2 R1 2 ;
C
2
-C
4 alkynyl substituted with 0-2 R1 2 ;
C
6
-C
10 aryl substituted with 0-4 R12b;
C
3
-C
6 carbocycle substituted with 0-4 R1 2 b; or 5 to 6 membered heterocycle containing 1 to 4 15 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R1 2 b; Ring B is a 7 membered lactam, 20 wherein the lactam is saturated, partially saturated or unsaturated; wherein each additional lactam carbon is substituted with 0-2 Ri 1 ; and, optionally, the lactam contains a heteroatom selected 25 from -N=, -NH-, -N(R1 0 )-, -0-, -S-, -S(=O)-, and -S(=0)2-; additionally, two R1l substituents on adjacent atoms may be combined to form C 3
-C
6 carbocycle fused radical, a 30 benzo fused radical, or a 5 to 6 membered heteroaryl fused radical, wherein said 5 to 6 membered heteroaryl fused radical comprises 1-2 heteroatoms selected from N, 0, and S; wherein said benzo fused radical or 5 to 6 membered 35 heteroaryl fused radical is substituted with 0-3 R 13 ; -16- WO 01/19797 PCT/USOO/24967
R
1 0 is H, C(=O)R 1 7 , C(=O)OR 1 7 , C(=O)NR 1 8
R
1 9 , S(=0) 2 NR1 8
R
1 9 , S (=0) 2
R
1 7 ; Ci-C 6 alkyl substituted with 0-2 R 10 a.
C
6
-C
10 aryl substituted with 0-4 R10b; 5 C 3
-C
10 carbocycle substituted with 0-3 R10b; 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 optionally substituted with 0-3 10 R10b;
R
10 a, at each occurrence, is independently selected from H, Ci-C 6 alkyl, OR 1 4 , Cl, F, Br, I, =0, CN, NO 2 , NR 1 5
R
1 6 ,
CF
3 , or aryl substituted with 0-4 R10b; 15 R10b, at each occurrence, is independently selected from H, OH, Ci-C 6 alkyl, Ci-C 4 alkoxy, Cl, F, Br, I, CN, NO 2 ,
NR
1 5
R
1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH 3 , S(=O) 2
CH
3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, 20 and Ci-C 4 haloalkyl-S-;
R
11 , at each occurrence, is independently selected from H,
CI-C
4 alkoxy, Cl, F, Br, I, =0, CN, NO 2 , NR 1 8
R
1 9 ,
C(=O)R
1 7 , C(=O)OR 1 7 , C(=O)NR1 8
R
9 , S(=0) 2 NR1 8
R
1 9 , 25
CF
3 ; Ci-C 6 alkyl substituted with 0-1 R11a;
C
6
-C
1 0 aryl substituted with 0-3 R11b;
C
3
-C
10 carbocycle substituted with 0-3 R11b; or 5 to 10 membered heterocycle containing 1 to 4 30 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R11b; -17- WO 01/19797 PCT/USOO/24967 R11a, at each occurrence, is independently selected from H, Ci-C 6 alkyl, OR 1 4 , Cl, F, Br, I, =0, CN, NO 2 , NR 1 5
R
1 6 ,
CF
3 ; phenyl substituted with 0-3 R11b; 5 C 3
-C
10 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 Rilb; 10 R11b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 1 5
R
1 6 , CF 3 , acetyl, SCH 3 ,
S(=O)CH
3 , S(=0) 2
CH
3 , CI-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, and Ci-C 4 haloalkyl-S-; 15
R
12 at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 1 5
R
1 6 , -C(=O)NR 1 5
R
1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2
CH
3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, and Ci-C 4 20 haloalkyl-S-;
C
6
-C
1 0 aryl substituted with 0-4 R1 2 b;
C
3
-C
1 o carbocycle substituted with 0-4 R1 2 b; or 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and 25 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, NO 2 , NR 1 5
R
1 6 , CF 3 , acetyl, SCH 3 , 30 S(=O)CH 3 , S(=0) 2
CH
3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, and Ci-C 4 haloalkyl-S-; R1 3 , at each occurrence, is independently selected from H, OH, Ci-C 6 alkyl, Ci-C 4 alkoxy, Cl, F, Br, I, CN, NO 2 , 35 NR 1 5
R
1 6 , and CF 3 ; -18- WO 01/19797 PCT/USOO/24967
R
14 , at each occurrence, is independently selected from H, phenyl, benzyl, Ci-C 6 alkyl, and C 2
-C
6 alkoxyalkyl; 5 R 15 , at each occurrence, is independently selected from H,
C
1
-C
6 alkyl, phenyl, benzyl, phenethyl, (Ci-C 6 alkyl) C(=O)-, (Ci-C 6 alkyl)-O-C(=O)- and (Ci-C 6 alkyl) S(=0)2-; 10 R1 6 , at each occurrence, is independently selected from H, OH, Ci-C 6 alkyl, phenyl, benzyl, phenethyl, (Ci-C 6 alkyl)-C(=O)-, (Ci-C 6 alkyl)-O-C(=O)- and (Ci-C 6 alkyl)-S(=0) 2 -; 15 alternatively, -NR1 5
R
16 may be a heterocyclic ring selected from the group piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, homopiperidinyl, piperazinyl, and N-methylpiperizinyl; 20 R1 7 is H, aryl, aryl-CH 2 -, Ci-C 6 alkyl, or C 2
-C
6 alkoxyalkyl; R1 8 , at each occurrence, is independently selected from H, Ci-C 6 alkyl, phenyl, benzyl, phenethyl, (Ci-C 6 alkyl) 25 C(=O)- and (Ci-C 6 alkyl)-S(=0) 2 -;
R
19 , at each occurrence, is independently selected from H, OH, Ci-C 6 alkyl, phenyl, benzyl, phenethyl, (Ci-C 6 alkyl)-C(=O)- and (Ci-C 6 alkyl)-S(=0) 2 -; 30 alternatively, -NR 17
R
18 may be a heterocyclic ring selected from the group piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, homopiperidinyl, piperazinyl, and N-methylpiperizinyl; 35
R
20 is H, OH, Ci-C 4 alkyl, phenyl, benzyl, or phenethyl; -19- WO 01/19797 PCT/USOO/24967
R
21 , at each occurrence, is independently selected from H, Ci-C 6 alkyl, phenyl, benzyl, and phenethyl; and 5 R 22 , at each occurrence, is independently selected from H, Ci-C 6 alkyl, phenyl, benzyl, and phenethyl. [2] In a preferred embodiment the present invention provides a compound of Formula (I) wherein Ring B is 10 selected from: 0 0 0 N N N S R11 R -)' R- R RR1 7 0N 0 NA0
N
4 RR1/
R"
1 / \ 15 o 0 0 N N N X R" R R O or N N--0 -20- WO 01/19797 PCT/USOO/24967 wherein each benzo fused radical is substituted with 0-3
R
1 3 . 5 [4] In a preferred embodiment the present invention provides a compound of Formula (Ia):
R
5
R
5 a 0 R N B W-X-Y-Z OH 0 (Ia) or a pharmaceutically acceptable salt form or prodrug 10 thereof, wherein: Q is Q 1 , (Ci-C 3 alkyl)-O-Ql, (Ci-C 3 alkyl) -S-Ql, 15 (Ci-C 3 alkyl)-S(=O)-Q 1 , (Ci-C 3 alkyl)-S(=0) 2 -Ql, or (Ci-C 3 alky-1) -N (R 2 0 ) -Q 1 ;
Q
1 is Ci-C 6 alkyl substituted with 0-3 Ria; 20 C 2
-C
6 alkenyl substituted with 0-3 Ria;
'C
2
-C
6 alkynyl substituted with 0-3 Ria;
C
3
-C
10 cycloalkyl substituted with 0-3 Rib;
C
3 -C1O carbocycle substituted with 0-3 Rib;
C
6
-C
10 aryl substituted with 0-3 Rib; or 25 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 Rib; 30 Ria, at each occurrence, is independently selected from H, Ci-C 6 alkyl, OR1 4 , Cl, F, Br, I, NR 1 5
R
1 6 , CF 3 ; C3-C1O carbocycle substituted with 0-3 Rib; -21- WO 01/19797 PCT/USOO/24967
C
6 -CiO aryl substituted with 0-3 Rib; and 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered 5 heterocycle is substituted with 0-3 Rib; Rib, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 1 5
R
16 , CF 3 , acetyl, SCH 3 ,
S(=O)CH
3 , S(=0) 2
CH
3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 10 haloalkyl, CI-C 4 haloalkoxy, Ci-C 4 haloalkyl-S-, and (Ci-C 6 alkyl) -0-C(=O)-;
R
2 is H, methyl, or ethyl; 15 R 5 is H, OR 14 ;
C
1
-C
6 alkyl substituted with 0-3 R5b; Ci-C 6 alkoxy substituted with 0-3 R5b;
C
2
-C
6 alkenyl substituted with 0-3 R 5 b;
C
2
-C
6 alkynyl substituted with 0-3 R5b; 20 C 3
-C
10 cycloalkyl substituted with 0-3 R 5 c;
C
3
-C
1 O carbocycle substituted with 0-3 R 5 c;
C
6 -Cio aryl substituted with 0-3 R 5 c; or 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and 25 sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3R 5 c;
R
5 a is H, Ci-C 4 alkyl, or C 2
-C
4 alkenyl; 30 alternatively, R 5 and R 5 a may be combined to form a 3-7 membered cycloalkyl ring substituted with 0-3 R 5 c;
R
5 b, at each occurrence, is independently selected from: H, Ci-C 6 alkyl, CF 3 , OR 14 , Cl, F, Br, I, =0, CN, NO 2 , 35 NR 1 5
R
1 6 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2
CH
3 , C 2
-C
6 -22- WO 01/19797 PCT/USOO/24967 alkenyl, C 2
-C
6 alkynyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, and Ci-C 4 haloalkyl-S-,
C
3
-C
10 cycloalkyl substituted with 0-3 R 5 c; 5 C 3
-C
10 carbocycle substituted with 0-3 R 5 c;
C
6
-C
1 0 aryl substituted with 0-3 R 5 c; and 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered 10 heterocycle is substituted with 0-3 R 5 c;
R
5 c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 1 5
R
1 6 , CF 3 , acetyl, SCH 3 ,
S(=O)CH
3 , S(=0) 2
CH
3 , Cl-C6 alkyl, Ci-C 4 alkoxy, Ci-C 4 15 haloalkyl, Ci-C 4 haloalkoxy, and Ci-C 4 haloalkyl-S-; W is -(CR8R 8 a)p-; p is 0, 1, or 2; 20
R
8 and R 8 a, at each occurrence, are independently selected from H, F, methyl, and ethyl; X is a bond; 25 phenyl substituted with 0-3 RXb; C3-C 6 cycloalkyl substituted with 0-3 RXb; or 5 to 6 membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle 30 is substituted with 0-2 RXb; RXb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 1 5
R
1 6 , CF 3 , acetyl, SCH 3 ,
S(=O)CH
3 , S(=0) 2
CH
3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 35 haloalkyl, Ci-C 4 haloalkoxy, and C 1
-C
4 haloalkyl-S-; Y is a bond or -(CR9R9alt-V-(CR9R9alu-; -23- WO 01/19797 PCT/USOO/24967 t is 0, 1, or 2; u is 0, 1, or 2; 5
R
9 and R9a, at each occurrence, are independently selected from H, F, methyl, and ethyl; V is a bond, -C(=O)-, -0-, -S-, -S(=0)-, -S(=0) 2 -, 10 -N(R 1 9 )-, -C(=O)NH-, or -NHC(=0)-; Z is H, halo; C1-C 4 alkyl substituted with 0-2 R1 2 ;
C
2
-C
4 alkenyl substituted with 0-2 R1 2 ; 15 C 2
-C
4 alkynyl substituted with 0-2 R1 2 ;
C
6
-C
10 aryl substituted with 0-4 R1 2 b;
C
3
-C
6 carbocycle substituted with 0-4 R1 2 b; or 5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and 20 sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R12b. Ring B is selected from: 0 O N 0 N 13 N
__R
13 R R RR R 1 and R 13 -~~ R/ ; 25
R
11 , at each occurrence, is independently selected from H, Ci-C 4 alkoxy, Cl, F, Br, I, =0, CN, NO 2 , NR 1 8 R1 9 ,
C(=O)R
1 7 , C(=O)OR 1 7 , C(=O)NR 1 8
R
1 9 , S(=0) 2
NR
1 8 R1 9 , 30 CF 3 ; Ci-C 6 alkyl substituted with 0-1 R11a; -24- WO 01/19797 PCT/USOO/24967
C
6 -C1O aryl substituted with 0-3 R11b;
C
3 -Cio carbocycle substituted with 0-3 R11b; or 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and 5 sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R11b;
R
11 a, at each occurrence, is independently selected from H, Ci-C 6 alkyl, OR 14 , Cl, F, Br, I, =0, CN, NO 2 , NR 1 5
R
1 6 , 10
CF
3 ; phenyl substituted with 0-3 R11b;
C
3
-C
1 o carbocycle substituted with 0-3 R11b; or 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and 15 sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R11b; R11b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 1 5
R
1 6 , CF 3 , acetyl, SCH 3 , 20 S(=O)CH 3 , S(=0) 2
CH
3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, and C1-C 4 haloalkyl-S-; R12 at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 1 5
R
1 6 , -C(=O)NR1 5 R1 6 , CF 3 , 25 acetyl, SCH3, S(=O)CH 3 , S(=0) 2
CH
3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, C1-C 4 haloalkyl, Ci-C 4 haloalkoxy, and Ci-C 4 haloalkyl-S-;
C
6 -Cio aryl substituted with 0-4 R1 2 b;
C
3
-C
10 carbocycle substituted with 0-4 R1 2 b; or 30 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; -25- WO 01/19797 PCT/USOO/24967 Ri2b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR1 5
R
1 6 , CF 3 , acetyl, SCH 3 ,
S(=O)CH
3 , S(=0) 2
CH
3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, and Ci-C 4 haloalkyl-S-; 5
R
13 , at each occurrence, is independently selected from H, OH, Ci-C 6 alkyl, Ci-C 4 alkoxy, Cl, F, Br, I, CN, NO 2 ,
NR
1 5
R
1 6 , and CF 3 ; 10 R1 4 , at each occurrence, is independently selected from H, phenyl, benzyl, Ci-C 6 alkyl, and C 2
-C
6 alkoxyalkyl; R1 5 , at each occurrence, is independently selected from H, Ci-C 6 alkyl, phenyl, benzyl, phenethyl, (Ci-C 6 alkyl) 15 C(=O)-, (Ci-C 6 alkyl)-O-C(=O)- and (Ci-C 6 alkyl) S(=0)2-; Ri 6 , at each occurrence, is independently selected from H, OH, Ci-C 6 alkyl, phenyl, benzyl, phenethyl, (Ci-C 6 20 alkyl)-C(=O)-, (Ci-C 6 alkyl)-O-C(=O)- and (Ci-C 6 alkyl)-S(=0)2-; alternatively, -NR 15
R
16 may be a heterocyclic ring selected from the group piperidinyl, morpholinyl, 25 thiomorpholinyl, pyrrolidinyl, homopiperidinyl, piperazinyl, and N-methylpiperizinyl;
R
17 is H, aryl, aryl-CH 2 -, Ci-C 6 alkyl, or C 2
-C
6 alkoxyalkyl; 30
R
18 , at each occurrence, is independently selected from H, Ci-C 6 alkyl, phenyl, benzyl, phenethyl, (Ci-C 6 alkyl) C(=O)- and (Ci-C 6 alkyl)-S(=0) 2 -; -26- WO 01/19797 PCT/USOO/24967
R
19 , at each occurrence, is independently selected from H, OH, Ci-C 6 alkyl, phenyl, benzyl, phenethyl, (Ci-C 6 alkyl)-C(=O)- and (Ci-C 6 alkyl)-S(=0) 2 -; 5 alternatively, -NR 1 8
R
1 9 may be a heterocyclic ring selected from the group piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, homopiperidinyl, piperazinyl, and N-methylpiperizinyl; and 10 R 20 is H, OH, Ci-C 4 alkyl, phenyl, benzyl, or phenethyl. [5] In a preferred embodiment the present invention provides a compound of Formula (Ia): 15 R5 RaH O R r SfN ,W -X-Y-Z OHO B (Ia) wherein: Ring B is selected from: 0 0 N N Nb 13 R- NR R 13R R R1 20 R; ; and Q is Q1 or (Ci-C 3 alkyl)-O-Q 1 ; Q1 is Ci-C 6 alkyl substituted with 0-3 Ria. 25 C 2
-C
6 alkenyl substituted with 0-3 Ria;
C
2
-C
6 alkynyl substituted with 0-3 Ria;
C
3
-C
10 cycloalkyl substituted with 0-3 Rib;
C
3
-C
1 o carbocycle substituted with 0-3 Rib;
C
6 -C1O aryl substituted with 0-3 Rib; or -27- WO 01/19797 PCT/USOO/24967 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 Rib; 5
R
1 a, at each occurrence, is independently selected from H, Ci-C 6 alkyl, OR 1 4 , Cl, F, Br, I, NR 15
R
1 6 , CF 3 ;
C
3
-C
10 carbocycle substituted with 0-3 Rib;
C
6
-C
10 aryl substituted with 0-3 Rib; and 10 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 Rib; 15 Rib, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 15
R
1 6 , CF 3 , acetyl, SCH 3 ,
S(=O)CH
3 , S(=0) 2
CH
3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, Ci-C 4 haloalkyl-S-, and (Ci-C 6 alkyl)-O-C(=O)-; 20
R
2 is H, methyl, or ethyl;
R
5 is H, OR 14 ; Ci-C 6 alkyl substituted with 0-3 R5b; 25 C 2
-C
6 alkenyl substituted with 0-3 R 5 b;
C
2
-C
6 alkynyl substituted with 0-3 R5b;
C
3
-C
6 cycloalkyl substituted with 0-3 R 5 c;
C
3
-C
6 carbocycle substituted with 0-3 R 5 c. phenyl substituted with 0-3 R 5 c; or 30 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3R 5 c; 35 R 5 a is H, Ci-C 4 alkyl, or C 2
-C
4 alkenyl; -28- WO 01/19797 PCT/USOO/24967 alternatively, R 5 and R 5 a may be combined to form a C 4
-C
7 cycloalkyl ring; R5b, at each occurrence, is independently selected from: 5 H, Ci-C 6 alkyl, CF 3 , OR 1 4 , Cl, F, Br, I, =0, CN, NO 2 ,
NR
1 5
R
1 6 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2
CH
3 , C 2
-C
6 alkenyl, C 2
-C
6 alkynyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, and Ci-C 4 haloalkyl-S-, 10 C 3
-C
10 cycloalkyl substituted with 0-3 R 5 c;
C
3
-C
10 carbocycle substituted with 0-3 R 5 c;
C
6 -CiO aryl substituted with 0-3 R 5 c; and 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and 15 sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R 5 c;
R
5 c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 1 5
R
1 6 , CF 3 , acetyl, SCH 3 , 20 S(=O)CH 3 , S(=0) 2
CH
3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, and Ci-C 4 haloalkyl-S-; W is -(CR 8
R
8 a)p-; *25 p is 0, 1, or 2;
R
8 and R 8 a, at each occurrence, are independently selected from H, methyl, and ethyl; 30 X is a bond; phenyl substituted with 0-3 Rxb;
C
3
-C
6 cyclolakyl substituted with 0-3 RXb; or 5 to 6 membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and 35 sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-2 RXb; -29- WO 01/19797 PCT/USOO/24967 RXb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 1 5
R
1 6 , CF 3 , acetyl, SCH 3 ,
S(=O)CH
3 , S(=0)2CH 3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, and C1-C 4 haloalkyl-S-; 5 Y is a bond or -(CR 9
R
9 a)t-V-(CR 9
R
9 a)u-; t is 0, 1, or 2; 10 u is 0, 1, or 2;
R
9 and R 9 a, at each occurrence, are independently selected from H, F, methyl, and ethyl; 15 V is a bond, -C(=O)-, -0-, -S-, -S(=O)-, -S(=0) 2 -,
-N(R
1 9 )-, -NHC(=O)-, or -C(=0)NH-; Z is H, F, Cl, Br; Ci-C 4 alkyl substituted with 0-2 R1 2 ; 20 C 2
-C
4 alkenyl substituted with 0-2 R1 2 ;
C
2
-C
4 alkynyl substituted with 0-2 R1 2 ;
C
6 -Cio aryl substituted with 0-4 R12b;
C
3
-C
6 carbocycle substituted with 0-4 R1 2 b; or 5 to 6 membered heterocycle containing 1 to 4 25 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R1 2 b;
R
1 l, at each occurrence, is independently selected from 30 H, =0, NR 1 8
R
19 , C(=O)R1 7 , C(=O)OR 1 7 , C(=O)NR1 8
R
1 9 , S(=0) 2 NR1 8
R
1 9 , CF 3 ; Ci-C 6 alkyl substituted with 0-1 R11a; phenyl substituted with 0-3 R11b;
C
3
-C
6 carbocycle substituted with 0-3 R11b; or -30- WO 01/19797 PCT/USOO/24967 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R11b; 5
R
11 a, at each occurrence, is independently selected from H, Ci-C 4 alkyl, OR 1 4 , Cl, F, Br, =0, CN, NO 2 , NR 1 5
R
1 6 ,
CF
3 ; phenyl substituted with 0-3 R11b; 10 C 3
-C
6 carbocycle substituted with 0-3 R11b; or 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R11b; 15 R11b, at each occurrence, is independently selected from H, OH, Cl, F, Br, CN, NO 2 , NR 15 R1 6 , CF 3 , acetyl, SCH 3 ,
S(=O)CH
3 , S(=0) 2
CH
3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, C 1
-C
4 haloalkoxy, and Ci-C 4 haloalkyl-S-; 20
R
12 at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 1 5
R
1 6 , -C(=O)NR 1 5 R1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2
CH
3 , Ci-C6 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, and C 1
-C
4 25 haloalkyl-S-;
C
6 -Cio aryl substituted with 0-4 R12b;
C
3
-C
1 o carbocycle substituted with 0-4 R12b; or 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and 30 sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R1 2 b; R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 1 5
R
1 6 , CF 3 , acetyl, SCH 3 , -31- WO 01/19797 PCT/USOO/24967
S(=O)CH
3 , S(=O) 2
CH
3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, C 1
-C
4 haloalkyl, Ci-C 4 haloalkoxy, and Ci-C 4 haloalkyl-S-;
R
13 , at each occurrence, is independently selected from H, 5 OH, Ci-C 6 alkyl, C 1
-C
4 alkoxy, Cl, F, Br, I, CN, NO 2 ,
NR
1 5
R
1 6 , and CF 3 ;
R
14 , at each occurrence, is independently selected from H, phenyl, benzyl, Ci-C 6 alkyl, and C 2
-C
6 alkoxyalkyl; 10
R
15 , at each occurrence, is independently selected from H, Ci-C 6 alkyl, phenyl, benzyl, phenethyl, (Ci-C 6 alkyl) C (=O) -, (Ci-C 6 alkyl) -O-C (=O) - and (Ci-C 6 alkyl) S (=0)2-; 15 R1 6 , at each occurrence, is independently selected from H, OH, Ci-C 6 alkyl, phenyl, benzyl, phenethyl, (Ci-C 6 alkyl)-C(=O)-, (Ci-C 6 alkyl)-O-C(=O)- and (Ci-C 6 alkyl) -S(=0)2-; 20 alternatively, -NR 15
R
16 may be a heterocyclic ring selected from the group piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, homopiperidinyl, piperazinyl, and N-methylpiperizinyl; and 25
R
17 is H, aryl, aryl-CH 2 -, Ci-C 6 alkyl, or C 2
-C
6 alkoxyalkyl;
R
18 , at each occurrence, is independently selected from H, 30 Ci-C 6 alkyl, phenyl, benzyl, phenethyl, (Ci-C 6 alkyl) C(=O)- and (Ci-C 6 alkyl)-S(=0) 2 -; alternatively, -NR1 8 R1 9 may be a heterocyclic ring selected from the group piperidinyl, morpholinyl, -32- WO 01/19797 PCT/USOO/24967 thiomorpholinyl, pyrrolidinyl, homopiperidinyl, piperazinyl, and N-methylpiperizinyl; and
R
19 , at each occurrence, is independently selected from H, 5 OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl. [5] In a preferred embodiment the present invention provides a compound of Formula (Ia) wherein: 10 Q is Q'; Q1 is Ci-C 6 alkyl substituted with 0-3 R 1 a. C2-C6 alkenyl substituted with 0-3 Ra; 15 C 2
-C
6 alkynyl substituted with 0-3 Ria; C3-C1 cycloalkyl substituted with 0-3 Rb.
C
3 -Cio carbocycle substituted with 0-3 Rib;
C
6
-C
1 0 aryl substituted with 0-3 Rib; or 5 to 10 membered heterocycle containing 1 to 4 20 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 Rib.
R
1 a, at each occurrence, is independently selected from H, 25 Ci-C 6 alkyl, OR 14 , Cl, F, Br, I, NR 1 5
R
1 6 , CF 3 ;
C
3
-C
1 o carbocycle substituted with 0-3 Rib;
C
6
-C
10 aryl substituted with 0-3 Rib; and 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and 30 sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 Rib. Rib, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 1 5
R
1 6 , CF 3 , acetyl, SCH 3 , 35 S(=O)CH 3 , S(=0) 2
CH
3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 -33- WO 01/19797 PCT/USOO/24967 haloalkyl, Ci-C 4 haloalkoxy, Ci-C 4 haloalkyl-S-, and (Ci-C 6 alkyl)-O-C(=O)-;
R
2 is H, methyl, or ethyl; 5
R
5 is H, OR 14 ; Ci-C 6 alkyl substituted with 0-3 R5b;
C
2
-C
6 alkenyl substituted with 0-3 R5b; or
C
2
-C
6 alkynyl substituted with 0-3 R 5 b; 10
R
5 a is H, methyl, ethyl, propyl, butyl, or C 2
-C
4 alkenyl; alternatively, R 5 and R 5 a may be combined to form a C 4
-C
7 cycloalkyl ring; 15 R5b, at each occurrence, is independently selected from: H, methyl, ethyl, propyl, butyl, CF 3 , OR 14 , Cl, F, Br, I, =0, NRi 5
R
1 6 ,
C
3
-C
7 cycloalkyl substituted with 0-3 R 5 c; 20 C 3
-C
7 carbocycle substituted with 0-3 R 5 c. phenyl substituted with 0-3 R 5 c; and 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle 25 is substituted with 0-3 R 5 c;
R
5 c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 1 5
R
1 6 , CF 3 , acetyl, SCH 3 ,
S(=O)CH
3 , S(=0) 2
CH
3 , Ci-C 4 alkyl, Ci-C 3 alkoxy, Ci-C 2 30 haloalkyl, and Ci-C 2 haloalkoxy; W is -(CHR 8 )pp is 0 or 1; 35
R
8 is H, methyl, or ethyl; -34- WO 01/19797 PCT/USOO/24967 X is a bond; phenyl substituted with 0-2 RXb;
C
5
-C
6 cycloalkyl substituted with 0-3 Rxb; or 5 to 6 membered heterocycle containing 1 to 3 5 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-2 RXb; Rxb, at each occurrence, is independently selected from H, 10 OH, Cl, F, Br, I, CN, NO 2 , NR 1 5
R
1 6 , CF 3 , acetyl, SCH 3 ,
S(=O)CH
3 , S(=0) 2
CH
3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, and Ci-C 4 haloalkyl-S-; Y is a bond, -V-, -CH 2 -V-, -V-CH 2 -, or -CH 2
-V-CH
2 -; 15 V is a bond, -C(=O)-, -0-, -S-, -S(=O)-, -S(=0) 2 -, or -N(R1 9 ) -; Z is H, F, Cl, Br, 20 Cl-C 4 alkyl substituted with 0-2 R1 2 ;
C
2
-C
4 alkenyl substituted with 0-2 R1 2 ;
C
2
-C
4 alkynyl substituted with 0-2 R1 2 ;
C
6
-C
1 0 aryl substituted with 0-4 R1 2 b;
C
3
-C
6 carbocycle substituted with 0-4 R1 2 b; or 25 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 R12b; 30 R 11 , at each occurrence, is independently selected from H, =0, NR1 8
R
19 , C(=O)R 1 7 , C(=O)OR1 7 , C(=O)NR1 8 R1 9 , S(=0) 2
NR
1 8 R1 9 , CF 3 ; Ci-C 6 alkyl substituted with 0-1 R11a; phenyl substituted with 0-3 R11b; 35 C 3
-C
6 carbocycle substituted with 0-3 R11b; or -35- WO 01/19797 PCT/USOO/24967 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R11b; wherein said 5 to 7 5 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl; 10
R
11 a, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Cl, F, =0, NR 1 5
R
1 6 , CF 3 ; phenyl substituted with 0-3 R11b; 15 C 3
-C
6 carbocycle substituted with 0-3 R11b; or 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R11b; wherein said 5 to 7 20 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl; 25 R11b, at each occurrence, is independently selected from H, OH, Cl, F, NR 15
R
1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2
CH
3 , methyl, ethyl, propyl, butyl, methoxy, 30 ethoxy, propoxy, Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy; R1 2 at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 1 5
R
1 6 , -C(=O)NR1 5 R1 6 , CF 3 , 35 acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2
CH
3 , C 1
-C
6 alkyl, Ci-C 4 -36- WO 01/19797 PCT/USOO/24967 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, and C 1
-C
4 haloalkyl-S-;
C
6 -Cio aryl substituted with 0-4 R12b;
C
3
-C
1 o carbocycle substituted with 0-4 R1 2 b; or 5 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 Ri 2 b; 10 Ri2b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 15
R
1 6 , CF 3 , acetyl, SCH 3 ,
S(=O)CH
3 , S(=0) 2
CH
3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, and Ci-C 4 haloalkyl-S-; 15 R 13 , at each occurrence, is independently selected from H, OH, Ci-C 6 alkyl, Ci-C 4 alkoxy, Cl, F, Br, I, CN, NO 2 ,
NR
1 5
R
1 6 , and CF 3 ;
R
14 , at each occurrence, is independently selected from H, 20 phenyl, benzyl, Ci-C 4 alkyl, and C 2
-C
4 alkoxyalkyl;
R
15 , at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; 25
R
16 , at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, phenethyl, CH 3
CH
2 C(=O)-, CH 3 C(=O)-, CH3CH 2 0C(=O)-,
CH
3 0C(=O)-, CH 3
CH
2 S(=0) 2 - and CH 3 S(=0) 2 -; 30
R
1 7 is H, phenyl, benzyl, C 1
-C
4 alkyl, or C 2
-C
4 alkoxyalkyl; R1 8 , at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and 35 phenethyl; and -37- WO 01/19797 PCT/USOO/24967 R1 9 , at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, and butyl. 5 [7] In a preferred embodiment the present invention provides a compound of Formula (Ia) wherein: Q is Q1, 10 Q 1 is Ci-C 6 alkyl substituted with 0-3 Ria;
C
2
-C
6 alkenyl substituted with 0-3 Ria;
C
2
-C
6 alkynyl substituted with 0-3 Ria;
C
3
-C
6 cycloalkyl substituted with 0-3 Rib; phenyl substituted with 0-3 Rib; or 15 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 Rib; 20 Ria, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, OR1 4 , Cl, F, Br, I,
NR
1 5
R
1 6 , CF 3 ;
C
3
-C
6 carbocycle substituted with 0-3 Rib; phenyl substituted with 0-3 Rib; and 25 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 Rib; 30 Rib, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 1 5
R
1 6 , CF 3 , acetyl, SCH 3 ,
S(=O)CH
3 , S(=0) 2
CH
3 , methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Ci-C 2 haloalkyl, C 1
-C
2 haloalkoxy, (methyl)OC(=O)-, (ethyl)OC(=o)-, 35 (propyl)OC(=O)-, and (butyl)OC(=O)-; -38- WO 01/19797 PCT/USOO/24967
R
2 is H or methyl;
R
5 is H, OR14 5 Cl-C 4 alkyl substituted with 0-1 R5b;
C
2
-C
4 alkenyl substituted with 0-1 R 5 b; or
C
2
-C
4 alkynyl substituted with 0-1 R 5 b;
R
5 a is H, methyl, ethyl, propyl, or butyl; 10 alternatively, R 5 and R 5 a may be combined to form a cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl ring; 15 R5b, at each occurrence, is independently selected from: H, methyl, ethyl, propyl, butyl, CF 3 , OR 1 4 , Cl, F, =0, NR1 5
R
1 6 ,
C
3
-C
7 cycloalkyl substituted with 0-3 R 5 c;
C
3
-C
7 carbocycle substituted with 0-3 R 5 c; 20 phenyl substituted with 0-3 R 5 c; and 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R 5 c; wherein said 5 to 7 25 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl; 30
R
5 c, at each occurrence, is independently selected from H, OH, Cl, F, NR 1 5
R
1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2
CH
3 , methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Ci-C 2 haloalkyl, and Ci-C 2 35 haloalkoxy; W is a bond, -CH 2 -, or -CH(CH 3 )-; -39- WO 01/19797 PCT/USOO/24967 X is a bond; phenyl substituted with 0-1 RXb;
C
5
-C
6 cycloalkyl substituted with 0-1 RXb; or 5 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 0-1 RXb; wherein said 5 to 6 membered heterocycle is selected from pyridinyl, 10 pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, and isoxazolyl; RXb, at each occurrence, is independently selected from 15 H, OH, Cl, F, Br, NR 1 5
R
1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2
CH
3 , methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy; 20 Y is a bond, -V-, -V-CH 2 -, or -CH 2 V-; V is a bond, -C(=O)-, -0-, -S-, -S(=O)-, -S(=0) 2 -, or
-N(R
19 ) -; 25 Z is H, F, Cl, Br, Ci-C 4 alkyl substituted with 0-2 R1 2 ;
C
2
-C
4 alkenyl substituted with 0-2 R1 2 ;
C
2
-C
4 alkynyl substituted with 0-2 R1 2 ;
C
6 -Cio aryl substituted with 0-4 R1 2 b; 30 C 3
-C
6 carbocycle substituted with 0-4 R12b; 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 R1 2 b; 35 -40- WO 01/19797 PCT/USOO/24967
R
11 , at each occurrence, is independently selected from H, NR 1 8
R
1 9 , CF 3 ; Ci-C 4 alkyl substituted with 0-1 R11a; phenyl substituted with 0-3 R11b; 5 C 3
-C
6 carbocycle substituted with 0-3 R11b; or 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R11b; wherein said 5 to 7 10 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl; 15
R
11 a, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Cl, F, =0, NR 1 5
R
1 6 , CF 3 ; phenyl substituted with 0-3 R11b; 20 C 3
-C
6 carbocycle substituted with 0-3 R11b; or 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R11b; wherein said 5 to 7 25 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl; 30 R11b, at each occurrence, is independently selected from H, OH, Cl, F, NR 1 5
R
1 6 , CF 3 , methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C 2 haloalkyl, and Ci-C 2 35 haloalkoxy; -41- WO 01/19797 PCT/USOO/24967
R
12 at each occurrence, is independently selected from H, OH, Cl, F, Br, NR1 5
R
1 6 , -C(=O)NR1 5
R
1 6 , CF 3 , acetyl,
SCH
3 , S(=O)CH 3 , S(=0)2CH 3 , methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C 1
-C
2 haloalkyl, and 5 Cl-C 2 haloalkoxy; phenyl substituted with 0-4 R12b;
C
3
-C
6 carbocycle substituted with 0-4 R1 2 b; or 5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and 10 sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R1 2 b; R1 2 b, at each occurrence, is independently selected from H, OH, Cl, F, Br, NR 1 5
R
1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH 3 , 15 S(=0) 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, 20 OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Cl, F, Br, CN, NR 15
R
1 6 , and CF 3 ;
R
14 , at each occurrence, is independently selected from H, phenyl, benzyl, methyl, ethyl, propyl, and butyl; 25
R
15 , at each occurrence, is independently selected from H, methyl, ethyl, propyl, or butyl; R1 6 , at each occurrence, is independently selected from H, 30 OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
R
18 , at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl and, 35 phenethyl; and -42- WO 01/19797 PCT/USOO/24967 R1 9 , at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl and, phenethyl. 5 [8] In a preferred embodiment the present invention provides a compound of Formula (Ia) wherein: Q 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
2
CH
2
CH
3 , -CH 2
CH
2
CH
2
CH
2
CH
2
CH
3 , -CH(CH 3 )2, 10 -CH(CH 3
)CH
2
CH
3 , -CH 2
CH(CH
3
)
2 , -CH 2
C(CH
3
)
3 , -CF3, -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=C(CH
3
)
2 , 15 -CH 2
CH
2
CH=CH
2 , -CH 2
CH
2
C(CH
3
)=CH
2 , -CH 2
CH
2
CH=C(CH
3 )2, cis-CH 2
CH=CH(CH
3 ), cis-CH 2
CH
2
CH=CH(CH
3 ), trans-CH 2
CH=CH(CH
3 ), trans-CH 2
CH
2
CH=CH(CH
3 ); -C=CH, -CH 2 CECH, -CH 2
C=C(CH
3 ), 20 cyclopropyl-, cyclobutyl-, cyclopentyl-, cyclohexyl-, 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 -, 25 phenyl-, 2-F-phenyl-, 3-F-phenyl-, 4-F-phenyl-, 4-methoxyphenyl-,4-ethoxyphenyl-, 4-propoxyphenyl-, 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 -, 30 (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 -, 35 (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 -, -43- WO 01/19797 PCT/USOO/24967 (3-F-4-Cl-phenyl)CH 2 -, (3-F-5-C1-phenyl)CH 2 -, (3-Cl-4-F-phenyl) CH 2 -, 2-furanyl-CH 2 -, 3-furanyl-CH 2 -, 2-thienyl-CH 2 -, 5 3-thienyl-CH 2 -, 2-pyridyl-CH 2 -, 3-pyridyl-CH 2 -, 4-pyridyl-CH 2 -, 1-imidazolyl-CH 2 -, 2-oxazolyl-CH 2 -, 4-oxazolyl-CH 2 -, 5-oxazolyl-CH 2 -, 3-isoxazolyl-CH 2 -, 4-isoxazolyl-CH 2 -, 5-isoxazolyl-CH 2 -, 10 phenyl-CH 2
CH
2 -, (2-F-phenyJ4CH 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-C1-phenyl)CH 2
CH
2 -, (4-Ci-phenyl) CH 2
CH
2 -, (2,3-diF-phenyl)CH 2
CH
2 -, (2,4-diF-phenyl)CH 2
CH
2 -, 15 (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 -, 20 (3-F-4-C1-phenyl)CH 2
CH
2 -, (3-F-5-C1-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 -, isoxazolyl-CH 2
CH
2 -, 3,5-dimethylisoxazol-4-yl-CH 2
CH
2 -, 25 phenyl-propyl-; benzyl-CH(NH 2 )-, benzyl-CH(NHC(=O)-O-tBu) -, benzyloxy-CH 2 -, pyrrolidin-2-yl-, or 3 -t-butoxycarbonylpyrrolidin-2 -yl -; 30
R
2 is H or methyl;
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 , 35 -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 CH3,
-CH
2
CH
2 CH (CH 3 ) 2, -CH (CH 2
CH
3 ) 2 ,
-CF
3 . -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 , -44- WO 01/19797 PCT/USOO/24967
-CH=CH
2 , -CH 2
CH=CH
2 , -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-CI- 2
CH=CHCH
2
CH
3 , 5 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 ), -CMCH, -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 ), 10 -CH 2
CH
2
CH
2 C=-CH, -CH 2
CH
2
CH
2 C=C (CH 3 ) , -CH 2
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 -, 15 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 -, 20 (4-F-phenyl)CH 2 -, (3,5-diF-phenyl)CH 2 -, 2-furanyl-CH 2 -, 3-furanyl-CH 2 -, 2-thienyl-CH 2 -, 3-thienyl-CH 2 -, 2 -pyridyl-CH 2 -, 3 -pyridyl -CH 2 -, 4-pyridyl-CH 2 -, 1-imidazolyl-CH 2 -, 2-oxazolyl-CH 2 -, 4-oxazolyl-CH 2 -, 5-oxazolyl-CH 2 -, 3-isoxazolyl-CH 2 -, 25 4-isoxazolyl-CH 2 -, 5-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 -, 30 isoxazolyl-CH 2
CH
2 -; methoxy, ethoxy, propoxy, or butoxy;
R
5 a is H; 35 alternatively, R 5 and R 5 a may be combined to form cyclopentyl, cyclohexyl, or cycloheptyl; -45- WO 01/19797 PCT/USOO/24967 W is a bond, -CH 2 -, or -CH(CH3)-; X is a bond; 5 50NN ; or N Y is a bond, -CH 2 -V-, -V-, or -V-CH 2 -; 10 V is a bond, -C(=O)-, -0-, -S-, -S(=0)-, -S(=0)2-, -NH-, or
-N(CH
3 ) -; Z is H, F, Cl, Br, methyl, ethyl, n-propyl, i-propyl, n 15 butyl, i-butyl, s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 20 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, 25 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 0-phenyl, 3-CF 3 O-phenyl, 4-CF 3 0-phenyl, 30 furanyl, thienyl, pyridyl, 2-Me-pyridyl, 3-Me-pyridyl, 4-Me-pyridyl, 1-imidazolyl, oxazolyl, isoxazolyl, 1-benzimidazolyl, morpholino, N-piperinyl, 35 phenyl-CH 2 -, (2-F-phenyl)CH 2 -, (3-F-phenyl)CH 2 -, -46- WO 01/19797 PCT/USOO/24967 (4-F-phenyl)CH 2 -, (2-C1-phenyl)CH 2 -, (3-C1-phenyl)CH 2 -, (4-C1-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 -, 5 (3,5-diF-pheiyl)CH 2 -, (2,3-diCl-phenyl)CH 2 -, (2,4-diCl-phenyl)CH 2 -, (2,5-diCl-phenyl)CH 2 -, (2,6-diCl-pheiyl)CH 2 -, (3,4-diCl-phenyl)CH 2 -, (3,5-diCl-phenyl)CH 2 -, (3-F-4-C1-phenyl)CH 2 -, (3-F-5-C1-phenyl)CH 2 -, (3-C1-4-F-phenyl)CH 2 -, 10 (2-MeO-phenyl)CH 2 -, (3-MeO-phenyl)CH 2 -, (4-MeO-phenyl) CH 2 -, (2-Pho-phenyl) CH 2 -, (3-PhO-phenyl)CH 2 -, (4-Pho-phenyl)CH 2 -, (2-Me-phenyl)CH 2 -, (3-Me-phenyl)CH 2 -, (4-Me-phenyl)CH 2 -, (2-MeS-phenyl) CH 2 -, 15 (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-CF3O-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 -, 20 (isoxazolyl)CH 2 -, (1-benzimidazolyl)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 -, 25 (3-F-phenyl)CH 2
CH
2 -, (4-F-phenyl)CH 2
CH
2 -, (2-C1-phenyl)CH 2
CH
2 -, (3-C1-phenyl)CH 2
CH
2 -, (4-C1-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 -, 30 (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-C1-phenyl)CH 2
CH
2 -, (3-F-5-C1-phenyl)CH 2
CH
2 -, (3-C1-4-F-phenyl)CH 2
CH
2 -, 35 (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 -, -47- WO 01/19797 PCT/USOO/24967 (4-MeS-phenyl)CH 2
CH
2 -, (2-CF 3 0-phenyl)CH 2
CH
2 -, (3-CF 3 0-phenyl)CH 2
CH
2 -, (4-CF 3 0-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 -, 5 (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 10 (N-pipridinyl)CH 2
CH
2 -;
R
11 , at each occurrence, is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s butyl, t-butyl, phenyl, benzyl, phenethyl, cyclopropyl, 15 cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, 2-F-phenyl-, 3-F-phenyl, 4-F-phenyl, 4-Cl-phenyl, 4-CH 3 20 phenyl, 4-MeO-phenyl-, 4-CF 3 -phenyl, (4-F-phenyl)CH 2 -, (4-Cl-phenyl)CH 2 -, (4-CH 3 -phenyl)CH 2 -, (4-CF 3 -phenyl)CH 2 -, (4-F-phenyl)CH 2
CH
2 -, (4-Cl-phenyl)CH 2
CH
2 -, (4-CH 3 -phenyl)CH 2
CH
2 -, (4-CF 3 -phenyl)CH 2
CH
2 -, pyridin-2-yl-, pyridin-3-yl-, 25 4-CF 3 -pyridin-2-yl-, 4-CH 3 -pyridin-2-yl-, thiazol-2-yl-, azapan-1-yl, N,N-dimethylamino, N,N-diethylamino, N,N dipropylamino, and N,N-dibutylamino; and
R
13 , at each occurrence, is independently selected from H, 30 MeO, F, and Cl. [9] In a preferred embodiment the present invention provides a compound of Formula of Formula (Ic); R5 R 5 aH O RQ) N NW-X-Y-Z OH O 35 R' -48- WO 01/19797 PCT/USOO/24967 (Ic) or a pharmaceutically acceptable salt form or prodrug thereof. 5 [10] In a preferred embodiment the present invention provides a compound of Formula (Id); R5 RaH O RQ N 2>N'W-X-Y-Z OH 0 N\
R
13 (Id) 10 or a pharmaceutically acceptable salt form or prodrug thereof. [111 In a preferred embodiment the present invention provides a compound of Formula (Ie): 15 R5 RaH O RQ Y>S N NW-X-Y-Z OH O R13 R1\'
/-R
1 (Ie) or a pharmaceutically acceptable salt form or prodrug thereof. 20 [12] In a preferred embodiment the present invention provides a compound selected from: 3-(2(R)-Cyclopentylmethyl-3(S)-hydroxyl-l-oxo-5 25 phenylpentyl) amino-l-methyl- 5-phenyl-2, 3-dihydro-lH-1, 4 benzodiazepin-2-one; 3-(2(R)-Cyclopentylmethyl-3(S)-hydroxyl-l-oxo-5 phenylpentyl)amino-l-methyl-5-(4-fluoro-phenyl)-2,3 30 dihydro-lH-1, 4-benzodiazepin-2-one; -49- WO 01/19797 PCT/USOO/24967 3-(2(R)-Benzyl-3(S)-hydroxyl-1-oxo-5-phenylpentyl)amino-1 methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one; 5 3-(2(R)-Isopropyl-3(S)-hydroxyl-1-oxo-5-phenylpentyl)amino 1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one; 3-(2(R)-Cyclopentylmethyl-3(S)-hydroxyl-1-oxo-4-(3,5 difluorophenoxy)butyl)amino-1-methyl-5-phenyl-2,3-dihydro 10 1H-1,4-benzodiazepin-2-one; 3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-4-(3,5 difluorophenoxy)butyl)amino-1-methyl-5-phenyl-2,3-dihydro 1H-1,4-benzodiazepin-2-one; 15 3-(2(R)-Cyclopentylmethyl-3(S)-hydroxyl-1-oxo-4 phenoxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro 1H-1,4-benzodiazepin-2-one; 20 3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-4-phenoxybutyl)amino 7-chloro-1-methyl-5-(4-fluorophenyl)-2,3-dihydro-1H-1,4 benzodiazepin-2-one; 3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-4 25 cyclohexyloxybutyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H 1,4-benzodiazepin-2-one; 3-(2(R)- Isobutyl -3(S)-hydroxyl-1-oxo-4 cyclohexyloxybutyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H 30 1,4-benzodiazepin-2-one; 3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-4-phenoxybutyl)amino-7 chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin 2-one; 35 -50- WO 01/19797 PCT/USOO/24967 3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-4-phenoxybutyl)amino 7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one; 5 3-(2(R)-Benzyl-3(S)-hydroxyl-1-oxo-4 cyclohexyloxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3 dihydro-1H-1,4-benzodiazepin-2-one; 3-(2(R)-Cyclopentylmethyl-3(S)-hydroxyl-1-oxo-4 10 cyclohexyloxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3 dihydro-lH-1,4-benzodiazepin-2-one; 3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-4 cyclohexyloxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3 15 dihydro-1H-1,4-benzodiazepin-2-one; 3-(2(R)-Isopropyl-3(S)-hydroxyl-1-oxo-4 cyclohexyloxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3 dihydro-1H-1,4-benzodiazepin-2-one; 20 3-(2(R)-Methoxy-3(S)-hydroxyl-1-oxo-4-(4 trifluoromethylbenzyloxy)butyl)amino-7-chloro-1-methyl-5 phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one; 25 3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-4-(2,4 difluorobenzyloxy)butyl)amino-7-chloro-1-methyl-5-phenyl 2,3-dihydro-1H-1,4-benzodiazepin-2-one; 3-(2(R)-Vinyl-3(S)-hydroxyl-1-oxo-4-benzyloxybutyl)amino-7 30 chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin 2-one; 3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-4 cyclohexyloxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3 35 dihydro-lH-1,4-benzodiazepin-2-one; -51- WO 01/19797 PCT/USOO/24967 3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-5- phenylpentyl)amino 1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one; 3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-3 5 cyclopropylpropyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H 1,4-benzodiazepin-2-one; 3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-heptyl)amino-1-methyl 5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one; 10 3-(R)-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-heptyl)amino-1 methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one; 3-(S)-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-heptyl)amino-1 15 methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one; 3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-nonyl)amino-1-methyl 5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one; 20 3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-hexyl)amino-1-methyl 5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one; 3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-4- phenylbutyl)amino 1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one; 25 3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-5- phenylpentyl)amino-1 methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one; 3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-6- phenylhexyl)amino-1 30 methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one; 3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-butyl)amino-i-methyl 5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one; 35 3-(2(R)-Isobutyl-3(S)-hydroxyl-l-oxo-octyl)amino-1-methyl 5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one; -52- WO 01/19797 PCT/USOO/24967 3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-heptyl)amino-1-methyl-5 phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one; 3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-3- phenylpropyl)amino-1 5 methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one; 3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-5,5-dimethyl hexyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one; 10 3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-hexyl)amino-1-methyl-5 phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one; 3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-3-(4 15 propoxyphenyl)propyl)amino-1-methyl-5-phenyl-2,3-dihydro 1H-1,4-benzodiazepin-2-one; 2-(R)-cyclopropylmethyl-3-(S)-hydroxylheptanoic acid (2 oxo-1-(3-phenoxybenzyl)azapan-3-(S)-yl) amide; 20 2(R)-cyclopropylmethyl-5-(3,5-difluorophenyl)-3-(S) hydroxypentanoic acid (2-oxo-1-(3-phenoxybenzyl)azapan-3 (S) -yl)amide; 25 4-cyclopentyl-2-(R)-cyclopropylmethyl-3-(S)-hydroxybutanoic acid (2-oxo-1-(3-phenoxybenzyl)azapan-3-(S)-yl) aide; 2-(R)-cyclopropylmethyl-3-(S)-hydroxyheptanioc acid (1-(5 bromo-3-pyridinyl)methyl-2-oxo-azapan-3-(S)-yl) amide; 30 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-5-(2-fluorophenyl)-1-methyl-2,3-dihydro-1H 1,4-benzodiazepin-2-one; 35 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-5-(azapan-1-yl)-1-methyl-2,3-dihydro-1H 1,4-benzodiazepin-2-one; -53- WO 01/19797 PCT/USOO/24967 3-(2-(R)-cyclopropylmethyl-5-(3,5-difluorophenyl)-3(S) hydroxyl-1-oxopentyl)amino-1-methyl-5-(pyridn-2-yl)-2,3 dihydro-1H-1,4-benzodiazepin-2-one; 5 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxopentyl)amino-1-methyl-5-(4-chlorophenyl)-2,3-dihydro-1H 1,4-benzodiazepin-2-one; 10 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-5-(4-methoxyphenyl)1-methyl-2,3-dihydro-1H 1,4-benzodiazepin-2-one; 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 15 oxoheptyl)amino-5-(4-methoxyphenyl)-1-methyl-2,3-dihydro 1H-1,4-benxodiazepin-2-one; 3-(S)-(4-cyclopentyl-2-(R)-cyclopropylmethyl-3-(S) hydroxyl-1-oxobutyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H 20 1,4-benzodiazepin-2-one; 3-(S)-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxohept-6 enyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one; 25 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxohept-6 enyl)amino-1-methyl-5-(4-trifluoromethyl-phenyl)-2,3 dihydro-1H-1,4-benzodiazepin-2-one; 30 3-(S)-(2-(R)-cyclopropylmethyl-5-(3,5-dimethylisoxazol-4 yl)-3-(S)-hydroxyl-1-oxopentyl)amino-1-methyl-5-phenyl-2,3 dihydro-1H-1,4-benzodiazepin-2-one; 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 35 oxoheptyl)amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H 1,4-benzodiazepin-2-one; -54- WO 01/19797 PCT/USOO/24967 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-1-methyl-(pyridin-2-yl)-2,3-dihydro-1H-1,4 benzodiazepin-2-one; 5 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-5-(4-fluorophenyl)-1-methyl-2,3-dihydro-1H 1,4-benzodiazepin-2-one; 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 10 oxoheptyl)amino-1-methyl-5-(4-trifouoromethylphenyl)-2,3 dihydro-1H-1,4-benzodiazepin-2-one; 3-(5-cyclopentyl-2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxopentyl)amino-1-methyl-5-(pyridin-2-yl)-2,3-dihydro-1H 15 1,4-benzodiazepin-2-one; 3-(2-(R)-iso-butyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1 methyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4 benzodiazepin-2-one; 20 3-(S)-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxo-5 (thiophen-2-yl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one; 25 3-(S)-(2-(R)-cyclopropylmethyl-5-(furan-2-yl)3-(S) hydroxyl-1-oxopentyl)amino-1-methyl-5-phenyl-2,3-dihydro 1H-1,4-benzodiazepin-2-one; 3-(5-cyclopentyl-2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 30 oxopentyl)amino-5-(4-fluorophenyl)-1-methyl-2,3-dihydro-1H 1,4-benzodiazepin-2-one; 3-(S)-(2-(R)-cyclopropylmethyl-5-(3,5-difluorophenyl)-3 (S)-hydroxy-1-oxopentyl)amino-1-methyl-5-phenyl-2,3 35 dihydro-1H-1,4-benzodiazepin-2-one; -55- WO 01/19797 PCT/USOO/24967 3-(S)-(3-(S)-hydroxyl-2-(R)-(thiophen-2-yl)methyl-1 oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one; 5 3-(S)-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-7-methyl-5-phenyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one; 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 10 oxoheptyl)amino-7-methoxy-1-methyl-5-phenyl-2,3-dihydro-1H 1,4-benzodiazepin-2-one; 3-(S)-(2-(R)-cyclobutylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4 15 benzodiazepin-2-one; 3-(S)-(2-(R)-(3,5-difluorobenzyl)-3-(S)-hydroxyl-1 oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydor-1H-1,4 benzodiaxepin-2-one; 20 3-(S)-(2-(R)-(furan-2-yl)methyl-3-(S)-hydroxyl-1 oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one; 25 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxl-1-oxo-5 pheylpentyl)amino-1-methyl-5-(pyridin-2-yl)-2,3-dihydro-1H benzodiazepin-2-one; 3-(2-(R)-iso-butyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-(4 30 fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2 one; 3-(2-(R)-iso-butyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-(4 fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2 35 one; -56- WO 01/19797 PCT/USOO/24967 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxo-5 phenylpentyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one; 5 3-(2-(R)-cyclopropylmethyl-5-(furan-2-yl)-3-(S)-hydroxyl-1 oxopentyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3 dihydro-1H-1,4-benzodiazepin-2-one; 10 3-(5-cyclopentyl-2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxopentyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3 dihydro-1H-1,4-benzodiazepin-2-one; 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxooctyl)amino 15 1-methyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4 benzodiazepin-2-one; 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxononyl)amino 1-methyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4 20 benzodiazepin-2-one; 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-1-methyl-5-(4-trifluoromethyl(pyridin-2 yl))-2,3-dihydro-1H-1,4-benzodiazepin-2-one; 25 3-(2-(R)-cyclobutylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino 1-methyl-5-(40trifluoromethylphenyl)-2,3-dihydro-1H-1,4 benzodiazepin-2-one; 30 3-(2-(R)-cyclopentylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3 dihydro-1H-1,4-benzodiazepin-2-one; 35 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-1-methyl-5-(4-methyl-2-pyridiyl)-2,3 dihydro-1H-1,4-benzodiazepin-2-one; -57- WO 01/19797 PCT/USOO/24967 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-1-methyl-5-(4-methyl-2-pyridyl)-2,3 dihydro-1H-1,4-benzodiazepin-2-one; 5 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxobutyl)amino 1-methyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4 benzodiazepin-2-one; 10 3-(S)-(2-(R)-(3-butenyl)-3-(S)-hydroxyl-1-oxoheptyl)amino 1-methyl-5-phenyl-2,3-dihydro-lH-1,4-benzodiazepin-2-one; 3-(S)-(2-(R)-(3-methylbutyl)3-(S)-hydroxyl-1 oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydro-lH-1,4 15 benzodiazepin-2-one; 3-(S)-(2-(R)-ethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1 methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one; 20 3-(S)-(2-(R)-propyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1 methyl-5-phenyl-2,3-dihydro-1,4-benzodiazepin-2-one; 3-(S)-(2-(R)-butyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1 methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one; 25 3-(4-(S)-amino-3-(R)-hydroxyl-2-(R)-methyl-1-oxo-5 phenylpentyl)amino-7-chloro-5-(2-fluorophenyl)-1-methyl 2,3-dihydro-1H-1,4-benzodiazepin-2-one; 30 3-(4-(S)-(tert-butoxycarbonylamino-3-(R)-hydroxyl-2-(R) methyl-1-oxo-5-phenylpentyl)amino-7-chloro-5-(2 fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2 one; 35 3-(3-(tert-butoxycarbonylpyrrolidin-2-(R)-yl)-3-(R) hydroxyl-2-(R)-methyl-1-oxopropyl)amino-7-chloro-5-(2 -58- WO 01/19797 PCT/USOO/24967 fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2 one; 3-(3-(R)-hydroxyl-2-(R)-methyl-1-oxo-3-(pyrrolidin-2-(R) 5 yl)propyl)-amino-7-chloro-5-(2-fluorophenyl)-1-methyl-2,3 dihydro-1H-1,4-benzodiazepin-2-one; 3-(4-benzyloxy-3-(R)-hydroxyl-2-(R)-iso-propyl-1-oxobutyl amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4 10 benzodiazepin-2-one; 2-(4-(S)-amino-3-(S)-hydroxyl-2-(S)-methyl-1-oxo-5 phenylpentyl)amino-7-chloro-5-(2-flourophenyl)-1-methyl 2,3-dihydro-1H-1,4-benzodiazepin-2-one; 15 2-(4-(S)-(tert-butoxycarbonylamino-3-(S)hydroxyl-2-(S) methyl-1-oxo-5-phenylpentyl)amino-7-chloro-5-(2 fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2 one; 20 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-1-methyl-5-(thiazol-2-yl)-2,3-dihydro-1H 1,4-benzodiazepin-2-one; 25 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-1-cyclopropylmethyl-5-(thiazol-2-yl)-2,3 dihydro-1H-1,4benzodiazepin-2-one; 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 30 oxoheptyl)amino-1-cyclopropylmethyl-5-(4 trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2 one; 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 35 oxoheptyl)amino-1-benzyl-5-(4-trifluoromethylphenyl)-2,3 dihydro-1H-1,4-benzodiazepin-2-one; -59- WO 01/19797 PCT/USOO/24967 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-i-(3-phenoxybenzyl)-5-(4-trifluoromethyl phenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one; 5 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-i-(3-pyridinylmethyl)-5-(4-trifluoromethyl phenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one; 10 3-(2-(S)-cyclopropylmethyl-3-(R)-hydroxyl-1 oxoheptyl)amino-1-methyl-5-(4-trifluoromethyl-phenyl)-2,3 dihydro-1H-1,4-benzodiazepin-2-one; 15 3-(2-(S)-cyclopropylmethyl-3-(R)-hydroxyl-1 oxoheptyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3 dihydro-1H-1,4-benzodiazepin-2-one; 3-(2-(R)-cyclopropylmethyl-3-(R)-hydroxyl-1 20 oxoheptyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3 dihydro-1H-1,4-benzodiazepin-2-one; 3-(2-(S)-cyclopropylmethyl-3-(S)-hydroxyl-1 25 oxoheptyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3 dihydro-1H-1,4-benzodiazepin-2-one; 3-(2-(S)-cyclopropylmethyl-3-(S)-hydroxyl-1 30 oxoheptyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3 dihydro-1H-1,4-benzodiazepin-2-one; 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-3-(S)-methyl-1 oxoheptyl)amino-1-methyl-5-(4-trifluoromethyl-phenyl)-2,3 35 dihydro-1H-1,4-benzodiazepin-2-one; -60- WO 01/19797 PCT/USOO/24967 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-i-(3-phenoxybenzyl)-5-methyl-2,3-dihydro 1H-1,4-benzodiazepin-2-one; 5 3-(2-(R)-cyclopropylmehtyl-3-(S)-hydroxyl-1 oxoheptyl)amino-1-benzyl-5-methyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one; 3-(3-(S)-acetoxy-2-(R)-iso-butyl-1-oxoheptyl)amino-5-(4 10 fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2 one; 3-(S)-(5-cyclopentyl-2-(R)-cyclopropylmethyl-3-(S)-methoxy 1-oxopentyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4 15 benzodiazepin-2-one; 1-(1-hydroxypentyl)cyclohexanecarboxylic acid(5-(4 fluorophenyl)-1-methyl-2-oxo-2,3-dihydro-1H-1,4 benzodiazepin-3-yl)amide; 20 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one; 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxooctyl)amino 25 5-methyl-5H,7H-dibenzo[b,d]azepin-6-one; 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxononyl)amino 5-methyl-5H,7H-dibenzo[b,d]azepin-6-one; 30 3-(2-(R)-cyclopropylmethyl-5-(furan-2-yl)-3-(S)-hydroxyl-1 oxopentyl)amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one; 2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-heptanoic acid (2 oxo-1-(3-phenylamino-benzyl)azapan-3-(S)-yl) amide; 35 -61- WO 01/19797 PCT/USOO/24967 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-5-cyclopentyl-1-methyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one; 5 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-5-benzyl-1-methyl-2,3-dihydro-IH-1,4 benzodiazepin-2-one; 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 10 oxoheptyl)amino-5-benzyl-1-butyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one; 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-5-cycloheptyl-1-methyl -2,3-dihydro-1H-1,4 15 benzodiazepin-2-one; 3-(2-(R)-cycloropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino 1-benzyl-5-cycloheptyl-2,3-dihydro-1H-1,4-benzodiazepin-2 one; 20 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-1-butyl-5-cycloheptyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one; 25 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-i-(2-pyridinylmethyl)-5-(4 trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2 one; 30 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-i-(3-pyridinylmethyl)-5-(2-fluorophenyl) 2,3-dihydro-1H-1,4-benzodiazepin-2-one; 3-(2-(S)-cyclopropylmethyl-3-(S)-hydroxyl-1 35 oxopentyl)amino-i-(3-pyridynylmethyl)-5-(4 trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2 one; -62- WO 01/19797 PCT/USOO/24967 3-(2-1(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-1-methyl-5-(N,N-dibutylamino)-2,3-dihydro 1H-1,4-benzodiazepin-2-one; 5 3-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-1-n-butyl-5-t-butyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one; 10 3-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-i-(2-oxo-3,3-dimethylbutyl)-5-n-butyl-2,3 dihydro-1H-1,4-benzodiazepin-2-one; 3-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1 15 oxoheptyl)amino-1-benzyl-5-t-butyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one; 3-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-1-(2-picolyl)-5-n-butyl-2,3-dihydro-1H-1,4 20 benzodiazepin-2-one; 3-(2-(R)-Isobutyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1 methyl-5-homopiperidino-2,3-dihydro-1H-1,4-benzodiazepin-2 one; 25 3-(2-(R)-cyclopropylmethyl-1,3-dioxoheptyl)amino-i-methyl 5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4 benzodiazepin-2-one; and 30 1-pentyrylcyclohexanecarboxylic acid (5-(4-fluorophenyl)-1 methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl) amide. [13] In a preferred embodiment the present invention provides a compound of Formula (I) wherein the 35 stereochemistry of carbon 3 in lactam ring B is of the S configuration. -63- WO 01/19797 PCT/USOO/24967 [141 In a preferred embodiment the present invention provides a compound of Formula (I) wherein the stereochemistry of carbon 3 in lactam ring B is of the R configuration. 5 [15] In a preferred embodiment the present invention provides a compound of Formula (Ib)
R
5 R 5a H 0 Q O ,W-X-Y-Z OH O B (Ib) 10 wherein: Ring B is selected from: 0 0 0 N N/ N N\ R R 1 3 R13 ; R; and
Q
1 is Ci-C 6 alkyl substituted with 0-3 Ria; 15 C 2
-C
6 alkenyl substituted with 0-3 Ria.;
C
2
-C
6 alkynyl substituted with 0-3 Ria;
C
3
-C
10 cycloalkyl substituted with 0-3 Rib;
C
3
-C
10 carbocycle substituted with 0-3 Rib;
C
6 -C1O aryl substituted with 0-3 Rib; or 20 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 Rib; 25 Ria, at each occurrence, is independently selected from H, C1-C 6 alkyl, OR1 4 , Cl, F, Br, I, NR1 5 R1 6 , CF 3 ; C3-C1O carbocycle substituted with 0-3 Rib; C6-C1O aryl substituted with 0-3 Rib; and -64- WO 01/19797 PCT/USOO/24967 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 Rib; 5 Rib, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 1 5
R
1 6 , CF 3 , acetyl, SCH 3 ,
S(=O)CH
3 , S(=0) 2
CH
3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, Ci-C 4 haloalkyl-S-, and 10 (Ci-C 6 alkyl)-O-C(=O)-;
R
5 is OR 14 ; C1-C 6 alkyl substituted with 0-3 R5b;
C
2
-C
6 alkenyl substituted with 0-3 R5b; or 15 C 2
-C
6 alkynyl substituted with 0-3 R5b;
R
5 a is H, methyl, ethyl, propyl, butyl, or C 2
-C
4 alkenyl; alternatively,
R
5 and R 5 a may be combined to form a C 4
-C
7 20 cycloalkyl ring;
R
5 b, at each occurrence, is independently selected from: H, methyl, ethyl, propyl, butyl, CF 3 , OR 14 , Cl, F, Br, I, =0, NR 1 5
R
1 6 , 25 C 3
-C
7 cycloalkyl substituted with 0-3 R 5 c;
C
3
-C
7 carbocycle substituted with 0-3 R 5 c; phenyl substituted with 0-3 R 5 c; and 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and 30 sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R 5 c;
R
5 c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 1 5
R
1 6 , CF 3 , acetyl, SCH 3 , 35 S(=O)CH 3 , S(=0) 2
CH
3 , Ci-C 4 alkyl, Ci-C 3 alkoxy, Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy; -65- WO 01/19797 PCT/USOO/24967 W is -(CHR 8 )p_ p is 0 or 1; 5 R 8 is H, methyl, or ethyl; X is a bond; phenyl substituted with 0-2 Rxb;
C
5
-C
6 cycloalkyl substituted with 0-3 RXb; or 10 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 0-2 RXb; 15 RXb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 1 5
R
1 6 , CF 3 , acetyl, SCH 3 ,
S(=O)CH
3 , S(=0) 2
CH
3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, and Ci-C 4 haloalkyl-S-; 20 Y is a bond, -V-, -CH 2 -V-, -V-CH 2 -, or -CH 2
-V-CH
2 -; V is a bond, -C(=O)-, -0-, -S-, -S(=O)-, -S(=0) 2 -, or
-N(R
1 9 ) -; 25 Z is H, F, Cl, Br, Ci-C 4 alkyl substituted with 0-2 R1 2 ;
C
2
-C
4 alkenyl substituted with 0-2 R1 2 ;
C
2
-C
4 alkynyl substituted with 0-2 R1 2 ;
C
6 -Cio aryl substituted with 0-4 R1 2 b; 30 C 3
-C
6 carbocycle substituted with 0-4 R1 2 b; 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 R12b; 35 -66- WO 01/19797 PCT/USOO/24967
R
1 1, at each occurrence, is independently selected from H, =0, NR 1 8
R
1 9 , C(=0)R 1 7 , C(=0)OR1 7 , C(=O)NR 1 8 R1 9 , S(=0) 2
NR
1 8
R
1 9 , CF 3 ;
C
1
-C
6 alkyl substituted with 0-1 R11a; 5 phenyl substituted with 0-3 R11b;
C
3
-C
6 carbocycle substituted with 0-3 R11b; or 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle 10 is substituted with 0-3 R11b; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, 15 isoxazolyl, and tetrazolyl;
R
11 a, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Cl, F, =0, NR 1 5
R
16 , CF 3 ; 20 phenyl substituted with 0-3 R11b;
C
3
-C
6 carbocycle substituted with 0-3 R11b; or 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle 25 is substituted with 0-3 R11b; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, 30 isoxazolyl, and tetrazolyl; R11b, at each occurrence, is independently selected from H, OH, Cl, F, NR 1 5 R1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2
CH
3 , methyl, ethyl, propyl, butyl, methoxy, 35 ethoxy, propoxy, Ci-C 2 haloalkyl, and Ci-C2 haloalkoxy; -67- WO 01/19797 PCT/USOO/24967 Ri 2 at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR1 5
R
1 6 , -C(=O)NR1 5 R1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2
CH
3 , Ci-C 6 alkyl, Ci-C 4 5 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, and Ci-C 4 haloalkyl-S-;
C
6
-C
1 0 aryl substituted with 0-4 R1 2 b;
C
3
-C
1 o carbocycle substituted with 0-4 R12b; or 5 to 10 membered heterocycle containing 1 to 4 10 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R1 2 b; Ri2b, at each occurrence, is independently selected from H, 15 OH, Cl, F, Br, I, CN, NO 2 , NR 1 5
R
1 6 , CF 3 , acetyl, SCH 3 ,
S(=O)CH
3 , S(=0) 2
CH
3 , Ci-C 6 alkyl, CI-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, and Ci-C 4 haloalkyl-S-; R1 3 , at each occurrence, is independently selected from H, 20 OH, Ci-C 6 alkyl, Ci-C 4 alkoxy, Cl, F, Br, I, CN, NO 2 , NR1 5
R
1 6 , and CF 3 ; R1 4 , at each occurrence, is independently selected from H, phenyl, benzyl, C 1
-C
4 alkyl, and C 2
-C
4 alkoxyalkyl; 25
R
15 , at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; 30 R 16 , at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, phenethyl, CH 3
CH
2 C(=O)-, CH 3 C(=O)-, CH 3
CH
2 0C(=O)-,
CH
3 0C(=O)-, CH 3
CH
2 S(=0) 2 - and CH 3 S(=0) 2 -; 35 R 1 7 is H, phenyl, benzyl, Ci-C 4 alkyl, or C 2
-C
4 alkoxyalkyl; -68- WO 01/19797 PCT/USOO/24967
R
18 , at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and 5
R
19 , at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, and butyl. [16] In a preferred embodiment the present invention 10 provides a compound of Formula (Ib) :
Q
1 is C 1
-C
6 alkyl substituted with 0-3 Ria;
C
2
-C
6 alkenyl substituted with 0-3 Ria;
C
2
-C
6 alkynyl substituted with 0-3 Ria;. 15 C 3
-C
6 cycloalkyl substituted with 0-3 Rib; phenyl substituted with 0-3 Rib; or 5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle 20 is substituted with 0-3 Rib;
R
1 a, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, OR 1 4 , Cl, F, Br, I,
NR
1 5
R
1 6 , CF 3 ; 25 C 3
-C
6 carbocycle substituted with 0-3 Rib; phenyl substituted with 0-3 Rib; and 5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle 30 is substituted with 0-3 Rib; Rib, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 1 5
R
1 6 , CF 3 , acetyl, SCH 3 ,
S(=O)CH
3 , S(=O) 2
CH
3 , methyl, ethyl, propyl, butyl, 35 methoxy, ethoxy, propoxy, Ci-C 2 haloalkyl, Ci-C 2 -69- WO 01/19797 PCT/USOO/24967 haloalkoxy, (methyl)OC(=O)-, (ethyl)OC(=O)-, (propyl)OC(=O)-, and (butyl)OC(=0)-;
R
5 is OR 14 ; 5 Cl-C 4 alkyl substituted with 0-1 R5b;
C
2
-C
4 alkenyl substituted with 0-1 R5b; or
C
2
-C
4 alkynyl substituted with 0-1 R5b;
R
5 a is H, methyl, ethyl, propyl, or butyl; 10 alternatively, R 5 and R 5 a may be combined to form a cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl ring; 15 R 5 b, at each occurrence, is independently selected from: H, methyl, ethyl, propyl, butyl, CF 3 , OR 1 4 , Cl, F, =0, NR 1 5
R
1 6 ,
C
3
-C
7 cycloalkyl substituted with 0-3 R 5 c;
C
3
-C
7 carbocycle substituted with 0-3 R 5 c; 20 phenyl substituted with 0-3 R 5 c; and 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R 5 c; wherein said 5 to 7 25 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl; 30
R
5 c, at each occurrence, is independently selected from H, OH, Cl, F, NR 1 5
R
1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2
CH
3 , methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Ci-C 2 haloalkyl, and Ci-C 2 35 haloalkoxy; W is a bond, -CH 2 -, or -CH(CH 3 )-; -70- WO 01/19797 PCT/USOO/24967 X is a bond; phenyl substituted with 0-1 Rxb;
C
5
-C
6 cycloalkyl substituted with 0-1 RXb; or 5 to 6 membered heterocycle containing 1 to 3 5 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-1 RXb; wherein said 5 to 6 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, 10 thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, and isoxazolyl; RXb, at each occurrence, is independently selected from H, OH, Cl, F, Br, NR1 5
R
1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH 3 , 15 S(=0) 2
CH
3 , methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy; Y is a bond, -V-, -V-CH 2 -, or -CH 2 V-; 20 V is a bond, -C(=O)-, -0-, -S-, -S(=O)-, -S(=0)2-, or
-N(R
1 9 ) -; Z is H, F, Cl, Br, 25 Ci-C 4 alkyl substituted with 0-2 R1 2 ;
C
2
-C
4 alkenyl substituted with 0-2 R1 2 ;
C
2
-C
4 alkynyl substituted with 0-2 R1 2 ;
C
6 -Cio aryl substituted with 0-4 R12b;
C
3
-C
6 carbocycle substituted with 0-4 R1 2 b; or 30 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 R12b; 35 R1l, at each occurrence, is independently selected from -71- WO 01/19797 PCT/USOO/24967 H, NR 1 8
R
1 9 , CF 3 ; Ci-C 4 alkyl substituted with 0-1 R11a; phenyl substituted with 0-3 R11b;
C
3
-C
6 carbocycle substituted with 0-3 R11b; or 5 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R11b; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, 10 pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl; 15 R 11 a, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Cl, F, =0, NR 1 5 R1 6 , CF 3 ; phenyl substituted with 0-3 R11b;
C
3
-C
6 carbocycle substituted with 0-3 R11b; or 20 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R11b; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, 25 pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl; 30 R11b, at each occurrence, is independently selected from H, OH, Cl, F, NR 1 5 R1 6 , CF 3 , methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Ci-C 2 haloalkyl, and C1-C 2 haloalkoxy; 35 R 12 at each occurrence, is independently selected from H, OH, Cl, F, Br, NR 1 5
R
1 6 , -C(=O)NR 15
R
1 6 , CF 3 , acetyl, -72- WO 01/19797 PCT/USOO/24967
SCH
3 , S(=O)CH 3 , S(=O) 2
CH
3 , methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy; phenyl substituted with 0-4 R1 2 b; 5 C 3
-C
6 carbocycle substituted with 0-4 R1 2 b; 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 R12b; 10 R1 2 b, at each occurrence, is independently selected from H, OH, Cl, F, Br, NR 1 5
R
1 6 , CF3, acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2
CH
3 , methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C 2 haloalkyl, and Ci-C 2 15 haloalkoxy;
R
13 , at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Cl, F, Br, CN, NR 1 5
R
1 6 , and CF 3 ; 20 R1 4 , at each occurrence, is independently selected from H, phenyl, benzyl, methyl, ethyl, propyl, and butyl;
R
15 , at each occurrence, is independently selected from H, 25 methyl, ethyl, propyl, or butyl;
R
16 , at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; 30
R
18 , at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl and, phenethyl; and -73- WO 01/19797 PCT/USOO/24967
R
19 , at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl and, phenethyl. 5 [17] In a preferred embodiment the present invention provides a compound of Formula (Ib)wherein:
Q
1 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
2
CH
2
CH
3 , -CH 2
CH
2
CH
2
CH
2
CH
2
CH
3 , -CH (CH 3 ) 2, 10 -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=CH
2 , -CH 2
CH=CH
2 , -CH 2
C(CH
3
)=CH
2 , -CH 2
CH=C(CH
3 )2, 15 -CH 2
CH
2
CH=CH
2 , -CH 2
CH
2
C(CH
3
)=CH
2 , -CH 2
CH
2
CH=C(CH
3
)
2 , cis-CH 2
CH=CH(CH
3 ), cis-CH 2
CH
2
CH=CH(CH
3 ), trans-CH 2
CH=CH(CH
3 ), trans-CH 2
CH
2
CH=CH(CH
3 ); -C=CH, -CH 2 C=CH, -CH 2
C=C(CH
3 ), 20 cyclopropyl-, cyclobutyl-, cyclopentyl-, cyclohexyl-, 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 -, 25 phenyl-, 2-F-phenyl-, 3-F-phenyl-, 4-F-phenyl-, 4-methoxyphenyl-,4-ethoxyphenyl-, 4-propoxyphenyl-, 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 -, 30 (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 -, 35 (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 -, -74- WO 01/19797 PCT/USOO/24967 (3-F-4-C1-phenyl)CH 2 -, (3-F-5-Cl-phenyl)CH 2 -, (3-C1-4-F-phenyl) CH 2 -, 2-furanyl-CH 2 -, 3-furariyl-CH 2 -, 2-thienyl-CH 2 -, 5 3-thienyl-CH 2 -, 2-pyridyl-CH 2 -, 3-pyridyl-CH 2 -, 4-pyridyl-CH 2 -, 1-imidazolyl-CH 2 -, 2-oxazolyl-CH 2 -, 4-oxazolyl-CH 2 -, 5-oxazolyl-CH 2 -, 3-isoxazolyl-CH 2 -, 4-isoxazolyl-CH 2 -, 5-isoxazolyl-CH 2 -, 10 phenyl-CH 2
CH
2 -, (2-F-phenyl) CH 2
CH
2 -, (3-F-pherayl)CH 2
CH
2 -, (4-F-pheriyl)CH 2
CH
2 -, (2-C1-phenyl)CH 2
CH
2 -, (3-Cl-phenyl)CH 2
CH
2 -, (4-C1-pheiyl) CH 2
CH
2 -, (2,3-diF-phenyl)CH 2
CH
2 -, (2,4-diF-pheriyl)CH 2
CH
2 -, 15 (2,5-diF-pheriyl)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 -, 20 (3-F-4-Cl-phenyl)CH 2
CH
2 -, (3-F-5-C1-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 -, isoxazolyl-CH 2
CH
2 -, 3,5-dirnethylisoxazol-4-yl-CH 2
CH
2 -, 25 phenyl-propyl-; benzyl-CH (NH 2 )-, benzyl-CH(NHC(=O) -O-tBu) -, benzyloxy-CH 2 -, pyrrolidin-2-yl-, or 3 -t-butoxycarbonylpyrrolidin-2 -yl-; 30
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, 35
-CF
3 . -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 2
CH
2
CH=CH
2 , -CH=CHCH 3 , -75- WO 01/19797 PCT/USOO/24967 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 ), 5 -C=CH, -CH 2 CECH, -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 ),
-CH
2
CH
2
CH
2 C=CH, -CH 2
CH
2
CH
2
C=C(CH
3 ), -CH 2
CH
2
CH
2
C=C(C
6
H
5 ), 10 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 -, 15 (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 -, (3,5-diF-phenyl)CH 2 -, 2-furanyl-CH 2 -, 3-furanyl-CH 2 -, 2-thienyl-CH 2 -, 3-thienyl-CH 2 -, 20 2-pyridyl-CH 2 -, 3-pyridyl-CH 2 -, 4-pyridyl-CH 2 -, 1-imidazolyl-CH 2 -, 2-oxazolyl-CH 2 -, 4-oxazolyl-CH 2 -, 5-oxazolyl-CH 2 -, 3-isoxazolyl-CH 2 -, 4-isoxazolyl-CH 2 -, 5-isoxazolyl-CH 2 -, 25 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 -, isoxazolyl-CH 2
CH
2 -; 30 methoxy, ethoxy, propoxy, or butoxy;
R
5 a is H; alternatively, R 5 and R 5 a may be combined to form 35 cyclopentyl, cyclohexyl, or cycloheptyl; W is a bond, -CH 2 -, or -CH(CH 3 )-; -76- WO 01/19797 PCT/USOO/24967 X is a bond; 5 NO; ; or N Y is a bond, -CH 2 -V-, -V-, or -V-CH 2 -; V is a bond, -C(=O)-, -0-, -S-, -S(=O)-, -S(=0) 2 -, -NH-, or 10 -N (CH3) Z is H, F, Cl, Br, methyl, ethyl, n-propyl, i-propyl, n butyl, i-butyl, s-butyl, t-butyl, 15 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 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, 20 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, 25 3-Me-phenyl, 4-Me-phenyl, 2-MeS-phenyl, 3-MeS-phenyl, 4-MeS-phenyl, 2-CF 3 0-phenyl, 3-CF 3 0-phenyl, 4-CF 3 0-phenyl, furanyl, thienyl, pyridyl, 2-Me-pyridyl, 3-Me-pyridyl, 30 4-Me-pyridyl, 1-imidazolyl, oxazolyl, isoxazolyl, 1-benzimidazolyl, 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 -, 35 (4-Cl-phenyl)CH 2 -, (2,3-diF-phenyl)CH 2 -, -77- WO 01/19797 PCT/USOO/24967 (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-diCIl-phenyl)CH 2 -, (2,5-diCl-phenyl)CH 2 -, 5 (2,6-diCl-phenyl)CH 2 -, (3,4-diCl-phenyl)CH 2 -, (3,5-diCl-phenyl)CH 2 -, (3-F-4-C1-phenyl)CH 2 -, (3-F-5-C1-phenyl)CH 2 -, (3-C1-4-F-phenyl)CH 2 -, (2-MeO-phenyl) CH 2 -, (3-MeO-phenyl) CH 2 -, (4-MeO-phenyl)CH 2 -, (2-Pho-phenyl)CH 2 -, 10 (3-PhO-phenyl) CH 2 -, (4-PhO-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 -, 15 (4-CF 3 O-phenyl)CH 2 -, (furariyl)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 -, 20 (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-C1-phenyl)CH 2
CH
2 -, (3-C1-phenyl)CH 2
CH
2 -, 25 (4-C1-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 -, 30 (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-C1-phenyl)CH 2
CH
2 -, (3-F-5-C1-phenyl)CH 2
CH
2 -, (3-C1-4-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 -, 35 (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 -, -78- WO 01/19797 PCT/USOO/24967 (3-CF 3 0-phenyl)CH 2
CH
2 -, (4-CF 3 0-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 -, 5 (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-pipridinyl)CH 2
CH
2 -; 10
R
11 , at each occurrence, is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s butyl, t-butyl, phenyl, benzyl, phenethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 15 cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, 2-F-phenyl-, 3-F-phenyl, 4-F-phenyl, 4-Cl-phenyl, 4-CH 3 phenyl, 4-MeO-phenyl-, 4-CF 3 -phenyl, (4-F-phenyl)CH 2 -, 20 (4-Cl-phenyl)CH 2 -, (4-CH 3 -phenyl)CH 2 -, (4-CF 3 -phenyl)CH 2 -, (4-F-phenyl)CH 2
CH
2 -, (4-Cl-phenyl)CH 2
CH
2 -, (4-CH 3 -phenyl)CH 2
CH
2 -, (4-CF 3 -phenyl)CH 2
CH
2 -, pyridin-2-yl-, pyridin-3-yl-, 4-CF 3 -pyridin-2-yl-, 4-CH 3 -pyridin-2-yl-, thiazol-2-yl-, 25 azapan-1-yl, N,N-dimethylamino, N,N-diethylamino, N,N dipropylamino, and N,N-dibutylamino; and
R
13 , at each occurrence, is independently selected from H, MeO, F, and Cl. 30 [18] In a preferred embodiment the present invention provides a compound of Formula (If); R5 R 5 a H 0 N N'W-X-Y-Z OH OR1, 35 (If) -79- WO 01/19797 PCT/USOO/24967 or a pharmaceutically acceptable salt form or prodrug thereof. [19] In a preferred embodiment the present invention 5 provides a compound of Formula (Ig);
R
5 R5a 0 Q N'W-X-Y-Z OH 0 N\
R
1 3 (Ig) or a pharmaceutically acceptable salt form or prodrug 10 thereof. [20] In a preferred embodiment the present invention provides a compound of Formula (Ih); R5 R H 0 N ,W-X-Y-Z OH O \R 15 13- (Ih) or a pharmaceutically acceptable salt form or prodrug thereof. 20 In another preferred embodiment the present invention provides all herein disclosed embodiments with the proviso that when R 5 and R 5 a are not simultaneaously H. In another preferred embodiment the present invention 25 provides all herein disclosed embodiments with the proviso that when Q is a 9 membered benzofused heterocyclic group substituted by 0, 1, or 2 R 1 a, then R 3 is H. -80- WO 01/19797 PCT/USOO/24967 In another preferred embodiment the present invention provides all herein disclosed embodiments with the proviso that when -WXYZ is a tertiary butyl group and R 5 is either
CI-C
4 alkyl or C 2 alkenyl, then Q is not phenyl substituted 5 by 0, 1 or 2 Ra. In another preferred embodiment the present invention provides all herein disclosed embodiments with the proviso that when R 5 is Ci-C 3 alkyl, then Q is not phenyl 10 substituted by 0, 1 or 2 Ria. In another preferred embodiment the present invention provides all herein disclosed embodiments with the proviso that the moiety:
R
5
R
5 a R2 15 OH 0 of Formula (I), et seq., is not a Ci-C 8 alkyl, C 2
-C
8 alkenyl, C 2
-C
8 alkynyl, C 3
-C
10 cycloalkyl-Ci-C 4 alkyl, C 3
-C
10 cycloalkyl, C 1
-C
4 alkyl-O-Ci-C 4 alkyl, C 1
-C
4 alkyl-S-Ci-C 4 alkyl, C 2
-C
4 alkyl-NR 20
-C
2
-C
4 alkyl, C 2
-C
4 alkyl-C 6 -Ci 0 20 aryl, C 2
-C
4 alkyl-C 6
-C
1 0 cycloalkyl, C 2
-C
8 alkenyl, C 6
-C
10 aryl-Ci-C 4 alkyl, C 6
-C
1 0 aryl-C2-C 4 -alkynyl, indol-3-yl-Ci
C
3 alkyl, and imidazol-4-yl-Ci-C 3 alkyl; where any alkyl group is substituted with OH. 25 In a second embodiment, the present invention provides a pharmaceutical composition comprising a compound of Formula (I) and a pharmaceutically acceptable carrier. In a third embodiment, the present invention provides 30 a method for the treatment of a neurological disorder associated with P-amyloid production comprising administering to a host in need of such treatment a -81- WO 01/19797 PCT/USOO/24967 therapeutically effective amount of a compound of Formula (I). In a preferred embodiment the neurological disorder 5 associated with P-amyloid production is Alzheimer's Disease. In a fourth embodiment, the present invention provides a method for inhibiting y-secretase activity for the 10 treatment of a physiological disorder associated with inhibiting -secretase activity comprising administering to a host in need of such inhibition a therapeutically effective amount of a compound of Formula (I) that inhibits 7-secretase activity. 15 In a preferred embodiment the physiological disorder associated with inhibiting 7-secretase activity is Alzheimer's Disease. 20 In a fifth embodiment, the present invention provides a compound of Formula (I) for use in therapy. In a preferred embodiment the present invention provides a compound of Formula (I) for use in therapy of 25 Alzheimer's Disease. In a sixth embodiment, the present invention provides for the use of a compound of Formula (I) for the manufacture of a medicament for the treatment of 30 Alzheimer's Disease. DEFINITIONS As used herein, the term "AP" denotes the protein designated A$, 0-amyloid peptide, and sometimes P/A4, in the art. AP is an approximately 4.2 kilodalton (kD) 35 protein of about 39 to 43 amino acids found in amyloid plaques, the walls of meningeal and parenchymal arterioles, -82- WO 01/19797 PCT/USOO/24967 small arteries, capillaries, and sometimes, venules. The isolation and sequence data for the first 28 amino acids are described in U.S. Pat. No 4,666,829. The 43 amino acid sequence is: 1 Asp Ala Glu Phe Arg His Asp Ser Gly Tyr 11 Glu Val His His Gln Lys Leu Val Phe Phe 21 Ala Glu Asp Val Gly Ser Asn Lys Gly Ala 31 Ile Ile Gly Leu Met Val Gly Gly Val Val 41 Ile Ala Thr 5 The term "APP", as used herein, refers to the protein known in the art as $ amyloid precursor protein. This protein is the precursor for AD and through the activity of "secretase" enzymes, as used herein, it is processed into 10 A3. Differing secretase enzymes, known in the art, have been designated P secretase, generating the N-terminus of AP, a secretase cleaving around the 16/17 peptide bond in A$, and "y secretases", as used herein, generating C terminal AP fragments ending at position 38, 39, 40, 42, 15 and 43 or generating C-terminal extended precursors which are subsequently truncated to the above polypeptides The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in 20 optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, C=N double bonds, and the like can also be present 25 in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and -83- WO 01/19797 PCT/USOO/24967 trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric 5 forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. The term "substituted," as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that 10 the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., =0), then 2 hydrogens on the atom are replaced. When any variable (e.g., R 1 a, R 4 a, R 1 3 etc.) occurs 15 more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-3
R
1 a, then said group may optionally be substituted with up 20 to three Ria groups and R 1 a at each occurrence is selected independently from the definition of Ria. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. 25 When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a 30 given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. As used herein, "alkyl" or "alkylene" is intended to 35 include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; for example, "Ci-C 6 alkyl" denotes alkyl -84- WO 01/19797 PCT/USOO/24967 having 1 to 6 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl. Preferred "alkyl" group is "C 1
-C
4 alkyl" wherein methyl, 5 ethyl, n-propyl, i-propyl, n-butyl, and i-butyl, are specifically preferred. As used herein, "Ci-C 3 alkyl", whether a terminal substituent or a alkylene group linking two substituents, is understood to specifically include both branched and straight-chain methyl, ethyl, and propyl. 10 As used herein, "alkenyl" or "alkenylene" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain. Examples of "C 2
-C
6 alkenyl" include, but 15 are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1 butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 2 pentenyl, 3-pentenyl, hexenyl, and the like. As used herein, "alkynyl" or "alkynylene" is intended to include hydrocarbon chains of either a straight or 20 branched configuration and one or more carbon-carbon triple bonds which may occur in any stable point along the chain, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2 butynyl, 3-butynyl, and the like. "Alkoxy" or "alkyloxy" represents an alkyl group as 25 defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. Preferred alkoxy groups are 30 methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy. Similarly, "alkylthio" or "thioalkoxy" is represents an alkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge. 35 "Halo" or "halogen" as used herein refers to fluoro, chloro, bromo, and iodo. Unless otherwise specified, preferred halo is fluoro and chloro. "Counterion" is used -85- WO 01/19797 PCT/USOO/24967 to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like. "Haloalkyl" is intended to include both branched and 5 straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example -CyFw where v = 1 to 3 and w = 1 to (2v+l)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, 10 pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, heptafluoropropyl, and heptachloropropyl. "Haloalkoxy" is intended to mean a haloalkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge; for 15 example trifluoromethoxy, pentafluoroethoxy, 2,2,2 trifluoroethoxy, and the like. "Halothioalkoxy" is intended to mean a haloalkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge. 20 "Cycloalkyl" is intended to include saturated ring groups, having the specified number of carbon atoms. For example, "C 3
-C
6 cycloalkyl" denotes such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. As used herein, "carbocycle" is intended to mean any 25 stable 3- to 7-membered monocyclic or bicyclic or 7- to 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 30 cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin). Preferred example of "C 3
-C
1 0 carbocycle" or "C 3
-C
6 carbocycle" is C 3 35 C 6 cycloalkyl, specifically cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. -86- WO 01/19797 PCT/USOO/24967 As used herein, the term "heterocycle" or "heterocyclic ring" is intended to mean a stable 5- to 7 membered monocyclic or bicyclic or 7- to 14-membered bicyclic heterocyclic ring which is saturated partially 5 unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3 or 4 heteroatoms, preferably 1, 2, or 3 heteroatoms, independently selected from the group consisting of N, 0 and S and including any bicyclic group in which any of the above-defined heterocyclic rings is 10 fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on 15 carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and 0 atoms in the heterocycle exceeds 1, then these heteroatoms are not 20 adjacent to one another. It is preferred that the total number of S and 0 atoms in the heterocycle is not more than 1. Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 25 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, 30 benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, 35 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, -87- WO 01/19797 PCT/USOO/24967 morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, 5 phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, 10 pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 15 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 20 1,3,4-triazolyl, xanthenyl. Preferred 5 to 10 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl, benzofuranyl, benzothiofuranyl, indolyl, 25 benzimidazolyl, 1H-indazolyl, oxazolidinyl, isoxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl, and isoquinolinyl. Preferred 5 to 7 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, 30 pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl; more preferred 5 to 7 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, piperazinyl, piperidinyl, 35 homopiperidinyl, pyrazolyl, imidazolyl, and tetrazolyl. Preferred 5 to 6 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, -88- WO 01/19797 PCT/USOO/24967 thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl; Also included are fused ring and containing, for example, the above heterocycles. 5 As used herein, the term "aryl", "C 6
-C
1 0 aryl" or aromatic residue, is intended to mean an aromatic moiety containing the specified number of carbon atoms; for example phenyl, pyridinyl or naphthyl. Unless otherwise specified, "aryl" may be unsubstituted or substituted with 10 0 to 3 groups selected from H, OH, OCH 3 , Cl, F, Br, I, CN,
NO
2 , NH 2 , N(CH 3 )H, N(CH 3
)
2 , CF 3 , OCF 3 , C(=O)CH 3 , SCH 3 ,
S(=O)CH
3 , S(=0) 2
CH
3 , CH 3 , CH 2
CH
3 , CO 2 H, and CO 2
CH
3 . The phrase "additional lactam carbons", as used herein, is intended to denote the number of optional carbon 15 atoms in the lactam ring B of Formula (I). Formula (Ia): 0 3 2 1NI B (Ia) represents the lactam ring B of Formula (I). Additional 20 lactam carbons are carbons in lactam ring B other than the carbons numbered 2 and 3 in the backbone of the formula. The additional lactam carbons may be optionally replaced by a heteroatom selected from oxygen, nitrogen and sulfur. Lactam ring B contains 1, 2, 3, 4, 5, 6 or 7 optional 25 carbons, wherein one optional carbon may optionally be replaced by a heteroatom, such that the total number of members of lactam ring B, including atoms numbered 1, 2 and 3 in the backbone, does not exceed 10. It is preferred that the total number of atoms of lactam ring B is 6, 7 or 30 8; it is more preferred that the total number of atoms of lactam ring B is seven. Examples of lactam ring B include: -89- WO 01/19797 PCT/USOO/24967 o 0 0 N N N" S R R R - i Rio Bi B2 B3 o 0 N R N s >R1 N1/ l1 -b 5 B4 B5 B6 0 0 0 NN ,N 0 B7 B8 B9 0 0 0 NN NA B10 Bli B12 o 0 0 N N~ N -90- WO 01/19797 PCT/USOO/24967 B13 B14 B15 0 SNA R10-N B16 5 but are not intended to limit the invention. Preferred examples of lactam ring B are B1, B2, B5, B6, B8, B9, B13, and B16; more preferred examples of lactam ring B are B1, B6, B8, B9, and B13. Preferred examples of substituent R10 or R1l on lactam B are methyl, ethyl, phenyl, 4 10 fluorophenyl, 4-chlorophenyl, 4-trifluorophenyl, (4 fluorophenyl)methyl, (4-chlorophenyl)methyl, and (4 trifluorophenyl)methyl. Preferred examples of substituent R13 on fused rings of lactam B are methyl, fluoro, and chloro. 15 The compounds herein described may have asymmetric centers. One enantiomer of a compound of Formula (I) may display superior biological activity over the opposite enantiomer. For example carbon 3 of lactam ring B Formula (I") may exist in either an S or R configuration. Thus, an 20 R or S configuration at carbon 3 in Formula (I") is considered part of the invention. An example of such configuration includes, Q H 0 R H 0 N NCH 3 N
CH
3 HO O N 1 3 HO 0 N 1 3 R and R 25 but is not intended to be limited to this example of ring B. When required, separation of the racemic material can be achieved by methods known in the art. Additionally, the -91- WO 01/19797 PCT/USOO/24967 carbon atoms to which the OH and R 5 are attached may describe chiral carbons which may display superior biological activity over the opposite enantiomer. For example, where Q and R 5 are not H, then the configuration 5 of the two centers may be described as (2R,3R), (2R,3S), (2S,3R), or (2S,3S). All configurations are considered part of the invention; however, the (2R,3S) and the (2S,3R) are preferred and the (2R,3S) is more preferred. The phrase "pharmaceutically acceptable" is employed 10 herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, 15 or other problem or complication, commensurate with a reasonable benefit/risk ratio. As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts 20 thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the 25 conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, 30 sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 35 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like. -92- WO 01/19797 PCT/USOO/24967 The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting 5 the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists 10 of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is hereby incorporated by reference. "Prodrugs" are intended to include any covalently 15 bonded carriers which release the active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of formula (I) are prepared by modifying functional groups present in the compound in such a way 20 that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of formula (I) is administered to a 25 mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I), and the like. 30 "Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. 35 SYNTHESIS The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of -93- WO 01/19797 PCT/USOO/24967 organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as 5 appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety by reference. The novel compounds of this invention may be prepared 10 using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, 15 it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be 20 readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents which are 25 compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used. Scheme 1 -94- WO 01/19797 PCT/USOO/24967 1. BuLi R5 N O 1. Bu 2 BOTf, TEA 2.R 5
CH
2 COCI 2.Q-CHO Bn Bn 1. 2 OHO O OHO LIOHO H0 2 _ _ NA 0 OH, H202 Q OH Bn THF, H 2 0 R5 3 4 Aldol derivatives can be prepared by the procedure of Evans (D. A. Evans et al, Org. Synth. 1990, 68, 83-90), 5 which is outlined in Scheme 1 where acylation of an oxazolidinone with an acid chloride provides structure 2. Asymmetric aldol reaction to form 3 followed by cleavage of the chiral auxiliary yielding P-hydroxycarboxylic acid 4. Additional examples are found in D. A. Evans Aldrichimica 10 Acta 1982, 15, 23-32. Alternative syntheses of structures 4 can be accomplished by the methods of Crimmins ( M. T. Crimmins et al, J. Am. Chem. Soc. 1997, 119, 7883-7884), Paterson (I. Paterson et al, Org. React. 1997, 51, 1-200) and Mukaiyama (T. Mukaiyama et al, Org. React. 1994, 1 15 104) . Anti-aldols may be synthesized according to: (a) A. K. Ghosh, J. Am. Chem. Soc. 1996, 118, 2527-2528, or (b) S. Masamune et al., J. Am. Chem. Soc. 1997, 119, 2586. Scheme 2 ZYXW 13 ZYXW -- 13 OH0 oN\0 OH +O/HO 0 Q OH + O N EDC, HOBt O N 5 H 2 N N R1 1 TEA, CH 2
CI
2 H NR 20 6 Carboxylic acids of formula 4 can be coupled to anappropriate lactam intermediate using methods commonly used in peptide syntheses, such as DCC, EDC, CDI, BOP, PyBOP, HATU, HBTU and phenyl ester mediated coupling, as -95- WO 01/19797 PCT/USOO/24967 described in A. R. Chamberlin, Chem. Rev. 1997, 97, 2243 2266. Compound 6 is synthesized, as illustrated in Scheme 2, by coupling acid 4 with 3-amino-1,4-benzodiazepin-2-one 5 under the catalysis of EDC and HOBt providing the final 5 compound 6 (S. Nozaki et al, Bull. Chem. Soc. Jpn. 1982, 55, 2165-2168) . Similarly, Schemes 2a and 2b illustrate synthesis of bisbenzodiazepine and lactam compounds of the present invention: 10 Scheme 2a WXYZ ZYXW OHO O R13 -N Rs OHOO \ Q "OH + H 2 N EDC, HOBt OH 0 s TEA, CH 2
CI
2 s N R \ R - \ R 13 4a 4b 4 Scheme 2b 0wYxYz w~xYz OHO N Q" OH + H 2 N EDC, HOBt A5 TEA, CH 2
CI
2 - H 15 4b 5b 5 15 5 Methods for the synthesis of lactam intermediates as contemplated by the present invention useful in the synthesis of compounds of Formula (I), including amino 20 benzodiazepinones, dibenzo azepinones and other related heterocycles, are known in the art and are disclosed in a number of references including PCT publication number WO 98/28268, WO 99/66934, WO 00/07995, and WO 00/38618, which are hereby incorporated by reference. Additional 25 references include Bock, et al, J. Org. Chem., 1987, 52, 3232-3239; Sherrill et al, J. Org. Chem., 1995, 60, 730 -96- WO 01/19797 PCT/USOO/24967 734; and Walsh, D. A., Synthesis, September 1980, p.677; and Brown, et al., Tetrahedron Letters, 1971, 8, 667-670. Synthetic approaches to aminobenzodiazepines are widely described in the literature and well known to one 5 skilled in the art. The typical methods are illustrated, but are not limited to, the following references. See (a) M. G. Bock et al., J. Org. Chem., 1987, 52, 3232; (b) R. G. Sherrill et al., J. Org. Chem., 1995, 60, 734; (c) M. G. Bock et al., J. Med. Chem., 1989, 32, 13-16; (d) J. L. 10 Castro et al., J. Med. Chem., 1997, 40, 2491-2501; (e) M. S. Chambers et al., Bioorg. & Med. Chem. Lett., 1993, 3 (10), 1919-1924; (f) J. H. Gogerty et al., J. Med. Chem., 1977, 20 (7), 952; (g) G. Semple et al., Bioorg. & Med. Chem. Lett., 1996, 6(1), 51-54; (h) G. Semple et al., J. 15 Med. Chem., 1997, 40, 331-341; (i) G. Semple et al., Bioorg. & Med. Chem. Lett., 1996, 6 (1), 55-58; (j) G. Semple et al., Synth. Commun., 1996, 26 (4), 721-727; and (k) G. A. Showell et al., J. Med. Chem., 1994, 37, 719 721. For general synthetic descriptions of 2 20 aminobenzophenone with various substitutions used in the preparation of benzodiazepine, see D. A. Walsh, Synthesis 1980, 677. Scheme 3 25 1. NaH, DMF OsO4, NalO 4 0 2. allyl bromide, KI Q Et 2 0-H 2 0 Q1- H 7 8 9 The preparation of aldehyde Q-CHO with general structure of 9 is shown in Scheme 3 (H. C. Arndt, Synthesis 30 1979, 202-204). Allyl ether 8 can be made from the action of an alkoxide generated in DMF with allyl bromide, which is converted to a-alkoxy- or aryloxyaldehyde 9 using a two phase osmium tetraoxide oxidation. 35 Scheme 4 -97- WO 01/19797 PCT/USOO/24967 - Br 1. NaH, THF O 2. allyl alcohol, KI R R 10 11 Os0 4 , NalO 4 OH Et 2 0-H 2 0 / O R 12 As shown in Scheme 4, aldehyde Q-CHO of general structure 12 can be prepared in the same fashion from the 5 corresponding allyl benzyl ether, which is readily available according to the procedure described by P. Kocienski (P. Kocienski Tetrahedron 1990, 46, 1767-1782). The aldehydes used in Scheme 1 are either commercially 10 available, prepared from commercially available or readily accessible alcohols, or prepared from commercially available or readily accessible carboxylic acids. For preparation of other non-commercially available aldehydes from commercially available or readily accessible alcohols 15 by oxidation of the corresponding alcohols, see(a) S. V. Ley et al Synthesis 1994, 639; (b) D. Swern, Synthesis 1981, 165-185; and (c) R. C. Larock, Comprehensive Organic Transformations, Wiley-VCH: 1989; pp604-614. For preparation of other non-commercially available aldehydes 20 from commercially available or readily accessible carboxylic acids by reducing the corresponding Weinreb amides or reduction of carboxylic acid derivatives, see (a) S. M. Weinreb et al. Tetrahedron Lett. 1981, 22, 3815-3818; (b) M. Braun, Synthesis 1989, 856; and (c) D. A. Evans, J. 25 Org. Chem. 1993, 58, 2446-2453. Aminoaldehydes used in the synthesis of the compounds of the invention may be prepared by oxidation of corresponding amino alcohols or reduction of corresponding amino acids; see(a) J. Jurczak et al., Synlett 1993, 241; 30 and (b) S. G. Davis et al., Synlett 1995, 700. -98- WO 01/19797 PCT/USOO/24967 Sulfur containing aldehydes used in the synthesis of compounds of the invention may be made by conjugate addition of a thiol to a,$ -unsaturated aldehydes or reaction of a thiol with a halosubstituted aldehyde. See 5 T. Cohen et al., J. Org. Chem. 1995, 60, 2022; Tetrahdron 1994, 50, 12793-12810; J. Org. Chem. 1992, 57, 6; Phosphorus, Sulfur, and Silicon 1993, 74, 1; and Tetrahdron 1994, 50, 11569-11584. Sulfoxides and sulfones are prepared from the 10 corresponding sulfide by oxidation. See M. Hudlicky, Oxidations in Organic Chemistry, ACS, 1990; pp 250-264. The acid chlorides used in Scheme 1 are either commercially available or prepared from commercially available or readily accessible carboxylic acids by the 15 action of oxalyl chloride or thionyl chloride. See R. C. Larock, Comprehensive Organic Transformations, Wiley-VCH: 1989; pp963-964. Examples 20 Chemical abbreviations used in the Examples are defined as follows: "DMPU" for 1,3-dimethyl-3,4,5,6 tetrahydro-2(lH)-pyrimidone; "TBTU" for 0-(lH-benzotriazol 1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; "BOP" for benzotriazol-1-yloxytris-dimethylamino) 25 phosphonium hexafluorophosphate; "Bu 2 BOTf" for dibutylboron triflate; "EDC" for 1-[3-(dimethylamine)propyl]-3 ethylcarbodiimide hydrochloride; "HOBt" for 1 hydroxybenzotriazole; and "TEA" for triethylamine. "HPLC" is an abbreviation used herein for high 30 pressure liquid chromatography. Compounds of the present invention are generally purified by HPLC using conditions known to one skilled in the art. However, unless otherwise indicated, the following conditions are generally applicable. Reverse-phase HPLC can be carried out using a 35 Vydac C-18 column with gradient elution from 10% to 100 % buffer B in buffer A (buffer A: water containing 0.1% trifluoroacetic acid, buffer B: 10% water, 90% -99- WO 01/19797 PCT/USOO/24967 acetonitrile containing 0.1% trifluoroacetic acid). Alternatively, reverse-phase HPLC can be carried out using a Vydac C-18 column with gradient elution from 10% to 90 % acetonitrile in water. 5 Example 1. 3- (2 (R) -Cyclopentylmethyl-3 (S) -hydroxyl-1-oxo-5 phenylpentyl) amino-i-methyl- 5-phenyl-2, 3-dihydro-lH-1, 4 benzodiazepin-2-one. 10 (R)-3-(3-cyclopentyl-l-oxopropyl)-4-(phenylmethyl)-2 oxazolidinone (2). 0 0 0 1. BuLi 2. 3-cyclopentylpropionyl chloride 1 2 A dry round bottom flask was charged with of (R)-4 15 (phenylmethyl)-2-oxazilidinone (1, 17.7 g, 0.100 mol). Anhydrous tetrahydrofuran (300 mL) was then added, and the solution was cooled to -780C. A solution of butyllithium (42.0 mL, 0.105 mol, 2.50 M in hexane) was added to the reaction flask over a 10-min period. After a few minutes, 20 3-Cyclopentylpropionyl chloride (16.8 mL, 0.110 mol) was added. The resulting solution was stirred for 30 min at 78 0 C, then allowed to warm to ambient temperature over a 30-min period. Excess 3-cyclopentylpropionyl chloride was quenched by the addition of 60 mL of saturated aqueous 25 ammonium chloride. The bulk of the tetrahydrofuran and hexane was removed on a rotary evaporator, and the slurry was extricated with two 80 mL portion of dichloromethane. The combined organic layers were washed with 75 mL of 1 M sodium hydroxide and 75 mL of brine, dried over anhydrous 30 magnesium sulfate, and filtered. The solvent was removed under reduced preddure. The residue was trituated with hexane to provide 16.5 g of desired product 2 as a white solid. 1H NMR (300 MHz, CDCl 3 ) 8 7.18 - 7.40 (5 H, m), -100- WO 01/19797 PCT/USOO/24967 4.67 (1 H, m), 4.12 - 4.22 (2 H, m), 3.30 (1 H, dd, J = 13.4, 3.1 Hz), 2.84 - 3.06 (2 H, m), 2.76 (1 H, dd, J = 13.4, 9.6 Hz), 1.42 - 1.96 (9 H, m), 1.15 (2 H, br, m). 5 3-(2 (R) -cyclopentylmethyl-3 (S) -hydroxyl-5-phenyl-1 oxopentyl)-4(R)-(phenylmethyl)-2-oxazolidinone (3). 0 OH O O 1. Bu 2 BOTf, TEA Ph 2. PhCH 2
CH
2 CHO Bn Bni 2 3 To a solution of acyloxazolidinone 2 (1.57 g, 5.00 10 mmol) in 20 mL of dichloromethane, cooled to -780C under nitrogen atmosphere, dibutylboron triflate (1.40 mL, 5.50 mmol) was added dropwise, followed by the addition of triethylamine. The mixture was warmed slowly to 0 0 C and was stirred at 0 0 C for an additional hour. The resultant 15 boryl enolate solution was then cooled to -780C, and 3 phenylpropanal (0.80 mL, 5.5 mmol) was added over a 5-min period time. The solution was stirred for 1 h at -78 0 C, then for 1 h at 0 0 C. The reaction mixture was quenched by the addition of 4 mL of a pH 7 aqueous phosphate buffer 20 and 12 mL of methanol. To this cloudy solution was added 8 mL of methanol and 10 mL of 30% aqueous hydrogen peroxide at such a rate as to keep the internal temperature below 10 0 C. After the solution was stirred for one additional hour, the volatile material was removed in a rotary 25 evaporator. The resulting slurry was extracted with three 20 mL portions of diethyl ether. The combined organic layers was washed with 20 mL of 5% aqueous sodium bicarbonate and 20 mL of brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced 30 pressure. Purification by flash column chromatography (25% ethyl acetate - hexane) provided 1.11 g (56%) of aldol 3 as a colorless oil. 1 H NMR (300 MHz, CDCl 3 ) 8 7.15 - 7.38 (m, 10 H), 4.72 (m, 1 H), 4.12 - 4.28 (m, 3 H), 3.85 (m, 1 H), -101- WO 01/19797 PCT/USOO/24967 3.34 (1 H, dd, J = 13.4, 3.1 Hz), 2.80 - 2.95 (1 H, m), 2.60 - 2.78 (2 H, m), 1.95 - 2.05 (1 H, m), 1.40 - 1.90 (10 H, m), 1.10 (2 H, m). 5 2(R)-cyclopentylmethyl-3(S)-hydroxyl-5-phenylpentanoic acid (4). OH O 0 OH O Ph NO LiOH, H 2 0 2 Ph OH Bn THF, H 2 0 3 4 Acyloxazolidinone 3 (226 mg, 0.500 mmol) was dissolved in 3 mL of THF and 1 mL of distilled water. The resulting 10 solution was cooled to 0 0 C. To this solution was added 30% aqueous hydrogen peroxide (0.40 mL, 4.0 mmol), followed by a solution of lithium hydroxide (19 mg, 0.80 mmol) in 0.5 mL of distilled water. After the solution was stirred for 16 h, sodium sulfite (567 mg, 4.50 mmol) in 3 mL of 15 distilled water was added. The bulk of tetrahydrofuran was removed under reduced pressure, and the resulting mixture (pH 12 ~ 13) was extracted with three 20 mL portion of methylene chloride to remove the oxazolidinone auxiliary. The aqueous layer was cooled in an ice bath and acidified 20 to pH 1 with 6 M aqueous hydrochloric acid. The resulting cloudy solution was extracted with five portion of 30 mL ethyl acetate. The combined organic layers are dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to yield 230 mg (81%) of the desired 25 acid 4 as a white solid. 1H NMR (300 MHz, CDC1 3 ) 6 7.18 7.35 (5 H, m), 3.87 (1 H, m), 2.81 - 2.87 (1 H, m), 2.60 2.76 (1 H, m); 2.54 - 2.60 (1 H, m), 1.00 - 1.95 (m, 13 H). 3- (2(R) -Cyclopentylmethyl-3 (S) -hydroxyl-l-oxo-5 30 phenylpentyl) amino-l-methyl- 5-phenyl-2, 3-dihydro-lH-1, 4 benzodiazepin-2-one (6). -102- WO 01/19797 PCT/USOO/24967 O N H N EDC, HOBt OH 0 4 + TsOH- H 2 N N TEA, CH 2
CI
2 Ph N N / \ H 5 6 A mixture of acid 4 (250 mg, 0.900 mmol) and 3-amino 1-methyl- 5-phenyl-2, 3-dihydro-lH-1, 4-benzodiazepin-2-one 5 p-toluenesulfonate salt (364 mg, 0.820 mmol) in 4 mL of methylene chloride was stirred at OOC. 1-Hydroxy benzotriazole hydrate (133 mg, 0.980 mmol), 1-[3 (dimethylamine)propyl]-3-ethylcarbodiimide hydrochloride (314 mg, 1.64 mmol) and triethylamine (0.51 mL, 3.7 mmol) 10 were added sequentially. After the mixture was stirred for 16 h, 30 mL of ethyl acetate was added. The organic layer was washed with 1 M HCl (15 mL), 5% NaHCO 3 (30 mL) and brine (30 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Purification by 15 chromatotron (30% ethyl acetate - hexane) afforded two diastereomers A and B. A: 120 mg (25%); 1 H NMR (300 MHz, CDCl 3 ) 8 7.20 - 7.70 (15 H, m), 5.54 (1 H, d, J = 8.0 Hz), 4.02 (1 H, m), 3.48 (3 H, s), 2.83 - 3.00 (1 H, m), 2.62 2.74 (1 H, m), 2.40 - 2.48 (1 H, m), 1.00 - 2.00 (13 H, m); 20 MS (ESI): 524 (M+H), 546 (M+Na), 522 (M-H), 558 (M+Cl). B: 120 mg (25%); 1 H NMR (300 MHz, CDCl 3 ) 8 7.60 (1 H, d, J = 6.9 Hz), 7.20 - 7.45 (14 H, m), 5.56 (1 H, d, J = 8.4 Hz), 3.84 (1 H, m), 3.48 (3 H, s), 2.83 - 3.00 (1 H, m), 2.62 2.74 (1 H, m), 2.50 - 2.60 (1 H, m), 1.00 - 1.95 (13 H, m); 25 MS (ESI): 524 (M+H), 546 (M+Na), 522 (M-H). Examples 2-135 The general procedure for Example 1 was followed using the corresponding acid chloride, aldehyde, and substituted 30 benzodiazepine, azepane or bisbenzodiazepine. Starting materials were either commercially available or prepared by methods known to one skilled in the art. -103- WO 01/19797 PCT/USOO/24967 Example 2. 3-(2(R)-Cyclopentylmethyl-3(S)-hydroxyl-1-oxo-5 phenylpentyl)amino-1-methyl-5-(4-fluoro-phenyl)-2,3 dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 542 (M+H). 5 Example 3. 3-(2(R)-Benzyl-3(S)-hydroxyl-1-oxo-5 phenylpentyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one. MS (ESI): 532 (M+H). 10 Example 4. 3-(2(R)-Isopropyl-3(S)-hydroxyl-1-oxo-5 phenylpentyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one. MS (ESI): 484 (M+H). Example 5. 3-(2(R)-Cyclopentylmethyl-3(S)-hydroxyl-1-oxo-4 15 (3,5-difluorophenoxy)butyl)amino-1-methyl-5-phenyl-2,3 dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 562 (M+H). Example 6. 3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-4-(3,5 difluorophenoxy)butyl)amino-1-methyl-5-phenyl-2,3-dihydro 20 1H-1,4-benzodiazepin-2-one. MS (ESI): 536 (M+H). Example 7. 3-(2(R)-Cyclopentylmethyl-3(S)-hydroxyl-1-oxo-4 phenoxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro 1H-1,4-benzodiazepin-2-one. MS (ESI): 560 (M+H). 25 Example 8. 3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-4 phenoxybutyl)amino-7-chloro-1-methyl-5-(4-fluorophenyl) 2,3-dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 552 (M+H). 30 Example 9. 3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-4 cyclohexyloxybutyl)amino-1-methyl-5-phenyl-2,3-dihydro-lH 1,4-benzodiazepin-2-one. MS (ESI): 464 (M+H). 35 Example 10. 3-(2(R)- Isobutyl -3(S)-hydroxyl-1-oxo-4 cyclohexyloxybutyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H 1,4-benzodiazepin-2-one. MS (ESI): 506 (M+H). -104- WO 01/19797 PCT/USOO/24967 Example 11. 3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-4 phenoxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro 1H-1,4-benzodiazepin-2-one. MS (ESI): 492 (M+H). 5 Example 12. 3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-4 phenoxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro 1H-1,4-benzodiazepin-2-one. MS (ESI): 534 (M+H). 10 Example 13. 3-(2(R)-Benzyl-3(S)-hydroxyl-1-oxo-4 cyclohexyloxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3 dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 574 (M+H). Example 14. 3-(2(R)-Cyclopentylmethyl-3(S)-hydroxyl-1-oxo 15 4-cyclohexyloxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3 dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 566 (M+H). Example 15. 3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-4 cyclohexyloxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3 20 dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 540 (M+H). Example 16. 3-(2(R)-Isopropyl-3(S)-hydroxyl-1-oxo-4 cyclohexyloxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3 dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 526 (M+H). 25 Example 17. 3-(2(R)-Methoxy-3(S)-hydroxyl-1-oxo-4-(4 trifluoromethylbenzyloxy)butyl)amino-7-chloro-1-methyl-5 phenyl-2,3-dihydro-lH-1,4-benzodiazepin-2-one. MS (ESI): 590 (M+H). 30 Example 18. 3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-4-(2,4 difluorobenzyloxy)butyl)amino-7-chloro-1-methyl-5-phenyl 2,3-dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 542 (M+H). 35 -105- WO 01/19797 PCT/USOO/24967 Example 20. 3-(2(R)-Vinyl-3(S)-hydroxyl-1-oxo-4 benzyloxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3 dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 536 (M+H). 5 Example 21. 3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-4 cyclohexyloxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3 dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 498 (M+H). Example 23. 3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-5 10 phenylpentyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one. MS (ESI): 498 (M+H). Example 24. 3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-3 cyclopropylpropyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H 15 1,4-benzodiazepin-2-one. MS (ESI): 434 (M+H). Example 25a. 3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo heptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one. MS (ESI): 450 (M+H). 20 Example 25b. 3-(R)-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo heptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one. MS (ESI): 450 (M+H). 25 Example 25c. 3-(S)-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo heptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one. MS (ESI): 450 (M+H). Example 26. 3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo 30 nonyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one. MS (ESI): 478 (M+H). Example 27. 3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo hexyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4 35 benzodiazepin-2-one. MS (ESI): 436 (M+H). -106- WO 01/19797 PCT/USOO/24967 Example 28. 3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-4 phenylbutyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one. MS (ESI): 484 (M+H). 5 Example 29. 3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-5 phenylpentyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one. MS (ESI): 442 (M+H). Example 30. 3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-6 10 phenylhexyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one. MS (ESI): 470 (M+H). Example 31. 3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo butyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4 15 benzodiazepin-2-one. MS (ESI): 408 (M+H). Example 32. 3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo octyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one. MS (ESI): 464 (M+H). 20 Example 33. 3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo heptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one. MS (ESI): 408 (M+H). 25 Example 34. 3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-3 phenylpropyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one. MS (ESI): 428 (M+H). Example 35. 3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-5,5 30 dimethyl-hexyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one. MS (ESI): 422 (M+H). Example 36. 3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-hexyl)amino 1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one. 35 MS (ESI): 394 (M+H). -107- WO 01/19797 PCT/USOO/24967 Example 37. 3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-3-(4 propoxyphenyl)propyl)amino-1-methyl-5-phenyl-2,3-dihydro 1H-1,4-benzodiazepin-2-one. MS (ESI): 486 (M+H). 5 Example 38. 2-(R)-cyclopropylmethyl-3-(S) hydroxylheptanoic acid (2-oxo-1-(3-phenoxybenzyl)azapan-3 (S)-yl) amide. MS (ESI): 493 (M+H), 491 (M-H), 527 (M+Cl). Example 39. 2(R)-cyclopropylmethyl-5-(3,5-difluorophenyl) 10 3-(S)-hydroxypentanoic acid (2-oxo-1-(3 phenoxybenzyl)azapan-3-(S)-yl)amide. MS (ESI): 577 (M+H), 575 (M-H), 599 (M+Na). Example 40. 4-cyclopentyl-2-(R)-cyclopropylmethyl-3-(S) 15 hydroxybutanoic acid (2-oxo-1-(3-phenoxybenzyl)azapan-3 (S)-yl) amide. MS (ESI): 519 (M+H), 541 (M+Na), 517 (M-H). Example 41. 2-(R)-cyclopropylmethyl-3-(S)-hydroxyheptanioc acid (1-(5-bromo-3-pyridinyl)methyl-2-oxo-azapan-3-(S)-yl) 20 amide. MS (ESI): 480 (M( 7 9 Br)+H), 482 (M( 81 Br+H), 478
(M(
7 9 Br)+H), 480 (M( 8 1 Br)-H). Example 42. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-5-(2-fluorophenyl)-1-methyl-2,3-dihydro-1H 25 1,4-benzodiazepin-2-one. MS (ESI): 466 (M+H), 488 (M+Na), 464 (M-H). Chromatography Note b and Note c. Example 43. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-5-(azapan-1-yl)-1-methyl-2,3-dihydro-1H 30 1,4-benzodiazepin-2-one. MS (ESI): 469 (M+H), 491 (M+Na), 467 (M-H). Chromatography Note b and Note c. Example 44. 3-(2-(R)-cyclopropylmethyl-5-(3,5 difluorophenyl)-3(S)-hydroxyl-1-oxopentyl)amino-1-methyl-5 35 (pyridn-2-yl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 533 (M+H), 555 (M+Na), 531 (M-H). Chromatography Note b and Note c. -108- WO 01/19797 PCT/USOO/24967 The 3-(3,5-difluorophenyl)propanal used in the aldol reaction was prepared from trans-3,5-difluorocinnamic acid by: (1) hydrogenation to 3-(3,5-difluorophenyl)propionic acid (L. Kruse et al J. Med. Chem. 1987, 30, 486-494); (2) 5 formation of Weinreb amide (M. Braun Synthesis 1989, 856); and (3) reduction to aldehyde (D. A. Evans J. Org. Chem. 1993, 58, 2446-2453). Example 45. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 10 oxopentyl)amino-1-methyl-5-(4-chlorophenyl)-2,3-dihydro-1H 1,4-benzodiazepin-2-one. MS (ESI): 482 (M+H), 504 (M+Na), 480 (M-H). Chromatography Note i and Note k. Example 46. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 15 oxoheptyl)amino-5-(4-methoxyphenyl)1-methyl-2,3-dihydro-1H 1,4-benzodiazepin-2-one. MS (ESI): 466 (M+H), 488 (M+Na), 464 (M-H). Chromatography Note b and Note c. Example 47. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 20 oxoheptyl)amino-5-(4-methoxyphenyl)-1-methyl-2,3-dihydro 1H-1,4-benxodiazepin-2-one. MS (ESI): 479 (M+H), 500 (M+Na), 476 (M-H). Chromatography Note m. Example 48. 3-(S)-(4-cyclopentyl-2-(R)-cyclopropylmethyl 25 3-(S)-hydroxyl-1-oxobutyl)amino-1-methyl-5-phenyl-2,3 dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 474 (M+H), 496 (M+Na), 472 (M-H). Example 49. 3-(S)-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl 30 1-oxohept-6-enyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H 1,4-benzodiazepin-2-one. MS (ESI): 446 (M+H), 468 (M+Na), 444 (M-H). Example 50. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 35 oxohept-6-enyl)amino-1-methyl-5-(4-trifluoromethyl-phenyl) 2,3-dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 514 (M+H). Chromatography Note i. -109- WO 01/19797 PCT/USOO/24967 Example 51. 3-(S)-(2-(R)-cyclopropylmethyl-5-(3,5 dimethylisoxazol-4-yl)-3-(S)-hydroxyl-l-oxopentyl)amino-l methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one. 5 MS (ESI): 515 (M+H), 537 (M+Na), 513 (M-H). The 3-(3,5-dimethyl-4-isoxazole)propanal used in the aldol reaction was prepared from: (1) methyl 3-(3,5 dimethyl-4-isoxazole)propionate (M. C. Marcotullio J. Org. Chem 1994, 59, 2884); (2) DIBAL-H reduction to alcohol ( N. 10 M. Yoon et al J. Org. Chem. 1985, 50, 2443-2450); and (3) TPAP/NMO oxidation to aldehyde (S. V. Ley et al Synthesis 1994, 639). Example 52. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-l 15 oxoheptyl)amino-7-chloro-l-methyl-5-phenyl-2,3-dihydro-lH 1,4-benzodiazepin-2-one. MS (ESI): 482 (M+H), 504 (M+Na), 480 (M-H). Chromatography Note n and Note o. Example 53. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-l 20 oxoheptyl)amino-l-methyl-(pyridin-2-yl)-2,3-dihydro-lH-1,4 benzodiazepin-2-one. MS (ESI): 449 (M+H), 471 (M+Na), 447 (M-H). Chromatography Note b and Note c. Example 54. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-l 25 oxoheptyl)amino-5-(4-fluorophenyl)-l-methyl-2,3-dihydro-lH 1,4-benzodiazepin-2-one. MS (ESI): 466 (M+H), 500 (M+Cl). Chromatography Note h. Example 55. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-l 30 oxoheptyl)amino-l-methyl-5-(4-trifouoromethylphenyl)-2,3 dihydro-lH-1,4-benzodiazepin-2-one. MS (ESI): 516 (M+H), 514 (M-H), 550 (M+Cl). Chromatography Note i. The 3-cycloproyl propionic acid, which was converted to 3-cycloproyl propionyl chloride used in the aldol 35 reaction, was prepared according to: A. Donetti J. Med. Chem. 1972, 15, (6), 590-592. -110- WO 01/19797 PCT/USOO/24967 Example 56. 3-(5-cyclopentyl-2-(R)-cyclopropylmethyl-3 (S)-hydroxyl-1-oxopentyl)amino-1-methyl-5-(pyridin-2-yl) 2,3-dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 489 (M+H), 511 (M+Na), 487 (M-H). Chromatography Note b and 5 Note c. Example 57. 3-(2-(R)-iso-butyl-3-(S)-hydroxyl-1 oxoheptyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3 dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 518 (M+H), 10 540 (M+Na), 516 (M-H). Chromatography Note b and Note c. Example 58. 3-(S)-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl 1-oxo-5-(thiophen-2-yl)amino-1-methyl-5-phenyl-2,3-dihydro 1H-1,4-benzodiazepin-2-one. MS (ESI): 502 (M+H), 524 15 (M+Na), 500 (M-H). Example 59. 3-(S)-(2-(R)-cyclopropylmethyl-5-(furan-2 yl)3-(S)-hydroxyl-1-oxopentyl)amino-1-methyl-5-phenyl-2,3 dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 486 (M+H), 20 508 (M+Na), 484 (M-H). Example 60. 3-(5-cyclopentyl-2-(R)-cyclopropylmethyl-3 (S)-hydroxyl-1-oxopentyl)amino-5-(4-fluorophenyl)-1-methyl 2,3-dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 506 25 (M+H), 528 (M+Na), 504 (M-H). Chromatography Note h. Example 61. 3-(S)-(2-(R)-cyclopropylmethyl-5-(3,5 difluorophenyl)-3-(S)-hydroxy-1-oxopentyl)amino-1-methyl-5 phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one. 30 MS (ESI): 532 (M+H), 554 (M+Na), 530 (M-H). Example 62. 3-(S)-(3-(S)-hydroxyl-2-(R)-(thiophen-2 yl)methyl-1-oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydro 1H-1,4-benzodiazepin-2-one. MS (ESI): 448 (M+H), 470 35 (M+Na), 446 (M-H). -111- WO 01/19797 PCT/USOO/24967 Example 63. 3-(S)-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl 1-oxoheptyl)amino-7-methyl-5-phenyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one. MS (ESI): 490 (M+H), 512 (M+Na), 488 (M-H). 5 Example 64. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-7-methoxy-1-methyl-5-phenyl-2,3-dihydro-1H 1,4-benzodiazepin-2-one. MS (ESI): 478 (M+H), 500 (M+Na), 476 (M-H). Chromatography Note 1. 10 Example 65. 3-(S)-(2-(R)-cyclobutylmethyl-3-(S)-hydroxyl 1-oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydro-lH-1,4 benzodiazepin-2-one. MS (ESI): 462 (M+H), 484 (M+Na). The 3-cyclobutyl propionic acid, which was converted 15 to 3-cyclobutyl propionyl chloride used in the aldol reaction, was prepared according to: A. Donetti J. Med. Chem. 1972, 15, (6), 590-592. Example 66. 3-(S)-(2-(R)-(3,5-difluorobenzyl)-3-(S) 20 hydroxyl-l-oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydor 1H-1,4-benzodiaxepin-2-one. MS (ESI): 520 (M+H), 518 (M H). Example 67. 3-(S)-(2-(R)-(furan-2-yl)methyl-3-(S) 25 hydroxyl-1-oxoheptyl)amino-l-methyl-5-phenyl-2,3-dihydro 1H-1,4-benzodiazepin-2-one. MS (ESI): 474 (M+H), 472 (M-H). Example 68. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxl-1 oxo-5-pheylpentyl)amino-1-methyl-5-(pyridin-2-yl)-2,3 30 dihydro-1H-benzodiazepin-2-one. MS (ESI): 514 (M+H), 536 (M+Na), 512 (M-H). Chromatography Note h. Example 69. 3-(2-(R)-iso-butyl-3-(S)-hydroxyl-1 oxoheptyl)amino-5-(4-fluorophenyl)-1-methyl-2,3-dihydro-1H 35 1,4-benzodiazepin-2-one. MS (ESI): 497 (M+H), 519 (M+Na), 495 (M-H). Chromatography Note b and Note c. -112- WO 01/19797 PCT/USOO/24967 Example 70. 3-(2-(R)-iso-butyl-3-(S)-hydroxyl-1 oxoheptyl)amino-5-(4-fluorophenyl)-1-methyl-2,3-dihydro-1H 1,4-benzodiazepin-2-one. MS (ESI): 468 (M+H), 502 (M+Cl). Chromatography Note h. 5 Example 71. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxo-5-phenylpentyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H 1,4-benzodiazepin-2-one. MS (ESI): 421 (M+H), 443 (M+Na), 419 (M-H). Chromatography Note b and Note c. 10 Example 72. 3-(2-(R)-cyclopropylmethyl-5-(furan-2-yl)-3 (S)-hydroxyl-1-oxopentyl)amino-1-methyl-5-(4 trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2 one. MS (ESI): 554 (M+H), 576 (M+Na), 552 (M-H). 15 Chromatography Note i. Example 73. 3-(5-cyclopentyl-2-(R)-cyclopropylmethyl-3 (S)-hydroxyl-1-oxopentyl)amino-1-methyl-5-(4 trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2 20 one. MS (ESI): 542 (M+H), 564 (M+Na), 540 (M-H). Chromatography Note i. Example 74. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxooctyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3 25 dihydro-lH-1,4-benzodiazepin-2-one. MS (ESI): 530 (M+H), 552 (M+Na), 528 (M-H). Chromatography Note i. Example 75. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxononyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3 30 dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 544 (M+H), 566 (M+Na), 542 (M-H). Chromatography Note i. Example 76. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-1-methyl-5-(4-trifluoromethyl(pyridin-2 35 yl))-2,3-dihydro-lH-1,4-benzodiazepin-2-one. MS (ESI): 517 (M+H), 539 (M+Na), 515 (M-H). Chromatography Note i. -113- WO 01/19797 PCT/USOO/24967 Example 77. 3-(2-(R)-cyclobutylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-1-methyl-5-(40trifluoromethylphenyl)-2,3 dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 530 (M+H), 552 (M+Na), 528 (M-H). Chromatography Note i. 5 Example 78. 3-(2-(R)-cyclopentylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3 dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 544 (M+H), 542 (M-H), 578 (M+Cl). Chromatography Note i. 10 Example 79. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-1-methyl-5-(4-methyl-2-pyridiyl)-2,3 dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 463 (M+H). Chromatography Note cc. 15 Example 80. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-1-methyl-5-(4-methyl-2-pyridyl)-2,3 dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 463 (M+H). Chromatography Note dd. 20 Example 81. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxobutyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3 dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 474 (M+H). Chromatography Note i. 25 Example 82. 3-(S)-(2-(R)-(3-butenyl)-3-(S)-hydroxyl-1 oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one. MS (ESI): 448 (M+H). 30 Example 83. 3-(S)-(2-(R)-(3-methylbutyl)3-(S)-hydroxyl-1 oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one. MS (ESI): 464 (M+H). Example 84. 3-(S)-(2-(R)-ethyl-3-(S)-hydroxyl-1 35 oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one. MS (ESI): 422 (M+H). -114- WO 01/19797 PCT/USOO/24967 Example 85. 3-(S)-(2-(R)-propyl-3-(S)-hydroxyl-1 oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1,4 benzodiazepin-2-one. MS (ESI): 436 (M+H). 5 Example 86. 3-(S)-(2-(R)-butyl-3-(S)-hydroxyl-1 oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one. MS (ESI): 450 (M+H). Example 87. 3-(4-(S)-amino-3-(R)-hydroxyl-2-(R)-methyl-1 10 oxo-5-phenylpentyl)amino-7-chloro-5-(2-fluorophenyl)-1 methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 523 (M+H), 521 (M-H). Chromatography Note x. Example 88. 3-(4-(S)-(tert-butoxycarbonylamino-3-(R) 15 hydroxyl-2-(R)-methyl-1-oxo-5-phenylpentyl)amino-7-chloro 5-(2-fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one. MS (ESI): 645 (M+H), 621 (M-H). Chromatography Note a and Note u. 20 Example 89. 3-(3-(tert-butoxycarbonylpyrrolidin-2-(R)-yl) 3-(R)-hydroxyl-2-(R)-methyl-1-oxopropyl)amino-7-chloro-5 (2-fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin 2-one. MS (ESI): 523 (M+H), 521 (M-H). Chromatography Note u and Note v. 25 Example 90. 3-(3-(R)-hydroxyl-2-(R)-methyl-1-oxo-3 (pyrrolidin-2-(R)-yl)propyl)-amino-7-chloro-5-(2 fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2 one. MS (ESI): 473 (M+H), 471 (M-H). Chromatography Note y 30 and Note z. Example 91. 3-(4-benzyloxy-3-(R)-hydroxyl-2-(R)-iso propyl-1-oxobutyl-amino-7-chloro-1-methyl-5-phenyl-2,3 dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 534- (M+H), 35 556 (M+Na), 532 (M-H). Chromatography Note u and Note v. -115- WO 01/19797 PCT/USOO/24967 Example 92. 2-(4-(S)-amino-3-(S)-hydroxyl-2-(S)-methyl-l oxo-5-phenylpentyl)amino-7-chloro-5-(2-flourophenyl)-1 methyl-2,3-dihydro-lH-1,4-benzodiazepin-2-one. MS (ESI): 523 (M+H), 521 (M-H). Chromatography Note w. 5 Example 93. 2-(4-(S)-(tert-butoxycarbonylamino-3 (S)hydroxyl-2-(S)-methyl-1-oxo-5-phenylpentyl)amino-7 chloro-5-(2-fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one. MS (ESI): 645 (M+Na), 621 (M-H). 10 Chromatography Note a and Note v. Example 94. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-l-methyl-5-(thiazol-2-yl)-2,3-dihydro-lH 1,4-benzodiazepin-2-one. MS (ESI): 455 (M+H), 477 (M+Na), 15 453 (M-H). Chromatography Note b and Note c. The benzodiazepine was made from 2-aminophenyl 2'thiazolylketone (see A. Furstner et al., Tetrahedron 1995, 51 (3), 773-786) following the synthetic sequence from: R. G. Sherrill et al., J. Org. Chem. 1995, 60, 734. 20 Example 95. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-l oxoheptyl)amino-1-cyclopropylmethyl-5-(thiazol-2-yl)-2,3 dihydro-lH-1,4benzodiazepin-2-one. MS (ESI): 495 (M+H), 517 (M+Na), 493 (M-H). Chromatography Note c. 25 The benzodiazepine was made from 2-aminophenyl 2'thiazolylketone (see A. Furstner et al., Tetrahedron 1995, 51 (3), 773-786) following the synthetic sequence from: R. G. Sherrill et al., J. Org. Chem. 1995, 60, 734. 30 Example 96. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-l oxoheptyl)amino-1-cyclopropylmethyl-5-(4 trifluoromethylphenyl)-2,3-dihydro-lH-1,4-benzodiazepin-2 one. MS (ESI): 556 (M+H), 578 (M+Na), 554 (M-H). Chromatography Note j and Note p. 35 Example 97. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-l oxoheptyl)amino-1-benzyl-5-(4-trifluoromethylphenyl)-2,3 -116- WO 01/19797 PCT/USOO/24967 dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 592 (M+H), 614 (M+Na), 590 (M-H). Chromatography Note b and Note c. Example 98. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 5 oxoheptyl)amino-1-(3-phenoxybenzyl)-5-(4-trifluoromethyl phenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 684 (M+H), 706 (M+Na), 682 (M-H). Chromatography Note q and Note r. 10 Example 99. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-i-(3-pyridinylmethyl)-5-(4-trifluoromethyl phenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 593 (M+H), 615 (M+Na), 519 (M-H). Chromatography Note q and Note r. 15 Example 100. 3-(2-(S)-cyclopropylmethyl-3-(R)-hydroxyl-1 oxoheptyl)amino-1-methyl-5-(4-trifluoromethyl-phenyl)-2,3 dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 516 (M+H), 538 (M+Na), 514 (M-H). Chromatography Note i. 20 The syn-aldol was made according to Scheme 1, except that (S)-4-(phenylmethyl)-2-oxazolidinone was used instead of the (R)-isomer shown in Scheme 1. Example 101. 3-(2-(S)-cyclopropylmethyl-3-(R)-hydroxyl-1 25 oxoheptyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3 dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 516 (M+H), 538 (M+Na), 514 (M-H). Chromatography Note k. The syn-aldol was made according to Scheme 1, except that (S)-4-(phenylmethyl)-2-oxazolidinone was used instead 30 of the (R)-isomer shown in Scheme 1. Example 102. 3-(2-(R)-cyclopropylmethyl-3-(R)-hydroxyl-1 oxoheptyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3 dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 516 (M+H), 35 538 (M+Na), 514 (M-H). Chromatography Note i. -117- WO 01/19797 PCT/USOO/24967 NHTs 0 DIPEA NHTs O OH IO 2. C 4
H
9 CHO, Ti 4 O OH LiOH, THF-H 2 0 HO The anti-aldols were made by the method described in: A. K. Ghosh, J. Am. Chem. Soc. 1996, 118, 2527-2528. The carboxylic acid shown was coupled with the corresponding 5 benzodiazepine following a procedure analogous to the procedure of the last step in Example 1. Example 103. 3-(2-(S)-cyclopropylmethyl-3-(S)-hydroxyl-l oxoheptyl)amino-l-methyl-5-(4-trifluoromethylphenyl)-2,3 10 dihydro-lH-1,4-benzodiazepin-2-one. MS (ESI): 516 (M+H), 538 (M+Na), 514 (M-H). Chromatography Note i. Followed the synthetic sequence of Example 102, except the opposite enantiomer of the chiral auxiliary was used. 15 Example 104. 3-(2-(S)-cyclopropylmethyl-3-(S)-hydroxyl-l oxoheptyl)amino-l-methyl-5-(4-trifluoromethylphenyl)-2,3 dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 516 (M+H), 514 (M-H). Chromatography Note k. Followed the synthetic sequence of Example 102, except 20 the opposite enantiomer of the chiral auxiliary was used. Example 105. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-3 (S)-methyl-1-oxoheptyl)amino-1-methyl-5-(4-trifluoromethyl phenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 25 530 (M+H), 552 (M+Na), 528 (M-H). Chromatography Note i. Addition of a methyl group to Example 135 was performed with an organocerium reagent generated from methylmagnesium bromide and cerium trichloride according to: T. Imamoto et al (a) J. Org. Chem. 1984, 49, 3904-3912, 30 and (b) J. Am. Chem. Soc. 1989, 111, 4392-4398. -118- WO 01/19797 PCT/USOO/24967 Example 106. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-1-(3-phenoxybenzyl)-5-methyl-2,3-dihydro 1H-1,4-benzodiazepin-2-one. MS (ESI): 554 (M+H). 5 Chromatography Note aa and Note bb. Example 107. 3- (2- (R) -cyclopropylmehtyl-3-(S) -hydroxyl-1 oxoheptyl) amino-l-benzyl-5-methyl-2, 3-dihydro-1H-1, 4 benzodiazepin-2-one. MS (ESI): 462 (M+H). Chromatography 10 Note b and Note c. Example 108. 3-(3-(S)-acetoxy-2-(R)-iso-butyl-1 oxoheptyl)amino-5-(4-fluorophenyl)-1-methyl-2,3-dihydro-lH 1,4-benzodiazepin-2-one. MS (ESI): 510 (M+H), 532 (M+Na), 15 508 (M-H). Chromatography Note h. Example 109. 3-(S) -(5-cyclopentyl-2- (R) -cyclopropylmethyl 3- (S) -methoxy-1-oxopentyl) amino-1-methyl-5-phenyl-2, 3 dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 502 (M+H), 20 524 (M+Na). OH O O O0 O N O Me 3 0BF 4 N 000 Bn)- proton sponge B O0 O LiOH, THF-H 2 0 OH v' Methylation of the corresponding aldol was carried out according to: (a) D. A. Evans et al., Tetrahedron Lett. 1994, 35 (39), 7171-7172; (b) G. R. Pettit, Synthesis 1996, 25 719-725. The carboxylic acid shown was then coupled with the corresponding benzodiazepine following a procedure analogous to the procedure of the last step in Example 1. Example 113. 1- (1-hydroxypentyl) cyclohexanecarboxylic 30 acid(5-(4-fluorophenyl)-l-methyl-2-oxo-2,3-dihydro-lH-1,4 -119- WO 01/19797 PCT/USOO/24967 benzodiazepin-3-yl)amide. MS (ESI): 480 (M+H), 502 (M+Na), 478 (M-H). Chromatography Note t and Note h. 0 0 OH 0 0 N 1. Bu 2 BOTf, TEA , N N Ph 2. C 4 HCHO Ph OH O OH LiOH, THF-H 2 0 The corresponding aldol was made according to (a) A. 5 S. Kende et al., Tetrahedron Lett. 1989, 30 (43), 5821 5824; (b) H. Mulzer et al., Tetrahedron Lett. 1995, 36 (42), 7643-7646. The carboxylic acid shown was coupled with benzodiazepine following a procedure analogous to the procedure of the last step in Example 1. 10 Example 114. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-l oxoheptyl)amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one. MS (ESI): 421 (M+H), 443 (M+Na), 419 (M-H). Chromatography Note s. 15 Example 115. 3- (2- (R) -cyclopropylmethyl-3- (S) -hydroxyl-l oxooctyl) amino-5-methyl-5H, 7H-dibenzo [b, d] azepin-6-one. MS (ESI): 435 (M+H), 457 (M+Na), 433 (M-H). Chromatography Note s. 20 Example 116. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-l oxononyl)amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one. MS (ESI): 449 (M+H), 471 (M+Na), 447 (M-H). Chromatography Note s. 25 Example 117. 3- (2- (R) -cyclopropylmethyl-5- (furan-2-yl) -3 (S) -hydroxyl-l-oxopentyl) amino-5-methyl-5H, 7H dibenzo[b,d]azepin-6-one. MS (ESI): 459 (M+H), 481 (M+Na), 457 (M-H). Chromatography Note s. 30 -120- WO 01/19797 PCT/USOO/24967 Example 118. 2-(R)-cyclopropylmethyl-3-(S)-hydroxyl heptanoic acid (2-oxo-1-(3-phenylamino-benzyl)azapan-3-(S) yl) amide. MS (ESI): 492 (M+H), 514 (M+Na), 490 (M-H). Step 1: [2-Oxo-l-(3-phenylamino-benzyl)-azepan-3-yl] 5 carbamic acid tert-butyl ester: In a 100 ml round bottomed flask Binap, (S)-(-)2,2'-Bis(diphenylphosphino)-1,1' binaphthyl, ( 0.210 g , 0.3375 mmol) dissolved in 15mL toluene was stirred at 80 0 C for 1 minute . To the flask cooled to room temperature under inert atmosphere Pd(OAC) 2 10 (0.050 g , 0.225 mmol) was added and the solution was stirred at room temperature for 2 minutes. To the reaction mixture [1-(3-Iodo-benzyl)-2-oxo-azepan-3-yl]-carbamic acid tert-butyl ester ( 1.0 g , 2.25 mmol) dissolved in 15mL toluene , aniline (1.047 g , 11.25 mmol) and Sodium tert 15 butoxide (0.259 g , 2.70 mmol ) were added and the solution was stirred at 80 0 C for 18 h. The reaction was cooled to room temperature, diluted with 200mL of water, and extracted twice with 100 mL of ethyl acetate. The organic layer was dried with anhydrous sodium sulfate, filtered and 20 concentrated to an oil. The oil was purified on flash silica gel column using 10-30% ethyl acetate in hexanes as eluent to yield 0.562 g (61%). MS (ESI) M+H = 432.5 Step 2: 3-Amino-l-(3-phenylamino-benzyl)-azepan-2-one, trifluoroacetic acid salt: In a 25mL round bottomed flask 25 the ester from Step 1 above ( 0.025 g , 0.06 mmol ) was dissolved in 10mL of 50%TFA / CH 2 Cl 2 and was stirred at room temperature for 1 h. The solvent was concentrated to an oil and dried under high vacuum to yield 0.025 g (100%). MS (ESI) M+H = 310.4 30 Step 3: 2-Cyclopropylmethyl-3-hydroxy-heptanoic acid [2-oxo-1-(3-phenylamino-benzyl)-azepan-3-yl]-amide: In a 25mL round bottomed flask 2-Cyclopropylmethyl-3-hydroxy heptanoic acid ( 0.0125g , 0.061mmol ) was dissolved in 1mL DMF. To the reaction mixture HATU, O-(7-Azabenzotriazol-l 35 yl) -N,N,N',N'-tetramethyluronium hexafluorophosphate, (0.029 g , 0.0734 mmol ) and N-Methyl morpholine (0.018 g, 0.018 mmol) were added and the reaction solution was -121- WO 01/19797 PCT/USOO/24967 stirred at room tenperature for 10 minutes. To the reaction mixture the compound from Step 2 above (0.025 g, 0.06 mmol) dissolved in 1mL of DMF was added and the reaction solution was stirred at room tenperature for 18 h. 5 The solution was diluted with 50 mL of water and extracted twice with 20 mL of ethyl acetate. The combined organic layers were dried with anhydrous Sodium sulfate, filtered, and concentrated to an oil. The oil was purified on a flash silica gel column using 20-40% ethyl acetate in 10 hexanes as eluent to yield 6.0 mg (20%). MS (ESI) M+H = 492.6 Example 119. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-l oxoheptyl)amino-5-cyclopentyl-l-methyl-2,3-dihydro-lH-1,4 15 benzodiazepin-2-one. MS (ESI): 440 (M+H). Chromatography Note a. Synthesis of 2-aminophenyl cyclopentylmethanone: To a solution of anthranilonitrile (15.0 g) in diethyl ether (600 mL) was added a solution of 2.0 M cyclopentylmagnesium 20 bromide in diethyl ether (159 mL) at 0 0 C under nitrogen. The mixture was stirred at room temperature overnight (20 hours). 500 ml of 5 N HCl in H 2 0 was added very slowly at 0 0 C. The mixture was stirred at room temperature for 1 hour. The aqueous layer was neutralized with 50% NaOH/H 2 0 25 to pH = 12. 2 X 500 mL of ethyl acetate was used to extract the aqueous layer. The combined organic layers were dried over Na 2
SO
4 . The solvent was removed to give the crude product 22.5 g (93.6% yield). HINMR(CDCl 3 ): 86.62-7.82 (m, 4H), 3.64-3.78 (m, 1H), 1.50-1.96 (m, 8H). 30 The 2-aminophenyl cyclopentylmethanone was converted to benzodiazepine following: R. G. Sherrill et al J. Org. Chem. 1995, 60, 734. Example 120. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-l 35 oxoheptyl)amino-5-benzyl-l-methyl-2,3-dihydro-lH-1,4 benzodiazepin-2-one. MS (ESI): 462 (M+H), 460 (M-H). Chromatography Note b and Note c. -122- WO 01/19797 PCT/USOO/24967 The benzodiazepine was made from 1-(2-aminophenyl)-2 phenylethanone (see M. W. Partridge et al., J. Chem. Soc. 1964, 3673) following the synthetic sequence from: R. G. Sherrill, J. Org. Chem. 1995, 60, 734. 5 Example 121. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-l oxoheptyl)amino-5-benzyl-l-butyl-2,3-dihydro-lH-1,4 benzodiazepin-2-one. MS (ESI): 504 (M+H), 502 (M-H). Chromatography Note b and Note c. 10 Example 122. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-l oxoheptyl)amino-5-cycloheptyl-l-methyl -2,3-dihydro-lH-1,4 benzodiazepin-2-one. MS (ESI): 468 (M+H), 466 (M-H). Chromatography Note b and Note c. 15 Example 123. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-l oxoheptyl)amino-l-benzyl-5-cycloheptyl-2,3-dihydro-lH-1,4 benzodiazepin-2-one. MS (ESI): 544 (M+H), 542 (M-H). Chromatography Note a. 20 Example 124. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-l oxoheptyl)amino-l-butyl-5-cycloheptyl-2,3-dihydro-lH-1,4 benzodiazepin-2-one. MS (ESI): 510 (M+H), 508 (M-H). Chromatography Note b and Note c. 25 Example 125. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-l oxoheptyl)amino-i-(2-pyridinylmethyl)-5-(4 trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2 one. MS (ESI): 593 (M+H), 615 (M+Na), 591 (M-H). 30 Chromatography Note a. Example 126. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-i-(3-pyridinylmethyl)-5-(2-fluorophenyl) 2,3-dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 543 35 (M+H), 541 (M-H). Chromatography Note d and Note e. -123- WO 01/19797 PCT/USOO/24967 Example 127. 3-(2-(S)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxopentyl)amino-i-(3-pyridinylmethyl)-5-(4 trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2 one. MS (ESI): 565 (M+H), 563 (M-H). Chromatography Note f 5 and Note g. Example 128. 3-(2-1(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-1-methyl-5-(N,N-dibutylamino)-2,3-dihydro 1H-1,4-benzodiazepin-2-one. MS (ESI): 499 (M+H). 10 Chromatography Note a. Example 129. 3-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-1-n-butyl-5-t-butyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one. MS (ESI): 470 (M+H). Chromatography 15 Note b and Note c. Example 130. 3-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-1-(2-oxo-3,3-dimethylbutyl)-5-n-butyl-2,3 dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 512 (M+H). 20 Chromatography Note b. Example 131. 3-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-1-benzyl-5-t-butyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one. MS (ESI): 504 (M+H). Chromatography 25 Note a. Example 132. 3-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-i-(2-picolyl)-5-n-butyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one. MS (ESI): 505 (M+H). Chromatography 30 Note b and Note c. Example 133. 3-(2-(R)-Isobutyl-3-(S)-hydroxyl-1 oxoheptyl)amino-1-methyl-5-homopiperidino-2,3-dihydro-1H 1,4-benzodiazepin-2-one. MS (ESI): 471 (M+H). 35 Chromatography Note b and Note c. -124- WO 01/19797 PCT/USOO/24967 Example 135. 3-(2-(R)-cyclopropylmethyl-1,3 dioxoheptyl)amino-l-methyl-5-(4-trifluoromethylphenyl)-2,3 dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 514 (M+H), 536 (M+Na), 512 (M-H). Chromatography Note i. 5 Example 55 was oxidized to the dicarbonyl compound by TPAP/NMO, see S. V. Ley et al., Synthesis 1994, 639. Example 136. 1-pentyrylcyclohexanecarboxylic acid (5-(4 fluorophenyl)-l-methyl-2-oxo-2,3-dihydro-1H-1,4 10 benzodiazepin-3-yl) amide. MS (ESI): 478 (M+H), 500 (M+Na), 476 (M-H). Chromatography Note h. Chromatography Notes: Note a: epimeric mixture at BZD. 15 Note b: 1 st eluting peak on CHIRALPAK AD chiral column with 10 - 35% i-PrOH/hexane. Note c: 2 nd eluting peak on CHIRALPAK AD chiral column with 10 - 35% i-PrOH/hexane. Note d: 1 st eluting peak on CHIRALCEL OD chiral column with 20 2/200/800 ratio of MeOH/i-PrOH/Hexane. Note e: 2nd eluting peak on CHIRALCEL OD chiral column with 2/200/800 ratio of MeOH/i-PrOH/Hexane. Note f: 1 st eluting peak on silica gel column with 2% MeOH/CH 2 Cl 2 . 25 Note g: 2 nd eluting peak on silica gel column with 2% MeOH/CH 2 Cl 2 . Note k: made from BZD-amine which in Cbz protected form was the 2 nd eluting peak on CHIRALPAK AD column with acetonitrile. 30 Note m: made from BZD-amine which in Cbz protected form was the 1 st eluting peak on CHIRALPAK AS with methanol. Note n: made from BZD-amine which was the 1 st eluting peak on CHIRALPAK AS with 0.1% diethylamine/methanol. 35 Note o: made from BZD-amine which was the 2nd eluting peak on CHIRALPAK AS with 0.1% diethylamine/methanol. Note h: made from BZD-amine which was the 1 st eluting peak on CHIRALPAK AD column with 0.1% diethylamine/MeOH. 40 Note i: made from BZD-amine which in Cbz protected form was the 1 st eluting peak on CHIRALPAK AD column with acetonitrile. Note 1: made from BZD-amine which in Cbz protected was the 1 st eluting peak on CHIRALCEL OJ with 1:4 of 45 hexane/ethanol. Note j: 1 st eluting peak on CHIRALPAK AD column with acetonitrile/water. -125- WO 01/19797 PCT/USOO/24967 Note p: 2 nd eluting peak on CHIRALPAK AD column with acetonitrile/water. Note q: 1st eluting peak on CHIRALCEL OD with 10% i propanol/hexane. 5 Note r: 2 nd eluting peak on CHIRALCEL OD with 10% i propanol/hexane. Note s: made from bisbenazapine amine which was the 1 st peak on CHIRALCEL OD with 20% i-PrOH/hexane with diethylamine. 10 Note t: made from BZD-amine which was the 2nd eluting peak on CHIRALPAK AD column with 0.1% diethylamine/MeOH. Note w: derived from Example 93 by treatment with TFA. Note x: derived from Example 88 by treatment with TFA. 15 Note u: 2 nd eluting peak on silica gel column with 30-80% EtOAc/hexane. Note v: 1 st eluting peak on silica gel column with 30-80% EtOAc/hexane. Note y: derived from Example 89 by treatment with TFA. 20 Note z: derived from Example 89 by treatment with TFA. Note aa: 1st eluting peak on CHIRALPAK AD with 20:80 of water/MeCN. Note bb: 2 nd eluting peak on CHIRALPAK AD with 20:80 of water/MeCN. 25 Note cc: made from BZD-amine which in Cbz protected form was the 2 nd eluting peak on CHIRALCEL OD column with 1/300/700 ratio of diethtlamine/EtOH/CO 2 . Note dd: made from BZD-amine which in Cbz protected form was the 1 st eluting peak on CHIRALCEL OD column 30 with 1/300/700 ratio of diethtlamine/EtOH/CO2. Tables 1-8 below provide representative Examples of the compounds of Formula (I) of the present invention. -126- WO 01/19797 PCT/USOO/24967 Table 1
CH
3 I OH 0O N \ /
R
13 Q E HN N 5 R"i R 5 Ex.# Q R5 R1l R 13 Mass (M+H) 1 phenethyl cyclopentylmethyl phenyl H 524 2 phenethyl cyclopentylmethyl 4-F-phenyl H 542 3 phenethyl benzyl phenyl H 532 4 phenethyl i-propyl phenyl H 484 5 3,5-diF- cyclopentylmethyl phenyl H 562 phenoxymethyl 6 3,5-diF- i-butyl phenyl H 536 phenoxymethyl 7 phenoxymethyl cyclopentylmethyl phenyl Cl 560 8 phenoxymethyl i-butyl 2-F-phenyl Cl 552 9 cyclohexyl- methyl phenyl H 464 oxymethyl 10 cyclohexyl- i-butyl phenyl H 506 oxymethyl 11 phenoxymethyl methyl phenyl Cl 492 12 phenoxymethyl i-butyl phenyl Cl 534 13 cyclohexyl- benzyl phenyl Cl 574 oxymethyl 14 cyclohexyl- cyclopentylmethyl phenyl Cl 566 oxymethyl 15 cyclohexyl- i-butyl phenyl Cl 540 oxymethyl 16 cyclohexyl- i-propyl phenyl Cl 526 oxymethyl 17 4-CF3-benzyl- methoxy phenyl Cl 590 oxymethyl 18 2,4-diF-benzyl- methyl phenyl Cl 542 oxymethyl 20 benzyloxymethyl vinyl phenyl Cl 536 21 cyclohexyl- methyl phenyl Cl 498 oxymethyl 22 23 phenethyl i-butyl phenyl H 498 24 cyclopropyl i-butyl phenyl H 434 25a n-butyl i-butyl phenyl H 450 25b n-butyl i-butyl phenyl H 450 25c n-butyl i-butyl phenyl H 450 26 n-hexyl i-butyl phenyl H 478 -127- WO 01/19797 PCT/USOO/24967 27 n-propyl i-butyl phenyl H 436 28 benzyl i-butyl phenyl H 484 29 phenethyl methyl phenyl H 442 30 phenpropyl methyl phenyl H 470 31 methyl i-butyl phenyl H 408 32 n-pentyl i-butyl phenyl H 464 33 n-butyl methyl phenyl H 408 34 phenyl methyl phenyl H 428 35 2,2-dimethyl- methyl phenyl H 422 propyl 36 n-propyl methyl phenyl H 394 37 4-propoxyphenyl methyl phenyl H 486 25a: the chiral carbon of the benzodiazepine ring is racemic. 25b: the chiral carbon of the benzodiazepine ring is (R). 25c: the chiral carbon of the benzodiazepine ring is (S). 5 Table 2 W-X-Y-Z QH 0 N Q ZN H Ex.# Q Z-Y-X-W 38 n-butyl 3-phenoxybenzyl 39 3,5-diF-phenethyl 3-phenoxybenzyl 40 cyclopentylmethyl 3-phenoxybenzyl 41 n-butyl 5-bromo-3-pyridinyl 118 n-butyl 3-(phenyl)amino-benzyl 10 -128- WO 01/19797 PCT/USOO/24967 Table 3
CH
3 I OH O O \ /
R
1 3 Q HNN RR Ex.# Q R 5 Ril R 13 42 n-butyl cyclopropylmethyl 2-F-phenyl H 43 n-butyl cyclopropylmethyl azapan-1-yl H 44 3,5-diF- cyclopropylmethyl pyridin-2-yl H phenethyl 45 n-butyl cyclopropylmethyl 4-Cl-phenyl H 46 n-butyl cyclopropylmethyl 3-F-phenyl H 47 n-butyl cyclopropylmethyl 4-MeO-phenyl H 48 cyclopentyl cyclopropylmethyl phenyl H methyl 49 but-3-enyl cyclopropylmethyl phenyl H 50 but-3-enyl cyclopropylmethyl 4-CF 3 -phenyl H 51 2-(3,5-dimethyl cyclopropylmethyl phenyl H isoxazol-4-yl) ethyl 52 n-butyl cyclopropylmethyl phenyl Cl 53 n-butyl cyclopropylmethyl pyridin-2-yl H 54 n-butyl cyclopropylmethyl 4-F-phenyl H 55 n-butyl cyclopropylmethyl 4-CF 3 -phenyl H 56 2-cyclopentyl- cyclopropylmethyl pyridin-2-yl H ethyl 57 n-butyl i-butyl 4-CF 3 -phenyl H 58 2-(thiophen-2- cyclopropylmethyl phenyl H yl) -ethyl 59 2-(furan-2-yl)- cyclopropylmethyl phenyl H ethyl 60 2-cyclopentyl- cyclopropylmethyl 4-F-phenyl H ethyl 61 3,5-diF- cyclopropylmethyl phenyl H phenethyl 62 n-butyl cyclopropylmethyl phenyl H -129- WO 01/19797 PCT/USOO/24967 63 n-butyl thiophen-2-yl- phenyl H methyl 64 n-butyl cyclopropylmethyl phenyl MeO 65 n-butyl cyclobutylmethyl phenyl H 66 n-butyl 3,5-diF-phenyl- phenyl H methyl 67 n-butyl furan-2-yl-methyl phenyl H 68 phenethyl cyclopropylmethyl 4-F-phenyl H 69 phenethyl cyclopropylmethyl pyridin-2-yl H 70 n-butyl i-butyl 4-F-phenyl H 71 phenethyl cyclopropylmethyl phenyl H 72 2-furan-2-yl- cyclopropylmethyl 4-CF 3 -phenyl H ethyl 73 2-cyclopentyl- cyclopropylmethyl 4-CF 3 -phenyl H ethyl 74 n-pentyl cyclopropylmethyl 4-CF 3 -phenyl H 75 n-hexyl cyclopropylmethyl 4-CF 3 -phenyl H 76 n-butyl cyclopropylmethyl 4-CF 3 -pyridin- H 2-yl 77 n-butyl cyclobutylmethyl 4-CF 3 -phenyl H 78 n-butyl cyclopentylmethyl 4-CF 3 -phenyl H 79 n-butyl cyclopropylmethyl 4-methyl- H pyridin-2-yl 80 n-butyl cyclopropylmethyl 4-methyl- H pyridin-2-yl 81 methyl cyclopentylmethyl 4-CF 3 -phenyl H 82 n-butyl but-3-enyl phenyl H 83 n-butyl 3-methyl-butyl phenyl H 84 n-butyl ethyl phenyl H 85 n-butyl propyl phenyl H 86 n-butyl n-butyl phenyl H 87 1-(S)-amino- methyl 2-F-phenyl Cl phenethyl 88 1-(S)-(BOC-NH)- methyl 2-F-phenyl Cl phenethyl 89 N-BOC- methyl 2-F-phenyl Cl pyrrolidin-2 (R)-yl 90 pyrrolidin-2- methyl 2-F-phenyl Cl (R)-yl -130- WO 01/19797 PCT/USOO/24967 91 benzyloxy-methyl i-propyl phenyl C1 119 n-butyl cyclopropylmethyl cyclopentyl H 120 n-butyl cyclopropylmethyl benzyl H 122 n-butyl cyclopropylmethyl cycloheptyl H 128 n-butyl cyclopropylmethyl N,N-dibutyl- H amino 133 n-butyl i-butyl homopiperidino H 134 n-butyl i-butyl spiro-cyclo- H pentyl Table 4
CH
3 I OH O O N\ R 13 Q HN N
R
11 5 R5 Ex.# Q R5 Rll R13 92 1-(S)-amino- Methyl 2-F-phenyl Cl phenethyl 93 1-(S)-(BOC-NH)- Methyl 2-F-phenyl Cl phenethyl 100 n-butyl cyclopropylmethyl 4-CF 3 -phenyl H 101 n-butyl cyclopropylmethyl 4-CF 3 -phenyl H -131- WO 01/19797 PCT/USOO/24967 Table 5A W-X-Y-Z I HQ R2 0 0 N\/ Q N N' l -H R Ex.# Q R2 Z-Y-X-W- Ri 94 n-butyl H methyl thiazol-2-yl 95 n-butyl H cyclopropylmethyl thiazol-2-yl 96 n-butyl H cyclopropylmethyl 4-CF 3 -phenyl 97 n-butyl H benzyl 4-CF 3 -phenyl 98 n-butyl H 3-phenoxy-benzyl 4-CF 3 -phenyl 99 n-butyl H 3-pyridinyl-methyl 4-CF 3 -phenyl 105 n-butyl Me methyl 4-CF 3 -phenyl 106 n-butyl H 3-phenoxy-benzyl methyl 107 n-butyl H benzyl methyl 121 n-butyl H n-butyl benzyl 123 n-butyl H benzyl cycloheptyl 124 n-butyl H n-butyl cycloheptyl 125 n-butyl H 2-pyridinyl-methyl 4-CF 3 -phenyl 126 n-butyl H 3-pyridinyl-methyl 2-F-phenyl 129 n-butyl H n-butyl t-butyl 130 n-butyl H 2-oxo-3,3- n-butyl dimethylbutyl 131 n-butyl H benzyl t-butyl 132 n-butyl H 2-pyridinyl-methyl n-butyl 5 -132- WO 01/19797 PCT/USOO/24967 Table 5B W-X-Y-Z I NN H R1 Vl- 2 Ex.# Q R2 Z-Y-X-W- R" 102 n-butyl H methyl 4-CF 3 -phenyl 5 Table 5C W-X-Y-Z HO O H R Ex.# Q R2 Z-Y-X-W- Rl 103 n-butyl H methyl 4-CF 3 -phenyl 104 n-butyl H methyl 4-CF 3 -phenyl 127 ethyl H 3-pyridinyl-methyl 4-CF 3 -phenyl 10 -133- WO 01/19797 PCT/USOO/24967 Table 6
CH
3 Q HN N R
R
5 R5a 5 Ex.# R Q 5 /R5a R 1 5 108 acetyl n-butyl R 5a= i-butyl 4-F-phenyl R =H 5 2-cyclo R = cyclopropyl 109 methyl pentyl methyl phenyl ethyl R5a =H 5 5a 113 H n-butyl CR R 4-F-phenyl = 1,1-cyclohexyl -134- WO 01/19797 PCT/USOO/24967 Table 8
CH
3 I O~o~yN OH o \ / Q- -- ~ N "'+ H Ex.# 114 n-butyl 115 n-pentyl 116 n-hexyl 117 2-(furan-2-yl)-ethyl 5 UTILITY AS production has been implicated in the pathology of Alzheimer's Disease (AD). The compounds of the present 10 invention have utility for the prevention and treatment of AD by inhibiting AP production. Methods of treatment target formation of AS production through the enzymes involved in the proteolytic processing of P amyloid precursor protein. Compounds that inhibit $ or ysecretase 15 activity, either directly or indirectly, control the production of AP. Such inhibition of $ or ysecretases reduces production of AS, and is expected to reduce or prevent the neurological disorders associated with Approtein, such as Alzheimer's Disease. 20 Cellular screening methods for inhibitors of AP production, testing methods for the in vivo suppression of AP production, and assays for the detection of secretase activity are known in the art and have been disclosed in -135- WO 01/19797 PCT/USOO/24967 numerous publications, including PCT publication number WO 98/22493, EPO publication number 0652009, US patent 5703129 and US patent 5593846; all hereby incorporated by reference. 5 The compounds of the present invention have utility for the prevention and treatment of disorders involving A$ production, such as cerebrovascular disorders. Compounds of the present invention have been shown to inhibit AS production, as determined by the secretase 10 inhibition assay described below. Compounds of the present invention have been shown to inhibit AS production, utilizing the C-terminus P amyloid precursor protein accumulation assay described below. Compounds of Formula (I) are expected to possess 7 15 secretase inhibitory activity. The y-secretase inhibitory activity of the compounds of the present invention is demonstrated using assays for such activity, for example, using the assay described below. Compounds of the present invention have been shown to inhibit the activity of y 20 secretase, as determined by the A$ immunoprecipitation assay. Compounds provided by this invention should also be useful as standards and reagents in determining the ability of a potential pharmaceutical to inhibit AS production. 25 These would be provided in commercial kits comprising a compound of this invention. As used herein "ig" denotes microgram, "mg" denotes milligram, "g" denotes gram, "iL" denotes microliter, "mL" denotes milliliter, "L" denotes liter, "nM" denotes 30 nanomolar, "PM" denotes micromolar, "mM" denotes millimolar, "M" denotes molar, "nm" denotes nanometer, "SDS" denotes sodium dodecyl sulfate, and "DMSO" denotes dimethyl sulfoxide, and "EDTA" denotes ethylenediaminetetraacetato. -136- WO 01/19797 PCT/USOO/24967 A compound is considered to be active if it has an
IC
5 0 or Ki value of less than about 100 p1M for the inhibition of AS production. 5 $ amyloid precursor protein accumulation assay A novel assay to evaluate the accumulation of AS protein was developed to detect potential inhibitors of secretase. The assay uses the N 9 cell line, characterized for expression of exogenous APP by immunoblotting and 10 immunoprecipitation. The effect of test compounds on the accumulation of A$ in the conditioned medium is tested by immunoprecipitation. Briefly, N 9 cells are grown to confluency in 6-well plates and washed twice with 1 x Hank's buffered salt solution. 15 The cells are starved in methionine/cysteine deficient media for 30 min, followed by replacement with fresh deficient media containing 150uCi S35 Translabel (Amersham). Test compounds dissolved in DMSO (final concentration 1%) are added together with the addition of 20 radiolabel. The cells are incubated for 4 h at 37 0 C in a tissue culture incubator. At the end of the incubation period, the conditioned medium is harvested and pre-cleared by the addition of 5 pl normal mouse serum and 50ul of protein A Sepharose 25 (Pharmacia), mixed by end-over-end rotation for 30 minutes at 4 0 C, followed by a brief centrifugation in a microfuge. The supernatant is then harvested and transferred to fresh tubes containing 5ug of a monoclonal antibody (clone 1101.1; directed against an internal peptide sequence in 30 A$) and 50 p1 protein A Sepharose. After incubation overnight at 4 0 C, the samples are washed three times with high salt washing buffer (50mM Tris, pH 7.5, 500mM NaCl, 5mM EDTA, 0.5% Nonidet P-40), three times with low salt wash buffer (50mM Tris, pH 7.5, 150mM NaCl, 5mM EDTA, 0.5% 35 Nonidet P-40), and three times with 10mM Tris, pH 7.5. The pellet after the last wash is resuspended in SDS sample -137- WO 01/19797 PCT/USOO/24967 buffer (Laemmli, 1970) and boiled for 3 minutes. The supernatant is then fractionated on either 10-20% Tris/Tricine SDS gels or on 16.5% Tris/Tricine SDS gels. The gels are dried and exposed to X-ray film or analyzed by 5 phosphorimaging. The resulting image is analyzed for the presence of AP polypeptides. The steady-state level of AP in the presence of a test compound is compared to wells treated with DMSO (1%) alone. A typical test compound blocks AP accumulation in the conditioned medium, and is 10 therefore considered active, with an IC 5 0 less than 100 pM. C-Terminus $ Amyloid Precursor Protein Accumulation Assay The effect of test compounds on the accumulation of C terminal fragments is determined by immunoprecipitation of 15 APP and fragments thereof from cell lysates. N 9 cells are metabolically labeled as above in the presence or absence of test compounds. At the end of the incubation period, the conditioned medium are harvested and cells lysed in RIPA buffer (10 mM Tris, pH 8.0 containing 1% Triton X-100, 20 1% deoxycholate, 0.1% SDS, 150mM NaCl, 0.125% NaN 3
)
Again, lysates are precleared with Sul normal rabbit serum / 50ul protein A Sepharose, followed by the addition of BC 1 antiserum (15p1l;) and 50pl protein A Sepharose for 16 hours at 4 0 C. The immunoprecipitates are washed as above, 25 bound proteins eluted by boiling in SDS sample buffer and fractionated by Tris/Tricine SDS-PAGE. After exposure to X-ray film or phosphorimager, the resulting images are analyzed for the presence of C-terminal APP fragments. The steady-state level of C-terminal APP fragments is compared 30 to wells treated with DMSO (1%) alone. A typical test compound stimulates C-terminal fragment accumulation in the cell lysates, and is therefore considered active, with an
IC
5 0 less than 100 pM. 35 AD Immunoprecipitation Assay -138- WO 01/19797 PCT/USOO/24967 This immunoprecipitation assay is specific for y secretase (i.e., proteolytic activity required to generate the C-terminal end of A$ either by direct cleavage or generating a C-terminal extended species which is 5 subsequently further proteolyzed). N 9 cells are pulse labeled in the presence of a reported y secretase inhibitor (MDL 28170) for 1 h, followed by washing to remove radiolabel and MDL 28170. The media is replaced and test compounds are added. The cells are chased for increasing 10 periods of times and A $ is isolated from the conditioned medium and C-terminal fragments from cell lysates (see above). The test compounds are characterized whether a stabilization of C-terminal fragments is observed and whether AP is generated from these accumulated precursor. 15 A typical test compound prevents the generation of AP out of accumulated C-terminal fragments and is considered active with an IC 50 less than 100 piM. Dosage and Formulation 20 The compounds of the present invention can be administered orally using any pharmaceutically acceptable dosage form known in the art for such administration. The active ingredient can be supplied in solid dosage forms such as dry powders, granules, tablets or capsules, or in 25 liquid dosage forms, such as syrups or aqueous suspensions. The active ingredient can be administered alone, but is generally administered with a pharmaceutical carrier. A valuable treatise with respect to pharmaceutical dosage forms is Remington's Pharmaceutical Sciences, Mack 30 Publishing. The compounds of the present invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, 35 tinctures, suspensions, syrups, and emulsions. Likewise, they may also be administered in intravenous (bolus or -139- WO 01/19797 PCT/USOO/24967 infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be 5 employed to prevent or treat neurological disorders related to P-amyloid production or accumulation, such as Alzheimer's disease and Down's Syndrome. The compounds of this invention can be administered by any means that produces contact of the active agent with 10 the agent's site of action in the body of a host, such as a human or a mammal. They can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be 15 administered alone, but generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. The dosage regimen for the compounds of the present 20 invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the 25 symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient,and the effect desired. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug 30 required to prevent, counter, or arrest the progress of the condition. Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, 35 or four times daily. The compounds for the present invention can be administered in intranasal form via topical use of suitable -140- WO 01/19797 PCT/USOO/24967 intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches wall known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration 5 will, of course, be continuous rather than intermittant throughout the dosage regimen. In the methods of the present invention, the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable 10 pharmaceutical diluents, excipients, or carriers (collectively referred to herein as carrier materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional 15 pharmaceutical practices. For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, 20 glucose, methyl callulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, 25 glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or P-lactose, corn 30 sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium 35 acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like. -141- WO 01/19797 PCT/USOO/24967 The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamallar vesicles, and multilamellar vesicles. Liposomes can be formed from a 5 variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines. Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, 10 polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in 15 achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or 20 amphipathic block copolymers of hydrogels. Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed 25 tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the 30 atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance. In general, water, a suitable oil, saline, aqueous dextrose 35 (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for -142- WO 01/19797 PCT/USOO/24967 parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or 5 ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol. 10 Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field. -143-

Claims (14)

  1. 2. A compound of Claim 1, or a pharmaceutically acceptable salt form or prodrug thereof, wherein: 10 Q is Ql, (C 1 -C 3 alkyl) -O-Q 1 , (C 1 -C 3 alkyl) -S-Q 1 , (C1-C 3 alkyl)-S(=O)-Q1, (C 1 -C 3 alkyl)-S(=0) 2 -Q1, or 15 (C 1 -C 3 alkyl)-N(R 2 0 )-Q; Q 1 is Ci-C 6 alkyl substituted with 0-3 Ria; C 2 -C 6 alkenyl substituted with 0-3 Ria; C 2 -C 6 alkynyl substituted with 0-3 Ria; 20 C 3 -C 10 cycloalkyl substituted with 0-3 Rib; C 3 -C 10 carbocycle substituted with 0-3 Rib; C 6 -C 10 aryl substituted with 0-3 Rib; or 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and 25 sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 Rib; R 1 a, at each occurrence, is independently selected from H, Ci-C 6 alkyl, OR 1 4 , Cl, F, Br, I, NR 1 5 R1 6 , CF 3 ; 30 C 3 -C1O carbocycle substituted with 0-3 Rib; C 6 -C 10 aryl substituted with 0-3 Rib; and 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and -152- WO 01/19797 PCT/USOO/24967 sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 Rib; Rib, at each occurrence, is independently selected from H, 5 OH, Cl, F, Br, I, CN, NO 2 , NR 1 5 R 1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2 CH 3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, C 1 -C 4 haloalkoxy, Ci-C 4 haloalkyl-S-, and (Ci-C 6 alkyl)-O-C(=O)-; 10 R 2 is H, methyl, ethyl, propyl, or butyl; R 3 is H, Ci-C 4 alkyl, -C(=O) (Ci-C 4 alkyl), -C(=S) (Ci-C 4 alkyl), or -C(=0)NR21R22. 15 R 5 is H, OR 1 4 ; Ci-C 6 alkyl substituted with 0-3 R5b; Ci-C 6 alkoxy substituted with 0-3 R5b; C 2 -C 6 alkenyl substituted with 0-3 R5b; C 2 -C 6 alkynyl substituted with 0-3 R 5 b; 20 C 3 -C 10 cycloalkyl substituted with 0-3 R 5 c; C 3 -C 10 carbocycle substituted with 0-3 R 5 c; C 6 -C 10 aryl substituted with 0-3 R 5 c; or 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and 25 sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3R 5 c; R 5 a is H, Ci-C 4 alkyl, or C 2 -C 4 alkenyl; 30 alternatively, R 5 and R 5 a may be combined to form a 3-7 membered cycloalkyl ring substituted with 0-3 R 5 c. R5b, at each occurrence, is independently selected from: H, Ci-C 6 alkyl, CF 3 , OR 1 4 , Cl, F, Br, I, =0, CN, NO 2 , 35 NR 1 5 R 1 6 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2 CH 3 , C 2 -C 6 -153- WO 01/19797 PCT/USOO/24967 alkenyl, C 2 -C 6 alkynyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, and Ci-C 4 haloalkyl-S-, C 3 -C 10 cycloalkyl substituted with 0-3 R 5 c; 5 C 3 -C 10 carbocycle substituted with 0-3 R 5 c; C6-C1O aryl substituted with 0-3 R 5 c; and 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered 10 heterocycle is substituted with 0-3 R 5 c; R 5 c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 1 5 R 1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2 CH 3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 15 haloalkyl, Ci-C 4 haloalkoxy, and Ci-C 4 haloalkyl-S-; R 6 is H, methyl, or ethyl; W is -(CR8R8a)p_; 20 p is 0, 1, or 2; R 8 and R 8 a, at each occurrence, are independently selected from H, F, methyl, and ethyl; 25 X is a bond; phenyl substituted with 0-3 RXb; C 3 -C 6 cycloalkyl substituted with 0-3 RXb; or 5 to 6 membered heterocycle substituted with 0-2 RXb; 30 RXb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 1 5 R 1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2 CH 3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, and Ci-C 4 haloalkyl-S-; 35 Y is a bond or -(CR 9 R 9 a)t-V-(CR 9 R 9 a)u-; -154- WO 01/19797 PCT/USOO/24967 t is 0, 1, or 2; u is 0, 1, or 2; 5 R 9 and R 9 a, at each occurrence, are independently selected from H, F, methyl, and ethyl; V is a bond, -C(=O)-, -0-, -S-, -S(=O)-, -S(=0) 2 -, -N(R1 9 )-, -C(=O)NH-, -NHC(=O)-, -NHS(=0) 2 -, or 10 -S(=0) 2 NH-; Z is H, halo; Ci-C 4 alkyl substituted with 0-2 R1 2 ; C 2 -C 4 alkenyl substituted with 0-2 R1 2 ; 15 C 2 -C 4 alkynyl substituted with 0-2 R1 2 ; C 6 -C 10 aryl substituted with 0-4 R12b; C 3 -C 6 carbocycle substituted with 0-4 R12b; or 5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and 20 sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R1 2 b; Ring B is a 7 membered lactam, wherein the lactam is saturated, partially saturated 25 or unsaturated; wherein each additional lactam carbon is substituted with 0-2 Ri'; and, optionally, the lactam contains a heteroatom selected from -N=, -NH-, -N(R 1 0 )-, -0-, -S-, -S(=O)-, and 30 -S(=0)2-; additionally, two R 1 substituents on adjacent atoms may be combined to form C 3 -C 6 carbocycle fused radical, a benzo fused radical, or a 5 to 6 membered heteroaryl 35 fused radical, -155- WO 01/19797 PCT/USOO/24967 wherein said 5 to 6 membered heteroaryl fused radical comprises 1-2 heteroatoms selected from N, 0, and S; wherein said benzo fused radical or 5 to 6 membered heteroaryl fused radical is substituted with 0-3 R13; 5 R 1 0 is H, C(=O)R 1 7 , C(=O)OR 17 , C(=O)NR 1 8 R 1 9 , S(=0) 2 NR1 8 R 1 9 , S(=0) 2 R1 7 ; Ci-C 6 alkyl substituted with 0-2 R10a; C 6 -C 1 0 aryl substituted with 0-4 R10b; 10 C 3 -C 10 carbocycle substituted with 0-3 Riob; 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 optionally substituted with 0-3 15 R10b; R 10 a, at each occurrence, is independently selected from H, C 1 -C 6 alkyl, OR 1 4 , Cl, F, Br, I, =0, CN, NO 2 , NR1 5 R 1 6 , CF 3 , or aryl substituted with 0-4 R10b; 20 R10b, at each occurrence, is independently selected from H, OH, Ci-C 6 alkyl, Ci-C 4 alkoxy, Cl, F, Br, I, CN, NO 2 , NR 1 5 R 1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2 CH 3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, 25 and Ci-C 4 haloalkyl-S-; R 11 , at each occurrence, is independently selected from H, Ci-C 4 alkoxy, Cl, F, Br, I, =0, CN, NO 2 , NR 1 8 R 1 9 , C(=O)R 1 7 , C(=O)OR 1 7 , C(=O)NR 1 8 R 1 9 , S(=0) 2 NR 1 8 R1 9 , 30 CF 3 ; Ci-C 6 alkyl substituted with 0-1 R11a; C 6 -C 10 aryl substituted with 0-3 R11b; C 3 -C 10 carbocycle substituted with 0-3 R11b; or 5 to 10 membered heterocycle containing 1 to 4 35 heteroatoms selected from nitrogen, oxygen, and -156- WO 01/19797 PCT/USOO/24967 sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R11b; R 11 a, at each occurrence, is independently selected from H, 5 Cl-C 6 alkyl, OR 1 4 , Cl, F, Br, I, =0, CN, NO 2 , NR 1 5 R 1 6 , CF 3 ; phenyl substituted with 0-3 R11b; C 3 -C 10 carbocycle substituted with 0-3 Riib; or 5 to 10 membered heterocycle containing 1 to 4 10 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R11b; R11b, at each occurrence, is independently selected from H, 15 OH, Cl, F, Br, I, CN, NO 2 , NR 1 5 R 1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2 CH 3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, and Ci-C 4 haloalkyl-S-; R 12 at each occurrence, is independently selected from H, 20 OH, Cl, F, Br, I, CN, NO 2 , NR 1 5 R 1 6 , -C(=O)NRi 5 R1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2 CH 3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, and Ci-C 4 haloalkyl-S-; C 6 -Cio aryl substituted with 0-4 R1 2 b; 25 C 3 -C 1 o carbocycle substituted with 0-4 R1 2 b; 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 Ri 2 b; 30 R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 1 5 R 1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2 CH 3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C4 haloalkyl, Ci-C 4 haloalkoxy, and Ci-C 4 haloalkyl-S-; 35 -157- WO 01/19797 PCT/USOO/24967 R 13 , at each occurrence, is independently selected from H, OH, Ci-C 6 alkyl, CI-C 4 alkoxy, Cl, F, Br, I, CN, NO 2 , NR 15 R 1 6 , and CF 3 ; 5 R 14 , at each occurrence, is independently selected from H, phenyl, benzyl, Ci-C 6 alkyl, and C 2 -C 6 alkoxyalkyl; R 15 , at each occurrence, is independently selected from H, Ci-C 6 alkyl, phenyl, benzyl, phenethyl, (Ci-C 6 alkyl) 10 C(=O)-, (Ci-C 6 alkyl)-O-C(=O)- and (C1-C 6 alkyl) S (=0)2-; R1 6 , at each occurrence, is independently selected from H, OH, Ci-C 6 alkyl, phenyl, benzyl, phenethyl, (Ci-C 6 15 alkyl)-C(=O)-, (C1-C 6 alkyl)-O-C(=O)- and (Ci-C 6 alkyl) -S (=0)2-; alternatively, -NR 15 R 1 6 may be a heterocyclic ring selected from the group piperidinyl, morpholinyl, 20 thiomorpholinyl, pyrrolidinyl, homopiperidinyl, piperazinyl, and N-methylpiperizinyl; R1 7 is H, aryl, aryl-CH 2 -, Ci-C 6 alkyl, or C 2 -C 6 alkoxyalkyl; 25 R 18 , at each occurrence, is independently selected from H, Ci-C 6 alkyl, phenyl, benzyl, phenethyl, (C 1 -C 6 alkyl) C(=O)- and (C 1 -C 6 alkyl)-S(=0) 2 -; 30 R 19 , at each occurrence, is independently selected from H, OH, Ci-C 6 alkyl, phenyl, benzyl, phenethyl, (Ci-C 6 alkyl)-C(=O)- and (Ci-C 6 alkyl)-S(=0) 2 -; alternatively, -NR 17 R 1 8 may be a heterocyclic ring selected 35 from the group piperidinyl, morpholinyl, -158- WO 01/19797 PCT/USOO/24967 thiomorpholinyl, pyrrolidinyl, homopiperidinyl, piperazinyl, and N-methylpiperizinyl; R 20 is H, OH, Ci-C 4 alkyl, phenyl, benzyl, or phenethyl; 5 R 21 , at each occurrence, is independently selected from H, Ci-C 6 alkyl, phenyl, benzyl, and phenethyl; and R 22 , at each occurrence, is independently selected from H, 10 Cl-C 6 alkyl, phenyl, benzyl, and phenethyl.
  2. 3. A compound of Claim 2 wherein Ring B is selected from: o 0 0 N N N RR R" R 15 o 0 0 N N'' s~~NRl Ru 7 R 1 1 b \ 0 00 N N N -159- WO 01/19797 PCT/USOO/24967 0 N0 No N N N O or N N R10 R10 wherein each benzo fused radical is substituted with 0-3 R 13 . 5
  3. 4. A compound of Claim 2, of Formula (Ia): Rs R 5 a 0 R2 N W-X-Y-Z OH 0 (Ia) or a pharmaceutically acceptable salt form or prodrug 10 thereof, wherein: Q is Q 1 , (Ci-C 3 alkyl) -O-Q 1 , (Ci-C 3 alkyl) -S-Q 1 , 15 (Ci-C 3 alkyl)-S(=O)-Q 1 , (Ci-C 3 alkyl)-S(=0) 2 -Q 1 , or (C 1 -C 3 alkyl)-N(R 20 )-Ql; Q 1 is Ci-C 6 alkyl substituted with 0-3 Ria; 20 C 2 -C 6 alkenyl substituted with 0-3 Ria; C 2 -C 6 alkynyl substituted with 0-3 Ria; C 3 -C 1 0 cycloalkyl substituted with 0-3 Rib; C 3 -CiO carbocycle substituted with 0-3 Rib; C 6 -Cio aryl substituted with 0-3 Rib; or 25 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 Rib. -160- WO 01/19797 PCT/USOO/24967 R 1 a, at each occurrence, is independently selected from H, Ci-C 6 alkyl, OR 1 4 , Cl, F, Br, I, NR 1 5 R 1 6 , CF 3 ; C3-C 1 O carbocycle substituted with 0-3 Rib; 5 C 6 -Cio aryl substituted with 0-3 Rib; 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 Rib; 10 Rib, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 1 5 R 1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2 CH 3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, C 1 -C 4 haloalkyl-S-, and 15 (Ci-C 6 alkyl)-O-C(=O)-; R 2 is H, methyl, or ethyl; R 5 is H, OR14; 20 Cl-C 6 alkyl substituted with 0-3 R5b; Ci-C 6 alkoxy substituted with 0-3 R 5 b; C 2 -C 6 alkenyl substituted with 0-3 R5b; C 2 -C 6 alkynyl substituted with 0-3 R 5 b; C 3 -Clo cycloalkyl substituted with 0-3 R 5 c; 25 C 3 -C 10 carbocycle substituted with 0-3 R 5 c; C 6 -Clo aryl substituted with 0-3 R 5 c; or 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered 30 heterocycle is substituted with 0-3R 5 c; R 5 a is H, Ci-C 4 alkyl, or C 2 -C 4 alkenyl; alternatively, R 5 and R 5 a may be combined to form a 3-7 35 membered cycloalkyl ring substituted with 0-3 R 5 c; -161- WO 01/19797 PCT/USOO/24967 R5b, at each occurrence, is independently selected from: H, Ci-C 6 alkyl, CF 3 , OR 1 4 , Cl, F, Br, I, =0, CN, NO 2 , NR 1 5 R 1 6 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2 CH3, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 4 alkoxy, Ci-C 4 5 haloalkyl, C 1 -C 4 haloalkoxy, and C 1 -C 4 haloalkyl-S-, C 3 -C 10 cycloalkyl substituted with 0-3 R 5 c; C 3 -Cio carbocycle substituted with 0-3 R 5 c; C 6 -Cio aryl substituted with 0-3 R 5 c; and 10 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 5 c; 15 R 5 c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 1 5 R 1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2 CH 3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, C 1 -C 4 haloalkoxy, and Ci-C 4 haloalkyl-S-; 20 W is -(CR8R8a)p; p is 0, 1, or 2; R 8 and R 8 a, at each occurrence, are independently selected 25 from H, F, methyl, and ethyl; X is a bond; phenyl substituted with 0-3 Rxb; C 3 -C 6 cycloalkyl substituted with 0-3 RXb; or 30 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 0-2 RXb; 35 RXb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 1 5 R 1 6 , CF 3 , acetyl, SCH 3 , -162- WO 01/19797 PCT/USOO/24967 S(=O)CH 3 , S(=0) 2 CH 3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, and Ci-C 4 haloalkyl-S-; Y is a bond or -(CR 9 R 9 a)t-V-(CR 9 R 9 a)u-; 5 t is 0, 1, or 2; u is 0, 1, or 2; 10 R 9 and R 9 a, at each occurrence, are independently selected from H, F, methyl, and ethyl; V is a bond, -C(=O)-, -0-, -S-, -S(=O)-, -S(=0) 2 -, -N(R 1 9 )-, -C(=O)NH-, or -NHC(=O)-; 15 Z is H, halo; Ci-C 4 alkyl substituted with 0-2 R1 2 ; C 2 -C 4 alkenyl substituted with 0-2 R1 2 ; C 2 -C 4 alkynyl substituted with 0-2 R1 2 ; 20 C 6 -Cio aryl substituted with 0-4 R1 2 b; C 3 -C 6 carbocycle substituted with 0-4 R1 2 b; or 5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle 25 is substituted with 0-3 R12b. Ring B is selected from: 0 0 N1 N 1
  4. 13-. [A /N~ an 1R13 RR 30 R 1 l, at each occurrence, is independently selected from H, -163- WO 01/19797 PCT/USOO/24967 Ci-C 4 alkoxy, Cl, F, Br, I, =0, CN, NO 2 , NR 1 8 R 1 9 , C(=O)R1 7 , C(=O)OR 1 7 , C(=O)NR1 8 R 1 9 , S(=0) 2 NR 1 8 R 1 9 , CF 3 ; Ci-C 6 alkyl substituted with 0-1 R11a; 5 C 6 -Cio aryl substituted with 0-3 R11b; C 3 -C 1 o 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 10 heterocycle is substituted with 0-3 Riib; R 11 a, at each occurrence, is independently selected from H, Ci-C 6 alkyl, OR 1 4 , Cl, F, Br, I, =0, CN, NO 2 , NR 1 5 R 1 6 , CF 3 ; 15 phenyl substituted with 0-3 R11b; C 3 -C1O 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 20 heterocycle is substituted with 0-3 Riib; Rilb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 1 5 R 1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2 CH 3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 25 haloalkyl, Ci-C 4 haloalkoxy, and C 1 -C 4 haloalkyl-S-; R12 at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 1 5 R 1 6 , -C(=O)NR1 5 R1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2 CH 3 , Ci-C6 alkyl, Ci-C 4 30 alkoxy, C1-C 4 haloalkyl, Ci-C 4 haloalkoxy, and Ci-C 4 haloalkyl-S-; C 6 -C 1 0 aryl substituted with 0-4 R1 2 b; C 3 -C 10 carbocycle substituted with 0-4 R1 2 b; or 5 to 10 membered heterocycle containing 1 to 4 35 heteroatoms selected from nitrogen, oxygen, and -164- WO 01/19797 PCT/USOO/24967 sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 Ri 2 b; R1 2 b, at each occurrence, is independently selected from H, 5 OH, Cl, F, Br, I, CN, NO 2 , NR 1 5 R 1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2 CH 3 , Ci-C 6 alkyl, CI-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, and Ci-C 4 haloalkyl-S-; R1 3 , at each occurrence, is independently selected from H, 10 OH, Ci-C 6 alkyl, Ci-C 4 alkoxy, Cl, F, Br, I, CN, NO 2 , NR 1 5 Ri 6 , and CF 3 ; R 14 , at each occurrence, is independently selected from H, phenyl, benzyl, Ci-C 6 alkyl, and C 2 -C 6 alkoxyalkyl; 15 R 15 , at each occurrence, is independently selected from H, Ci-C 6 alkyl, phenyl, benzyl, phenethyl, (Ci-C 6 alkyl) C(=O)-, (C1-C 6 alkyl)-O-C(=O)- and (C1-C 6 alkyl) S(=0)2-; 20 R 16 , at each occurrence, is independently selected from H, OH, Ci-C 6 alkyl, phenyl, benzyl, phenethyl, (Ci-C 6 alkyl)-C(=O)-, (Ci-C 6 alkyl)-O-C(=O)- and (C1-C 6 alkyl)-S(=0)2-; 25 alternatively, -NR 15 R 16 may be a heterocyclic ring selected from the group piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, homopiperidinyl, piperazinyl, and N-methylpiperizinyl; 30 R1 7 is H, aryl, aryl-CH 2 -, Ci-C 6 alkyl, or C 2 -C 6 alkoxyalkyl; -165- WO 01/19797 PCT/USOO/24967 R 18 , at each occurrence, is independently selected from H, Ci-C 6 alkyl, phenyl, benzyl, phenethyl, (C 1 -C 6 alkyl) C(=O)- and (Ci-C 6 alkyl)-S(=0) 2 -; 5 R1 9 , at each occurrence, is independently selected from H, OH, Ci-C 6 alkyl, phenyl, benzyl, phenethyl, (Ci-C 6 alkyl)-C(=O)- and (Ci-C 6 alkyl)-S(=0) 2 -; alternatively, -NR1 8 R 1 9 may be a heterocyclic ring selected 10 from the group piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, homopiperidinyl, piperazinyl, and N-methylpiperizinyl; and R 20 is H, OH, Ci-C 4 alkyl, phenyl, benzyl, or phenethyl. 15 5. A compound, according to Claim 4, of Formula (Ia); R5 R 5 a H O RQ N , W-X-Y-Z OHO B 20 (Ia) wherein: Ring B is selected from: 0 0 NO N Nl RMNR RL-- . RM R R ; ; and 25 Q is Q1 or (Ci-C 3 alkyl)-O-Q 1 ; Q 1 is Ci-C 6 alkyl substituted with 0-3 Ria; C 2 -C 6 alkenyl substituted with 0-3 Ria; 30 C 2 -C 6 alkynyl substituted with 0-3 Ria; -166- WO 01/19797 PCT/USOO/24967 C 3 -C 10 cycloalkyl substituted with 0-3 Rib; C 3 -C1O carbocycle substituted with 0-3 Rib; C 6 -C 10 aryl substituted with 0-3 Rib; or 5 to 10 membered heterocycle containing 1 to 4 5 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 Rib; R 1 a, at each occurrence, is independently selected from H, 10 Ci-C 6 alkyl, OR 1 4 , Cl, F, Br, I, NR 1 5 R 1 6 , CF 3 ; C 3 -C 10 carbocycle substituted with 0-3 Rib; C 6 -Cio aryl substituted with 0-3 Rib; and 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and 15 sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 Rib; Rib, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 1 5 R 1 6 , CF 3 , acetyl, SCH 3 , 20 S(=O)CH3, S(=0) 2 CH 3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, Ci-C 4 haloalkyl-S-, and (Ci-C 6 alkyl)-O-C(=O)-; R 2 is H, methyl, or ethyl; 25 R 5 is H, OR 14 ; Ci-C 6 alkyl substituted with 0-3 R 5 b; C 2 -C 6 alkenyl substituted with 0-3 R5b; C 2 -C 6 alkynyl substituted with 0-3 R5b; 30 C 3 -C 6 cycloalkyl substituted with 0-3 R 5 c; C 3 -C 6 carbocycle substituted with 0-3 R 5 c; phenyl substituted with 0-3 R 5 c; or 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and -167- WO 01/19797 PCT/USOO/24967 sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3R 5 c; R 5 a is H, Ci-C 4 alkyl, or C 2 -C 4 alkenyl; 5 alternatively, R 5 and R 5 a may be combined to form a C 4 -C 7 cycloalkyl ring; R5b, at each occurrence, is independently selected from: 10 H, Ci-C 6 alkyl, CF 3 , OR 1 4 , Cl, F, Br, I, =0, CN, NO 2 , NR 1 5 R 1 6 , acetyl, SCH3, S(=O)CH 3 , S(=O) 2 CH 3 , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, and Ci-C 4 haloalkyl-S-, 15 C 3 -C 10 cycloalkyl substituted with 0-3 R 5 c; C 3 -C 1 o carbocycle substituted with 0-3 R 5 c; C 6 -Cio aryl substituted with 0-3 R 5 c; and 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and 20 sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R 5 c; R 5 c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 1 5 R 1 6 , CF 3 , acetyl, SCH 3 , 25 S(=O)CH 3 , S(=O) 2 CH 3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, and Ci-C 4 haloalkyl-S-; W is -(CR 8 R8a)p_; 30 p is 0, 1, or 2; R 8 and R 8 a, at each occurrence, are independently selected from H, methyl, and ethyl; 35 X is a bond; phenyl substituted with 0-3 RXb; C 3 -C 6 cyclolakyl substituted with 0-3 RXb; or -168- WO 01/19797 PCT/USOO/24967 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 0-2 RXb; 5 RXb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 1 5 R 1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2 CH 3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, and Ci-C 4 haloalkyl-S-; 10 Y is a bond or -(CR9R9a)t-V-(CR9R9alu-; t is 0, 1, or 2; 15 u is 0, 1, or 2; R 9 and R 9 a, at each occurrence, are independently selected from H, F, methyl, and ethyl; 20 V is a bond, -C(=O)-, -0-, -S-, -S(=O)-, -S(=0) 2 -, -N(R1 9 )-, -NHC(=O)-, or -C(=O)NH-; Z is H, F, Cl, Br; Ci-C 4 alkyl substituted with 0-2 R1 2 ; 25 C 2 -C 4 alkenyl substituted with 0-2 R1 2 ; C 2 -C 4 alkynyl substituted with 0-2 R1 2 ; C 6 -C 1 0 aryl substituted with 0-4 R1 2 b; C 3 -C 6 carbocycle substituted with 0-4 R1 2 b; or 5 to 6 membered heterocycle containing 1 to 4 30 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R1 2 b; Ril, at each occurrence, is independently selected from -169- WO 01/19797 PCT/USOO/24967 H, =0, NR 1 8 R 1 9 , C(=O)R 1 7 , C(=O)OR1 7 , C(=O)NR1 8 R1 9 , S(=0) 2 NR1 8 R 1 9 , CF 3 ; Ci-C 6 alkyl substituted with 0-1 R11a; phenyl substituted with 0-3 R11b; 5 C 3 -C 6 carbocycle substituted with 0-3 R11b; or 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R11b; 10 R 11 a, at each occurrence, is independently selected from H, Ci-C 4 alkyl, OR 1 4 , Cl, F, Br, =0, CN, NO 2 , NR 1 5 R 1 6 , CF 3 ; phenyl substituted with 0-3 R11b; 15 C 3 -C 6 carbocycle substituted with 0-3 R11b; or 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R11b; 20 R11b, at each occurrence, is independently selected from H, OH, Cl, F, Br, CN, NO 2 , NR1 5 R 1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2 CH 3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, and C 1 -C 4 haloalkyl-S-; 25 R 12 at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 1 5 R1 6 , -C(=O)NR1 5 R 1 6, CF 3 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2 CH 3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, and C1-C 4 30 haloalkyl-S-; C 6 -C1 0 aryl substituted with 0-4 R1 2 b; C 3 -C1O carbocycle substituted with 0-4 R12b; or 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and -170- WO 01/19797 PCT/USOO/24967 sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R1 2 b; Ri2b, at each occurrence, is independently selected from H, 5 OH, Cl, F, Br, I, CN, NO 2 , NR 1 5 R 1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2 CH 3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, and Ci-C 4 haloalkyl-S-; R1 3 , at each occurrence, is independently selected from H, 10 OH, Ci-C 6 alkyl, Ci-C 4 alkoxy, Cl, F, Br, I, CN, NO 2 , NR 1 5 R1 6 , and CF 3 ; R1 4 , at each occurrence, is independently selected from H, phenyl, benzyl, C 1 -C 6 alkyl, and C 2 -C 6 alkoxyalkyl; 15 R 15 , at each occurrence, is independently selected from H, Ci-C 6 alkyl, phenyl, benzyl, phenethyl, (Ci-C 6 alkyl) C(=O)-, (C1-C 6 alkyl)-O-C(=O)- and (Ci-C 6 alkyl) S(=0)2-; 20 R1 6 , at each occurrence, is independently selected from H, OH, Ci-C 6 alkyl, phenyl, benzyl, phenethyl, (Ci-C 6 alkyl)-C(=O)-, (C 1 -C 6 alkyl)-O-C(=O)- and (C 1 -C 6 alkyl)-S(=0) 2 -; 25 alternatively, -NR 1 5 R 1 6 may be a heterocyclic ring selected from the group piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, homopiperidinyl, piperazinyl, and N-methylpiperizinyl; and 30 R 1 7 is H, aryl, aryl-CH 2 -, C 1 -C 6 alkyl, or C 2 -C 6 alkoxyalkyl; -171- WO 01/19797 PCT/USOO/24967 R 18 , at each occurrence, is independently selected from H, Ci-C 6 alkyl, phenyl, benzyl, phenethyl, (Ci-C 6 alkyl) C(=O)- and (Ci-C 6 alkyl)-S(=0) 2 -; 5 alternatively, -NR 1 8 R 1 9 may be a heterocyclic ring selected from the group piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, homopiperidinyl, piperazinyl, and N-methylpiperizinyl; and 10 R 19 , at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl. 6. A compound of Claim 5 wherein: 15 Q is Q 1 ; Q 1 is Ci-C 6 alkyl substituted with 0-3 Ria; C 2 -C 6 alkenyl substituted with 0-3 Ria; 20 C 2 -C 6 alkynyl substituted with 0-3 Ria; C 3 -C 10 cycloalkyl substituted with 0-3 Rib; C 3 -C1O carbocycle substituted with 0-3 Rib; C 6 -C 10 aryl substituted with 0-3 Rib; or 5 to 10 membered heterocycle containing 1 to 4 25 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 Rib; R 1 a, at each occurrence, is independently selected from H, 30 Cl-C 6 alkyl, OR 1 4 , Cl, F, Br, I, NR 1 5 R 1 6 , CF 3 ; C 3 -C 10 carbocycle substituted with 0-3 Rib; C 6 -C 10 aryl substituted with 0-3 Rib; and 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and -172- WO 01/19797 PCT/USOO/24967 sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 Rib; Rib, at each occurrence, is independently selected from H, 5 OH, Cl, F, Br, I, CN, NO 2 , NR 15 R 1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2 CH 3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, Ci-C 4 haloalkyl-S-, and (Ci-C 6 alkyl) -0-C (=0)-; 10 R 2 is H, methyl, or ethyl; R 5 is H, OR 14 ; Ci-C 6 alkyl substituted with 0-3 R5b; C 2 -C 6 alkenyl substituted with 0-3 R 5 b; or 15 C 2 -C 6 alkynyl substituted with 0-3 R5b; R 5 a is H, methyl, ethyl, propyl, butyl, or C 2 -C 4 alkenyl; alternatively, R 5 and R 5 a may be combined to form a C 4 -C 7 20 cycloalkyl ring; R5b, at each occurrence, is independently selected from: H, methyl, ethyl, propyl, butyl, CF 3 , OR 14 , Cl, F, Br, I, =0, NR 1 5 R 1 6 , 25 C 3 -C 7 cycloalkyl substituted with 0-3 R 5 c; C 3 -C 7 carbocycle substituted with 0-3 R 5 c; phenyl substituted with 0-3 R 5 c; and 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and 30 sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R 5 c; R 5 c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 1 5 R 1 6 , CF 3 , acetyl, SCH 3 , 35 S(=O)CH 3 , S(=0) 2 CH 3 , Ci-C 4 alkyl, Ci-C 3 alkoxy, Ci-C 2 haloalkyl, and C 1 -C 2 haloalkoxy; -173- WO 01/19797 PCT/USOO/24967 W is -(CHR 8 )p_. p is 0 or 1; 5 R 8 is H, methyl, or ethyl; X is a bond; phenyl substituted with 0-2 RXb; C 5 -C 6 cycloalkyl substituted with 0-3 Rxb; or 10 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 0-2 RXb; 15 RXb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 15 R 1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH3, S(=0) 2 CH 3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, and Ci-C 4 haloalkyl-S-; 20 Y is a bond, -V-, -CH 2 -V-, -V-CH 2 -, or -CH 2 -V-CH 2 -; V is a bond, -C(=O)-, -0-, -S-, -S(=O)-, -S(=0) 2 -, or -N(R 1 9 ) -; 25 Z is H, F, Cl, Br, Ci-C 4 alkyl substituted with 0-2 R1 2 ; C 2 -C 4 alkenyl substituted with 0-2 R1 2 ; C 2 -C 4 alkynyl substituted with 0-2 R1 2 ; C 6 -Cio aryl substituted with 0-4 Ri2b; 30 C 3 -C 6 carbocycle substituted with 0-4 R12b; 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 Ri 2 b; 35 -174- WO 01/19797 PCT/USOO/24967 R 11 , at each occurrence, is independently selected from H, =0, NR 1 8 R 1 9 , C(=O)R1 7 , C(=O)OR 17 , C(=O)NR 1 8 R 1 9 , S(=0) 2 NR 1 8 R 1 9 , CF 3 ; Ci-C 6 alkyl substituted with 0-1 R11a; 5 phenyl substituted with 0-3 R11b; C 3 -C 6 carbocycle substituted with 0-3 R11b; or 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle 10 is substituted with 0-3 R11b; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, 15 isoxazolyl, and tetrazolyl; R 11 a, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Cl, F, =0, NR 1 5 R 1 6 , CF 3 ; 20 phenyl substituted with 0-3 R11b; C 3 -C 6 carbocycle substituted with 0-3 R11b; or 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle 25 is substituted with 0-3 R11b; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, 30 isoxazolyl, and tetrazolyl; R11b, at each occurrence, is independently selected from H, OH, Cl, F, NR 15 R 1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH 3 , 35 S(=0) 2 CH 3 , methyl, ethyl, propyl, butyl, methoxy, -175- WO 01/19797 PCT/USOO/24967 ethoxy, propoxy, Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy; R 12 at each occurrence, is independently selected from H, 5 OH, Cl, F, Br, I, CN, NO 2 , NR 1 5 R 1 6 , -C(=O)NR 1 5 R1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2 CH 3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, and C 1 -C 4 haloalkyl-S-; C 6 -Cio aryl substituted with 0-4 R12b; 10 C 3 -C 1 o 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; 15 R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 1 5 R 1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2 CH 3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, and Ci-C 4 haloalkyl-S-; 20 R 13 , at each occurrence, is independently selected from H, OH, Ci-C 6 alkyl, Ci-C 4 alkoxy, Cl, F, Br, I, CN, NO 2 , NR 1 5 R 1 6 , and CF 3 ; 25 R 14 , at each occurrence, is independently selected from H, phenyl, benzyl, Ci-C 4 alkyl, and C 2 -C 4 alkoxyalkyl; R 15 , at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and 30 phenethyl; R 16 , at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, phenethyl, CH 3 CH 2 C(=O)-, CH 3 C(=O)-, CH 3 CH 2 0C(=O)-, 35 CH 3 0C(=O)-, CH 3 CH 2 S(=0) 2 - and CH3S(=0) 2 -; -176- WO 01/19797 PCT/USOO/24967 R 1 7 is H, phenyl, benzyl, Ci-C 4 alkyl, or C 2 -C 4 alkoxyalkyl; R 18 , at each occurrence, is independently selected from H, 5 methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and R 19 , at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, and butyl. 10 7. A compound of Claim 6 wherein: Q is Ql, 15 Q1 is Ci-C 6 alkyl substituted with 0-3 Ria; C 2 -C 6 alkenyl substituted with 0-3 Ria; C 2 -C 6 alkynyl substituted with 0-3 Ria; C 3 -C 6 cycloalkyl substituted with 0-3 Rib; phenyl substituted with 0-3 Rib; or 20 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 Rib; 25 Ria, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, OR 14 , Cl, F, Br, I, NR 1 5 R 1 6 , CF 3 ; C 3 -C 6 carbocycle substituted with 0-3 Rib; phenyl substituted with 0-3 Rib; and 30 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 Rib; -177- WO 01/19797 PCT/USOO/24967 Rib, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 1 5 R 1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2 CH 3 , methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Ci-C 2 haloalkyl, Ci-C 2 5 haloalkoxy, (methyl)OC(=O)-, (ethyl)OC(=O)-, (propyl)OC(=O)-, and (butyl)OC(=O)-; R 2 is H or methyl; 10 R 5 is H, OR 14 ; Ci-C 4 alkyl substituted with 0-1 R5b; C 2 -C 4 alkenyl substituted with 0-1 R5b; or C 2 -C 4 alkynyl substituted with 0-1 R5b; 15 R 5 a is H, methyl, ethyl, propyl, or butyl; alternatively, R 5 and R 5 a may be combined to form a cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl ring; 20 R 5 b, at each occurrence, is independently selected from: H, methyl, ethyl, propyl, butyl, CF 3 , OR 1 4 , Cl, F, =0, NR 1 5 R 1 6 , C 3 -C 7 cycloalkyl substituted with 0-3 R 5 c. 25 C 3 -C 7 carbocycle substituted with 0-3 R 5 c; phenyl substituted with 0-3 R 5 c; and 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle 30 is substituted with 0-3 R 5 c; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, 35 isoxazolyl, and tetrazolyl; -178- WO 01/19797 PCT/USOO/24967 R 5 c, at each occurrence, is independently selected from H, OH, Cl, F, NR 1 5 R 1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2 CH 3 , methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Ci-C 2 haloalkyl, and Ci-C 2 5 haloalkoxy; W is a bond, -CH 2 -, or -CH(CH 3 )-; X is a bond; 10 phenyl substituted with 0-1 RXb; C 5 -C 6 cycloalkyl substituted with 0-1 RXb; or 5 to 6 membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle 15 is substituted with 0-1 RXb; wherein said 5 to 6 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, and isoxazolyl; 20 Rxb, at each occurrence, is independently selected from H, OH, Cl, F, Br, NR 1 5 R 1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2 CH 3 , methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C 2 haloalkyl, and Ci-C 2 25 haloalkoxy; Y is a bond, -V-, -V-CH 2 -, or -CH 2 V-; V is a bond, -C(=O)-, -0-, -S-, -S(=O)-, -S(=0) 2 -, or 30 -N(R19)-; Z is H, F, Cl, Br, Ci-C 4 alkyl substituted with 0-2 R1 2 ; C 2 -C 4 alkenyl substituted with 0-2 R1 2 ; 35 C 2 -C 4 alkynyl substituted with 0-2 R1 2 ; C 6 -C 10 aryl substituted with 0-4 R12b; -179- WO 01/19797 PCT/USOO/24967 C 3 -C 6 carbocycle substituted with 0-4 R12b; or 5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle 5 is substituted with 0-3 R12b; R 11 , at each occurrence, is independently selected from H, NR 1 8 R 1 9 , CF 3 ; Ci-C 4 alkyl substituted with 0-1 R11a; 10 phenyl substituted with 0-3 R11b; C 3 -C 6 carbocycle substituted with 0-3 R11b; or 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle 15 is substituted with 0-3 R11b; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, 20 isoxazolyl, and tetrazolyl; R 11 a, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Cl, F, =0, NR 1 5 R 1 6 , CF 3 ; 25 phenyl substituted with 0-3 R11b; C 3 -C 6 carbocycle substituted with 0-3 R11b; or 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle 30 is substituted with 0-3 R11b; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, 35 isoxazolyl, and tetrazolyl; -180- WO 01/19797 PCT/USOO/24967 R11b, at each occurrence, is independently selected from H, OH, Cl, F, NR 1 5 R 1 6 , CF 3 , methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Ci-C 2 haloalkyl, and Ci-C 2 5 haloalkoxy; R1 2 at each occurrence, is independently selected from H, OH, Cl, F, Br, NR 1 5 R 1 6 , -C(=O)NR1 5 R1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2 CH 3 , methyl, ethyl, propyl, 10 butyl, methoxy, ethoxy, propoxy, Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy; phenyl substituted with 0-4 R1 2 b; C 3 -C 6 carbocycle substituted with 0-4 R1 2 b; or 5 to 6 membered heterocycle containing 1 to 4 15 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R12b; R1 2 b, at each occurrence, is independently selected from 20 H, OH, Cl, F, Br, NR 1 5 R 1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2 CH 3 , methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C 1 -C 2 haloalkyl, and Ci-C 2 haloalkoxy; 25 R1 3 , at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Cl, F, Br, CN, NR 1 5 R 1 6 , and CF 3 ; R1 4 , at each occurrence, is independently selected from H, 30 phenyl, benzyl, methyl, ethyl, propyl, and butyl; R 1 5 , at each occurrence, is independently selected from H, methyl, ethyl, propyl, or butyl; -181- WO 01/19797 PCT/USOO/24967 R1 6 , at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; 5 R 18 , at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl and, phenethyl; and R 19 , at each occurrence, is independently selected from H, 10 OH, methyl, ethyl, propyl, butyl, phenyl, benzyl and, phenethyl. 8. A compound of Claim 7 wherein: 15 Q 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 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH(CH3)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 , 20 -CH=CH 2 , -CH 2 CH=CH 2 , -CH 2 C(CH 3 )=CH 2 , -CH 2 CH=C(CH 3 )2, -CH 2 CH 2 CH=CH 2 , -CH 2 CH 2 C(CH 3 )=CH 2 , -CH 2 CH 2 CH=C(CH 3 )2, cis-CH 2 CH=CH(CH 3 ), cis-CH 2 CH 2 CH=CH(CH 3 ), trans-CH 2 CH=CH(CH 3 ), trans-CH 2 CH 2 CH=CH(CH 3 ); 25 -C=CH, -CH 2 CmCH, -CH 2 CEC(CH 3 ), cyclopropyl-, cyclobutyl-, cyclopentyl-, cyclohexyl-, cyclopropyl-CH 2 -, cyclobutyl-CH 2 -, cyclopentyl-CH 2 -, 30 cyclohexyl-CH 2 -, cyclopropyl-CH 2 CH 2 -, cyclobutyl-CH 2 CH 2 -, cyclopentyl-CH 2 CH 2 -, cyclohexyl-CH 2 CH 2 -, phenyl-, 2-F-phenyl-, 3-F-phenyl-, 4-F-phenyl-, 4-methoxyphenyl-,4-ethoxyphenyl-, 4-propoxyphenyl-, 35 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 -, -182- WO 01/19797 PCT/USOO/24967 (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 -, 5 (2,3-diCl-phenyl)CH 2 -, (2,4-diCl-phenyl)CH 2 -, (2,5-diCl-pheiyl)CH 2 -, (2,6-diCl-pheiyl)CH 2 -, (3,4-diCl-phenyl)CH 2 -, (3.5-diCl-phenyl)CH 2 -, (3-F-4-C1-phenyl)CH 2 -, (3-F-5-Cl-phenyl)CH 2 -, (3-Cl-4-F-pheiyl) CH 2 -, 10 2-furanyl-CH 2 -, 3-furanyl-CH 2 -, 2-thienyl-CH 2 -, 3-thienyl-CH 2 -, 2-pyridyl-CH 2 -, 3-pyridyl-CH 2 -, 4-pyridyl-CH 2 -, 1-imidazolyl-CH 2 -, 2-oxazolyl-CH 2 -, 4-oxazolyl-CH 2 -, 5-oxazolyl-CH 2 -, 3-isoxazolyl-CH 2 -, 15 4-isoxazolyl-CH 2 -, 5-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 -, (2-C1-phenyl)CH 2 CH 2 -, (3-Cl-phenyl)CH 2 CH 2 -, 20 (4-C1-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 -, 25 (2,5-diCl-phenyl)CH 2 CH 2 -, (2, 6-diCl-pheiyl)CH 2 CH 2 -, (3,4-diCl-phenyl)CH 2 CH 2 -, (3,5-diCl-phenyl)CH 2 CH 2 -, (3-F-4-C1-phenyl)CH 2 CH 2 -, (3-F-5--C1-phenyl)CH 2 CH 2 -; furanyl-CH 2 CH 2 -, thienyl-CH 2 CH 2 -, pyridyl-CH 2 CH 2 -, 30 1-imidazolyl-CH 2 CH 2 -, oxazolyl-CH 2 CH 2 -, isoxazolyl-CH 2 CH 2 -, 3,5-dimethylisoxazol-4-yl-CH 2 CH 2 -, phenyl-propyl-; benzyl-CH(NH 2 )-, benzyl-CH(NHC(=O)-O-tBu)-, 35 benzyloxy-CH 2 -, pyrrolidin-2-yl-, or 3 -t-butoxycarbonylpyrrolidin-2 -yl-; R 2 is H or methyl; -183- WO 01/19797 PCT/USOO/24967 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 , 5 -CH 2 CH 2 CH(CH 3 ) 2 , -CH(CH 2 CH 3 ) 2 , -CF 3 . -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=CI{ 2 , -CH 2 CH=CH 2 , -CH 2 CH 2 CH=CH 2 , -CH=CHCH 3 , 10 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 ), 15 -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=CCH) -CH 2 CH 2 C= (C 6 H 5 ), -CH 2 CH 2 CH 2 C=-CH, -CH 2 CH 2 CH 2 C=C(CH 3 ) , -CH 2 CH 2 CH 2 C=C (C 6 H 5 ), cyclopropyl-CH 2 -, cyclobutyl-CH 2 -, cyclopentyl-CH 2 -, 20 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 -, cycloperityl-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 -, 25 phenyl-CH 2 -, (2-F-phenyl)CH 2 -, (3-F-phenyl)CH 2 -, (4-F-phenyl)CH 2 -, (3,5-diF-phenyl)CH 2 -, 2-furanyl-CH 2 -, 3-furanyl-CH 2 -, 2-thienyl-CH 2 -, 3-thienyl-CH 2 -, 2 -pyridyl-CH 2 -, 3 -pyridyl-CH 2 -, 30 4-pyridyl-CH 2 -, 1-imidazolyl-CH 2 -, 2-oxazolyl-CH 2 -, 4-oxazolyl-CH 2 -, 5-oxazolyl-CH 2 -, 3-isoxazolyl-CH 2 -, 4-isoxazolyl-CH 2 -, 5-isoxazolyl-CH 2 -, phenyl-CH 2 CH 2 -, (2-F-phenyl)CH 2 CH 2 -, (3-F-phenyl) CH 2 CH 2 -, 35 (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 -, isoxazolyl-CH 2 CH 2 -; -184- WO 01/19797 PCT/USOO/24967 methoxy, ethoxy, propoxy, or butoxy; R 5 a is H; 5 alternatively, R 5 and R 5 a may be combined to form cyclopentyl, cyclohexyl, or cycloheptyl; W is a bond, -CH 2 -, or -CH(CH 3 )-; 10 X is a bond; ; or 15 Y is a bond, -CH 2 -V-, -V-, or -V-CH 2 -; V is a bond, -C(=O)-, -0-, -S-, -S(=O)-, -S(=0) 2 -, -NH-, or -N(CH 3 ) -; 20 Z is H, F, Cl, Br, methyl, ethyl, n-propyl, i-propyl, n butyl, i-butyl, s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 25 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, 30 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, 35 4-MeS-phenyl, 2-CF 3 0-phenyl, 3-CF 3 O-phenyl, -185- WO 01/19797 PCT/USOO/24967 4-CF 3 O-phenyl, furanyl, thienyl, pyridyl, 2-Me-pyridyl, 3-Me-pyridyl, 4-Me-pyridyl, 1-imidazolyl, oxazolyl, isoxazolyl, 5 1-benzimidazolyl, morpholino, N-piperinyl, phenyl-CH 2 -, (2-F-phenyl)CH 2 -, (3-F-phenyl)CH 2 -, (4-F-phenyl)CH 2 -, (2-C1-phenyl)CH 2 -, (3-C1-phenyl)CH 2 -, (4-C1-phenyl)CH 2 -, (2,3-diF-phenyl)CH 2 -, 10 (2,4-diF-phenyl)CH 2 -, (2,5-diF-pheriyl)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-pheiyl)CH 2 -, (2,5-diCl-phenyl)CH 2 -, (2,6-diCIl-phenyl)CH 2 -, (3,4-diCl-phenyl)CH 2 -, 15 (3,5-diCl-phenyl)CH 2 -, (3-F-4-C1-phenyl)CH 2 -, (3-F-5-Cl-phenyl)CH 2 -, (3-C1-4-F-phenyl)CH 2 -, (2-MeO-phenyl) CH 2 -, (3-MeO-phenyl) CH 2 -, (4-Meo-phenyl) CH 2 -, (2-Pho-phenyl)CH 2 -, (3-PhO-phenyl)CH 2 -, (4-Pho-phenyl)CH 2 -, 20 (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 -, 25 (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-pipridinyl)CH 2 -, 30 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-C1-phenyl)CH 2 CH 2 -, (4-C1-phenyl)CH 2 CH 2 -, (2,3-diF-phenyl)CH 2 CH 2 -, 35 (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-diC1-phenyl)CH 2 CH 2 -, -186- WO 01/19797 PCT/USOO/24967 (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-4-F-phenyl)CH 2 CH 2 -, 5 (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 0-phenyl)CH 2 CH 2 -, 10 (3-CF 3 0-phenyl)CH 2 CH 2 -, (4-CF 3 0-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 -, 15 (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-pipridinyl) CH 2 CH 2 -; 20 Ril, at each occurrence, is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s butyl, t-butyl, phenyl, benzyl, phenethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, 25 cyclohexylmethyl, cycloheptylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, 2-F-phenyl-, 3-F-phenyl, 4-F-phenyl, 4-Cl-phenyl, 4-CH 3 phenyl, 4-MeO-phenyl-, 4-CF 3 -phenyl, (4-F-phenyl)CH 2 -, (4-Cl-phenyl)CH 2 -, (4-CH 3 -phenyl)CH 2 -, 30 (4-CF 3 -phenyl)CH 2 -, (4-F-phenyl)CH 2 CH 2 -, (4-Cl-phenyl)CH 2 CH 2 -, (4-CH 3 -phenyl)CH 2 CH 2 -, (4-CF 3 -phenyl)CH 2 CH 2 -, pyridin-2-yl-, pyridin-3-yl-, 4-CF 3 -pyridin-2-yl-, 4-CH 3 -pyridin-2-yl-, thiazol-2-yl-, azapan-1-yl, N,N-dimethylamino, N,N-diethylamino, N,N 35 dipropylamino, and N,N-dibutylamino; and R1 3 , at each occurrence, is independently selected from H, MeO, F, and Cl. -187- WO 01/19797 PCT/USOO/24967 9. A compound, according to one of Claims 5, 6, 7, or 8, of Formula (Ic); 5 R5 R 5 a H O RQ ?N W-X-Y-Z OH O R" (Ic) or a pharmaceutically acceptable salt form or prodrug thereof. 10 10. A compound, according to one of Claims 5, 6, 7, or 8, of Formula (Id); R5 R 5 aH O N N'W-X-Y-Z OH 0 N R 1 3 15 R 1 1 ~R13 (Id) or a pharmaceutically acceptable salt form or prodrug thereof. 20 11. A compound, according to one of Claims 5, 6, 7, or 8, of Formula (Ie); R5 RaH a Q5>y~N ,W-X-Y-Z N OH O /13/ R R ~~ 25 (Ie) or a pharmaceutically acceptable salt form or prodrug thereof. -188- WO 01/19797 PCT/USOO/24967 12. A compound of selected from: 3-(2(R)-Cyclopentylmethyl-3(S)-hydroxyl-l-oxo-5 phenylpentyl)amino-i-methyl- 5-phenyl-2,3-dihydro-lH-1,4 5 benzodiazepin-2-one; 3-(2(R)-Cyclopentylmethyl-3(S)-hydroxyl-l-oxo-5 phenylpentyl)amino-l-methyl-5-(4-fluoro-phenyl)-2,3 dihydro-lH-1,4-benzodiazepin-2-one; 10 3-(2(R)-Benzyl-3 (S)-hydroxyl-l-oxo-5-phenylpentyl)amino-i methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one; 3-(2(R)-Isopropyl-3(S)-hydroxyl-l-oxo-5-phenylpentyl)amino 15 1-methyl-5-phenyl-2,3-dihydro-lH-1,4-benzodiazepin-2-one; 3-(2(R)-Cyclopentylmethyl-3(S)-hydroxyl-l-oxo-4-(3,5 difluorophenoxy)butyl)amino-l-methyl-5-phenyl-2,3-dihydro 1H-1,4-benzodiazepin-2-one; 20 3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-4-(3,5 difluorophenoxy)butyl)amino-l-methyl-5-phenyl-2,3-dihydro 1H-1,4-benzodiazepin-2-one; 25 3-(2(R)-Cyclopentylmethyl-3(S)-hydroxyl-l-oxo-4 phenoxybutyl)amino-7-chloro-l-methyl-5-phenyl-2,3-dihydro 1H-1,4-benzodiazepin-2-one; 3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-4-phenoxybutyl)amino 30 7-chloro-l-methyl-5-(4-fluorophenyl)-2,3-dihydro-lH-1,4 benzodiazepin-2-one; 3-(2(R)-Methyl-3(S)-hydroxyl-l-oxo-4 cyclohexyloxybutyl)amino-l-methyl-5-phenyl-2,3-dihydro-lH 35 1,4-benzodiazepin-2-one; -189- WO 01/19797 PCT/USOO/24967 3-(2(R)- Isobutyl -3(S)-hydroxyl-1-oxo-4 cyclohexyloxybutyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H 1,4-benzodiazepin-2-one; 5 3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-4-phenoxybutyl)amino-7 chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin 2-one; 3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-4-phenoxybutyl)amino 10 7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one; 3-(2(R)-Benzyl-3(S)-hydroxyl-1-oxo-4 cyclohexyloxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3 15 dihydro-1H-1,4-benzodiazepin-2-one; 3-(2(R)-Cyclopentylmethyl-3(S)-hydroxyl-1-oxo-4 cyclohexyloxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3 dihydro-1H-1,4-benzodiazepin-2-one; 20 3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-4 cyclohexyloxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3 dihydro-1H-1,4-benzodiazepin-2-one; 25 3-(2(R)-Isopropyl-3(S)-hydroxyl-1-oxo-4 cyclohexyloxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3 dihydro-1H-1,4-benzodiazepin-2-one; 3-(2(R)-Methoxy-3(S)-hydroxyl-1-oxo-4-(4 30 trifluoromethylbenzyloxy)butyl)amino-7-chloro-1-methyl-5 phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one; 3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-4-(2,4 difluorobenzyloxy)butyl)amino-7-chloro-1-methyl-5-phenyl 35 2,3-dihydro-1H-1,4-benzodiazepin-2-one; -190- WO 01/19797 PCT/USOO/24967 3-(2(R)-Vinyl-3(S)-hydroxyl-1-oxo-4-benzyloxybutyl)amino-7 chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin 2-one; 5 3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-4 cyclohexyloxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3 dihydro-1H-1,4-benzodiazepin-2-one; 3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-5- phenylpentyl)amino 10 1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one; 3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-3 cyclopropylpropyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H 1,4-benzodiazepin-2-one; 15 3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-heptyl)amino-1-methyl 5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one; 3-(R)-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-heptyl)amino-i 20 methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one; 3-(S)-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-heptyl)amino-i methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one; 25 3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-nonyl)amino-1-methyl 5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one; 3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-hexyl)amino-1-methyl 5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one; 30 3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-4- phenylbutyl)amino 1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one; 3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-5- phenylpentyl)amino-1 35 methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one; -191- WO 01/19797 PCT/USOO/24967 3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-6- phenylhexyl)amino-1 methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one; 3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-butyl)amino-1-methyl 5 5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one; 3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-octyl)amino-1-methyl 5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one; 10 3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-heptyl)amino-1-methyl-5 phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one; 3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-3- phenylpropyl)amino-1 methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one; 15 3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-5,5-dimethyl hexyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one; 20 3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-hexyl)amino-1-methyl-5 phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one; 3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-3-(4 propoxyphenyl)propyl)amino-1-methyl-5-phenyl-2,3-dihydro 25 1H-1,4-benzodiazepin-2-one; 2-(R)-cyclopropylmethyl-3-(S)-hydroxylheptanoic acid (2 oxo-1-(3-phenoxybenzyl)azapan-3-(S)-yl) amide; 30 2(R)-cyclopropylmethyl-5-(3,5-difluorophenyl)-3-(S) hydroxypentanoic acid (2-oxo-1-(3-phenoxybenzyl)azapan-3 (S)-yl)amide; 4-cyclopentyl-2-(R)-cyclopropylmethyl-3-(S)-hydroxybutanoic 35 acid (2-oxo-1-(3-phenoxybenzyl)azapan-3-(S)-yl) amide; -192- WO 01/19797 PCT/USOO/24967 2-(R)-cyclopropylmethyl-3-(S)-hydroxyheptanioc acid (1-(5 bromo-3-pyridinyl)methyl-2-oxo-azapan-3-(S)-yl) amide; 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 5 oxoheptyl)amino-5-(2-fluorophenyl)-1-methyl-2,3-dihydro-1H 1,4-benzodiazepin-2-one; 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-5-(azapan-1-yl)-1-methyl-2,3-dihydro-1H 10 1,4-benzodiazepin-2-one; 3-(2-(R)-cyclopropylmethyl-5-(3,5-difluorophenyl)-3(S) hydroxyl-1-oxopentyl)amino-1-methyl-5-(pyridn-2-yl)-2,3 dihydro-1H-1,4-benzodiazepin-2-one; 15 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxopentyl)amino-1-methyl-5-(4-chlorophenyl)-2,3-dihydro-1H 1,4-benzodiazepin-2-one; 20 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-5-(4-methoxyphenyl)1-methyl-2,3-dihydro-1H 1,4-benzodiazepin-2-one; 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 25 oxoheptyl)amino-5-(4-methoxyphenyl)-1-methyl-2,3-dihydro 1H-1,4-benxodiazepin-2-one; 3-(S)-(4-cyclopentyl-2-(R)-cyclopropylmethyl-3-(S) hydroxyl-1-oxobutyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H 30 1,4-benzodiazepin-2-one; 3-(S)-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxohept-6 enyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one; 35 -193- WO 01/19797 PCT/USOO/24967 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxohept-6 enyl)amino-1-methyl-5-(4-trifluoromethyl-phenyl)-2,3 dihydro-1H-1,4-benzodiazepin-2-one; 5 3-(S)-(2-(R)-cyclopropylmethyl-5-(3,5-dimethylisoxazol-4 yl)-3-(S)-hydroxyl-1-oxopentyl)amino-1-methyl-5-phenyl-2,3 dihydro-1H-1,4-benzodiazepin-2-one; 10 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H 1,4-benzodiazepin-2-one; 15 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-i-methyl-(pyridin-2-yl)-2,3-dihydro-1H-1,4 benzodiazepin-2-one; 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-l 20 oxoheptyl)amino-5-(4-fluorophenyl)-1-methyl-2,3-dihydro-1H 1,4-benzodiazepin-2-one; 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 25 oxoheptyl)amino-1-methyl-5-(4-trifouoromethylphenyl)-2,3 dihydro-1H-1,4-benzodiazepin-2-one; 3-(5-cyclopentyl-2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxopentyl)amino-1-methyl-5-(pyridin-2-yl)-2,3-dihydro-1H 30 1,4-benzodiazepin-2-one; 3-(2-(R)-iso-butyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1 methyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4 benzodiazepin-2-one; 35 -194- WO 01/19797 PCT/USOO/24967 3-(S)-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxo-5 (thiophen-2-yl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one; 5 3-(S)-(2-(R)-cyclopropylmethyl-5-(furan-2-yl)3-(S) hydroxyl-1-oxopentyl)amino-1-methyl-5-phenyl-2,3-dihydro 1H-1,4-benzodiazepin-2-one; 3-(5-cyclopentyl-2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 10 oxopentyl)amino-5-(4-fluorophenyl)-1-methyl-2,3-dihydro-1H 1,4-benzodiazepin-2-one; 3-(S)-(2-(R)-cyclopropylmethyl-5-(3,5-difluorophenyl)-3 (S)-hydroxy-1-oxopentyl)amino-1-methyl-5-phenyl-2,3 15 dihydro-1H-1,4-benzodiazepin-2-one; 3-(S)-(3-(S)-hydroxyl-2-(R)-(thiophen-2-yl)methyl-1 oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one; 20 3-(S)-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-7-methyl-5-phenyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one; 25 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-7-methoxy-1-methyl-5-phenyl-2,3-dihydro-1H 1,4-benzodiazepin-2-one; 3-(S)-(2-(R)-cyclobutylmethyl-3-(S)-hydroxyl-1 30 oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one; 3-(S)-(2-(R)-(3,5-difluorobenzyl)-3-(S)-hydroxyl-1 oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydor-1H-1,4 35 benzodiaxepin-2-one; -195- WO 01/19797 PCT/USOO/24967 3-(S)-(2-(R)-(furan-2-yl)methyl-3-(S)-hydroxyl-1 oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one; 5 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxl-1-oxo-5 pheylpentyl)amino-1-methyl-5-(pyridin-2-yl)-2,3-dihydro-1H benzodiazepin-2-one; 3-(2-(R)-iso-butyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-(4 10 fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2 one; 3-(2-(R)-iso-butyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-(4 fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2 15 one; 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxo-5 phenylpentyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one; 20 3-(2-(R)-cyclopropylmethyl-5-(furan-2-yl)-3-(S)-hydroxyl-1 oxopentyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3 dihydro-1H-1,4-benzodiazepin-2-one; 25 3-(5-cyclopentyl-2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxopentyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3 dihydro-1H-1,4-benzodiazepin-2-one; 30 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxooctyl)amino 1-methyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4 benzodiazepin-2-one; 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxononyl)amino 35 1-methyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4 benzodiazepin-2-one; -196- WO 01/19797 PCT/USOO/24967 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-1-methyl-5-(4-trifluoromethyl(pyridin-2 yl))-2,3-dihydro-1H-1,4-benzodiazepin-2-one; 5 3-(2-(R)-cyclobutylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino 1-methyl-5-(40trifluoromethylphenyl)-2,3-dihydro-1H-1,4 benzodiazepin-2-one; 10 3-(2-(R)-cyclopentylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3 dihydro-1H-1,4-benzodiazepin-2-one; 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 15 oxoheptyl)amino-1-methyl-5-(4-methyl-2-pyridiyl)-2,3 dihydro-lH-1,4-benzodiazepin-2-one; 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-1-methyl-5-(4-methyl-2-pyridyl)-2,3 20 dihydro-1H-1,4-benzodiazepin-2-one; 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxobutyl)amino 1-methyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-lH-1,4 benzodiazepin-2-one; 25 3-(S)-(2-(R)-(3-butenyl)-3-(S)-hydroxyl-1-oxoheptyl)amino 1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one; 3-(S)-(2-(R)-(3-methylbutyl)3-(S)-hydroxyl-1 30 oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydro-lH-1,4 benzodiazepin-2-one; 3-(S)-(2-(R)-ethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1 methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one; 35 3-(S)-(2-(R)-propyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1 methyl-5-phenyl-2,3-dihydro-1,4-benzodiazepin-2-one; -197- WO 01/19797 PCT/USOO/24967 3-(S)-(2-(R)-butyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1 methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one; 5 3-(4-(S)-amino-3-(R)-hydroxyl-2-(R)-methyl-1-oxo-5 phenylpentyl)amino-7-chloro-5-(2-fluorophenyl)-1-methyl 2,3-dihydro-lH-1,4-benzodiazepin-2-one; 3-(4-(S)-(tert-butoxycarbonylamino-3-(R)-hydroxyl-2-(R) 10 methyl-1-oxo-5-phenylpentyl)amino-7-chloro-5-(2 fluorophenyl)-1-methyl-2,3-dihydro-lH-1,4-benzodiazepin-2 one; 3-(3-(tert-butoxycarbonylpyrrolidin-2-(R)-yl)-3-(R) 15 hydroxyl-2-(R)-methyl-1-oxopropyl)amino-7-chloro-5-(2 fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2 one; 3-(3-(R)-hydroxyl-2-(R)-methyl-1-oxo-3-(pyrrolidin-2-(R) 20 yl)propyl)-amino-7-chloro-5-(2-fluorophenyl)-1-methyl-2,3 dihydro-1H-1,4-benzodiazepin-2-one; 3-(4-benzyloxy-3-(R)-hydroxyl-2-(R)-iso-propyl-1-oxobutyl amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro-lH-1,4 25 benzodiazepin-2-one; 2-(4-(S)-amino-3-(S)-hydroxyl-2-(S)-methyl-1-oxo-5 phenylpentyl)amino-7-chloro-5-(2-flourophenyl)-1-methyl 2,3-dihydro-1H-1,4-benzodiazepin-2-one; 30 2-(4-(S)-(tert-butoxycarbonylamino-3-(S)hydroxyl-2-(S) methyl-1-oxo-5-phenylpentyl)amino-7-chloro-5-(2 fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2 one; 35 -198- WO 01/19797 PCT/USOO/24967 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-1-methyl-5-(thiazol-2-yl)-2,3-dihydro-1H 1,4-benzodiazepin-2-one; 5 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-1-cyclopropylmethyl-5-(thiazol-2-yl)-2,3 dihydro-1H-1,4benzodiazepin-2-one; 10 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-1-cyclopropylmethyl-5-(4 trifluoromethylphenyl)-2,3-dihydro-1H-l,4-benzodiazepin-2 one; 15 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-1-benzyl-5-(4-trifluoromethylphenyl)-2,3 dihydro-1H-1,4-benzodiazepin-2-one; 20 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-l-(3-phenoxybenzyl)-5-(4-trifluoromethyl phenyl)-2,3-dihydro-lH-1,4-benzodiazepin-2-one; 25 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-l-(3-pyridinylmethyl)-5-(4-trifluoromethyl phenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one; 30 3-(2-(S)-cyclopropylmethyl-3-(R)-hydroxyl-1 oxoheptyl)amino-1-methyl-5-(4-trifluoromethyl-phenyl)-2,3 dihydro-lH-1,4-benzodiazepin-2-one; 35 -199- WO 01/19797 PCT/USOO/24967 3-(2-(S)-cyclopropylmethyl-3-(R)-hydroxyl-1 oxoheptyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3 dihydro-1H-1,4-benzodiazepin-2-one; 5 3-(2-(R)-cyclopropylmethyl-3-(R)-hydroxyl-1 oxoheptyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3 dihydro-1H-1,4-benzodiazepin-2-one; 10 3-(2-(S)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3 dihydro-1H-1,4-benzodiazepin-2-one; 15 3-(2-(S)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3 dihydro-1H-1,4-benzodiazepin-2-one; 20 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-3-(S)-methyl-1 oxoheptyl)amino-1-methyl-5-(4-trifluoromethyl-phenyl)-2,3 dihydro-1H-1,4-benzodiazepin-2-one; 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-l 25 oxoheptyl)amino-i-(3-phenoxybenzyl)-5-methyl-2,3-dihydro 1H-1,4-benzodiazepin-2-one; 3-(2-(R)-cyclopropylmehtyl-3-(S)-hydroxyl-1 oxoheptyl)amino-1-benzyl-5-methyl-2,3-dihydro-1H-1,4 30 benzodiazepin-2-one; 3-(3-(S)-acetoxy-2-(R)-iso-butyl-1-oxoheptyl)amino-5-(4 fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2 one; 35 -200- WO 01/19797 PCT/USOO/24967 3-(S)-(5-cyclopentyl-2-(R)-cyclopropylmethyl-3-(S)-methoxy 1-oxopentyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one; 5 1-(1-hydroxypentyl)cyclohexanecarboxylic acid(5-(4 fluorophenyl)-1-methyl-2-oxo-2,3-dihydro-1H-1,4 benzodiazepin-3-yl)amide; 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 10 oxoheptyl)amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one; 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxooctyl)amino 5-methyl-5H,7H-dibenzo[b,d]azepin-6-one; 15 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxononyl)amino 5-methyl-5H,7H-dibenzo[b,d]azepin-6-one; 3-(2-(R)-cyclopropylmethyl-5-(furan-2-yl)-3-(S)-hydroxyl-1 oxopentyl)amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one; 20 2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-heptanoic acid (2 oxo-1-(3-phenylamino-benzyl)azapan-3-(S)-yl) amide; 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 25 oxoheptyl)amino-5-cyclopentyl-1-methyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one; 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-5-benzyl-1-methyl-2,3-dihydro-1H-1,4 30 benzodiazepin-2-one; 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-5-benzyl-1-butyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one; 35 -201- WO 01/19797 PCT/USOO/24967 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-5-cycloheptyl-1-methyl -2,3-dihydro-1H-1,4 benzodiazepin-2-one; 5 3-(2-(R)-cycloropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino 1-benzyl-5-cycloheptyl-2,3-dihydro-1H-1,4-benzodiazepin-2 one; 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 10 oxoheptyl)amino-1-butyl-5-cycloheptyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one; 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-i-(2-pyridinylmethyl)-5-(4 15 trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2 one; 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-i-(3-pyridinylmethyl)-5-(2-fluorophenyl) 20 2,3-dihydro-1H-1,4-benzodiazepin-2-one; 3-(2-(S)-cyclopropylmethyl-3-(S)-hydroxyl-1 oxopentyl)amino-i-(3-pyridynylmethyl)-5-(4 trifluoromethylphenyl)-2,3-dihydro-iH-1,4-benzodiazepin-2 25 one; 3-(2-1(R)-Cyclopropylmethyl-3-(S)-hydroxyl-i oxoheptyl)amino-1-methyl-5-(N,N-dibutylamino)-2,3-dihydro 1H-1,4-benzodiazepin-2-one; 30 3-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-1-n-butyl-5-t-butyl-2,3-dihydro-iH-1,4 benzodiazepin-2-one; 35 3-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-1-(2-oxo-3,3-dimethylbutyl)-5-n-butyl-2,3 dihydro-1H-1,4-benzodiazepin-2-one; -202- WO 01/19797 PCT/USOO/24967 3- (2- (R) -Cyclopropylmethyl-3- (S) -hydroxyl-1 oxoheptyl)amino-l-benzyl-5-t-butyl-2,3-dihydro-1H-1,4 benzodiazepin-2-one; 5 3-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1 oxoheptyl)amino-1-(2-picolyl) -5-n-butyl-2,3-dihydro-lH-1,4 benzodiazepin-2-one; 10 3-(2-(R)-Isobutyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1 methyl-5-homopiperidino-2,3-dihydro-1H-1,4-benzodiazepin-2 one; 3-(2-(R)-cyclopropylmethyl-1,3-dioxoheptyl)amino-1-methyl 15 5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4 benzodiazepin-2-one; and 1-pentyrylcyclohexanecarboxylic acid (5-(4-fluorophenyl)-1 methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl) amide. 20 13. A compound of Claim 12 wherein the stereochemistry of carbon 3 in lactam ring B is of the S configuration.
  5. 14. A compound of Claim 12 wherein the stereochemistry of 25 carbon 3 in lactam ring B is of the R configuration.
  6. 15. A compound of Formula (Ib) RA 5 R 5a H 0 N O ,W-X-Y-Z OH O B 30 (Ib) wherein: Ring B is selected from: -203- WO 01/19797 PCT/USOO/24967 0N0 1 0 ~ ' ON 13 13 11 R R13 R -. R ;1 ; and ; Q1 is Ci-C 6 alkyl substituted with 0-3 Ria; C 2 -C 6 alkenyl substituted with 0-3 Ria; 5 C 2 -C 6 alkynyl substituted with 0-3 Ria; C 3 -C1O cycloalkyl substituted with 0-3 Rib; C 3 -C1O carbocycle substituted with 0-3 Rib; C 6 -C 10 aryl substituted with 0-3 Rib; or 5 to 10 membered heterocycle containing 1 to 4 10 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 Rib; R 1 a, at each occurrence, is independently selected from H, 15 Ci-C6 alkyl, OR1 4 , Cl, F, Br, I, NR 1 5 R 1 6 , CF 3 ; C3-C1O carbocycle substituted with 0-3 Rib; C 6 -Cio aryl substituted with 0-3 Rib; and 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and 20 sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 Rib; Rib, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR1 5 R1 6 , CF 3 , acetyl, SCH 3 , 25 S(=O)CH 3 , S(=0) 2 CH 3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, Ci-C 4 haloalkyl-S-, and (Ci-C 6 alkyl)-O-C(=O)-; R 5 is ORi 4 ; 30 Ci-C 6 alkyl substituted with 0-3 R5b; C 2 -C 6 alkenyl substituted with 0-3 R5b; or -204- WO 01/19797 PCT/USOO/24967 C 2 -C 6 alkynyl substituted with 0-3 R 5 b; R 5 a is H, methyl, ethyl, propyl, butyl, or C 2 -C 4 alkenyl; 5 alternatively, R 5 and R 5 a may be combined to form a C 4 -C 7 cycloalkyl ring; R5b, at each occurrence, is independently selected from: H, methyl, ethyl, propyl, butyl, CF 3 , OR 1 4 , Cl, F, Br, 10 I, =0, NR 1 5 R 1 6 , C 3 -C 7 cycloalkyl substituted with 0-3 R 5 c; C 3 -C 7 carbocycle substituted with 0-3 R 5 c; phenyl substituted with 0-3 R 5 c; and 5 to 7 membered heterocycle containing 1 to 4 15 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R 5 c; R 5 c, at each occurrence, is independently selected from H, 20 OH, Cl, F, Br, I, CN, NO 2 , NR 1 5 R 1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2 CH 3 , Ci-C 4 alkyl, Ci-C 3 alkoxy, Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy; W is -(CHR 8 ) 25 p is 0 or 1; R 8 is H, methyl, or ethyl; 30 X is a bond; phenyl substituted with 0-2 Rxb; C 5 -C 6 cycloalkyl substituted with 0-3 RXb; or 5 to 6 membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and 35 sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-2 RXb; -205- WO 01/19797 PCT/USOO/24967 RXb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 1 5 R 1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2 CH 3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, and Ci-C 4 haloalkyl-S-; 5 Y is a bond, -V-, -CH 2 -V-, -V-CH 2 -, or -CH 2 -V-CH 2 -; V is a bond, -C(=O)-, -0-, -S-, -S(=O)-, -S(=0) 2 -, or -N(R 1 9 )-; 10 Z is H, F, Cl, Br, Ci-C 4 alkyl substituted with 0-2 R1 2 ; C 2 -C 4 alkenyl substituted with 0-2 R1 2 ; C 2 -C 4 alkynyl substituted with 0-2 R1 2 ; 15 C 6 -C 1 0 aryl substituted with 0-4 R1 2 b; C 3 -C 6 carbocycle substituted with 0-4 R12b; or 5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle 20 is substituted with 0-3 R12b. R1l, at each occurrence, is independently selected from H, =0, NR 1 8 R 1 9 , C(=O)R 1 7 , C(=O)OR1 7 , C(=O)NR 1 8 R 1 9 , S(=0) 2 NR1 8 R 19 , CF3; 25 Cl-C 6 alkyl substituted with 0-1 R11a; phenyl substituted with 0-3 R11b; C 3 -C 6 carbocycle substituted with 0-3 R11b; or 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and 30 sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R11b; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, -206- WO 01/19797 PCT/USOO/24967 homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl; R 11 a, at each occurrence, is independently selected from H, 5 methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Cl, F, =0, NR 1 5 R 1 6 , CF 3 ; phenyl substituted with 0-3 R11b; C 3 -C 6 carbocycle substituted with 0-3 R11b; or 5 to 7 membered heterocycle containing 1 to 4 10 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R11b; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, 15 thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl; 20 R11b, at each occurrence, is independently selected from H, OH, Cl, F, NR 1 5 R 1 6 , CF 3 , acetyl, SCH 3 , S(=0)CH 3 , S(=0) 2 CH 3 , methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy; 25 R 12 at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 1 5 R 1 6 , -C(=O)NR 1 5 R1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2 CH 3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, and Ci-C 4 30 haloalkyl-S-; C 6 -C 1 0 aryl substituted with 0-4 R12b; C 3 -C 10 carbocycle substituted with 0-4 R12b; or 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and 35 sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b; -207- WO 01/19797 PCT/USOO/24967 R1 2 b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NR 1 5 R1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2 CH 3 , Ci-C 6 alkyl, Ci-C 4 alkoxy, Ci-C 4 5 haloalkyl, C 1 -C 4 haloalkoxy, and Ci-C 4 haloalkyl-S-; R1 3 , at each occurrence, is independently selected from H, OH, Ci-C 6 alkyl, Ci-C 4 alkoxy, Cl, F, Br, I, CN, NO 2 , NR 1 5 R 1 6 , and CF 3 ; 10 R1 4 , at each occurrence, is independently selected from H, phenyl, benzyl, Ci-C 4 alkyl, and C 2 -C 4 alkoxyalkyl; R 15 , at each occurrence, is independently selected from H, 15 methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; R1 6 , at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, 20 phenethyl, CH 3 CH 2 C(=O)-, CH 3 C(=O)-, CH 3 CH 2 OC(=O)-, CH 3 0C(=O)-, CH 3 CH 2 S(=0) 2 - and CH 3 S(=0) 2 -; R1 7 is H, phenyl, benzyl, Ci-C 4 alkyl, or C 2 -C 4 alkoxyalkyl; 25 R 18 , at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and R 19 , at each occurrence, is independently selected from H, 30 OH, methyl, ethyl, propyl, and butyl.
  7. 16. A compound of Claim 15 wherein: Q 1 is Ci-C 6 alkyl substituted with 0-3 Ria; 35 C 2 -C 6 alkenyl substituted with 0-3 Ria; -208- WO 01/19797 PCT/USOO/24967 C 2 -C 6 alkynyl substituted with 0-3 Ria; C 3 -C 6 cycloalkyl substituted with 0-3 Rib; phenyl substituted with 0-3 Rib; or 5 to 6 membered heterocycle containing 1 to 4 5 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 Rib; R 1 a, at each occurrence, is independently selected from 10 H, methyl, ethyl, propyl, butyl, OR 1 4 , Cl, F, Br, I, NR 1 5 R 1 6 , CF 3 ; C 3 -C 6 carbocycle substituted with 0-3 Rib; phenyl substituted with 0-3 Rib; and 5 to 6 membered heterocycle containing 1 to 4 15 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 Rib; Rib, at each occurrence, is independently selected from H, 20 OH, Cl, F, Br, I, CN, NO 2 , NR 1 5 R 1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2 CH 3 , methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Ci-C 2 haloalkyl, Ci-C 2 haloalkoxy, (methyl)OC(=O)-, (ethyl)OC(=O)-, (propyl)OC(=O)-, and (butyl)OC(=O)-; 25 R 5 is OR 14 ; Ci-C 4 alkyl substituted with 0-1 R 5 b; C 2 -C 4 alkenyl substituted with 0-1 R5b; or C 2 -C 4 alkynyl substituted with 0-1 R5b; 30 R 5 a is H, methyl, ethyl, propyl, or butyl; alternatively, R 5 and R 5 a may be combined to form a cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl 35 ring; -209- WO 01/19797 PCT/USOO/24967 R 5 b, at each occurrence, is independently selected from: H, methyl, ethyl, propyl, butyl, CF 3 , OR 14 , Cl, F, =0, NR 1 5 R 1 6 , C 3 -C 7 cycloalkyl substituted with 0-3 R 5 c; 5 C 3 -C 7 carbocycle substituted with 0-3 R 5 c; phenyl substituted with 0-3 R 5 c; and 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle 10 is substituted with 0-3 R 5 c; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, 15 isoxazolyl, and tetrazolyl; R 5 c, at each occurrence, is independently selected from H, OH, Cl, F, NR 1 5 R 1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH3, S(=0) 2 CH 3 , methyl, ethyl, propyl, butyl, methoxy, 20 ethoxy, propoxy, Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy; W is a bond, -CH 2 -, or -CH(CH 3 )-; 25 X is a bond; phenyl substituted with 0-1 RXb; C 5 -C 6 cycloalkyl substituted with 0-1 Rxb; or 5 to 6 membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and 30 sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-1 RXb; wherein said 5 to 6 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, 35 pyrazolyl, imidazolyl, oxazolyl, and isoxazolyl; RXb, at each occurrence, is independently selected from -210- WO 01/19797 PCT/USOO/24967 H, OH, Cl, F, Br, NR 1 5 R 1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2 CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy; 5 Y is a bond, -V-, -V-CH 2 -, or -CH 2 V-; V is a bond, -C(=O)-, -0-, -S-, -S(=O)-, -S(=0) 2 -, or -N(R 19 )-; 10 Z is H, F, Cl, Br, Ci-C 4 alkyl substituted with 0-2 R1 2 ; C 2 -C 4 alkenyl substituted with 0-2 R1 2 ; C 2 -C 4 alkynyl substituted with 0-2 R1 2 ; 15 C 6 -Cio aryl substituted with 0-4 R1 2 b; C 3 -C 6 carbocycle substituted with 0-4 R12b; or 5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle 20 is substituted with 0-3 R12b; R 11 , at each occurrence, is independently selected from H, NR 1 8 R 1 9 , CF 3 ; Ci-C 4 alkyl substituted with 0-1 R11a; 25 phenyl substituted with 0-3 R11b; C 3 -C 6 carbocycle substituted with 0-3 R11b; or 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle 30 is substituted with 0-3 R11b; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, 35 isoxazolyl, and tetrazolyl; -211- WO 01/19797 PCT/USOO/24967 R 1 1 a, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Cl, F, =0, NR1 5 R 1 6 , CF 3 ; 5 phenyl substituted with 0-3 R11b; C 3 -C 6 carbocycle substituted with 0-3 R11b; or 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle 10 is substituted with 0-3 R11b; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, 15 isoxazolyl, and tetrazolyl; R11b, at each occurrence, is independently selected from H, OH, Cl, F, NR 1 5 R 1 6 , CF 3 , methyl, ethyl, propyl, butyl, 20 methoxy, ethoxy, propoxy, Ci-C 2 haloalkyl, and C1-C 2 haloalkoxy; R 12 at each occurrence, is independently selected from H, OH, Cl, F, Br, NR 1 5 R 1 6 , -C(=O)NR1 5 R 1 6 , CF 3 , acetyl, 25 SCH 3 , S(=O)CH 3 , S(=0) 2 CH 3 , methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy; phenyl substituted with 0-4 R1 2 b; C 3 -C 6 carbocycle substituted with 0-4 R12b; or 30 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 R1 2 b; 35 R12b, at each occurrence, is independently selected from -212- WO 01/19797 PCT/USOO/24967 H, OH, Cl, F, Br, NR 1 5 R 1 6 , CF 3 , acetyl, SCH 3 , S(=O)CH 3 , S(=0) 2 CH 3 , methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy; 5 R 13 , at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Cl, F, Br, CN, NR 1 5 R 1 6 , and CF 3 ; 10 R 14 , at each occurrence, is independently selected from H, phenyl, benzyl, methyl, ethyl, propyl, and butyl; R 15 , at each occurrence, is independently selected from H, methyl, ethyl, propyl, or butyl; 15 R 16 , at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; 20 R1 8 , at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl and, phenethyl; and R 19 , at each occurrence, is independently selected from H, 25 OH, methyl, ethyl, propyl, butyl, phenyl, benzyl and, phenethyl.
  8. 17. A compound of Claim 16 wherein: 30 Q 1 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 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 , -CH(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 , 35 -CH=CH 2 , -CH 2 CH=CH 2 , -CH 2 C(CH 3 )=CH 2 , -CH 2 CH=C(CH 3 )2, -213- WO 01/19797 PCT/USOO/24967 -CH 2 CH 2 CH=CH 2 , -CH 2 CH 2 C (CH 3 ) =CH 2 , -CH 2 CH 2 CH=C (CH 3 ) 2 , cis-CH 2 CH=CH(CH 3 ), cis-CH 2 CH 2 CH=CH(CH 3 ), trans-CH 2 CH=CH(CH 3 ), trans-CH 2 CH 2 CH=CH(C- 3 ); 5 -C=-CH, -CH 2 C=-CH, -CH 2 C=EC(CH 3 ), cyclopropyl-, cyclobutyl-, cyclopentyl-, cyclohexyl-, cyclopropyl-CH 2 -, cyclobutyl-CH 2 -, cycloperityl-CH 2 -, cyclohexyl-CH 2 -, cyclopropyl-CH 2 CH 2 -, cyclobutyl-CH 2 CH 2 -, 10 cyclopentyl-CH 2 CH 2 -, cyclohexyl-CH 2 CH 2 -, phenyl-, 2-F-phenyl-, 3-F-phenyl-, 4-F-phenyl-, 4 -methoxyphenyl -, 4-ethoxyphenyl-, 4 -propoxyphenyl-, phenyl-CH 2 -, (2-F-phenyl)CH 2 -, (3-F-phenyl)CH 2 -, 15 (4-F-phenyl)CH 2 -, (2-C1-phenyl)CH 2 -, (3-C1-phenyl)CH 2 -, (4-Ci-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 -, 20 (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-C1-phenyl)CH 2 -, (3-F-5-C1-phenyl)CH 2 -, 25 (3-C1-4-F-phenyl)CH 2 -, 2-furanyl-CH 2 -, 3-furanyl-CH 2 -, 2-thienyl-CH 2 -, 3-thienyl-CH 2 -, 2-pyridyl-CH 2 -, 3-pyridyl-CH 2 -, 4-pyridyl-CH 2 -, 1-imidazolyl-CH 2 -, 2-oxazolyl-CH 2 -, 30 4-oxazolyl-CH 2 -, 5-oxazolyl-CH 2 -, 3-isoxazolyl-CH 2 -, 4-isoxazolyl-CH 2 -, 5-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 -, 35 (2-C1-phenyl)CH 2 CH 2 -, (3-C1-phenyl)CH 2 CH 2 -, (4-Ci-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 -, -214- WO 01/19797 PCT/USOO/24967 (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 C- 2 -, (3,5-diCl-phenyl)CH 2 CH 2 -, 5 (3-F-4-C1-phenyl)CH 2 CH 2 -, (3-F-5-C1-phenyl)CH 2 CH 2 -; furariyl-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 -, isoxazolyl-CH 2 CH 2 -, 3, 5-dimethylisoxazol-4-yl-CH 2 CH 2 -, 10 pheriyl-propyl-; benzyl-CH(NH 2 )-, benzyl-CH(NHC(=O)-O-tBu)-, benzyloxy-CH 2 -, pyrrolidin-2-yl-, or 3 -t-butoxycarbonylpyrrolidin-2 -yl-; 15 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 , 20 -CE 3 , -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 2 CH 2 CH=CH 2 , -CH=CHCH 3 , cis-CH 2 CH=CH (CH 3 ), trans-CH 2 CH=CH(CH 3 ), 25 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 ), tranis 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 ), 30 -CH 2 CH 2 C--CH, -CH 2 CH 2 C=C (CH 3 ), -CH 2 CH 2 C=C (C 6 H 5 ), -CH 2 CH 2 CH 2 C--CH, -CH 2 CH 2 CH 2 C-=C(CH 3 ), -CH 2 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 -, 35 (3-CH 3 -cyclobutyl) CH 2 -, cyclopropyl-CH 2 CH 2 -, cyclobutyl-CH 2 CH 2 -, cyclopentyl-CH 2 CH 2 -, cyclohexyl-CH 2 C- 2 -, (2-CH 3 -cyclopropyl)CH 2 CH 2 -, (3-CH 3 -cyclobutyl) CH 2 CH 2 -, -215- WO 01/19797 PCT/USOO/24967 phenyl-CH 2 -, (2-F-phenyl)CH 2 -, (3-F-phenyl)CH 2 -, (4-F-phenyl)CH 2 -, (3,5-diF-phenyl)CH 2 -, 2-furanyl-CH 2 -, 3-furanyl-CH 2 -, 2-thienyl-CH 2 -, 3-thienyl-CH 2 -, 5 2-pyridyl-CH 2 -, 3-pyridyl-CH 2 -, 4-pyridyl-CH 2 -, 1-imidazolyl-CH 2 -, 2-oxazolyl-CH 2 -, 4-oxazolyl-CH 2 -, 5-oxazolyl-CH 2 -, 3-isoxazolyl-CH 2 -, 4-isoxazolyl-CH 2 -, 5-isoxazolyl-CH 2 -, 10 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 -, isoxazolyl-CH 2 CH 2 -; 15 methoxy, ethoxy, propoxy, or butoxy; R 5 a is H; alternatively, R 5 and R 5 a may be combined to form 20 cyclopentyl, cyclohexyl, or cycloheptyl; W is a bond, -CH 2 -, or -CH(CH 3 )-; X is a bond; 25 j<NAN N ; ; or I-N 30 Y is a bond, -CH 2 -V-, -V-, or -V-CH 2 -; V is a bond, -C(=O)-, -0-, -S-, -S(=0)-, -S(=0)2-, -NH-, or -N(CH 3 )-; -216- WO 01/19797 PCT/USOO/24967 Z is H, F, Cl, Br, methyl, ethyl, n-propyl, i-propyl, n butyl, i-butyl, s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5 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, 10 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, 15 4-MeS-phenyl, 2-CF 3 0-phenyl, 3-CF 3 0-phenyl, 4-CF 3 0-phenyl, furanyl, thienyl, pyridyl, 2-Me-pyridyl, 3-Me-pyridyl, 4-Me-pyridyl, 1-imidazolyl, oxazolyl, isoxazolyl, 20 1-benzimidazolyl, 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 -, 25 (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 -, 30 (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-PhO-phenyl)CH 2 -, (3-PhO-phenyl)CH 2 -, (4-Pho-phenyl)CH 2 -, 35 (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 0-phenyl)CH 2 -, (3-CF 3 0-phenyl)CH 2 -, -217- WO 01/19797 PCT/USOO/24967 (4-CF 3 0-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 -, 5 (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 -, 10 (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 -, 15 (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-4-F-phenyl)CH 2 CH 2 -, (2-MeO-phenyl)CH 2 CH 2 -, (3-MeO-phenyl)CH 2 CH 2 -, 20 (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 0-phenyl)CH 2 CH 2 -, (3-CF 3 0-phenyl)CH 2 CH 2 -, (4-CF 3 0-phenyl)CH 2 CH 2 -, 25 (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 -, 30 (cyclobutyl)CH 2 CH 2 -, (cyclopentyl)CH 2 CH 2 -, (cyclohexyl)CH 2 CH 2 -, (morpholino)CH 2 CH 2 -, or (N-pipridinyl) CH 2 CH 2 -; R 11 , at each occurrence, is independently selected from H, 35 methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s butyl, t-butyl, phenyl, benzyl, phenethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, -218- WO 01/19797 PCT/USOO/24967 cyclohexylmethyl, cycloheptylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, 2-F-phenyl-, 3-F-phenyl, 4-F-phenyl, 4-Cl-phenyl, 4-CH 3 phenyl, 4-MeO-phenyl-, 4-CF 3 -phenyl, (4-F-phenyl)CH 2 -, 5 (4-Cl-phenyl)CH 2 -, (4-CH 3 -phenyl)CH 2 -, (4-CF 3 -phenyl)CH 2 -, (4-F-phenyl)CH 2 CH 2 -, (4-Cl-phenyl)CH 2 CH 2 -, (4-CH 3 -phenyl)CH 2 CH 2 -, (4-CF 3 -phenyl)CH 2 CH 2 -, pyridin-2-yl-, pyridin-3-yl-, 4-CF 3 -pyridin-2-yl-, 4-CH 3 -pyridin-2-yl-, thiazol-2-yl-, 10 azapan-1-yl, N,N-dimethylamino, N,N-diethylamino, N,N dipropylamino, and N,N-dibutylamino; and R 13 , at each occurrence, is independently selected from H, MeO, F, and Cl. 15
  9. 18. A compound, according to one of Claims 15, 16, or 17, of Formula (If); R 5 OH 0 OH0N , W-X-Y-Z 20 R" (If) or a pharmaceutically acceptable salt form or prodrug thereof. 25
  10. 19. A compound, according to one of Claims 15, 16, or 17, of Formula (Ig); R5 R Ha 0 1 N'W-X-Y-Z OH 0 N R1 3 30 (Ig) -219- WO 01/19797 PCT/USOO/24967 or a pharmaceutically acceptable salt form or prodrug thereof.
  11. 20. A compound, according to one of Claims 15, 16, or 17, 5 of Formula (Ih); R 5 a H 0 N NW-X-Y-Z Qi N OH O \R RR /R />-R 1 (Ih) or a pharmaceutically acceptable salt form or prodrug 10 thereof.
  12. 21. A pharmaceutical composition comprising a compound of Claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 and a pharmaceutically acceptable 15 carrier.
  13. 22. A method for the treatment of neurological disorders associated with $-amyloid production comprising administering to a host in need of such treatment a 20 therapeutically effective amount of a compound of Claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  14. 23. A method for inhibiting y-secretase activity 25 comprising administering to a host in need of such inhibition a therapeutically effective amount of a compound of Claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 that inhibits y-secretase activity. -220-
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