CYCLIC MALONAMIDES AS INHIBITORS OF Abeta PROTEIN PRODUCTION

FIELD OF THE INVENTION

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

BACKGROUND OF THE INVENTION

Alzheimer's disease (Aβ) is a degenerative brain disorder characterized clinically by progressive loss of memory, temporal and local orientation, cognition, reasoning, judgment and emotionally stability. Aβ is a common cause of progressive dementia in humans and is one of the major causes of death in the United States. Aβ has been observed in all races and ethnic groups worldwide, and is a major present and future health problem. No treatment that effectively prevents Aβ 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 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 neurofibrillar tangles in the cerebral cortex of such patients. Similar alterations were observed in patients with Trisomy 21 (Down's syndrome), and hereditary cerebral 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 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 to 43 amino acids. This protein was designated Aβ, β-amyloid peptide, and sometimes β/A4; referred to herein as Aβ. In addition to its deposition in amyloid plaques, Aβ is also found in the walls of meningeal and parenchymal arterioles, small arteries, capillaries, and sometimes, venules. Aβ 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.

Compelling evidence accumulated during the last decade revealed that Aβ is an internal polypeptide derived from a type 1 integral membrane protein, termed β amyloid precursor protein (APP). β APP is normally produced by many cells both in vivo and in cultured cells, derived from various animals and humans. Aβ 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 β secretase(s), generating the N-terminus of Aβ, α secretase(s) cleaving around the 16/17 peptide bond in Aβ, and γ secretases, generating C-terminal Aβ fragments ending at position 38, 39, 40, 42, and 43 or generating C-terminal extended precursors which are subsequently truncated to the above polypeptides.

Several lines of evidence suggest that abnormal accumulation of Aβ plays a key role in the pathogenesis of Aβ. Firstly, Aβ is the major protein found in amyloid plaques. Secondly, Aβ is neurotoxic and may be causally related to neuronal death observed in Aβ patients. Thirdly, missense DNA mutations at position 717 in the 770 isoform of β APP can be found in effected members but not unaffected members of several families with a genetically determined (familiar) form of Aβ. In addition, several other β APP mutations have been described in familiar forms of Aβ. Fourthly, similar neuropathological changes have been observed in transgenic animals overexpressing mutant forms of human β APP. Fifthly, individuals with Down's syndrome have an increased gene dosage of β APP and develop early-onset Aβ. Taken together, these observations strongly suggest that Aβ depositions may be causally related to the Aβ.

It is hypothesized that inhibiting the production of Aβ will prevent and reduce neurological degeneration, by controlling the formation of amyloid plaques, reducing neurotoxicity and, generally, mediating the pathology associated with Aβ production. One method of treatment methods would therefore be based on drugs that inhibit the formation of Aβ in vivo.

Methods of treatment could target the formation of Aβ through the enzymes involved in the proteolytic processing of β amyloid precursor protein. Compounds that inhibit P or γ secretase activity, either directly or indirectly, could control the production of Aβ. Advantageously, compounds that specifically target γ secretases, could control the production of Aβ. Such inhibition of β or γ secretases could thereby reduce production of Aβ, which, thereby, could reduce or prevent the neurological disorders associated with Aβ protein.

PCT publication number WO 96/29313 discloses the general formula

covering metalloprotease inhibiting compounds useful for the treatment of diseases associated with excess and/or unwanted matrix metalloprotease activity, particularly collagenase and or stromelysin activity.

Compounds of general formula:

are disclosed in PCT publication number WO 95/22966 relating to matrix metalloprotease inhibitors. The compounds of the invention are useful for the treatment of conditions associated with the destruction of cartilage, including corneal ulceration, osteoporosis, periodontitis and cancer.

European Patent Application number EP 0652009A1 relates to the general formula:

and discloses compounds that are protease inhibitors that inhibit Aβ production.

U.S. Pat. No. 5,703,129 discloses the general formula:

which covers 5-amino-6-cyclohexyl-4-hydroxy-hexanamide derivatives that inhibit Aβ production and are useful in the treatment of Alzheimer's disease.

Copending, commonly assigned U.S. patent application Ser. No. 09/370,089 filed Aug. 7, 1999 (equivalent to international application PCT US99/17717) discloses lactams of general formula:

wherein the lactam ring B is substituted by succinamide and a carbocyclic, aryl, or heteroaryl group. These compounds inhibit the processing of amyloid precursor protein and, more specifically, inhibit the production of Aβ-peptide, thereby acting to prevent the formation of neurological deposits of amyloid protein.

None of the above references teaches or suggests the compounds of the present invention which are described in detail below.

SUMMARY OF THE INVENTION

One object of the present invention is to provide novel compounds which are useful as inhibitors of the production of Aβ 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 effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.

It is another object of the present invention to provide a method for treating degenerative neurological 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 or prodrug form thereof.

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):

or a stereoisomer, pharmaceutically acceptable salt or prodrug forms thereof, wherein R³, R⁶, B, C, W, X, Y, and Z are defined below, are effective inhibitors of the production of Aβ.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Thus, in a first embodiment, the present invention provides a novel compound of Formula (I):

or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, wherein:

- L is —NR²⁶C(═O)—, —C(═O)NR²⁶—, —NR²⁶C(═O)O—, —OC(═O)NR²⁶, or —NR²⁶C(O)NR²⁶—;
R³is —(CR⁷R^7a)_n—R⁴,
- —(CR⁷R^7a)_l—S— (CR⁷R^7a)_m—R⁴,
- —(CR⁷R^7a)_l—O— (CR⁷R^7a)_m—R⁴,
- —(CR⁷R^7a)_l—N(R^7b)— (CR⁷R^7a)_m—R⁴,
- —(CR⁷R^7a)_l—S(═O)— (CR⁷R^7a)_m—R⁴,
- —(CR⁷R^7a)_l—S(═O)₂—(CR⁷R^7a)_m—R⁴,
- —(CR⁷R^7a)_l—C(═O)— (CR⁷R^7a)_m—R⁴,
- —(CR⁷R^7a)_l—N(R^7b)C(═O)— (CR⁷R^7a)_m—R⁴,
- —(CR⁷R^7a)_l—C(═O)N(R^7b)— (CR⁷R^7a)_m—R⁴,
- —(CR⁷R^7a)_l—N(R^7b)S(═O)₂—(CR⁷R^7a)_m—R⁴, or
- —(CR⁷R^7a)_l—S(═O)₂N(R^7b)— (CR⁷R^7a)_m—R⁴
n is 0, 1, 2, or 3;
m is 0, 1, 2, or 3;
l is 1, 2, or 3;
Ring C is a 3 to 8 membered carbocycle,
- wherein the carbocycle is saturated or partially saturated;
- optionally, the carbocycle contains a heteroatom selected from —O—, —S—, —S(═O)—, —S(═O)₂—, and —N(R²⁰)—; and
- wherein the carbocycle is substituted with 0-4 R²¹;
R⁴is H, OH, OR^14a,
- C₁-C₈alkyl substituted with 0-3 R^4a,
- C₂-C₈alkenyl substituted with 0-3 R^4a,
- C₂-C₈alkynyl substituted with 0-3 R^4a,
- C₃-C₁₀carbocycle substituted with 0-3 R^4b,
- C₆-C₁₀aryl substituted with 0-3 R^4b, or
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^4b;
R^4a, at each occurrence, is independently selected from H, OH, F, Cl, Br, I, NR¹⁵R¹⁶, CF₃,
- C₃-C₁₀carbocycle substituted with 0-3 R^4b,
- C₆-C₁₀aryl substituted with 0-3 R^4b, and
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^4b;
R^4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl, C₁-C₄haloalkoxy, and C₁-C₄haloalkyl-S—;
R⁶is H;
- C₁-C₆alkyl substituted with 0-3 R^6a;
- C₃-C₁₀carbocycle substituted with 0-3 R^6b; or
- C₆-C₁₀aryl substituted with 0-3 R^6b;
R⁶, at each occurrence, is independently selected from H, C₁-C₆alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, aryl and CF₃;
R^6b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl, and C₁-C₄haloalkoxy;
R⁷, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, CF₃, C₁-C₄alkyl, phenyl substituted with 0-5 R^7c;
R^7a, at each occurrence, is independently selected from H, Cl, F, Br, I, CN, CF₃, and C₁-C₄alkyl;
R^7bis independently selected from H and C₁-C₄alkyl;
R^7c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, CF₃, C₁-C₄alkoxy, and C₁-C₄alkyl;
B is a 5 to 10 membered lactam,
- wherein the lactam is saturated, partially saturated or unsaturated;
- wherein each additional lactam carbon is substituted with 0-2 R¹¹; and,
- optionally, the lactam contains an additional heteroatom selected from —O—, —S—, —S(═O)—, —S(═O)₂—, —N═, —NH—, and —N(R¹⁰)—;
R¹⁰is H, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹,
- S(═O)₂NR¹⁸R¹⁹, S(═O)₂R¹⁷;
- C₁-C₆alkyl optionally substituted with 0-3 R^10a;
- C₆-C₁₀aryl substituted with 0-4 R^10b;
- C₃-C₁₀carbocycle substituted with 0-3 R^10b; or
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^10b;
R^10a, at each occurrence, is independently selected from H, C₁-C₆alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, aryl substituted with 0-4 R^10b; C₃-C₁₀carbocycle substituted with 0-3 R^10b, and 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^10b;
R^10b, at each occurrence, is independently selected from H, OH, C₁-C₆alkyl, C₁-C₄alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl, C₁-C₄haloalkoxy, and C₁-C₄haloalkyl-S—;
R¹¹, at each occurrence, is independently selected from H, C₁-C₄alkoxy, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁸R¹⁹, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, CF₃;
- C₁-C₆alkyl optionally substituted with 0-3 R^11a; C₆-C₁₀aryl substituted with 0-3 R^11b;
- C₃-C₁₀carbocycle substituted with 0-3 R^11b; and
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^11b;
R^11a, at each occurrence, is independently selected from H, C₁-C₆alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃;
- phenyl substituted with 0-3 R^11b;
- C₃-C₆cycloalkyl substituted with 0-3 R^11b; and
- 5 to 6 membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R^11b;
R^11b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,
- C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl,
- C₁-C₄haloalkoxy, and C₁-C₄haloalkyl-S—;
additionally, two R¹¹substituents on adjacent atoms may be combined to form a 5 to 6 membered heteroaryl fused radical, wherein said 5 to 6 membered heteroaryl fused radical comprises 1 or 2 heteroatoms selected from N, O, and S; wherein said 5 to 6 membered heteroaryl fused radical is substituted with 0-3 R¹³;
additionally, two R¹¹substituents on the same or adjacent carbon atoms may be combined to form a C₃-C₆carbocycle substituted with 0-3 R¹³;
additionally, two R¹¹substituents on adjacent atoms may be combined to form a benzo fused radical; wherein said benzo fused radical is substituted with 0-4 R¹³;
W is —(CR⁸R^8a)_p—;
p is 0, 1, 2, 3, or 4;
R⁸and R^8a, at each occurrence, are independently selected from H, F, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl and C₃-C₈cycloalkyl;
X is a bond;
- C₆-C₁₀aryl substituted with 0-3 R^Xb;
- C₃-C₁₀carbocycle substituted with 0-3 R^Xb; or
- 5 to 10 membered heterocycle substituted with 0-2 R^Xb;
R^Xb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl, C₁-C₄haloalkoxy, and C₁-C₄halothioalkoxy;
Y is a bond or —(CR⁹R^9a) t-V—(CR⁹R^9a)_u—;
t is 0, 1, 2, or 3;
u is 0, 1, 2, or 3;
R⁹and R^9a, at each occurrence, are independently selected from H, F, C₁-C₆alkyl and C₃-C₈cycloalkyl;
V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R¹⁹)—, —C(═O)NR^19b—, —NR^19bC(═O)—, —NR^19bS(═O)₂—, —S(═O)₂NR^19b—, —NR^19bS(═O)—, —S(═O)NR^19b—, —C(═O)O—, or —OC(═O)—;
Z is H;
- C₁-C₈alkyl substituted with 1-3 R¹²; C₂-C₄alkenyl substituted with 1-3 R¹²;
- C₂-C₄alkynyl substituted with 1-3 R¹²; C₁-C₈alkyl substituted with 0-3 R^12a;
- C₂-C₄alkenyl substituted with 0-3 R^12a; C₂-C₄alkynyl substituted with 0-3 R^12a;
- C₆-C₁₀aryl substituted with 0-4 R^12b;
- C₃-C₁₀carbocycle substituted with 0-4 R^12b; or
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^12b;
R¹², at each occurrence, is independently selected from C₆-C₁₀aryl substituted with 0-4 R^12b;
- C₃-C₁₀carbocycle substituted with 0-4 R^12b; and
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^12b;
R^12a, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, —C(═O)NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,
- C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl, C₁-C₄haloalkoxy, and C₁-C₄haloalkyl-S—;
R^12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,
- C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl,
- C₁-C₄haloalkoxy, and C₁-C₄haloalkyl-S—;
R¹³, at each occurrence, is independently selected from H, OH, C₁-C₆alkyl, C₁-C₄alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, and CF₃;
R¹⁴is H, phenyl substituted with 0-4 R^14b, benzyl substituted with 0-4 R^14b, C₁-C₆alkyl, C₂-C₆alkoxyalkyl, or C₃-C₆cycloalkyl;
R^14ais H, C₆-C₁₀aryl, benzyl, heterocycle, or C₁-C₄alkyl;
R^14b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,
- C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl,
- C₁-C₄haloalkoxy, and C₁-C₄haloalkyl-S—;
R¹⁵, at each occurrence, is independently selected from H, C₁-C₆alkyl, aryl-(C₁-C₆alkyl)- wherein the aryl is substituted with 0-4 R^15b, (C₁-C₆alkyl)-C(═O)—, and (C₁-C₆alkyl)-S(═O)₂—;
R^15b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,
- C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl, C₁-C₄haloalkoxy, and C₁-C₄haloalkyl-S—;
R¹⁶, at each occurrence, is independently selected from H, C₁-C₆alkyl, benzyl, phenethyl, (C₁-C₆alkyl)-C(═O)—, and (C₁-C₆alkyl)-S(═O)₂—;
R¹⁷is H, C₁-C₆alkyl, C₂-C₆alkoxyalkyl, aryl substituted by 0-4 R^17a, or
- —CH₂-aryl substituted by 0-4 R^17a;
R^17ais H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, —OH, F, Cl, Br, I, CF₃, OCF₃, SCH₃, S(O)CH₃, SO₂CH₃, —NH₂, —N(CH₃)₂, or C₁-C₄haloalkyl;
R¹⁸, at each occurrence, is independently selected from H, C₁-C₆alkyl, phenyl, benzyl, phenethyl, (C₁-C₆alkyl)-C(═O)—, and (C₁-C₆alkyl)-S(═O)₂—;
R¹⁹, at each occurrence, is independently selected from H, OH, C₁-C₆alkyl, phenyl, benzyl, phenethyl, (C₁-C₆alkyl)-C(═O)—, and (C₁-C₆alkyl)-S(═O)₂—;
R²⁰is H, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, S(═O)₂R¹⁷;
- C₁-C₆alkyl optionally substituted with 0-2 R^20a; C₆-C₁₀aryl substituted with 0-4 R^20b;
- C₃-C₁₀carbocycle substituted with 0-3 R^20b; or
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^20b;
R^20a, at each occurrence, is independently selected from H, C₁-C₆alkyl, OR¹⁴, F, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, aryl substituted with 0-4 R^20b, and heterocycle substituted with 0-4 R^20b;
R^20b, at each occurrence, is independently selected from H, OH, C₁-C₆alkyl, C₁-C₄alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl, C₁-C₄haloalkoxy, and C₁-C₄haloalkyl-S—;
R²¹, at each occurrence, is independently selected from H, C₁-C₄alkoxy, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁸R¹⁹, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, CF₃;
- C₁-C₆alkyl optionally substituted with 0-3 R^21a;
- C₆-C₁₀aryl substituted with 0-3 R^21b;
- C₃-C₁₀carbocycle substituted with 0-3 R^21b; and
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^21b;
R^21a, at each occurrence, is independently selected from H, C₁-C₆alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃;
- phenyl substituted with 0-3 R^21b;
- C₃-C₆cycloalkyl substituted with 0-3 R^21b; and
- 5 to 6 membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R^21b;
R^21b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,
- C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl, C₁-C₄haloalkoxy, and C₁-C₄haloalkyl-S—;
additionally, two R²¹substituents on adjacent atoms may be combined to form a 5 to 6 membered heteroaryl fused radical, wherein said 5 to 6 membered heteroaryl fused radical comprises 1 or 2 heteroatoms selected from N, O, and S; wherein said 5 to 6 membered heteroaryl fused radical is substituted with 0-3 R²³;
additionally, two R²¹substituents on the same or adjacent carbon atoms may be combined to form a C₃-C₆carbocycle substituted with 0-3 R²³;
additionally, two R²¹substituents on adjacent atoms may be combined to form a benzo fused radical; wherein said benzo fused radical is substituted with 0-4 R²³;
R²³, at each occurrence, is independently selected from H, OH, C₁-C₆alkyl, C₁-C₄alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, and CF₃;
R²⁶is H;
- C₁-C₆alkyl substituted with 0-3 R^26a;
- C₃-C₁₀carbocycle substituted with 0-3 R^26b; or
- C₆-C₁₀aryl substituted with 0-3 R^26b;
R^26a, at each occurrence, is independently selected from H, C₁-C₆alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, aryl and CF₃; and
R^26b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl, and C₁-C₄haloalkoxy.

[2] In a preferred embodiment the present invention provides a compound of Formula (I), wherein:

- L is —NR²⁶C(═O)—, —C(═O)NR²⁶—, or —OC(═O)NR²⁶—;
R³is —(CHR⁷)_n—R⁴,
- —(CHR⁷)_l—N—(CR⁷R^7a)_m—R⁴, or
- —(CHR⁷)_l—O— (CR⁷R^7a)_m—R⁴;
n is 0, 1 or 2;
m is 0, 1 or 2;
l is 1;
Ring C is a 3 to 8 membered carbocycle substituted with 0-4 R²¹; optionally, the carbocycle contains a heteroatom selected from —O— and —N(R²⁰)—;
R⁴is H, OH, OR^14a,
- C₁-C₆alkyl substituted with 0-3 R^4a, C₂-C₆alkenyl substituted with 0-2 R^4a,
- C₂-C₆alkynyl substituted with 0-1 R^4a,
- C₃-C₆carbocycle substituted with 0-3 R^4b,
- C₆-C₁₀aryl substituted with 0-3 R^4b, or
- 5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R^4b;
R^4a, at each occurrence, is independently selected from H,
- OH, F, Cl, Br, I, NR¹⁵R¹⁶, CF₃,
- C₃-C₆carbocycle substituted with 0-3 R^4b, phenyl substituted with 0-3 R^4b, and
- 5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R^4b;
R^4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₄alkyl, C₁-C₃alkoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy;
R⁶is H;
R⁷, at each occurrence, is independently selected from H, OH, F, CF₃, methyl, and ethyl;
Ring B is a 7 membered lactam,
- wherein the lactam is saturated, partially saturated or unsaturated;
- wherein each additional lactam carbon is substituted with 0-2 R¹¹; and,
- optionally, the lactam contains a heteroatom selected from —O—, —S—, —S(═O)—, —S(═O)₂—, —N═, —NH—, and —N(R¹¹)—;
R¹⁰is H, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, S(═O)₂R¹⁷;
- C₁-C₆alkyl optionally substituted with 0-2 R^1a; C₆-C₁₀aryl substituted with 0-4 R^10b;
- C₃-C₁₀carbocycle substituted with 0-3 R^1b; or
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^10b;
R^10a, at each occurrence, is independently selected from H, C₁-C₆alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, phenyl substituted with 0-4 R^10b; and 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^10b;
R^10b, at each occurrence, is independently selected from H, OH, C₁-C₆alkyl, C₁-C₄alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, and CF₃;
R¹¹, at each occurrence, is independently selected from H, C₁-C₄alkoxy, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁸R¹⁹, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, CF₃;
- C₁-C₆alkyl optionally substituted with 0-3 R^11a;
- C₆-C₁₀aryl substituted with 0-3 R^11b;
- C₃-C₁₀carbocycle substituted with 0-3 R^11b; and
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^11b;
R^11a, at each occurrence, is independently selected from H, C₁-C₆alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl substituted with 0-3 R^11b;
R^11b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl, and C₁-C₄haloalkoxy;
additionally, two R¹¹substituents on adjacent atoms may be combined to form a benzo fused radical; wherein said benzo fused radical is substituted with 0-2 R¹³;
additionally, two R¹¹substituents on adjacent atoms may be combined to form a 5 to 6 membered heteroaryl fused radical, wherein said 5 to 6 membered heteroaryl fused radical comprises 1 or 2 heteroatoms selected from N, O, and S; wherein said 5 to 6 membered heteroaryl fused radical is substituted with 0-2 R¹³;
additionally, two R¹¹substituents on the same or adjacent carbon atoms may be combined to form a C₃-C₆carbocycle substituted with 0-2 R¹³;
W is a bond, —CH₂—, —CH(CH₃)—, —CH₂CH₂— or —CH(CH₃)CH₂—;
X is a bond;
- phenyl substituted with 0-2 R^Xb;
- C₃-C₆cycloalkyl substituted with 0-2 R^Xb; or
- 5 to 6 membered heterocycle substituted with 0-2 R^Xb;
R^Xb, at each occurrence, is independently selected from H, OH, Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₄alkyl, C₁-C₃alkoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy;
Y is a bond, —CH₂—V—, —V—, or —V—CH₂—;
V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —N(CH₃)—, or —N(CH₂CH₃)—,
Z is H; C₁-C₆alkyl; C₂-C₄alkenyl; C₂-C₄alkynyl;
- C₁-C₃alkyl substituted with 1-2 R¹²;
- C₂-C₃alkenyl substituted with 1-2 R¹²; C₂-C₃alkynyl substituted with 1-2 R¹²;
- C₆-C₁₀aryl substituted with 0-4 R^12b;
- C₃-C₆carbocycle substituted with 0-3 R^12b; or
- 5 to 10 membered heterocycle substituted with 0-3 R^12b;
R¹², at each occurrence, is independently selected from C₆-C₁₀aryl substituted with 0-4 R^12b;
- C₃-C₁₀carbocycle substituted with 0-4 R^12b; and
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^12b;
R^12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,
- C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl,
- C₁-C₄haloalkoxy, and C₁-C₄haloalkyl-S—;
R¹³, at each occurrence, is independently selected from H, OH, C₁-C₆alkyl, C₁-C₄alkoxy, Cl, F, Br, I, ON, NO₂, NR¹⁵R¹⁶, and CF₃;
R¹⁴is H, phenyl, benzyl, C₁-C₄alkyl, or C₂-C₄alkoxyalkyl;
R^14ais H, phenyl, benzyl, or C₁-C₄alkyl;
R¹⁵, at each occurrence, is independently selected from H, C₁-C₄alkyl, benzyl, phenethyl, (C₁-C₄alkyl)-C(═O)—, and (C₁-C₄alkyl)-S(═O)₂—;
R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₄alkyl, benzyl, phenethyl, (C₁-C₄alkyl)-C(═O)—, and (C₁-C₄alkyl)-S(═O)₂—;
R¹⁷is H, methyl, ethyl, propyl, butyl, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, phenyl substituted by 0-3 R^17a, or —CH₂-phenyl substituted by 0-3 R^17a;
R^17ais H, methyl, methoxy, —OH, F, Cl, CF₃, or OCF₃;
R¹⁸, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
R¹⁹, at each occurrence, is independently selected from H, methyl, and ethyl;
R²⁰is H or C(═O)OR¹⁷;
R²⁶is H, methyl, or ethyl.

[3] In another preferred embodiment the present invention provides a compound of Formula (I), wherein:

Ring C is selected from:

wherein Ring C is substituted with 0-2 R²¹; and

Ring B is selected from:

[4] In another more preferred embodiment the present invention provides a compound of Formula (I), wherein:

- L is —NHC(═O)—, —C(═O)NH—, or —OC(═O)NH—;
R³is R⁴, —CH₂OR⁴, or —CH₂CH₂OR⁴;
R⁴is C₁-C₆alkyl substituted with 0-3 R^4a, C₂-C₆alkenyl substituted with 0-1 R^4a, or C₂-C₆alkynyl substituted with 0-1 R^4a;
R^4a, at each occurrence, is independently selected from H, OH, F, NR¹⁵R¹⁶, CF₃,
- C₃-C₆carbocycle substituted with 0-3 R^4b, phenyl substituted with 0-3 R^4b, and
- 5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R^4b; wherein said 5 to 6 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
R^4b, at each occurrence, is independently selected from H, OH, Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy;
W is a bond, —CH₂—, —CH(CH₃)—, —CH₂CH₂— or —CH(CH₃)CH₂—;
X is a bond, phenyl, C₃-C₆cycloalkyl, or
- 5 to 6 membered heterocycle;
Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —N(CH₃)—, or —N(CH₂CH₃)—,
Z is H; C₁-C₆alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₃alkyl substituted with 1-2 R¹²;
- C₂-C₃alkenyl substituted with 1-2 R¹²; C₂-C₃alkynyl substituted with 1-2 R¹²;
- C₆-C₁₀aryl substituted with 0-4 R^12b;
- C₃-C₆carbocycle substituted with 0-3 R^12b; or
- 5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R^12b; wherein said 5 to 6 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
R¹², at each occurrence, is independently selected from C₆-C₁₀aryl substituted with 0-4 R^12b;
- C₃-C₆carbocycle substituted with 0-3 R^12b; and
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^12b; wherein said 5 to 6 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
R^12b, at each occurrence, is independently selected from H, OH, Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy;
R¹³, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, Cl, F, Br, CN, NR¹⁵R¹⁶, and CF₃;
R¹⁴is H, phenyl, benzyl, methyl, ethyl, propyl, or butyl;
R¹⁵, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl;
R¹⁶, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, benzyl, phenethyl, methyl-C(═O)—, ethyl-C(═O)—, methyl-S(═O)₂—, ethyl-S(═O)₂—, and propyl-S(═O)₂—;
R¹⁸, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
R¹⁹, at each occurrence, is independently selected from H, methyl, and ethyl;
R²⁰is H.

[5] In another more preferred embodiment the present invention provides a compound of Formula (I), wherein:

- L is —NHC(═O)—, —C(═O)NH—, or —OC(═O)NH—;
R³is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)₂, —CH₂(CH₃)₂, —CH(CH₃)CH₂CH₃, —CH₂CH(CH₃)₂, —CH₂C(CH₃)₃, —CF₃, —CH₂CF₃, —CH₂CH₂CF₃, —CH₂CH₂CH₂CF₃, —CH(OH)CH₂CH(CH₃)₂, —CH(OH)CH(CH₃)₂, —CH(NH₂)CH₂CH(CH₃)₂, —CH₂CH₂OCH₃, —CH₂OCH₂CH₃, —CF₂CH₂CH(CH₃)₂, —CH(NHCH₃)CH₂CH(CH₃)₂, —CH(NHSO₂CH₂CH₂CH₃)CH₂CH(CH₃)₂, cyclohexyl-, cyclopentyl-, cyclopropyl-CH₂—, cyclobutyl-CH₂—, cyclopentyl-CH₂—, cyclohexyl-CH₂—, cyclopropyl-CH₂CH₂—, cyclobutyl-CH₂CH₂—, cyclopentyl-CH₂CH₂—, cyclohexyl-CH(OH)—, cyclohexyl-CH₂CH₂—, 1—NH₂-cyclopentyl, phenyl-CH₂—, (2-F-phenyl)CH₂—, (3-F-phenyl)CH₂—, (4-F-phenyl)CH₂—, (2-Cl-phenyl)CH₂—, (3-Cl-phenyl)CH₂—, (4-Cl-phenyl)CH₂—, (2,3-diF-phenyl)CH₂—, (2,4-diF-phenyl)CH₂—, (2,5-diF-phenyl)CH₂—, (2,6-diF-phenyl)CH₂—, (3,4-diF-phenyl)CH₂—, (3,5-diF-phenyl)CH₂—, (2,3-diCl-phenyl)CH₂—, (2,4-diCl-phenyl)CH₂—, (2,5-diCl-phenyl)CH₂—, (2,6-diCl-phenyl)CH₂—, (3,4-diCl-phenyl)CH₂—, (3,5-diCl-phenyl)CH₂—, (3-F-4-Cl-phenyl)CH₂—, (3-F-5-Cl-phenyl)CH₂—, (3-Cl-F-phenyl)CH₂—, phenyl-CH₂CH₂—, (2-F-phenyl)CH₂CH₂—, (3-F-phenyl)CH₂CH₂—, (4-F-phenyl)CH₂CH₂—, (2-Cl-phenyl)CH₂CH₂—, (3-Cl-phenyl)CH₂CH₂—, (4-Cl-phenyl)CH₂CH₂—, (2,3-diF-phenyl)CH₂CH₂—, (2,4-diF-phenyl)CH₂CH₂—, (2,5-diF-phenyl)CH₂CH₂—, (2,6-diF-phenyl)CH₂CH₂—, (3,4-diF-phenyl)CH₂CH₂—, (3,5-diF-phenyl)CH₂CH₂—, (2,3-diCl-phenyl)CH₂CH₂—, (2,4-diCl-phenyl)CH₂CH₂—, (2,5-diCl-phenyl)CH₂CH₂—, (2,6-diCl-phenyl)CH₂CH₂—, (3,4-diCl-phenyl)CH₂CH₂—, (3,5-diCl-phenyl)CH₂CH₂—, (3-F-4-Cl-phenyl)CH₂CH₂—, (3-F-5-Cl-phenyl)CH₂CH₂—, 4-piperidinyl-CH₂CH₂—, phenyl-CH₂CH₂CF₂—, phenyl-CH₂CH(OH)—, imidazolyl-CH₂CH(OH)—, or phenyl-CH₂OCH₂—;

Ring C is selected from:

Ring B is selected from:

wherein each benzo fused ring is substituted with 0-1 R¹³;

W is a bond or —CH₂—;
X is a bond;

Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, or —N(CH₃)—,

Z is phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl, 2,5-diF-phenyl, 2,6-diF-phenyl, 3,4-diF-phenyl, 3,5-diF-phenyl, 2,3-diCl-phenyl, 2,4-diCl-phenyl, 2,5-diCl-phenyl, 2,6-diCl-phenyl, 3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl, 3-Cl-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-CF₃O-phenyl, 3-CF₃O-phenyl, 4-CF₃O-phenyl, furanyl, thienyl, pyridyl, 2-Me-pyridyl, 3-Me-pyridyl, 4-Me-pyridyl, 1-imidazolyl, oxazolyl, isoxazolyl, 1-benzimidazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholino, N-piperinyl, phenyl-CH₂—, (2-F-phenyl)CH₂—, (3-F-phenyl)CH₂—, (4-F-phenyl)CH₂—, (2-Cl-phenyl)CH₂—, (3-Cl-phenyl)CH₂, (4-Cl-phenyl)CH₂—, (2,3-diF-phenyl)CH₂—, (2,4-diF-phenyl)CH₂—, (2,5-diF-phenyl)CH₂—, (2,6-diF-phenyl)CH₂—, (3,4-diF-phenyl)CH₂—, (3,5-diF-phenyl)CH₂—, (2,3-diCl-phenyl)CH₂—, (2,4-diCl-phenyl)CH₂—, (2,5-diCl-phenyl)CH₂—, (2,6-diCl-phenyl)CH₂—, (3,4-diCl-phenyl)CH₂—, (3,5-diCl-phenyl)CH₂—, (3-F-4-Cl-phenyl)CH₂—, (3-F-5-Cl-phenyl)CH₂—, (3-Cl-F-phenyl)CH₂—, (2-MeO-phenyl)CH₂—, (3-MeO-phenyl)CH₂—, (4-MeO-phenyl)CH₂—, (2-Me-phenyl)CH₂—, (3-Me-phenyl)CH₂—, (4-Me-phenyl)CH₂—, (2-MeS-phenyl)CH₂—, (3-MeS-phenyl)CH₂—, 4-MeS-phenyl)CH₂—, (2-CF₃O-phenyl)CH₂—, (3-CF₃O-phenyl)CH₂—, (4-CF₃O-phenyl)CH₂—, (furanyl)CH₂—, (thienyl)CH₂—, (pyridyl)CH₂—, (2-Me-pyridyl)CH₂—, (3-Me-pyridyl)CH₂—, (4-Me-pyridyl)CH₂—, (1-imidazolyl)CH₂—, (oxazolyl)CH₂—, (isoxazolyl)CH₂—, (1-benzimidazolyl)CH₂—, (cyclopropyl)CH₂—, (cyclobutyl)CH₂—, (cyclopentyl)CH₂—, (cyclohexyl)CH₂—, (morpholino)CH₂—, (N-piperidinyl)CH₂—, phenyl-CH₂CH₂—, (phenyl)₂CHCH₂—, (2-F-phenyl)CH₂CH₂—, (3-F-phenyl)CH₂CH₂—, (4-F-phenyl)CH₂CH₂—, (2-Cl-phenyl)CH₂CH₂—, (3-Cl-phenyl)CH₂CH₂—, (4-Cl-phenyl)CH₂CH₂—, (2,3-diF-phenyl)CH₂CH₂—, (2,4-diF-phenyl)CH₂CH₂—, (2,5-diF-phenyl)CH₂CH₂—, (2,6-diF-phenyl)CH₂CH₂—, (3,4-diF-phenyl)CH₂CH₂—, (3,5-diF-phenyl)CH₂CH₂—, (2,3-diCl-phenyl)CH₂CH₂—, (2,4-diCl-phenyl)CH₂CH₂—, (2,5-diCl-phenyl)CH₂CH₂—, (2,6-diCl-phenyl)CH₂CH₂—, (3,4-diCl-phenyl)CH₂CH₂—, (3,5-diCl-phenyl)CH₂CH₂—, (3-F-4-Cl-phenyl)CH₂CH₂—, (3-F-5-Cl-phenyl)CH₂CH₂—, (3-Cl-F-phenyl)CH₂CH₂—, (2-MeO-phenyl)CH₂CH₂—, (3-MeO-phenyl)CH₂CH₂—, (4-MeO-phenyl)CH₂CH₂—, (2-Me-phenyl)CH₂CH₂—, (3-Me-phenyl)CH₂CH₂—, (4-Me-phenyl)CH₂CH₂—, (2-MeS-phenyl)CH₂CH₂—, (3-MeS-phenyl)CH₂CH₂—, (4-MeS-phenyl)CH₂CH₂—, (2-CF₃₀-phenyl)CH₂CH₂—, (3-CF₃O-phenyl)CH₂CH₂—, (4-CF₃O-phenyl)CH₂CH₂—, (furanyl)CH₂CH₂—, (thienyl)CH₂CH₂—, (pyridyl)CH₂CH₂—, (2-Me-pyridyl)CH₂CH₂—, (3-Me-pyridyl)CH₂CH₂—, (4-Me-pyridyl)CH₂CH₂—, (imidazolyl)CH₂CH₂—, (oxazolyl)CH₂CH₂—, (isoxazolyl)CH₂CH₂—, (benzimidazolyl)CH₂CH₂—, (cyclopropyl)CH₂CH₂—, (cyclobutyl)CH₂CH₂—, (cyclopentyl)CH₂CH₂—, (cyclohexyl)CH₂CH₂—, (morpholino)CH₂CH₂—, or (N-piperidinyl)CH₂CH₂—;

R¹⁰is H, methyl, ethyl, phenyl, benzyl, phenethyl, 4-F-phenyl, (4-F-phenyl)CH₂—, (4-F-phenyl)CH₂CH₂—, 4-Cl-phenyl, (4-Cl-phenyl)CH₂—, (4-Cl-phenyl)CH₂CH₂—, 4-CH₃-phenyl, (4-CH₃-phenyl)CH₂—, (4-CH₃-phenyl)CH₂CH₂—, 4-CF₃-phenyl, (4-CF₃-phenyl)CH₂—, or (4-CF₃-phenyl)CH₂CH₂—;

R¹¹, at each occurrence, is independently selected from H, ═O, methyl, ethyl, phenyl, benzyl, phenethyl, 4-F-phenyl, (4-F-phenyl)CH₂—, (4-F-phenyl)CH₂CH₂—, 3-F-phenyl, (3-F-phenyl)CH₂—, (3-F-phenyl)CH₂CH₂—, 2-F-phenyl, (2-F-phenyl)CH₂—, (2-F-phenyl)CH₂CH₂—, 4-Cl-phenyl, (4-Cl-phenyl)CH₂—, (4-Cl-phenyl)CH₂CH₂—, 3-Cl-phenyl, (3-Cl-phenyl)CH₂—, (3-Cl-phenyl)CH₂CH₂—, 4-CH₃-phenyl, (4-CH₃-phenyl)CH₂—, (4-CH₃-phenyl)CH₂CH₂—, 3-CH₃-phenyl, (3-CH₃-phenyl)CH₂—, (3-CH₃-phenyl)CH₂CH₂—, 4-CF₃-phenyl, (4-CF₃-phenyl)CH₂—, (4-CF₃-phenyl)CH₂CH₂—, cyclopentyl, pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl;

R¹³, at each occurrence, is independently selected from H, F, Cl, OH, —CH₃, —CH₂CH₃, —OCH₃, and —CF₃; and

R²⁰is H.

In another preferred embodiment the present invention provides a compound of Formula (I), wherein:

R³is —(CR⁷R^7a)_n—R⁴,
- —(CR⁷R^7a)_l—S— (CR⁷R^7a)_m—R⁴,
- —(CR⁷R^7a)_l—O—(CR⁷R^7a)_m—R⁴, or
- —(CR⁷R^7a)_l—N(R^7b)— (CR⁷R^7a)_m—R⁴;
n is 0, 1, or 2;
m is 0, 1, or 2;
l is 1 or 2;
Ring C is a 3 to 8 membered carbocycle substituted with 0-4 R²¹; optionally, the carbocycle contains a heteroatom selected from —O—, and —N(R²⁰)—;
R⁴is H, OH, OR^14a,
- C₁-C₆alkyl substituted with 0-3 R^4a,
- C₂-C₆alkenyl substituted with 0-3 R^4a, C₂-C₆alkynyl substituted with 0-3 R^4a,
- C₃-C₁₀carbocycle substituted with 0-3 R^4b, C₆-C₁₀aryl substituted with 0-3 R^4b, or
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^4b;
R^4a, at each occurrence, is independently selected from is H, F, Cl, Br, I, CF₃,
- C₃-C₁₀carbocycle substituted with 0-3 R^4b,
- C₆-C₁₀aryl substituted with 0-3 R^4b, or
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^4b;
R^4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl, and C₁-C₄haloalkoxy;
R⁶is H, methyl, or ethyl;
R⁷, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, CF₃, phenyl and C₁-C₄alkyl;
R^7a, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, CF₃, and C₁-C₄alkyl;
R^7bis independently selected from H, methyl, ethyl, propyl, and butyl;
Ring B is a 7 membered lactam,
- wherein the lactam is saturated, partially saturated or unsaturated;
- wherein each additional lactam carbon is substituted with 0-2 R¹¹; and,
- optionally, the lactam contains a heteroatom selected from, —O—, —S—, —S(═O)—, —S(═O)₂—, —N═, —NH—, and —N(R¹⁰)—;
R¹⁰is H, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹,
- S(═O)₂NR¹⁸R¹⁹, S(═O)₂R¹⁷;
- C₁-C₆alkyl optionally substituted with 0-2 R^10a; C₆-C₁₀aryl substituted with 0-4 R^10b;
- C₃-C₁₀carbocycle substituted with 0-3 R^10b; or
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^10b;
R^10a, at each occurrence, is independently selected from H, C₁-C₆alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, phenyl substituted with 0-4 R^10b; or 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^10b;
R^10b, at each occurrence, is independently selected from H, OH, C₁-C₆alkyl, C₁-C₄alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, or CF₃;
R¹¹, at each occurrence, is independently selected from H, C₁-C₄alkoxy, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁸R¹⁹, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, CF₃;
- C₁-C₆alkyl optionally substituted with 0-3 R^11a; C₆-C₁₀aryl substituted with 0-3 R^11b;
- C₃-C₁₀carbocycle substituted with 0-3 R^11b; or
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^11b;
R^11a, at each occurrence, is independently selected from H, C₁-C₆alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl substituted with 0-3 R^11b;
R^11bat each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl, and C₁-C₄haloalkoxy;
additionally, two R¹¹substituents on adjacent atoms may be combined to form a benzo fused radical; wherein said benzo fused radical is substituted with 0-3 R¹³;
additionally, two R¹¹substituents on adjacent atoms may be combined to form a 5 to 6 membered heteroaryl fused radical, wherein said 5 to 6 membered heteroaryl fused radical comprises 1 or 2 heteroatoms selected from N, O, and S; wherein said 5 to 6 membered heteroaryl fused radical is substituted with 0-3 R¹³;
additionally, two R¹¹substituents on the same or adjacent carbon atoms may be combined to form a C₃-C₆carbocycle substituted with 0-3 R¹³;
W is —(CR⁸R^8a)_p—;
p is 0, 1, or 2;
R⁸and R^6a, at each occurrence, are independently selected from H, F, C₁-C₃alkyl, C₂-C₃alkenyl, C₂-C₃alkynyl and C₃-C₆cycloalkyl;
X is a bond;
- C₆-C₁₀aryl substituted with 0-3 R^Xb;
- C₃-C₁₀carbocycle substituted with 0-2 R^Xb; or
- 5 to 10 membered heterocycle substituted with 0-2 R^Xb;
R^Xb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl, and C₁-C₄haloalkoxy;
Y is a bond or —(CR⁹R^9a)_t—V—(CR⁹R^9a)_u—;
t is 0, 1, or 2;
u is 0, 1, or 2;
R⁹and R^9a, at each occurrence, are independently selected from H, F, C₁-C₄alkyl or C₃-C₆cycloalkyl;
V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R¹⁹)—, —C(═O)NR^19b—, —NR^19bC(═O)—, —NR^19bS(═O)₂—, —S(═O)₂NR^19b—, —NR^19bS(═O)—, or —S(═O)NR^19b—;
Z is H;
- C₁-C₃alkyl substituted with 1-2 R¹²;
- C₆-C₁₀aryl substituted with 0-4 R^12b;
- C₃-C₁₀carbocycle substituted with 0-4 R^12b; or
- 5 to 10 membered heterocycle substituted with 0-3 R^12b;
R^12a, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl, and C₁-C₄haloalkoxy;
R¹³, at each occurrence, is independently selected from H, OH, C₁-C₆alkyl, C₁-C₄alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R^16fand CF₃;
R¹⁴is H, phenyl, benzyl, C₁-C₆alkyl, or C₂-C₆alkoxyalkyl;
R^14ais H, phenyl, benzyl, methyl, ethyl, propyl, or butyl;
R¹⁵, at each occurrence, is independently selected from H, C₁-C₆alkyl, benzyl, phenethyl, (C₁-C₆alkyl)-C(═O)—, and (C₁-C₆alkyl)-S(═O)₂—;
R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₆alkyl, benzyl, phenethyl, (C₁-C₆alkyl)-C(═O)—, and (C₁-C₆alkyl)-S(═O)₂—;
R¹⁷is H, C₁-C₆alkyl, C₂-C₆alkoxyalkyl, aryl substituted by 0-4 R^17a, or —CH₂-aryl substituted by 0-4 R^17a;
R^17ais H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, —OH, F, Cl, Br, I, CF₃, OCF₃, SCH₃, S(O)CH₃, SO₂CH₃, —NH₂, —N(CH₃)₂, or C₁-C₄haloalkyl;
R¹⁸, at each occurrence, is independently selected from H, C₁-C₆alkyl, phenyl, benzyl, phenethyl, (C₁-C₆alkyl)-C(═O)—, and (C₁-C₆alkyl)-S(═O)₂—; and
R¹⁹, at each occurrence, is independently selected from H, OH, C₁-C₆alkyl, phenyl, benzyl, phenethyl, (C₁-C₆alkyl)-C(═O)—, and (C₁-C₆alkyl)-S(═O)₂—R²⁰is H or C(═O)R¹⁷;
R²¹, at each occurrence, is independently selected from H, C₁-C₄alkoxy, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁸R¹⁹, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, CF₃;
- C₁-C₆alkyl optionally substituted with 0-3 R^21a; C₆-C₁₀aryl substituted with 0-3 R^21b;
- C₃-C₁₀carbocycle substituted with 0-3 R^21b; or
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^21b;
R^21a, at each occurrence, is independently selected from H, C₁-C₆alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃;
- phenyl substituted with 0-3 R^21b;
- C₃-C₆cycloalkyl substituted with 0-3 R^21b; and
- 5 to 6 membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R^21b;
R^21b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,
- C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl, C₁-C₄haloalkoxy, and C₁-C₄haloalkyl-S—;
additionally, two R²¹substituents on the same or adjacent carbon atoms may be combined to form a C₃-C₆carbocycle substituted with 0-3 R²³;
additionally, two R²¹substituents on adjacent atoms may be combined to form a benzo fused radical; wherein said benzo fused radical is substituted with 0-4 R²³; and
R²³, at each occurrence, is independently selected from H, OH, C₁-C₆alkyl, C₁-C₄alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, and CF₃.

[6] In another preferred embodiment the present invention provides a compound of Formula (I):

or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, wherein:

- L is —NR²⁶C(═O)—, —C(═O)NR²⁶—, —NR²⁶C(═O)O—, —OC(═O)NR²⁶, or NR^26c(═O)NR²⁶—;
R³is —(CR⁷R^7a)_n—R⁴,
- —(CR⁷R^7a)_l—S—R⁴,
- —(CR⁷R^7a)_l—O—R⁴;
- —(CR⁷R^7a)_l—N(R^7b)—R⁴,
- —(CR⁷R^7a)_l—S(═O)—R⁴, or
- —(CR⁷R^7a)_l—S(═O)₂—R⁴;
n is 0, 1 or 2;
l is 1 or 2;
R⁴is H,
- C₁-C₈alkyl substituted with 0-3 R^4a, C₂-C₈alkenyl substituted with 0-3 R^4a,
- C₂-C₈alkynyl substituted with 0-3 R^4a, C₃-C₁₀carbocycle substituted with 0-3 R^4b,
- C₆-C₁₀aryl substituted with 0-3 R^4b, or
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^4b;
R^4a, at each occurrence, is independently selected from H, OH, F, Cl, Br, I, NR¹⁵R¹⁶, CF₃,
- C₃-C₁₀carbocycle substituted with 0-3 R^4b,
- C₆-C₁₀aryl substituted with 0-3 R^4b, and
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^4b;
R^4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,
- C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl,
- C₁-C₄haloalkoxy, and C₁-C₄haloalkyl-S—;
Ring C is a 3-8 membered carbocycle;
- wherein said 3-8 membered carbocycle is saturated or partially unsaturated;
- wherein said 3-8 membered carbocycle is substituted with 0-4 R²¹; and
- optionally, the carbocycle contains a heteroatom selected from —O— and —N(R²⁰)—;
additionally, two R²¹substituents on adjacent atoms may be combined to form a benzo fused radical; wherein said benzo fused radical is substituted with 0-4 R²³;
additionally, two R²¹substituents on adjacent atoms may be combined to form a 5 to 6 membered heteroaryl fused radical, wherein said 5 to 6 membered heteroaryl fused radical comprises 1 or 2 heteroatoms selected from N, O, and S; wherein said 5 to 6 membered heteroaryl fused radical is substituted with 0-3 R²³;
additionally, two R²¹substituents on the same or adjacent carbon atoms may be combined to form a C₃-C₆carbocycle substituted with 0-3 R²³;
R²¹, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, NR¹⁵R¹⁶, OR^14a, C₁-C₄alkyl, C₂-C₆alkenyl, alkynyl, C₁-C₄alkoxy, C₁-C₄haloalkyl,
- C₁-C₄haloalkoxy, and C₁-C₄haloalkyl-S—,
- C₃-C₆carbocycle, phenyl, and a
- 5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur;
R⁶is H, methyl, or ethyl;
R⁷, at each occurrence, is independently H or C₁-C₄alkyl;
R^7a, at each occurrence, is independently H or C₁-C₄alkyl;
R^7bis H or C₁-C₄alkyl;

Ring B is selected from:

R¹⁰is H, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹,
- S(═O)₂NR¹⁸R¹⁹, S(═O)₂R¹⁷;
- C₁-C₆alkyl optionally substituted with 0-3 R^10a; C₆-C₁₀aryl substituted with 0-4 R^10b;
- C₃-C₁₀carbocycle substituted with 0-3 R^10b; or
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^10b;

R^10a, at each occurrence, is independently selected from H, C₁-C₆alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or aryl substituted with 0-4 R^10b;

R^10b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl, C₁-C₄haloalkoxy, and C₁-C₄haloalkyl-S—;

R¹¹, at each occurrence, is independently selected from H, C₁-C₄alkoxy, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁸R¹⁹, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, CF₃;
- C₁-C₆alkyl optionally substituted with 0-3 R^11a; C₆-C₁₀aryl substituted with 0-3 R^11b;
- C₃-C₁₀carbocycle substituted with 0-3 R^11b; and
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^11b;

R^11a, at each occurrence, is independently selected from H, C₁-C₆alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃;
- phenyl substituted with 0-3 R^11b;
- C₃-C₆cycloalkyl substituted with 0-3 R^11b; and
- 5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R^11b;

R^11b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,
- C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl,
- C₁-C₄haloalkoxy, and C₁-C₄haloalkyl-S—;

W is a bond or —(CH₂)_p—;

p is 1 or 2;

X is a bond;
- phenyl substituted with 0-2 R^Xb;
- C₃-C₆carbocycle substituted with 0-2 R^Xb; or
- 5 to 6 membered heterocycle substituted with 0-2 R^Xb;

R^Xb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₄alkyl, C₁-C₃alkoxy, C₁-C₃haloalkyl, C₁-C₃haloalkoxy, and C₁-C₃halothioalkoxy;

Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R¹⁹)—, —C(═O)NR^19b—, —NR^19bC(═O)—, —NR^19bS(═O)₂—, —S(═O)₂NR^19b—, —NR^19bS(═O)—, —S(═O)NR^19b—, —C(═O)O—, or —OC(═O)—;

Z is H;
- C₁-C₁₀alkyl substituted with 0-3 R^12a;
- C₂-C₆alkenyl substituted with 0-3 R^12a;
- C₂-C₆alkynyl substituted with 0-3 R^12a;
- C₆-C₁₀aryl substituted with 0-4 R^12b;
- C₃-C₁₀carbocycle substituted with 0-4 R^12b; or
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^12b;

R^12a, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, —C(═O)NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,
- C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl,
- C₁-C₄haloalkoxy, C₁-C₄haloalkyl-S—,
- C₆-C₁₀aryl substituted with 0-4 R^12b;
- C₃-C₁₀carbocycle substituted with 0-4 R^12b; and
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^12b;

R^12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,
- C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl,
- C₁-C₄haloalkoxy, and C₁-C₄haloalkyl-S—;

R¹³, at each occurrence, is independently selected from H, OH, C₁-C₆alkyl, C₁-C₄alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, and CF₃;

R¹⁴is H, phenyl, benzyl, C₁-C₆alkyl, C₂-C₆alkoxyalkyl, or C₃-C₆cycloalkyl;

R^14ais H, phenyl, benzyl, or C₁-C₄alkyl;

R¹⁵, at each occurrence, is independently selected from H, C₁-C₆alkyl, benzyl, phenethyl, (C₁-C₆alkyl)-C(═O)—, and (C₁-C₆alkyl)-S(═O)₂—;

R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₆alkyl, benzyl, phenethyl, (C₁-C₆alkyl)-C(═O)—, and (C₁-C₆alkyl)-S(═O)₂—;

R¹⁷is H, C₁-C₆alkyl, C₂-C₆alkoxyalkyl, aryl substituted by 0-4 R^17a, or
- —CH₂-aryl substituted by 0-4 R^17a;

R^17ais H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, —OH, F, Cl, Br, I, CF₃, OCF₃, SCH₃, S(O)CH₃, SO₂CH₃, —NH₂, —N(CH₃)₂, or C₁-C₄haloalkyl;

R¹⁸, at each occurrence, is independently selected from H, C₁-C₆alkyl, phenyl, benzyl, phenethyl, (C₁-C₆alkyl)-C(═O)—, and (C₁-C₆alkyl)-S(═O)₂—;

R¹⁹, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;

R^19b, at each occurrence, is independently is H or C₁-C₄alkyl;

R²⁰is H, C₁-C₄alkyl, or C(═O)OR¹⁷;

R²³, at each occurrence, is independently selected from H, OH, C₁-C₆alkyl, C₁-C₄alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, and CF₃; and

R²⁶is H or C₁-C₄alkyl.

[7] In another preferred embodiment the present invention provides a compound of Formula (Ia):

or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, wherein:

- L is —NR²⁶C(═O)—, —C(═O)NR²⁶—, —NR^26c(═O)O—, —OC(═O)NR²⁶, or —NR^26c(═O)NR²⁶—;
R³is —(CHR⁷)_n—R⁴,
- —(CHR⁷)_l—S—R⁴,
- —(CHR⁷)_l—O—R⁴;
- —(CR⁷R^7a)_l—N(R^7b)—R⁴,
- —(CR⁷R^7a)_l—S(═O)—R⁴, or
- —(CR⁷R^7a)_l—S(═O)₂—R⁴;
n is 0, 1 or 2;
l is 1 or 2;
R⁴is H,
- C₁-C₈alkyl substituted with 0-3 R^4a,
- C₂-C₈alkenyl substituted with 0-3 R^4a,
- C₂-C₈alkynyl substituted with 0-3 R^4a,
- C₃-C₁₀carbocycle substituted with 0-3 R^4b,
- C₆-C₁₀aryl substituted with 0-3 R^4b, or
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^4b;
R^4a, at each occurrence, is independently selected from H, OH, F, Cl, Br, I, NR¹⁵R¹⁶, CF₃,
- C₃-C₁₀carbocycle substituted with 0-3 R^4b,
- C₆-C₁₀aryl substituted with 0-3 R^4b, and
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^4b;
R^4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,
- C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl,
- C₁-C₄haloalkoxy, and C₁-C₄haloalkyl-S—;
Ring C is a 3-8 membered carbocycle;
- wherein said 3-8 membered carbocycle is saturated or partially unsaturated;
- wherein said 3-8 membered carbocycle is substituted with 0-4 R²¹;
- optionally, the carbocycle contains a heteroatom selected from —O—, and —N(R²⁰)—;
additionally, two R²¹substituents on adjacent atoms may be combined to form a benzo fused radical; wherein said benzo fused radical is substituted with 0-4 R²³;
additionally, two R²¹substituents on the same or adjacent carbon atoms may be combined to form a C₃-C₆carbocycle substituted with 0-3 R²³;
R²¹, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, NR¹⁵R¹⁶, OR^14a, C₁-C₄alkyl, C₂-C₆alkenyl, alkynyl, C₁-C₄alkoxy, C₁-C₄haloalkyl,
- C₁-C₄haloalkoxy, and C₁-C₄haloalkyl-S—,
- C₃-C₆carbocycle, phenyl, and a
- 5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur;
R⁷, at each occurrence, is independently H, methyl, or ethyl;
R^7bis H, methyl, or ethyl;

Ring B is selected from:

R¹¹at each occurrence, is independently selected from H, C₁-C₄alkoxy, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁸R¹⁹, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, CF₃;
- C₁-C₆alkyl optionally substituted with 0-3 R^11a; C₆-C₁₀aryl substituted with 0-3 R^11b;
- C₃-C₁₀carbocycle substituted with 0-3 R^11b; and
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^11b;

R^11a, at each occurrence, is independently selected from H, C₁-C₆alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃;
- phenyl substituted with 0-3 R^11b;
- C₃-C₆cycloalkyl substituted with 0-3 R^11b; and
- 5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R^11b;

R^11b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl,
- C₁-C₄haloalkoxy, and C₁-C₄haloalkyl-S—;

W is a bond or —(CH₂)_p—;

p is 1 or 2;

X is a bond;
- phenyl substituted with 0-2 R^Xb;
- C₃-C₆carbocycle substituted with 0-2 R^Xb; or
- 5 to 6 membered heterocycle substituted with 0-2 R^Xb;

R^Xb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₄alkyl, C₁-C₃alkoxy, C₁-C₃haloalkyl, C₁-C₃haloalkoxy, and C₁-C₃halothioalkoxy;

Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R¹⁹)—, —C(═O)NR^19b—, —NR^19bC(═O)—, —NR^19bS(═O)₂—, —S(═O)₂NR^19b—, —NR^19bS(═O)—, —S(═O)NR^19b—, —C(═O)O—, or —OC(═O)—;

Z is H;
- C₁-C₁₀alkyl substituted with 0-3 R^12a;
- C₂-C₆alkenyl substituted with 0-3 R^12a;
- C₂-C₆alkynyl substituted with 0-3 R^12a;
- C₆-C₁₀aryl substituted with 0-4 R^12b;
- C₃-C₁₀carbocycle substituted with 0-4 R^12b; or
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^12b;

R^12a, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, —C(═O)NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,
- C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl,
- C₁-C₄haloalkoxy, C₁-C₄haloalkyl-S—,
- C₆-C₁₀aryl substituted with 0-4 R^12b;
- C₃-C₁₀carbocycle substituted with 0-4 R^12b; and
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^12b;

R^12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,
- C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl,
- C₁-C₄haloalkoxy, and C₁-C₄haloalkyl-S—;

R¹³, at each occurrence, is independently selected from H, OH, C₁-C₆alkyl, C₁-C₄alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, and CF₃;

R¹⁴is H, phenyl, benzyl, C₁-C₆alkyl, C₂-C₆alkoxyalkyl, or C₃-C₆cycloalkyl;

R^14ais H, phenyl, benzyl, or C₁-C₄alkyl;

R¹⁵, at each occurrence, is independently selected from H, C₁-C₆alkyl, benzyl, phenethyl, (C₁-C₆alkyl)-C(═O)—, and (C₁-C₆alkyl)-S(═O)₂—;

R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₆alkyl, benzyl, phenethyl, (C₁-C₆alkyl)-C(═O)—, and (C₁-C₆alkyl)-S(═O)₂—;

R¹⁷is H, C₁-C₆alkyl, C₂-C₆alkoxyalkyl, aryl substituted by 0-4 R^17a, or —CH₂-aryl substituted by 0-4 R^17a;

R^17ais H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, —OH, F, Cl, Br, I, CF₃, OCF₃, SCH₃, S(O)CH₃, SO₂CH₃, —NH₂, —N(CH₃)₂, or C₁-C₄haloalkyl;

R¹⁸, at each occurrence, is independently selected from H, C₁-C₆alkyl, phenyl, benzyl, phenethyl, (C₁-C₆alkyl)-C(═O)—, and (C₁-C₆alkyl)-S(═O)₂—;

R¹⁹, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, phenethyl;

R²⁰is H, C₁-C₄alkyl, or C(═O)OR¹⁷;

R²³, at each occurrence, is independently selected from H, OH, C₁-C₆alkyl, C₁-C₄alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, and CF₃; and

R²⁶is H or C₁-C₄alkyl.

[8] In another preferred embodiment the present invention provides a compound of Formula (Ic):

or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, wherein:

- L is —NHC(═O)—, —C(═O)NH—, or —OC(═O)NH—;
R³is —(CH₂)_n—R⁴,
- —(CH₂)_l—S—R⁴,
- —(CH₂)_l—O—R⁴, or
- (CH₂)_l—N(R^7b)—R⁴;
n is 0, 1 or 2;
l is 1 or 2;
R⁴is C₁-C₈alkyl substituted with 0-3 R^4a,
- C₂-C₈alkenyl substituted with 0-3 R^4a,
- C₂-C₈alkynyl substituted with 0-3 R^4a,
- C₃-C₁₀carbocycle substituted with 0-3 R^4b,
- C₆-C₁₀aryl substituted with 0-3 R^4b, or
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^4b;
R^4a, at each occurrence, is independently selected from H, OH, F, Cl, Br, I, NR¹⁵R¹⁶, CF₃,
- C₃-C₁₀carbocycle substituted with 0-3 R^4b,
- C₆-C₁₀aryl substituted with 0-3 R^4b, and
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^4b;
R^4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,
- C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl,
- C₁-C₄haloalkoxy, and C₁-C₄haloalkyl-S—;
R^7bis H, methyl, or ethyl;
Ring C is a 3-8 membered carbocycle;
- wherein said 3-8 membered carbocycle is saturated or partially unsaturated;
- wherein said 3-8 membered carbocycle is substituted with 0-3 R²¹; optionally, the carbocycle contains a heteroatom selected from —O—, and —N(R²⁰)—;
R²¹, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, NR¹⁵R¹⁶, OR^14a, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₁-C₄haloalkyl, C₁-C₄haloalkoxy, and C₁-C₄haloalkyl-S—;
W is a bond, —CH₂—, —CH₂CH₂—;
X is a bond;
- phenyl substituted with 0-2 R^Xb;
- C₃-C₆cycloalkyl substituted with 0-2 R^Xb; or
- 5 to 6 membered heterocycle substituted with 0-2 R^Xb;
R^Xb, at each occurrence, is independently selected from H, OH, Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₄alkyl, C₁-C₃alkoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy;
Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R¹⁹)—, C(═O)NR^19b—, —NR^19bC(═O)—, —NR^19bS(═O)₂—, —S(═O)₂NR^19b—, —NR^19bS(═O)—, —S(═O)NR^19b—, —C(═O)O—, or —OC(═O)—;
Z is H;
- C₁-C₈alkyl substituted with 0-3 R^12a;
- C₂-C₆alkenyl substituted with 0-3 R^12a;
- C₂-C₆alkynyl substituted with 0-3 R^12a;
- C₆-C₁₀aryl substituted with 0-4 R^12b;
- C₃-C₁₀carbocycle substituted with 0-4 R^12b; or
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^12b;
R^12a, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, —C(═O)NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,
- C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl,
- C₁-C₄haloalkoxy, C₁-C₄haloalkyl-S—,
- C₆-C₁₀aryl substituted with 0-4 R^12b;
- C₃-C₁₀carbocycle substituted with 0-4 R^12b; and
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^12b;
R^12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,
- C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl,
- C₁-C₄haloalkoxy, and C₁-C₄haloalkyl-S—;
R¹³, at each occurrence, is independently selected from H, OH, C₁-C₆alkyl, C₁-C₄alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, and CF₃;
R^14ais H, phenyl, benzyl, or C₁-C₄alkyl;
R¹⁵, at each occurrence, is independently selected from H, C₁-C₆alkyl, benzyl, phenethyl, (C₁-C₄alkyl)-C(═O)—, and (C₁-C₄alkyl)-S(═O)₂—;
R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₆alkyl, benzyl, phenethyl, (C₁-C₄alkyl)-C(═O)—, and (C₁-C₄alkyl)-S(═O)₂—; and
R²⁰is H or C₁-C₄alkyl.

[9] In another preferred embodiment the present invention provides a compound of Formula (Ic) wherein:

- L is —NHC(═O)—, —C(═O)NH—, or —OC(═O)NH—;
R³is —R⁴, —CH₂R⁴, —CH₂CH₂R⁴, —CH₂OR⁴, or —CH₂CH₂OR⁴;
R⁴is C₁-C₆alkyl substituted with 0-3 R^4a,
- C₂-C₆alkenyl substituted with 0-3 R^4a,
- C₂-C₆alkynyl substituted with 0-3 R^4a,
- C₃-C₆carbocycle substituted with 0-3 R^4b, phenyl substituted with 0-3 R^4b, or
- 5 to 6 membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R^4b;
R^4a, at each occurrence, is independently selected from H, OH, F, Cl, Br, I, NR¹⁵R¹⁶, CF₃,
- C₃-C₆carbocycle substituted with 0-3 R^4b, phenyl substituted with 0-3 R^4b, and
- 5 to 6 membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R^4b;
R^4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,
- C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl,
- C₁-C₄haloalkoxy, and C₁-C₄haloalkyl-S—;
Ring C is a 3-6 membered carbocycle;
- wherein said 3-6 membered carbocycle is saturated or partially unsaturated;
- wherein said 3-6 membered carbocycle is substituted with 0-2 R²¹;
- optionally, the carbocycle contains a heteroatom selected from —O—, and —N(R²⁰)—;
R²¹, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, CF₃, acetyl, SCH₃, methyl, ethyl, methoxy, ethoxy, allyl, —OCF₃, and —SCF₃;
W is a bond, —CH₂—, —CH₂CH₂—;
X is a bond;
- phenyl substituted with 0-1 R^Xb;
- C₃-C₆cycloalkyl substituted with 0-1 R^Xb; or
- 5 to 6 membered heterocycle substituted with 0-1 R^Xb;
R^Xbis selected from H, OH, Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, and —OCF₃;
Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —N(CH₃)—, or —N(CH₂CH₃)—;
Z is H;
- C₁-C₈alkyl substituted with 0-3 R^12a;
- C₂-C₆alkenyl substituted with 0-3 R^12a;
- C₂-C₆alkynyl substituted with 0-3 R^12a; C₆-C₁₀aryl substituted with 0-4 R^12b;
- C₃-C₁₀carbocycle substituted with 0-4 R^12b; or
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^12b;
R^12a, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, —C(═O)NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,
- C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl,
- C₁-C₄haloalkoxy, C₁-C₄haloalkyl-S—,
- C₆-C₁₀aryl substituted with 0-4 R^12b;
- C₃-C₁₀carbocycle substituted with 0-4 R^12b; and
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^12b;
R^12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,
- C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl,
- C₁-C₄haloalkoxy, and C₁-C₄haloalkyl-S—;
R¹³, at each occurrence, is independently selected from H, OH, C₁-C₆alkyl, C₁-C₄alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, and CF₃;
R¹⁵, at each occurrence, is independently selected from H, C₁-C₄alkyl, and benzyl;
R¹⁶, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, benzyl, phenethyl, methyl-C(═O)—, ethyl-C(═O)—, methyl-S(═O)₂—, ethyl-S(═O)₂—, and propyl-S(═O)₂—; and
R²⁰is H or C₁-C₄alkyl.

[10] In another preferred embodiment the present invention provides a compound of Formula (Ic) wherein:

- L is —NHC(═O)—, —C(═O)NH—, or —OC(═O)NH—;
R³is —R⁴, —CH₂R⁴, —CH₂CH₂R⁴, —CH₂OR⁴, or —CH₂CH₂OR⁴;
R⁴is C₁-C₆alkyl substituted with 0-3 R^4a,
- C₂-C₆alkenyl substituted with 0-3 R^4a, or
- C₂-C₆alkynyl substituted with 0-3 R^4a;
R^4a, at each occurrence, is independently selected from is H, OH, F, Cl, Br, I, NR¹⁵R¹⁶, CF₃,
- C₃-C₆carbocycle substituted with 0-3 R^4b, phenyl substituted with 0-3 R^4b, and
- 5 to 6 membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R^4b; wherein said 5 to 6 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
R^4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,
- C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl,
- C₁-C₄haloalkoxy, and C₁-C₄haloalkyl-S—;
Ring C is a 3-6 membered carbocycle selected from:

- wherein said 3-6 membered carbocycle is substituted with 0-1 R²¹;

R²¹is selected from H, OH, Cl, F, CN, CF₃, methyl, ethyl, methoxy, ethoxy, allyl, and —OCF₃;

W is a bond or —CH₂—;

X is a bond, phenyl, C₃-C₆cycloalkyl or 5 to 6 membered heterocycle;

Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—,
- —N(CH₃)—, or —N(CH₂CH₃)—;

Z is H;
- C₁-C₈alkyl substituted with 0-3 R^12a;
- C₂-C₆alkenyl substituted with 0-3 R^12a;
- C₂-C₆alkynyl substituted with 0-3 R^12a;
- C₆-C₁₀aryl substituted with 0-4 R^12b;
- C₃-C₁₀carbocycle substituted with 0-4 R^12b; or
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^12b;

R^12a, at each occurrence, is independently selected from H, OH, Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy;
- phenyl substituted with 0-4 R^12b;
- C_3-6carbocycle substituted with 0-4 R^12b; and
- 5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R^12b;

R^12b, at each occurrence, is independently selected from H, OH, Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy;

R¹³, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, Cl, F, Br, CN, NR¹⁵R¹⁶, and CF₃;

R¹⁵, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl; and

R¹⁶, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, benzyl, and phenethyl; and

R²⁰is H, methyl, or ethyl.

[11] In another preferred embodiment the present invention provides a compound of Formula (Ic) wherein:

- L is —NHC(═O)—, —C(═O)NH—, or OC(═O)NH—;
  
  Ring C is selected from:

R³is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)₂, —CH₂(CH₃)₂, —CH(CH₃)CH₂CH₃, —CH₂CH(CH₃)₂, —CH₂C(CH₃)₃, —CF₃, —CH₂CF₃, —CH₂CH₂CF₃, —CH₂CH₂CH₂CF₃, —CH(OH)CH₂CH(CH₃)₂, —CH(OH)CH(CH₃)₂, —CH(NH₂)CH₂CH(CH₃)₂, —CH₂CH₂OCH₃, —CH₂OCH₂CH₃, —CF₂CH₂CH(CH₃)₂, —CH(NHCH₃)CH₂CH(CH₃)₂, —CH(NHSO₂CH₂CH₂CH₃)CH₂CH(CH₃)₂, cyclohexyl-, cyclopentyl-, cyclopropyl-CH₂—, cyclobutyl-CH₂—, cyclopentyl-CH₂—, cyclohexyl-CH₂—, cyclopropyl-CH₂CH₂—, cyclobutyl-CH₂CH₂—, cyclopentyl-CH₂CH₂—, cyclohexyl-CH(OH)—, cyclohexyl-CH₂CH₂—, 1-NH₂-cyclopentyl, phenyl-CH₂—, (2-F-phenyl)CH₂—, (3-F-phenyl)CH₂—, (4-F-phenyl)CH₂—, (2-Cl-phenyl)CH₂—, (3-Cl-phenyl)CH₂—, (4-Cl-phenyl)CH₂—, (2,3-diF-phenyl)CH₂—, (2,4-diF-phenyl)CH₂—, (2,5-diF-phenyl)CH₂—, (2,6-diF-phenyl)CH₂—, (3,4-diF-phenyl)CH₂—, (3,5-diF-phenyl)CH₂—, (2,3-diCl-phenyl)CH₂—, (2,4-diCl-phenyl)CH₂—, (2,5-diCl-phenyl)CH₂—, (2,6-diCl-phenyl)CH₂—, (3,4-diCl-phenyl)CH₂—, (3,5-diCl-phenyl)CH₂—, (3-F-4-Cl-phenyl)CH₂—, (3-F-5-Cl-phenyl)CH₂—, (3-Cl-F-phenyl)CH₂—, phenyl-CH₂CH₂—, (2-F-phenyl)CH₂CH₂—, (3-F-phenyl)CH₂CH₂—, (4-F-phenyl)CH₂CH₂—, (2-Cl-phenyl)CH₂CH₂—, (3-Cl-phenyl)CH₂CH₂—, (4-Cl-phenyl)CH₂CH₂—, (2,3-diF-phenyl)CH₂CH₂—, (2,4-diF-phenyl)CH₂CH₂—, (2,5-diF-phenyl)CH₂CH₂—, (2,6-diF-phenyl)CH₂CH₂—, (3,4-diF-phenyl)CH₂CH₂—, (3,5-diF-phenyl)CH₂CH₂—, (2,3-diCl-phenyl)CH₂CH₂—, (2,4-diCl-phenyl)CH₂CH₂—, (2,5-diCl-phenyl)CH₂CH₂—, (2,6-diCl-phenyl)CH₂CH₂—, (3,4-diCl-phenyl)CH₂CH₂—, (3,5-diCl-phenyl)CH₂CH₂—, (3-F-4-Cl-phenyl)CH₂CH₂—, (3-F-5-Cl-phenyl)CH₂CH₂—, 4-piperidinyl-CH₂CH₂—, phenyl-CH₂CH₂CF₂—, phenyl-CH₂CH(OH)—, imidazolyl-CH₂CH(OH)—, or phenyl-CH₂OCH₂—;

W is a bond or —CH₂—;

X is a bond;

Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, or —N(CH₃)—,

Z is methyl, ethyl, i-propyl, n-propyl, n-butyl, i-butyl, s-butyl, t-butyl, allyl, phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl, 2,5-diF-phenyl, 2,6-diF-phenyl, 3,4-diF-phenyl, 3,5-diF-phenyl, 2,3-diCl-phenyl, 2,4-diCl-phenyl, 2,5-diCl-phenyl, 2,6-diCl-phenyl, 3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl, 3-Cl-F-phenyl, 2-MeO-phenyl, 3-MeO-phenyl, 4-MeO-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-MeS-phenyl, 3-MeS-phenyl, 4-MeS-phenyl, 2-CF₃O-phenyl, 3-CF₃O-phenyl, 4-CF₃O-phenyl, furanyl, thienyl, pyridyl, 2-Me-pyridyl, 3-Me-pyridyl, 4-Me-pyridyl, 1-imidazolyl, oxazolyl, isoxazolyl, 1-benzimidazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholino, N-piperinyl, phenyl-CH₂—, (2-F-phenyl)CH₂—, (3-F-phenyl)CH₂—, (4-F-phenyl)CH₂—, (2-Cl-phenyl)CH₂—, (3-Cl-phenyl)CH₂, (4-Cl-phenyl)CH₂—, (2,3-diF-phenyl)CH₂—, (2,4-diF-phenyl)CH₂—, (2,5-diF-phenyl)CH₂—, (2,6-diF-phenyl)CH₂—, (3,4-diF-phenyl)CH₂—, (3,5-diF-phenyl)CH₂—, (2,3-diCl-phenyl)CH₂—, (2,4-diCl-phenyl)CH₂—, (2,5-diCl-phenyl)CH₂—, (2,6-diCl-phenyl)CH₂—, (3,4-diCl-phenyl)CH₂—, (3,5-diCl-phenyl)CH₂—, (3-F-4-Cl-phenyl)CH₂—, (3-F-5-Cl-phenyl)CH₂—, (3-Cl-F-phenyl)CH₂—, (2-MeO-phenyl)CH₂—, (3-MeO-phenyl)CH₂—, (4-MeO-phenyl)CH₂—, (2-Me-phenyl)CH₂—, (3-Me-phenyl)CH₂—, (4-Me-phenyl)CH₂—, (2-MeS-phenyl)CH₂—, (3-MeS-phenyl)CH₂—, 4-MeS-phenyl)CH₂—, (2-CF₃O-phenyl)CH₂—, (3-CF₃O-phenyl)CH₂—, (4-CF₃O-phenyl)CH₂—, (furanyl)CH₂—, (thienyl)CH₂—, (pyridyl)CH₂—, (2-Me-pyridyl)CH₂—, (3-Me-pyridyl)CH₂—, (4-Me-pyridyl)CH₂—, (1-imidazolyl)CH₂—, (oxazolyl)CH₂—, (isoxazolyl)CH₂—, (1-benzimidazolyl)CH₂—, (cyclopropyl)CH₂—, (cyclobutyl)CH₂—, (cyclopentyl)CH₂—, (cyclohexyl)CH₂—, (morpholino)CH₂—, (N-piperidinyl)CH₂—, phenyl-CH₂CH₂—, (phenyl)₂CHCH₂—, (2-F-phenyl)CH₂CH₂—, (3-F-phenyl)CH₂CH₂—, (4-F-phenyl)CH₂CH₂—, (2-Cl-phenyl)CH₂CH₂—, (3-Cl-phenyl)CH₂CH₂—, (4-Cl-phenyl)CH₂CH₂—, (2,3-diF-phenyl)CH₂CH₂—, (2,4-diF-phenyl)CH₂CH₂—, (2,5-diF-phenyl)CH₂CH₂—, (2,6-diF-phenyl)CH₂CH₂—, (3,4-diF-phenyl)CH₂CH₂—, (3,5-diF-phenyl)CH₂CH₂—, (2,3-diCl-phenyl)CH₂CH₂—, (2,4-diCl-phenyl)CH₂CH₂—, (2,5-diCl-phenyl)CH₂CH₂—, (2,6-diCl-phenyl)CH₂CH₂—, (3,4-diCl-phenyl)CH₂CH₂—, (3,5-diCl-phenyl)CH₂CH₂—, (3-F-4-Cl-phenyl)CH₂CH₂—, (3-F-5-Cl-phenyl)CH₂CH₂—, (3-Cl-F-phenyl)CH₂CH₂—, (2-MeO-phenyl)CH₂CH₂—, (3-MeO-phenyl)CH₂CH₂—, (4-MeO-phenyl)CH₂CH₂—, (2-Me-phenyl)CH₂CH₂—, (3-Me-phenyl)CH₂CH₂—, (4-Me-phenyl)CH₂CH₂—, (2-MeS-phenyl)CH₂CH₂—, (3-MeS-phenyl)CH₂CH₂—, (4-MeS-phenyl)CH₂CH₂—, (2-CF₃O-phenyl)CH₂CH₂—, (3-CF₃O-phenyl)CH₂CH₂—, (4-CF₃O-phenyl)CH₂CH₂—, (furanyl)CH₂CH₂—, (thienyl)CH₂CH₂—, (pyridyl)CH₂CH₂—, (2-Me-pyridyl)CH₂CH₂—, (3-Me-pyridyl)CH₂CH₂—, (4-Me-pyridyl)CH₂CH₂—, (imidazolyl)CH₂CH₂—, (oxazolyl)CH₂CH₂—, (isoxazolyl)CH₂CH₂—, (benzimidazolyl)CH₂CH₂—, (cyclopropyl)CH₂CH₂—, (cyclobutyl)CH₂CH₂—, (cyclopentyl)CH₂CH₂—, (cyclohexyl)CH₂CH₂—, (morpholino)CH₂CH₂—, or (N-piperidinyl)CH₂CH₂—;

R¹³, at each occurrence, is independently selected from H, F, Cl, OH, —CH₃, —CH₂CH₃, —OCH₃, or —CF₃.

R²⁰is H, methyl, or ethyl.

[12] In another preferred embodiment the present invention provides a compound of Formula (Id) and (Ie)

or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, wherein:

- L is —NHC(═O)—, —C(═O)NH—, or —OC(═O)NH—;
R³is—(CH₂)_n—R⁴,
- —(CH₂)_l—S—R⁴,
- —(CH₂)_l—O—R⁴, or
- —(CH₂)_l—N(R^7b)—R⁴;
n is 0, 1 or 2;
l is 1 or 2;
R⁴is C₁-C₈alkyl substituted with 0-3 R^4a,
- C₂-C₈alkenyl substituted with 0-3 R^4a,
- C₂-C₈alkynyl substituted with 0-3 R^4a,
- C₃-C₁₀carbocycle substituted with 0-3 R^4b,
- C₆-C₁₀aryl substituted with 0-3 R^4b, or
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^4b;
R^4a, at each occurrence, is independently selected from H, OH, F, Cl, Br, I, NR¹⁵R¹⁶, CF₃,
- C₃-C₁₀carbocycle substituted with 0-3 R^4b,
- C₆-C₁₀aryl substituted with 0-3 R^4b, and
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^4b;
R^4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,
- C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl,
- C₁-C₄haloalkoxy, and C₁-C₄haloalkyl-S—;
R^7bis H, methyl, or ethyl;
Ring C is a 3-8 membered carbocycle;
- wherein said 3-8 membered carbocyclic moiety is saturated or partially saturated;
- wherein said 3-8 membered carbocyclic moiety is substituted with 0-3 R²¹;
- optionally, the carbocycle contains a heteroatom selected from —O— and —N(R²⁰)—;
R²¹, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, NR¹⁵R¹⁶, OR^14a, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₁-C₄haloalkyl, C₁-C₄haloalkoxy, and C₁-C₄haloalkyl-S—;
R¹¹, at each occurrence, is independently selected from H, ═O, NR¹⁸R¹⁹, CF₃;
- C₁-C₄alkyl optionally substituted with 0-1 R^11a;
- phenyl substituted with 0-3 R^11b;
- C₃-C₆carbocycle substituted with 0-3 R^11b; and
- 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R^11b; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, homopiperidinyl, and tetrazolyl;
R^11a, at each occurrence, is independently selected from H, C₁-C₄alkyl, OR¹⁴, F, Cl, ═O, NR¹⁵R¹⁶, CF₃, or phenyl substituted with 0-3 R^11b;
R^11b, at each occurrence, is independently selected from H, OH, Cl, F, NR¹⁵R¹⁶, CF₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy;
W is a bond, —CH₂—, —CH₂CH₂—;
X is a bond;
- phenyl substituted with 0-2 R^Xb;
- C₃-C₆cycloalkyl substituted with 0-2 R^Xb; or
- 5 to 6 membered heterocycle substituted with 0-2 R^Xb;
R^Xb, at each occurrence, is independently selected from H, OH, Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₄alkyl, C₁-C₃alkoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy;
Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R¹⁹)—, —C(═O)NR^19b—, —NR^19bC(═O)—, —NR^19bS(═O)₂—, —S(═O)₂NR^19b—, —NR^19bS(═O)—, —S(═O)NR^19b—, —C(═O)O—, or —OC(═O)—;
Z is H;
- C₁-C₈alkyl substituted with 0-3 R^12a;
- C₂-C₆alkenyl substituted with 0-3 R^12a;
- C₂-C₆alkynyl substituted with 0-3 R^12a; C₆-C₁₀aryl substituted with 0-4 R^12b;
- C₃-C₁₀carbocycle substituted with 0-4 R^12b; or
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^12b;
R^12a, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, —C(═O)NR¹⁵R¹⁶,
- CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,
- C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl,
- C₁-C₄haloalkoxy, C₁-C₄haloalkyl-S—,
- C₆-C₁₀aryl substituted with 0-4 R^12b;
- C₃-C₁₀carbocycle substituted with 0-4 R^12b; and
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^12b;
R^12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,
- C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl,
- C₁-C₄haloalkoxy, and C₁-C₄haloalkyl-S—;
R¹³, at each occurrence, is independently selected from H, OH, C₁-C₆alkyl, C₁-C₄alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, and CF₃;
R¹⁴is H, phenyl, benzyl, C₁-C₆alkyl, C₂-C₆alkoxyalkyl, or C₃-C₆cycloalkyl;
R^14ais H, phenyl, benzyl, or C₁-C₄alkyl;
R¹⁵, at each occurrence, is independently selected from H, C₁-C₆alkyl, benzyl, phenethyl, (C₁-C₆alkyl)-C(═O)—, and (C₁-C₆alkyl)-S(═O)₂—;
R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₆alkyl, benzyl, phenethyl, (C₁-C₄alkyl)-C(═O)—, and (C₁-C₄alkyl)-S(═O)₂—;
R¹⁸, at each occurrence, is independently selected from H, C₁-C₆alkyl, phenyl, benzyl, phenethyl, (C₁-C₆alkyl)-C(═O)—, and (C₁-C₆alkyl)-S(═O)₂—;
R¹⁹, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, phenethyl; and
R²⁰is H or C₁-C₄alkyl.

[13] In another preferred embodiment the present invention provides a compound of Formula (Id) and (Ie) wherein:

- L is —NHC(═O)—, —C(═O)NH—, or —OC(═O)NH—;
R³is —R⁴, —CH₂R⁴, —CH₂CH₂R⁴, —CH₂OR⁴, or —CH₂CH₂OR⁴;
R⁴is C₁-C₆alkyl substituted with 0-3 R^4a,
- C₂-C₆alkenyl substituted with 0-3 R^4a,
- C₂-C₆alkynyl substituted with 0-3 R^4a,
- C₃-C₆carbocycle substituted with 0-3 R^4b, phenyl substituted with 0-3 R^4b, or
- 5 to 6 membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R^4b;
R^4a, at each occurrence, is independently selected from is H, OH, F, Cl, Br, I, NR¹⁵R¹⁶, CF₃,
- C₃-C₆carbocycle substituted with 0-3 R^4b,
- phenyl substituted with 0-3 R^4b, or
- 5 to 6 membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R^4b;
R^4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,
- C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl,
- C₁-C₄haloalkoxy, and C₁-C₄haloalkyl-S—;
Ring C is a 3-6 membered carbocycle;
- wherein said 3-6 membered carbocyclic moiety is saturated or partially unsaturated;
- wherein said 3-6 membered carbocyclic moiety is substituted with 0-2 R²¹;
- optionally, the carbocycle contains a heteroatom selected from —O— and —N(R²⁰)—;
R²¹, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, CF₃, acetyl, SCH₃, methyl, ethyl, methoxy, ethoxy, allyl, —OCF₃, and —SCF₃;
R¹¹, at each occurrence, is independently selected from H, ═O, NR¹⁸R¹⁹, CF₃;
- C₁-C₄alkyl optionally substituted with 0-1 R^11a;
- phenyl substituted with 0-3 R^11b;
- C₃-C₆carbocycle substituted with 0-3 R^11b; and
- 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R^11b; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, homopiperidinyl, and tetrazolyl;
R^11a, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, phenoxy, F, Cl, ═O, NR¹⁵R¹⁶, CF₃, or phenyl substituted with 0-3 R^11b;
R^11b, at each occurrence, is independently selected from H OH, Cl, F, NR¹⁵R¹⁶, CF₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy;
W is a bond, —CH₂—, —CH₂CH₂—;
X is a bond;
- phenyl substituted with 0-1 R^Xb;
- C₃-C₆cycloalkyl substituted with 0-1 R^Xb; or
- 5 to 6 membered heterocycle substituted with 0-1 R^Xb;
R^Xbis selected from H, OH, Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, and —OCF₃;
Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —N(CH₃)—, or —N(CH₂CH₃)—;
Z is H;
- C₁-C₈alkyl substituted with 0-3 R^12a;
- C₂-C₆alkenyl substituted with 0-3 R^12a;
- C₂-C₆alkynyl substituted with 0-3 R^12a;
- C₆-C₁₀aryl substituted with 0-4 R^12b;
- C₃-C₁₀carbocycle substituted with 0-4 R^12b; or
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^12b;
R^12a, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, —C(═O)NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,
- C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl,
- C₁-C₄haloalkoxy, C₁-C₄haloalkyl-S—,
- C₆-C₁₀aryl substituted with 0-4 R^12b;
- C₃-C₁₀carbocycle substituted with 0-4 R^12b; or
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^12b;
R^12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,
- C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl,
- C₁-C₄haloalkoxy, and C₁-C₄haloalkyl-S—;
R¹³, at each occurrence, is independently selected from H, OH, C₁-C₆alkyl, C₁-C₄alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, and CF₃;
R¹⁴is H, phenyl, benzyl, C₁-C₄alkyl, or C₂-C₄alkoxyalkyl;
R¹⁵, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, benzyl, and phenethyl;
R¹⁶, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, benzyl, phenethyl, methyl-C(═O)—, ethyl-C(═O)—, methyl-S(═O)₂—, and ethyl-S(═O)₂—;
R¹⁸, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
R¹⁹, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl;
R²⁰is H or C₁-C₄alkyl.

[14] In another preferred embodiment the present invention provides a compound of Formula (Id) and (Ie) wherein:

- L is —NHC(═O)—, —C(═O)NH—, or —OC(═O)NH—;
R³is —R⁴, —CH₂R⁴, —CH₂CH₂R⁴, —CH₂OR⁴, or —CH₂CH₂OR⁴;
R⁴is C₁-C₆alkyl substituted with 0-3 R^4a,
- C₂-C₆alkenyl substituted with 0-3 R^4a, or
- C₂-C₆alkynyl substituted with 0-3 R^4a;
R^4a, at each occurrence, is independently selected from is H, OH, F, Cl, Br, I, NR¹⁵R¹⁶, CF₃,
- C₃-C₆carbocycle substituted with 0-3 R^4b,
- phenyl substituted with 0-3 R^4b, or
- 5 to 6 membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R^4b; wherein said 5 to 6 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
R^4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,
- C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl,
- C₁-C₄haloalkoxy, and C₁-C₄haloalkyl-S—;
Ring C is a 3-6 membered carbocycle selected from:

- wherein said 3-6 membered carbocycle is substituted with 0-1 R²¹;

R²¹is selected from H, OH, Cl, F, CN, CF₃, methyl, ethyl, methoxy, ethoxy, allyl, and —OCF₃;

R¹¹, at each occurrence, is independently selected from H, ═O, NR¹⁸R¹⁹;
- C₁-C₄alkyl optionally substituted with 0-1 R^11a;
- phenyl substituted with 0-3 R^11b;
- 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^11b; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, homopiperidinyl, and tetrazolyl;

R^11a, at each occurrence, is independently selected from H, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, phenoxy, F, Cl, ═O, NR¹⁵R¹⁶, CF₃, or phenyl substituted with 0-3 R^11b;

R^11b, at each occurrence, is independently selected from H OH, Cl, F, NR¹⁵R¹⁶, CF₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy;

W is a bond or —CH₂—;

X is a bond, phenyl, C₃-C₆cycloalkyl or 5 to 6 membered heterocycle;

Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —N(CH₃)—, or —N(CH₂CH₃)—;

Z is H;
- C₁-C₈alkyl substituted with 0-3 R^12a;
- C₂-C₆alkenyl substituted with 0-3 R^12a;
- C₂-C₆alkynyl substituted with 0-3 R^12a;
- C₆-C₁₀aryl substituted with 0-4 R^12b;

C₃-C₁₀carbocycle substituted with 0-4 R^12b; or

- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^12b;
R^12a, at each occurrence, is independently selected from H, OH, Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy;
- phenyl substituted with 0-4 R^12b;
- C_3-6carbocycle substituted with 0-4 R^12b; or
- 5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R^12b;
R^12b, at each occurrence, is independently selected from H, OH, Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy;
R¹³, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, Cl, F, Br, CN, NR¹⁵R¹⁶, and CF₃;
R¹⁴is H, phenyl, benzyl, methyl, ethyl, propyl, or butyl;
R¹⁵, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl; and
R¹⁶, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, benzyl, and phenethyl.
R¹⁸, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
R¹⁹, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl; and
R²⁰is H, methyl, or ethyl.

[15] In another preferred embodiment the present invention provides a compound of Formula (Id) and (Ie) wherein:

- L is —NHC(═O)—, —C(═O)NH—, or OC(═O)NH—;
  
  Ring C is selected from:

R³is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)₂, —CH₂(CH₃)₂, —CH(CH₃)CH₂CH₃, —CH₂CH(CH₃)₂, —CH₂C(CH₃)₃, —CF₃, —CH₂CF₃, —CH₂CH₂CF₃, —CH₂CH₂CH₂CF₃, —CH(OH)CH₂CH(CH₃)₂, —CH(OH)CH(CH₃)₂, —CH(NH₂)CH₂CH(CH₃)₂, —CH₂CH₂OCH₃, —CH₂OCH₂CH₃, —CF₂CH₂CH(CH₃)₂, —CH(NHCH₃)CH₂CH(CH₃)₂, —CH(NHSO₂CH₂CH₂CH₃)CH₂CH(CH₃)₂, cyclohexyl-, cyclopentyl-, cyclopropyl-CH₂—, cyclobutyl-CH₂—, cyclopentyl-CH₂—, cyclohexyl-CH₂—, cyclopropyl-CH₂CH₂—, cyclobutyl-CH₂CH₂—, cyclopentyl-CH₂CH₂—, cyclohexyl-CH(OH)—, cyclohexyl-CH₂CH₂—, 1—NH₂-cyclopentyl, phenyl-CH₂—, (2-F-phenyl)CH₂—, (3-F-phenyl)CH₂—, (4-F-phenyl)CH₂—, (2-Cl-phenyl)CH₂—, (3-Cl-phenyl)CH₂—, (4-Cl-phenyl)CH₂—, (2,3-diF-phenyl)CH₂—, (2,4-diF-phenyl)CH₂—, (2,5-diF-phenyl)CH₂—, (2,6-diF-phenyl)CH₂—, (3,4-diF-phenyl)CH₂—, (3,5-diF-phenyl)CH₂—, (2,3-diCl-phenyl)CH₂—, (2,4-diCl-phenyl)CH₂—, (2,5-diCl-phenyl)CH₂—, (2,6-diCl-phenyl)CH₂—, (3,4-diCl-phenyl)CH₂—, (3,5-diCl-phenyl)CH₂—, (3-F-4-Cl-phenyl)CH₂—, (3-F-5-Cl-phenyl)CH₂—, (3-Cl-F-phenyl)CH₂—, phenyl-CH₂CH₂—, (2-F-phenyl)CH₂CH₂—, (3-F-phenyl)CH₂CH₂—, (4-F-phenyl)CH₂CH₂—, (2-Cl-phenyl)CH₂CH₂—, (3-Cl-phenyl)CH₂CH₂—, (4-Cl-phenyl)CH₂CH₂—, (2,3-diF-phenyl)CH₂CH₂—, (2,4-diF-phenyl)CH₂CH₂—, (2,5-diF-phenyl)CH₂CH₂—, (2,6-diF-phenyl)CH₂CH₂—, (3,4-diF-phenyl)CH₂CH₂—, (3,5-diF-phenyl)CH₂CH₂—, (2,3-diCl-phenyl)CH₂CH₂—, (2,4-diCl-phenyl)CH₂CH₂—, (2,5-diCl-phenyl)CH₂CH₂—, (2,6-diCl-phenyl)CH₂CH₂—, (3,4-diCl-phenyl)CH₂CH₂—, (3,5-diCl-phenyl)CH₂CH₂—, (3-F-4-Cl-phenyl)CH₂CH₂—, (3-F-5-Cl-phenyl)CH₂CH₂—, 4-piperidinyl-CH₂CH₂—, phenyl-CH₂CH₂CF₂—, phenyl-CH₂CH(OH)—, imidazolyl-CH₂CH(OH)—, or phenyl-CH₂OCH₂—;

W is a bond or —CH₂—;

X is a bond;

Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, or —N(CH₃)—,

Z is methyl, ethyl, i-propyl, n-propyl, n-butyl, i-butyl, s-butyl, t-butyl, allyl, phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl, 2,5-diF-phenyl, 2,6-diF-phenyl, 3,4-diF-phenyl, 3,5-diF-phenyl, 2,3-diCl-phenyl, 2,4-diCl-phenyl, 2,5-diCl-phenyl, 2,6-diCl-phenyl, 3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl, 3-Cl-F-phenyl, 2-MeO-phenyl, 3-MeO-phenyl, 4-MeO-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-MeS-phenyl, 3-MeS-phenyl, 4-MeS-phenyl, 2-CF₃O-phenyl, 3-CF₃O-phenyl, 4-CF₃O-phenyl, furanyl, thienyl, pyridyl, 2-Me-pyridyl, 3-Me-pyridyl, 4-Me-pyridyl, 1-imidazolyl, oxazolyl, isoxazolyl, 1-benzimidazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholino, N-piperinyl, phenyl-CH₂—, (2-F-phenyl)CH₂—, (3-F-phenyl)CH₂—, (4-F-phenyl)CH₂—, (2-Cl-phenyl)CH₂—, (3-Cl-phenyl)CH₂, (4-Cl-phenyl)CH₂—, (2,3-diF-phenyl)CH₂—, (2,4-diF-phenyl)CH₂—, (2,5-diF-phenyl)CH₂—, (2,6-diF-phenyl)CH₂—, (3,4-diF-phenyl)CH₂—, (3,5-diF-phenyl)CH₂—, (2,3-diCl-phenyl)CH₂—, (2,4-diCl-phenyl)CH₂—, (2,5-diCl-phenyl)CH₂—, (2,6-diCl-phenyl)CH₂—, (3,4-diCl-phenyl)CH₂—, (3,5-diCl-phenyl)CH₂—, (3-F-4-Cl-phenyl)CH₂—, (3-F-5-Cl-phenyl)CH₂—, (3-Cl-F-phenyl)CH₂—, (2-MeO-phenyl)CH₂—, (3-MeO-phenyl)CH₂—, (4-MeO-phenyl)CH₂—, (2-Me-phenyl)CH₂—, (3-Me-phenyl)CH₂—, (4-Me-phenyl)CH₂—, (2-MeS-phenyl)CH₂—, (3-MeS-phenyl)CH₂—, 4-MeS-phenyl)CH₂—, (2-CF₃O-phenyl)CH₂—, (3-CF₃O-phenyl)CH₂—, (4-CF₃O-phenyl)CH₂—, (furanyl)CH₂—, (thienyl)CH₂—, (pyridyl)CH₂—, (2-Me-pyridyl)CH₂—, (3-Me-pyridyl)CH₂—, (4-Me-pyridyl)CH₂—, (1-imidazolyl)CH₂—, (oxazolyl)CH₂—, (isoxazolyl)CH₂—, (1-benzimidazolyl)CH₂—, (cyclopropyl)CH₂—, (cyclobutyl)CH₂—, (cyclopentyl)CH₂—, (cyclohexyl)CH₂—, (morpholino)CH₂—, (N-piperidinyl)CH₂—, phenyl-CH₂CH₂—, (phenyl)₂CHCH₂—, (2-F-phenyl)CH₂CH₂—, (3-F-phenyl)CH₂CH₂—, (4-F-phenyl)CH₂CH₂—, (2-Cl-phenyl)CH₂CH₂—, (3-Cl-phenyl)CH₂CH₂—, (4-Cl-phenyl)CH₂CH₂—, (2,3-diF-phenyl)CH₂CH₂—, (2,4-diF-phenyl)CH₂CH₂—, (2,5-diF-phenyl)CH₂CH₂—, (2,6-diF-phenyl)CH₂CH₂—, (3,4-diF-phenyl)CH₂CH₂—, (3,5-diF-phenyl)CH₂CH₂—, (2,3-diCl-phenyl)CH₂CH₂—, (2,4-diCl-phenyl)CH₂CH₂—, (2,5-diCl-phenyl)CH₂CH₂—, (2,6-diCl-phenyl)CH₂CH₂—, (3,4-diCl-phenyl)CH₂CH₂—, (3,5-diCl-phenyl)CH₂CH₂—, (3-F-4-Cl-phenyl)CH₂CH₂—, (3-F-5-Cl-phenyl)CH₂CH₂—, (3-Cl-F-phenyl)CH₂CH₂—, (2-MeO-phenyl)CH₂CH₂—, (3-MeO-phenyl)CH₂CH₂—, (4-MeO-phenyl)CH₂CH₂—, (2-Me-phenyl)CH₂CH₂—, (3-Me-phenyl)CH₂CH₂—, (4-Me-phenyl)CH₂CH₂—, (2-MeS-phenyl)CH₂CH₂—, (3-MeS-phenyl)CH₂CH₂—, (4-MeS-phenyl)CH₂CH₂—, (2-CF₃O-phenyl)CH₂CH₂—, (3-CF₃O-phenyl)CH₂CH₂—, (4-CF₃O-phenyl)CH₂CH₂—, (furanyl)CH₂CH₂—, (thienyl)CH₂CH₂—, (pyridyl)CH₂CH₂—, (2-Me-pyridyl)CH₂CH₂—, (3-Me-pyridyl)CH₂CH₂—, (4-Me-pyridyl)CH₂CH₂—, (imidazolyl)CH₂CH₂—, (oxazolyl)CH₂CH₂—, (isoxazolyl)CH₂CH₂—, (benzimidazolyl)CH₂CH₂—, (cyclopropyl)CH₂CH₂—, (cyclobutyl)CH₂CH₂—, (cyclopentyl)CH₂CH₂—, (cyclohexyl)CH₂CH₂—, (morpholino)CH₂CH₂—, or (N-piperidinyl)CH₂CH₂—;

R¹¹, at each occurrence, is independently selected from H, ═O, methyl, ethyl, phenyl, benzyl, phenethyl, 4-F-phenyl, (4-F-phenyl)CH₂—, (4-F-phenyl)CH₂CH₂—, 3-F-phenyl, (3-F-phenyl)CH₂—, (3-F-phenyl)CH₂CH₂—, 2-F-phenyl, (2-F-phenyl)CH₂—, (2-F-phenyl)CH₂CH₂—, 4-Cl-phenyl, (4-Cl-phenyl)CH₂—, (4-Cl-phenyl)CH₂CH₂—, 3-Cl-phenyl, (3-Cl-phenyl)CH₂—, (3-Cl-phenyl)CH₂CH₂—, 4-CH₃-phenyl, (4-CH₃-phenyl)CH₂—, (4-CH₃-phenyl)CH₂CH₂—, 3-CH₃-phenyl, (3-CH₃-phenyl)CH₂—, (3-CH₃-phenyl)CH₂CH₂—, 4-CF₃-phenyl, (4-CF₃-phenyl)CH₂—, (4-CF₃-phenyl)CH₂CH₂—, cyclopentyl, pyrid-2-yl, pyrid-3-yl, or pyrid-4-yl; and

R¹³, at each occurrence, is independently selected from H, F, Cl, OH, —CH₃, —CH₂CH₃, —OCH₃, or —CF₃.

[16] In another preferred embodiment the present invention provides a compound of Formula (If):

or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, wherein:

- L is —NHC(═O)—, —C(═O)NH—, or —OC(═O)NH—;
R³is —(CH₂)_n—R⁴,
- —(CH₂)_l—S—R⁴,
- —(CH₂)_l—O—R⁴, or
- —(CH₂)_l—N(R^7b)—R⁴;
n is 0, 1 or 2;
l is 1 or 2;
R⁴is C₁-C₈alkyl substituted with 0-3 R^4a,
- C₂-C₈alkenyl substituted with 0-3 R^4a,
- C₂-C₈alkynyl substituted with 0-3 R^4a,
- C₃-C₁₀carbocycle substituted with 0-3 R^4b,
- C₆-C₁₀aryl substituted with 0-3 R^4b, or
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^4b;
R^4a, at each occurrence, is independently selected from H, OH, F, Cl, Br, I, NR¹⁵R¹⁶, CF₃,
- C₃-C₁₀carbocycle substituted with 0-3 R^4b,
- C₆-C₁₀aryl substituted with 0-3 R^4b, and
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^4b;
R^4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,
- C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl,
- C₁-C₄haloalkoxy, and C₁-C₄haloalkyl-S—;
R^7bis H, methyl, or ethyl;

Ring C is a 3-8 membered carbocycle;
- wherein said 3-8 membered carbocyclic moiety is saturated or partially saturated;
- wherein said 3-8 membered carbocyclic moiety is substituted with 0-3 R²¹;
- optionally, the carbocycle contains a heteroatom selected from —O— and —N(R²⁰)—;
R²¹, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, NR¹⁵R¹⁶, OR^14a, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₁-C₄haloalkyl, C₁-C₄haloalkoxy, and C₁-C₄haloalkyl-S—;
R¹¹is selected from
- H, ═O, NR¹⁸R¹⁹, CF₃;
- C₁-C₄alkyl optionally substituted with 0-1 R^11a;
- phenyl substituted with 0-3 R^11b;
- C₃-C₆carbocycle substituted with 0-3 R^11b; and
- 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R^11b; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, homopiperidinyl, and tetrazolyl;
R^11a, at each occurrence, is independently selected from H, C₁-C₄alkyl, OR¹⁴, F, Cl, ═O, NR¹⁵R¹⁶, CF₃, or phenyl substituted with 0-3 R^11b;
R^11b, at each occurrence, is independently selected from H, OH, Cl, F, NR¹⁵R¹⁶, CF₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy;
W is a bond, —CH₂—, —CH₂CH₂—;
X is a bond;
- phenyl substituted with 0-2 R^Xb;
- C₃-C₆cycloalkyl substituted with 0-2 R^Xb; or
- 5 to 6 membered heterocycle substituted with 0-2 R^Xb;
R^Xb, at each occurrence, is independently selected from H, OH, Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₄alkyl, C₁-C₃alkoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy;
Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R¹⁹)—, —C(═O)NR^19b—, —NR^19bC(═O)—, —NR^19bS(═O)₂, —S(═O)₂NR^19b—, —NR^19bS(═O)—, —S(═O)NR^19b—, —C(═O)O—, or —OC(═O)—;
Z is H;
- C₁-C₈alkyl substituted with 0-3 R^12a;
- C₂-C₆alkenyl substituted with 0-3 R^12a;
- C₂-C₆alkynyl substituted with 0-3 R^12a;
- C₆-C₁₀aryl substituted with 0-4 R^12b;
- C₃-C₁₀carbocycle substituted with 0-4 R^12b; or
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^12b;
R^12a, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, —C(═O)NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,
- C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl,
- C₁-C₄haloalkoxy, C₁-C₄haloalkyl-S—,
- C₆-C₁₀aryl substituted with 0-4 R^12b;
- C₃-C₁₀carbocycle substituted with 0-4 R^12b; and
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^12b;
R^12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,
- C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl,
- C₁-C₄haloalkoxy, and C₁-C₄haloalkyl-S—;
R¹⁴is H, phenyl, benzyl, C₁-C₆alkyl, C₂-C₆alkoxyalkyl, or C₃-C₆cycloalkyl;
R^14ais H, phenyl, benzyl, or C₁-C₄alkyl;
R¹⁵, at each occurrence, is independently selected from H, C₁-C₆alkyl, benzyl, phenethyl, (C₁-C₆alkyl)-C(═O)—, and (C₁-C₆alkyl)-S(═O)₂—;
R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₆alkyl, benzyl, phenethyl, (C₁-C₄alkyl)-C(═O)—, and (C₁-C₄alkyl)-S(═O)₂—;
R¹⁸, at each occurrence, is independently selected from H, C₁-C₆alkyl, phenyl, benzyl, phenethyl, (C₁-C₆alkyl)-C(═O)—, and (C₁-C₆alkyl)-S(═O)₂—;
R¹⁹, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, phenethyl; and
R²⁰is H or C₁-C₄alkyl.

[17] In another preferred embodiment the present invention provides a compound of Formula (If) wherein:

- L is —NHC(—O)—, —C(═O)NH—, or —OC(═O)NH—;
R³is —R⁴, —CH₂R⁴, —CH₂CH₂R⁴, —CH₂OR⁴, or —CH₂CH₂OR⁴;
R⁴is C₁-C₆alkyl substituted with 0-3 R^4a,
- C₂-C₆alkenyl substituted with 0-3 R^4a,
- C₂-C₆alkynyl substituted with 0-3 R^4a,
- C₃-C₆carbocycle substituted with 0-3 R^4b,
- phenyl substituted with 0-3 R^4b, or
- 5 to 6 membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R^4b;
R^4a, at each occurrence, is independently selected from is H, OH, F, Cl, Br, I, NR¹⁵R¹⁶, CF₃,
- C₃-C₆carbocycle substituted with 0-3 R^4b, phenyl substituted with 0-3 R^4b, or
- 5 to 6 membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R^4b;
R^4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,
- C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl,
- C₁-C₄haloalkoxy, and C₁-C₄haloalkyl-S—;
Ring C is a 3-6 membered carbocycle;
- wherein said 3-6 membered carbocyclic moiety is saturated or partially unsaturated;
- wherein said 3-6 membered carbocyclic moiety is substituted with 0-2 R²¹;
- optionally, the carbocycle contains a heteroatom selected from —O— and —N(R²⁰)—;
R²¹, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, CF₃, acetyl, SCH₃, methyl, ethyl, methoxy, ethoxy, allyl, —OCF₃, and —SCF₃;
R¹¹is selected from H, ═O, NR¹⁸R¹⁹, CF₃;
- C₁-C₄alkyl optionally substituted with 0-1 R^11a;
- phenyl substituted with 0-3 R^11b;
- C₃-C₆carbocycle substituted with 0-3 R^11b; and
- 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R^11b; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, homopiperidinyl, and tetrazolyl;
R^11a, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, phenoxy, F, Cl, ═O, NR¹⁵R¹⁶, CF₃, or phenyl substituted with 0-3 R^11b;
R^11b, at each occurrence, is independently selected from H, OH, Cl, F, NR¹⁵R¹⁶, CF₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy;
W is a bond, —CH₂—, —CH₂CH₂—;
X is a bond;
- phenyl substituted with 0-1 R^Xb;
- C₃-C₆cycloalkyl substituted with 0-1 R^Xb; or
- 5 to 6 membered heterocycle substituted with 0-1 R^Xb;
R^Xbis selected from H, OH, Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, and —OCF₃;
Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —N(CH₃)—, or —N(CH₂CH₃)—;
Z is H;
- C₁-C₈alkyl substituted with 0-3 R^12a;
- C₂-C₆alkenyl substituted with 0-3 R^12a;
- C₂-C₆alkynyl substituted with 0-3 R^12a;
- C₆-C₁₀aryl substituted with 0-4 R^12b;
- C₃-C₁₀carbocycle substituted with 0-4 R^12b; or
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^12b;
R^12a, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, —C(═O)NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,
- C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl,
- C₁-C₄haloalkoxy, C₁-C₄haloalkyl-S—,
- C₆-C₁₀aryl substituted with 0-4 R^12b;
- C₃-C₁₀carbocycle substituted with 0-4 R^12b; or
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^12b;
R^12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,
- C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl,
- C₁-C₄haloalkoxy, and C₁-C₄haloalkyl-S—;
R¹⁴is H, phenyl, benzyl, C₁-C₄alkyl, or C₂-C₄alkoxyalkyl;
R¹⁵, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, benzyl, and phenethyl;
R¹⁶, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, benzyl, phenethyl, methyl-C(═O)—, ethyl-C(═O)—, methyl-S(═O)₂—, and ethyl-S(═O)₂—;
R¹⁸, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
R¹⁹, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl;
R²⁰is H or C₁-C₄alkyl.

[18] In another preferred embodiment the present invention provides a compound of Formula (If) wherein:

- L is —NHC(═O)—, —C(═O)NH—, or —OC(═O)NH—;
R³is —R⁴, —CH₂R⁴, —CH₂CH₂R⁴, —CH₂OR⁴, or —CH₂CH₂OR⁴;
R⁴is C₁-C₆alkyl substituted with 0-3 R^4a,
- C₂-C₆alkenyl substituted with 0-3 R^4a, or
- C₂-C₆alkynyl substituted with 0-3 R^4a;
R^4a, at each occurrence, is independently selected from is H, OH, F, Cl, Br, I, NR¹⁵R¹⁶, CF₃,
- C₃-C₆carbocycle substituted with 0-3 R^4b,
- phenyl substituted with 0-3 R^4b, or
- 5 to 6 membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R^4b; wherein said 5 to 6 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
R^4b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃,
- C₁-C₆alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl,
- C₁-C₄haloalkoxy, and C₁-C₄haloalkyl-S—;
Ring C is a 3-6 membered carbocycle selected from:

- wherein said 3-6 membered carbocycle is substituted with 0-1 R²¹;

R²¹is selected from H, OH, Cl, F, CN, CF₃, methyl, ethyl, methoxy, ethoxy, allyl, and —OCF₃;

R¹¹is selected from
- H, ═O, NR¹⁸R¹⁹;
- C₁-C₄alkyl optionally substituted with 0-1 R^11a;
- phenyl substituted with 0-3 R^11b;
- 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^11b; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, homopiperidinyl, and tetrazolyl;

R^11a, at each occurrence, is independently selected from H, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, phenoxy, F, Cl, ═O, NR¹⁵R¹⁶, CF₃, or phenyl substituted with 0-3 R^11b;

R^11b, at each occurrence, is independently selected from H, OH, Cl, F, NR¹⁵R¹⁶, CF₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy;

W is a bond or —CH₂—;

X is a bond, phenyl, C₃-C₆cycloalkyl or 5 to 6 membered heterocycle;

Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —N(CH₃)—, or —N(CH₂CH₃)—;

Z is H;
- C₁-C₈alkyl substituted with 0-3 R^12a;
- C₂-C₆alkenyl substituted with 0-3 R^12a;
- C₂-C₆alkynyl substituted with 0-3 R^12a;
- C₆-C₁₀aryl substituted with 0-4 R^12b;
- C₃-C₁₀carbocycle substituted with 0-4 R^12b; or
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R^12b;

R^12a, at each occurrence, is independently selected from H, OH, Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy;
- phenyl substituted with 0-4 R^12b;
- C_3-6carbocycle substituted with 0-4 R^12b; or
- 5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R^12b;

R^12b, at each occurrence, is independently selected from H, OH, Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy;

R¹⁴is H, phenyl, benzyl, methyl, ethyl, propyl, or butyl;

R¹⁵, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl; and

R¹⁶, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, benzyl, and phenethyl.

R¹⁸, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;

R¹⁹, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl; and

R²⁰is H, methyl, or ethyl.

[19] In another preferred embodiment the present invention provides a compound of Formula (If) wherein:

- L is —NHC(O)—, —C(═O)NH—, or —OC(═O)NH—;
  
  Ring C is selected from:

R³is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)₂, —CH₂(CH₃)₂, —CH(CH₃)CH₂CH₃, —CH₂CH(CH₃)₂, —CH₂C(CH₃)₃, —CF₃, —CH₂CF₃, —CH₂CH₂CF₃, —CH₂CH₂CH₂CF₃, —CH(OH)CH₂CH(CH₃)₂, —CH(OH)CH(CH₃)₂, —CH(NH₂)CH₂CH(CH₃)₂, —CH₂CH₂CCH₃, —CH₂OCH₂CH₃, —CF₂CH₂CH(CH₃)₂, —CH(NHCH₃)CH₂CH(CH₃)₂, —CH(NHSO₂CH₂CH₂CH₃)CH₂CH(CH₃)₂, cyclohexyl-, cyclopentyl-, cyclopropyl-CH₂—, cyclobutyl-CH₂—, cyclopentyl-CH₂—, cyclohexyl-CH₂—, cyclopropyl-CH₂CH₂—, cyclobutyl-CH₂CH₂—, cyclopentyl-CH₂CH₂—, cyclohexyl-CH(OH)—, cyclohexyl-CH₂CH₂—, 1—NH₂-cyclopentyl, phenyl-CH₂—, (2-F-phenyl)CH₂—, (3-F-phenyl)CH₂—, (4-F-phenyl)CH₂—, (2-Cl-phenyl)CH₂—, (3-Cl-phenyl)CH₂—, (4-Cl-phenyl)CH₂—, (2,3-diF-phenyl)CH₂—, (2,4-diF-phenyl)CH₂—, (2,5-diF-phenyl)CH₂—, (2,6-diF-phenyl)CH₂—, (3,4-diF-phenyl)CH₂—, (3,5-diF-phenyl)CH₂—, (2,3-diCl-phenyl)CH₂—, (2,4-diCl-phenyl)CH₂—, (2,5-diCl-phenyl)CH₂—, (2,6-diCl-phenyl)CH₂—, (3,4-diCl-phenyl)CH₂—, (3,5-diCl-phenyl)CH₂—, (3-F-4-Cl-phenyl)CH₂—, (3-F-5-Cl-phenyl)CH₂—, (3-Cl-F-phenyl)CH₂—, phenyl-CH₂CH₂—, (2-F-phenyl)CH₂CH₂—, (3-F-phenyl)CH₂CH₂—, (4-F-phenyl)CH₂CH₂—, (2-Cl-phenyl)CH₂CH₂—,
- (3-Cl-phenyl)CH₂CH₂—, (4-Cl-phenyl)CH₂CH₂—, (2,3-diF-phenyl)CH₂CH₂—, (2,4-diF-phenyl)CH₂CH₂—, (2,5-diF-phenyl)CH₂CH₂—, (2,6-diF-phenyl)CH₂CH₂—, (3,4-diF-phenyl)CH₂CH₂—, (3,5-diF-phenyl)CH₂CH₂—, (2,3-diCl-phenyl)CH₂CH₂—, (2,4-diCl-phenyl)CH₂CH₂—, (2,5-diCl-phenyl)CH₂CH₂—, (2,6-diCl-phenyl)CH₂CH₂—, (3,4-diCl-phenyl)CH₂CH₂—, (3,5-diCl-phenyl)CH₂CH₂—, (3-F-4-Cl-phenyl)CH₂CH₂—, (3-F-5-Cl-phenyl)CH₂CH₂—, 4-piperidinyl-CH₂CH₂—, phenyl-CH₂CH₂CF₂—, phenyl-CH₂CH(OH)—, imidazolyl-CH₂CH(OH)—, or phenyl-CH₂OCH₂—;

W is a bond or —CH₂—;

X is a bond;

Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, or —N(CH₃)—,

Z is methyl, ethyl, i-propyl, n-propyl, n-butyl, i-butyl, s-butyl, t-butyl, allyl, phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl, 2,5-diF-phenyl, 2,6-diF-phenyl, 3,4-diF-phenyl, 3,5-diF-phenyl, 2,3-diCl-phenyl, 2,4-diCl-phenyl, 2,5-diCl-phenyl, 2,6-diCl-phenyl, 3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl, 3-Cl-F-phenyl, 2-MeO-phenyl, 3-MeO-phenyl, 4-MeO-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-MeS-phenyl, 3-MeS-phenyl, 4-MeS-phenyl, 2-CF₃O-phenyl, 3-CF₃O-phenyl, 4-CF₃O-phenyl, furanyl, thienyl, pyridyl, 2-Me-pyridyl, 3-Me-pyridyl, 4-Me-pyridyl, 1-imidazolyl, oxazolyl, isoxazolyl, 1-benzimidazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholino, N-piperinyl, phenyl-CH₂—, (2-F-phenyl)CH₂—, (3-F-phenyl)CH₂—, (4-F-phenyl)CH₂—, (2-Cl-phenyl)CH₂—, (3-Cl-phenyl)CH₂, (4-Cl-phenyl)CH₂—, (2,3-diF-phenyl)CH₂—, (2,4-diF-phenyl)CH₂—, (2,5-diF-phenyl)CH₂—, (2,6-diF-phenyl)CH₂—, (3,4-diF-phenyl)CH₂—, (3,5-diF-phenyl)CH₂—, (2,3-diCl-phenyl)CH₂—, (2,4-diCl-phenyl)CH₂—, (2,5-diCl-phenyl)CH₂—, (2,6-diCl-phenyl)CH₂—, (3,4-diCl-phenyl)CH₂—, (3,5-diCl-phenyl)CH₂—, (3-F-4-Cl-phenyl)CH₂—, (3-F-5-Cl-phenyl)CH₂—, (3-Cl-F-phenyl)CH₂—, (2-MeO-phenyl)CH₂—, (3-MeO-phenyl)CH₂—, (4-MeO-phenyl)CH₂—, (2-Me-phenyl)CH₂—, (3-Me-phenyl)CH₂—, (4-Me-phenyl)CH₂—, (2-MeS-phenyl)CH₂—, (3-MeS-phenyl)CH₂—, 4-MeS-phenyl)CH₂—, (2-CF₃O-phenyl)CH₂—, (3-CF₃O-phenyl)CH₂—, (4-CF₃O-phenyl)CH₂—, (furanyl)CH₂—, (thienyl)CH₂—, (pyridyl)CH₂—, (2-Me-pyridyl)CH₂—, (3-Me-pyridyl)CH₂—, (4-Me-pyridyl)CH₂—, (1-imidazolyl)CH₂—, (oxazolyl)CH₂—, (isoxazolyl)CH₂—, (1-benzimidazolyl)CH₂—, (cyclopropyl)CH₂—, (cyclobutyl)CH₂—, (cyclopentyl)CH₂—, (cyclohexyl)CH₂—, (morpholino)CH₂—, (N-piperidinyl)CH₂—, phenyl-CH₂CH₂—, (phenyl)₂CHCH₂—, (2-F-phenyl)CH₂CH₂—, (3-F-phenyl)CH₂CH₂—, (4-F-phenyl)CH₂CH₂—, (2-Cl-phenyl)CH₂CH₂—, (3-Cl-phenyl)CH₂CH₂—, (4-Cl-phenyl)CH₂CH₂—, (2,3-diF-phenyl)CH₂CH₂—, (2,4-diF-phenyl)CH₂CH₂—, (2,5-diF-phenyl)CH₂CH₂—, (2,6-diF-phenyl)CH₂CH₂—, (3,4-diF-phenyl)CH₂CH₂—, (3,5-diF-phenyl)CH₂CH₂—, (2,3-diCl-phenyl)CH₂CH₂—, (2,4-diCl-phenyl)CH₂CH₂—, (2,5-diCl-phenyl)CH₂CH₂—, (2,6-diCl-phenyl)CH₂CH₂—, (3,4-diCl-phenyl)CH₂CH₂—, (3,5-diCl-phenyl)CH₂CH₂—, (3-F-4-Cl-phenyl)CH₂CH₂—, (3-F-5-Cl-phenyl)CH₂CH₂—, (3-Cl-F-phenyl)CH₂CH₂—, (2-MeO-phenyl)CH₂CH₂—, (3-MeO-phenyl)CH₂CH₂—, (4-MeO-phenyl)CH₂CH₂—, (2-Me-phenyl)CH₂CH₂—, (3-Me-phenyl)CH₂CH₂—, (4-Me-phenyl)CH₂CH₂—, (2-MeS-phenyl)CH₂CH₂—, (3-MeS-phenyl)CH₂CH₂—, (4-MeS-phenyl)CH₂CH₂—, (2-CF₃O-phenyl)CH₂CH₂—, (3-CF₃O-phenyl)CH₂CH₂—, (4-CF₃O-phenyl)CH₂CH₂—, (furanyl)CH₂CH₂—, (thienyl)CH₂CH₂—, (pyridyl)CH₂CH₂—, (2-Me-pyridyl)CH₂CH₂—, (3-Me-pyridyl)CH₂CH₂—, (4-Me-pyridyl)CH₂CH₂—, (imidazolyl)CH₂CH₂—, (oxazolyl)CH₂CH₂—, (isoxazolyl)CH₂CH₂—, (benzimidazolyl)CH₂CH₂—, (cyclopropyl)CH₂CH₂—, (cyclobutyl)CH₂CH₂—, (cyclopentyl)CH₂CH₂—, (cyclohexyl)CH₂CH₂—, (morpholino)CH₂CH₂—, or (N-piperidinyl)CH₂CH₂—; and

R¹¹, at each occurrence, is independently selected from H, ═O, methyl, ethyl, phenyl, benzyl, phenethyl, 4-F-phenyl, (4-F-phenyl)CH₂—, (4-F-phenyl)CH₂CH₂—, 3-F-phenyl, (3-F-phenyl)CH₂—, (3-F-phenyl)CH₂CH₂—, 2-F-phenyl, (2-F-phenyl)CH₂—, (2-F-phenyl)CH₂CH₂—, 4-Cl-phenyl, (4-Cl-phenyl)CH₂—, (4-Cl-phenyl)CH₂CH₂—, 3-Cl-phenyl, (3-Cl-phenyl)CH₂—, (3-Cl-phenyl)CH₂CH₂—, 4-CH₃-phenyl, (4-CH₃-phenyl)CH₂—, (4-CH₃-phenyl)CH₂CH₂—, 3-CH₃-phenyl, (3-CH₃-phenyl)CH₂—, (3-CH₃-phenyl)CH₂CH₂—, 4-CF₃-phenyl, (4-CF₃-phenyl)CH₂—, (4-CF₃-phenyl)CH₂CH₂—, cyclopentyl, pyrid-2-yl, pyrid-3-yl, or pyrid-4-yl.

[20] In another preferred embodiment the present invention provides a compound of Formula (I) selected from:

{[N-(3-methylbutyl)carbamoyl]cyclopentyl}-N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carboxamide;
{[N-(3-methylbutyl)carbamoyl]cyclopentyl}-N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carboxamide;
[(N-butylcarbamoyl)cyclopentyl]-N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carboxamide;
2-(3,5-difluorophenyl)-N-{[N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclohexyl}acetamide;
2-(3,5-difluorophenyl)-N-{[N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclopentyl}acetamide;
2-(3,5-difluorophenyl)-N-{[N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclopropyl}acetamide;
3-cyclopentyl-N-{[N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclohexyl}propanamide;
2-(3,5-difluorophenyl)-N-{4-[N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carbamoyl](4-piperidyl)}acetamide;
phenyl 4-[2-(3,5-difluorophenyl)acetylamino]-4-[N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]piperidinecarboxylate;
4-methyl-N-{[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}pentanamide;
N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}{[(phenylmethoxy)carbonylamino]cyclopentyl}carboxamide;
(2S)—N-{[N-(1-{[3-(4-fluorophenoxy)phenyl]methyl}-2-oxoazaperhydroepin-3-yl)carbamoyl]cyclopropyl}-2-hydroxy-4-methylpentanamide;
(2S)—N-{[N-(1-{[3-(4-fluorophenoxy)phenyl]methyl}-2-oxoazaperhydroepin-3-yl)carbamoyl]cyclopentyl}-2-hydroxy-3-methylbutanamide;
2,2-difluoro-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]-4-phenylbutanamide;
N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]-3-(4-piperidyl)propanamide;
(2S)-2-hydroxy-4-methyl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]pentanamide;
3-cyclopropyl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]propanamide;
(2R)-2-hydroxy-3-imidazol-2-yl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]propanamide;
2-ethoxy-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]acetamide;
3-cyclopentyl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]propanamide;
(2S)-2-hydroxy-3-methyl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]butanamide;
(2S)-2-cyclohexyl-2-hydroxy-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]acetamide;
(2R)-2-cyclohexyl-2-hydroxy-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]acetamide;
(2S)-2-amino-4-methyl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]pentanamide;
[(cyclohexylcarbonylamino)cyclopentyl]-N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carboxamide;
{[N-(3-methylbutyl)carbamoyl]cyclopentyl}-N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carboxamide;
4-methyl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]pentanamide;
(2S)-2-hydroxy-4-methyl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]pentanamide;
3-methoxy-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]propanamide;
(2S)-2-hydroxy-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]-3-phenylpropanamide;
N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]-2-(phenylmethoxy)acetamide;
(2S)-2-hydroxy-3-methyl-N-{[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}butanamide;
(2S)-2-hydroxy-4-methyl-N-{[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}pentanamide;
3-cyclopentyl-N-{[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}propanamide;
(2S)-2-cyclohexyl-2-hydroxy-N-{[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}acetamide;
3-cyclopropyl-N-{[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}propanamide;
N-{[N-(1-butyl-5-cyclopentyl-2-oxo(3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclopentyl}-4-methylpentanamide;
N-{[N-(5-cyclopentyl-1-methyl-2-oxo(3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclopentyl}-4-methylpentanamide;
(2S)-2-hydroxy-3-methyl-N—[(N-[2-oxo-1-benzyl(3H,4H,5H-benzo[f]azaperhydroepin-3-yl)]carbamoyl]cyclopentyl) butanamide;
(2S)-4-methyl-N-{[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}-2-[(propylsulfonyl)amino]pentanamide;
(2S)-2-amino-4-methyl-N-{[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}pentanamide;
2,2-difluoro-4-methyl-N-{[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}pentanamide;
4-methyl-N-{[N-(6-oxo(5H,7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}pentanamide;
N—({N-[5-(3,3-dimethyl-2-oxobutyl)-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl)]carbamoyl}cyclopentyl)-4-methylpentanamide;
4-methyl-N—[(N-{6-oxo-5-[(3-phenoxyphenyl)methyl](7H-dibenzo[d,f]azaperhydroepin-7-yl)}carbamoyl)cyclopentyl]pentanamide;
N-{[N-(5-butyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}-4-methylpentanamide;
4-methyl-N—[(N-{6-oxo-5-benzyl(7H-dibenzo[d,f]azaperhydroepin-7-yl)]carbamoyl}cyclopentyl)pentanamide;
N—({N-[5-(tert-butyl)-1-methyl-2-oxo(3H-benzo[f]1,4-diazepin-3-yl)]carbamoyl}cyclopentyl)-4-methylpentanamide;
N—({N-[5-(tert-butyl)-1-butyl-2-oxo(3H-benzo[f]1,4-diazepin-3-yl)]carbamoyl}cyclopentyl)-4-methylpentanamide; and
N—({N-[5-butyl-2-oxo-1-(2-pyridylmethyl)(3H-benzo[f]1,4-diazepin-3-yl)]carbamoyl}cyclopentyl)-4-methylpentanamide.

In another embodiment the present invention provides for a method for the treatment of neurological disorders associated with β-amyloid production comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of Formula (I):

or a pharmaceutically acceptable salt or prodrug thereof.

It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment to describe additional even more preferred embodiments of the present invention.

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 a method for the treatment of neurological disorders associated with β-amyloid production comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of Formula (I).

In a preferred embodiment the neurological disorder associated with β-amyloid production is Alzheimer's Disease.

In a fourth embodiment, the present invention provides a method for inhibiting γ-secretase activity for the treatment of a physiological disorder associated with inhibiting γ-secretase activity comprising administering to a host in need of such inhibition a therapeutically effective amount of a compound of Formula (I) that inhibits γ-secretase activity.

Thus, the present invention provides a method for inhibiting γ-secretase activity comprising administering to a host in need of such inhibition a therapeutically effective amount of a compound of Formula (I) that inhibits γ-secretase activity.

In a preferred embodiment the physiological disorder associated with inhibiting γ-secretase activity is Alzheimer's Disease.

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 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 Alzheimer's Disease.

DEFINITIONS

As used herein, the term “Aβ” denotes the protein designated Aβ, β-amyloid peptide, and sometimes β/A4, in the art. Aβ is an approximately 4.2 kilodalton (kD) protein of about 39 to 43 amino acids found in amyloid plaques, the walls of meningeal and parenchymal arterioles, 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

The term “APP”, as used herein, refers to the protein known in the art as β amyloid precursor protein. This protein is the precursor for Aβ and through the activity of “secretase” enzymes, as used herein, it is processed into Aβ. Differing secretase enzymes, known in the art, have been designated β secretase, generating the N-terminus of Aβ, a secretase cleaving around the 16/17 peptide bond in Aβ, and “γ secretases”, as used herein, generating C-terminal Aβ fragments ending at position 38, 39, 40, 42, 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 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 in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and 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 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 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., ═O), then 2 hydrogens on the atom are replaced.

When any variable (e.g., R^5b) occurs 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 0-2 R^5b, then said group may optionally be substituted with up to two R^5bgroups and R^5bat each occurrence is selected independently from the definition of R^5b. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

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 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 include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; for example, “C₁-C₆alkyl” denotes alkyl having 1, 2, 3, 4, 5, or 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, unless otherwise specified, is “C₁-C₄alkyl”. Additionally, unless otherwise specified, “propyl” denotes n-propyl or i-propyl; “butyl” denotes n-butyl, i-butyl, sec-butyl, or t-butyl.

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 “C₂-C₆alkenyl” include, but 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 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 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 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.

“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 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 straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example —C_vF_wwhere v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, 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 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.

“Cycloalkyl” is intended to include saturated ring groups, having the specified number of carbon atoms. For example, “C₃-C₆cycloalkyl” denotes such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

As used herein, “carbocycle” is intended to mean any 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, 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 “carbocycle” are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

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 unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is 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 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 O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O 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, 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, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 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, 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, benzimidazolyl, 1H-indazolyl, oxazolidinyl, isoxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl, and isoquinolinyl. Preferred 5 to 6 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl; more preferred 5 to 6 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, and tetrazolyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.

As used herein, the term “aryl”, “C₆-C₁₀aryl” or aromatic residue, is intended to mean an aromatic moiety containing the specified number of carbon atoms; for example phenyl, pyridinyl or naphthyl. Preferred “aryl” is phenyl. Unless otherwise specified, “aryl” may be unsubstituted or substituted with 0 to 3 groups selected from H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, amino, hydroxy, Cl, F, Br, I, CF₃, SCH₃, S(O)CH₃, SO₂CH₃, —N(CH₃)₂, N(CH₃)H, CN, NO₂, OCF₃, C(═O)CH₃, CO₂H, CO₂CH₃, or C₁-C₄haloalkyl.

The phrase “additional lactam carbons”, as used herein, is intended to denote the number of optional carbon atoms in the lactam ring B of Formula (I). Formula (I″):

represents the lactam ring B of Formula (I). Additional 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 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 8; it is more preferred that the total number of atoms of lactam ring B is seven. It is further understood that lactam ring B may optionally be unsaturated or partially unsaturated (i.e. two adjacent atoms in the ring form a double bond) wherein the backbone of lactam ring B may contain one, two or three double bonds. Examples of lactam ring B include:

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 R¹⁰or R¹¹on lactam B are methyl, ethyl, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, (4-fluorophenyl)methyl, (4-chlorophenyl)methyl, (4-trifluoromethylphenyl)methyl, and 2-, 3-, and 4-pyridinyl. Preferred examples of R¹³on lactam B are F, Cl, OH, methyl, ethyl, methoxy, and trifluoromethyl.

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 R or S configuration at carbon 3 in Formula (I″) is considered part of the invention. An example of such configuration includes,

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.

The phrase “pharmaceutically acceptable” is employed 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, 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 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 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, 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, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

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 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 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 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 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 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.

“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.

Synthesis

The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of 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 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 herein by reference.

The novel compounds of this invention may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and which are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and work-up procedures, are chosen to be the conditions standard for that reaction, which should be 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 compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.

In a preferred method of synthesis, the compounds of Formula (I) of the present invention can be prepared from carboxylic acid 1 and amine 2 using amide bond syntheses known in the art, including methods commonly used in peptide syntheses, such as HATU, TBTU, BOP, EDC, CDI, and DCC-mediated couplings, as illustrated in Scheme 1. Depending on the structure of the final product, it is appreciated by those skilled in the art that protecting groups or precursor functionality convertible to the desired groups may be desirable. Protecting groups and their use in synthesis are described in Green and Wuts, Protective Groups in Organic Synthesis, (Wiley 1991).

Additionally, the syntheses of a representative malonamide and a representative acetamide of Formula (I) are illustrated in Scheme 2 and Scheme 3, respectively. As will be readily apparent to those of ordinary skill in the art, the synthetic procedure illustrated in Scheme 2 and 3, and the reaction conditions described below can be modified by selecting the appropriate starting materials and reagents to allow the preparation of other compounds of the present invention.

Methods for the synthesis of lactams useful as intermediates in the synthesis of compounds of the present invention, including amino bisbenzodiazepine 5 and amino benzodiazepine 8, are known in the art and are disclosed in a number of references including PCT publication number WO 98/28268, WO 99/66934, and WO00/07995, which are hereby incorporated by reference. Additional references include Bock, et. al., J. Org. Chem., 1987, 52, 3232-3239; Sherrill et. al., J. Org. Chem., 1995, 60, 730-734; Walsh, D. A., Synthesis, September 1980, p. 677; and Brown, at. al., Tetrahedron Letters, 1971, 8, 667-670.

Cyclic carboxylic acid intermediates, such as 4, are useful for the synthesis of the current invention, and may be synthesized by a number of ways well known in the art. One of the preferred syntheses of the compounds of this invention is shown in Scheme 4. Typically a convergent route is employed, which joins the acid 11 and the amine together to afford the key intermediate 12 using standard bond-forming procedures (Synthesis 1989, 37-38). The desired carboxylic acid 4 may be prepared from the known malonate ester 10 (e.g. Chung, S. K. Korean J. Med. Chem. 1995, 5, 94-111) via a three-step protocol as shown in Scheme 4.

One of the preferred syntheses of cyclic amino acids, such as 7 which is useful in the preparation of compounds of Formula (I), is outlined in Scheme 5. As illustrated for the synthesis of carboxylic acid 7, the desired intermediate ester 18 is prepared by the initial coupling reaction of acid 14 and amine 13 under standard conditions using EDC and HOBt. Both the acids and the amines employed as starting materials in this invention are either commercially available or can be prepared from commercially available materials using conventional procedures and reagents. As apparent to those of ordinary skill in the art, the synthetic procedure illustrated in Scheme 5 and the reaction conditions described will allow the preparation of many other analogs of 7 by selecting the appropriate starting materials and reagents.

Methods for the synthesis of lactams useful as intermediates in the synthesis of compounds of the present invention are known in the art and are disclosed in a number of references including PCT publication number WO 98/28268, WO 99/66934, and WO00/07995, which are hereby incorporated by reference. Additional references include Bock, et. al., J. Org. Chem., 1987, 52, 3232-3239; Sherrill et. al., J. Org. Chem., 1995, 60, 730-734; Walsh, D. A., Synthesis, September 1980, p. 677; and Brown, at. al., Tetrahedron Letters, 1971, 8, 667-670.

One of the preferred syntheses of the lactam intermediates, such as 23, is outlined in Scheme 6.

a) Preparation of 21

To a suspension of 19 (30.0 g, 155 mmol) in dry Et₂O (300 mL) under N₂at −70° C. was added t-BuLi (205 mL, 1.7 M in pentane) and stirred for 4 h between −20° C. and −10° C. The reaction was cooled to −70° C. and transferred via canula to a round bottom containing 20 (23.0 mL, 186 mmol) in dry Et₂O (150 mL) under N₂at −70° C. The reaction was stirred while warming to rt for 14 h and quenched with 20% citric acid. The resulting layers were separated and the organic layer was washed with sat. NaHCO₃, brine, dried over Na₂SO₄, filtered and concentrated to give a yellow oil. The oil was dissolved in EtOH—HCl (200 mL) and stirred overnight. The solvent was removed in vacuo at 70° C. and the resulting oil triturated with Et₂O. The resultant solid was filtered and washed with Et₂O to afford 21 HCl (23.9 g, 64%) as a orange solid: ¹H NMR (500 MHz, CD₃OD) δ 8.10 (d, 1H), 7.66 (t, 1H), 7.56 (t, 1H), 7.51 (d, 1H), 1.41 (s, 9H); ESI MS m/z=178 [C₁₁H₁₅NO+H]⁺.

The orange solid was dissolved in 1N NaOH and EtOAC and the layers were separated. The organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated to afford 21 (21 g, 99%) as a yellow oil: ¹H NMR (500 MHz, CD₃OD) δ 7.70 (d, 1H), 7.16 (t, 1H), 6.78 (d, 1H), 6.59 (t, 1H), 1.38 (s, 9H)

b) Preparation of Example 23

To a solution of 22 (5.5 g, 17.0 mmol) in dry THF (50 mL) at 0° C. was added oxalyl chloride (1.47 mL, 17.0 mmol) and DMF (0.2 mL) and stirred for 1.25 h. A solution of 21 (3.3 g, 15.4 mmol) and N-methylmorpholine (4.7 mL, 42.4 mmol) in dry THF (20 mL) was added to the reaction dropwise and the reaction was stirred at rt for 1.5 h. The reaction was filtered and MeOH (100 mL) and NH₄OH (50 mL) was added to the filtrate and the reaction was sealed. After 45 min, the reaction was concentrated to half its volume and added dropwise to a cooled solution (15° C.) of ammonium acetate (5.75 g) in acetic acid (120 ml). The reaction was stirred over night at rt, dissolved in Et₂O (100 mL), made basic with 6 N NaOH, and cooled in ice while stirring for 1 h. The resulting solid was filtered, washed with H₂O and Et₂O, and dried in a vacuum oven at 30° C. to afford 23 (3.5 g, 63%) as a white solid: ¹H NMR (500 MHz, CD₃OD) δ 7.78-7.16 (m, 10H), 5.12 (s, 2 H), 1.27 (s, 9H).

Abbreviations used in the description of the chemistry and in the examples that follow are:

Ac acetyl or acetate
aq aqueous
Bn benzyl
Boc t-butyloxycarbonyl
Cbz benzyloxycarbonyl
DIEA N,N′-diisopropylethylamine
DMAP 4-dimethylaminopyridine
DME ethylene glycol dimethyl ether
DMF N,N′-dimethylformamide
DMSO dimethylsulfoxide or methyl sulfoxide
EDC•HCL 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
HOBT 1-hydroxybenzotriazole
HPLC high performance liquid chromatography
LiHMDS lithium hexamethyldisilazide
MeCN acetonitrile
MS mass spectrometry
satd saturated
rt or RT room temperature
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC thin layer chromatography

EXAMPLES

The examples provided are intended to assist in a further understanding of the invention. Particular materials employed, species and conditions are intended to be further illustrate of the invention and not limit the reasonable scope thereof.

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. HPLC Condition A: reverse-phase HPLC can be carried out using a 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% acetonitrile containing 0.1% trifluoroacetic acid). Alternatively: HPLC Condition B: reverse-phase HPLC can be carried out using a Vydac C-18 column with gradient elution from 10% to 90% acetonitrile in water.

Example 1
{[N-(3-methylbutyl)carbamoyl]cyclopentyl}-N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carboxamide

(a) Methyl 1-[N-(3-methylbutyl)carbamoyl]cyclopentane-carboxylate

To 1-(methoxycarbonyl)cyclopentanecarboxylic acid (630 mg, 3.7 mmol) in CH₂Cl₂/DMF (5:1, 37 mL) at 0° C. was added HOBT (730 mg, 4.8 mmol) and EDC (920 mg, 4.8 mmol). The mixture was stirred for 10 min then 3-methylbutylamine (640 mg, 7.4 mmol) was added and stirring was continued for 1 h. The solution was poured into water and the layers separated. The aqueous layer was extracted with methylene chloride and the combined extracts were washed with water, 1N HCl, sat'd NaHCO₃, dried over magnesium sulfate, and concentrated to a glassy solid (800 mg, 90%). MS [M+H]⁺243.

(b) Methyl 1-[N-(3-methylbutyl)carbamoyl]cyclopentane-carboxylic acid

To a solution of methyl 1-[N-(3-methylbutyl)carbamoyl]cyclopentanecarboxylate (820 mg, 3.4 mmol) in 25 mL of THF cooled to 0° C. was added dropwise a solution of lithium hydroxide monohydrate (260 mg, 6.12 mmol) in 5.0 mL of water. The reaction mixture was stirred at rt for 16 h. THF was removed under reduced pressure to give a yellow oil which was diluted with 10 mL of 1N HCl. The aqueous phase was extracted with CH₂Cl₂(8×15 mL), and the extracts were combined, dried over Na₂SO₄, and concentrated to afford 700 mg (90%) of methyl 1-[N-(3-methylbutyl)carbamoyl]-cyclopentanecarboxylic acid as a white solid. MS [M+H]⁺ 228.

To 1-[N-(3-methylbutyl)carbamoyl]cyclopentane carboxylic acid (38 mg, 0.16 mmol) in CH₂Cl₂/DMF (5:1, 15 mL) at 0° C. was added HOBT (28 mg, 0.18 mmol) and EDC (34 mg, 0.18 mmol). The mixture was stirred for 10 min then 7-amino-5-methyl-7H-dibenzoazaperhydroepin-6-one (40 mg, 0.16 mmol) (obtained as the first eluting peak of a racemic mixture on a CHIRALCEL OD column with 20% iPrOH/Hexane with diethylamine) was added and stirring was continued for 1 h. The solution was poured into water and the layers separated. The aqueous layer was extracted with methylene chloride and the combined extracts were washed with water, 1N HCl, sat'd NaHCO₃, dried over magnesium sulfate, and concentrated to a glassy solid (67 mg, 94%). ¹H NMR (300 MHz, CD₃OD) δ 7.20-7.80 (m, 9H), 6.25 (m, 1H), 5.25 (d, 1H), 3.38 (s, 3H), 3.27 (m, 1H), 2.58-2.05 (m, 5H), 1.80-1.25 (m, 8H), 0.95, (m, 6H). MS [M+H]⁺ 448.

Example 2
{[N-(3-Methylbutyl)carbamoyl]cyclopentyl}-N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carboxamide

The title compound was prepared in a manner similar to that described for Example 1. The product was obtained as a solid. MS [M+H]⁺ 475.

Example 3
[(N-Butylcarbamoyl)cyclopentyl]-N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carboxamide

The title compound was prepared in a manner similar to that described for Example 1. The product was obtained as a solid. MS [M+H]⁺ 461.

Example 4
2-(3,5-Difluorophenyl)-N-{[N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclohexyl}-acetamide

(a) {[(tert-Butoxy)carbonylamino]cyclohexyl}-N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carboxamide

Diisopropylethylamine (2.5 mL, 15.0 mmol) and HATU (2.85 g, 7.5 mmol) were added to a solution of 1-[(tert-butoxy)carbonylamino]cyclohexanecarboxylic acid (1.75 g, 7.2 mmol) in CH₂Cl₂(10 mL) at 0° C. and stirred for 10 min. (S)-3-amino-1-methyl-5-phenyl-3H-benzoazepin-2-one (3.0 g, 6.0 mmol) was then added. The solution was allowed to warm to room temperature and stirred overnight. The reaction was quenched with water. The organic layer was separated and washed with a saturated solution of NaHCO₃, 20% citric acid, brine, dried over Na₂SO₄, filtered and concentrated to afford a white solid (2.98 g, 99%). This compound underwent no further purification: ¹H NMR (500 MHz, CD₃OD) δ 7.33-7.13 (m, 9H), 5.35 (s, 1H), 3.48 (s, 3H), 2.21-1.29 (m, 10H), 1.50, (s, 9H).

(b) (Aminocyclohexyl)-N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carboxamide

A saturated solution of HCl in EtOAc (50 mL) was added to a solution of {[(tert-butoxy)carbonylamino]cyclohexyl}-(S)-3-N-(1-methyl-2-oxo-5-phenyl(3H-benzoazepin-3-yl))carboxamide (2.9 g, 5.9 mmol) in EtOAc (75 mL) and stirred at room temperature overnight. The reaction was quenched with 1N NaOH (100 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered and concentrated to give a white solid (1.76 g, 77%). mp 106-110° C.; ¹H NMR (500 MHz, CD₃OD) δ 7.33-7.13 (m, 9H), 5.32 (s, 1H), 3.48 (s, 3H), 1.98-1.25 (m, 10H); CI MS m/z=391 [C₂₃H₂₆N₄O₂+H]⁺; HPLC 100%, t_r=9.17 min. (HPLC Conditions A).

(c) 2-(3,5-Difluorophenyl)-N-{[N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]-cyclohexyl}acetamide

Diisopropylethylamine (0.87 ml, 5.15 mmol) and HATU (979 mg, 2.58 mmol) were added to a solution of 2-(3,5-difluorophenyl)acetic acid (426 mg, 2.47 mmol) in CH₂Cl₂(40 mL) at 0° C. and stirred for 5 min. (Aminocyclohexyl)-(S)-3-N-(1-methyl-2-oxo-5-phenyl(3H-benzoazepin-3-yl))carboxamide (800 mg, 2.06 mmol) was then added, and the solution was allowed to warm to room temperature and stirred overnight. The reaction was quenched with water. The organic layer was separated and washed with a saturated solution of NaHCO₃, 20% citric acid, brine, dried over Na₂SO₄, filtered and concentrated to give a white solid. Further purification by flash column chromatography afforded the title compound (659 mg, 60%) as a white solid:

mp 126-129° C.; ¹H NMR (500 MHz, CD₃OD) δ 7.72-7.32 (m, 9H), 6.97 (d, 2H), 6.80 (t, 1H), 5.31 (s, 1H), 3.70 (s, 2H), 3.48 (s, 3H), 2.24-1.30 (m 10H); API MS m/z=545 [C₃₁H₃₀F₂N₄O₃+H]⁺; HPLC 99.5%, t_r=22.26 min. (HPLC Conditions A).

Example 5
2-(3,5-Difluorophenyl)-N-{[N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclopentyl}-acetamide

The title compound was prepared in a manner similar to that described for Example 4. The product was obtained as a solid. mp 112-117° C.; ¹H NMR (500 MHz, CD₃OD) δ 7.72-7.31 (m, 9H), 6.96 (d, 2H), 6.81 (t, 1H) 5.33 (s, 1H), 3.63 (s, 2H), 3.47 (s, 3H), 2.41-1.72 (m, 8H); API MS m/z=531 [C₃₀H₂₈F₂N₄O₃+H]⁺; HPLC 99.4%, t_r=21.23 min. (HPLC Conditions A).

Example 6
2-(3,5-Difluorophenyl)-N-{[N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclopropyl}-acetamide

The title compound was prepared in a manner similar to that described for Example 4. The product was obtained as a solid. mp 212-214° C.; ¹H NMR (500 MHz, CD₃OD) δ 7.71-7.30 (m, 9H), 6.98 (d, 2H), 6.81 (t, 1H), 5.28 (s, 1H), 3.65 (s, 2H), 3.48 (s, 3H), 1.48 (m, 2H), 1.08 (m, 2H); API MS m/z=503 [C₂₈H₂₄F₂N₄O₃+H]⁺; HPLC 97.7%, t_r=19.48 min. (HPLC Conditions A).

Example 7
3-Cyclopentyl-N-{[N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclohexyl}propanamide

The title compound was prepared in a manner similar to that described for Example 4. The product was obtained as a solid. mp 88-103° C.; ¹H NMR (500 MHz, CD₃OD) δ 7.71-7.30 (m, 9H), 5.28 (d, 1H), 3.51 (d, 3H), 2.39-0.82 (m, 23 H); CI MS m/z=516 [C₃₁H₃₈N₄O₃+H]⁺; HPLC 96.5%, t_r=14.79 min. (HPLC Conditions A).

Example 8
2-(3,5-Difluorophenyl)-N-{4-[N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carbamoyl](4-piperidyl)}acetamide

The title compound was prepared in a manner similar to that described for Example 4. The product was obtained as an oil. ¹H NMR (300 MHz, CD₃OD) δ 7.15-7.60 (m, 10H), 6.05-6.80 (m, 3H), 5.40 (d, 1H), 3.60 (s, 2H), 3.40 (s, 3H), 2.90 (m, 2H), 2.60 (m, 2H), 2.05, (m, 4H). MS [M+H]⁺ 546.

Example 9
Phenyl 4-[2-(3,5-difluorophenyl)acetylamino]-4-[N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]piperidine carboxylate

The title compound was prepared in a manner similar to that described for Example 4. The product was obtained as an oil. ¹H NMR (300 MHz, CD₃OD) δ 7.20-7.40 (m, 15H), 6.45-6.80 (m, 3H), 5.40 (d, 1H), 5.15 (s, 2H), 4.85 (s, 3H), 3.85 (m, 1H), 3.60 (s, 2H), 3.40 (s, 3H), 2.20, (m, 4H). MS [M+H]⁺ 680.

Example 10
4-Methyl-N-{[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}pentanamide

The title compound was prepared in a manner similar to that described for Example 4. This compound was made from the amino bisbenzazepine obtained as the first eluting peak of a racemic mixture on a CHIRALCEL OD column with 20% iPrOH/Hexane with diethylamine. The product was obtained as an oil. ¹H NMR (300 MHz, CD₃OD) δ 7.20-7.60 (m, 8H), 6.59 (s, 1H), 5.20 (d, 1H), 3.40 (s, 3H), 2.40-1.60 (m, 13H), 0.9, (d, 6H). MS [M+H]⁺ 448.

Example 11
N-{1-Methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}{[(phenylmethoxy)carbonylamino]-cyclopentyly}carboxamide

The title compound was prepared in a manner similar to that described for Example 4. This compound was made from the corresponding amino benzodiazepine that, as the CBz protected form, was the first eluting peak of the racemic mixture on a CHIRALCEL Aβ column using acetonitrile. The product was obtained as an oil. ¹H NMR (300 MHz, CD₃OD) δ 7.20-7.40 (m, 13H), 5.2 (s, 2H), 5.60 (m, 1H), 5.40 (d, 1H), 5.15 (s, 2H), 3.45 (s, 3H), 2.40 (m, 2H), 2.05-1.80 (m, 6H). MS [M+H]⁺ 579.

Example 12
(2S)—N-{[N-(1-{[3-(4-Fluorophenoxy)phenyl]methyl}-2-oxoazaperhydroepin-3-yl)carbamoyl]cyclopropyl}-2-hydroxy-4-methylpentanamide

The title compound was prepared in a manner similar to that described for Example 4. The product was obtained as an oil. ¹H NMR (300 MHz, CD₃OD) δ 7.00-6.70 (m, 8H), 4.45 (m, 5H), 4.15 (m, 1H), 3.10-3.40 (m, 2H), 2.00-1.00 (m, 12H), 0.90, (m, 6H). MS [M+H]+526.

Example 13
(2S)—N-{[N-(1-{[3-(4-Fluorophenoxy)phenyl]methyl}-2-oxoazaperhydroepin-3-yl)carbamoyl]cyclopentyl}-2-hydroxy-3-methylbutanamide

The title compound was prepared in a manner similar to that described for Example 4. The product was obtained as an oil. ¹H NMR (300 MHz, CD₃OD) δ 7.20-6.80 (m, 8H), 4.60 (m, 3H), 4.00 (d, 1H), 3.5 (m, 1H), 3.20 (m, 1H), 2.40-1.05 (m, 17H), 1.00 (d, 3H), 0.90 (d, 3H). MS [M+H]⁺ 540.

Example 14
2,2-Difluoro-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]-4-phenylbutanamide

The title compound was prepared in a manner similar to that described for Example 4 using the amino benzodiazepine employed in Example 1. The product was obtained as an oil. ¹H NMR (300 MHz, CD₃OD) δ 7.90-7.00 (m, 13H), 5.45 (d, 1H), 3.45 (s, 3H), 2.80 (m, 2H), 2.60-2.20 (m, 6H), 1.80-1.90 (m, 8H). MS [M+H]⁺ 627.

Example 15
N—[(N-{1-Methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]-3-(4-piperidyl)propanamide

The title compound was prepared in a manner similar to that described for Example 4 using the amino benzodiazepine employed in Example 1. The product was obtained as an oil. ¹H NMR (300 MHz, CD₃OD) δ 8.00-7.20 (m, 9H), 6.10 (s, 1H), 5.40 (d, 1H), 5.15 (s, 2H), 3.60 (m, 1H), 3.40 (3, 3H), 3.15 (m, 1H), 2.60-1.20 (m, 14H). MS [M+H]⁺ 584.

Example 16
(2S)-2-Hydroxy-4-methyl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]pentanamide

The title compound was prepared in a manner similar to that described for Example 4 using the amino benzodiazepine employed in Example 1. The product was obtained as an oil. MS [M+H]⁺ 559.

Example 17
3-Cyclopropyl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]propanamide

The title compound was prepared in a manner similar to that described for Example 4 using the amino benzodiazepine employed in Example 1. The product was obtained as an oil. ¹H NMR (300 MHz, CD₃OD) δ 7.60-7.20 (m, 8H), 5.40 (m, 1H), 3.45 (s, 3H), 2.70 (s, 2H), 2.40 (m, 4H), 2.05-1.09 (m, 14H), 0.4 (m, 1H), 0.00 (m, 1H). MS [M+H]⁺ 541.

Example 18
(Aminocyclopentyl)-N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carboxamide

The title compound was prepared in a manner similar to that described for Example 4. This compound was made from the BZD amine that, as a CBz protected form, was the first peak of the racemic mixture on the CHIRALCEL Aβ column with acetonitrile. The product was obtained as an oil. ¹H NMR (300 MHz, CD₃OD) δ 7.20-7.80 (m, 8H), 5.45 (m, 1H), 3.45 (s, 3H), 2.20 (m, 3H), 2.00-1.60 (m, 5H). MS [M+H]⁺ 445.

Example 19
{[(Aminocyclopentyl)carbonylamino]cyclopentyl}-N—((S)1-methyl-2-oxo-5-phenyl(3H-benzo[f]1,4-diazepin-3-yl))carboxamide

The title compound was prepared in a manner similar to that described for Example 4. The product was obtained as an oil. ¹H NMR (300 MHz, CD₃OD) δ 7.20-7.60 (m, 9H), 5.45 (d, 1H), 3.45 (s, 3H), 2.80-2.00 (m, 8H), 1.90-1.50 (m, 8H). MS [M+H]⁺ 445.

Example 20
(2R)-2-Hydroxy-3-imidazol-2-yl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]propanamide

The title compound was prepared in a manner similar to that described for Example 4 using the amino benzodiazepine employed in Example 1. The product was obtained as an oil. ¹H-NMR (CDCl₃) 9.16 (d, 1H), 7.69-7.52 (m, 5H), 7.33 (d, 1H), 7.24-7.15 (m, 3H), 5.45 (d, 1H), 3.42 (s, 3H), 2.24-2.14 (m, 3H), 2.11-1.84 (m, 1H), 1.83-1.72 (m, 4H), 1.66-1.56 (m, 2H); MS [M+H]⁺ 583.

Example 21
2-Ethoxy-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]acetamide

The title compound was prepared in a manner similar to that described for Example 4 using the amino benzodiazepine employed in Example 1. The product was obtained as an oil. ¹H-NMR (CDCl₃) 8.17 (d, 1H), 7.76-7.60 (m, 5H), 7.40 (d, 1H), 7.32-7.23 (m, 1H), 6.99 (s, 1H), 5.52 (d, 1H), 4.01 (d, 2H), 3.67-3.60 (q, 2H), 3.48 (s, 3H), 2.48-2.40 (m, 2H), 2.14-2.08 (m, 2H), 1.89-1.83 (m, 3H), 1.64 (s, 2H), 1.29 (s, 3H); MS [M+H]⁺ 531.

Example 22
3-Cyclopentyl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]propanamide

The title compound was prepared in a manner similar to that described for Example 4 using the amino benzodiazepine employed in Example 1. The product was obtained as an oil. ¹H-NMR (CDCl₃) 8.00 (d, 1H), 7.68-7.51 (m, 5H), 7.32 (d, 1H), 7.23-7.17 (m, 2H), 5.85 (s, 1H), 5.41 (d, 1H), 3.39 (s, 3H), 2.42-2.22 (m, 2H), 2.20 (t, 2H), 2.10-1.90 (m, 2H), 1.76-1.44 (m, 13H), 1.10-1.0 (m, 2H); MS [M+H]⁺569.

Example 23
(2S)-2-Hydroxy-3-methyl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]butanamide

The title compound was prepared in a manner similar to that described for Example 4 using the amino benzodiazepine employed in Example 1. The product was obtained as an oil. ¹H-NMR (CDCl₃) 8.50 (d, 1H), 7.76-7.61 (m, 4H), 7.41 (d, 1H), 7.32-7.28 (m, 1H), 7.03 (s, 1H), 5.53-5.51 (m, 1H), 4.06 (d, 1H), 3.48 (s, 3H), 2.57-2.35 (m, 2H), 2.30-2.10 (m, 2H), 2.09-1.90 (m, 1H), 1.80-1.70 (m, 5H), 1.05 (d, 3H), 0.94 (d, 3H); MS [M+H]⁺ 545.

Example 24
(2S)-2-Cyclohexyl-2-hydroxy-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]acetamide

The title compound was prepared in a manner similar to that described for Example 4 using the amino benzodiazepine employed in Example 1. The product was obtained as an oil. ¹H-NMR (CDCl₃) 8.04 (d, 1H), 7.67-7.51 (m, 4H), 7.31 (d, 1H), 7.23-7.18 (m, 1H), 7.02 (s, 1H), 5.42 (d, 1H), 3.94 (m, 1H), 3.78 (s, 3H), 2.42-2.25 (m, 2H), 2.18-1.90 (m, 2H), 1.80-1.65 (m, 9H), 1.30-1.00 (m, 6H); MS [M+H]⁺ 585.

Example 25
(2R)-2-Cyclohexyl-2-hydroxy-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]acetamide

The title compound was prepared in a manner similar to that described for Example 4 using the amino benzodiazepine employed in Example 1. The product was obtained as an oil. ¹H-NMR (CDCl₃) 8.17 (d, 1H), 7.67-7.52 (m, 4H), 7.32 (d, 1H), 7.23-7.15 (m, 1H), 6.89 (s, 1H), 5.45 (d, 1H), 3.92 (d, 1H), 3.39 (s, 3H), 2.45-2.25 (m, 2H), 2.10-1.95 (m, 2H), 1.80-1.50 (m, 10H), 1.25-1.00 (m, 6H); MS [M+H]⁺ 585.

Example 26
(2S)-2-Amino-4-methyl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]pentanamide

The title compound was prepared in a manner similar to that described for Example 4 using the amino benzodiazepine employed in Example 1. The product was obtained as an oil. ¹H-NMR (CDCl₃) 8.95 (s, 1H), 7.79-7.63 (m, 5H), 7.40-7.30 (m, 2H), 5.46 (s, 1H), 4.20 (d, 2H), 4.0-3.90 (m, 1H), 3.51 (s, 3H), 2.40-2.20 (m, 2H), 2.10 2.00 (m, 2H), 1.90-1.70 (m, 4H), 1.40-1.20 (m, 2H), 1.10-1.00 (m, 3H), 1.00-0.90 (m, 3H); MS [M+H]⁺ 559.

Example 27
[(Cyclohexylcarbonylamino)cyclopentyl]-N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carboxamide

The title compound was prepared in a manner similar to that described for Example 4 using the amino benzodiazepine employed in Example 1. The product was obtained as an oil. ¹H-NMR (CDCl₃) 8.10 (d, 1H), 7.75-7.62 (m, 3H), 7.42-7.39 (m, 3H), 7.30-7.20 (m, 1H), 6.11 (s, 1H), 5.47 (d, 1H), 3.46 (s, 3H), 2.50-2.45 (m, 2H), 2.30-2.10 (m, 1H), 2.09-1.75 (m, 9H), 1.70-1.60 (m, 1H), 1.50-1.40 (m, 2H), 1.39-1.20 (m, 3H); MS [M+H]⁺ 555.

Example 29
{[N-(3-Methylbutyl)carbamoyl]cyclopentyl}-N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carboxamide

The title compound was prepared in a manner similar to that described for Example 4 using the amino benzodiazepine employed in Example 1. The product was obtained as an oil. ¹H NMR (300 MHz CDCl₃) 7.78-7.60 (m, 5H), 7.48-7.22 (m, 3H), 5.47 (d, 1H), 3.49 (s, 3H), 3.30 (m, 2H), 2.38-2.22 (m, 4H), 1.84-1.38 (m, 7H), 0.90 (d, 6H). MS [M+H]⁺ 543.

Example 30
4-Methyl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]pentanamide

The title compound was prepared in a manner similar to that described for Example 4 using the amino benzodiazepine employed in Example 1. The product was obtained as an oil. ¹H NMR (300 MHz CDCl₃) 7.78-7.56 (m, 5H), 7.42-7.20 (m, 3H), 5.46 (d, 1H), 3.44 (s, 3H), 2.48-2.20 (m, 4H), 2.05 (m, 2H), 1.80 (m, 4H), 1.58 (m, 3H), 0.88 (d, 6H). MS [M+H]⁺543.

Example 31
(2S)-2-Hydroxy-4-methyl-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]pentanamide

The title compound was prepared in a manner similar to that described for Example 4 using the amino benzodiazepine employed in Example 1. The product was obtained as an oil. ¹H NMR (300 MHz CDCl₃) 7.78-7.58 (m, 5H), 7.43-7.20 (m, 3H), 5.49 (d, 1H), 4.17 (m, 1H), 3.45 (s, 3H), 2.40 (m, 2H), 2.10 (m, 2H), 1.92-1.50 (m, 8H), 0.92 (m, 6H). MS [M+H]⁺ 559.

Example 32
3-Methoxy-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]propanamide

The title compound was prepared in a manner similar to that described for Example 4 using the amino benzodiazepine employed in Example 1. The product was obtained as an oil. ¹H NMR (300 MHz CDCl₃) 7.78-7.56 (m, 5H), 7.40-7.20 (m, 3H), 5.51 (d, 1H), 3.72 (m, 2H), 3.44 (s, 3H), 3.39 (s, 3H), 2.58-2.30 (m, 4H), 2.02 (m, 2H), 1.88 (m, 4H). MS [M+H]⁻531.

Example 33
(2S)-2-Hydroxy-N—[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]-3-phenylpropanamide

The title compound was prepared in a manner similar to that described for Example 4 using the amino benzodiazepine employed in Example 1. The product was obtained as an oil. ¹H NMR (300 MHz CDCl₃) 7.72-7.57 (m, 5H), 7.40-7.20 (m, 3H), 5.48 (d, 1H), 4.37 (m, 1H), 3.42 (s, 3H), 3.20 (q, 1H), 2.97 (q, 1H), 2.38 (m, 2H), 1.96 (m, 2H), 1.80-1.52 (m, 4H). MS [M+H]⁺593.

Example 34
N—[(N-{1-Methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]-2-(phenylmethoxy)acetamide

The title compound was prepared in a manner similar to that described for Example 4 using the amino benzodiazepine employed in Example 1. The product was obtained as an oil. ¹H NMR (300 MHz CDCl₃) 7.74-7.55 (m, 5H), 7.40-7.20 (m, 3H), 5.48 (d, 1H), 4.61 (q, 2H), 4.12 (q, 2H), 3.44 (s, 3H), 2.42 (m, 2H), 2.05 (m, 2H), 1.80 (m, 4H). MS [M+H]⁺ 593.

Example 35
(2S)-2-Hydroxy-3-methyl-N-{[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}-butanamide

The title compound was prepared in a manner similar to that described for Example 4 using the amino bisbenzazepine employed in Example 10. The product was obtained as an oil. ¹H NMR (300 MHz CDCl₃) 7.64-7.35 (m, 8H), 5.25 (d, 1H), 4.06 (d, 1H), 3.35 (s, 3H), 2.42-2.05 (m, 6H), 1.80 (m, 4H), 1.05 (d, 3H), 0.95 (d, 3H). MS [M+H]⁺ 450.

Example 36
(2S)-2-Hydroxy-4-methyl-N-{[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}pentanamide

The title compound was prepared in a manner similar to that described for Example 4 using the amino bisbenzazepine employed in Example 10. The product was obtained as an oil. ¹H NMR (300 MHz CDCl₃) 7.64-7.32 (m, 8H), 5.24 (d, 1H), 4.20 (q, 1H), 3.34 (s, 3H), 2.38 (m, 2H), 2.20-1.60 (m, 9H), 0.97 (m, 6H). MS [M+H]⁺ 464.

Example 37
3-Cyclopentyl-N-{[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}propanamide

Example 38
(2S)-2-Cyclohexyl-2-hydroxy-N-{[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}-acetamide

The title compound was prepared in a manner similar to that described for Example 4 using the amino bisbenzazepine employed in Example 10. The product was obtained as an oil. ¹H NMR (300 MHz CDCl₃) 7.62-7.36 (m, 8H), 5.24 (d, 1H), 3.98 (d, 1H), 3.33 (s, 3H), 2.42-1.04 (m, 19H). MS [M+H]⁺ 490.

Example 39
3-Cyclopropyl-N-{[N—((S)-5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}-propanamide

The title compound was prepared in a manner similar to that described for Example 4. The product was obtained as an oil. ¹H NMR (300 MHz CDCl₃) 7.56-7.24 (m, 8H), 5.16 (d, 1H), 3.27 (s, 3H), 2.38-2.15 (m, 4H), 2.10-1.82 (m, 2H), 1.78-1.42 (m, 6H), 0.64 (m, 1H), 0.36 (m, 2H), 0.02 (m, 2H). MS [M+H]⁺ 446.

Example 40
N-{[N-(1-Butyl-5-cyclopentyl-2-oxo(3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclopentyl}-4-methylpentanamide

The amino benzodiazepine core was made in a manner similar to that described in the Scheme 6. The title compound was prepared in a manner similar to that described for Example 4. The product was obtained as an oil. ¹H NMR (300 MHz CDCl₃) 7.60-7.22 (m, 4H), 5.25 (d, 1H), 4.36 (m, 1H), 3.56 (m, 1H), 3.31 (m, 1H), 2.40-0.78 (m, 34H). MS [M+H]⁺ 509.

Example 41
N-{[N-(5-Cyclopentyl-1-methyl-2-oxo(3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclopentyl}-4-methylpentanamide

The amino benzodiazepine core was made in a manner similar to that described in the Scheme 6. The title compound was prepared in a manner similar to that described for Example 4. The product was obtained as an oil. ¹H NMR (300 MHz CDCl₃) 7.58-7.20 (m, 4H), 5.30 (d, 1H), 3.38 (s, 3H), 3.30 (m, 1H), 2.40-1.20 (m, 21H), 0.89 (d, 6H). MS [M+H]⁺467.

Example 42
(2S)-2-Hydroxy-3-methyl-N—({N-[2-oxo-1-benzyl(3H,4H,5H-benzo[f]azaperhydroepin-3-yl)]carbamoyl}cyclopentyl) butanamide

The amino benzoazepine core was made in a manner similar to that described in J. Med. Chem. 1999, 42, 2621. The title compound was prepared in a manner similar to that described for Example 4. The product was obtained as an oil. ¹H NMR (300 MHz CDCl₃) 7.34-7.10 (m, 9H), 5.16 (m, 1H), 4.76 (m, 1H), 4.42 (m, 1H), 3.94 (m, 1H), 2.64-1.64 (m, 13H), 1.00-0.86 (m, 6H). MS [M+H]⁺ 478.

Example 43
(2S)-4-Methyl-N-{[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}-2-[(propylsulfonyl)amino]pentanamide

The title compound was prepared in a manner similar to that described for Example 4 using the amino bisbenzazepine employed in Example 10. The product was obtained as an oil. ¹H NMR (300 MHz CDCl₃) 7.62-7.32 (m, 8H), 5.40 (d, 1H), 5.24 (d, 1H), 4.02 (m, 1H), 3.34 (s, 3H), 2.98 (m, 2H), 2.42-1.58 (m, 13H), 0.94-0.85 (m, 9H). MS [M+H]⁺ 569.

Example 44
(2S)-2-Amino-4-methyl-N-{[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}pentanamide

The title compound was prepared in a manner similar to that described for Example 4 using the amino bisbenzazepine employed in Example 10. The product was obtained as an oil. ¹H NMR (300 MHz CDCl₃) 7.60-7.30 (m, 8H), 5.22 (d, 1H), 3.32 (s, 3H), 3.08 (m, 1H), 2.48 (s, 3H), 2.46-1.45 (m, 11H), 0.98-0.92 (q, 6H). MS [M+H]⁺ 477.

Example 45
2,2-Difluoro-4-methyl-N-{[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}-pentanamide

The title compound was prepared in a manner similar to that described for Example 4 using the amino bisbenzazepine employed in Example 10. The product was obtained as an oil. ¹H NMR (300 MHz CDCl₃) 7.62-7.30 (m, 8H), 5.23 (d, 1H), 3.34 (s, 3H), 2.42-1.80 (m, 11H), 1.00 (d, 6H). MS [M+H]⁺ 484.

Example 56
4-Methyl-N-{[N-(6-oxo(5H,7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}pentanamide

The title compound was prepared in a manner similar to that described for Example 4. The product was obtained as an oil. ¹H NMR (300 MHz, CD₃OD): δ 7.91 (d, J=6.7 Hz, 1H), 7.63 (m, 1H), 7.51-7.28 (m, 7H), 7.08 (d, J=7.0 Hz, 1H), 5.84 (s, 1H), 5.25 (d, J=6.7 Hz, 1H), 2.41-0.89 (m, 19H); ESI MS m/z=434 [C₂₆H₃₁N₃O₃+H]⁺.

Example 57
N—({N-[5-(3,3-Dimethyl-2-oxobutyl)-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl)]carbamoyl}cyclopentyl)-4-methylpentanamide

To a solution of 4-methyl-N-{[N-(6-oxo(5H,7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}pentanamide (540 mg, 1.3 mmol), in DMF (25 mL) was added K₂CO₃(0.52 g, 3.7 mmol) and bromopinacolone (0.45 g, 2.5=mol), and the solution was allowed to stir for 40 h at room temperature. The contents of the flask were partitioned between EtOAc and a 5% LiCl solution (150 mL each), the organic phase washed with 5% LiCl (2×50 mL), dried over anhydrous Na₂SO₄and concentrated to yield a white solid. This was further purified by column chromatography [silica gel, EtOAc/hexanes (35:6)] to yield the title compound (340 mg, 51%) as a white solid. The title compound were separated by chiral HPLC using the following conditions: Column, Chiralpak AD column (5 cm×50 cm); Eluent, 96:4 Hexanes/2-Propanol; Flow rate, 100 mL/min; Monitoring wavelength, 220 nm.

Enantiomer A: 158 mg: mp 126-130° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.89 (d, J=6.7 Hz, 1H), 7.62-7.13 (m, 8H), 5.82 (s, 1H), 5.35 (d, J=7.4 Hz, 1H), 4.62 (q b, J=14.1 Hz, 2H), 2.47-1.59 (m, 13H), 1.22 (s, 9H), 0.92 (d, J=5.8 Hz, 6H); IR (KBr) 3410, 2958, 2475, 1724, 1663 cm⁻¹; ESI MS m/z=532 [C₃₂H₄₁N₃O₄+H]⁺; HPLC 97.8%, t_r=24.83 min. (HPLC Conditions A).

Enantiomer B: 165 mg; mp 126-130° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.89 (d, J=6.7 Hz, 1H), 7.62-7.13 (m, 8H), 5.82 (s, 1H), 5.35 (d, J=7.4 Hz, 1H), 4.62 (q_ab, J=14.1 Hz, 2H), 2.47-1.59 (m, 13H), 1.22 (s, 9H), 0.92 (d, J=5.8 Hz, 6H); IR (KBr) 3410, 2958, 2475, 1724, 1663 cm⁻¹; ESI MS m/z 532 [C₃₂H₄₁N₃O₄+H]⁺; HPLC 97.8%, t_r=24.83 min. (HPLC Conditions A).

Example 58
4-Methyl-N—[(N-{6-oxo-5-[(3-phenoxyphenyl)methyl](7H-dibenzo[d,f]azaperhydroepin-7-yl)}carbamoyl)cyclopentyl]pentanamide

The title compound was prepare in a manner similar to that described for Example 57. The product was obtained as a white solid: mp 94-100° C.; ¹H NMR (500 MHz, CDCl₃) δ 7.99 (d, J=6.9 Hz, 1H), 7.58-6.43 (m, 17H), 5.82 (a, 1H), 5.39 (d, J=7.4 Hz, 1H), 5.12 (q_ab, J=14.5 Hz, 2H), 2.47-1.57 (m, 13H), 0.82 (d, J=6.1 Hz, 6H); IR (KBr) 3332, 2955, 1660, 1584, 1487 cm⁻¹; ESI MS m/z=616 [C₃₉H₄₁N₃O₄+H]; HPLC 99.4%, t_r=19.54 min. (HPLC Conditions A).

Example 59
N-{[N-(5-Butyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}-4-methylpentanamide

The title compound was prepared in a manner similar to that described for Example 57. The product was obtained as a white solid. The enantiomers were separated by chiral HPLC using the following conditions: Column, Chiralcel OD column (5 cm×50 cm); Eluent, 95:5 Hexanes/2-Propanol; Flow rate, 100 mL/min; Monitoring wavelength, 270 nm.

Enantiomer A: 197 mg: mp 123-126° C.; ¹H NMR (500 MHz, CDCl₃) δ 7.99 (d, J=7.0 Hz, 1H), 7.58-6.43 (m, 8H), 5.91 (s, 1H), 5.26 (d, J=7.4 Hz, 1H), 4.29 (m, 2H), 3.52 (m, 2H), 2.43-1.19 (m, 15H), 0.95 (d, J=6.1 Hz, 6H), 0.62 (m, 3H); IR (KBr) 3325, 2957, 2871, 1655, 1498 cm⁻¹; ESI MS m/z=490 [C₃₀H₃₉N₃O₃+H]⁺; HPLC 100%, t_r=20.25 min. (HPLC Conditions A).

Enantiomer B: 167 mg: mp 110-115° C.; ¹H NMR (500 MHz, CDCl₃) δ 7.99 (d, J=7.0 Hz, 1H), 7.58-6.43 (m, 8H), 5.91 (s, 1H), 5.26 (d, J=7.4 Hz, 1H), 4.29 (m, 2H), 3.52 (m, 2H), 2.43-1.19 (m, 15H), 0.95 (d, J=6.1 Hz, 6H), 0.62 (m, 3H); IR (KBr) 3325, 2957, 2871, 1655, 1498 cm⁻¹; ESI MS m/z=490 [C₃₀H₃₉N₃O₃+H]⁻; HPLC 100%, t_r=20.26 min. (HPLC Conditions A).

Example 60
4-Methyl-N—({N-[6-oxo-5-benzyl(7H-dibenzo[d,f]azaperhydroepin-7-yl)]carbamoyl}cyclopentyl)pentanamide

The title compound was prepared in a manner similar to that described for Example 57. The product was obtained as a white solid:

mp 103-106° C.; ¹H NMR (500 MHz, CDCl₃) δ 8.01 (d, J=6.8 Hz, 1H), 7.52-7.25 (m, 8H), 7.05 (m, 3H), 6.78 (m, 2H), 5.84 (s, 1H), 5.36 (d, J=7.4 Hz, 1H), 5.04 (q_ab, J=14.7 Hz, 2H), 2.41-1.26 (m, 13H), 0.91 (d, J=5.8 Hz, 6H); IR (KBr) 3325, 2956, 1655, 1498, 1396 cm¹; ESI MS m/z=524 [C₃₃H₃₇N₃O₃+H]⁺; HPLC 100%, t_r=27.04 min. (HPLC Conditions A).

Example 61
N—({N-[5-(tert-Butyl)-1-methyl-2-oxo(3H-benzo[f]1,4-diazepin-3-yl)]carbamoyl}cyclopentyl)-4-methylpentanamide

c) Preparation of 25

To a stirred solution of 23 (see Scheme 6) (1.0 equiv) in CH₂Cl₂(0.1 M) was added a 30% solution of HBr in acetic acid (16 equiv). The mixture was stirred for 14 h. The reaction mixture was concentrated in vacuo and dissolved in EtOAc and water and separated. The aqueous layer was made basic using 6 N NaOH and was extracted with CH₂Cl₂. The organic extracts were washed with brine, dried over Na₂SO₄, filtered and concentrated. The resulting solid was dissolved in CH₂Cl₂and added to a stirring solution of the acid 24 (1.2 equiv), EDC-HCl (1.5 equiv), HOBt (1.5 equiv), and DIPEA (5.0 equiv) in CH₂Cl₂(0.15 M). The reaction was stirred overnight, quenched with water, washed with 20% citric acid (3×), sat NaHCO₃(2×), brine, dried over Na₂SO₄, filtered and concentrated. Crude material was recrystallized from EtOAc and Et₂O to give 25 (4.4 g, 95%) as a white powder: ¹H NMR (500 MHz, CDCl₃) δ 7.71-6.98 (m, 6H), 5.87 (s, 1H), 5.29 (d, 1H), 2.38 (m, 2H), 2.21 (t, 2H) 2.01 (m, 2H), 1.52 (m, 7H), 1.23 (s, 9H), 0.88 (d, 6H).

d) Preparation of Example 61.

To a suspension of 25 (1 equiv) and freshly powdered K₂CO₃(3.0 equiv) in DMF (0.05 M) was added methyl iodide (1.5 equiv). The mixture was stirred (5 h). To the reaction was added EtOAc and water and the layers separated. The organic layer was washed with 5% LiCl (2×), brine, dried over Na₂SO₄, filtered and concentrated. The resulting material was dissolved in Et₂O and concentrated in vacuo providing N—({N-[5-(tert-butyl)-1-methyl-2-oxo(3H-benzo[f]1,4-diazepin-3-yl)]carbamoyl}-cyclopentyl)-4-methylpentanamide (60 mg, 66%) as a white powder: mp 175-178° C.; ¹H NMR (500 MHz, CDCl₃) δ 7.71-7.17 (m, 5 H), 5.89 (s, 1H), 5.23 (d, 1H), 3.34 (s, 3H), 2.41-2.29 (m, 3H), 2.21 (m, 2H), 2.04 (m, 3H), 1.80 (m, 4H), 1.60 (m, 1H), 1.18 (s, 9 H), 0.90 (d, 6H); ESI MS m/z=455 [C₂₆H₃₈N₄O₃+H]⁺; IR (KBr)=3324, 2958, 1677, 1508, 1366, 1197 cm⁻¹; HPLC 96.8%, t_r=15.75 min. (HPLC Conditions A).

Example 62
N—({N-[5-(tert-Butyl)-1-butyl-2-oxo(3H-benzo[f]1,4-diazepin-3-yl)]carbamoyl}cyclopentyl)-4-methylpentanamide

The title compound was prepared in a manner similar to that described for Example 62. The product was obtained as a white powder (450 mg, 70%): mp 175-177° C.; ¹H NMR (500 MHz, CDCl₃) δ 7.71-7.13 (m, 5H), 5.89 (s, 1H), 5.20 (d, 1 H), 4.36 (m, 1H), 3.50 (m, 1H), 2.32 (m, 3H) 2.20 (m, 2 H), 2.02 (m, 3H), 1.80 (m, 4H), 1.57 (m, 1H), 1.35 (m, 2 H) 1.26 (s, 9H), 1.21 (m, 2H), 0.89 (d, 6H), 0.83 (t, 3 H); ESI MS m/z=497 [C₂₉H₄₄N₄O₃+H]⁺; IR (KBr)=3321, 2959, 2363, 1676, 1508, 1365 cm⁻¹; HPLC 95.4%, t_r=19.69 min. (HPLC Conditions A).

Example 63
N—({N-[5-Butyl-2-oxo-1-(2-pyridylmethyl)(3H-benzo[f]1,4-diazepin-3-yl)]carbamoyl}cyclopentyl)-4-methylpentanamide

The title compound was prepared in a manner similar to that described for Example 62. The product was obtained as a white powder: mp 63-67° C.; ¹H NMR (CDCl₃) δ 8.46-7.11 (m, 8H), 5.89 (s, 1H), 5.40 (d, J=6.87 Hz, 1H), 5.28 (d, J=15.77 Hz, 1H), 5.12 (d, J=15.82 Hz, 1H), 2.74 (m, 2 H), 2.43-0.77 (m, 27H); ESI MS m/z=532 [C₃₁H₄₁N₅O₃+H]⁺; IR (KBr) 3310 (br.), 1670 cm⁻¹; HPLC>95% % t_r=17.07 min. (HPLC Conditions A). Anal. Calcd for [C₃₁H₄₁N₅O₃.0.5H₂O]: C, 68.86; H, 7.83; N, 12.95. Found: C, 68.73; H, 7.86; N, 12.79.

Tables 1-4 below provide representative Examples of the compounds of Formula (I) of the present invention.

TABLE 1

Ex#
R³
L
C
-WXYZ
R¹¹

2
3-Me-butyl
NHC(═O)
cyclopentyl
Me
phenyl

3
n-butyl
NHC(═O)
cyclopentyl
Me
phenyl

4
3,5-diF-benzyl
C(═O)NH
cyclohexyl
Me
phenyl

5
3,5-diF-benzyl
C(═O)NH
cyclopentyl
Me
phenyl

6
3,5-diF-benzyl
C(═O)NH
cyclopropyl
Me
phenyl

7
cyclopentyl ethyl
C(═O)NH
cyclohexyl
Me
phenyl

8
3,5-diF-benzyl
C(═O)NH
4-piperidyl
Me
phenyl

9
3,5-diF-benzyl
C(═O)NH
N-benzyloxy-
Me
phenyl

carbonyl-4-piperidyl

11
benzyl
O—C(═O)NH
cyclopentyl
Me
4-CF₃-phenyl

14
3-phenyl-1,1-
C(═O)NH
cyclopentyl
Me
4-CF₃-phenyl

diF-propyl

15
2-(4-piperidyl)
C(═O)NH
cyclopentyl
Me
4-CF₃-phenyl

ethyl

16
1-hydroxy-3-
C(═O)NH
cyclopentyl
Me
4-CF₃-phenyl

Me-butyl

17
2-cyclopropyl-ethyl
C(═O)NH
cyclopentyl
Me
4-CF₃-phenyl

19
1-amino cyclopentyl
C(═O)NH
cyclopentyl
Me
phenyl

20
1-hydroxy-2-
C(═O)NH
cyclopentyl
Me
4-CF₃-phenyl

imidazol-2-yl-ethyl

21
ethyoxy-methyl
C(═O)NH
cyclopentyl
Me
4-CF₃-phenyl

22
2-cyclopentyl-ethyl
C(═O)NH
cyclopentyl
Me
4-CF₃-phenyl

23
1-hydroxy-2-Me-
C(═O)NH
cyclopentyl
Me
4-CF₃-phenyl

propyl

24*
1-hydroxy-1-
C(═O)NH
cyclopentyl
Me
4-CF₃-phenyl

cyclohexyl-methyl

25*
1-hydroxy-1-
C(═O)NH
cyclopentyl
Me
4-CF₃-phenyl

cyclohexyl-methyl

26
1-NH₂-3-Me-
C(═O)NH
cyclopentyl
Me
4-CF₃-phenyl

butyl

27
cyclohexyl
C(═O)NH
cyclopentyl
Me
4-CF₃-phenyl

29
3-Me-butyl
NHC(═O)
cyclopentyl
Me
4-CF₃-phenyl

30
3-Me-butyl
C(═O)NH
cyclopentyl
Me
4-CF₃-phenyl

31
1-hydroxy-3-Me-
C(═O)NH
cyclopentyl
Me
4-CF₃-phenyl

butyl

32
2-methoxy-ethyl
C(═O)NH
cyclopentyl
Me
4-CF₃-phenyl

33
1-hydroxy-2-phenyl-
C(═O)NH
cyclopentyl
Me
4-CF₃-phenyl

ethyl

34
benzyloxy-methyl
C(═O)NH
cyclopentyl
Me
4-CF₃-phenyl

39
2-cyclopropyl-ethyl
C(═O)NH
cyclopentyl
Me
phenyl

40
3-Me-butyl
C(═O)NH
cyclopentyl
n-butyl
cyclopentyl

41
3-Me-butyl
C(═O)NH
cyclopentyl
Me
cyclopentyl

61
3-Me-butyl
C(═O)NH
cyclopentyl
Me
t-butyl

62
3-Me-butyl
C(═O)NH
cyclopentyl
n-butyl
t-butyl

63
3-Me-butyl
C(═O)NH
cyclopentyl
2-
n-butyl

pyridyl-

methyl

*stereoisomers

TABLE 2

Ex. #
R³
L
C
Z-Y-X-W-

1
3-Me-butyl
NHC(═O)
cyclopentyl
Me

10
3-Me-butyl
C(═O)NH
cyclopentyl
Me

35
1-hydroxy-2-Me-
C(═O)NH
cyclopentyl
Me

propyl

36
1-hydroxy-3-Me-
C(═O)NH
cyclopentyl
Me

butyl

37
2-cyclopentyl-ethyl
C(═O)NH
cyclopentyl
Me

38
1-hydroxy-1-
C(═O)NH
cyclopentyl
Me

cyclohexyl-methyl

43
1-(propyl-
C(═O)NH
cyclopentyl
Me

sulfamide)-3-Me-

butyl

44
1-(N-Me-amino)-3-
C(═O)NH
cyclopentyl
Me

Me-butyl

45
1,1-diF-3-Me-butyl
C(═O)NH
cyclopentyl
Me

56
3-Me-butyl
C(═O)NH
cyclopentyl
H

57
3-Me-butyl
C(═O)NH
cyclopentyl
3,3-dimethyl-

2-oxobutyl

58
3-Me-butyl
C(═O)NH
cyclopentyl
3-phenoxy-

benzyl

59
3-Me-butyl
C(═O)NH
cyclopentyl
n-butyl

60
3-Me-butyl
C(═O)NH
cyclopentyl
benzyl

TABLE 3

Ex. #
R³
L
C
Z-Y-X-W-

12
1-hydroxy-3-Me-
C(═O)NH
cyclopropyl
3-(4-F-phenoxy)-

butyl

benzyl

13
1-hydroxy-3-Me-
C(═O)NH
cyclopentyl
3-(4-F-phenoxy)-

propyl

benzyl

TABLE 4

Ex. #
R³
L
C
Z-Y-X-W-

42
1-hydroxy-2-Me-
C(═O)NH
cyclopentyl
benzyl

propyl

Utility

Aβ production has been implicated in the pathology of Alzheimer's Disease (Aβ). The compounds of the present invention have utility for the prevention and treatment of Aβ by inhibiting Aβ production. Methods of treatment target formation of Aβ production through the enzymes involved in the proteolytic processing of β amyloid precursor protein. Compounds that inhibit β or γ secretase activity, either directly or indirectly, control the production of Aβ. Such inhibition of β or γ secretases reduces production of Aβ, and is expected to reduce or prevent the neurological disorders associated with Aβ protein, such as Alzheimer's Disease.

Cellular screening methods for inhibitors of Aβ production, testing methods for the in vivo suppression of Aβ production, and assays for the detection of secretase activity are known in the art and have been disclosed in numerous publications, including J. Med. Chem. 1999, 42, 3889-3898, PCT publication number WO 98/22493, EPO publication number 0652009, U.S. Pat. No. 5,703,129 and U.S. Pat. No. 5,593,846; all hereby incorporated by reference.

The compounds of the present invention have utility for the prevention and treatment of disorders involving Aβ production, such as cerebrovascular disorders.

Compounds of Formula (I) are expected to possess 7-secretase inhibitory activity. The γ-secretase inhibitory activity of the compound 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 γ-secretase, as determined by the Aβ immunoprecipitation assay.

Compounds provided by this invention should also be useful as a standard and reagent in determining the ability of a potential pharmaceutical to inhibit Aβ production. These would be provided in commercial kits comprising a compound of this invention.

As used herein “μg” denotes microgram, “mg” denotes milligram, “g” denotes gram, “μL” “μL” denotes microliter, “mL” denotes milliliter, “L” denotes liter, “nM” denotes nanomolar, “μM” denotes micromolar, “mM” denotes millimolar, “M” denotes molar, “nm” denotes nanometer, “SDS” denotes sodium dodecyl sulfate, and “DMSO” denotes dimethyl sulfoxide, and “EDTA” denotes ethylenediaminetetraacetic acid.

A compound is considered to be active if it has an IC₅₀or K_ivalue of less than about 100 μM for the inhibition of Aβ production. Preferrably the IC₅₀or K_ivalue is less than about 10 μM; more preferrably the IC₅₀or K_ivalue is less than about 0.1 μM. The present invention has been shown to inhibit Aβ protein production with an IC₅₀or K_ivalue of less than 100 μM.

β Amyloid Precursor Protein Accumulation Assay

A novel assay to evaluate the accumulation of Aβ 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 immunoprecipitation.

The effect of test compounds on the accumulation of Aβ 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× Hank's buffered salt solution. The cells are starved in methionine/cysteine deficient media for 30 min, followed by replacement with fresh deficient media containing 150 uCi S35 Translabel (Amersham). Test compounds dissolved in DMSO (final concentration 1%) are added together with the addition of radiolabel. The cells are incubated for 4 h at 37° 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 μl normal mouse serum and 50 μl of protein A Sepharose (Pharmacia), mixed by end-over-end rotation for 30 minutes at 4° C., followed by a brief centrifugation in a microfuge. The supernatant is then harvested and transferred to fresh tubes containing 5 ug of a monoclonal antibody (clone 1101.1; directed against an internal peptide sequence in Aβ) and 50 μl protein A Sepharose. After incubation overnight at 4° C., the samples are washed three times with high salt washing buffer (50 mM Tris, pH 7.5, 500 mM NaCl, 5 mM EDTA, 0.5% Nonidet P-40), three times with low salt wash buffer (50 mM Tris, pH 7.5, 150 mM NaCl, 5 mM EDTA, 0.5% Nonidet P-40), and three times with 10 mM Tris, pH 7.5. The pellet after the last wash is resuspended in SDS sample 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 phosphorimaging. The resulting image is analyzed for the presence of Aβ polypeptides. The steady-state level of Aβ in the presence of a test compound is compared to wells treated with DMSO (1%) alone. A typical test compound blocks Aβ accumulation in the conditioned medium, and is therefore considered active, with an IC₅₀less than 100 μM.

C-Terminus β Amyloid Precursor Protein Accumulation Assay

The effect of a test compound on the accumulation of C-terminal fragments is determined by immunoprecipitation of 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, 1% deoxycholate, 0.1% SDS, 150 mM NaCl, 0.125% NaN₃). Again, lysates are precleared with 5 ul normal rabbit serum/50 ul protein A Sepharose, followed by the addition of BC-1 antiserum (15 μl;) and 50 μl protein A Sepharose for 16 hours at 4° C. The immunoprecipitates are washed as above, 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 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 IC₅₀less than 100 μM. Aβ-Immunoprecipitation Assay

This immunoprecipitation assay is specific for γ-secretase (i.e., proteolytic activity required to generate the C-terminal end of Aβ either by direct cleavage or generating a C-terminal extended species which is subsequently further proteolyzed). N 9 cells are pulse labeled in the presence of a reported γ-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 periods of times and Aβ is isolated from the conditioned medium and C-terminal fragments from cell lysates (see above). The test compound is characterized whether a stabilization of C-terminal fragments is observed and whether Aβ is generated from these accumulated precursor. A typical test compound prevents the generation of Aβ out of accumulated C-terminal fragments and is considered active with an IC₅₀less than 100 μM.

Dosage and Formulation

The compound 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 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 Publishing.

The compound 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, tinctures, suspensions, syrups, and emulsions. Likewise, they may also be administered in intravenous (bolus or 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 employed to prevent or treat neurological disorders related to β-amyloid production or accumulation, such as Alzheimer's disease and Down's Syndrome.

The compound of this invention can be administered by any means that produces contact of the active agent with the agent's site of action in the body of a host, such as a human or a mammal. The compound 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. The compound can be 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 compound of the present 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 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 required to prevent, counter, or arrest the progress of the condition.

Advantageously, the 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, or four times daily.

The compound for the present invention can be administered in intranasal form via topical use of suitable 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 will, of course, be continuous rather than intermittent throughout the dosage regimen.

In the methods of the present invention, the compound herein described in detail can form the active ingredient, and is typically administered in admixture with suitable 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 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, glucose, methyl cellulose, 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, 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 β-lactose, corn 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 acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

The compound 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 variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

Compound of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, 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 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 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 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 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 (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for 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 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.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.

	Number	Date	Country
Parent	12142145	Jun 2008	US
Child	12433925		US
Parent	11841081	Aug 2007	US
Child	12142145		US
Parent	11327721	Jan 2006	US
Child	11841081		US
Parent	10746769	Dec 2003	US
Child	11327721		US
Parent	09825211	Apr 2001	US
Child	10746769		US

CYCLIC MALONAMIDES AS INHIBITORS OF Abeta PROTEIN PRODUCTION

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CROSS-REFERENCE TO RELATED APPLICATIONS

Provisional Applications (1)

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