AU783914B2 - Hydroxyalkanoyl aminolactams and related structures as inhibitors of a beta protein production - Google Patents

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

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AU783914B2
AU783914B2 AU74797/00A AU7479700A AU783914B2 AU 783914 B2 AU783914 B2 AU 783914B2 AU 74797/00 A AU74797/00 A AU 74797/00A AU 7479700 A AU7479700 A AU 7479700A AU 783914 B2 AU783914 B2 AU 783914B2
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phenyl
substituted
methyl
occurrence
alkyl
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Hong Liu
Richard Eric Olson
Lorin Andrew Thompson Iii
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Bristol Myers Squibb Pharma Co
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Bristol Myers Squibb Pharma Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
    • C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
    • C07D243/24—Oxygen atoms

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  • Neurology (AREA)
  • Hospice & Palliative Care (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
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Description

WO 01/19797 PCT/USOO/24967
TITLE
HYDROXYALKANOYLAMINOLACTAMS AND RELATED STRUCTURES AS INHIBITORS OF A3 PROTEIN PRODUCTION FIELD OF THE INVENTION This invention relates to novel lactams having drug and bio-affecting properties, their pharmaceutical compositions and methods of use. These novel compounds inhibit the processing of amyloid precursor protein and, more specifically, inhibit the production of Ap-peptide, thereby acting to prevent the formation of neurological deposits of amyloid protein. More particularly, the present invention relates to the treatment of neurological disorders related to 0-amyloid production such as Alzheimer's disease and Down's Syndrome.
BACKGROUND OF THE INVENTION Alzheimer's disease (AD) is a degenerative brain disorder characterized clinically by progressive loss of memory, temporal and local orientation, cognition, reasoning, judgment and emotionally stability. AD is a common cause of progressive dementia in humans and is one of the major causes of death in the United States. AD has been observed in all races and ethnic groups worldwide, and is a major present and future health problem. No treatment that effectively prevents AD or reverses the clinical symptoms and underlying pathophysiology is currently available (for review, Dennis J. Selkoe; Cell Biology of the amyloid (beta)-protein precursor and the mechanism of 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 WO 01/19797 PCT/US00/24967 hemorrhage with amyloidosis of the Dutch-type.
Neurofibrillar tangles are nonmembrane-bound bundles of abnormal proteinaceous filaments and biochemical and immunochemical studies led to the conclusion that their 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 Ap, 3amyloid peptide, and sometimes P/A4; referred to herein as Ap. In addition to its deposition in amyloid plaques, AD is also found in the walls of meningeal and parenchymal arterioles, small arteries, capillaries, and sometimes, venules. AD 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 AD is an internal polypeptide derived from a type 1 integral membrane protein, termed 0 amyloid precursor protein (APP). P APP is normally produced by many cells both in vivo and in cultured cells, derived from various animals and humans. AD is derived from cleavage of P 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 0 secretase(s), generating the N-terminus of AD, a secretase(s) cleaving around the 16/17 peptide bond in AD, and y secretases, generating C-terminal AD fragments ending at position 38, 39, 40, 42, and 43 or generating C-terminal extended precursors which are subsequently truncated to the above polypeptides.
-2- WO 01/19797 PCT/US00/24967 Several lines of evidence suggest that abnormal accumulation of AD plays a key role in the pathogenesis of AD. Firstly, A is the major protein found in amyloid plaques. Secondly, AD is neurotoxic and may be causally related to neuronal death observed in AD patients.
Thirdly, missense DNA mutations at position 717 in the 770 isoform of P APP can be found in effected members but not unaffected members of several families with a genetically determined (familiar) form of AD. In addition, several other p APP mutations have been described in familiar forms of AD. Fourthly, similar neuropathological changes have been observed in transgenic animals overexpressing mutant forms of human P APP. Fifthly, individuals with Down's syndrome have an increased gene dosage of P APP and develop early-onset AD. Taken together, these observations strongly suggest that AP depositions may be causally related to the AD.
It is hypothesized that inhibiting the production of AP will prevent and reduce neurological degeneration, by controlling the formation of amyloid plaques, reducing neurotoxicity and, generally, mediating the pathology associated with AO production. One method of treatment methods would therefore be based on drugs that inhibit the formation of AD in vivo.
Methods of treatment could target the formation of AD through the enzymes involved in the proteolytic processing of P amyloid precursor protein. Compounds that inhibit B or ysecretase activity, either directly or indirectly, could control the production of AD. Advantageously, compounds that specifically target y secretases, could control the production of Ap. Such inhibition of 0 or ysecretases could thereby reduce production of AP, which, thereby, could reduce or prevent the neurological disorders associated with Approtein.
03/11 '05 11:13 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB AS PATENT OFFICE 14004 SUMMARY OF THE INvENTION The present invention provides in one form a compound of tbe formula R5 RSa R Rs RsB R O RQ I I W13 -X-Y-Z OR? O or a pharmaceutically acceptable salt form or prodrug thereof, wherein: Q is Q1 10 -(CI-C3 alkylene)-O-Q1, -(C-C3 alkylene)-S-Q, i -(C1-C3 alkylene)-S(=)-Q 1 -(Cj-C3 alkylene)-S(=0)2-Q 1 or -(Ci-C3 Qp is C 1 -CS alkyl substituted with 0-3 Rla;
C
2 -CS alkenyl substituted with 0-3 Rla; :.*C2-CS alkynyl substituted with 0-3 Ria; C3-C10 cycloalkyl substituted with 0-3 Rib; C3-CO10 carbocycle substituted with 0-3 Rib; aryl substituted with 0-3 Rlb; or to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered hbeterocycle is substituted with 0-3 Rlb; Rla, at each occurrence, is independently selected from H, C-C6 alcyl, OR 1 4 Cl, F, Br, I, NR 15
R
16 CF3; C3-C1O carbocycle substituted with 0-3 Rb; 03.11 DS3.1252..caip -4- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:14 FAX 61 3 9859 1588 CALLINAN LAWRIE HELBALS 4 PATENT OFFICE 141005 aryl substituted with 0- 3 Rib; and to 10 membered heterocycle containing I to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R1Ib; Rb, at each occurrence, is independently selected frorn H, OH, Cl, F, Br, 1, CN, N402, NRI 5
RI
6 CF3, acetyl, SCH3, S(-O)CH3, S(=0)2CH3, C1-C6 alkyi, C 1 -C4 alkoxy, C1-C4 haloalkyl, C 1-C4 haloalkoxy, C1-C4 haloalkyl-S-, and (C1-C6 alkyl)-O-C(O)-; is H, methyl, ethyl, propyl, or butyl; R3 is H; 15 R5 is H, OR 14 C1-C6 alkyl substituted with 0-3 C1-C6 alkoxy substituted with 0-3 C2-C6 alkenyl substituted with 0-3 C2-C6 alkynyl substituted with 0-3 20 C3-C10 cycloalkyl substituted with 0-3 C3-C10 carbocycle substituted with 0-3 aryl substituted with 0-3 R5; or 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 0-3R5c;
R
5 a is H, C1-C4 alkyl, or C2-C4 alkenyl; alternatively, R5 and R5a may be combined to form a 3-7 membered cycloalkyl ring substituted with 0-3 R5c; optionally the cycloalkyl ring formed by combining
R
COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:14 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB AITUS 4 PATENT OFFICE Idj0OO and R 5 a may be benzo fused, wherein the benizo fused ring may be substituted with 0-3 R 5 0; at each occurence, is independently selected from:. NR R ctl C3 C 1-06 alkyl, CF3, OR, 14 Cl, F, Br, 1, O, ON, N02,,Nt 5 1 6 ctl C3 SQ-O)CHI3, SQ=O0)20 11 3, 02-06 alkeriyl, 02-06 alkynyl, CjI -04 alkoxy, 01-04 haloalkyl, 01-04 haloalkoxY, 01-04 haloalkyl-S-.
03-030 cycloalkyl substituted with 0-3 1(~c; C3-010 carbocycle substituted with 0-3 BiG; aryl substituted with 0-3 RS5C; and 5 to 10 membered heterocycle containing 1 to 4 heteroatoins selected frm nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered beterocycle is substituted with 0-3 R~c;
R
5 c, at each occurrence, is independently selected from H, OH-, Cl, F, Br, 1, ON, N02,
NR
15
R
1 6 0P3, acetyl, SCH3, S(-O)CH43. SQO)2CH3, 01-06 alkyl, 01-04 alkoxy, 01.-C4 haloalkyl, 01-04 bakoalkoxy, and 01.-04 haloalkyl-S-;
R
6 is H- Or C0I-C6 alkyl; W is -(CR6R~a)p-; p isO0, 1, 2, 3, or 4
R
8 and R 8 a, at each occurrence, are independently selected from H, F, C I1-04 alkyl, 02-04 alkenyl, C2-04 alkylayl and 03-CS cycloalkyl; X is a bond; aryl substituted with 0-3 RXb; 03-010 cycloallcyl substituted with 0-3 Rb 0311 inj,An2525.pewip.
6 -6- COMS IDNo; SBMI-01 882249 Received by IP Australia: Time (I-tm) 11:50 Date 2005-11-03 03/11 '05 11:14 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB ITS4 PATENT OFFICE 10007 C3-C10 carbocycle substituted with 0-3 RXb; or to 10 membered heterocycle substituted with 0-2 R Xb, at each occurrence, is independetly selected from H, 01-O, Cl, F, Br, 1, CN, NO2, NR 15
R
16 CF3, acetyl, SCH3, S(=Q)CH3, S(=0)2CH3. Cl-C6 alkyl, C1-C4 S alkoxy, CI-C4 haloalkyl,
C
1 -C4 haloalkoxy, and C1-C4 haloalkyl-S-; Y is a bond or -(CR9R9a)t-V-(CR 9
R
9 a)u-; t is 0, 1, 2, or 3; u is 0, 1, 2, or 3;
R
9 and R 9 a, at each occurrence, are independently selected from H, F, C1-C6 alkyl or C3- C8 cycloalkyl; V is a bond,
-N(R
1
-C(=O)NR
1 9b-, -NR19bC(=-O)-,
-NR
1 9bS(0) 2 2 NR1 9 or 20 Z is H; C-CS alkyl substituted with 0-2 R12; C2-C4 alkenyl substituted with 0-2 RI 2 C2-C4 alkynyl substituted with 0-2 RI 2 aryl substituted with 0-4 R 2b;
C
3 -C10 carbocycle substituted with 0-4 RI2b; or to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R1 2 b; Ring B is selected from: 03 /i/.1S.a225.gp pp 7 -7- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:14 FAX 61 3 9859 1588 CALLINAIN LAWRIE MELB AU5S 4 PATENT OFFICE IJU 0 0 0 0
A
SR11 R-
R
1 0 0
NN
o oor N
N
R
10
R
1 wherein each benzo fused radical is substituted with 0-3 R 13 R1 0 is H, C('-O)RI 7 C& O)0R 17 c(--O)N-R1 8 Rl 9 S(=O)2NR 18 R'1 9 S(=O0)2R 1 7; C1-C6 alkyl substituted with 0-2 R] Oa, aryl substituted with 0-4 1b C3-C1O carbOcycle substituted with 0-3 R10b; or D3/i jioj.mL252S.spc1DEsL..
COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11 -03 03/11 '05 11:15 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB Ai.- PATENT OFFICE 14009 to 10 membered heterocycle containing 1 to 4 heteroatorns selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is optionally substituted with 0-3 RIOb;
R
10 a, at each occurrence, is independently selected from H, CI-C6 alkyl, OR1 4 Cl, F, Br, 1, CN, N02, NR 15
R
1 6, CF3; aryl substituted with 0-4 R 1 Ob; C3-CIO carbocycle substituted with 0-3 R10b; or to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is optionally substituted with 0-3 RiOb, at each occurrence, is independently selected from H, OH, Cl-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, N02,NR15R'6, CF3, acetyl, SCH3, S(O)CH3, S(=0)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalky)l, C1-C4 haloalkoxy, and C1-C4 haloalkyl-S-; is selected from H, C-C4 alkoxy, Cl, F, Br, I, CN, NO 2 NRIsR 19
C(=O)RI
7
C(=O)OR
1 7 S 20
C(=O)NR
18 R'1 9 S(=0) 2
NR'
8
R
1 9
CF
3
C
1 -C6 alkyl substituted with 0-1 R1la; aryl substituted with 0-3 R 1 1b; C3-C10 carbocycle substituted with 0-3 R' b; or to 10 membered heterocycle containing 1 to 4 beteroatoms selected from nitrogem oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 Rub; RI la, at each occurrence, is independently selected from H, C-C6 alcyl, OR 14 Cl, F, Br, I, CN, N02, NRISR 16
CF
3 phenyl substituted with 0-3 RI 1 b; C3-CI10 carbocycle substituted with 0-3 Ri 1b; or 0311/OSx, 52. s ipdns, 9 -9- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:15 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB ALS4 PATENT OFFICE 191010 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulpbur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R Ib;
R
1 b, at each occurrence, is independently selected from H, 1OH, Cl, F, Br, I, CN, NO2, NR1 5 R1 6
CF
3 acetyl, SCH3, S(=O)CH3, S(O)2CH3, C1-C6 alkyl, C-C4 alkoxy, CI-C4 haloalkyl,
C
1 -C4 haloalkoxy, and CI-C4 haloallcyl-S-; R12 at each occurrence, is independently selected from H, OH, Cl, F, Br, 1, CN, N02, NR1 5
R'
6
-C(VO)NRSR
16 CF3, acetyl, SCH3, S(=0)CH 3
S(-O)
2 CH3, C1-C6 alkcyl, C 1
-C
4 alkoxy, C 1 -C4 haloalkyl,
C
1 -C4 haloalkoxy, and C 1
-C
4 haloalkyl-Saryl substituted with 0-4 R12b; C3-Clo carbocycle substituted with 0-4 RI2b; or to 10 membered heterocycle containing 1 to 4 heteroatoms selected from Is nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, N02, SNR1
R'
6 CF3, acetyl, SCH 3 S(=O)CH3, S(=O)2CH3,
C
1
-C
6 alkyl, C 1 -C4 alkoxy, 20 C1-C 4 haloalkyl,
C
1 -C4 haloalkoxy, and Cj-C4 haloalkyl-S-;
S
R13, at each occurrence, is independently selected from 1, OH, C 1 -C alkyl, C 1 -C4 alkoxy, Cl, F, Br, I, CN, N02, NRi 5
R
16 and CF 3
R
14 at each occurrence, is independently selected from H, phenyl, benzyl, C1-C6 alkyl, and C 2
-C
6 alkoxyalkyl; R1 4 a is H, phenyl, benzyl, or C 1 -C6 alkyl; 03 11,/05,12325S pdP. COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:15 FAX 61 3 9859 1588 CALLINAN LAWRIE HELD AUS AETOFIE Lji
R,'
5 at each ocreciideednlslctd from H, Cji-C6 alkyl, phenyl, benzyl,
RI
6 ,at eah occurrenre, is independetly selectedomI,0hc- 6 aylpbn] bel penethyl, (Ckj-C aky)- CQ'YIC-C 6 a kyl0-=)-Oad-C(O> ad (Cialkyl)-S&0()2-; alternatively, 5
R
1 6 may be a heteOCYoliC ring selected from the group piperidinyl, morpholinyl, thionmorpholill pyrroliditlyl, homopipetidinYl, piperazinyl, and Ntethylpiperiziflyl;
R
17 is H, Cj-C6 alkyl, or C 2 -C6 alkoxyalkyl, 0 aryi substituted by 0-4 R 17 2, or 15 aryl-CI-k- wherein said aryl is substituted by by 0-4 R 17 a;
R
17 a is mnethyl, ethyl, propyl, butyl, mnethoxy, ethoxy, propoxy, butoxy, -OH, F, Cl, Br, CF3, OCF 3 SCH4 3 S(=O)C-13, S(=O)zCH3,
-NH
2 -N(CH3)2, or -C haloalkyl;
R
18 at each occurrence, is independently selected from H, CjC6 alkyl, phenyl, benzyl, Cphenethyl, (CI-C6 alkyl)-CtO)- and (C 1
-C
6 aikyl)-S(tO-)2-1 alternatively,
-NR
1 7
R'
8 may be a heterocycl ic ring selected from the group piperidinyl, ynorpholinyl, thiomorpholiflyl, pyrrolidinyl, homopiperldifl3l, piperazinyl, and Nmethylpiperizinyt;
R
1 9 at each occurrence, i s independently selected from HI, OH-, C I C6 alkyl, phenyl, benzyl, phenethyl,
(C
1
-C
6 alkyl)-C&=O)- and (C 1
-C
6 alkyl)-SQ('O)2-; Ri19b, at each o ccurrence, is independently selected from H and C I-C6 alkyl; COMS ID No.SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:15 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB AUS PATENT OFFICE 11012
R
20 is H, OH, C -C4 alkyl, phenyl, benzyl, or phenethyl;
R
21 at each occurrence, is independently selected from H. Ci-C6 alkyl, phenyl, benzyl, and phenethyl; and
R
22 at each occurrence, is independently selected from H, CI-C6 alkyl, phenyl, benzyl, and phenethyL The present invention also provides 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 form or prodrug form thereof.
**The present invention further provides a method for treating degenerative S.S 15 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 form or prodrug form thereof.
The invention has been achieved by the discovery that compounds of Formula R Ra R 6 0
RW-X-Y-Z
OR 0 (1) or pharmaceutically acceptable salt form or prodrug forms thereof, wherein Q, R2, R3, R 5 R6, B, W, X, Y, and Z are defined below, are effective inhibitors of the production of Ap DETAILED DESCRIPTON OF PREFPRRED
EMBODIMENTS
Thus, in a first embodiment, the present invention provides a novel compound of Formula fl/-12ll-/a.t lecip,12 -12- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:16 FAX 61 3 9859 1588 CALLINAN LAWRIE NELB AUITS .tATENT OFFICE wIU13
R
5
R
5 a R 6
O
r2N
,W-X-Y-Z
OR O
(I)
or a pharmaceutically acceptable salt form or prodrug thereof, wherein: Q is Q, -(Ci-C 3 alkylene)-O-Q 1
-(C-C
3 alkylene)-S-Q',
-(C
1
-C
3 alkylene)-S(&O)-Q1, 10 -(C 1
-C
3 alkylene)-S(=O)-Q1' or 0:4 -(C 1 -C3 aikylne)-N(R 2 0
Q
1 is C 1 -Cs alkyl substituted with 0-3 Rla;
C
2 -Cs alkenyl substituted with 0-3 Rla; 91*40 C2-Cs alkynyl substituted with 0-3 R 1 C3-CLO cycloallcyl substituted with 0-3 Rib; C3-Clo carbocycle substituted with 0-3 Rib; S. aryl substituted with 0-3 RIb; or to 10 membered heterocycle containing 1 to 4 heteroatoms selected from S 20 nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered beterocycle is substituted with 0-3 Rib; Rla, at each occurrence, is independently selected from H, C i-C6 allkyl, OR 14 Cl, F, Br, I,
NR
1 5
RI
6 CF3; C3-C10 carbocycle substituted with 0-3 Rib; aryl substituted with 0-3 Rib; and 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 Rlb; 03/1105.&t1 2 5 25 Apecpps.13 -13- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:16 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB AUS 4ATENT UFFICE WJ14 Rib, at each occurrence, is independently selected from H, OH, Cl, F, Br, 1, (CN, N02, 16
CF
3 acetyl, SCH3, S(0)CH3, S(=0) 2 CH3, C1-C6 alkyl, Cr-C4 alkoxy, Ci-C4 haloalkyl, CI-C4 haloalkoxy,
C
1 -C4 haloalkyl-S-, and (CI-Cs alkyl)-O- C( R2 is H, methyl, ethyl, propyl, or butyl; R3 is 1; is H, OR' 4 C,-C6 alkyl substituted with 0-3 C-C6 alkoxy substituted with 0-3
C
2 -C6 alenyl substituted with 0-3 C2-C6 alkynyl substituted with 0-3 C3-Cio cycloalkyl substituted with 0-3
C
3 -Clo carbocycle substituted with 0-3 R 5 c; aryl substituted with 0-3 RSc; or .5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from 20 nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle 20 irga xen is substituted with 0-3R5c; RSa is H, Cj-C4 alkyl, or C2-C4 alkenyl; alternatively, R 5 and R 5 a may be combined to form a 3-7 membered cycloalkyl ring substituted with 0-3 RSC; optionally the cycloalkyl ring formed by combining
R
and R5a may be benzo fused, wherein the benzo fused ring may be substituted with 0-3 R5b, at each occurrence, is independently selected froNm: H, C 1 -C6 alkyl, CF 3
OR
1 4 Cl, F, Br, I, GN, N02, N'R' 5
R
1 6, acetyl, SCH 3 S(=O)CH3, SO(-)2CH3,
C
2 -C6 alkenyl,
C
2 -C6 alkynyl, C1-C4 alkoxy, Ci-C4 haloalkyl,
C
1 -C4 haloalkoxy, C;-C4 haloalkyl-S-,
C
3 -Co10 cycloalkyl substituted with 0-3 RSc; a3/11y05.t12523 p cisl.
1 4 -14- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:16 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB AUS PATE OFFICE 141015
C
3 -Clo carbocycle substituted with 0-3 R 5 c aryl substituted with 0-3 R5c; and to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R 5 c; RSc, at each occurrence, is independently selected from H, OH, Cl, F, Br, 1, CN, NO 2
NR
15
R
16 CF3, acetyl, SCH 3 S( O)CH3, S(0)2H3, C1-C6 alkyl, C 1 -C4 alkoxy,
C)-C
4 haloalkyl, C1-C4 haloalkoxy, and C 1 -C4 haloalkyl-S-; R6 is H or CI-C6 alkyl; W is -(CRR8a)p.
15 pis 0, 1,2, 3, or 4;
R
8 and RS, at each occurrence, axe independently selected from H, F, C 1 -C4 alkyl, C 2
-C
4 alkenyl, C 2 -C4 alkynyl and C 3 -Cg cycloalky); X is a bond; aryl substituted with 0-3 RXb;
C
3 -Clo cycloalkyl substituted with 0-3 Rxb;
C
3 -Clo carbocycle substituted with 0-3 Rxb; or 5 to 10 membered heterocycle substituted with 0-2 Rb; RXb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN. N02,
NR'IR'
6
CF
3 acetyl, SCH 3 S(-O)CII,
S&O)
2 CH3, -C6 alkyl, C 1
-C
4 alkoxy,
C
1 -C4 haloalkyl, CI-C4 haloalkoxy, and C1-C4 haloalkyl-S-; Y is a bond or -(CR9R9a-V(CR 9
R
9 a)U,; t is 0, 1, 2, or 3; u is 0, 1, 2, or 3; -15-3l h iS 1 COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:16 FAX 61 3 9859 1588 CALLINA LAWRIE MELB AUTS ATENT OFFICE 1JUlt R9 and R 9 a, at each occurrence, are independently selected from H, F, Cj-Cs alkyl or C3-
C
8 cycloalkyl; V is a bond, -S(&0)2-s
-N(R
1 9 -C(=O)NRl 9 .NRt9bC(O)-, -NRl 9 bS(=O)2-, -S(-Oh)2NR 9 or
S
555 Z is H; Cl-Cg alkyl substituted with 0-2 R1 2
C
2 -C4 alkenyl substituted with 0-2 Ri 2
C
2
-C
4 alkynyl substituted with 0-2 R1 2 aryl substituted with 0-4 R12b C3-C1io carbocycle substituted with 0-4 R12b; or to 10 membered heterocycle containing I to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 Rl2b; Ring B is selected from: 0 0o A I, R 0
N
OR'"
0 1 I/O5.M1 252 5 r.q Wp I 1 6 COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:16 FAX 61 3 9859 1588 CALLINAIN LAWKIE IELB AUS+ 4 PTENT OFFICE i~l 017 0 0
RA
wherein each benzo fused radical is substituted with 0-3 R' 3 R1 0 is H, 0)R 17 C(0--)0R 1 7 CQ( O)NR 18
R
19 S(=O)2NRi 8 Rl 9 S(=O)2Rl 7 Cl-C6 alkYl substituted with 0-2 1a aryl substituted with 0-4 RlOb; C3-C 10~ carbocycle substituted with 0-3 R1iOb; or to 10 membered heterocycle containing I to 4 heteroatofls selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is optionally substituted with 0-3 RI0b; RI0a, at each occurrence, is independently selected from H, Cl-C6 alkyl, OR 14 Cl, F, Br, I, CN, N02, NR 5 R 16 C-F3; aryl substituted with 0-4 Rl Ob; 03/i UI/05.13S ipocipp.17 COMS IDNo. SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11 -03 03/11 '05 11:17 FAX 61 3 9859 1588 CALLINAN LAWRIE KELB AUS PATENT OUYFICt ihJU± C3-C10 carbocycle substituted with 0-3 RO10b; or to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is optionally substituted with 0-3
S
RI0b, at each occurrence, is independently selected from H, 1OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F. Br, I, CN, NO2, NR 1 5
R
1 6 CF3, acetyl, SCH3, S(-O)C3.
S(=0)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloallkyl-S-; R' 1 is selected from H, Cl-C4 alkoxy, CI, F, Br, I, CN, NO2, NR)BR 1 9
C(Q)R'
7
C(=)OR
1 7
C(=O)NR
1 8
R
19
S(-O)
2
NR'R'
9
CF
3 Cl-Ct alkyl substituted with 0-1 R 1 I H; aryl substituted with 0-3 R11b;
C
3 -Co10 carbocycle substituted with 0-3 R 1 b; or 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said S to 10 membered heterocycle is substituted with 0-3 R 1 1b
R
1 18, at each occurrence, is independentlY selected from I, C 1 alkyl, OR 1 4 Cl, F, Br, 1, (CN, N02, NR5R1 6
CF
3 phenyl substituted with 0-3 R11b; C3-Clo carbocycle substituted with 0-3 R Ilb; or 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered beterocycle is substituted with 0-3 R 1 lb R' lb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, N02, NRI5R16, CF3, acetyl, SCHj, S(-O)CH3, S(-O)2CH3, CI-C6 alkyl, CI-C4 alkoxy, Ci-C4 haloalkyl,
C
1
-C
4 haloalkoxy, and CI-C4 haloalkyl-S- 03 11 10tolS2525.spciVpps.
-18- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:17 FAX 81 3 9859 1588 CALLINAN LAWRIE MELB AK§ t± PATENT OFFICE I9i019
R
12 at each occurrence, is independently selected from H, OH., Cl, F, Br, i, ON, N02,
NRJ
5 R1 6 -C(=0)NR15Rl 6
CF
3 acetyl, SCH3, S(O)CH3, S Y0)2CH3, CI-C6 alCyl, C 1 -C4 alkoxy, 01-C4 haloalkyl, CI-4 haloulkoXy, and Cr04 haloalkyl-Spryl substituted with 0-4 Rl2b; 03-Cia carbocyole substituted with 0-4 Rl2b; or to 10 rnembered heterocycle containing I to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 Rl2b; R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, ON, NO 2 999.
NR
5
R
16
CF
3 acetyl,
SCH
3 S(0O)CH3, SQO)2CHS, CIC6 alkyl, C-C4 alkoxy, C1-C 4 haloalkyl, 01-C4 haloalkoxy, and 01-04 haloalkyl-S-;
R)
3 at each occurrence, is independently selected from H, OH, CI-C6 alkyl, 01-C4 alkoxy, Cl, F, Br, I, ON, N02, NR1 5
R
1 6 and OF 3 R1 4 at each occurrence, is indepeuideltly selected from H, phenyl, benzyl, C1-C6 alkyl, and 02-06 alkoxyalkyl; 9
R
1 4a is H, phenyl, beuzyl, or 1-06 alkyl; 9R 15 at each occurrence, is independently selected from H. C-C6 alkyl, phenyl, benzyl, phenethyl, (C1-06 alky1)-C&O)-, (01-C6 alkyl)-0-C&O)- and (01-06 alkyl)- S(0)2-;
R
16 at each occurrence, is independentlY selected from H, OH, 01-06 alkyl, phenyl, beuzyl, phenethyl, (01-C6 alkyl)-C(=O)-, (01-06 alkyl)-O-C(=O)- and (01-06 alkYl)-S(-O)2-; 03/I/0 l.W2525spw'&' 19 -19- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11 50 Date 2005-11-03 03/11 '05 11:17 FAX 61 3 9859 1588 CALLINA4 LAWRIE MELB AS t EAiBNT OFFICE 10020 alteratively,
-NR
15
R
16 may be a heterocycliC ring selected from the group pipen'dinyl morpholinyl, tbiomorpholinyl, pyrrolidinyl, homopiperidinyl, piperazinyl, and Nmethylpiperizinylp17 is H, 01-06 alkyl, or C--C6 Blkoxyalkyl, aryl substituted by 0-4 R' 7 a, or aryl-CH2- wherein said aryl is substituted by by 0-4 Rl 7 a; R1 7 a is H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, -01-1, F, Cl, Br, I, CF 3 0CF 3
SC
3 S(=-O)CH3. S(-0)2Cl3, -NH2, -N(CHJ)2, 0r C1-C4 haloalkyl;
R
1 at each occurrence, is independently selected from H, Cp-C6 alkyl, phenyl, benzyl, phenethyl, (Cj-C6 alkyl)-C(O)- and (01-C6 allyl)-S(eO)2i 9999*15 alternatively,
-NR'
7
R
1 8 may be a heterocyclic ring selected from the group piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, horopiperidinyl, piperazinyl, and N- :ethylpiperizinyl;
R
19 at each occurrence, is independently selected from H, C 1-C6 alkyl. phenyl, benzyl, phenethyl, (01-06 alky)-C& and (CI-C6 alkyl)-S0)-; Rl9b, at each occurrence, is independentlY selected from H and CIC6 alkyl;
R
2 0 is H, 011, Cj-C4 alkyl, phenyl, benzyl, or phenethyl;
R
21 at each occurrence, is independently selected from H, 01-06 alcyl, phenyl, benzyl, and phenethy; and R22. at each occurrence, is independently selected from Cj -C6 alkyl, phenyl, beazyl, and phenethyl.
OVII j/ 0 5p02525I.rpCCipULZQ COMS ID No; SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:17 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB AUS PA NT OFFICE imOZ1 In a preferred mbodiment, the present invention provides a compound of Formula (Ia): Rs Ra O
Q
N
,W-X-Y-Z
RBN
OH O (Ia) or a pharmaceutically acceptable salt form or prodrug thereof, wherein: Q is Q 1
-(C
1 -C3 alkylene)-O-Q 1 10 1 -C3 alkylene)-S-Q 1 0:* -(Cl-C3 alkylene)-S(=0)-Q, S-(C1-C3 alkylene)-S(-)2-Q 1 or -(C1-C3 alkylene)-N(R 2 0 )-Q1;
Q
1 is C1-C6 alkyl substituted with 0-3 Ria; C2-C6 alkenyl substituted with 0-3 Rla;
C
2 -C6 alkynyl substituted with 0-3 R a;
C
3 -C10 cycloalkyl substituted with 0-3 Rib; C3-C10 carbocycle substituted with 0-3 Rib; aryl substituted with 0-3 Rib; or to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 Rib; Rla, at each occurrence, is independently selected from H, Cl-C6 alkyl, OR 14 Cl, F, Br, I, NR 15
R
16 CF3;
C
3 -C10 carbocycle substituted with 0-3 Rlb; aryl substitutd with 0-3 RIb; and 03o11 jiOS .al255specipP.
2 1 -21- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:17 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB AUS PATENT OFFICE i4 022 to 10 membered heterocycle containing i to 4 heteroatOms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 Rlb; Rib, at each occurrence, is independently selected from I, OH, Cl, F, Br, 1, CN, N02, NR1 5 R1 6 CF3, acetyl, SCH3, S(7O)CH3, S(=0)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 haloalkyl-S-, and (C1-C6 alkyl)-O-C(=O)-; io R2 is H, methyl, or ethyl; is H, OR 14 C1-C6 alkyl substituted with 0-3 CI-C6 alkoxy substituted with 0-3 15 C2-C6 alkenyl substituted with 0-3 C2-C6 alkynyl substituted with 0-3 Rb; C3-C10 cycloalkyl substituted with 0-3 C3-C10 carbocycle substituted with 0-3 aryl substituted with 0-3 R5c; or
C
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 0-3R5C;
R
5 a is H, C1-C4 alkyl, or C2-C4 alkeiyl; alternatively,
R
5 and R 5 a may be combined to formn a 3-7 membered cycloalkyl ring substituted with 0-3 at each occurrence, is independently selected from: -22- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:18 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB ATS PANT OFFICE 1023 H, C1-C6 alky), CF3, OR 1 4 Cl, F, Br, I, CN, N02, NR 1 5
R
1 6 acetyl, SCJ3, S(=O)CH3, S( O) 2 CH3, C2-C6 alkenyl,
C
2 -C6 alkynyl, C1 -C4 alkoxy, CI-C4 haloalkyl, C1 -C4 haloalkoxy, and C1-C4 haloallcyl-S-, s C3-C10 cycloalkyl substituted with 0-3 C3-C10 carbocycle substituted with 0-3 RSC; aryl substituted with 0-3 R5c; and to 10 mnembered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R5c, at each occurrence, is independently selected from OH, Cl, F, Br, I, CN, N02, 6 CF3, acetyl, SCH3, S(=0)CH3, S(>O)2CH3,
C
1 -C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
C
1 -C4 haloalkoxy, and C1-C4 baloalkyl-S-; W is -(CR8R8a)p-, pis 0, 1, or 2; 20 R8 and Rga, at each occurrence, are independently selected from H, F, methyl, and ethyl; X is a bond; or Y is a bond or -(CR9R9a)t-V-(CR9R9a -23- COMS ID No SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:18 FAX 61 3 9859 1588 CALLINAN LAWRIE MELBMA154 PATENT OFFICE 10024 t is 0, 1, or 2; u is 0, 1, or 2;
R
9 and R 9 a, at each occurrence, are independently selected from H, F, methyl, and ethyl; V is a bond, or a a a Z is H; C1-C4 alkyl substituted with 0-2 R 2 C2-C4 alkenyl substituted with 0-2 R1 2 C2-C4 alkynyl substituted with 0-2 R 2; aryl substituted with 0-4 R1 2 b; C3-C6 carbocycle substituted with 0-4 R2b; or to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R12b; Ring B is selected from: 0
N
N R" /o 0
N
0R" o03/11/05.. 525 .pep s,24 -24- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:18 FAX 61 3 9859 1588 CALLINAN LAWRIEMELB AIUS PATENT OFFICE~ I~JU v U z
RA
N
RR
"I
wherein each benzo fused radical is subtituted with 0-3 R" 3
R
10 is 14, C(=O)R 1 7 C&-O)OR1 7 C(-O0)NR 1 8
R
19 S&7-)2NR18RI 9 SQ=)2R' 7 ClI-C6 alkyl substituted with 0-2 RIlOa; aryl substituted with 0-4 RI~b;
C
3 -ClO carbocycle substituted with 0-3 RI0b; or to 10 memnbered heterocycle containing I to 4 heteroatoflS selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 memnbered heterocycle is Optionally substituted with 0.3 p1b 03/ 1i05,&f l2525.#p-ipV'.2 COMS ID No: SBMI-01882249 Received by IP Australia: TMme 11:50 Date 2005-11-03 03/11 '05 11:18 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB AU-* PATENT OFFICE igjazu
R
10 a, at each occurrence, is independently selected from i, C1-C6 alkyl, ORI 4 Cl, F, Br, I, 0, CN, N02, NR 1 5R 16 CF3, or aryl substituted with 0-4 RlOb; RlOb, at each occurrence, is independently selected from OH, CI-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, N02, NR1 5
R
1 6 CF3, acetyl, SCH3, S(O)CH3, S(=O)2CH3, CI-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and CI-C4 haloalkyl-S-;
R
1 1, at each occurrence, is independently selected from H, C-C4 alkoxy, Cl, F, Br, I, CN, N02, NR 1 8
R
19
C(-O)R
1 7 C(r0)OR 1 7 C(O)NRI 8
R
1 9, S(--0)2NRI 8
R
1 I9, CF3; C1-C6 alkyl substituted with 0-1 R1l1a; aryl substituted with 0-3 Rllb; C3-C10 carbocycle substituted with 0-3 R 1 Ib; or 15 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 1 b;
R
1 Ia, at each occurrence, is independently selected from iH, C1-C6 alkyl, OR 1 4 Cl, F, Br, 20 I, CN, N0 2 NR1 5 R16, CF3; phenyl substituted with 0-3 R 1 b; C3-C10 carbocycle substituted with 0-3 R11 b; or to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulpbur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R 1 b; Rl b, at each occurrence, is independently selected from 4, OH, C1. F, Br, I, CN, NO2, NR5R1 6 CF3, acetyl, SCH3, S(=0)CH3, S(=0O)2CH3, C1-C6 alkyl, Cl-C4 alkoxy, C1-C4 haloalkyl, Cl-C4 haloalkoxy, and C 1 -C4 haloalkyl-S-; 031 IV 225.r pecip.2r -26- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:19 FAX 61 3 9859 1588 CALLINAN LAWRE MELB AUS-LLTENT OFFICE t92Z
R
1 2 at each occurrence, is independentlY selected from H, OH, Cl, F, CN, N02, NR1 5
R
16 _C(tO)NElSRl 6 CF3, acetyl, SCH3, S(=O)CH3, S&O)2CH3, C1-C6 alkyl, C;-C4 alkoxy, Cj-C4 haloflkyl, CI-C4 haloalkoxy, and C 1 -C4 haloalkyl-S-; aryl substituted with 0-4 Rl2b; C3-C10 carbocycle substituted with 0-4 Rl2b; or to 10 membered heterocycle cotining I to 4 heteroatoins selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b; Rl 2 b, at each occurrence, is independently selected from H, OH, C1, F, Br, I, CN, N02,
NR
1 5
R
1 6 CF3, aetyl, SCH3, SQO)CFI3, SQO)2CH3, CI-C6 alkyl, CI-C4 alkoxy, CI-C4 haloalkyl, Cl-C4 haloalkoxy, and Cl-C4 haloalky]-S-; RI 3at each occurrence, is independently selected from H, OH, C1-C6 alkyl, CJ-C4 alkoxy, Cl, F, Br, I, CN, N02, 1516, and CF3; R14, at each occurrence, is independently selected from H, phenyl, benzyl, CI-C6 aikyl, and C2-C6 alkoxyilcyl; 2o R 2 5, at each occurrence, is independently selected from H, CI-C6 alkyl, phenyl, berizyl, phenethYl, (Cl-C6 a4kyl)-C(O)-, (CI-C6 allyl)-0-C(=O)- and (CI-C6 alkyl)- S-0)2-; 16, at each occurrence, is independently selected from 14, OH, CI-C6 alkyl, phenyl, benzyl, phenetbyl, (C1-C6 a1kyl)-C(O). (C1-C6 alkyl)-O-C(O)- and (Cl-C6 alkcyl)-S(=0)2-; alternatively,
-NR'
5
R
16 may be a heterocyclic ring selected from the group piperidinyl, morpbolinyl, thiomorpholifyl. pyrrolidiiyl, homopiperidinyl, piperazinyl, and Nmthylpiperizinyl; OVI IM1,nIZ23-spvCC5
-Z
-27- COMS ID No SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:19 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB A -S 4 PATENT OFFICE I028
R
17 is H, aryl, aryl-CH2-, C1-C6 alkyl, or C2-C6 alkoxyalkyl; R18, at each occurrence, is independently selected from H, C1-C6 alkyl, phenyl, benzyl, phenethyl, (C1-C6 allyl)-C(=O)- and (C1 -C6 alkyl)-S(=0)2- R19, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, phenyl, benzyl. phenethyl, (01-06 alkyl)-C(-O)- and (C1-C6 alkyl)-S(=O)2io alternatively, -NR1 8
R
19 may be a heterocyclic ring selected from the group piperidinyl, morpholinyl, thiomorpholinyl. pyrrolidinyl, homopiperidinyl, piperazinyl, and Nmethylpiperizinyl; and 1
*R
20 is H, OH, C1-C4 alkyl, phenyl, benzyl, or phenethyl.
*999 In a preferred embodiment, the present invention provides a compound of Formula (Ia) wherein: .9' Q is Q 1
Q
1 is C1-C6 alkyl substituted with 0-3 IRla; C2-C6 alkenyl substituted with 0-3 Ri a; C2-C6 alkynyl substituted with 0-3 RIa; C3-C10 cycloalkyl substituted with 0-3 Rib; C3-C10 carbocycle substituted with 0-3 Rib; aryl substituted with 0-3 RIb; or to O10 membered heterocycle containing I to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 Rib; 031/5.Vr12SZ5.QfpCsh 2 -28- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:19 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB AUS -4 PATENT OFFICE 10029
R
1 a, at each occurrence, is independently selected from H, C1-C6 allcyl, OR 14 Cl, F, Br, I,NR15R1 6 CF3; C3-C10 carbocycle substituted with 0-3 Rib; aryl substituted with 0-3 Rib; and 5 to 10 memrbered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 RIb; Rlb, at each occurrence, is independently selected from H, 1OH, Cl, F, Br, I, CN, N02,
NR
1 5
R
1 6 CF3, acetyl, SCH3, S(=O)CH3, S(#0)2CH3, CI-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
C
1 -C4 haloalkoxy, C1-C4 haloalkyl-S-, and (C1-C6 alkyl)-O-C(= 0
'R
2 is H, methyl, or ethyl; is H, OR 14 C1-C6 alkyl substituted with 0-3 C2-C6 alkenyl substituted with 0-3 Rb; or C2-C6 alkynyl substituted with 0-3 is H, methyl, ethyl, propyl, butyl, or C2-C4 alkenyl; alternatively, RS and R5a may be combined to form a C4-C7 cycloalkyl ring; RSb, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, CF3, OR 1 4 CL, F, Br, 1, NR15R16,
C
3 -C7 cycloalkyl substituted with 0-3 RSC; C3-C7 carbocycle substituted with 0-3 phenyl substituted with 0-3 R5c; and 0311 /o,tl25..peipP,29 -29- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:19 FAX 61 3 9859 1588 CALLINAN LAWRIEELB A1XINT UkI'CB IUJU 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 j R5c, at each occurrence, is independently selected from O, Cl, F, Br, I, CN, N02, NR15R16, CF3, acetyl, SCH3, S(O)CH3, S(=0)2CH3, C1-C4 alkyl, C 1 -C3 alkoxy, Cl-C2 haloalkyl, and C1-C2 haloalkoxy; W is a bond; X is a bond; Y is a bond; 'Z is H, C1-C4 alkyl substituted with 0-2 R1 2 i'
C
2 -C4 alkenyl substituted with 0-2 R 1 2; C2-C4 alcynyl substituted with 0-2 R1 2 aryl substituted with 0-4 R12b; C3-C6 carbocycle substituted with 0-4 R1 2 b; or to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R12b Ring B is selected from: 0
N
R0 wherein the benzo fused radical is substituted with 0-3 R"; and 0-30-11 i5.X2515,spq p o.
3 COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:19 FAX 61 3 9859 1588 CALLINAN LAWRIE MELD AUS -4 PATENT OFFICE J01 0 0 Z I R NR13 1R1
R
1 3
L
1 0
R
1 0 is 11, C(--O)R 1 7 C&=O)0R 1 7 C(0)NR 8 RI 9 S&=0) 2 NRI 8 RI 9 S(=O)2R 17 5. Cl-C6 alkyl substituted with 0-2 Rl()a; aryl substituted with 0-4 *C3 -C10 carbocycle substituted with 0-3 RI Ob; or to 10 mnembered heterocycle containing 1 to 4 heteroatolos selected froin nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle 1 is optionally substituted with 0-Rib RI~a ateac occrreceis independently selected frorn H, C1-C6 alkyl, OR1', Cl, F, Br, I, =0O, CN, N02, NRI 5 RI 6 CF3; :aryl substituted with, 0-4 R IOb; C3-C1O carbocycle substituited v~th 0-3 Ri0b; or to 10 menabered heterocycle containing I to 4 heteroatomls selected from nitrogenl, oxygen, and sulphur, wherein said 5 to 10 membered heter-ocycle is optionally substituted with 0-3 RI Ob; 2o R10b, at each occurrence, is independently selected from H, 01-i, CI-C6 alkyl, Gi-C4 alkoxy, C1, F, Br, 1, CN, N02, NR15R1 6 CF3, acetyl, SCH3, S( O)CH3, -31- COMS ID No: SBMI-01882249 Received by IP Australia: Time (Hin) 11:50 Date 2005-11-03 03/11 '05 11:20 FAX 81 3 9859 1588 CALLINAN LAWRIE hMELB43t-. PATENT OFFICE IM032 S(=0)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
C
1 -C4 haloalkOxy, and C1-C4 haloalkyl-S-
R
11 is selected from H, NRl8Rl9, C(=0)R1 7 C(=O)OR'7,
C(=O)NR
1 8
R
19 S(0)2NR1R9 CF3 Cl-C6 alkyl substituted with 0-1 R 1 1a; phenyl substituted with 0-3 R 1 b; C3-C6 carbocycle substituted with 0-3 R 1 b; or to 7 membered heterocycle containing 1 to 4 heteroatoms selected from mtrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R 1 b; wherein said 5 to 7 membered heterocycle is *selected from pyridinyl, pyrimridinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl; Is
.R
11 a, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, methoxy, etboxy, propoxy, Cl, NR 5
R
1 6 CF3; phenyl substituted with 0-3 R 1b;
C
3 -C6 carbocycle substituted with 0-3 R 1 b; or 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R 1 b; wherein said 5 to 7 membered heterocycle is .:selected from pyridinyl, pyrimidinyl, triazinyl, furayl, thienyl, thiazolyl.
pyrrolyl, piperazinyl, piperidiDyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl; R1 1b, at each occurrence, is independently selected from H, OH, CL, F, NR 15 R1 6 CF3 acetyl, SCH3, S(Q)CH13, S(Q0)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and CI-C2 haloalkoxy; 03111/0.tl252S.p-P s'.U 2 -32- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:20 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB AL- ATENT OFFICE 110333
R
12 at each occurrence, is independently selected from H, OH, C1, F, Br, I. CN, N02,
NRI
5 R1 6 -C(=O)NR15R1 6 CF3, acetyl, SCH3, S(--O)CH3, S(=0)2CH3, C1-C6 alkyl, CI-C4 alkoxy, C1-C4 halaloalkyl, C1-C4 haloalkoxy, and CI-C4 haloalkyl-S'aryl substituted with 0-4 R12b; C3-C10 carbocycle substituted with 0-4 R12b; or to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b; Rl2b, at each occurrence, is independently selected from H, O, Cl, F, Br, I, CN, N02, 6 CF3, acetyl, SCH13, S(jO)CH3, S(=O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C3-C4 haloalkoxy, and C1-C4 haloalkyl-S-; .4
R
13 at each occurrence, is independently selected from H, OH, C1-C6 alkyl, CI-C4 15 alkoxy, Cl, F, Br, I, CN, N02, NR1 5
R
16 and CF3; R14, at each occurrence, is independently selected from H, phenyl, benzyl, C1-C4 alkyl, and C2-C4 alkoxyalkyl, 20 Rl 5 at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; .4 R16, at each occurrence, is independently selected from 1, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, phenethyl, CH3CH2C(0)-,
CH
3 CH2OC(=)-, CH30C(=O)-, CH3CH2S(&0)2- and CH3S(=0)2-; R1 7 is H, phenyl, benzyl, C1-C4 alkyl, or C2-C4 alkoxyalkyl;
R
18 at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and C3/11 i/)O,s25Z5.#p'"pp, 3 3 -33- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:20 FAX 61 3 9859 1588 CALLINAN LAWRIE ELB AS NT OFFICE 034 at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, and R19, at each occurrence, is independenl butyl.
In a preferred embodiment, the present invention provides a compound of Formula (la) wherein: Q is Q' or (C 1
-C
3 alkylene)-O-Q', Q' is CL-Cd alkyl substituted with 0-3 RF; C2-C6 alkenyl substituted with 0-3 R a;
C
2 -C6 alkynyl substituted with 0-3 R 1 a; see C3-C6 cycloalkyl substituted with 0-3 Rib; S0 phenyl substituted with 0-3 Rlb; or 15 5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected fr6m nitrogen, oxygen, and sulphur. wherein said 5 to 6 membered heterocycle is substituted with 0-3 Rib; R1 at each occurrence, is independently selected from H, methyl, ethyl, propyl,butyl,
OR'
4 C, F, Br, I, NR' 5
CF
3 C3-C6 carbocycle substituted with 0-3 Rb; phenyl substituted with 0-3 Rib; and to 6 membered heterocycle containing 1 to 4 heteroatoms selected from Ditrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 Rib; Rib, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, N02, NR 5
RI
6
CF
3 acetyl, SCH 3 S(O)CH 3 S(O)2CH3, methyl, ethyl, propyl, butyl, rethoxy, ethoxy, propoxy,
C
1 -C2 baloalkyl, CI-C2 baloalkoxy, (methyl)OC(=O)-, (ethyl)OC(-O)-, (propyl)OC(=0)-, and (butyl)OC(O0)-; 311oVO0Uoa25.MpcsipgWB, -34- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:20 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB AS PATENT OFFICE 141035
R
2 is H or methyl; R is H, OR 14 C1-C4 alkyl substituted with 0-1 C2-C4 alkenyl substituted with 0-1 R5b; or
C
2 -C4 alkynyl substituted with 0-1
R
5 a is H, methyl, ethyl, propyl, or butyl; o alternatively, R5 and RSa may be combined to form a cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl ring;
R
9 at each occurrence, is independently selected from: H, methyl, ethyl, propyl, butyl, CF3, OR 14, Cl, F, NR15RL 6
C
3 -C7 cycloalkyl substituted with 0-3
C
3 carbocycle substituted with 0-3 *phenyl substituted with 0-3 R5c; 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 herein said 5 to 7 embered eterocycle is 20 substituted with 0-3 R5c; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl; R5c, at each occurrence, is independently selected from H, OH, Cl, F, NR 1 5
R
16 CF3, acetyl, SCH3, S(-O)CH3, S(=0)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy,
C
1
-C
2 haloalky, and C 1 -C2 haloalkoxy; W is a bond; X is a bond; Y is a bond; 03-35-/11 l/Q5*i3Z5.%SpGWg COMS ID No SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:21 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB AUS 4 PATENT OFFICE wIJU36 Z is H,
C
1 -C4 alkyl substituted with 0-2 R1 2
C
2 -C4 alkenyl substituted with 0-2 R 12
C
2 -C4 alkynyl substituted with 0-2 R 1 2; aryl substituted with 0-4 Rl 2 b;
C
3 -C6 carbocycle substituted with 0-4 RL2b; or 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 RJ2b; Ring B is selected from: 0 *o.0 0 0 0 00.0 0 0000 and
R
1 L is selected from 1, NR 1
&R'
9
CE
3 CI-C4 alkyl substituted with 0-1 R1Ia; phenyl substituted with 0-3 R' I1b;
C
3 -Cs carbocycle substituted with 0-3 R 1 1b; or to 7 membered beterocycle containing I to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R 1 ilb; wherein said 5 to 7 membered heterocycle is O3/t1/MAtl25 speipS 6
J
COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:21 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB AL1S YATtINT UFFICE WJ UJ7 selected from pyridinyl, pyrirnidinyl. triazinyl. furanyl thienyl, thiazolyl, pyitolyl, piperazinyli piperidinyL hbimtopiperidinyli pyrazolyl, imidazolyJ, oxazolyl, isoxazolyl, and tetrazolyl R1 la, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Cl, F, NR 5
R
1 6
CE
3 phenyl substituted with 0-3 R 1 1b; C3-C6 carbocycle substituted with 0-3 R 1 lb; or to 7 menbered 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' 1b; wherein said 5 to 7 membered heterocycle is 9* selected from pyridinyl. pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, pipeidiDyl, houopiperidinyl, pyrazolyl. imidazolyl, oxazolyl, isoxazolyl, and tetrazol.yl; R1 b, at each occurrence, is independently selected from H, 01-, Cl, F, NR' 5
R
1 6
CE,
methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Cr-C2 haloalkyl, and CI-C2 haloalkoxY: 0311 1/05.u1123S pvcJpS'.
-37- COMS ID No. SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:21 FAX 61 3 9859 1588 CALLINAIN LAWRIE MELB ALIS 1AIhINT Ufl-kb igjuh igj U j 0 S S (Pages 3 8 to 41 have been left intentionally blank) 03/11 V,,t12Z S. M-P A -38 -41- COMS ID No: SBMI-01882249 Received by IP Australia: Tine (I-tm) 1150 Date 2005-11-03 WO 01/19797 PCT/US00/24967
R
12 at each occurrence, is independently selected from H, OH, Cl, F, Br, NR 15
R
16 -C(=O)NR15R 1 6
CF
3 acetyl,
SCH
3
S(=O)CH
3 S(=0)2CH 3 methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C 1
-C
2 haloalkyl, and C1-C 2 haloalkoxy; phenyl substituted with 0-4 R 1 2b;
C
3
-C
6 carbocycle substituted with 0-4 R 12 b; or 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 12 b;
R
12 b, at each occurrence, is independently selected from H, OH, Cl, F, Br, NR 1 5
R
1 6 CF3, acetyl, SCH 3
S(=O)CH
3 S(=0) 2
CH
3 methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Ci-C 2 haloalkyl, and C 1
-C
2 haloalkoxy;
R
13 at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Cl, F, Br, CN, NR 15
R
16 and CF 3
R
14 at each occurrence, is independently selected from H, phenyl, benzyl, methyl, ethyl, propyl, and butyl;
R
15 at each occurrence, is independently selected from H, methyl, ethyl, propyl, or butyl;
R
16 at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
R
18 at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl and, phenethyl; and -42- WO 01/19797 PTUO/46 PCT/USOO/24967
R
19 at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl and, phenethyl.
In a preferred embodiment the present invention provides a compound of Formula (Ia) wherein: Q is -CH 3
-CH
2
CH
3
-CH
2
CH
2
CH
3
-CH
2
CH
2
CH
2
CH
3
-CH
2
CH
2
CH
2
CH
2
CH
3
-CH
2
CH
2
CH
2
CH
2
CH
2
CH
3 -CH (CR 3 2'
-CH(CH
3
)CH
2
CH
3
-CH
2
CH(CH
3 2
-CH
2
C(CH
3 3 -CF3, -CH 2
CF
3
-CH
2
CH
2
CF
3
-CH
2
CH
2
CH
2
CF
3
-CH=CH
2
-CH
2
CH=CH
2
-CH
2 C (CH 3
=CH
2
-CH-
2 CH=C (CH 3 2'
-CH
2
CH
2
CH=CH
2
-CH
2
CH
2 C (CH 3
=CH
2
-CH
2
CH
2 CH=C (CH 3 2' cis-CH 2
CH=CH(CH
3 cis-CH 2
CH
2
CH=CH(CH
3 trans-CH 2 CH=CH (CH 3 tr-ns-CH 2
CH
2 CH=CH (CH 3 -CinECH, -CH 2
-CH
2
C-=C(CH
3 cyclopropyl-, cyclobutyl-, cyclopentyl-, cyclohexyl-, cyclopropyl-CH2-, cyclobutyl-CH 2 cyclopentyl-CH2-, cyclohexyl-CH2-, cyclopropyl-CH 2 CH2-, cyclobutyl-CH2CH2-, cyclopentyl-CH2CH2-, cyclohexyl-CH 2 CH2-, phenyl-, 2-F-phenyl-, 3-F-phenyl-, 4-F-phenyl-, 4-methoxyphenyl-, 4-ethoxyphenyl-, 4 -propoxyphenyl-, phenyl-CH 2 (2-F-phenyl)CH 2 (3-F-phenyl)CH 2 (4-F-phenyl)CH 2 (2-Cl-phenyl)CH 2 (3-Cl-phenyl)CH2-, (4-Cl-phenyl)CH 2 (2,3-diF-phenyl)CH 2 (2,4-diF-phenyl)CH 2 5-diF-phenyl)CH 2 (2,6-diF-phenyl)CH 2 (3,4-diF-phenyl)CH 2 (3,5-diF-phenyl)CH 2 (2,3-diCl-phenyl)CH 2 (2,4-diCl-phenyl)CH 2 2 (2,6-diCl-phenyl)CH 2 (3,4-diCl-phenyl)CH 2 (3,5-diCl-phenyl)CH 2 -43- WO 01/19797 WO 0119797PCTIUSOO/24967 (3-F-4-C1-phenyl)CH 2 (3-F-5-C1-phenyl)CH 2 (3-C1-4-F-pheriyl)CH 2 2-furanyl-CH 2 3-furanyl-CH 2 2-thienyl-C1 2 3-thienyl-CH 2 2-pyridyl-CH 2 3-pyridyl-CH 2 4-pyridyl-CH 2 l-imidazolyl-CH 2 2-oxazolyl-CH2-, 4-oxazolyl-CH 2 5-oxazolyl-CH 2 3-isoxazolyl-CH 2 4-isoxazolyl-CH2-, 5-isoxazolyl-CH 2 phenyl-CH 2
CH
2 (2-F--phenyl)CH 2
CH
2 (3-F-phenyl)CH 2
CH
2 (4-F-phenyl)CH 2
CH
2 (2-C1-phenyl)CH 2
CH
2 (3-C1-phenyl)CH 2
CH
2 (4-Cl -phenyl) CH 2
CH
2 (2,3-diF-phenyl)CH 2
CH
2 (2,4-diF-phenyl)CH 2
CH
2 (2,5-diF-phenyl)CH 2
CH
2 (2,6-diF-phenyl)CH 2
CH
2 4-diF-phenyl)CH 2
CH
2 5-diF-phenyl)CH 2
CH
2 (2,3-diCl-phenyl)CH 2
CH
2 (2,4-diCl-phenyl)CH 2
CH
2 5-diCl-phenyl)CH 2
CH
2 6-diCl-phenyl)CH 2
CH
2 (3,4-diCl-phenyl)CH 2
CH
2 (3,5-diCl-phenyl)CH 2
CH
2 (3-F-4-C1-phenyl)CH 2
CH
2 (3-F-5-Cl-phenyl)CH 2
CR
2 furanyl -CH2CH 2 thienyl -CH 2
CH
2 pyridyl -CH 2
CH
2 1-imidazolyl-CH 2
CH
2 oxazolyl-CH 2
CH
2 isoxazolyl-CH 2 CH2-, 3, 5-dimethylisoxazol-4-yl-CH2CH 2 phenyl-propyl-; benzyl-CH(NH 2 benzyl-CH(NHC(=O)--O-tBu) benzyloxy-CH 2 pyrrolidin-2-yl-, or 3-t-butoxycarbonylpyrrolidin-2-yl-;
R
2 is H or methyl;
R
5 is -CH 3
-CH
2
CH
3
-CH
2
CH
2
CH
3
-CH(CH
3 2
-CH
2
CH
2
CH
2
CH
3 -CH (CH 3
CH
2 CH3, -CH 2 CH (CH3) 2' -CH 2 C (CH 3 3, -CH2CH 2
CH
2
CH
2
CH
3 -CH (CH 3
)CH
2
CH
2
CH
3
-CH
2 CH (CH 3
)CH
2
CH
3
-CH
2
CH
2 CH (CH 3 2, -CH (CH 2
CH
3 2,
-CF
3
-CH
2
CF
3
-CH
2
CH
2 CF3, -CH 2
CH
2
CH
2 CF3, -CH 2
CH
2
CH
2
CH
2
CF
3 -44- WO 01/19797 WO 0119797PCTfUS4JO/24967
-CH=CH
2
-CH
2
CH=CH
2
-CH
2
CH
2
CH=CH
2
-CH=CHCH
3 cis-CH 2
CH=CH(CH
3 trans-CH 2
CH=CH(CH
3 trans-CH 2
CH=CH(C
6 H5), -CH 2 CI{C (CH 3 2, cis-CH 2
CH=CHCH
2
CH
3 trans-CH 2
CH=CHCH
2
CH
3 cis-CH 2
CH
2
CH=CH(CH
3 trans-
CH
2
CH
2
CH=CH(CH
3 )L trans -CH 2
CH=CHCH
2
(C
6
H
5 -CSCH, -CH 2 CaCH, -CH 2 C-=C(CH3), -CH 2 C C(C 6
H
5
-CH
2
CH
2 C=-CH, -CH 2
CH
2
-CH
2
CH
2
C=-C(C
6
H
5
-CH
2
CH
2
CH
2 C=-CH, -CH 2
CH
2
CH
2
C=-C(CH
3
-CH
2
CH
2
CH
2
C=-C(C
6
H
5 cyclopropyl-CH 2 cyclobutyl-CH 2 cyclopentyl-CH 2 cyclohexyl-CH 2 (2-CH3-cyclopropyl) CH 2 (3-CH- 3 -cyclobutyl)CH 2 cyclopropyl-CH 2
CH
2 cyclobutyl-CH 2
CH
2 cyclopentyl-CH 2
CH
2 cyclohexyl-CH 2
CH
2 (2-CH 3 -cyclopropyl) CH 2
CH
2 (3 -CH 3 -eyelobutyl) CH 2
CH
2 phenyl-CH 2 (2-F-phenyl)CH 2 (3-F-phenyl)CH 2 (4-F-phenyl)CH 2 (3,5-diF-phenyl)CH 2 2-furanyl-CH 2 3-furanyl-CH 2 2-thienyl-CH 2 3-thienyl-CH 2 2-pyridyl-CH 2 3-pyridyl-CH 2 4-pyridyl-CH 2 1-imidazolyl-CH 2 2-oxazolyl-CH 2 4-oxazolyl-CH 2 5-oxazolyl-CH 2 3-isoxazolyl-CH 2 4-isoxazolyl-CH 2 5-isoxazolyl-CH 2 phenyl-CH 2
CH
2 (2-F-phenyl) CH 2
CH
2 (3-F-phenyl) CH 2
CH
2 (4-F-phenyl)CH 2
CH
2 furanyl-CH 2
CH
2 thienyl-CH 2
CH
2 pyridyl-CH 2
CH
2 1-imidazolyl-CH 2
CH
2 oxazolyl-CH 2
CH
2 isoxazolyl-CH 2
CH
2 methoxy, ethoxy, propoxy, or butoxy;
R
5 a is H; alternatively, R 5 and R 5 a may be combined to form cyclopentyl, cyclohexyl, or cycloheptyl; WO 01/19797 WO 0119797PCTIUSOO/24967 W is a bond, -CH 2 or -CH(CH3)-; is a bond; or Y is a bond, -CH 2 or -V-CE 2 V is a bond, -C 2 or
-N(CH
3 Z is H, F, Cl, Br, methyl, ethyl, n-propyl, i-propyl, nbutyl, i-butyl, s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Ci-phenyl, 3-Ci-phenyl, 4-Ci-phenyl, 2, 3-diF-phenyl, 2, 4-diF-phenyl, 2, 2, 6-diF-phenyl, 3, 4-diF-phenyl, 3, 2,3-diCl-phenyl, 2,4-diCi-phenyl, 2,6-diCi-phenyl, 3,4-diCi-phenyl, 3-F-4-C1-phenyl, 3-F-5-Cl-phenyl, 3-C1-4-F-phenyl, 2-MeO-phenyl, 3-MeO-phenyl, 4-Meo-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-MeS-phenyl, 3-MeS-phenyl, 4-MeS-phenyl, 2-CF 3 O-phenyl, 3-CF3O-phenyl, 4-CF 3 O-phenyl, furanyl, thienyl, pyridyl, 2-Me-pyridyl, 3-Me-pyridyl, 4-Me-pyridyl, 1-imidazolyl, oxazolyl, isoxazolyl, 1-benz imidazolyl, morpholino, N-piperinyl, phenyl-CH 2 (2-F-phenyl)CH 2 (3-F-phenyl)CH 2 -46- WO 01/19797 WO 0119797PCT/USOO/24967 (4-F-phenyl)CH 2 (2-C1--phenyl)CH2-, (3-C1-phenyl)CH 2 (4-Cl-phenyl)CH 2 3-diF-phenyl)CH2-, (2,4-diF-phenyl)CH 2 (2,5-diF-phenyl)CH 2 (2,6-diF-phenyl)CH 2 (3,4-diF-phenyl)CH 2 (3,5-diF-phenyl)CH 2 (2,3-diCl-phenyl)CH 2 (2,4-diCl-phenyl)CH 2 (2,5-diCl-phenyl)CH 2 (2.6-diCl-phenyl)CH 2 (3,4-diCl-phenyl)CH 2 2 (3-F-4-Cl-phenyl)CH 2 (3-F-5-C1-phenyl)CH 2 (3-C1-4-F-phenyl) CH 2 (2-MeO-phenyl)CH 2 (3-MeO-phenyl)CH 2 (4-MeO-phenyl) CH 2 (2-Pho-phenyl) CH-2-, (3-PhO-phenyl)CH 2 (4-PhO--phenyl)CH 2 (2-Me-phenyl)CH 2 (3-Me-phenyl)CH 2 (4-Me-phenyl)CH 2 (2-MeS-phenyl) CH 2 (3-MeS-phenyl) CH 2 4-MeS-phenyl) CH 2 (2-CFjO--phenyl)CH 2 (3-CF 3 O-pheriyl)CH 2 (4-CF 3 O-phenyl)CH 2 (furanyl)CH 2 (thienyl)CH 2 (pyridyl)CH 2 (2-Me--pyridyl)CH 2 (3-Me-pyridyl)CH 2 (4-Me-pyridyl)CH 2 (1-imidazolyl)CH 2 (oxazolyl)CH 2 (isoxazolyl)CH 2 (1-benzimidazolyl)CH 2 (cyclopropyl) CH 2 (cyclobutyl) CH 2 (cyclopentyl)CH2-, (cyclohexyl)CH 2 (morpholino)CH 2 (N-pipridinyl)CH 2 phenyl-CH 2 CH2-, (phenyl) 2
CHCH
2 (2-F-phenyl) CH 2
CH
2 (3-F-phenyl)CH 2
CH
2 (4-F-phenyl)CH 2
CH
2 (2-C1-phenyl)CH 2
CH
2 (3-C1-phenyl)CH 2
CH
2 (4-Cl-phenyl)CH 2
CH
2 3-diF-phenyl) CH 2
CH
2 (2,4-diF-phenyl)CH 2
CH
2 5-diF-phenyl)CH 2
CH
2 6-diF-phenyl)CH 2
CH
2 4-diF-phenyl)CH 2
CH
2 (3,5-diF-phenyl)CH 2
CH
2 (2,3-diCl-phenyl)CH 2
CH
2 (2,4-diCl-phenyl)CH 2
CH
2 (2,5-diCl-phenyl)CH 2
CH
2 (2,6-diCl-phenyl)CH 2
CH
2 (3,4-diCl--phenyl)CH 2
CH
2 (3,S-diCl-phenyl)CH 2
CH
2 (3-F-4-C1-phenyl)CH 2
CH
2 (3-F-5-C1-phenyl)CH 2
CH
2 (3-C1-4-F-phenyl)CH 2
CH
2 (2-Meo-phenyl)CH 2
CH
2 (3-MeO-phenyl)CH 2
CH
2 (4-Meo-phenyl)CH 2
CH
2 (2-Me-phenyl)CH 2
CH
2 (3-Me-phenyl) CH 2
CH
2 (4-Me-phenyl)CH 2
CH
2 (2-MeS-phenyl) CH 2
CH
2 (3-MeS-phenyl) CH 2
CH
2 -47- WO 01119797 WO 0119797PCTfUSOO/24967 (4-MeS-phenyl) CH 2
CH
2 (2-CF 3 O-phenyl)CH 2
CH
2 (3-CF3O-phenyl)CH 2
CH
2 (4-CF 3 O--phenyl)CH 2
CH
2 (furanyl)CH 2
CH
2 (thienyl)CH 2
CH
2 (pyridyl) CH 2
CH
2 (2 -Me -pyr idyl) CH 2
CH
2 (3 -Me -pyr idyl) CH 2
CH
2 (4-Me-pyridyl)CH 2
CH
2 (imidazolyl)CH 2
CH
2 (oxazolyl)CH 2 CH2-, (isoxazolyl)CH 2
CH
2 (benzimidazolyl) CH 2
CH
2 (cyclopropyl) CH 2
CH
2 (cyclobutyl)CH2CH 2 (cyclopentyl) CH 2
CH
2 (cyclohexyl)CH 2
CH
2 (morpholino)CH 2
CH
2 Or (N-pipridinyl)CH 2
CH
2
R
11 at each occurrence, is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sbutyl, t-butyl, phenyl, benzyl, phenethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, 2-F-phenyl-, 3-F-phenyl, 4-F-phenyl, 4-Cl-phenyl, 4-CH 3 phenyl, 4-MeO-phenyl-, 4-CF 3 -phenyl, (4-F-phenyl)CH 2 (4-Cl-phenyl)CH 2 (4-CH 3 phenyl)CH 2 (4-CF 3 -phenyl)CH 2 (4-F-phenyl)CH 2
CH
2 (4-Cl-phenyl)CH 2
CH
2 (4-CH 3 -phenyl)CH 2
CH
2 (4-CF 3 -phenyl)CH 2
CH
2 pyridin-2-yl-, pyridin-3-yl-, 4-CF 3 -pyridin-2-yl-, 4-CH 3 -pyridin-2-yl-, thiazol-2-yl-, azapan-l-yl, N,N-dimethylamino, N,N-diethylamino, N,Ndipropylanino, and N,N-dibutylamino; and
R
13 at each occurrence, is independently selected from H, MeO, F, and Cl.
In a preferred embodiment the present invention provides a compound of Formula of Formula (Ic); R5aH 0 OHO 0 R1 -48- WO 01/19797 WO 0119797PCTIUSOO/24967 (Ic) or a pharmaceutically acceptable salt form or prodrug thereof.
[10] In a preferred embodiment the present invention provides a compound of Formula (Id); R~H w OH 0 N\ R 1 3 (Id) or a pharmaceutically acceptable salt form or prodrug thereof.
till In a preferred embodiment the present invention provides a compound of Formula (Ie): R~aH 0 0 N NXY- OHO0R1 (Te) or a pharmaceutically acceptable salt form or prodrug thereof.
[12] In a preferred embodiment the present invention provides a compound selected from: 3- -Cyclopentylmethyl-3 phenylpentyl)amino-l-methyl- 5-phenyl-2, 3-dihydro-lH-l, 4benzodiazepin-2-one; 3- -Cyclopentylmethyl-3 phenylpentyl) amino-l-methyl-5- (4-f luoro-phenyl) -2,3dihydro-lH-1, 4-benzodiazepin-2-one; -49- WO 01/19797 WO 0119797PCTUSOO/24967 3- -Benzyl-3 methyl-5-phenyl-2, 3-dihydro-1H-1, 4-benzodiazepin-2-one; 3- -Isopropyl-3 1-methyl-5--phenyl-2, 3-dihydro-1H-1, 4-benzodiazepin-2-one; 3- -Cyclopentylxnethyl-3 -hydroxy1-1-oxo-4- difluorophenoxy) butyl) anino-1-methyl-5-phenyl-2, 3-dihydro- 1H-1, 4-benzodiazepin-2-one; 3- -Isobutyl-3 -hydroxyl-1-oxo-4- difluorophenoxy)butyl)amino-l-methyl-5-phenyl-2 ,3-dihydro- 1H-1, 4-benzodiazepin-2-one; 3- -Cyclopentylmethyl-3 -hydroxyl-1-oxo-4phenoxybutyl)amino-7-chloro-1-methyl-5-phenyl-2, 3-dihydro- 1H-1, 4-benzodiazepin-2-one; 3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-4-phenoxybutyl)anino- 7-chloro-l-methyl-5-(4-fluorophenyl)-2,3-dihydro-1H-1,4benzodiazepin-2 -one; 3- -Methyl-3 -hydroxyl-1-oxo-4cyclohexyloxybutyl)amino-1-methyl-5-phenyl-2, 3-dihydro-1H- 1, 4-benzodiazepin-2-one; Isobutyl -3 (S)-hydroxyl-l-oxo-4cyclohexyloxybutyl) amino-1-methyl-5-phenyl-2, 3-dihydro-1H- 1, 4-benzodiazepin-2-one; 3- -Methyl-3 (5)-hydroxyl-l-oxo-4-phenoxybutyl) amino-7chloro-1-methyl-5-phenyl-2, 3-dihydro-lH-1, 4-benzodiazepin- 2-one; WO 01/19797 WO 0119797PCT/USOO/24967 3- -Isobutyl-3 -hydroxyl-1--oxo-4-phenoxybutyl)amino- 7-chloro-1-methyl-5-phenyl-2, 3-dihydro-1H-1 .4benzodiazepin-2 -one; 3- (2 -Benzyl-3 (3)-hydroxyl-1-oxo-4cyclohexyloxybutyl) amino-7-chloro-1-methyl-5-phenyl-2, 3dihydro-lH-1, 4-benzodiazepin-2-one; 3- -Cyclopentylmethyl-3 (3)-hydroxyl-l-oxo-4cyclohexyloxybutyl)amino-7-chloro-1-methyl-5-phenyl-2, 3dihydro-1H-1, 4-benzodiazepin-2-one; 3- -Isobutyl-3 -hydroxyl-l-oxo-4cyclohexyloxybutyl) amino-7-chloro-l-methyl-5-phenyl-2, 3dihydro-1H-1, 4-benzodiazepin-2-one; 3- -Isopropyl-3 -hydroxyl-1-oxo-4cyclohexyloxybutyl) amino-7-chloro-l-methyl-5-phenyl-2, 3dihydro-1H-1, 4-benzodiazepin-2-one; 3- (2 -Methoxy-3 -hydroxyl-1-oxo-4- (4trifluoromethylbenzyloxy)butyl) axino-7-chloro-1-methyl-5phenyl-2, 3-dihydro-1H-1, 4-benzodiazepin-2-one; 3-(2(R)-Methyl-3(S)-hydroxyl-l-oxo-4-(2,4difluorobenzyloxy)butyl) axino-7-chloro-1-niethyl-5-phenyl- 2, 3-dihydro-1H-1, 4-benzodiazepin-2-one; 3- -Vinyl-3 -hydroxyl-1-oxo-4-benzyloxybutyl)amino-7chloro-1-methyl-5-phenyl-2, 3-dihydro-1H-1, 4-benzodiazepin- 2-one; 3- -Methyl-3 -hydroxyl-l-oxo-4cyclohexyloxybutyl)aniino-7-chloro-1-methyl-5-phenyl-2, 3dihydro-1H-1, 4-benzodiazepin-2-one; -51- WO 01/19797 WO 0119797PCTfUSOO/24967 3- -Isobutyl-3 (S)-hydroxyl-1-oxo-5- phenylpentyl) amino- 1-methyl-5-phenyl-2, 3-dihydro-1H-1, 4-benzodiazepin-2-one; 3- -Isobutyl-3 CS) -hydroxyl-1-oxo-3cyclopropyipropyl) amino-l-xnethyl--5-phenyl-2, 3-dihydro-lH- 1, 4-benzodiazepin-2-one; 3- -Isobutyl-3 -hydroxyl-1-oxo-heptyl)amino-1-methyl- 5-phenyl-2, 3-dihydro-1H-1, 4-benzodiazepin-2-one; 3- CR) -Isobutyl-3 (5)-hydroxyl-1-oxo-heptyl)amino-1methyl-5-phenyl-2,3-dihydro-lH-1, 4-benzodiazepin-2-one; -Isobutyl-3 CS) -hydroxyl-1-oxo-heptyl)amino-lmethyl-5-phenyl-2, 3-dihydro-1H-1, 4-benzodiazepin-2-one; 3- (2CR)-Isobutyl-3 -hydroxyl-1-oxo-nonyl)amino-1-methyl- 5-phenyl-2, 3-dihydro-1H-1, 4-benzodiazepin-2-one; 3-(2(R)-Isobutyl-3(S)-hydroxyl-l-oxo-hexyl)amino--methyl- 5-phenyl-2, 3-dihydro-lH-1, 4-benzodiazepin-2-one; 3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-4- phenylbutyl)amino- 1-methyl-5-phenyl-2, 3-dihydro-1H-1, 4-benzodiazepin-2-one; 3-(2(R)-Methyl-3 (S)-hydroxyl-1-oxo-5- phenylpentyl)amino-1methyl-5-phenyl-2. 3-dihydro-1H-1, 4-benzodiazepin-2-one; 3-(2(R)-Methyl-3(S)-hyclroxyl-1-oxo-6- phenylhexyl)amino-1methyl-5-phenyl-2. 3-dihydro-lH-1, 4-benzodiazepin-2-one; 3- (2CR)-Isobutyl-3 -hydroxyl-1-oxo-butyl)amino-1-methyl- 5-phenyl-2, 3-dihydro-lH-1, 4-benzodiazepin-2-one; 3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-octyl)amino-1-methyl- 5-phenyl-2, 3-dihydro-1H-1,4-benzodiazepin-2-one; -52- WO 01/19797 WO 0119797PCTUSOO/24967 3- -Methyl-3 -hydroxyl-1-oxo-heptyl)amino-1-methyl-5phenyl-2, 3-dihydro-1H-1, 4-benzodiazepin-2-one; 3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-3- phenylpropyl)axnino-1methyl-5-phenyl-2, 3-dihydro-1H-1, 4-benzodiazepin-2-one; 3- (2 -Methyl-3 -hydroxyl-1-oxo-5, hexyl)amino-1-methyl-5-phenyl-2, 3-dihydro-1H-1, 4benzodiazepin-2-one; 3- -Methyl-3 -hydroxyl-1-oxo-hexyl) phenyl-2, 3-dihydro-1H-1, 4-benzodiazepin-2-one; 3- -Methyl-3 -hydroxyl-1-oxo-3- (4propoxyphenyl) propyl) amino-1-methyl-5-phenyl-2, 3-dihydro- 1H-1, 4-benzodiazepin-2-one; 2- -cyclopropylmethyl-3- -hydroxyiheptanoic acid (2oxo-1- (3-phenoxybenzyl)azapan-3- -yl) amide; 2(R) -cyclopropylmethyl-5- 5-difluorophenyl) hydroxypentanoic acid (2-oxo-l- (3-phenoxybenzyl) azapan-3- -yl) amide; 4-cyclopentyl-2- -cyclopropylmethyl-3- -hydroxybutanoic acid (2-oxo-1-(3-phenoxybenzyl)azapan-3-(S)-yl) amide; 2- -cyclopropylmethyl-3- -hydroxyheptanioc acid bromo-3-pyridinyl)inethyl-2-oxo-azapan-3- -yl) amide; 3- -cyclopropylmethyl-3- -hydroxyl-1- (2-f luorophenyl) -1-methyl-2, 3-dihydro-1H- 1, 4-benzodiazepin-2-one; 3-(2-(R)-cyclopropylrnethyl-3-(S)-hydroxyl-1- (azapan-1-yl) -l-methyl-2,3-dihydro-lH- 1, 4-benzodiazepin-2-one; -53- WO 01/19797 WO 0119797PCTUSOO/24967 3- -cyclopropylmethyl-5- 5-difluorophenyl) -3 hydroxyl-1-oxopentyl)arnino-1-methyl-5-(pyridn-2-yl) -2,3dihydro-1H-1, 4-benzodiazepin-2-one; 3- -cyclopropylmethyl-3- -hydroxyl-1- (4-chiorophenyl) 3-dihydro-1H- 1, 4-benzodiazepin-2-one; 3-(2-CR)-cyclopropylmethyl-3-(S)-hydroxyl-1oxoheptyl) amino-5- (4-methoxyphenyl) 1-methyl-2, 3-dihydro-1H- 1, 4-benzodiazepin-2-one; 3- -cyclopropylmethyl-3- -hydroxyl-1oxoheptyl)amino-5- (4-methoxyphenyl) -1-methyl-2,3-dihydro- 1H-1, 4-benxodiazepin-2-one; 3-CS) -(4-cyclopentyl-2- CR) -cyclopropylmethyl-3- CS) hydroxyl-1-oxobutyl) amino-1-methyl-5-phenyl-2, 3-dihydro-1H- 1, 4-benzodiazepin-2-one; 3-CS) CR) -cyclopropylmethyl-3- CS) -hydroxyl-1-oxohept-6enyl) amino-1-methyl-5-phenyl-2, 3-dihydro-lH-1, 4benzodiazepin-2 -one; 3- -cyclopropylmethyl-3- (5)-hydroxyl-1-oxohept-6enyl)amino-1-methyl-5-(4-trifluoromethyl-phenyl)-2,3dihydro-1H-1, 4-benzodiazepin-2-one; 3-(S)-(2-(R)-cyclopropylmethyl-5-(3,5-dimethylisoxazol-4yl) CS) -hydroxyl-l-oxopentyl)amino-1-methyl-5-phenyl-2, 3dihydro-1H-1, 4-benzodiazepin-2-one; 3- CR) -cyclopropylmethyl-3- CS) -hydroxyl-loxoheptyl)arnino-7-chloro-1-methyl-5-phenyl-2, 3-dihydro-lH- 1, 4-benzodiazepin-2-one; -54- WO 01/19797 WO 0119797PCT/USOO/24967 3- -cyclopropylmethyl-3-CS) -hydroxyl-1oxoheptyl)amino-l-methyl- (pyridin-2-yl) 3-dihydro-lH-1, 4 benzodiazepin-2 -one; 3-(2-(R)-cyclopropylmrethyl-3-(S)-hydroxyl-1oxoheptyl) arino-5- (4-f luorophenyl) -1-methyl-2, 3-dihydro-1H- 1, 4-benzodiazepin-2-one; 3- -cyclopropylmethyl-3- -hydroxyl-1oxoheptyl)anino--nethyl-5- (4-trifouoromethylphenyl) -2,3dihydro-lH-1, 4-benzodiazepin-2-one; 3- (5-cyc2lopentyl-2- CR) -cyclopropylmethyl-3- (S)-hydroxyl-1- Cpyridin-2-yl) 3-dihydro-iM- 1, 4-benzodiazepin-2-one; 3- CR) -iso-buty2l-3- -hydroxyl-1-oxoheptyl)amino-lmethyl-5-(4-trifluoromethylphenyl) -2 ,3-dihydro-1H-1. 4benzodiazepin-2 -one; 3-CS) -cyclopropylmethyl-3- (thiophen-2-yl)amino-l-methyl-5-phenyl-2, 3-dihydro-1H-1, 4benzodiazepin-2 -one; 3-CS)-(2-(R)-cyclopropylmethyl-5-(furan-2-yl)3-CS)hydroxyl-1-oxopentyl) aiino-1-methyl-5-phenyl-2, 3-dihydro- 1H-1, 4-benzodiazepin-2-one; 3- C5-cyclopentyl-2- CR) -cyclopropylmethyl-3- CS) -hydroxyl-1oxopentyl) amino-5- C4-fluorophenyl) -l-methyl-2, 3-dihydro-1H- 1, 4-benzodiazepin-2-one; 3-CS) -cyclopropylmethyl-5- 5-difluorophenyl) -3- CS) -hydroxy-1-oxopentyl)amino-1-methyl-5-phenyl-2, 3dihydro-lH-1, 4-benzodiazepin-2-one; WO 01/19797 WO 0119797PCT/USOO/24967 3- CS) -hydroxyl-2- -(thiophen-2-yl)methyl-loxoheptyl) axino-1-rethyl-5-phenyl-2, 3-dihydro-1H-1, 4benzodiazepin-2 -one; 3-(S)-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-loxoheptyl)amino-7-methyl-5-phenyl-2, 3-dihydro-1H-1, 4benzodiazepin-2 -one; 3- CR) -cyclopropylmethyl-3- CS) -hydroxyl-1oxoheptyl)arnino-7-methoxy-1-methyl-5-phenyl-2, 3-dihydro-iR- 1, 4-benzodiazepin-2-one; 3-CS) CR) -cyclobutylmethyl-3- -hydroxyl-1oxoheptyl )amino-1-rrethyl-5-phenyl-2, 3-dihydro-1H-1, 4benzodiazepin-2 -one; 3- C2- CR) 5-difluorobenzyl) -3-CS) -hydroxyl-1oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydor-lH-1, 4benzodiaxepin-2 -one; 3-CS) furan-2-yl)methyl-3- CS) -hydroxyl-1oxoheptyl) amino-1-methyl-5-phenyl-2, 3-dihydro-1H-1, 4benzodiazepin-2 -one; 3-C2-CR)-cyclopropylmethyl-3-(S)-hydroxl-1-oxo-5- Cpyridin-2-yl) 3-dihydro-1Hbenzodiazepin-2 -one; 3- CR) -iso-butyl-3- CS) -hydroxyl-1-oxoheptyl)amino-5- (4fluorophenyl) -1-nethyl-2, 3-dihydro-1H-1, 4-benzodiazepin-2one; 3-C2- CR) -iso-butyl-3- CS) -hydroxyl-1-oxoheptyl)amino-5- (4fluorophenyl) -1-methyl-2, 3-dihydro-1H-1, 4-benzodiazepin-2one; -56- WO 01/19797 WO 0119797PCT/USOO/24967 3- CR) -cYcloPropylmethyl-3- phenylpentyl) amino-1-methyl-5-phenyl-2, 3-dihydro-lH-1, 4benzodiazepin-2-one; 3-(2-(R)-cyclopropylmethyl-5-(furan-2-yl)-3-(S)-hydroxyl-1oxopentyl) amino-1-methyl-5- (4-trifluoromethyiphenyl) -2,3dihydro-1H-1,4-benzodiazepin-2-one; 3-(5-cyclopentyl-2--(R)-cyclopropylmethyl-3-(S)-hydroxyl-1- (4-trifluoromethyiphenyl) -2,3dihydro-1H-1, 4-benzodiazepin-2-one; 3- -cyclopropylmethyl-3- -hydroxyl-l-oxooctyl)amino- 1-methyl-5- (4-trifluoromethyiphenyl) 3-dihydro-lH-1, 4benzodiazepin-2-one; 3- -cyclopropylmethyl-3- CS) -hydroxyl-1-oxononyl)amino- 1-methyl-5-(4-trifluoromethylphenyl)-2..3-dihydro-1H-1,4benzodiazepin-2-one; 3- CR) -cyclopropylmethyl-3- -hydroxyl-1oxoheptyl) amino-1-methyl-5- (4-trifluoromethyl (pyridin-2yl) 3-dihydro-lH-1,4-benzodiazepin-2-one; 3- CR) -cyclobutylmethyl-3- -hydroxyl-1-oxoheptyl) amino- (4Otrifluoromethylphenyl) 3-dihydro-lH-1, 4benzodiazepin-2 -one; 3- CR) -cyclopentylmethyl-3- CS) -hydroxyl-1oxoheptyl) amino-l-methyl-5- (4-trifluoromethyiphenyl) -2,3dihydro-1H-1, 4-benzodiazepin-2-one; 3-(2-CR)-cyclopropylmethyl-3-(S)-hydroxyl-1- C4-methyl-2-pyridiyl) -2,3dihydro-1H-1, 4-benzodiazepin-2-one; -57- WO 01/19797 WO 0119797PCTIUSOO/24967 3- CR) -cyclopropylmethyl-3- -hydroxyl-1- (4-methyl-2-pyridyl) -2,3dihydro-1H-1, 4-benzodiazepin-2-one; 3- CR) -cyclopropylmethyl-3- -hydroxyl-1-oxobutyl) amino- (4-trifluoromethylpheny1) 3-dihydro-lH-1, 4benzodiazepin-2-one; 3-(S)-(2-(R)-(3-butenyl)-3-(S)-hydroxyl-l-oxoheptyl)amino- 1-methyl-5-phenyl-2, 3-dihydro-1H-1, 4-benzodiazepin-2-one; 3- CR) -(3-methylbutyl) 3- -hydroxyl-1oxoheptyl)amino-l-methyl-5-phenyl-2, 3-dihydro-1H-1, 4benzodiazepin-2-one; 3- -ethyl-3- CS) -hydroxyl-1-oxoheptyl) amino-lmethyl-5-phenyl-2, 3-dihydro-1H-1,4-benzodiazepin-2-one; 3-(S)-(2-CR)-propyl-3-(S)-hydroxyl-l-oxoheptyl)anino-1methyl-5-phenyl-2, 3-dihydro-1,4-benzodiazepin-2-one; 3- CR) -butyl-3- CS) -hydroxyl-1-oxoheptyl) amino-imethyi-5-phenyl-2, 3-dihydro-1H-1, 4-benzodiazepin-2-one; 3- -amino-3- -hydroxyl-2- phenylpentyl) amino-7-chloro-5- (2-f luorophenyl) -1-methyl- 2, 3-dihydro-1H-1, 4-benzodiazepin-2-one; 3-(4-(S)-(tert-butoxycarbonylamino-3-(R)-hydroxyl-2-(R)methyl-1-oxo-5-phenylpentyl)amino-7-chloro-5- (2fluorophenyl) -1-methyl-2, 3-dihydro-1H-1, 4-benzodiazepin-2one; 3-(3-(tert-butoxycarbonylpyrrolidin-2-(R)-yl)-3-(R)hydroxyl-2-CR)-methyl-1-oxopropyl)amino-7-chloro-5-(2- -58- WO 01/19797 WO 0119797PCTIUSOO/24967 fluorophenyl) -1-methyl-2, 3-dihydro-1H-1, 4-benzodiazepin-2one; 3- -hydroxyl-2- -methyl-1-oxo-3- Cpyrrolidin-2- CR) yl)propyl)-amino-7-chloro-5-C2-fluorophenyl)-1-methyl-2,3dihydro-1H-1, 4-benzodiazepin-2-one; 3- (4-benzyloxy-3- CR) -hydroxyl-2- CR) -iso-propyl-1-oxobutylaxino-7-chloro-1-methyl-5-phenyl-2, 3-dihydro-1H-1, 4benzodiazepin-2-one; 2- CS) -amino-3- CS) -hydroxyl-2- phenylpentyl) amino-7-chloro-5- C2-flourophenyl) -1-methyl- 2, 3-dihydro-lH-1, 4-benzodiazepin-2-one; 2- C4- S) -(Ctert-butoxycarbonylamino-3- CS)hydroxyl-2- CS) methyl-l-oxo-5-phenylpentyl)anino-7-chloro-5- C2fluorophenyl) -1-methyl-2, 3-dihydro-lH-1, 4-benzodiazepin-2one; 3- CR) -cyclopropylniethyl-3- CS) -hydroxyl-1oxoheptyl) aiino-l-methyl-5- (thiazol-2-yl) 3-dihydro-lH- 1, 4-benzodiazepin-2-one; 3-C2-(R)-cyclopropylmethyl-3-CS)-hydroxyl-1- Cthiazol-2-y1) -2,3dihydro-1H-1, 4benzodiazepin-2-one; 3- CR) -cyclopropylmethyl-3- CS) -hydroxyl-loxoheptyl)amino-1-cyclopropylmethyl-5- (4trifluoromethyiphenyl) 3-dihydro-lH-1, 4-benzodiazepin-2one; 3-C2- CR) -cyclopropylmethyl-3- (5)-hydroxyl-1oxoheptyl)antino-l-benzyl-5- (4-trifluoromethyiphenyl) -2,3dihydro-lH-1, 4-benzodiazepin-2-one; -59- WO 01/19797 WO 0119797PCTUSOO/24967 3- -cyclopropylmethyl-3- -hydroxyl-1oxoheptyl)amino-1- (3-phenoxybenzyl) (4-trifluoromethylphenyl) 3-dihydro-H-1, 4-benzodiazepin-2-one; 3- -cyclopropylmethyl-3- -hydroxyl-1oxoheptyl) amino-i- (3-pyridinylmethyl) (4-trifluoromethylphenyl) 3-dihydro-1H-1, 4-benzodiazepin-2-one; 3- -cyclopropylmethyl-3- -hydroxyl-loxoheptyl) axino-1-methyl-5- (4-trifluoromethyl-phenyl) -2,3dihydro-lH-1, 4-benzodiazepin-2-one; 3-(2-(S)-cyciopropylmethyl-3-(R)-hydroxyl-1oxoheptyl) aiino-1-methyi-5- (4-trifluoromethyiphenyl) -2,3dihydro-1H-1, 4-benzodiazepin-2-one; 3- -cyclopropylmethyl-3- -hydroxyl-1oxoheptyl) amino-1-metzhyl-5- (4-trifluoromethyiphenyl) -2,3dihydro-1H-1, 4-benzodiazepin-2-one; 3- -cyclopropyinmethyl-3- -hydroxyl-1oxoheptyi)amino-1-methyl-5- (4-trifluoromethyiphenyl) -2,3dihydro-1H-1, 4-benzodiazepin-2-one; 3- -cyclopropylmethyi-3- -hydroxyl-loxoheptyl)amino-1-methyl-5- (4-trifluoromethyiphenyl) -2,3dihydro-1H-1, 4-benzodiazepin-2-one; 3- -cyclopropylmethyl-3- -hydroxyl-3- -methyl-i- (4-trifluoromethyl-phenyl) -2,3dihydro-1H-1, 4-benzodiazepin-2-one; WO 01/19797 WO 011979?PCT/USOO/24967 3- -CYcloPropylmethyl-3- (5)-hydroxyl-1oxoheptyl) amino-i- (3 -phenoxybenzyl) -5-rnethyl-2, 3-dihydro- 1H-1, 4-benzodiazepin-2-one; 3-(2-(R)-cyclopropylmehtyl-3-(S)-hydroxyl-1oxoheptyl)amino-1-benzyl-5-nethyl-2, 3-dihydro-lH-1, 4benzodiazepin-2 -one; 3- CS) -acetoxy-2- -iso-butyl-1-oxoheptyl) aiino-5- (4ifluorophenyl) -1-methyl-2, 3-dihydro-1H-1, 4-benzodiazepin-2one; 3- -(5-cyclopentyl-2- CR) -cyclopropylmethyl-3- -methoxy- I-oxopentyi)amino-1-methyl-5-phenyl-2, 3-dihydro-1H-1,4benzodiazepin-2-one; 1- (1-hydroxypentyl) cyclohexanecarboxylic acid(5- (4fluorophenyl) -i-rethyl-2-oxo-2, 3-dihydro-1H-1, 4benzodiazepin-3 -yl )amide; 3- -cyclopropylmethyl-3- CS) -hydroxyl-1- 7H-dibenzo [b,dazepin-6-one; 3- -cyclopropylmethyl-3- (5)-hydroxyl-1-oxooctyl)anino- 5-rethyl-5H,7H-dibenzo~b,d]azepin-6-one; 3- -cyclopropylmethyl-3- (5)-hydroxcyl-l-oxononyl) amino- 7H-dibenzo[b,dlazepin-6-one; 3-(2-(R)-cyclopropylmethyl-5-(furan-2-yl)-3-(S)-hydroxyl-1oxopentyl) amino-5-methyl-5H, 7H-dibenzo dl azepin-6-one; 2- -cyclopropylmethyl-3- (S)-hydroxyl-heptanoic acid (2oxo-1- (3-phenylamino-benzyl)azapan-3- -yl) amide; -61- WO 01/19797 WO 0119797PCT/USOO/24967 3- -CYclopropylmethyl-3- (S)-hydroxyl-loxoheptyl)axnino-5-cyclopentyl-1-methyl-2, 3-dihydro-lH-1, 4benzodiazepin-2 -one; 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-loxoheptyl)amino-5-benzyl-l-methyl-2, 3-dihydro-lH-1, 4benzodiazepin-2 -one; 3- -cyclopropylmethyl-3- -hydroxyl-1oxoheptyl)amino-5-benzyl-l-butyl-2, 3-dihydro-lH-1, 4benzodiazepin-2 -one; 3- -cyclopropylmethyl-3- CS) -hydroxyl-1oxoheptyl) amino-5-cycloheptyl-1-methyl 3-dihydro-lH-1, 4benzodiazepin-2-one; 3- -cycloropylmethyl-3- -hydroxyl-1-oxoheptyl) amino- 1-benzyl-5-cycloheptyl-2, 3-dihydro-lH-1, 4-benzodiazepin-2one; 3- CR) -cyclopropylmethyl-3- -hydroxyl-1oxoheptyl) amino-1-butyl-5-cycloheptyl-2 ,3-dihydro-1H-1. 4benzodiazepin-2 -one; 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-loxoheptyl)amino-1- (2-pyridinylmethyl) (4trifluoromethyiphenyl) 3-dihydro-lH-1, 4-benzodiazepin-2one; 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-loxoheptyl) amino-i- (3-pyridinylmethyl) (2-f luorophenyl) 2, 3-dihydro-lH-1, 4-benzodiazepin-2-one; 3- CS) -cyclopropylmethyl-3- CS) -hydroxyi-1oxopentyl)amino-1- (3-pyridynylmethyl) (4trifluoromethyiphenyl) 3-dihydro-1H-1, 4-benzodiazepin-2one; -62- WO 01/19797 WO 0119797PCTIUSOO/24967 3- (2-1 -Cyclopropyimethyl-3- (S)-hydroxyl-ioxoheptyl) amino-l-methyl-5- N-dibutylamino) 3-dihydro- 1H-1, 4-benzodiazepin-2-one; 3- -Cyclopropyimethyl-3- CS) -hydroxyl-1oxoheptyl)amino-l-n-butyl-5-t-butyl-2,3-dihydro-lH-1,4benzodiazepin-2 -one; 3-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1oxoheptyl) amino-i- (2-oxo-3, 3-dimethylbutyl) -5-n-butyl-2, 3dihydro-1H-1, 4-benzodiazepin-2-one; 3- -Cyclopropylmethyl-3- -hydroxyl-1oxoheptyl)amino-1-benzyl-5-t-butyl-2, 3-dihydro-1H-1, 4benzodiazepin-2 -one; 3- -Cyclopropylxnethyl-3- -hydroxyi-1oxoheptyl) amino-i- (2-picolyl) -5-n-butyl-2, 3-dihydro-1H-1, 4benzodiazepin-2-one; 3- CR) -Isobutyl-3- (S)-hydroxyl-1-oxoheptyl)amino-1methyl-5-homopiperidino-2, 3-dihydro-1H-1, 4-benzodiazepin-2one; 3- CR) -cyciopropylmethyl-1, 3-dioxoheptyl)anino-l-rnethyi- (4-trifluoromethyiphenyl) 3-dihydro-1H-1, 4benzodiazepin-2-one; and 1-pentyrylcyciohexanecarboxyiic acid (4-f luorophenyl) -1methyi-2-oxo-2, 3-dihydro-1H-1, 4-benzodiazepin-3-yi) amide.
[13] In a preferred embodiment the present invention provides a compound of Formula wherein the stereochemistry of carbon 3 in lactam, ring B is of the S configuration.
-63- WO 01/19797 PCT/US00/24967 [14] In a preferred embodiment the present invention provides a compound of Formula wherein the stereochemistry of carbon 3 in lactam ring B is of the R configuration.
In a preferred embodiment the present invention provides a compound of Formula (Ib)
R
s R H 0 N W-X-Y-Z (Ib) wherein: Ring B is selected from: 0 I 3 R 3 and
Q
1 is Ci-C 6 alkyl substituted with 0-3 Rla;
C
2
-C
6 alkenyl substituted with 0-3 Ra.;
C
2
-C
6 alkynyl substituted with 0-3 Rla;
C
3 -C10 cycloalkyl substituted with 0-3 Rib;
C
3
-C
1 0 carbocycle substituted with 0-3 Rib;
C
6
-C
10 aryl substituted with 0-3 R 1 b; or 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 Rlb; Rl a at each occurrence, is independently selected from H, C1-C 6 alkyl, OR 1 4 Cl, F, Br, I, NR 1 5
R
1 6
CF
3 C3-C 10 carbocycle substituted with 0-3 Rlb;
C
6 -CIo aryl substituted with 0-3 Rib; and -64- WO 01/19797 WO 0119797PCT/USOO/24967 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 memnbered heterocycle is substituted with 0-3 Rib; Rib, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2
NR
1 5
R
1 6
CF
3 acetyl, SCH 3 S(=O)CH3, S(=O) 2
CH
3 CI-C6 alkyl, C 1
-C
4 alkoxy, Cl-C 4 haloalkyl, Cl-C 4 haloalkoxy, C 1
-C
4 haloalkyl-S-, and
(C
1
-C
6 alkyl)-O-C(=O)-;
R
5 is OR 1 4
C
1
-C
6 alkyl substituted with 0-3 R~b;
C
2
-C
6 alkenyl substituted with 0-3 R5b; or
C
2
-C
6 alkynyl substituted with 0-3
R
5 a is H, methyl, ethyl, propyl, butyl, or C 2
-C
4 alkenyl; alternatively, R 5 and R 5 a may be combined to form a C 4
-C
7 cycloalkyl ring; at each occurrence, is independently selected from: H, methyl, ethyl, propyl, butyl, CF3, OR 1 4 Cl, F, Br, I,
NR
1 5
R
1 6
C
3 cycloalkyl substituted with 0-3 R 5 c;
C
3
-C
7 carbocycle substituted with 0-3 R 5 c; phenyl substituted with 0-3 R 5 c; and 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 RSc;
R
5 c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2
NR
1 5
R
1 6
CF
3 acetyl, SCH 3
S(=O)CH
3 S(=0) 2
CH
3
C
1
-C
4 alkyl, Cl-C3 alkoxy, Cl-C 2 haloalkyl, and CI-C 2 haloalkoxy; WO 01/19797 WO 0119797PCT/USOO/24967 W is (CHR 8 )pp is 0 or 1;
R
8 is H, methyl, or ethyl; X is a bond; phenyl substituted with 0-2 RXb;
C
5
-C
6 cycloalkyl. substituted with 0-3 RXb; or 5 to 6 membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-2 RXb; R~b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, N0 2
NR
1 5 R1 6
CF
3 acetyl, SCH 3
S(=O)CH
3
S(=O)
2
CH
3 Cl-C 6 alkyl, Cj-C 4 alkoxy, Cl-C 4 haloalkyl, C 1
-C
4 haloalkoxy, and Cl-C 4 haloalkyl-S-; Y is a bond, -CH 2
-V-CH
2 or -CH 2
-V--CH
2 V is a bond, 2 or -N (R1 9 Z is H, F, Cl, Br, Cl-C 4 alkyl. substituted with 0-2 Ri 2
C
2
-C
4 alkenyl. substituted with 0-2 R 12
C
2
-C
4 alkynyl substituted with 0-2 Ri 2
C
6
-CI
0 aryl substituted with 0-4 Rl2b; C3-C 6 carbocycle substituted with 0-4 R12b; or to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 mnembered heterocycle is substituted with 0-3 Ri2b; -66- WO 01/19797 WO 9119797PCT[USOO/24967
R
11 at each occurrence, is independently selected from H, NR1 8
R
1 9 C(=O)Rl 7 C(=O)0R 1 7
C(=O)NR
1 8 Rl 9 S 2 NR1 8
R
1 9
CF
3
C
1
-C
6 alkyl substituted with 0-1 Rila; phenyl substituted with 0-3 R11b;
C
3
-C
6 carbocycle substituted with 0-3 R11b; or to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R11b; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
R
11 a, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Cl, F, NR 1 5
RI
6
CF
3 pheniyl. substituted with 0-3 R11b;
C
3
-C
6 carbocycle substituted with 0-3 R11b; or to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R11b; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrirnidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl; R11b, at each occurrence, is independently selected from H, OH, Cl, F, NR 1 5
R
1 6
CF
3 acetyl, SCH 3
S(=O)CH
3
S(=O)
2
CH
3 methyl, ethyl, propyl, butyl, rnethoxy, ethoxy, propoxy, Cl-C2 haloalkyl, and Cl-C 2 haloalkoxy; -67- WO 01/19797 WO 0119797PCT/IJSOO/24967
R
1 2 at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2
NR
1 5
R
1 6
-C(=O)NR
1 5 Rl 6
CF
3 acetyl, SCH 3
S(=O)CH
3
S(=O)
2
CH
3
C
1
-C
6 alkyl, Cl-C 4 alkoxy, Cl-C 4 haloalkyl, Cl-C 4 haloalkoxy, and Cl-C 4 haloalkyl-S-;
C
6
-C
1 0 aryl. substituted with 0-4 R12b;
C
3
-C
1 0 carbocycle substituted with 0-4 R1 2 b; or to 10 memnbered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 memnbered heterocycle is substituted with 0-3 R1 2 b; R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2
NR
1 5
R
1 6
CF
3 acetyl, SCH 3
S(=O)CH
3
S(=O)
2
CH
3 Cl-C 6 alkyl, Cj-C 4 alkoxy, C 1
-C
4 haloalkyl, Cl-C 4 haloalkoxy, and Cl-C 4 haloalkyl-S-;
R
13 at each occurrence, is independently selected from H, OH, CI-C 6 alkyl, CI-C 4 alkoxy, Cl, F, Br, I, CN, NO 2 N1R 1 5
R
1 6 and CE 3
R
14 at each occurrence, is independently selected from H, phenyl, benzyl, CI-C 4 alkyl, and C 2
-C
4 alkoxyalkyl;
R
1 5 at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
R
1 6 at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, phenethyl, CH 3
CH
2
CH
3
CH
3
CH
2 OC(=O)
CH
3
CH
3
CH
2
S(=O)
2 and CH 3
S(=O)
2
R
1 7 is H, phenyl, benzyl, Cl-C 4 alkyl, or C 2
-C
4 alkoxyalkyl; -68- WO 01/19797 PCT/US00/24967
R
18 at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and
R
19 at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, and butyl.
[16] In a preferred embodiment the present invention provides a compound of Formula (Ib)
Q
1 is C 1
-C
6 alkyl substituted with 0-3 Ria;
C
2
-C
6 alkenyl substituted with 0-3 R 1 a;
C
2
-C
6 alkynyl substituted with 0-3 Rla;
C
3
-C
6 cycloalkyl substituted with 0-3 Rib; phenyl substituted with 0-3 Rib; or to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 Rib;
R
la at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, OR 14 Cl, F, Br, I,
NR
15
R
16
CF
3
C
3
-C
6 carbocycle substituted with 0-3 Rlb; phenyl substituted with 0-3 Rib; and 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 Rlb; Rlb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2
NR
15
R
16
CF
3 acetyl, SCH 3
S(=O)CH
3 S(=0) 2
CH
3 methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Ci-C 2 haloalkyl, Cl-C 2 -69- WO 01/19797 WO 0119797PCTIUSOO/24967 haloalkoxy, (methyl)OC(=O) (ethyl)OC(=O) (propyl)OC(=O)-, and (butyl)OC(=O)-;
R
5 is OR 14 cl-c 4 alkyl substituted with 0-1
C
2
-C
4 alkenyl substituted with 0-1 R~b; or
C
2
-C
4 alkynyl substituted with 0-1 R 5 b; R~a is H, methyl, ethyl, propyl, or butyl; alternatively, R 5 and R 5 a may be combined to form a cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl ring; R5b, at each occurrence, is independently selected from: H, methyl, ethyl, propyl, butyl, CF 3
OR
1 4 Cl, F,
NR
15
R
1 6
C
3
-C
7 cycloalkyl substituted with 0-3 R 5 c;
C
3
-C
7 carbocycle substituted with 0-3 RSc; phenyl substituted with 0-3 RSc; and to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R 5 c; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
R
5 c, at each occurrence, is independently selected from H, OH, Cl, F, NR 1 5
R
1 6
CF
3 acetyl, SCH 3
S(=O)CH
3
S(=O)
2
CH
3 methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C 1
-C
2 haloalkyl, and Cl-C 2 haloalkoxy; W is a bond, -CH 2 or -CH(CH 3 WO 01/19797 PCT/US00/24967 X is a bond; phenyl substituted with 0-1 RXb;
C
5
-C
6 cycloalkyl substituted with 0-1 RXb; or to 6 membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-1 RXb; wherein said 5 to 6 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, and isoxazolyl; RXb, at each occurrence, is independently selected from H, OH, Cl, F, Br, NR 15
R
16
CF
3 acetyl, SCH3, S(=O)CH 3
S(=O)
2
CH
3 methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C 1
-C
2 haloalkyl, and C 1
-C
2 haloalkoxy; Y is a bond, -V-CH 2 or -CH 2
V-;
V is a bond, 2 or
-N(R
1 9 Z is H, F, C1, Br,
C
1
-C
4 alkyl substituted with 0-2 R 12
C
2
-C
4 alkenyl substituted with 0-2 R 12
C
2
-C
4 alkynyl substituted with 0-2 R 12
C
6
-C
1 0 aryl substituted with 0-4 R 1 2b;
C
3
-C
6 carbocycle substituted with 0-4 R 12 b; or 5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R 12 b;
R
1 1 at each occurrence, is independently selected from -71- WO 01/19797 PCT/US00/24967 H, NR 1 8
R
1 9
CF
3
C
1
-C
4 alkyl substituted with 0-1 R 11 a; phenyl substituted with 0-3 R 11 b;
C
3
-C
6 carbocycle substituted with 0-3 R 11 b; or 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 Rlb; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl; at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Cl, F, NR 1 5
R
1 6 CF3; phenyl substituted with 0-3 R 11 b;
C
3
-C
6 carbocycle substituted with 0-3 R 1 b; or 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R 11 b; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
R
1 1 a
R
11 b, at each occurrence, is independently selected from H, OH, Cl, F, NR 15
R
16
CF
3 methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C 1
-C
2 haloalkyl, and C 1
-C
2 haloalkoxy;
R
12 at each occurrence, is independently selected from H, OH, Cl, F, Br, NR 15
R
16
-C(=O)NR
1 5
R
1 6
CF
3 acetyl, -72- WO 01/19797 PCT/US00/24967
SCH
3
S(=O)CH
3 S(=0) 2
CH
3 methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Ci-C 2 haloalkyl, and
C
1
-C
2 haloalkoxy; phenyl substituted with 0-4 R 12 b;
C
3
-C
6 carbocycle substituted with 0-4 R 12 b or 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 1 2b;
R
12 b, at each occurrence, is independently selected from H, OH, Cl, F, Br, NR 15
R
16
CF
3 acetyl, SCH 3
S(=O)CH
3 S(=0) 2
CH
3 methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C 1
-C
2 haloalkyl, and Ci-C 2 haloalkoxy;
R
13 at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Cl, F, Br, CN, NR 15
R
16 and CF3;
R
14 at each occurrence, is independently selected from H, phenyl, benzyl, methyl, ethyl, propyl, and butyl;
R
15 at each occurrence, is independently selected from H, methyl, ethyl, propyl, or butyl;
R
16 at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
R
18 at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl and, phenethyl; and -73- WO 01/19797 WO 0119797PCT/USOO/24967
R
19 at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl and, phenethyl.
[17] In a preferred embodiment the present invention provides a compound of Formula (Ib)wherein:
Q
1 is -CH3, -CH 2
CH
3
-CH
2
CH
2
CH
3
-CH
2
CH
2
CH
2
CH
3
-CH
2
CH
2
CH
2
CH
2
CH
3
-CH
2
CH
2
CH
2
CH
2
CH
2
CH
3 -CH (CH 3 2,
-CH(CH
3
)CH
2
CH
3
-CH
2
CH(CH
3 2
-CH
2
C(CH
3 3
-CF
3
-CH
2
CF
3
-CH
2
CH
2 CF3, -CH 2
CH
2
CH
2
CF
3
-CH=CH
2
-CH
2
CH=CH
2
-CH
2 C (CH 3
=CH
2
-CH
2 CH=C (CH 3 2,
-CH
2
CH
2
CH=CH
2
-CII
2
CH
2 C (CH 3
=CH
2
-CH
2
CH
2 CH=C (CH 3 2' cis-CH 2
CH=CH(CH
3 cis-CH 2
CH
2
CH=CH(CH
3 trans -CH 2 CH=CH (CH 3 trans -CH 2
CH
2 CH=CH (CH 3
-CH
2 Cm-CH, -CH 2 Cm-C(CH 3 cyclopropyl-, cyclobutyl-, cyclopentyl-, cyclohexyl-, cyclopropyl-CH2-, cyclobutyl-CH 2 cyclopentyl-CH2-, cyclohexyl-CH 2 cyclopropyl-CH 2
CH
2 cyclobutyl-CH2CH 2 cyclopentyl-CH 2
CH
2 cyclohexyl-CH 2 CH2-, phenyl-, 2-F-phenyl-, 3-F-phenyl-, 4-F-phenyl-, 4-methoxyphenyl-, 4-ethoxyphenyl-, 4-propoxyphenyl-, phenyl-CH 2 (2-F-phenyl)CH 2 (3-F-phenyl)CH 2 (4-F-phenyl)CH 2 (2-Cl-phenyl)CH 2 (3-Cl-phenyl)CH 2 (4-Cl-phenyl)CH 2 (2,3-diF-phenyl)CH 2 (2,4-diF-phenyl)CH 2 2 (2,6-diF-phenyl)CH 2 (3,4-diF-phenyl)CH 2 C3,5-diF-phenyl)CH 2 (2,3-diCl-phenyl)CH 2 (2,4-diCl-phenyl)CH 2 2 (2,6-diCl-phenyl)CH2-, (3,4-diCl-phenyl)CH 2 (3,5-diCl--phenyl)CH 2 -74- WO 01/19797 WO 0119797PCTUSOO/24967 (3-F-4-C1-phenyl)CH2-, (3-F-5-Cl-phenyl)CH2-, (3-Cl-4-F-phenyl)CH 2 2-furanyl-CH2-, 3-furanyl-CH 2 2-thienyl-CH 2 3-thienyl-CH 2 2-pyridyl-CH 2 3-pyridyl-CH 2 4-pyridyl-CH 2 1-imidazolyl-CH 2 2-oxazolyl-CH 2 4-oxazolyl-CH 2 5-oxazolyl-CH 2 3-isoxazolyl-CH2-, 4-isoxazolyl-CH 2 5-isoxazolyl-CH2-, phenyl-CH 2
CH
2 (2-F-phenyl)CH 2
CH
2 (3-F-phenyl)CH 2
CH
2 (4-F-phenyl)CH 2
CH
2 (2-C1-phenyl)CH 2
CH
2 (3-Cl-phenyl)CH 2
CH
2 (4-Ci--phenyl )CH 2
CH
2 3-diF-phenyl)CH 2
CH
2 4-diF-phenyl)CH 2
CH
2 (2,5-diF-phenyl)CH 2
CH
2 (2,6-diF-phenyl)CH 2
CH
2 (3,4-diF-phenyl)CH 2
CH
2 5-diF-phenyl)CH 2
CH
2 (2,3-diCl-phenyl)CH 2
CH
2 (2,4-diCl-phenyl)CH 2
CH
2 5-diCl-phenyl)CH 2
CH
2 6-diCl-phenyl)CH 2
CH
2 (3,4-diCl-phenyl)CH 2
CH
2 (3,5-diCl-phenyl)CH 2
CH
2 (3-F-4-C1-phenyl)CH 2
CH
2 (3-F-5-C1-phenyl)CH 2
CH
2 furanyl -CH 2
CH
2 thienyl -CH 2
CH
2 pyridyl -CH 2
CH-
2 1-imidazolyl-CH 2
CH
2 oxazolyl-CH 2
CH
2 isoxazolyl-CH 2
CH
2 3, 5-dimethylisoxazol-4-yl-CH 2 CH2-, phenyl -propyl benzyl-CH(NH 2 benzyl-CH(NHC(=O)-O-tBu)-, benzyloxy-CH 2 pyrrolidin-2-yl-, or 3- t-butoxycarbonylpyrrol idin- 2-yl
R
5 is -CH 3
-CH
2
CH
3
-CH
2
CH
2
CH
3
-CH(CH
3 2
-CH
2
CH
2
CH
2
CH
3
-CH(CH
3
)CH
2
CH
3
-CH
2
CH(CH
3 2
-CH
2
C(CH-
3 3
-CH
2
CH
2
CH
2
CH
2
CH
3 -CH (CH 3
)CH
2
CH
2
CH
3
-CH
2 CH (CH 3
)CH
2
CH
3
-CH
2
CH
2 CH (CH 3 2. -CH (CH 2
CH
3 2.
-CF
3
-CH
2
CF
3
-CH
2
CH
2
CF
3
-CH
2
CH
2
CH
2
CF
3
-CH
2
CH
2
CH
2
CH
2
CF
3
-CH=CH
2
-CH
2 CH= CH 2
-CH
2
CH
2
CH=CH
2
-CH=CHCH
3 WO 01/19797 WO 0119797PCTIUSOO/24967 cis-CH 2 CH=CH (CH 3 trans-CH 2 CH=CH (CH 3 trans -CH 2 CH=CH (C 6
H
5
-CH
2 CH=C (CH 3 2' Cis-CH 2
CH=CHCH
2
CH
3 trans -CH 2
CH=CHCH
2
CH
3 cis-CH 2
CH
2
CH=CH(CH
3 trans-
CH
2
CH
2
CHCH(CH
3 trans-CH 2
CH=CHCH
2
(C
6
H
5
-CH
2 C CH, -CH 2 CaC (CH 3
-CH
2 CEC (C6H 5
-CH
2
CH
2 C=-CH, -CH 2
CH
2
C-=C(CH
3
-CH
2
CH
2
C-=C(C
6
H
5
-CH
2
CH
2
CH
2
-CH
2
CH
2
CH
2 C=-C (CH 3
-CH
2
CH
2
CH
2 C C (C 6
H
5 cyclopropyl-CH 2 cyclobutyl-CH 2 cyclopentyl-CH 2 cyclohexyl-CH 2 (2-CH3-cyclopropyl) CH 2 (3-CH 3 -cyclobutyl)CH 2 cyclopropyl-CH 2
CH
2 cyclobutyl-CH 2
CH
2 cyclopentyl-CH 2
CH
2 cyclohexyl-CH 2
CH
2 (2-CH 3 -cyclopropyl) CH 2
CH
2 (3-CH 3 -cyclobutyl)CH 2
CH
2 phenyl-CH 2 (2-F-phenyl)CH 2 (3-F-phenyl)CH 2 (4-F-phenyl)CH 2 (3,5-diF-phenyl)CH 2 2-furanyl-CH 2 3-furanyl-CH 2 2-thienyl-CH 2 3-thienyl-CH 2 2-pyridyl-CH 2 3-pyridyl-CH 2 4-pyridyl-CH 2 1-imidazolyl-CH 2 2-oxazolyl-CH 2 4-oxazolyl-CH 2 5-oxazolyl-CH 2 3-isoxazolyl-CH2-, 4-isoxazolyl-CH 2 5-isoxazolyl-CH 2 phenyl-CH 2
CH
2 (2-F-phenyl) CH 2
CH
2 (3-F-phenyl)CH 2
CH
2 (4-F-phenyl)CH 2
CH
2 furanyl-CH 2
CH
2 thienyl-CH 2
CH
2 pyridyl-CH 2
CH
2 l-ixnidazolyl-CH 2
CH
2 oxazolyl-CH 2
CH
2 isoxazolyl-CH 2
CH
2 methoxy, ethoxy, propoxy, or butoxy;
R
5 a is H; alternatively, R 5 and R 5 a may be combined to form cyclopentyl, cyclohexyl, or cycloheptyl; W is a bond, -CH 2 or -CH(CH 3 -76- WO 01/19797 WO 0119797PCTIUSOO/24967 X is a bond; Y is a bond, -CH 2 or -V-CH 2 V is a bond, -C 2 or Z is H, F, Cl, Br, methyl, ethyl, n-propyl, i-propyl, nbutyl, i-butyl, s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Ci-phenyl, 3-Ci-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl, 2, 6-diF-phenyl, 3, 4-diF-phenyl, 3, 2, 3-diCl-phenyl, 2, 4-diCl-phenyl, 2, 2, 6-diCl-phenyl, 3,4-diCl-phenyl, 3, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl, 3-Cl-4-F-phenyl, 2-MeO-phenyl, 3-MeO-phenyl, 4-Meo-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-MeS-phenyl, 3-MeS-phenyl, 4 -MeS-phenyl, 2 -CF3O-phenyl, 3 -CF 3 O-phenyl, 4 -CF 3 O-phenyl, furanyl, thienyl, pyridyl, 2-Me-pyridyl, 3-Me-pyridyl, 4-Me-pyridyl, 1-imidazolyl, oxazolyl, isoxazolyl, 1-benzimidazolyl, morpholino, N-piperinyl, phenyl-CH 2 (2-F-phenyl)CH 2 (3-F-phenyl)CH 2 (4-F-phenyl)CH 2 (2-Cl-phenyl)CH 2 (3-Cl-phenyl)C8 2 (4-Cl-phenyl)CH 2 (2,3-diF-phenyl)CH 2 -77- WO 01/19797 WO 0119797PCTIUSOO/24967 (2,4-diF-phenyl)CH 2 (2,5-diF-phenyl)CH 2 6-diF-phenyl)CH 2 4-diF-phenyl)C- 2 5-diF-phenyl)CH 2 3-diCl-phenyl)CH 2 (2,4-diCl-phenyl)CH 2 (2,5-diCl--phenyl)CH 2 (2,6-diCl-phenyl)CH 2 (3,4-diCl-phenyl)CH 2 2 (3-F-4-C1-phenyl)CH 2 (3-F-5-C1-phenyl)CH 2 (3-C1-4-F-phenyl)Ci 2 (2-MeO-phenyl)CH 2 (3-MeO-phenyl)CH 2 (4-MeO-phenyl)CH 2 (2-PhO-phenyl)CH 2 (3-Pho-phenyl )CH 2 (4-PhO-phenyl) CH 2 (2-Me-phenyl)CH 2 (3-Me-phenyl)CH 2 (4-Me-phenyl)CH 2 (2-MeS-phenyl) CH2-, (3-MeS-phenyl) CH 2 4-MeS-phenyl) CH 2 (2-CF 3 O-phenyl)CH 2 (3-CF 3 O-phenyl )CH 2 (4-CF 3 O-phenyl)CH 2 (furanyl)CH 2 (thienyl)CH 2 (pyridyl)C{ 2 (2-Me-pyridyl)CH 2 (3-Me-pyridyl)CH 2 (4-Me-pyridyl)CH 2 (1-imidazolyl)CH 2 (oxazolyl)CH 2 (isoxazolyl)CH 2 (1-benzimidazolyl)CH 2 (cyclopropyl)CH 2 (cyclobutyl)CH 2 (cyclopentyl)CH 2 (cyclohexyl)CH 2 (morpholino)CH 2 (N-pipridinyl)CH 2 phenyl-CH 2
CH
2 (phenyl) 2
CHCH
2 (2-F-phenyl)CH2CH 2 (3-F-phenyl)CH 2
CH
2 (4-F-phenyl)CH 2
CH
2 (2-C1-phenyl)CH 2
CH
2 (3-C1-phenyl)CH 2
CH
2 (4-C1-phenyl)CH 2
CH
2 3-diF-phenyl)CH 2
CH
2 (2,4-diF-phenyl)CH 2
CH
2 (2,5-diF-phenyl)CH 2
CH
2 (2,6-diF-phenyl)CH 2
CH
2 (3,4-diF-phenyl)CH 2
CH
2 5-diF-phenyl)CH 2
CH
2 3-diCl-phenyl)CH 2
CH
2 (2,4-diCl-phenyl)CH 2
CH
2 5-diCl-phenyl)CH 2
CH
2 E-diCl-phenyl)CH 2
CH
2 4-diCl-phenyl)CH 2
CH
2 2
CH
2 (3-F-4-C1-phenyl)CH 2
CH
2 (3 -F-5-C1-phenyl) CH 2
CH
2 (3-C1-4-F-phenyl )CH 2
CH
2 (2-Meo-pheiyl) CH 2
CH
2 (3-MeO-phenyl) CH 2
CH
2 (4-MeO-phenyl)CH 2
CH
2 (2-Me-phenyl)CH 2
CH
2 (3-Me-phenyl)CH 2
CH
2 (4-Me-phenyl) CH 2
CH
2 (2-MeS-phenyl) CH 2
CH
2 (3-MeS-phenyl) CH 2
CH
2 (4-MeS-phenyl)CH 2
CH
2 (2-CF 3 O-phenyl)CH 2
CH
2 -78- WO 01/19797 WO 0119797PCTIUSOO/24967 (3-CF 3 O--phenyl) CH 2
CH
2 (4-CF 3 O-phenyl)CH 2 CH2-, (furanyl)CH 2
CH
2 (thienyl)CH 2
CH
2 (pyridyl)CH 2 CH2-, (2-Me-pyridyl) CH 2
CH
2 (3-Me-pyridyl) CH 2
CH
2 (4-Me-pyridyl) CH 2
CH
2 (imidazolyl) CH 2
CH
2 (oxazolyl)CH 2
CH
2 (isoxazolyl)CH 2
CH
2 (benzimidazolyl)CH 2
CH
2 (cyclopropyl) CH 2
CH
2 (cyclobutyl)CH 2
CH
2 (cyclopentyl)CH 2
CH
2 (cyclohexyl) CH 2
CH
2 (morpholino) CH 2
CH
2 or (N-pipridinyl) CH 2
CH
2
R
11 at each occurrence, is independently selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sbutyl, t-butyl, phenyl, benzyl, phenethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, 2-F-phenyl-, 3-F--phenyl, 4-F-phenyl, 4-Ci-phenyl, 4-CH 3 phenyl, 4-MeO-phenyl-, 4-CF 3 -phenyl, (4-F-phenyl) CH 2 (4-C1-phenyl)CH 2 (4-CH 3 -phenyl)CH 2 (4-CF 3 -phenyl)CH 2 (4-F-phenyl)CH 2
CH
2 (4-Cl-phenyl)CH 2
CH
2 (4-CH 3 -phenyl)CH 2
CH
2 (4-CF 3 -phenyl)CH 2
CH
2 pyridin-2-yl-, pyridin-3-yl-, 4-CF 3 -pyridin-2-yl-, 4-CH3-pyridin-2-yl-, thiazol-2-yl-, azapan-l-yl, N,N-dimethylamino, N,N-diethylamino, N,Ndipropylamino, and N, N-dibutylanino; and
R
13 at each occurrence, is independently selected from H, MeO, F, and Cl.
[18] In a preferred embodiment the present invention provides a compound of Formula (If);
R
NItNW-X-Y-Z OH 0 IRlI (if) -79- WO 01/19797 PCT/US00/24967 or a pharmaceutically acceptable salt form or prodrug thereof.
[19] In a preferred embodiment the present invention provides a compound of Formula (Ig);
R
s o1 N KNW-X-Y-Z OH 0 N
R
1
R
1 R13 (Ig) or a pharmaceutically acceptable salt form or prodrug thereof.
In a preferred embodiment the present invention provides a compound of Formula (Ih);
R
ol N ,W-X-Y-Z OH O 13 R13- (Ih) or a pharmaceutically acceptable salt form or prodrug thereof.
In another preferred embodiment the present invention provides all herein disclosed embodiments with the proviso that when R 5 and R 5 a are not simultaneaously H.
In another preferred embodiment the present invention provides all herein disclosed embodiments with the proviso that when Q is a 9 membered benzofused heterocyclic group substituted by 0, 1, or 2 R la then R 3 is H.
WO 01/19797 PCT/US00/24967 In another preferred embodiment the present invention provides all herein disclosed embodiments with the proviso that when -WXYZ is a tertiary butyl group and R 5 is either
C
1
-C
4 alkyl or C 2 alkenyl, then Q is not phenyl substituted by 0, 1 or 2 Rla.
In another preferred embodiment the present invention provides all herein disclosed embodiments with the proviso that when R 5 is C 1
-C
3 alkyl, then Q is not phenyl substituted by 0, 1 or 2 R 1 a.
In another preferred embodiment the present invention provides all herein disclosed embodiments with the proviso that the moiety: R2- OH O of Formula et seq., is not a CI-C 8 alkyl, C 2
-C
8 alkenyl, C 2
-C
8 alkynyl, C 3
-C
1 0 cycloalkyl-C 1
-C
4 alkyl, C 3 -Cio cycloalkyl, C 1
-C
4 alkyl-O-C 1
-C
4 alkyl, CI-C 4 alkyl-S-Cl-C 4 alkyl, C 2
-C
4 alkyl-NR 2 0
-C
2
-C
4 alkyl, C 2
-C
4 alkyl-C 6 -Clo aryl, C 2
-C
4 alkyl-C 6 -Cio cycloalkyl, C 2
-C
8 alkenyl, C 6
-C
1 0 aryl-C 1
-C
4 alkyl, C 6 -Cio aryl-C2-C 4 -alkynyl, indol-3-yl-C 1
C
3 alkyl, and imidazol-4-yl-C 1
-C
3 alkyl; where any alkyl group is substituted with OH.
In a second embodiment, the present invention provides a pharmaceutical composition comprising a compound of Formula and a pharmaceutically acceptable carrier.
In a third embodiment, the present invention provides a method for the treatment of a neurological disorder associated with P-amyloid production comprising administering to a host in need of such treatment a -81- WO 01/19797 PCT/US00/24967 therapeutically effective amount of a compound of Formula In a preferred embodiment the neurological disorder associated with P-amyloid production is Alzheimer's Disease.
In a fourth embodiment, the present invention provides a method for inhibiting y-secretase activity for the treatment of a physiological disorder associated with inhibiting y-secretase activity comprising administering to a host in need of such inhibition a therapeutically effective amount of a compound of Formula that inhibits y-secretase activity.
In a preferred embodiment the physiological disorder associated with inhibiting y-secretase activity is Alzheimer's Disease.
In a fifth embodiment, the present invention provides a compound of Formula for use in therapy.
In a preferred embodiment the present invention provides a compound of Formula for use in therapy of Alzheimer's Disease.
In a sixth embodiment, the present invention provides for the use of a compound of Formula for the manufacture of a medicament for the treatment of Alzheimer's Disease.
DEFINITIONS
As used herein, the term "Ap" denotes the protein designated AP, P-amyloid peptide, and sometimes P/A4, in the art. AP 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, -82- WO 01/19797 PCT/US00/24967 small arteries, capillaries, and sometimes, venules. The isolation and sequence data for the first 28 amino acids are described in U.S. Pat. No 4,666,829. The 43 amino acid sequence is: 1 Asp Ala Glu Phe Arg His Asp Ser Gly Tyr 11 Glu Val His His Gin 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 P amyloid precursor protein. This protein is the precursor for AP and through the activity of "secretase" enzymes, as used herein, it is processed into Ap. Differing secretase enzymes, known in the art, have been designated P secretase, generating the N-terminus of AP, a secretase cleaving around the 16/17 peptide bond in AP, and "y secretases", as used herein, generating Cterminal AP 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 -83- WO 01/19797 PCT/US00/24967 trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric 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 then 2 hydrogens on the atom are replaced.
When any variable R la
R
4a
R
13 etc.) 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 0-3
R
la then said group may optionally be substituted with up to three Rl a groups and R la at each occurrence is selected independently from the definition of R la 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, "C 1 -C6 alkyl" denotes alkyl -84- WO 01/19797 PCT/US00/24967 having 1 to 6 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl.
Preferred "alkyl" group is "C 1
-C
4 alkyl" wherein methyl, ethyl, n-propyl, i-propyl, n-butyl, and i-butyl, are specifically preferred. As used herein, "C 1
-C
3 alkyl", whether a terminal substituent or a alkylene group linking two substituents, is understood to specifically include both branched and straight-chain methyl, ethyl, and propyl.
As used herein, "alkenyl" or "alkenylene" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain. Examples of "C 2
-C
6 alkenyl" include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 2pentenyl, 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, 2butynyl, 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 WO 01/19797 PCT/US00/24967 to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.
"Haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example -CvFw where v 1 to 3 and w 1 to 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, 2,2,2trifluoroethoxy, 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, "C 3
-C
6 cycloalkyl" 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), [2.2.2.2bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin). Preferred example of "C 3
-C
10 carbocycle" or "C 3
-C
6 carbocycle" is C 3
C
6 cycloalkyl, specifically cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
-86- WO 01/19797 PCT/US00/24967 As used herein, the term "heterocycle" or "heterocyclic ring" is intended to mean a stable 5- to 7membered 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, preferably 1, 2, or 3 heteroatoms, independently selected from the group consisting of N, 0 and S and including any bicyclic group in which any of the above-defined heterocyclic rings is 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, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, -87- WO 01/19797 WO 0119797PCTUSOO/24967 morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piper idonyl, 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, l,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 memnbered 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 7 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl; more preferred 5 to 7 mnembered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, and tetrazolyl.
Preferred 5 to 6 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, -88- WO 01/19797 PCT/US00/24967 thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl; Also included are fused ring and containing, for example, the above heterocycles.
As used herein, the term "aryl", "C 6 -Cio aryl" or aromatic residue, is intended to mean an aromatic moiety containing the specified number of carbon atoms; for example phenyl, pyridinyl or naphthyl. Unless otherwise specified, "aryl" may be unsubstituted or substituted with 0 to 3 groups selected from H, OH, OCH 3 Cl, F, Br, I, CN,
NO
2
NH
2 N(CH3)H, N(CH 3 2
CF
3
OCF
3
C(=O)CH
3
SCH
3
S(=O)CH
3
S(=O)
2
CH
3 CH3, CH 2
CH
3
CO
2 H, and CO 2
CH
3 The phrase "additional lactam carbons", as used herein, is intended to denote the number of optional carbon atoms in the lactam ring B of Formula Formula (Ia): 0
B
(la) represents the lactam ring B of Formula 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. Examples of lactam ring B include: -89- WO 01/19797 WO 0119797PCT/USOO/24967 Bil 0
N
N-
0 I NA B6 0 B7 0 0
JL
0
N
Bi11 0 0
N
B12 WO 01/19797 PCT/US00/24967 B13 B14 o
R
10
-N
B16 but are not intended to limit the invention. Preferred examples of lactam ring B are Bl, 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 R 10 or R 1 1 on lactam B are methyl, ethyl, phenyl, 4fluorophenyl, 4-chlorophenyl, 4-trifluorophenyl, (4fluorophenyl)methyl, (4-chlorophenyl)methyl, and (4trifluorophenyl)methyl. Preferred examples of substituent
R
1 3 on fused rings of lactam B are methyl, fluoro, and chloro.
The compounds herein described may have asymmetric centers. One enantiomer of a compound of Formula may display superior biological activity over the opposite enantiomer. For example carbon 3 of lactam ring B Formula may exist in either an S or R configuration. Thus, an R or S configuration at carbon 3 in Formula is considered part of the invention. An example of such configuration includes,
R
5
R
N N CH 3 N N CH 3 HO O N 13 HO O N .R' 3
R
11 and R but is not intended to be limited to this example of ring B. When required, separation of the racemic material can be achieved by methods known in the art. Additionally, the -91- WO 01/19797 PCT/US00/24967 carbon atoms to which the OH and R 5 are attached may describe chiral carbons which may display superior biiological activity over the opposite enantiomer. For example, where Q and R 5 are not H, then the configuration of the two centers may be described as (2R,3R), (2R,3S), (2S,3R), or (2S,3S). All configurations are considered part of the invention; however, the (2R,3S) and the (2S,3R) are preferred and the (2R,3S) is more preferred.
The phrase "pharmaceutically acceptable" is employed 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.
-92- WO 01/19797 PCT/US00/24967 The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting 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 in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of formula 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 wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of formula 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 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 -93- WO 01/19797 PCT/US00/24967 organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below.
All references cited herein are hereby incorporated in their entirety by reference.
The novel compounds of this invention may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be 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.
Scheme 1 -94- WO 01/19797 PCT/US00/24967 HNJ 1. BuLi Rs' NA 1. Bu 2 BOTf, TEA LO 2.R 5
CH
2 COCI LO 2.Q-CHO Bn Bn 1 2 QH O 0 OH 0 Q N^ LiOH, H 2 0 2 0 OH R5 THF, H 2 0 RS Bn 3 4 Aldol derivatives can be prepared by the procedure of Evans A. Evans et al, Org. Synth. 1990, 68, 83-90), which is outlined in Scheme 1 where acylation of an oxazolidinone with an acid chloride provides structure 2.
Asymmetric aldol reaction to form 3 followed by cleavage of the chiral auxiliary yielding P-hydroxycarboxylic acid 4.
Additional examples are found in D. A. Evans Aldrichimica Acta 1982, 15, 23-32. Alternative syntheses of structures 4 can be accomplished by the methods of Crimmins M. T.
Crimmins et al, J. Am. Chem. Soc. 1997, 119, 7883-7884), Paterson Paterson et al, Org. React. 1997, 51, 1-200) and Mukaiyama Mukaiyama et al, Org. React. 1994, 1- 104). Anti-aldols may be synthesized according to: A.
K. Ghosh, J. Am. Chem. Soc. 1996, 118, 2527-2528, or S.
Masamune et al., J. Am. Chem. Soc. 1997, 119, 2586.
Scheme 2 ZYXW 13 ZYXW 13 OH O OH H H+ EDC, HOBt 5 H2N N 1 TEA, CH2C 2 0 N R Rs H R' 5 6 Carboxylic acids of formula 4 can be coupled to anappropriate lactam intermediate using methods commonly used in peptide syntheses, such as DCC, EDC, CDI, BOP, PyBOP, HATU, HBTU and phenyl ester mediated coupling, as WO 01/19797 PCT/US00/24967 described in A. R. Chamberlin, Chem. Rev. 1997, 97, 2243- 2266. Compound 6 is synthesized, as illustrated in Scheme 2, by coupling acid 4 with 3-amino-l,4-benzodiazepin-2-one under the catalysis of EDC and HOBt providing the final compound 6 Nozaki et al, Bull. Chem. Soc. Jpn. 1982, 2165-2168).
Similarly, Schemes 2a and 2b illustrate synthesis of bisbenzodiazepine and lactam compounds of the present invention: Scheme 2a 1Yzxw -3 WXYZ
ZYXW
OHO 0 0 R O N Q OH H 2 N EDC, HOBt L r TEA, CH 2
CI
2 i R 'R 4a 4b 4c Scheme 2b wxYz OH 0 o XYZ oN-
R
5 TEA, CH 2 Cl 2 R H
R
5 4b 5b Methods for the synthesis of lactam intermediates as contemplated by the present invention useful in the synthesis of compounds of Formula including amino benzodiazepinones, dibenzo azepinones and other related heterocycles, are known in the art and are disclosed in a number of references including PCT publication number WO 98/28268, WO 99/66934, WO 00/07995, and WO 00/38618, which are hereby incorporated by reference. Additional references include Bock, et al, J. Org. Chem., 1987, 52, 3232-3239; Sherrill et al, J. Org. Chem., 1995, 60, 730- -96- WO 01/19797 PCT/US00/24967 734; and Walsh, D. Synthesis, September 1980, p.677; and Brown, et al., Tetrahedron Letters, 1971, 8, 667-670.
Synthetic approaches to aminobenzodiazepines are widely described in the literature and well known to one skilled in the art. The typical methods are illustrated, but are not limited to, the following references. See (a) M. G. Bock et al., J. Org. Chem., 1987, 52, 3232; R. G.
Sherrill et al., J. Org. Chem., 1995, 60, 734; M. G.
Bock et al., J. Med. Chem., 1989, 32, 13-16; J. L.
Castro et al., J. Med. Chem., 1997, 40, 2491-2501; M.
S. Chambers et al., Bioorg. Med. Chem. Lett., 1993, 3 1919-1924; J. H. Gogerty et al., J. Med. Chem., 1977, 20 952; G. Semple et al., Bioorg. Med.
Chem. Lett., 1996, 51-54; G. Semple et al., J.
Med. Chem., 1997, 40, 331-341; G. Semple et al., Bioorg. Med. Chem. Lett., 1996, 6 55-58; G.
Semple et al., Synth. Commun., 1996, 26 721-727; and G. A. Showell et al., J. Med. Chem., 1994, 37, 719- 721. For general synthetic descriptions of 2aminobenzophenone with various substitutions used in the preparation of benzodiazepine, see D. A. Walsh, Synthesis 1980, 677.
Scheme 3 1. NaH, DMF Os0 4 NalO 4 0 Q'OH 2. allyl bromide, KI QtO Et 2 0-H 2 0 7 8 9 The preparation of aldehyde Q-CHO with general structure of 9 is shown in Scheme 3 C. Arndt, Synthesis 1979, 202-204). Allyl ether 8 can be made from the action of an alkoxide generated in DMF with allyl bromide, which is converted to a-alkoxy- or aryloxyaldehyde 9 using a twophase osmium tetraoxide oxidation.
Scheme 4 -97- WO 01/19797 PCT/US00/24967 Br 1.NaH, THF I S2. allyl alcohol, KI R R 11 Os0 4 NalO 4 0 QO H 2 0
R
12 As shown in Scheme 4, aldehyde Q-CHO of general structure 12 can be prepared in the same fashion from the corresponding allyl benzyl ether, which is readily available according to the procedure described by P.
Kocienski Kocienski Tetrahedron 1990, 46, 1767-1782) The aldehydes used in Scheme 1 are either commercially available, prepared from commercially available or readily accessible alcohols, or prepared from commercially available or readily accessible carboxylic acids. For preparation of other non-commercially available aldehydes from commercially available or readily accessible alcohols by oxidation of the corresponding alcohols, see(a) S. V.
Ley et al Synthesis 1994, 639; D. Swern, Synthesis 1981, 165-185; and R. C. Larock, Comprehensive Organic Transformations, Wiley-VCH: 1989; pp 6 04 6 14 For preparation of other non-commercially available aldehydes from commercially available or readily accessible carboxylic acids by reducing the corresponding Weinreb amides or reduction of carboxylic acid derivatives, see (a) S. M. Weinreb et al. Tetrahedron Lett. 1981, 22, 3815-3818; M. Braun, Synthesis 1989, 856; and D. A. Evans, J.
Org. Chem. 1993, 58, 2446-2453.
Aminoaldehydes used in the synthesis of the compounds of the invention may be prepared by oxidation of corresponding amino alcohols or reduction of corresponding amino acids; see(a) J. Jurczak et al., Synlett 1993, 241; and S. G. Davis et al., Synlett 1995, 700.
-98- WO 01/19797 PCT/US00/24967 Sulfur containing aldehydes used in the synthesis of compounds of the invention may be made by conjugate addition of a thiol to a,-unsaturated aldehydes or reaction of a thiol with a halosubstituted aldehyde. See T. Cohen et al., J. Org. Chem. 1995, 60, 2022; Tetrahdron 1994, 50, 12793-12810; J. Org. Chem. 1992, 57, 6; Phosphorus, Sulfur, and Silicon 1993, 74, 1; and Tetrahdron 1994, 50, 11569-11584.
Sulfoxides and sulfones are prepared from the corresponding sulfide by oxidation. See M. Hudlicky, Oxidations in Organic Chemistry, ACS, 1990; pp 250-264.
The acid chlorides used in Scheme 1 are either commercially available or prepared from commercially available or readily accessible carboxylic acids by the action of oxalyl chloride or thionyl chloride. See R. C.
Larock, Comprehensive Organic Transformations, Wiley-VCH: 1989; pp963-964.
Examples Chemical abbreviations used in the Examples are defined as follows: "DMPU" for 1,3-dimethyl-3,4,5,6tetrahydro-2(1H)-pyrimidone; "TBTU" for O-(1H-benzotriazoll-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; "BOP" for benzotriazol-l-yloxytris-dimethylamino)phosphonium hexafluorophosphate; "Bu 2 BOTf" for dibutylboron triflate; "EDC" for l-[3-(dimethylamine)propyl]-3ethylcarbodiimide hydrochloride; "HOBt" for 1hydroxybenzotriazole; and "TEA" for triethylamine.
"HPLC" is an abbreviation used herein for high pressure liquid chromatography. Compounds of the present invention are generally purified by HPLC using conditions known to one skilled in the art. However, unless otherwise indicated, the following conditions are generally applicable. Reverse-phase HPLC can be carried out using a 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, -99- WO 01/19797 PCT/US00/24967 acetonitrile containing 0.1% trifluoroacetic acid).
Alternatively, reverse-phase HPLC can be carried out using a Vydac C-18 column with gradient elution from 10% to 90 acetonitrile in water.
Example 1.
3-(2(R)-Cyclopentylmethyl-3(S)-hydroxyl-l-oxo-5phenylpentyl)amino-l-methyl- 5-phenyl-2,3-dihydro-1H-l,4benzodiazepin-2-one.
(R)-3-(3-cyclopentyl-l-oxopropyl)-4-(phenylmethyl)-2oxazolidinone HNAo 1. BuLi N S 2. 3-cyclopentylpropionyl chloride Bnr Bn 1 2 A dry round bottom flask was charged with of (phenylmethyl)-2-oxazilidinone 17.7 g, 0.100 mol).
Anhydrous tetrahydrofuran (300 mL) was then added, and the solution was cooled to -78 0 C. A solution of butyllithium (42.0 mL, 0.105 mol, 2.50 M in hexane) was added to the reaction flask over a 10-min period. After a few minutes, 3-Cyclopentylpropionyl chloride (16.8 mL, 0.110 mol) was added. The resulting solution was stirred for 30 min at 78 0 C, then allowed to warm to ambient temperature over a period. Excess 3-cyclopentylpropionyl chloride was quenched by the addition of 60 mL of saturated aqueous ammonium chloride. The bulk of the tetrahydrofuran and hexane was removed on a rotary evaporator, and the slurry was extricated with two 80 mL portion of dichloromethane.
The combined organic layers were washed with 75 mL of 1 M sodium hydroxide and 75 mL of brine, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced preddure. The residue was trituated with hexane to provide 16.5 g of desired product 2 as a white solid. 1 H NMR (300 MHz, CDC13) 8 7.18 7.40 (5 H, m), -100- WO 01/19797 PCT/US00/24967 4.67 (1 H, 4.12 4.22 (2 H, 3.30 (1 H, dd, J 13.4, 3.1 Hz), 2.84 3.06 (2 H, 2.76 (1 H, dd, J 13.4, 9.6 Hz), 1.42 1.96 (9 H, 1.15 (2 H, br, m).
3-(2(R)-cyclopentylmethyl-3(S)-hydroxyl-5-phenyl-loxopentyl)-4(R)-(phenylmethyl)-2-oxazolidinone OH 0 0 NO1. hBu2BOTf, TEA P-N BnJ 2. PhCH 2
CH
2 CHO B Bn C2H Bn 2 3 To a solution of acyloxazolidinone 2 (1.57 g, 5.00 mmol) in 20 mL of dichloromethane, cooled to -78 0 C under nitrogen atmosphere, dibutylboron triflate (1.40 mL, 5.50 mmol) was added dropwise, followed by the addition of triethylamine. The mixture was warmed slowly to 0°C and was stirred at 0°C for an additional hour. The resultant boryl enolate solution was then cooled to -78 0 C, and 3phenylpropanal (0.80 mL, 5.5 mmol) was added over a period time. The solution was stirred for 1 h at -78 0
C,
then for 1 h at 0°C. The reaction mixture was quenched by the addition of 4 mL of a pH 7 aqueous phosphate buffer and 12 mL of methanol. To this cloudy solution was added 8 mL of methanol and 10 mL of 30% aqueous hydrogen peroxide at such a rate as to keep the internal temperature below 0 C. After the solution was stirred for one additional hour, the volatile material was removed in a rotary evaporator. The resulting slurry was extracted with three mL portions of diethyl ether. The combined organic layers was washed with 20 mL of 5% aqueous sodium bicarbonate and 20 mL of brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography ethyl acetate hexane) provided 1.11 g of aldol 3 as a colorless oil. 1 H NMR (300 MHz, CDC13) 6 7.15 7.38 (m, 4.72 1 4.12 4.28 3 3.85 1 H), -101- WO 01/19797 PCT/US00/24967 3.34 (1 H, dd, J 13.4, 3.1 Hz), 2.80 2.95 (1 H, m), 2.60 2.78 (2 H, 1.95 2.05 (1 H, 1.40 1.90 H, 1.10 (2 H, m).
2(R)-cyclopentylmethyl-3(S)-hydroxyl-5-phenylpentanoic acid OH 0 0 OH 0 Ph N o LiOH, H202 ph OH /YQ Bn THF, H 2 0 3 4 Acyloxazolidinone 3 (226 mg, 0.500 mmol) was dissolved in 3 mL of THF and 1 mL of distilled water. The resulting solution was cooled to 0°C. To this solution was added aqueous hydrogen peroxide (0.40 mL, 4.0 mmol), followed by a solution of lithium hydroxide (19 mg, 0.80 mmol) in mL of distilled water. After the solution was stirred for 16 h, sodium sulfite (567 mg, 4.50 mmol) in 3 mL of distilled water was added. The bulk of tetrahydrofuran was removed under reduced pressure, and the resulting mixture (pH 12 13) was extracted with three 20 mL portion of methylene chloride to remove the oxazolidinone auxiliary.
The aqueous layer was cooled in an ice bath and acidified to pH 1 with 6 M aqueous hydrochloric acid. The resulting cloudy solution was extracted with five portion of 30 mL ethyl acetate. The combined organic layers are dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to yield 230 mg of the desired acid 4 as a white solid. 1 H NMR (300 MHz, CDC1 3 8 7.18 7.35 (5 H, 3.87 (1 H, 2.81 2.87 (1 H, 2.60 2.76 (1 H, 2.54 2.60 (1 H, 1.00 1.95 13 H).
3-(2(R)-Cyclopentylmethyl-3(S)-hydroxyl-l-oxo-5phenylpentyl)amino-l-methyl- 5-phenyl-2,3-dihydro-lH-l,4benzodiazepin-2-one -102- WO 01/19797 PCT/US0O/24967 1 EDC, HOBt OH 0
OH-
2 N TEA, CH 2 CI 2 6 A mixture of acid 4 (250 mg, 0.900 mmol) and 3-amino- 1-methyl- 5-phenyl-2,3-dihydro-lH-1,4-benzodiazepin-2-one p-toluenesulfonate salt (364 mg, 0.820 mmol) in 4 mL of methylene chloride was stirred at 0°C. 1-Hydroxybenzotriazole hydrate (133 mg, 0.980 mmol), 1-[3- (dimethylamine)propyl]-3-ethylcarbodiimide hydrochloride (314 mg, 1.64 mmol) and triethylamine (0.51 mL, 3.7 mmol) were added sequentially. After the mixture was stirred for 16 h, 30 mL of ethyl acetate was added. The organic layer was washed with 1 M HC1 (15 mL), 5% NaHCO 3 (30 mL) and brine (30 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Purification by chromatotron (30% ethyl acetate hexane) afforded two diastereomers A and B. A: 120 mg 1 H NMR (300 MHz, CDC13) 6 7.20 7.70 (15 H, 5.54 (1 H, d, J 8.0 Hz), 4.02 (1 H, 3.48 (3 H, 2.83 3.00 (1 H, 2.62 2.74 (1 H, 2.40 2.48 (1 H, 1.00 2.00 (13 H, m); MS (ESI): 524 546 522 558 B: 120 mg 1 H NMR (300 MHz, CDC13) 5 7.60 (1 H, d, J 6.9 Hz), 7.20 7.45 (14 H, 5.56 (1 H, d, J 8.4 Hz), 3.84 (1 H, 3.48 (3 H, 2.83 3.00 (1 H, 2.62 2.74 (1 H, 2.50 2.60 (1 H, 1.00 1.95 (13 H, m); MS (ESI): 524 546 522 Examples 2-135 The general procedure for Example 1 was followed using the corresponding acid chloride, aldehyde, and substituted benzodiazepine, azepane or bisbenzodiazepine. Starting materials were either commercially available or prepared by methods known to one skilled in the art.
-103- WO 01/19797 WO 0119797PCT/USOO/24967 Example 2. 3-(2CR)-Cyclopentylmethyl-3(S)-hydroxyl-l-oxo-5phenylpentyl) axino-1-methyl-5- (4-f luoro-phenyl) -2,3dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 542 Example 3. 3- -Benzyl-3 phenylpentyl) amino-1-methyl-5-phenyl-2, 3-dihydro-lH-1, 4benzodiazepin-2-one. MS (ESI): 532 Example 4. 3-(2(R)-Isopropyl-3(S)-hydroxyl-1-oxo-5phenylpentyl) amino-1-methyl-5-phenyl-2, 3-dihydro-1H-1, 4benzodiazepin-2-one. MS (ESI): 484 Example 5. 3- -Cyclopentylmethyl-3 -hydroxyl-l-oxo-4- 5-difluorophenoxy)butyl)amino-1-methyl-5-pheiyl-2,3dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 562 Example 6. 3-(2(R)-Isobutyl-3(S)-hydroxyl-l-oxo-4-(3,5difluorophenoxy) butyl) amino-1-xnethyl-5-phenyl-2, 3-dihydro- 1H-1,4-benzodiazepin-2-one. MS (EST): 536 Example 7. 3-(2 (R)-Cyclopentylmethyl-3(S)-hydroxyl-1-oxo-4phenoxybutyl )amino-7-chloro-l-methyl-5-phenyl-2, 3-dihydro- 1H-1,4-benzodiazepin-2-one. MS (ESI) 560 Example 8. 3-(2(R)-Isobutyl--3(S)-hydroxyl-1-oxo-4phenoxybutyl) amino-7-chloro-1-methyl-5- (4-f luorophenyl) 2, 3-dihydro-lH-1, 4-benzodiazepin-2-one. MS (ESI): 552 (Mi-H).
Example 9. 3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-4cyclohexyloxybutyl) amino-l-methyl-5-phenyl-2, 3-dihydro-1H- 1,4-benzodiazepin-2-one. MS (ESI): 464 (Mi-H).
Example 10. Isobutyl -3(S)-hydroxyl-1-oxo-4cyclohexyloxybutyl) amino-1-methyl-5-phenyl-2, 3-dihydro-1H- 1,4-benzodiazepin-2-one. MS (ESI): 506 -104- WO 01/19797 WO 0119797PCT/USOO/24967 Example 11. 3-(2(R)--Methyl-3 (S)-hydroxyl-l-oxo-4phenoxybutyl )amino-7-chloro--nethyl-5--phenyl-2, 3-dihydro- IH-1,4--benzodiazepin-2-one. MS (ESI): 492 Example 12. 3-(2(R)-Isobutyl-3 (S)-hydroxyl-1-oxo-4phenoxybutyl) amino-7-chloro-1-methyl-5-phenyl-2, 3-dihydro- 1H-1,4-benzodiazepin-2-one. MS (ESI): 534 Example 13. 3-(2(R)-Benzyl-3(S)-hydroxyl-1-oxo-4cyclohexyloxybutyl)ainino-7-chloro-1-methyl-5-phenyl-2, 3dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 574 Example 14. 3- -Cyclopentylmethyl-3 (3)-hydroxyl-1-oxo- 4-cyclohexyloxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 566 Example 15. 3- -Isobutyl-3 -hydroxyl-1-oxo-4cyclohexyloxybutyl) amino-7-chloro-1-methyl-5-phenyl-2, 3dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 540 Example 16. 3-(2(R)-Isopropyl-3(S)-hydroxyl-1-oxo-4cyclohexyloxybutyl)amino-7-chloro-1-methyl-5-phenyl-2, 3dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 526 Example 17. 3-(2(R)-Methoxy-3(S)-hydroxyl-1-oxo-4-(4phenyl-2, 3-dihydro-1H-1, 4-benzodiazepin-2-one. MS (ESI): 590 Example 18. 3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-4-(2,4difluorobenzyloxy)butyl) amino-7-chloro-1-methyl-5-phenyl- 2,3-dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 542 -105- WO 01/19797 WO 0119797PCT/USOO/24967 Example 20. 3- (2 -Vinyl-3 (5)-hydroxyl-1-oxo-4benzyloxybutyl )amino-7-chloro-1-methyl-5-phenyl-2, 3dihydro-lH-1,4-benzodiazepin-2-one. MS (ESI): 536 Example 21. 3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-4cyclohexyloxybutyl) axino-7-chloro-l-methyl-5-phenyl-2, 3dihydro-lH-1,4-benzodiazepin-2-one. MS (ESI): 498 Example 23. 3- (2CR) -Isobutyl-3 (5)-hydroxyl-1-oxo-5phenylpentyl) amino-1-methyl-5-phenyl-2 ,3-dihydro-lH-1, 4benzodiazepin-2-one. MS (ESI): 498 (Mi-H).
Example 24. 3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-3cyclopropyipropyl) amino-l-methyl-5-phenyl-2, 3-dihydro-1H- 1,4-benzodiazepin-2-one. MS (ESI): 434 (Mi-H).
Example 25a. 3-(2 (R)-Isobutyl-3(S)-hydroxyl-1-oxoheptyl)amino-l-methyl-5-phenyl-2,3-dihydro-1H-1, 4benzodiazepin-2-one. MS (ESI): 450 (Mi-H).
Example 25b. 3-(R)-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxoheptyl)a-mino-1-methyl-5-phenyl-2, 3-dihydro-1H-1, 4benzodiazepin-2-one. MS (ESI): 450 Example 25c. 3-(S)-(2(R)-Isobutyl-3(S)-hydroxyl-l-oxoheptyl)amino-l-methyl-5-phenyl-2, 3-dihydro-1H-1, 4benzodiazepin-2-one. MS (ESI): 450 (Mi-H).
Example 26. -Isobutyl-3 CS) -hydroxyl-1-oxononyl)amino-1--methy1-5-pheny1-2,3-dihydro-lH-1,4benzodiazepin-2-one. MS (ESI): 478 Example 27. 3-(2 (R)-Isobutyl-3(S)-hydroxyl-1-oxohexyl) amino-l-methyl-5-phenyl-2, 3-dihydro-1H-1, 4benzodiazepin-2-one. MS (ESI): 436 (Mi-H).
-106- WO 01/19797 PTUO/46 PCTIUSOO/24967 Example 28. 3-(2(R)-Isobutyl-3(S)-hydroxyl-l-oxo-4phenylbutyl)amino-1-methyl-5-phenyl-2, 3-dihydro-lH-l, 4benzodiazepin-2-one. MS (ESI): 484 Example 29. 3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-5phenylpentyl) amino-1-methyl-5-phenyl-2, 3-dihydro-1H-1, 4benzodiazepin-2-one. MS (ESI): 442 Example 30. 3-(2(R)-Methyl-3(S)-hydroxyl-l-oxo-6phenyihexcyl) amino-l-methyl-5-phenyl-2, 3-dihydro-1H-1, 4benzodiazepin-2-one. MS (ESI): 470 Example 31. 3-(2(R)-Isobutyl-3(S)-hydroxyl-l-oxobutyl)axnino-l-xethyl-5-phenyl-2.3-dihydro-1H-1,4benzodiazepin-2-one. MS (ESI): 408 Example 32. 3- -Isobutyl-3(S) -hydroxyl-1-oxooctyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4benzodiazepin-2-one. MS (ESI): 464 Example 33. 3- -Methyl-3 -hydroxyl-1-oxoheptyl)arnino-1-methyl-5-phenyl-2, 3-dihydro-lH-1, 4benzodiazepin-2-one. MS (ESI): 408 Example 34. 3-(2 (R)-MethyJ-3(S)-hydroxyl-1-oxo-3phenylpropyl)amino-1-methyl-5-phenyl-2, 3-dihydro-1H-1, 4benzodiazepin-2-one. MS (ESI): 428 Example 35. 3-(2(R)-Methyl-3(S)-hydroxcyl-1-oxo-5,5dimethyl-hexyl)amino-1-methyl-5-phenyl-2, 3-dihydro-1H-1,4benzodiazepin-2-one. MS (ESI): 422 Example 36. 3-(2(R)-Methyl-3(S)-hydroxyl-l-oxo-hexyl)aminol-methyl-5-phenyl-2, 3-dihydro-1H-1, 4-benzodiazepin-2-one.
MS (EST): 394 -107- WO 01/19797 WO 0119797PCT/USOO/24967 Example 37. 3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-3-(4propoxyphenyl)propyl) axino-1-methyl-5-phenyl-2, 3-dihydro- 1H-1,4-benzodiazepin-2-one. MS (ESI): 486 Example 38. 2-(R)-cyclopropylmethyl-3-(S)hydroxyiheptanoic acid (2-oxo-l- C3-phenoxybenzyl) azapan-3amide. MS (ESI): 493 491 527 (Mi-Cl).
Example 39. 2(R) -cyclopropylmethyl-5- 5-difluorophenyl) 3-(S)-hydroxypentanoic acid C2-oxo-1-(3phenoxybenzyl) azapan-3- CS) -yl) amide.
MS (EST): 577 575 599 (Mi-Na).
Example 40. 4-cyclopentyl-2- CR) -cyclopropylrnethyl-3- hydroxybutanoic acid (2-oxo-1- (3-phenoxybenzyl)azapan-3amide. MS (ESI): 519 541 (Mi-Na), 517 CM-H).
Example 41. 2-CR) -cyclopropylmethyl-3- CS) -hydroxyheptanioc acid Cl- (5-bromo-3-pyridinyl)xnethyl-2-oxo-azapan-3- CS) -yl) amnide. MS (ESI): 480 CM( 79 Br)i-H), 482 (M( 8 lBr-H), 478
CMC
7 9 480 (M(SlBr)-H).
Example 42. 3-(2-CR)-cyclopropylmethyl-3-CS)-hydroxyl-1oxoheptyl)amino-5-(2-fluorophenyl) -l-methyl-2, 3-dihydro-1H- 1,4-benzodiazepin-2-one. MS CESI): 466 488 (M+Na), 464 CM-H). Chromatography Note b and Note c.
Example 43. 3-(2-CR)-cyclopropylmethyl-3-(S)-hydroxyl-1- Cazapan-1-yl) -1-methyl-2, 3-dihydro-1H- 1,4-benzodiazepin-2-one. MS (ESI): 469 491 (Mi-Na), 467 CM-H). Chromatography Note b and Note c.
Example 44. 3-C2-CR)-cyclopropylmethyl-5-(3,5difluorophenyl) (pyridn-2-yl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one.
MS CESI): 533 555 (Mi-Na), 531 CM-H) Chromatography Note b and Note c.
-108- WO 01/19797 WO 0119797PCTUSOO124967 The 3-(3,5-difluorophenyl)propanal used in the aldol reaction was prepared from trans-3,5--difluorocinnamic acid by: hydrogenation to 3- acid Kruse et al J. Med. Chem. 1987, 30, 486-494); (2) formation of Weinreb amide Braun Synthesis 1989, 856); and reduction to aldehyde A. Evans J. Org. Chem.
1993, 58, 2446-2453).
Example 45. 3-(2-(R)-cyclopropyjlmethyl-3-(S)-hydroxyl-loxopentyl)amino-1-methyl-5- (4-chiorophenyl) 3-dihydro-1H- 1,4-benzodiazepin-2-one. MS (ESI): 482 504 (M+Na), 480 Chromatography Note i and Note k.
Example 46. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydrox-yl-loxoheptyl) amino-5- (4-methoxyphenyl) 1-methyl-2, 3-dihydro-1H- 1,4-benzodiazepin-2-one. MS (ESI): 466 488 (M+Na), 464 Chromatography Note b and Note c.
Example 47. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyloxoheptyl)ainino-5- (4-iethoxyphenyl) -1-methyl-2, 3-dihydro- 1H-1,4-benxodiazepin-2-one. MS (ESI): 479 500 476 Chromatography Note m.
Example 48. 3-(S)-(4-cyclopentyl-2-(R)-cyclopropylmethyl- 3-(S)-hydroxyl-1-oxobutyl)amino-l-methyl-5-phenyl-2,3dihydro-lH-1,4-benzodiazepin-2-one. MS (ESI): 474 496 472 Example 49. 3-(S)-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl- 1-oxohept-6-enyl)amino-1-methyl-5-phenyl-2, 3-dihydro-1H- 1,4-benzodiazepin-2-one. MS (ESI): 446 468 (M+Na), 444 Example 50. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1oxohept-6-eriyl)amino-1-methyl-5- (4-trifluoromethyl-phenyl) 2,3-dihydro-lH-1,4-benzodiazepin-2-one. MS (ESI): 514 Chromatography Note i.
-109- WO 01/19797 WO 0119797PCT/USOO/24967 Example 51. 3-(S)-(2-(R)-cyclopropylmethyl-5-(3,5dimethylisoxazol-4-yl) -hydroxyl-1-oxopentyl)amino-1methyl-5-phenyl-2, 3-dihydro-1H-1,4--benzodiazepin-2-one.
MS (ESI): 515 (M4-H) 537 (M+Na) 513 The 3- 5-dimethyl-4-isoxazole)propanal used in the aldol reaction was prepared from: methyl 3-(3,5dimethyl-4-isoxazole)propionate C. Marcotulio J. Org.
Chem 1994, 59, 2884); DIBAL-H reduction to alcohol N.
M. Yoon et al J. Org. Chem. 1985, 50, 2443-2450); and (3) TPAP/NMO oxidation to aldehyde V. Ley et al Synthesis 1994, 639).
Example 52. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-loxoheptyl)axnino-7-chloro-1-methyl-5-phenyl-2, 3-dihydro-lH- 1,4-benzodiazepin-2-one. MS (ESI): 482 504 (M4-Na), 480 CM-H). Chromatography Note n and Note o.
Example 53. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-loxoheptyl)amino-1-methyl- (pyridin-2-yl) 3-dihydro-1H-1, 4 benzodiazepin-2-one. MS (ESI): 449 (M+HL, 471 447 CM-H). Chromatography Note b and Note c.
Example 54. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1oxoheptyl)axnino-5- (4-f luorophenyl) -1-methyl-2, 3-dihydro-lH- 1,4-benzodiazepin-2-one. MS (ESI): 466 500 (M+C1).
Chromatography Note h.
Example 55. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1oxoheptyl)amino-1-methyl-5- (4-trifouoromethylphenyl) -2,3dihydro-1H-1,4-benzodiazepin-2-one. MS (EST) 516 514 550 (M+C1) Chromatography Note i.
The 3-cycloproyl propionic acid, which was converted to 3-cycloproyl propionyl chloride used in the aldol reaction, was prepared according to: A. Donetti J. Med.
Chem. 1972, 15, 590-592.
-110- WO 01/19797 WO 0119797PCTIUSOO/24967 Example 56. 3-(5-cyclopentyl-2-(R)-cyclopropylnethyl-3- CS) -hydroxyl-1-oxopentyl)axnino-1-methyl-5- (pyridin-2-yl) 2,3-dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 489 511 487 Chromatography Note b and Note c.
Example 57. 3-(2-(R)-iso-butyl-3-(S)-hydroxyl-1oxoheptyl) axino-1-methyl-5- (4-trifluoromethyiphenyl) -2,3dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 518 540 516 CM-H). Chromatography Note b and Note c.
Example 58. 3-CS)-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl- (thiophen-2-yl) amino-1-methyl-5-phenyl-2, 3-dihydro- 1H-1,4-benzodiazepin-2-one. MS CESI): 502 524 500 Example 59. 3-(S)-(2-(R)-cyclopropylmethyl-5-(furan-2yl) 3-CS) -hydraxyl-1-oxopentyl) amino-1-methyl-5-phenyl-2, 3dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 486 508 CM+Na), 484 Example 60. 3-(5-cyclopentyl-2-(R)-cyclopropylmethyl-3- -hydroxyl-1-oxopentyl)amino-5- (4-f luorophenyl) -1-methyl- 2,3-dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 506 528 CM+Na), 504 Chromatography Note h.
Example 61. 3-CS)-(2-(R)-cyclopropylmethyl-5-C3,5difluorophenyl) -3-CS) -hydroxy-l-oxopentyl) phenyl-2, 3-dihydro-1H-1, 4-benzodiazepin-2-one.
MS (ESI) 532 554 (Mi-Na) 530 Example 62. 3-CS)-(3-(S)-hydroxyl-2-(R)-Cthiophen-2yl)niethyl-1-oxoheptyl)amino-1-methyl-5-phenyl-2, 3-dihydro- 1H-1,4-benzodiazepin-2-one. MS CESI): 448 470 (Mi-Na) 446 CM-H).
-111- WO 01/19797 WO 0119797PCT/USOO/24967 Example 63. 3-(S)-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl- 1-oxoheptyl) amino-7-methyl-5-phenyl-2, 3-dihydro-1H-1, 4benzodiazepin-2-one. MS (ESI): 490 512 488 Example 64. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1oxoheptyl) amino-7-niethoxy-1-methy1-5-pheiyl-2, 3-dihydro-1H- 1,4-benzodiazepin-2-one. MS (ESI): 478 500 (M+Na), 476 Chromatography Note 1.
Example 65. 3-(S)-(2-(R)-cyclobutylmethyl-3-(S)-hydroxyl- 1-oxoheptyl) amino-1-methyl-5-phenyl-2, 3-dihydro-1H-1, 4benzodiazepin-2-one. MS (ESI): 462 484 (M+Na).
The 3-cyclobutyl propionic acid, which was converted to 3-cyclobutyl propionyl chloride used in the aldol reaction, was prepared according to: A. Donetti J. Med.
Chemn. 1972, 15, 590-592.
Example 66. 3- 5-difluorobenzyl) hydroxyl-1-oxoheptyl) amino-1-methyl-5-phenyl-2, 3-dihydor- 1H-1,4-benzodiaxepin-2-one. MS (ESI): 520 518 (M-
H).
Example 67. 3-(S)-(2-(R)-(furan-2-yl)methyl-3-(S)hydroxyl-1-oxoheptyl) aiino-1-methyl-5-phenyl-2, 3-dihydro- 1H-1,4-benzodiazepii-2-one. MS (ESI) 474 472 Example 68. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxl-1amino-1-methyl-5- (pyridin-2-yl) -2,3dihydro-1H-benzodiazepin-2-one. MS (ESI): 514 536 512 Chromatography Note h.
Example 69. 3-(2-(R)-iso-butyl-3-(S)-hydroxyl-1- (4-f luorophenyl) -1-methyl-2, 3-dihydro-1H- 1,4-benzodiazepin-2-one. MS (EST): 497 519 (M+Na), 495 Chromatography Note b and Nate c.
-112- WO 01/19797 WO 0119797PCTUSOO/24967 Example 70. -jso-butyl-3-(S)-hyd-roxyl-1oxoheptyl) anino-5- (4-f luorophenyl) -1-methyl-2, 3-dihydro-1H- 1,4-benzodiazepin-2-one. MS (ESI): 468 502 (Mi-Cl).
Chromatography Note h.
Example 71. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-lamino-1-inethyl-5-phenyl-2, 3-dihydro-1H- 1,4-benzodiazepin-2-one. MS (ESI): 421 443 (Mi-Na), 419 Chromatography Note b and Note c.
Example 72. 3-(2-(R)-cyclopropylmethyl-5-(furan-2-yl)-3- -hydroxyl-1-oxopentyl)amino-1-methyl-5- (4trifluoromethyiphenyl) -2,3-dihydro-1H-1, 4-benzodiazepin-2one. MS (ESI): 554 576 (M+Na) 552 Chromatography Note i.
Example 73. 3-(5-cyclopentyl-2-(R)-cyclopropylmethyl-3- CS) -hydroxyl-1-oxopentyl)amino-1-methyl-5- (4trifluoromethyiphenyl) -2,3-dihydro-1H-1, 4-benzodiazepin-2one. MS (ESI): 542 564 (M+Na) 540 Chromatography Note i.
Example 74. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1- (4-trifluoromethylphenyl) -2,3dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 530 (Mi-H), 552 528 Chromatography Note i.
Example 75. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-- (4-trifluoromethyiphenyl) -2,3dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 544 566 (Mi-Na), 542 Chromatography Note i.
Example 76. 3-(2-(R)-cyclopropylmethyl--3-(S)-hydroxyl-1- (4-trifluoromethyl (pyridin-2yl) )-2,3-dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 517 539 (Mi-Na), 515 Chromatography Note i.
-113- WO 01/19797 WO 0119797PCT/USOO/24967 Example 77. 3-(2-(R)-cyclobutylmethyl-3-(S)-hydroxyl-1- (4Qtrifluoromethylphenyl) -2,3dihydro-lH-1,4--benzodiazepin-2-one. MS (ESI): 530 552 528 Chromatography Note i.
Example 78. 3-(2-(R)-cyclopentylmethyl-3-(S)-hydroxyl-1- (4-trifJluoromethylphenyl) -2,3dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 544 542 578 Chromatography Note i.
Example 79. 3-(2--(R)-cyclopropyjlmethyl-3-(S)-hydroxyl-1oxoheptyl)amino-1-methyl-5-(4-methyl-2-pyridiyl) -2,3dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 463 Chromatography Note cc.
Example 80. -cyclopropylmethyl-3-(S)-hydroxyl-1oxoheptyl)amino-1-methyl-5-(4-methyl-2-pyridyl)-2,3dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 463 Chromatography Note dd.
Example 81. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1- (4-trifluoromethyiphenyl) -2,3dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 474 Chromatography Note i.
Example 82. 3-(S)-(2-(R)-(3-butenyl)-3-(S)-hydroxyl-1oxoheptyl)amino-l-methyl-5-phenyl-2, 3-dihydro-1H-1, 4benzodiazepin-2-one. MS (ESI): 448 (Mi-H).
Example 83. 3-(S)-(2-(R)-(3-methylbutyl)3-CS)-hydroxyl-loxoheptyl)amino-1-methyl-5-phenyl-2, 3-dihydro-1H-1, 4benzodiazepin-2-one. MS (ESI): 464 (Mi-H).
Example 84. 3-(S)-(2-(R)-ethyl-3-(S)-hydroxyl-1oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1, 4benzodiazepin-2-one. MS (ESI): 422 -114- WO 01/19797 WO 0119797PCT/USOO/24967 Example 85. 3-(S)-(2-(R)-propyl-3-(S)-hydroxyl-1oxoheptyl)amino-1-methyl-5-phenyl-2, 3-dihydro-1, 4benzodiazepin-2-one. MS (ESI): 436 Example 86. 3-(S)-(2-(R)-butyl-3-(S)-hydroxyl-1oxoheptyl) amino-1--methyl-5-phenyl-2, 3-dihydro-1H-1, 4benzodiazepin-2-one. MS CESI): 450 Example 87. 3-(4-(S)-ainino-3-(R)-hydroxyl-2-(R)-methyl-1oxo-5-phenylpentyl)amino-7-chloro-5- (2-f luorophenyl) -1methyl-2, 3-dihydro-1H-1, 4-benzodiazepin-2-one.
MS (ESI): 523 521 Chromatography Note x.
Example 88. 3-(4-(S)-(tert-butoxycarbonylanino-3-(R)hydroxyl-2- -methyl-1-oxo-5-phenylpentyl)amino-7-chloro- (2-f luorophenyl) -1-iethyl-2, 3-dihydro-1H-1, 4benzodiazepin-2-one. MS (ESI): 645 621 CM-H).
Chromatography Note a and Note u.
Example 89. 3- (ter-t-butoxycarbonylpyrrolidin-2- -yl) 3-CR) -hydroxyl-2- CR) (2-f luorophenyl) -1-rethyl-2, 3-dihydro-1H-1, 4-benzodiazepin- 2-one. MS (ESI): 523 521 Chromatography Note u and Note v.
Example 90. 3-(3-(R)-hydroxyl-2-(R)-methyl-1-oxo-3- (pyrrolidin-2- CR) -yl)propyl) -amino-7-chloro-5- (2fluorophenyl) -1-methyl-2, 3-dihydro-1H-1,4-benzodiazepin-2one. MS (ESI): 473 471 Chromatography Note y and Note z.
Example 91. 3-(4-benzyloxy-3--(R)-hydroxyl-2-(R)-isopropyl-1-oxobutyl-amino-7-chloro-1-methyl-5-phenyl-2, 3dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI) 534. 556 CM-iNa), 532 Chromatography Note u and Note v.
-115- WO 01/19797 WO 0119797PCT/USOO/24967 Example 92. 2-(4-(S)-amnino-3-(S)-hydroxyl--2-(S)-methyl-lamino-7-chloro-5- (2-f lourophenyl) -1methyl-2, 3-dihydro-1H-1, 4-benzodiazepin-2-one.
MS (ESI): 523 521 Chromatography Note w.
Example 93. 2- -(Ctert-butoxycarbonylamino-3- (S)hydroxyl-2- -rethyl-1-oxo-5-phenylpentyl)amino-7chloro-5-(2-fluorophenyl)-l-methyl-2,3-dihydro-1H-1,4benzodiazepin-2-one. MS (EST): 645 621 Chromatography Note a and Note v.
Example 94. 3-(2-(R)-cyclopropylmethyl-3-(S) -hydroxyl-loxoheptyl)amino-l-methyl-5-(thiazol-2-yl)-2,3-dihydro-1H- 1,4-benzodiazepin-2-one. MS (ESI): 455 477 (M+Na), 453 Chromatography Note b and Note c.
The benzodiazepine was made from 2-aminophenyl- 2'thiazolylketone (see A. Furstner et al., Tetrahedron 1995, 51 773-786) following the synthetic sequence from: R. G. Sherrill et al., J. Org. Chem. 1995, 60, 734.
Example 95. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1- (thiazol-2-yl) -2,3dihydro-1H-1, 4benzodiazepin-2-one. MS (ESI): 495 (M+H)o 517 493 Chromatography Note c.
The benzodiazepine was made from 2-aminophenyl- 21 thiazolylketone (see A. Furstner et al. Tetrahedron 1995, 51 773-786) following the synthetic sequence from: R. G. Sherrill et al., J. Org. Chem. 1995, 60, 734.
Example 96. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1oxoheptyl) amino-1-cyclopropylmethyl-5- (4trifluoromethyiphenyl) 3-dihydro-lH-1, 4-benzodiazepin-2one. MS (ESI) 556 (M44H), 578 554 Chromatography Note j and Note p.
Example 97. 3-C2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1oxoheptyl)amino-l-benzyl-5-(4-trifluoromethylphenyl) -2,3- -116- WO 01/19797 PTUO/46 PCT/USOO/24967 dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 592 614 590 Chromatography Note b and Note c.
Example 98. -cyclopropylmethyl-3-(S)-hydroxyl-ioxoheptyl) amino-i- (3-phenoxybenzyl) (4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 684 706 682 Chromatography Note q and Note r.
Example 99. 3-(2-(R)-cyclopropyimethyl-3-(S)-hydroxyl-1oxoheptyl) amino-i- (3-pyridinylmethyl) (4-trifluoromethylphenyl) 3-dihydro-1H-1, 4-benzodiazepin-2-one. MS (ESI): 593 615 519 Chromatography Note q and Note r.
Example 100. 3-(2-(S)-cyclopropylmethyl-3-(R)-hydroxyl-loxoheptyl) amino-1-rnethyl-5- (4-trifluoromethyl-phenyl) -2,3dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 516 538 514 Chromatography Note i.
The syn-aldol was made according to Scheme 1, except that (S)-4-(phenylmethyl)-2-oxazolidinone was used instead of the (R)-isomer shown in Scheme 1.
Example 101. 3-(2-(S)-cyclopropylmethyl-3-(R)-hydroxyl-1oxoheptyl)amino-l-methyl-5- (4-trifluoromethyiphenyl) -2,3dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 516 538 514 Chromatography Note k.
The syn-aldol was made according to Scheme 1, except that (phenylmethyl) -2-oxazolidinone was used instead of the (R)-isomer shown in Scheme 1.
Example 102. 3-(2-(R)-cyclopropylmethyl-3-(R)-hydroxyl-1- (4-trifluoromethyiphenyl) -2,3dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 516 538 514 Chromatography Note i.
-117- WO 01/19797 PCT/US00/24967 NHTs 0 a"' s 0 OH NHTs O 1. TiCI 4 DIPEA fIS OH 2. C 4
H
9 CHO, TiCl 4 O OH UOH, THF-H 2 0 HOy The anti-aldols were made by the method described in: A. K. Ghosh, J. Am. Chem. Soc. 1996, 118, 2527-2528. The carboxylic acid shown was coupled with the corresponding benzodiazepine following a procedure analogous to the procedure of the last step in Example 1.
Example 103. 3-(2-(S)-cyclopropylmethyl-3-(S)-hydroxyl-loxoheptyl)amino-l-methyl-5-(4-trifluoromethylphenyl)-2,3dihydro-1H-l,4-benzodiazepin-2-one. MS (ESI): 516 538 514 Chromatography Note i.
Followed the synthetic sequence of Example 102, except the opposite enantiomer of the chiral auxiliary was used.
Example 104. 3-(2-(S)-cyclopropylmethyl-3-(S)-hydroxyl-1oxoheptyl)amino-l-methyl-5-(4-trifluoromethylphenyl)-2,3dihydro-lH-l,4-benzodiazepin-2-one. MS (ESI): 516 514 Chromatography Note k.
Followed the synthetic sequence of Example 102, except the opposite enantiomer of the chiral auxiliary was used.
Example 105. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-3- (S)-methyl-l-oxoheptyl)amino-l-methyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-lH-l,4-benzodiazepin-2-one. MS (ESI): 530 552 528 Chromatography Note i.
Addition of a methyl group to Example 135 was performed with an organocerium reagent generated from methylmagnesium bromide and cerium trichloride according to: T. Imamoto et al J. Org. Chem. 1984, 49, 3904-3912, and J. Am. Chem. Soc. 1989, 111, 4392-4398.
-118- WO 01/19797 WO 0119797PCT/USOO/24967 Example 106. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-loxoheptyl) amino-i- (3-phenoxybenzyl) -5-methyl-2, 3-dihydrolH-l,4-benzodiazepin-2-one. MS (ESI): 554 Chromatography Note aa and Note bb.
Example 107. 3-(2-(R)-cyclopropylmehtyl-3-(S)-hydroxyl-1oxoheptyl) amino-l-benzyl-5-methyl-2, 3-dihydro-lH-1, 4benzodiazepin-2-one. MS (ESI): 462 Chromatography Note b and Note c.
Example 108. 3-(3-(S)-acetoxy-2-(R)-iso-butyl-1oxoheptyl) amino-5- (4-f luorophenyl) -1-methyl-2 ,3-dihydro-1H- 1,4-benzodiazepin-2-one. MS (ESI): 510 532 (M+Na), 508 Chromatography Note h.
Example 109. 3- -(5-cyclopentyl-2- -cyclopropylmethyl- 3- (S)-methoxy-1-oxopentyl) aiino-1-methyl-5-pheiyl-2, 3dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 502 524 (M+Na).
OH 0 0 0 0 0 N~Q Me 3
OBF
4
N
Bn ~proton sponge l*B)j 0 0 LiOH, THF-H 2 0 OH Methylation of the corresponding aldol was carried out according to: D. A. Evans et al., Tetrahedron Lett.
1994, 35 7171-7172; G. R. Pettit, Synthesis 1996, 719-725. The carboxylic acid shown was then coupled with the corresponding benzodiazepine following a procedure analogous to the procedure of the last step in Example 1.
Example 113. 1- (1-hydroxypentyl) cyclohexanecarboxylic acid(5-(4-fluorophenyl)-l-methyl-2-oxo-2,3-dihydro-lH-1,4- -119- WO 01/19797 WO 0119797PCT/USOO/24967 benzodiazepin-3-yl)amide. MS (ESI): 480 502 (M+Na), 478 Chromatography Note t and Note h.
0 0 OH 0 0 Nk1. BU 2 BOTf, TEA- N- N N' C12.
C
4 HqCHOPhk OH 0
OH
LiOH, THF-H 2 0 The corresponding aldol was made according to A.
S. Kende et al., Tetrahedron Lett. 1989, 30 5821- 5824; H. Muizer et al., Tetrahedron Lett. 1995, 36 7643-7646. The carboxylic acid shown was coupled with benzodiazepine following a procedure analogous to the procedure of the last step in Example 1.
Example 114. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-loxoheptyl)amino-5-methyl-5H,7H-dibenzo(b,d]azepin-6-one.
MS (ESI): 421 443 419 Chromatography Note s.
Example 115. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-loxooctyl) aiino-5-methyl-5H, 7H-dibenzo lb.dl azepin-6-one.
MS (ESI): 435 457 433 Chromatography Note s.
Example 116. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-l- 7H-dibenzo[b,d]azepin-6-one.
MS (ESI): 449 471 447 Chromatography Note s.
Example 117. 3-(2-(R)-cyclopropylmethyl-5-(furan-2-yl)-3- -hydroxyl-l-oxopentyl)amino-5-methyl-5H, 7Hdibenzo(b,d]azepin-6-one. MS (ESI): 459 481 (M+Na), 457 Chromatography Note s.
-120- WO 01/19797 PCT/US00/24967 Example 118. 2-(R)-cyclopropylmethyl-3-(S)-hydroxylheptanoic acid (2-oxo-l-(3-phenylamino-benzyl)azapan-3-(S)yl) amide. MS (ESI): 492 514 490 Step 1: [2-Oxo-l-(3-phenylamino-benzyl)-azepan-3-yl]carbamic acid tert-butyl ester: In a 100 ml round bottomed flask Binap, (S)-(-)2,2'-Bis(diphenylphosphino)-1,l'binaphthyl, 0.210 g 0.3375 mmol) dissolved in toluene was stirred at 80 0 C for 1 minute To the flask cooled to room temperature under inert atmosphere Pd(OAC) 2 (0.050 g 0.225 mmol) was added and the solution was stirred at room temperature for 2 minutes. To the reaction mixture [l-(3-Iodo-benzyl)-2-oxo-azepan-3-yl]-carbamic acid tert-butyl ester 1.0 g 2.25 mmol) dissolved in toluene aniline (1.047 g 11.25 mmol) and Sodium tertbutoxide (0.259 g 2.70 mmol were added and the solution was stirred at 80 0 C for 18 h. The reaction was cooled to room temperature, diluted with 200mL of water, and extracted twice with 100 mL of ethyl acetate. The organic layer was dried with anhydrous sodium sulfate, filtered and concentrated to an oil. The oil was purified on flash silica gel column using 10-30% ethyl acetate in hexanes as eluent to yield 0.562 g MS (ESI) M+H 432.5 Step 2: 3-Amino-l-(3-phenylamino-benzyl)-azepan-2-one, trifluoroacetic acid salt: In a 25mL round bottomed flask the ester from Step 1 above 0.025 g 0.06 mmol was dissolved in 10mL of 50%TFA CH 2 Cl 2 and was stirred at room temperature for 1 h. The solvent was concentrated to an oil and dried under high vacuum to yield 0.025 g (100%).
MS (ESI) M+H 310.4 Step 3: 2-Cyclopropylmethyl-3-hydroxy-heptanoic acid [2-oxo-l-(3-phenylamino-benzyl)-azepan-3-yl]-amide: In a round bottomed flask 2-Cyclopropylmethyl-3-hydroxyheptanoic acid 0.0125g 0.061mmol was dissolved in ImL DMF. To the reaction mixture HATU, O-(7-Azabenzotriazol-1yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, (0.029 g 0.0734 mmol and N-Methyl morpholine (0.018 g, 0.018 mmol) were added and the reaction solution was -121- WO 01/19797 PCT/US00/24967 stirred at room tenperature for 10 minutes. To the reaction mixture the compound from Step 2 above (0.025 g, 0.06 mmol) dissolved in ImL of DMF was added and the reaction solution was stirred at room tenperature for 18 h.
The solution was diluted with 50 mL of water and extracted twice with 20 mL of ethyl acetate. The combined organic layers were dried with anhydrous Sodium sulfate, filtered, and concentrated to an oil. The oil was purified on a flash silica gel column using 20-40% ethyl acetate in hexanes as eluent to yield 6.0 mg MS (ESI) M+H 492.6 Example 119. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-loxoheptyl)amino-5-cyclopentyl-l-methyl-2,3-dihydro-lH-l,4benzodiazepin-2-one. MS (ESI): 440 Chromatography Note a.
Synthesis of 2-aminophenyl cyclopentylmethanone: To a solution of anthranilonitrile (15.0 g) in diethyl ether (600 mL) was added a solution of 2.0 M cyclopentylmagnesium bromide in diethyl ether (159 mL) at 0C under nitrogen.
The mixture was stirred at room temperature overnight hours). 500 ml of 5 N HCI in H 2 0 was added very slowly at 0C. The mixture was stirred at room temperature for 1 hour. The aqueous layer was neutralized with 50% NaOH/H 2 0 to pH 12. 2 X 500 mL of ethyl acetate was used to extract the aqueous layer. The combined organic layers were dried over Na 2
SO
4 The solvent was removed to give the crude product 22.5 g (93.6% yield). H 1 NMR(CDC1 3 66.62-7.82 (m, 4H), 3.64-3.78 1H), 1.50-1.96 8H).
The 2-aminophenyl cyclopentylmethanone was converted to benzodiazepine following: R. G. Sherrill et al J. Org.
Chem. 1995, 60, 734.
Example 120. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1oxoheptyl)amino-5-benzyl-l-methyl-2,3-dihydro-lH-l,4benzodiazepin-2-one. MS (ESI): 462 460 Chromatography Note b and Note c.
-122- WO 01/19797 WO 0119797PCTIUSOO/24967 The benzodiazepine was made from l-(2-aminophenyl)-2phenylethanone (see M. W. Partridge et al., J. Chem. Soc.
1964. 3673) following the synthetic sequence from: R. G.
Sherrill, LT. Org. Chemn. 1995, 60, 734.
Example 121. 3-(2-(R)-cyclopropylmethyl-3-(S) -hydroxyl-loxoheptyl)aniino-5-berizyl-l-butyl-2, 3-dihydro-l{-l, 4benzodiazepin-2-one. MS (ESI): 504 502 Chromatography Note b and Note c.
Example 122. 3- (2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-loxoheptyl) amino-5-cycloheptyl-l-methyl 3-dihydro-lH-l, 4benzodiazepin-2-one. MS (ESI) 468 466 Chromatography Note b and Note c.
Example 123. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-loxoheptyl)ainino-l-benzyl-5-cycloheptyl-2, 3-dihydro-lH-l, 4benzodiazepin-2-one. MS (ESI): 544 542 Chromatography Note a.
Example 124. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-loxoheptyl) amino-l-butyl-5-cycloheptyl-2, 3-dihydro-lH-l, 4benzodiazepin-2-one. MS (ESI): 510 508 Chromatography Note b and Note c.
Example 125. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyi-loxoheptyi)amino-l- (2-pyridinylmethyl) (4trifluoromethyiphenyl) 3-dihydro-lH-l, 4-benzodiazepin-2one. MS (ESI): 593 615 591 Chromatography Note a.
Example 126. 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1oxoheptyl) amino-i- (3-pyridinylmethyl) (2-f luorophenyl) 2,3-dihydro-lH-l,4-benzodiazepin-2-one. MS (ESI): 543 541 Chromatography Note d and Note e.
-123- WO 01/19797 WO 0119797PCT/USOO/24967 Example 127. 3-(2-(S)-cyclopropylrnethyl-3-(S)-hydroxyl-loxopentyl)amino-l- (3-pyridinylmethyl) (4trifluorometihyiphenyl) 3-dihydro-H-l, 4-benzodiazepin-2one. MS (ESI): 565 563 Chromatography Note f and Note g.
Example 128. 3-(2-1(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1- N-dibutylamino) 3-dihydro- 1H-1,4-benzodiazepin-2-one. MS (ESI): 499 Chromatography Note a.
Example 129. 3-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1oxoheptyl) amino-1-n-butyl-5- t-butyl-2, 3-dihydro-lH-l, 4benzodiazepin-2-one. MS (ESI): 470 Chromatography Note b and Note c.
Example 130. 3-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyloxoheptyl)amino-1- (2-oxo-3, 3-dimethylbutyl) -5-ri-butyl-2, 3dihydro-1H-1,4-benzodiazepin-2-one. MS (ESI): 512 Chromatography Note b.
Example 131. 3-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1oxoheptyl)amino-1-benzyl-5-t-butyl-2,3-dihydro-lH-1, 4benzodiazepin-2-one. MS (ESI): 504 Chromatography Note a.
Example 132. 3-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1oxoheptyl) amino-i- (2-picolyl) -5-n-butyl-2, 3-dihydro-1H-1, 4benzodiazepin-2-one. MS (ESI): 505 Chromatography Note b and Note c.
Example 133. 3-(2-(R)-Isobutyl-3-(S)-hydroxyl-1oxoheptyl)amino-1-methyl-5-homopiperidino-2, 3-dihydro-1H- 1,4-benzodiazepin-2-one. MS (ESI): 471 Chromatography Note b and Note c.
-124- WO 01/19797 WO 0119797PCTUSOO/24967 Example 135. 3-(2-(R)-cyclopropylmethyl-l,3- (4-trifluoromethyiphenyl) -2,3dihydro-lH-1,4-benzodiazepin-2-one. MS (ESI): 514 536 512 Chromatography Note i.
Example 55 was oxidized to the dicarbonyl compound by TPAP/NMO, see S. V. Ley et al., Synthesis 1994, 639.
Example 136. 1-pentyrylcyclohexanecarboxylic acid fluorophenyl) -l-methyl-2-oxo-2, 3-dihydro-lH-l, 4benzodiazepin-3-yl) amnide. MS (ESI): 478 (M+HL, 500 (M-iNa), 476 Chromatography Note h.
Chromatography Notes: Note a: epimeric mixture at BZD.
Note b: 1 st eluting peak on CHIRAILPAK AD chiral column with 35% i-PrOH/hexane.
Note c: 2 nld eluting peak on CHIRALPAK AD chiral column with 10 35% i-PrOH/hexane.
Note d: 1 st eluting peak on CHIRALCEL OD chiral column with 2/200/800 ratio of MeOH/i-PrOH-/Hexane.
Note e: 2 nd eluting peak on CHIRALCEL OD chiral column with 2/200/800 ratio of MeOH-/i-PrOH/Hexane.
Note f: 1st eluting peak on silica gel column with 2% MeOH/CH 2 Cl 2 Note g: 2 nld eluting peak on silica gel column with 2% MeOH/CH 2 Cl 2 Note k: made from BZD-amine which in Cbz protected form was the 2nd eluting peak on CHIRALPAX AD column with acetonitrile.
Note m: made from BZD-amine which in Cbz protected form was the 1st eluting peak on CHIRALPAK AS with methanol.
Note n: made from BZD-amine which was the 1 5t eluting peak on CHIRALPAK AS with 0.1% diethylarnine/methanol.
Note o: made from BZD-amine which was the 2 nd eluting peak on CHIRALPAK AS with 0.1% diethylainine/methanol.
Note h: made from BZD-amine which was the lst eluting peak on CHIRAILPAK AD column with 0.1% diethylaxnine/MeOH.
Note i: made from BZD-axnine which in Cbz protected form was the 1 st eluting peak on CHIRALPAK AD column with acetonitrile.
Note 1: made from BZD-axnine which in Cbz protected was the ls eluting peak on CHIRALCEL OJ with 1:4 of hexane/ethanol.
Note j: 1St eluting peak on CHIRALPAK AD column with acetonitrile/water.
-125- WO 01/19797 PCT/US00/24967 Note p: 2 nd eluting peak on CHIRALPAK AD column with acetonitrile/water.
Note q: 1 s t eluting peak on CHIRALCEL OD with 10% ipropanol/hexane.
Note r: 2 nd eluting peak on CHIRALCEL OD with 10% ipropanol/hexane.
Note s: made from bisbenazapine amine which was the 1 st peak on CHIRALCEL OD with 20% i-PrOH/hexane with diethylamine.
Note t: made from BZD-amine which was the 2 nd eluting peak on CHIRALPAK AD column with 0.1% diethylamine/MeOH.
Note w: derived from Example 93 by treatment with TFA.
Note x: derived from Example 88 by treatment with TFA.
Note u: 2 nd eluting peak on silica gel column with 30-80% EtOAc/hexane.
Note v: 1 st eluting peak on silica gel column with 30-80% EtOAc/hexane.
Note y: derived from Example 89 by treatment with TFA.
Note z: derived from Example 89 by treatment with TFA.
Note aa: 1 st eluting peak on CHIRALPAK AD with 20:80 of water/MeCN.
Note bb: 2 nd eluting peak on CHIRALPAK AD with 20:80 of water/MeCN.
Note cc: made from BZD-amine which in Cbz protected form was the 2 nd eluting peak on CHIRALCEL OD column with 1/300/700 ratio of diethtlamine/EtOH/CO 2 Note dd: made from BZD-amine which in Cbz protected form was the 1 st eluting peak on CHIRALCEL OD column with 1/300/700 ratio of diethtlamine/EtOH/CO2.
Tables 1-8 below provide representative Examples of the compounds of Formula of the present invention.
-126- WO 01/19797 PTU0146 PCTIUSOO/24967 Table 1 Ex.# Q R 5 R R 3 Mass
(M+H)
1 2 3 4 6 7 8 9 11 12 13 14 16 17 phenethyl phenethyl phenethyl phenethyl 3, 5-diFphenoxymethyl 3, 5-diFphenoxyvmethyl phenoxymethyl phenoxymnethy.
cyclohexyloxymethyl cyclohexyl oxymethyl phenoxymethyl phenoxymethyl cyclohexyloxymethyl cyciohexyloxymethyl cyclohexyloxyme thyl cyclohexyloxyme thyl 4-CF3-benzyloxyme thyl 2, 4-diF-benzyloxymethyl benzyloxymethyl cyclohexyloxvme thvl cyc lopentylmethyl cyc lopentylmethyl benzyl i -propyl cyclopentylmethyl i -butyl cyclopentylmethyl i -buty.
methyl i-butyl methyl i-butyl benzyl phenyl H 524 4-F-phenyl H 542 phenyl phenyl phenyl phenyl
H
H
phenyl 2-F-phenyl phenyl phenyl phenyl phenyl phenyl.
phenyl phenyl phenyl phenyl
H
H
cl Cl Cl Cl Cl Cl 532 562 536 560 464 506 534 566 540 526 cyc lopentylmethyl i -butyl i-propyl me thoxy 18 21 22 23 24 2 5c 26 methyl vinyl methyl phenyl phenyl phenyl Cl 536 phenethyl cyclopropyl n-butyl n -bu tyl n-butyl n-hexyl i -butyl i-butyl i-butyl i -bu tyl i-butyl i -butyl phenyl phenyl phenyl phenyl phenyl phenyl H 434 H 450 H 450 -127- WO 01/19797 WO 0119797PCT/US00124967 27 n-propyl i-butyl phenyl H 436 28 benzyl i-butyl phenyl H 484 29 phenethyl methyl phenyl H 442 phenpropy. methyl phenyl H 470 31 methyl i-butyl phenyl H 408 32 n-pentyl i-butyl phenyl H 464 33 n-butyl methyl phenyl H 408 34 phenyl methyl phenyl H 428 2,2-.dimethyl- methyl phenyl H 422 propyl 36 n-propyl methyl phenyl H 394 37 4-propoxyphenyl methyl phenyl H 486 the chiral carbon the chiral carbon the chiral carbon of the benzodiazepine of the benzodiazepine of the benzodiazepine ring is ring is ring is racemic.
(S)
Table 2 w-x-Y-z OH 00
N
Ex.# Q Z-Y-X-W- 38 n-butyl 3-phenoxybenzyl 39 3, 5-diF-phenethyl 3-phenoxybenzyl cyclopentylmethyl 3 -phenoxybenzyl 41 n-butyl 5-bromo-3-pyridinyl 118 n-butyl 3-(phenyl)amino-benzyl -12 8- WO 01/19797 WO 0119797PCTUSOO/24967 Table 3
CH
3 OH00 N- R13 a HN N-
R
Ex.# 42 43 44 46 47 48 49 51 n-butyl n-butyl 3, 5-diFphenethyl n-butyl n-butyl n- butyl cyclopentyl methyl but-3 -enyl but-3-enyl 2- 5-dimethyl isoxazol-4-yl) ethyl n-butyl n-butyl n -bu tyl n-butyl 2 -cyclopentylethyl n- butyl 2- (thiophen-2yl) -ethyl 2- (furan-2-_yl) ethyl 2-cyclopentylethyl 3, 5-diFphenethyl n-butyl
R
5 cyc lopropylmeihyl cyc lopropylmethyl cyc lopropylmethyl cyc lopropylmethyl cyclopropylmethyl cyclopropylmethyl cyclopropylmethyl cyc lopropylmethyl cyc lopropylmet-hyl cyc lopropylmethyl cyclopropylmethyl cyci opropylmethyl cyclopropylmethyl cycl opropylmethyl cyclopropylmethyl i-butyl cyclopropylmethyl cyclopropylmethyl cyclopropylmethyl cyc lopropylmethyl cyc lopropylmethyl 2-F-phenyl azapan-l-yl pyridin-2-yl 4-Cl -phenyl 3-F-phenyl 4-MeO-phenyl phenyl phenyl 4-CF 3 -phenyl phenyl R1 3
H
H
H
H
H
H
H
H
H
H
57 phenyl pyridin-2-yl 4 -F-phenyl 4-CF 3 -phenyl pyridin-2 -yl 4-CF 3 -phenyl phenyl phenyl 4-F-phenyl phenyl phenyl Cl
H
H
H
H
H
H
H
H-
H
H
61 -129- WO 01/19797 WO 0119797PCTIUSOO/24967 64 n-butyl n- buty 1 n-butyl n-butyl n -bu tyl phenethyl thiophen-2-ylmethyl cyc lopropylmethyl cyc lobutylmethyl 3. 5-diF-phenylmethyl furan- 2-yl -methyl cyclopropylmethyl 67 72 73 phenethyl n-butyl phenethyl 2-furan-2-ylethyl 2-cyclopentylethyl n-pentyl n-hexyl n-butyl n-butyl n-butyl n-butyl n-butyl methyl n-butyl n-butyl n-butyl n-butyl cyclopropylmethyl i-butyl cyclopropylmethyl cyc lopropylmethyl cyc lopropylmethyl cyclopropylmethyl cyc lopropylmethyl cyc lopropylmethyl cyc lobutylmethyl cyclopentylmethyl cyc lopropylmethyl cyclopropylmethyl cyclopentylmethyl but-3-enyl 3-methyl-butyl ethyl propyl phenyl phenyl phenyl phenyl phenyl 4-F-phenyl pyridin-2 -yl 4-F-phenyl phenyl 4-CF 3 -phenyl 4-CF 3 -phenyl 4-CF 3 -phenyl 4-CF 3 -phenyl 4-CF 3 -pyridin- 2 -yJ.
4-CF 3 -pheflyl 4-CF 3 -phenyl 4-methylpyridin-2 -yl 4-methyl pyridin- 2-yl 4-CF 3 -phenyl phenyl phenyl phenyl phenyl phenyl 2-F-phenyl 2-F-phenyl 2-F-phenyl
H
MeO
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl Cl Cl 83 84 n-bu tyl 1- -aminophenethyl 1- -(BOC-NH) phenethyl
N-BOC-
pyrrolidin-2- -yl pyrrolidin-2- -yl n-butyl methyl methyl methyl 89 methyl 2-F-phenyl Cl -130- WO 01/19797 WO 0119797PCTUSOO/24967 120 benzyloxy-methyl n-butyl n-butyl n-butyl n-butyl i-propyl cyc lopropylmethyl cyc lopropylmethyl cyc lopropylmethyl cyclopropylmethyl phenyl cyclopentyl benzyl cycloheptyl N,N-dibutylamino
H
133 n-butyl i-butyl homopiperidino H 134 n-butyl i-butyl spiro-cyclo- H pentyl Table 4
CH
3 I O 00 N R 13 02)IHNYN i
R
Ex.# Q R5RlR 13 92 1-(S)-amino- Methyl 2-F-phenyl Cl phenethyl 93 Methyl 2-F-phenyl Cl phene thyl 100 n-butyl cyclopropylmethyl 4-CF 3 -phenyl H 101 n-butyl cyc3.opropylmethyl 4-CF 3 -phenyl H -131- WO 01/19797 WO 0119797PCTUSOO/24967 Table SA Ex. 94 96 97 98 99 105 106 107 121 123 124 125 126 129 130
Q
n- butyl nT- -but yl1 n-butyl ni---butyl1 n-butyl n bu tyl n- -u tyl nT--bu tyl n-buty 1 n-butyl n-butyl1 nbu tyl1 n-bu tyl n-t-butyl n-bu tyl n-butyl
R
2
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
z-y-x-wmethyl cyc 1lopropyirmethy-l cyc lopropylmethyl benzyl 3 -phenoxy-benzyl 3 -pyridinyl -me thyl methyl 3 -pherioxy-benzyl benzyl n-butyl Rhaol2" thiazol-2-yl 4-CF 3 -heyl 4-CF 3 -phenyl 4-CF 3 -phenyl 4-CF 3 -phenyl 4-CF 3 -phenyl met3-hyl methyl benzyl cycloheptyl cyc lohep tyl 4-CF 3 -phenyl 2 -F-phenyl t -butyl n-butyl benzyl n- bu tyl 2 -pyridinyl-methyl 3 -pyridinyl -methyl n- butyl 2-oxo-3, 3dimethylbutyl 131 n-butyl H benzyl t-butyl 132 n-butyl H 2-pyridinyl-methyl n-butyl -132- WO 01/19797 WOOI/9797PCTfUSOO/24967 Table SB w-x.Y-z HO 00 yN \N H H" Ex.# Q R 2 Z-Y-X-W- R 11 102 n-butyl H methyl 4-CF 3 -phenyl Table Ex. 103 104 127
Q
ni -butyl n-butyl z-y-x-w- Rll methyl 4-CF 3 -phenyl methyl 4-C F 3 -phenyl 3-pyridinyl -methyl 4-CF 3 -phenyl -133- WO 01/19797 WO 0119797PCT[USOO/24967 Table 6
CH
3 Ex.# R 3 Q R 5 /R5a R 11 108 acetyl n-butyl R 5a= i-butyl 4-F-phenyl R =H 5 2-cyclo R cyclopropyl 109 methyl pentyl methyl phenyl ethyl R 5a 113 HI n-butyl CR 5R 5a4-F-phenyl -1,1-cyclohexyl -134- WO 01/19797 PCT/US00/24967 Table 8 Ex.# 114 n-butyl 115 n-pentyl 116 n-hexyl 17 2-(furan-2-yl)-ethyl 117
UTILITY
AD production has been implicated in the pathology of Alzheimer's Disease The compounds of the present invention have utility for the prevention and treatment of AD by inhibiting AP production. Methods of treatment target formation of AP production through the enzymes involved in the proteolytic processing of P amyloid precursor protein. Compounds that inhibit 3 or ysecretase activity, either directly or indirectly, control the production of AD. Such inhibition of P or ysecretases reduces production of AD, and is expected to reduce or prevent the neurological disorders associated with A protein, such as Alzheimer's Disease.
Cellular screening methods for inhibitors of AD production, testing methods for the in vivo suppression of AP production, and assays for the detection of secretase activity are known in the art and have been disclosed in -135- WO 01/19797 PCT/US00/24967 numerous publications, including PCT publication number WO 98/22493, EPO publication number 0652009, US patent 5703129 and US patent 5593846; all hereby incorporated by reference.
The compounds of the present invention have utility for the prevention and treatment of disorders involving A3 production, such as cerebrovascular disorders.
Compounds of the present invention have been shown to inhibit AP production, as determined by the secretase inhibition assay described below.
Compounds of the present invention have been shown to inhibit AP production, utilizing the C-terminus P amyloid precursor protein accumulation assay described below.
Compounds of Formula are expected to possess Ysecretase inhibitory activity. The y-secretase inhibitory activity of the compounds of the present invention is demonstrated using assays for such activity, for example, using the assay described below. Compounds of the present invention have been shown to inhibit the activity of ysecretase, as determined by the AP immunoprecipitation assay.
Compounds provided by this invention should also be useful as standards and reagents in determining the ability of a potential pharmaceutical to inhibit AP production.
These would be provided in commercial kits comprising a compound of this invention.
As used herein "pg" denotes microgram, "mg" denotes milligram, denotes gram, "pL" denotes microliter, "mL" denotes milliliter, denotes liter, "nM" denotes nanomolar, denotes micromolar, "mM" denotes millimolar, denotes molar, "nm" denotes nanometer, "SDS" denotes sodium dodecyl sulfate, and "DMSO" denotes dimethyl sulfoxide, and "EDTA" denotes ethylenediaminetetraacetato.
-136- WO 01/19797 PCT/US00/24967 A compound is considered to be active if it has an
IC
50 or Ki value of less than about 100 M for the inhibition of AO production.
P amyloid precursor protein accumulation assay A novel assay to evaluate the accumulation of Ap 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 AP in the conditioned medium is tested by immunoprecipitation.
Briefly, N 9 cells are grown to confluency in 6-well plates and washed twice with 1 x Hank's buffered salt solution.
The cells are starved in methionine/cysteine deficient media for 30 min, followed by replacement with fresh deficient media containing 150uCi S35 Translabel (Amersham). Test compounds dissolved in DMSO (final concentration are added together with the addition of radiolabel. The cells are incubated for 4 h at 37 0 C in a tissue culture incubator.
At the end of the incubation period, the conditioned medium is harvested and pre-cleared by the addition of 5 pl normal mouse serum and 50ul of protein A Sepharose (Pharmacia), mixed by end-over-end rotation for 30 minutes at 4 0 C, followed by a brief centrifugation in a microfuge.
The supernatant is then harvested and transferred to fresh tubes containing 5ug of a monoclonal antibody (clone 1101.1; directed against an internal peptide sequence in AP) and 50 pl protein A Sepharose. After incubation overnight at 40C, the samples are washed three times with high salt washing buffer (50mM Tris, pH 7.5, 500mM NaC1, EDTA, 0.5% Nonidet P-40), three times with low salt wash buffer (50mM Tris, pH 7.5, 150mM NaC1, 5mM EDTA, Nonidet P-40), and three times with 10mM Tris, pH 7.5. The pellet after the last wash is resuspended in SDS sample -137- WO 01/19797 PCT/US00/24967 buffer (Laemmli, 1970) and boiled for 3 minutes. The supernatant is then fractionated on either 10-20% Tris/Tricine SDS gels or on 16.5% Tris/Tricine SDS gels.
The gels are dried and exposed to X-ray film or analyzed by phosphorimaging. The resulting image is analyzed for the presence of AP polypeptides. The steady-state level of AO in the presence of a test compound is compared to wells treated with DMSO alone. A typical test compound blocks AO accumulation in the conditioned medium, and is therefore considered active, with an IC 50 less than 100 pM.
C-Terminus 0 Amyloid Precursor Protein Accumulation Assay The effect of test compounds on the accumulation of Cterminal 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, 150mM NaC1, 0.125% NaN 3 Again, lysates are precleared with 5ul normal rabbit serum 50ul protein A Sepharose, followed by the addition of BC- 1 antiserum (15pl;) and 50pl protein A Sepharose for 16 hours at 4 0 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 alone. A typical test compound stimulates C-terminal fragment accumulation in the cell lysates, and is therefore considered active, with an
IC
50 less than 100 uM.
AD Immunoprecipitation Assay -138- WO 01/19797 PCT/US00/24967 This immunoprecipitation assay is specific for y secretase proteolytic activity required to generate the C-terminal end of AP 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 y secretase inhibitor (MDL 28170) for 1 h, followed by washing to remove radiolabel and MDL 28170. The media is replaced and test compounds are added. The cells are chased for increasing periods of times and A P is isolated from the conditioned medium and C-terminal fragments from cell lysates (see above). The test compounds are characterized whether a stabilization of C-terminal fragments is observed and whether AP is generated from these accumulated precursor.
A typical test compound prevents the generation of AP out of accumulated C-terminal fragments and is considered active with an IC 50 less than 100 uM.
Dosaae and Formulation The compounds of the present invention can be administered orally using any pharmaceutically acceptable dosage form known in the art for such administration. The active ingredient can be supplied in solid dosage forms such as dry powders, granules, tablets or capsules, or in 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 compounds of the present invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. Likewise, they may also be administered in intravenous (bolus or -139- WO 01/19797 PCT/US00/24967 infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed to prevent or treat neurological disorders related to P-amyloid production or accumulation, such as Alzheimer's disease and Down's Syndrome.
The compounds of this invention can be administered by any means that produces contact of the active agent with the agent's site of action in the body of a host, such as a human or a mammal. They can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
The dosage regimen for the compounds of the present 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, 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 compounds for the present invention can be administered in intranasal form via topical use of suitable -140- WO 01/19797 PCT/US00/24967 intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches wall known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittant throughout the dosage regimen.
In the methods of the present invention, the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable 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 callulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or p-lactose, corn 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.
-141- WO 01/19797 PCT/US00/24967 The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamallar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine 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 -142- WO 01/19797 PCT/US00/24967 parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or 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.
Where the terms "comprise", "comprises", "comprised" or "comprising" are used in this specification, they are to be interpreted as specifying the presence of the stated features, integers, steps or components referred to, but not to preclude the presence or addition of one or more other feature, integer, step, component or group thereof e eeee eeeoe -143-

Claims (8)

1. A compound of the formula R 5 R 5 e R O R2 N W-X-Y-Z R O (I) or a pharmaceutically acceptable salt form or prodrug thereof, wherein: Q is Q', S 10 -(C 1 -C 3 alkylene)-O-Q 1 S* -(C1-C 3 alkylene)-S-Q', -(C 1 -C3 alkylene-S(O)-Q 1 -C 3 alkylene)-S(-0)2Q'. or S-(C 1 -C 3 alkylene)-N(R 2 )Ql S. :l is Cl-Cs alkyl substituted with 0-3 R 1 C 2 -CS alkenyl substituted with 0-3 R 1 a; C 2 -Cg alynyl substituted with 0-3 Ria; C3-Co cycloalkyl substituted with 0-3 Rib; 20 C 3 -Cio carbocycle substituted with 0-3 RIb; aryl substituted with 0-3 RIb; or to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered ibetrocycle is substituted with 0-3 Rib; R 1 a, at each occurrence, is independently selected from H, C 1 -C 6 alkyl, OR14, CI, F, Br, 1, NR1 5 R 6 CF3 C3-C10 carbocycle substituted with 0-3 RIb; aryl substituted with 0-3 Rib; and -144-2.5/ .llZSI S elim0lS42 -144- COMS ID No SBMI-01882249 Received by IP Australia: Time 11.50 Date 2005-11-03 03/11 '05 11:21 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB4!JAL PATENT OFFICE 141040 to 10 memnbered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 meminbered beterocycle is substituted with 0-3 Rib; Rib, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, N02, NR 15 R 16 CF3, acetyl, SCH3, S(=O)CH3, S(O)2CH3, Cr-Cs alkyl, C 1 -C4 alkoxy, C-Choal, C1C 4 halalkyl, CC4 oalkoxy, Cp-C4 baloakyl-S-, and (C 1 -C 6 alkyl)-O- R 2 is H, methyl, ethyl, propyl, or butyl; 'R 3 is H; R 5 is H, OR 1 4 15 C 1 -C6 alkyl substituted with 0-3 Ci-C6 alkoxy substituted with 0-3 Rb; C2-C6 alkenyl substituted with 0-3 R%; C 2 -C6 alkynyl substituted with 0-3 Rh; C 3 -CLo cycloalkyl substituted with 0-3 20 C 3 -CIo carbocycle substituted with 0-3 RSc; aryl substituted with 0-3 R5c; or 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3RS5; R58 is H, Cj-C 4 alkyl, or C 2 -C 4 alkenyl; alternatively, R5 and R 5 3 may be combined to form a 3-7 membered cycloalkyl ring substituted with 0-3 R5c; optionally the cycloalkyl ring formed by combining R and R5a may be bcnzo fused, wherein the benzo fused ring may be substituted with 0-3 RsC; at each occurrence, is independently selected from: ZS/06/05,. 12525.,.hus,1A! -145- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11.50 Date 2005-11-03 03/11 '05 11:22 FAX 61 3 9859 1588 CALLINA LAWRIE MELD AUS PATENT OFFICE I91041 H, C 1 -C6 alk)1, Cr 3 ORp14, CF, Br, 1, CN, NO 2 yNpj 5 R 1 6 acetyl, SCH3, S(4)CH3, SQO2CH3, C 2 -C6 alkenyl. C 2 -C6 alkynyl, CI-C4 alkoxy, CI-C4 haloalkyl, CI-C4 haloalkOxY, C-C4 haloalkyl-S-, C 3 -C10 cycloalkYl substituted with 0-3 R 5 C 3 -Cio carbocycle substituted with 0-3 RSC; a.rl substituted with 0-3 RSC; and to 10 membered heterocycle containing 1 to 4 heteroatons selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 RSC, at each occurrence, is independently selected from OH, Cl, F, Br, I, CN, N02, NP' 5 R 16 CF3, acetyl, SCH3, S(43)CH3. 2 CH3, Cl-C6 alkyl, C 1 -C 4 alkoxy, C 1 -C4 haloalkyl, Cj-C 4 haloalkoxy, and C 1 -C4 haloalkyl-S-; R6 is H or C-C6BilkYl; W is -(CRSRa); pis O, l,2,3,or4; :R8 and R 8 at each occurrence, are indepedently selected from H, F, CJ-C4 alkyl, C2-C 4 alkcny), C 2 -C4 alkynyl and C3-Cg cycloalkyl; X is a bond; 25 aryl substituted with 0-3 RXb; C3-Clo cycloalkyl substituted with 0-3 RXb; C 3 -ClO carbocycle substituted with 0-3 RXb; or to 10 membered heterocycle substituted with 0-2 RXb; at each occurrence, is independently selected from H, OH, Cl, F, Br, 1, UN, NO 2 6 CF 3 acetyl, SCH3, S( O)CH3, S(-0)2CH3, Ci-C6 alkyl, Cl-C 4 alkoxy, CI-C 4 haloalyl, CI-C 4 haloalkoxy, and Cl-C4 haloalkyl-S-; Y is a bond or -(CR9R9a)rV-(CRQR 9 ax1a; -146-3.M;2S! caaf i i4 -146- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:22 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB AUi- PATENT OFFICE jU4 i9J U4Z t isO0, 1, 2, or 3; u isO0, 1, 2, or 3; 0 0 R9 and R9a, at each occurrence, are indeplendentlY selected from Ii, F, CI-C6 alkyl Or C 3 Cg cyolIoalkyl; V is a bond, -SCj!0) 2 NR1 9 or -C-O Z isH; C I-C8 alkyl substituted with 0-2 RI 2 C 2 -C4 aliceryl substituted with 0-2 Ri 2 C 2 -C4 alkyllYl substituted with 0-2 R 1 2, aryl Substituted. with 0-4 R12b; C 3 -C10 c&bocycle Substituted with 0-4 R12b; or 5 to 10 memnbered heterocycle~ containing 1 to 4 hetero atoil's selected ffrm nitrogen, oxygen, and sulphur, whereina said 5 to 10 mnembered b eterorcYcle is substituted with 0-3 Rl 2 b; Ring 1B is selected from: 0 N Jf Rl 0 R" 3 1 doi=.1 47 -147- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11 -03 03/11 '05 11:22 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB AITS 4 PATENT OFFICE 1JU43 0 N SR oR11 0 F01 R1 N *S 0* S 9 9 9e *559 'A 13 wherein each benzo fused radical is substituted with 0-3 R; 5 R10 isH, C(O)R17, C(==0)0R 17 C(=0)NRIR1 9, S(=0)2N 8 R19, S(=)2R17; C1-C6 alkyl substituted with 0-2 aryl substituted with 0-4 C3-C10 carbocyle substituted with 0-3 R10b; or to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is optionally substituted with 0-3 R1Ob; at each occurrence, is independently selected from H1, C1-C6 alkyl, OR 14 Cl, F, Br, I, CN, N02, NR1 SR 16 CF3; aryl substituted with 0-4 2510V05.t ID3 a I -148- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11 50 Date 2005-11-03 03/11 '05 11:22 FAX 61 3 9859 1588 CALLINAN LAWRI ELB AS 4 PATENT OFFICE 14044 C3-C10 carbocycle substituted with 0-3 RO10b; or to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is optionally substituted with 0-3 R1 Ob RIOb, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1 -C4 alkoxy, C1, F, Br, I, CN, N02, lR1 5 R 1 6 CF3, acetyl, SCH3, S(=O)CH3, S(=0)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C 1 -C4 baloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-S-; R 1 is selected from H S. C-C4 alkoxy, Cl, F, Br, 1, CN, N02, NR 1 8 R 1 9 7 C(0)OR' 7 C(O)NR 1 R 19 S(-O) 2 NRI 8 R1 9 CF3; Sa; C1-C6 alkyl substituted with 0-1 R 1 1a; 15 aryl substituted with 0-3 R1lb; C3-C10 carbocycle substituted with 0-3 R 1 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 Se-. is substituted with 0-3 R'l b; R1a, at each occurrence, is independently selected from H, CI-C6 alkyl, OR 14 Cl, F, Br, I, CN, NO02, NP 15 R 16 CF3; phenyl substituted with 0-3 R lb; carbocycle substituted with 0-3 Rl1b; or 5 to 10 membered heterocycle containing 1 to 4 heteroatomins selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R 1b; Rlb, at each occurrence, is independently selected from H, OH, F, Br, I, CN, N02, NR 15 R' 6 CF 3 acetyl, SCH3, S(=O)CH 3 S( O)2C]l3, 01-06 alyl, C;-04 alkoxy, C1-C4 haloalkyl, CI-C4 baloalkoxy, and C1-C4 haloalkyl-S-; 4 15/oB/.rnZlS: clacms.l e -149- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:22 FAX 61 3 9859 1588 CALLINAN LAWRIE HELB AITS 4 PATENT OFFICE 14045 R1 2 at each occurrence, is independentlY selected from H, OH, C1, F, Br, I, CN, N02, NR 15 R 1 6 -C(O)NRi 5 RI 6 CF 3 acetyl, SCH3, S(=0)CH3, S(-0)2CH3, Ci-C6 alkyl, C 1 -C4 alkoxy, C 1 -C4 haloalkcyl, C 1 -C 4 haloalkoxy, and C 1 -C 4 haloalkyl-S-; aryl substituted with 0-4 Rl2b; C 3 -Clo carbocycle substituted with 0-4 R12b; or to 10 memnbered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b; R12b, at each occurrence, is independently selected from H, OH, C, F, Br, I, CN, NO 2 NR 15 R 16 CF3, acetyl, SCH3, S(=O)CH3, S(Q0)2CH3, C 1 -C 6 alkyl, C1-C 4 alkoxy, SC 1 -C4 haloalkyl, CI-C4 haloalkoxy, and C 1 -C4 haloalkyl-S-; R 13 at each occurrence, is independently selected from H, OH, Ci-C6 alkyl, C 1 -C4 alkoxy, Cl, F, Br, 1, CN, NO 2 NR 15 R 1 6 and CF 3 S. R 14 at each occurrence, is independently selected from H, phenyl, benzy), C 1 -C6 alkyl, and C 2 -C 6 alkoxyalkyl; R 1 4a is H, phenyl, benzyl, or CI-C6 alkyl; R' 5 at each occurrence, is independently selected from H, C-C 6 alkyl, phenyl, benzyl, phenethyl, (C1-C6 alkyl)-C(=O)-, (C 1 -C 6 alkyl)-O-C(O)- and (Cj-C 6 alkyl)- R 1 6 at each occurrence, is independently selected from H, OH, CI-C 6 alkyl, phenyl, benzyl, phenethyl, (C 1 -Cs alkyl)-CO=)-, (CI-C6 alkyl)-O-C(O=0)- and (C 1 -C 6 alkyl)-S(=O)-; 2h,-150-22.clmu. -150- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:23 FAX 61 3 9859 1588 CALLINAIN LAWRIE MELB kUS 4- FATENT OFFICE 10J046 alternatively, -NR1SRl 6 may be a heterocyclir, ring selected from the groulp Pipeiidinlyl morpholinyl, thioymorphOIrnYl, pyrrolidin'yt homoppcrdlfll piperanl an N- methylpiperiZiflyl; R 17 is H, C 1 -C6 alicyl, Or C2-C6 alkoxYalkyll aryl substituted by 0-4 R 17 a, or aryl-CHJ2- wherein said aryl. is s ubstituted by by 0-4 R1la; R 17 a is, H, methyl, ethyl. propyl, butyt, inethoxy, ethoxy, propoxcy, butoxy, -OH, F, Cl, Br, l, CF 3 OCF 3 SCH3, S(=-O)CF-13, S(=Oh2CH3. -NH 2 -N(CH3)2, or -C haloalkyl; R 18 at each occurrence, is independently selected from H, Ci-C6 alkyl, phenyl, beazyl, phenethyl, (CI-C6 alkyl)-C&=O)- and (C I-C 6 alkyl)-St'O)2-; alternatively, -NR 17 R 18 may be a heterocyclic ring selected fiom the group pip eridinyl, morpholinyl, thiomorpholill pyrrolidinyl, homopiperidill piperazinyt, and N- methylpiperiZinyl; R 19 at each occurrence, is independently selected from H, OR, Cv-C6 alkcyl, phenyl, benzyl, phenethyl, (Cl-C6 alcyl)-C&-O)- and (Cl-C6 alkYl)-S(O0)2-; ~R R9b, at each occurrence, is independently selected fromn H and CI-C6 alkyl; R 20 is H, OH, C 1 I-C4 aliyl, phienyl, benzyl, or phenethyl; R 2 1 at each occurrence, is independently selected from H4, Cv-C6 alkyl, phenyl, beuzyl, and phenethyl; and R22, at each occurrence, is independently selected from H, Ct-C6 alkyl, phenyl, benzyl, and phenethyl. 1- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:23 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB ALTS PATENT OFFICE 41047
2. A compound of Claim 1, of Formula (la): RH (I N BN0, W-X-Y-Z OH 0 (1a) or a pharmaceuticaly acceptable salt form or prodrug thereof, wherein: Q is Q 1 -(C 1 -C 3 alkylenc)-O-Q' -(Ci-C3 alkylene)-S-Ql. -(Cl-C3 alkylene)-S(=0)-Q', -(Cl-C3 alkylene)-S(O=0)2-Q, or -(C 1 -C 3 allkylene)-N(R 20 QI is C 1 -C6 alkyl substituted with 0-3 Ria; C 2 -C6 alkenyl substituted with 0-3 R 1 a; C 2 -C6 alkynyl substituted with 0-3 RIa; C3-CIo cycloalkyl substituted with 0-3 RIb; C3-CLo carbocycle substituted with 0-3 Rb; aryl substituted with 0-3 Rib; or 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from S 20 nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle 20 ntoeoyeadslhr is substituted with 0-3 Rib; Rla, at each occurrence, is independently selected from H, C-Cs alkyl, OR' 4 Cl, F, Br, 1, NRISRl 6 CF 3 C 3 -Co10 carbocycle substituted with 0-3 Rib; aryl substituted with 0-3 Rib; and to 10 memnbered heterocycle containing 1 to 4 heteroatoms selected from nitrogen. oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 Rib; 0V) jM0.&t1252 3s/) m 152 -152- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:23 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB AITS 4 FATENT OFFICE 1048 Rib, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, N02, 16 CF3, acetyl, SCH3, S(=O)CH3, S(=0O)2CH3, C1-C6 alkyl, C 1 -C4 alkoxy, C 1 -C 4 haloalkyl, C 1 -C4 haloalkoxy, C1-C4 haloalkYl-S-, and (Cl-C6 alkyl)-O- R 2 is H, methyl, or ethyl; R 5 is H, OR 1 4 C-C alkyl substituted with 0-3 CI-C6 alkoxy substituted with 0-3 C 2 -C6 alkenyl substituted with 0-3 C 2 -C6 alkynyl substituted with 0-3 R%; C 3 -C10o cycloalkyl substituted with 0-3 RSc; S15S C 3 -C 10 carbocycle substituted with 0-3 RSc; aryl substituted with 0-3 R 2 c; or 5 to 10 membered beterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3R5c; iR 5 is H, C 1 -C4 alkyl, or C 2 -C4 alkenyl; alternatively, R5 and Rs may be combined to form a 3-7 membered cycloalkyl ring Ssubstituted with 0-3 Rn', at each occurrence, is independently selected from: C-C6 alyl, C3, OR 1 4 C 10 C, N02, NR 1 5 R 1 6 acetyl, SCH3, S(O)CH3, S(=0)2CH3, C 2 -C alkenyl, C2-C6 alkynyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, C 1 -C 4 b haloalkoxy, and C1-C4haloalkyl-S-, C 3 -Co10 cycloalkyl substituted with 0-3 RSc; C 3 -CIO carbocycle substituted with 0-3 R 5 c; aryl substituted with 0-3 RSC; and to 10 membered heterocycle containing I to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered beterocycle is substituted with 0-3 RSc; 05Mf5,maI25725..deh al),i -153- COMS ID No: SBMI-01882249 Received by IP Australia: Time 1150 Date 2005-11-03 03/11 '05 11:23 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB AUS PATENT UkflL± 9jU48 R 5 at each occurrence, is independentlY selected from H, OH, Cl, F, Br, ON, N02, NR' 5 R' 6 CF3, acetyl, SCH3, S&O)CH3, S&O) 2 CH3, Ci-C6 alkyl, 01-4 alkoxy, Gj-C4 haloaliyl, 01-04 haloalkOXY, and Cj-C4 haloaliyl-S-; W is -(CR 8 pis O, ,or2; R 8 and Ra, at each occurrence, are independently selected from H, F, methyl, and ethyl; X is a bond; N 1L)0 'tt t7c or Y is a bond or -(CR9R9)rV(CR 9 R 9 t is O, 1, or2; u is 0, 1, or 2; R9 and R 9 at each occurrence, are independently selected from H, F, methyl, and ethyl; V is a bond, -N(R' 9 or Z is H; C-C4 alky) substituted with 0-2 R12; C2-C4 alkenyl substituted with 0-2 R 1 2 C2-C4 alkynyl substituted with 0-2 R32; -154- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:24 FAX 61 3 9859 1588 CALLINAN LAWRIE NELB A! TENT OFFICE to 050 aryl substituted with 0-4 R12b; C 3 -C6 carbocycle substituted with 0-4 R 12 b; or to 6 Tnembered heterocycle containing 1 to 4 heteroatomS selected from nitroger, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R12b; Ring 13 is selected from: o 00 N N o Q 0 0 N R" R" R o 0 or- NN RR 10 COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:24 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB AL TENT OFFICE 051 13 wherein each benzo fused radical is substituted with 0-3 R R 1 0 is H, C(=O)R 17 C()0R 17 C(=O)NR1 8 RI9, S(=)2NR 8 Rl9, s(-=0)2R 1 7 C1-C6 alkyl substituted with 0-2 aryl substituted with 0-4 C3-CO1 carbocycle substituted with 0-3 RI0b; or to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is optionally substituted with 0-3 R 1 0 a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR 1 4 Cl, F, Br, 1, CN, N02, NR 1 5 R 1 6 CF3, or aryl substituted with 0-4 RI0b; RO10b, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, N02, NR 15 R 1 6 CF3, acetyl, SCH3, S(0)CH3, S()2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and Cl-C4 haloalkyl-S-; R 1 1 at each occurrence, is independently selected from H,
9.. c1-c 4 alkoxy, Cl, F, Br, I, CN, NO2, NR 8 sR 1 9 C(-O)R' 7 C(=0)OR 17 C(O)NR 18 R1 9 S(-0)2NRIR1 9 CF3J C1-C alkyl substituted with 0- 1 RI aryl substituted with 0-3 R 1 ib; C3-C10 carbocycle substituted with 0-3 R1 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 1 1b R 1 la, at each occurrence, is independently selected from H, Cj-C 6 alkyl, OR 1 4 Cl, F, Br, I, CN, N02, NR 1 5 R 16 CF3; 0 5 ,q I25S5.clam', G -156- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:24 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB M PATENT OFFICE iau-Z phenyl substituted with 0-3 R 1 b; C 3 -Co10 carbocycle substituted with 0-3 R11b; or 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 1 1b; R11b, at each occurrence, is independently selected from H, OH, C, F, Br, I, CN, N02, NR 1 5 R 16 CF3, acetyl, SCH 3 S(=O)C43, S(0) 2 CH3, C 1 -C 6 alkyl, Cj-C4 alkoxy, C 1 -C 4 baloalkyl, C1-C4 haloalkoxy, and C 1 -C4 haloalkyl-S-; oR 1 2 at each occurence, is independently selected from H, OH, Cl, F, Br, I, CN, N02, R12 at each occurrence, i nee NR1 5 R16, -C(O)NR'Ri 6 CF3, acetyl, SCH3, S(0)CH3, S(0) 2 CH3, C1-C6 alkyl, CC-C4 alkoxy, C1-C4 haloalkyl, C 1 -C4 haloalkoxy, and Cj-C4 haloalkyl-S-; S. aryl substituted with 0-4 Rl2b; 15 C3-Clo carbocycle substituted with 0-4 R12b; or to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b; R2b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, N02, R'2b, a each occurrence, is indepen 7tl *i NR 15 R 16 CF3, acetyl, SCH3, S(=0)CH3, S(O)2CH3, C 1 -C 6 alkyl, Cj-C4 alkoxy, Cl-C4 haloalkyl, C 1 -C4 haloalkoxy, and Cu-C4 haloalkyl-S- 9 R1 3 at each occurrence, is independently selected from H, 1OH, C 1 -C6 alkcyl, CI-C4 alkoxy, Cl, F, Br, I, CN, N2Oz, NR' 5 R1 6 and CF3; R 14 at each occurrence, is independently selected from H, phenyl, bevzyl, CI-C 6 allckyl, and C2-06 alkoxyalkyl; -157- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:24 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB AjiS PATENT OFFICE 4dj053 R 15 at each occurrence,is independently selected from H, C 1 -C 6 alkcyl, pbenyl, benzyl, phenethyl7 (C 1 -C 6 alkyl)-C(=O>. (CI-C 6 alkyl)-O-CQ=OV) and (Ci-C 6 alkyl)- R 16 at each occurrencc, is independently selected from H, OH, Cr-C6 alkyl, phenyl, benzyl, phenethyl, (Cl-C6 alkcyD-C&O>)-'(CI-C6 alkyl)-O-C( 0 and (Cl-C6 alkyl)-S&O--)2-1 alternatively, _NR1 5 R 16 may be a heterocyclic ring selected from the group piperidiuyl, morpholinlyl, thiomorpholillyl, pyrrolidinyl, homopiperidlillYl, piperazixiyl, and N- methylpipernzmy; R 17 is H, aryl, aryl-CH2-, C 1 -C6 alkyl, Or C2C6 alkoxyalkyl; 15 R, 18 at each occurrence, is independently selected from Hi, C 1 -C 6 alkyl, phenyl, benzyl, phenethyl, (Cj,-C6 alkyl)-C(--O)- and (Cl-06 alkyl)-S&O--)2- :.pR 19 at each occurrence, is independently selected from H. OH, C 1 -C 6 alkyl, ph~enyl, benzyl, phenethyl, (CI-C 6 alkyl)-Ce=O)- and (Cl-C6 alkYlYS(rO)2S alternatively, -NRtSRl 9 may be a heterocyclic ring selected from the group piperidinyl, morpholinyl. thiomorpholinyl, pyrrolidinyl, hornopiperidilYl, piperazinyl. and N- micthylpiperiziflyb and R 20 is H, OH, C 1 -C4 alkyl, phenyl, benzyl, or phenethyl. 3. A c-ompound of Claim 2 wherein: Q is Q 1 Q 1 is Cj-C6 alkyl substituted with 0-3 Rla; C2-C6 alkenyl substituted with 0-3 lRa :sV081o5azlL2z:Sclimsn, I COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:25 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB AIIS 4 PATENT OFFICE l054 C 2 -C6 alkynyl substituted with 0-3 RIa; C 3 -C10 cycloalkyl substituted with 0-3 Rib; C 3 -Clo carbocycle substituted with 0-3 Rib; aryl substituted with 0-3 Rib; or 5 to 10o membered heterocycle containing 1 to 4 beteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 memnbered heterocycle is substituted with 0-3 RIb; Rla, at each occurrence, is independently selected from H, Ci-C alkyl, OR 1 4 Cl, F, Br, I, NRLSR1 6 CF 3 C 3 -Clo carbocycle substituted with 0-3 Rib; aryl substituted with 0-3 Rib; and 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle 9 15 is substituted with 0-3 Rib; *99 Rib, at each occurrence, is independently selected from H, OH, Cl, F, 1r, i, CN, N02, NR' 5 R1 6 CF 3 acetyl, SCH 3 S(=O)CH 3 S(=O) 2 CH3, C1-C 6 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, CI-C 4 haloalkoxy, C1-C4 haloalkyl-S-, and (CI-C6 alkyl)-O- R 2 is H, methyl, or ethyl; RS is i, OR 14 01-06 alkyl substituted with 0-3 R 5 C2-C6 alkenyl substituted with 0-3 R; or C2-C6 alkynyl substituted with 0-3 R 5 b is H, methyl, ethyl, propyl, butyl, or C 2 -C4 alkenyl; alternatively, R5 and R5a may be combined to form a C4-C7 cycloalkyl ring; at each occurrence, is indeperdently selected from: 2S/OG/C5,4'12525.elai nS. I59 -159- COMS ID No SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:25 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB Al PATENT OFFICE 141055 H, methyl, ethyl, propyl, butyl, CF 3 OR 14 Cl, F, Br, 1, NR15R 16 C 3 -C 7 cycloalkyl substituted with 0-3 R 5 c; C3-C7 carbocycle substituted with 0-3 phenyl substituted with 0-3 R5c; and 5 to 7 membered heterocycle containilg 1 to 4 heteroatorns selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 at each occurrence, is independently selected from OH, C1, F, Br, 1, CN, N02, NR 15 R 16 CF3, acetyl, SCH3, S(=O)CH3, S(n0)2CH3, CI-C4 alkyl, C1-C3 alkoxy, CI-C2 haloalkyl, and C1-C2 haloalkoxy; W is a bond; X is a bond; S 15 Y isabond; 0 Z is H, 0..00 C1-C4 alkyl substituted with 0-2 Ri 2 C 2 -C 4 alkenyl substituted with 0-2 R1 2 C2-C4 alkynyl substituted with 0-2 R 1 2; :aryl substituted with 0-4 R12b; C3-C6 carbocycle substituted with 0-4 Rl2b; 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 S 25 substituted with 0-3 R12b; Ring B is selected from: 0 N- 13 R' wherein the benzo fused radical is substituted with 0-3 R and 25/fsltl5,a:62 2 S -160- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:25 FAX 61 3 9859 1588 CALLINAIN-_LA!RIU MELB ALIS rx4~ YkAJurrii gj; 0 0 113 R 7 S...RID is H, C(-O)R 17 C(=O)0RI 7, C(==O)NRI 8 RI 9, S&=C)2NRI 8 RI 9, S(=-0)2R 1 7; aryl 5 ubstitUt,_d with 0-4 RI Ob; epee C3-C 10 carbocycle substituted with 0-3R~;o 5 to 10 inenbered heterocycle containing 1 to 4 lieteroatotus selected froma nitrogen, oxygen and sulphur, Wherein said 5 to 10 mnembered heterocycle S 10 is optionally substituted with 0-3 R b Ip S R O, at each occurrence, is independentlY selected from HC-6akyO 4 ,lFBr 1, 0, CN, N0O2, NR~~ 1 ,C3 aryl substituted with 0-4 Ri0b; C 3 -CIO carbocycle substituted with 0-3 R10b; or to 10 memberd heterocycle containling I to 4 heteroatoms selected fro~m nitrogen, oxygent, and sulphur, wherein said 5 to I0 omembered heterocycle is optionally substituted with 0-3 RiOb;, p IOb, at each o ccurrenice, is independently selected from H, 0141, C I-C6 alkyl, C I-C4 alkoxy, Cl, F, Br, 1, ON, N02, N7R5R1 6 CF3, acetyl, SCII3, S(=~O)CH3, -161- COMS ID No: SBMI-01882249 Received by IP Australia: ime 11:50 Date 2005-11-03 03/11 '05 11:25 FAX 61 3 9859 1588 CALLINAN LAWRIE HELB AUS PATENT OFFICE 141057 S(=0)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 baloalkoxy, and C1-C4 haloalkyl-S-; R 11 is selected from H, NR 1 8 R 19 C(=O)Rl 7 C(=O0)OR' 1 C(QO)NR' 8 R 1 9 S(=O) 2 NR 18 R1 9 CF 3 C1-C6 alkyl substituted with 0-1 Rila; phenyl substituted with 0-3 R 1 Lb C 3 -C6 carbocycle substituted with 0-3 R1 1b; or to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, 0to oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R) 1b; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrirnidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl; S1 a, at each occurrence, is independently selected from H, methyl, ethyl, propyl, buty1, methoxy, ethoxy, propoxy, Cl, F, NR 15 R' 6 CF3; phenyl substituted with 0-3 R11b; S**.C3-C6 carbocycle substituted with 0-3 Rt1b; or 20 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, .oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R 1 1b; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, 25 oxazolyl, isoxazolyl, and tetrazolyl; R' Ib, at each occurrence, is independently selected from H, OH, Cl, F, NR' 5 R 1 6 CF 3 acetyl, SCH 3 S(=O)CH 3 S(=0)CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Cj-C 2 haloalkyl, and Ci-C2 haloalkoxy; 2!,0Sm1.fl2525.clAbS.162 -162- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:25 FAX 1 3 9859 1588 CALLINAN LAWRIE MELB AUS 4 PATENT OFFICE 4058 R 12 at each occurrence, is independently selected from H, OH, C1, F, Br, I, CN, NO 2 NR 15 R 16 -C(O)NR 15 R 16 CF3, acetyl, SCH 3 S(=O)CH 3 S(=0) 2 CH 3 C 1 -C 6 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, C1-C 4 haloalkoxy, and C 1 -C4 haloalkyl-S-; aryl substituted with 0-4 R12b; C3-Co10 carbocycle substituted with 0-4 RL2b; or to 10 membered heterocycle containing I to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b; R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 NR 1 5 R 1 6 CF 3 acetyl, SCH3, S(-O)CH 3 S(=0) 2 CH 3 C 1 -C 6 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, C 1 -C4 haloalkoxy, and C 1 -C 4 baloalkyl-S-; R 1 3 at each occurrence, is independently selected from H, OH, C 1 -C 6 alkyl, Cp-C 4 alkoxy, 15 C, F, Br, I, CN, NO 2 NRI 5 R 1 6 and CF 3 R1 4 at each occurrence, is independently selected from H, phenyl, benzyl, C 1 -C 4 alkyl, and C 2 -C 4 alkoxyalkyl; S 20 R' 5 at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; R 1 6 at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, phenethyl, CH3CH 2 CH 3 CH 3 CH 2 CH 3 CH 3 CH 2 and CH3S(0)2-; R 17 is H, phenyl, benzyl, C 1 -C 4 alk-yl, or C 2 -C4 alkoxyalkyl; R 18 at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and 2501/OS-.;12S52clixui,I63 -163- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:26 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB AUS -4 PATENT OFFICE 141059 R 19 at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, and butyl. 4. A compound of Claim 2 wherein: Q is Q 1 or (C 1 -C3 alkylene)-O-Q': Q1 is Ci-C 6 alkyl substituted with 0-3 Ria; C 2 -C6 alkenyl substituted with 0-3 Rla; C 2 -C6 alkynyl substituted with 0-3 Rla; C 3 -C 6 cycloalkyl substituted with 0-3 Rlb; phenyl substituted with 0-3 Rib; or 5 to 6 membered heterocycle containing I to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is 15 substituted with 0-3 R 1 b; S* R 1a at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, OR 14 Cl, F, Br, I, NR 15 R 1 6 CF3; C 3 -C 6 carbocycle substituted with 0-3 Rib; 20 phenyl substituted with 0-3 Rlb; and 5 to 6 membered heterocycle containing 1 to 4 beteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 Rlb; 25 Rib, at each occurrence, is independently selected from H, OH, CI, F, Br, I, CN, NO2, NR 1 5 R 1 6 CF3, acetyl, SCH 3 S(=O)CH 3 S(=0) 2 CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Ci-C 2 haloalkyl, Ci-C 2 haloalkoxy, (methyl)OC(-O)-, (ethyl)OC(=0)-, (propyl)OC(=0)-, and (butyl)OC(=0)-; R 2 is H or methyl; R 5 is H, OR 14 ?C 5.2-164-/5. -164- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:26 FAX 61 3 859 1588 CALLINAN LAWRIE MELB AUS 4 PATENT OFFICE 141060 C 1 -C4 alkyl substituted with 0-1 C2-C4 alkenyl substituted with 0-1 R5b; or C 2 -C 4 alkynyl substituted with 0-1 R; R5a is H, methyl, ethyl, propyl, or butyl; alternatively, R 5 and RSa may be combined to form a cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl ring; R~b, at each occurrence, is independently selected from: H, methyl, ethyl, propyl, butyl, CF 3 ORL 4 Cl, F, NR 5 R' 6 C 3 -C 7 cycloalkyl substituted with 0-3 C 3 -C 7 carbocycle substituted with 0-3 phenyl substituted with 0-3 R5c; and 15 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 R5c; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl; at each occurrence, is independently selected from H, OH, Cl, F, NRI 5 RI, CF 3 Sacetyl, SCH3, S(=C)CH3, S(=O) 2 CH3, methyl, ethyl, propyl, butyl, methoxy, :*:ethoxy, propoxy, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy; W is a bond; .X is a bond; Y is a bond; z is H, CI-C4 alkyl substituted with 0-2 R1 2 C2-C4 alkenyl substituted with 0-2 R1 2 C 2 -C 4 alkynyl substituted with 0-2 R12; aryl substituted with 0-4 R12b; C 3 -C6 carbocycle substituted with 0-4 R 1 2b; or 25'VS65-l325. 5 -165- COMS ID No: SBMI-01882249 Received by IP Australia: Time (H m) 11:50 Date 2005-11-03 03/11 '05 11:26 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB AUS PATENT OFFICE 9061 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R12b; Ring B is selected from: .9 9 99 9 999 9 9 9999 9 9999 0 13 R13 R' and R' R 11 is selected from H, NR 1 R 19 CF 3 C 1 -C4 alkyl substituted with 0-1 Rila; phenyl substituted with 0-3 R 1 1 b; C 3 -C 6 carbocycle substituted with 0-3 R11b; or 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R 1 1b; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl; R 1 la, at each occunence, is independently selected from H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, CI, F, NRI 5 R 16 CF 3 phenyl substituted with 0-3 R1b; 25f/0/D5,ul 2525c.h.tS,16I -166- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:26 FAX 61 3 98 15. CALLINAN LAWRIE MELB AUS -4 PATENT OFFICE tOO2 C 3 -C 6 carbocycle substituted with 0-3 R1Ib; or to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 mnembered heterocycle is substituted with 0-3 R 1 b; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triaziny], furanyl, thioenyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl; RI Ib, at each occurrence, is independently selected from H, OH, C, F, NR 15 R 1 6 CF 3 methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C 1 -C 2 haloalkyl, and C1-C2 haloalkoxy; R 12 at each occurrence, is independently selected from H, OH, Cl, F, Br, NR 1 5 R' 6 C(=0)NR 1 5 R1 6 CF3, acetyl, SCH3, S(-O)CH 3 S(=0) 2 CH 3 methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C 1 -C 2 haloalkyl, and C1-C2 haloalkoxy; phenyl substituted with 0-4 R12b a C 3 -C carbocycle substituted with 0-4 R12b; or to 6 membered heterocycle containing I to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R12b; R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, NR 1 5 RL6, CF3, acetyl, SCH 3 S(=O)CH 3 S(=0) 2 CH3, methyl, ethyl, propyl, butyl, methoxy, othoxy, propoxy, C1-C2 haloalkyl, and C 1 -C 2 haloalkoxy; R 13 at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C, F, Br, CN, NR15R 1 6 and CF 3 R' 4 at each occurrence, is independently selected from H, phenyl, benzyl, methyl, ethyl, propyl, and butyl; t51 /05..725!,cli.s .167 -167- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:27 FAX 61 &M985LI&0 CALLINAN LAWRIE NfLB AIUh 4 PATENT OFFICE 14J063 R 15 at each occurrence, is independently selected from H, methyl, ethyl, propyl, or butyl; pR1 6 at each occurrence, is independently selected from H, OHf, methyl, ethyl, propyl, butyl, phenyl, beazyl, and phenethyl; R 18 at each ocouITence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl and, phenethyl; and R 19 at each occuirrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl and, phenethyl. A compound of Claim 2 wherein: Q is -C-1 3 -CH 2 CH 3 -CH 2 CH 2 CH 3 -CH4 2 CH 2 CH2CH3, -CH 2 CH 2 CH 2 CH2CH3, -CH 2 CH 2 CH 2 CH 2 CH2CH3, -CH(CH 3 )2, 9..-CH(C11 3 )CH2CH3, -CHZCH(CH-A02, -CH 2 C(CH3)3, -CF3, -CH 2 CE3, -CH 2 CH1 2 CF 3 -CH 2 CH 2 CH2CF3, -CH=CH 2 -CH 2 CH=CH2, -Q.H 2 C(CHJ)-CH2, -CH 2 CH4=C(GH3)2, -CH 2 CH 2 CW=CH2, -CH 2 ClH 2 C(CH 3 Y=CHz, -CJ- 2 CH 2 CIH-C(CH3)2, cis-CH 2 CH CH(CH3), Cis-CH 2 CHtCH=CH-(CH3), trans-CH 2 CIP-CH(CH3), trans-CH 2 CH 2 CI{=CH(CH3); &CiH, -CH 2 CFCH, -CH 2 C-2-C(CH3), cyclopropyl-, cyclobutyl-, cyclopentyl-, cyclohexyl-, cyclopropYl-CH2-, cyclobutyl- CH 2 cycloPentyl-CH2-, cyc] ohexyl-CH2-, cyclopropyl-CH2CH2-, cyclobutyl- CH 2 CHZ-, cyclopentyl-CH 2 CH2-, cyclobexyl-CH2CH2-, phenyl-, 2-F-phenyl-, 3-F-phenyl-, 4-F-phenyl-, 4-methoxyphenyl-,4-et1OXyphefl-l 4-propoxypheflyl-, phenyl-CH2-, (2-F-phenyl)CH2-, (3 -F-pbenyl)GH2-, (4-F-phenyl)CH2-, (2-Cl-phcnyl)CH2-, (3 -C-phenyl)CH2-, (4-Gl-phenyl)CH2-, (2,3 -diF-phel)CH2-, (2,4-diF-phenyD)CH2-, 25,0B/05 Al252d.ak16 6 -168- COMS ID No: SBMI-01882249 Received by IP Australia: Time (I-tm) 11:50 Date 2005-11-03 03/11 '05 11:27 FAX.6 .IL 9859 1588 CALLINAN LAWRIE NELB AL'S 4PATENT OFFICE t100O4 (2,5-diF-phenyl)CH2-, (2,6-diF-pheny)C32., (3,4-diF-phenyl)CH2-, (3,5-di-F-phenyl)CH2-, (2,3-diCl-phenyl)CH42-, (2,4-.diCl-phenyl)CH2-, (2,5-diCl-phenyl)CH2-,(2,6-diCl-phenyl)CHr', (3,4-diCl-pheflyl)CH2-, (3,5-diCl-pheflyl)CHz 5 (3-F-4-C1-pheny1)CH2-. (3-F-5-C1-phenyl)CH2-, (3 -0C-4-F-phenyl)CH2-, 2-furanyl-CH2-, 3-furany1-CH2-, 2-thienyl-C142-, 3-tbienyl-CH2-, 2-pyridyl-CH2-, 3-pyridyl.-CH2-, 4-pyridyl-CH2-, 1 -imaidazoly1-CH2-, 2-oxazolyl-CH2-, 4-oxazolyl-CH2-, 5-oxaZOlyl-CH2-, 3-isoxazolyl-CH2-, 4-isoxazolyl-CH2-, 5-iSoxazo1y1-CHI2-, phenyl-CH 2 CJI2-, (2-F-phenyl)CH 2 CH2-, (3-F-phenyl)CH2CH2-, (4-F-phenyl)CH2CH2-, (2-0C-pheny1)CH2CH2-, (3-C1-pheny1)CH2CH2-, (4-&bphenlyl)CH4 2 CH2-, (2,3 -diF-phenyl)CH72CHZ-, (2,4.diF-pheny)CH2 CH- 2 (2,5-diiF-pheny1)CH2CH12-, (2,6-diF-pheny1OCH2CH2-; (3 ,4-diF-pheny)CH2CI2- 1 (3 ,5-diF-phenyl)CH2CH2-, (2,3-diCl-phenyl)GH2CH2-, (2,4-diCl-pheflyl)CH2CH-, 5-diCl-phenyl)CH42CH2-, (2,6-diC1-pheny1)CH2CH2-, (3 ,4-diCl-pbenyl)CII2CH2-, (3,5-diCl-pheflyl)CH2CH2-, (3-F-4-C1-phcnyl)CHi2CH2-, (3-F-.5-C1-phenyl)CH2CH2- furanyl-GHCH2-, thienyb-CH 2 CH2-, pyridyl-CH2CH2-, 1 -imidazolyl-CH2CH2-, oxazolyJ -CH 2 CH2-, isoxazolY-C11 2 CH2-, 3,5-dimethylisoxazo1-4-Y-CEl2CH2-, phentyl-propyl-; benzyl-CH4(NE2)-, bezy1-H(NRC&O)-O4BUY'. benzyloxy-GH2-, pyrrolidixx-2-yl-, or 3-t-butoxycarboflylpyrTolidifl-2-yk- R 2 is14 or nethyt; R 5 is -CH 3 -C1I 2 CH 3 -CH 2 CH 2 CH3, -CH(CH 3 -CH 2 CH 2 CH2CJ13, -CH(CH 3 )CH2CH3, -CH 2 CH(C113)2, -CH 2 C(CH 3 )3, 5al252S clwis.1 69 -169- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11.50 Date 2005-11-03 03/11 '05 11:27 FAX 61 3 985 1588 CALLINAN LAWRIE KELB AUS PATENT OFFICE Ij06 -CH 2 1CH 2 1CH 2 1CH 2 1CH3, -CH(CH 3 )CH2CH2CH3, -CH 2 CH(CH 3 )CH2CH3, -CH4 2 CH 2 CH(CH 3 -CH(CI-kCHJ)2, -CF 3 -CH 2 CFi, -CHi 2 CH 2 CF 3 -CH 2 CHZCH2CF3, -CH 2 CH 2 CH 2 CH 2 CFj, -CH=CH2, -CH 2 CH=CH 2 -CH 2 CHaCI PCH2, -CH=CHCH 3 ois-CH 2 CH=CH(CH3), trans-CH2CH CH(CH3) trans-CH 2 CH=CH(C615), -CHZCfHC(CH 3 cis-CH 2 CI-ICHCH2CH3, trans- CH 2 CH=CHCH2C HJ, cis-CH 2 CH',CW=CH(CH3), trans-CH 2 CH 2 CHfrCH(CH3), trans- CH 2 CW =CHCH2(C6H5), -CH 2 CEZ-CH, -CH 2 C=_C(CH 3 -CH 2 C=-C(C6Hs), -CII 2 CH 2 Ce-CH, -CH 2 CH2CsC(CH3), -21- 2 CH 2 C=C(C&Hs), -CH 2 1CH 2 1CH 2 1CMCH, -CH 2 CH 2 CH 2 CZ=C(CH3), -GH 2 CH 2 CH$2ZEC(C6Hs), t..cyclopropyI-CH2-, cyclobutyl-CH2-, cyvlopentyl-CH2-, cyolohexyl-C-2-. (2-CH 3 -cyclopropytlCH2-. (3-CHy-cydlobutyl)CH2-, cycloprOpyl-CH2CH2-, cycobuyl-H2C2-,cyvlOpefltyl-CH21CH2-, vyolohexyl-CH 2 CH2-, (2-CH 3 -cyclclpropyl)CH2CHZ-, (3 -C- 3 -cyclobutyl)CH 2 1CH2-, :phcnyl-C12-, (2 -F-phenyD)CH2-, (3 -F-phenyl)CH2-, (4-F-phenyl)CH2-, (3,5-dif-phenyl)CH2-, 2-furanyl-CH2-, 3-furanyl-GH2-, 2-thienyl- GH 2 3-thieny1-CH2-, S 2-pyridyl-CH2-, 3-pyridyl-CH2-, 4-pyridyl-C12-, 1 -imidazolyl-CH2-, 2-oxanl-CH2-, 4-oxazolyl-CH2-, 5-oxazolyl-CH2-, 3-isoxazolyi-CH2-, 4-isoxazolyl-C 11 5-isoxazolyl-CH2-, phenyl-CH 2 CH2-, (2-F-phenyl)C14 2 C2-, (3-F-phenyl)CH2CH2-, (4-F-phcnyl)CH2CI2-, furanyl-CH2CI2-, thienyl-CH 2 1CH2-, pyridyl-CH2CB2-, 1 -ilidazolyl-CH2CH2- 5 oxazoly1-CH2CH-, isoxaz.oy-CH2CH2-; metlioxy, ethoxy, propoxy, or butoxy; R~a is H; 25M5~,ml 1252 S.chia, 370 -170- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:27 FAX 81 3 985%j-1-j. CALLINAN LAWRIE MELB AITS 4 PATENT OFFICE IgJ UuU alternatively, R 5 and R 5 a may be cominxed to fort cyclopentyl, cyclobexyl, or cycloheptyl; W is a bond; sa od YXis a bond; Yo is a bond; Z is H, miethyl, ethyl, n-propyl, i-propyl, ni-butyl, i-butyl, s-butyl, t-b-utyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2-F-phenyL, 3-F-phenyl, 4-F-phenyl1, 2-CI-phenyl, 3 -CI-phenyl, 4-Ci-phenyl, 2,3-diF-pheflyl, 2,4-diF-phenyl, 2,6-diF-phenyl, 3 ,4-dff-phenyl, 3 2,3-diCi-phenyl, 2,4-diCi-phenyl, 2,6-diCl-phenyl, 3 ,4-diCl-phenyl, 3,5 -diCi-phenyl, :.c-hny,3MO-hnl 4-C1-4-phenyl. ephn 3-Me-phenyl, 4-Me- phenyl, 2-MeS-phenyl, 3-MeS-phenyl, 4-MeS-pheflyl, 2-CF 3 O-phenyl, 3-CF 3 O- phenyl, 4-CF3O-phODYl, fliranyl, thienyl, pyridyl, 2-Me-pyridyl, 3-Me-pyridyl, 4-Me-pyridyl, 1 -imidazolyl, oxazolyl, isoxazolyl, 1 -benzirnidazolyl iorpholino, N-piperinyl, pbenyl-C142-, (2-F-phenyl)CH2-, (3-F-phenyl)CH2-, (4-F-phenyl)CH2-, (2-CI-pheny])CH2-, (3-CI-phenyl)CH2-, (4-Cl-phenyl)CH2-, (2,3- diE-phenyl)CH2-, (2,4-diF-phenyl)CH2-, (2,5-dir-phenyl)CH2-, (2,6-diE-pheflyl)CH2-, (3 ,4-diF-phenyl)CH2-, (3,5-diF-phenyl)CH2-, (2,3-diCl-phenY)DCH2-, (2,4-diCl-phenyl)CH2-, (2,5-diCl-pheny1)CH2-, JtOLOS.5.t12f5 .e 1m,7l -171- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:28 FAX 61 3 9859jJ1588 CALLINAN LAWRIE MELB AUlS 4PATENT OFFICE 04067 (2,6-diCl-phenyl)CH2-, (3 ,4-diCl-phenyl)CH2-, (3 ,5-diCl-pbenyl)CH2-, (3-F-4-C]-phenfl)CH2-, (3-F-5-C1-pheny)C112-, (3-C1A4-F-phenyl)CH2-, (2--MeO-phenyl)CH2-, (3 -NMeO-pheny1)CH2-, (4-MCO-pheniyl)CH2-. (2-PhO-pheny)CH2-, (3-PhO-phenyl)CH2-, (4-PhO-pheny)C12-, (2-Me-phenyl)CH2-, (3-Me-phenyl)CR2-, (4-MO~e-phdnyl)C112-, (2.MCS-pheny)C12-, (3-MeS-phenyl)CE2-, 4-MeS-phenyO)CR2-, (2.-CF 3 O-phenyl)CH2-, (3-CF 3 O-phenyl)CH2-, (4-CF 3 O-pheIny1)CH2-. (furanyl)CH2-, (thienYl)H2-, (pyridyl)C-2-, (2-Me-pyridyl)CH2-, (3-Me-pyridyl)CH2-. (4-Me-pyridyl)CH2-, (1 ixidazolyl)CH2-, (oxazolyl)CH2-, (isoxazolyl)CH42-, (1- benziraidazolyl)CH2-, (cyclopropyl)0H2-, (cyclobutyl)C}12-, (cyc] opernyl)CH2-. (cyclohexyl)CH2-, (inorpholino)CH2-, (N-.pipridinyl)CH2-, *phenyl-CFI2CH2-, (Phenyl)2GHHI2t (2-E-pheny1)CfHzCH2-, (3-E-phenyI)CH2CH2-, (4-F-phenyl)CH2CH2 2 (2-CI-phenyl)CH2CLHz-.(3 -CI-pheniyl)CH2CH2-, (4-C1-phenyl)CH2CH2- (2,3-diF-pbeny1)CH2CH2-, (2,4-diiF-phenyl)CH2CH2-, (2.5-diF-phenyl)CE42CH2-, (2,6-diF-pheny)GH2CH2-, (3 ,4-diF-phcnyl)CH2CH2-, (3 ,5-diF-phenyl)CH2CH2-, (2,3-diCl-phenYl)CHi2CH2-, (2,4-diCl-pheflyl)CH2CJJ>, (2,5-cdiC1-phefly)CH2CH2-, (2,6-diCl-phefly1)CI{2Cf{2- 25 (3,.-diCl-pheny1)C}{2CH2-s (3,5-diC1-pheny1)CH2CH2-, (3-F-4-C1-pbenY1)CH2CH2-, (3-F-5-CI-phenyl)CH2CHr-, (3-C1-4--F-pheflyl)CH2C32-, (2-MeO-phefly1)CH2CH2- 1 (3 -MeO-phenyl)CH2CH2-, (4-MeO-phenyQ)CH2CH2-, (2-Me--phenyl)CI{2CH2 (3 -Me-pheny1)CH2CH2-, (4.Me-pheny1)CH2CH2-, (2-MeS-phenyD)CH2CE2ru, (3-MCS-phenyl)CH2CHZ-. (4-MeS-phenyl)CH42CH2 1 (2-C E-phenyl)CE{2CH2-, (3-CF 3 Ophefly1)CH2CHr., (4-CF 3 O-phenyl)CH2CH2-, (furanyl)CJ-hCH2- ,(thieny1)CH2CH2-, (pyridy1)CH12CH2-, (2-Me-pyridyU)CHzCfJ2- (3 -Me-pyridy1)CH2CH2-, (4-Me-pyridyl)CH2C82-, (im~idazo~yl)CHi2CH2-5 (oxazolyl)CH2GHr-, (isoxazolyl)CH2CH2-, (benzimidazoly1)CI12CH2,(cyc1OproPYl)CH2CH2-, (cyclobutyI)CH 2 Cri42,cyc10PentYl)Cl2CH2-, (cyclohcxyl)CH2CH2- ,Qmorphohino)CH2CH2-, or ZjtvI/S.. 1 152C16-. 177 -172- COMS IDNo. SBMI-01882249 Received by IF Australia: Time 11:50 Date 2005-11-03 03/11 '05 lt;2.LE&LAt 3 9859 1588 CALLINAN LAWRIE MIELB AUS PATENT OFFICE .(N-Pipridinyl)CH 2 CH2-; R1", at each occurrence, is independentlly selected from H, methyl, ethyl, n-propyl, i- propyl, n-butyl, i-butyl, s-batyl, t-butyl, pheny], benzyl, phenethyl, cyclopropyl,. cyclobutyl, cyclopentyl, cyclobexyl, cycloheptyl, cyolopropylmethyl, cyclobutybnethyl, cyciopentylmethyl, cyclohexyirnethyl, cycloheptylineihyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexyl ethyl, 2-F-phenyl-, 3-F-phenyl, 4-F-phenyl, 4-Ci-phenyl, 4-CH 3 -phenyl, 4-MeO-phenyl-, 4- CF 3 -phenyl, (4-F-phenyl)CHr-, (4-CI-phenyl)CH2-, (4-CH 3 -phenyl)CH2-, (4-CFr-phenyl)CH2-, (4-F-phenY1)CH2CH2-, (4-G-pheny)CH2CHr-, (4-CH 3 -phenyi)CH2CH2-, (4-CF 3 -phenyl)CH2CH2-, pyridin-2-yl-, pyridin-3-yl-, 4-CF 3 -pyridifl-2-yl-, 4.-CH 3 -pyridin-2-Y1-, thiazol-2-yl-, azapan-l1-yl, N,N- dimethylamino, NN-diethylaxnino, NN-dipropylamino, and N,N-dibutylarnino; and R 13 at each occurrence, is independently selected fromn H, MeC, F, and Cl. A comnpound, according to any one of Claims I to 5, of Formula (Id); OH 0 1 3 R1 13 R (1d) or a pharmaceutically acceptable salt formn or prodrug thereof 7. A compound, according to any one of Claims i to 5, of Formula (le); R5 Rsa 0 Q o -x-Y-z F2,OH 0 R 1 3 or a pharmaceutically acceptable salt form or prodrug thereof. -173- COMS ID No: SBMI-01882249 Received by IP Australia: Time (I-tm) 11:50 Date 2005-11-03 03/11 '05 11:28 FAX 81 3j9859 1588.. CALLINAN LAWRIE MELB AITS 4# PATENT OFFICE Ltj069 B. A compound or a pharmaceutically acceptable Salt form thereof, selected from: 3-(2(R)-Cyclopelty~fethY-3 (S)-hydroxyl-1 -oxo-5-phcnylpefltyl)lilo-l -methyl- phenyl-2,3-diliydro- IH-1 ,4-benzodiazcpin-2-Ofle; 3 -(2(R)-Cyclopentyht1YL-3 (S$IhYdoxYl- I -oxo-5 -phenyl-penty1) amino- 1 -methyl-5- (4- fluoro-phenyl)-2,3-dihydIOAlHil,4-benzodiazepffl-2-one; 3-(2(,R)-Benzyl-3 (S7-hydroxyl-l1-oxo-5-phenaylpefltyl)amflnO-lI-methyl-5-phenyl-2, 3 io dihydro-tH-l ,4-benzodiazepin-2-0flC 3 -(2(,R)-IsOprOpyl-3(S)-hydOXYb 1 -oxo-5-phenylpentyl)alil- .ethyl-5-pheflyl-2,3- dihydro-l11-1 ,4-benzodiazcpin-2-Ole; 15 3-(2(R)-CyclopentylmethYl-3 (S)-hydroxyl-l1-oxo-4-(3 ,5-difluorophenoxy)butyl)allnO-l methyl-5-phenyl-2,3-dihydro4l-,4-benzodiazepin- 2 -0flC 3-(2(R)-1sObUtyl-3(S)-bYdoxyk I -oxo-4-(3 ,5.difluorophenoxy)bUtyl)aflnlfI-methyl- phcnyl-2,3-dihydrf-lH- 1,4-benzodiazepil-2-orIC 3-(2(R)-CyclopentyhlmethYl-3 (S)-hydroxyl-1 -oxo-4-phenoxybutY1)amiflo-7-Ch1Oro-l methyl-5-phenyl-2,3-dihYdo IH- 1,4-benzodiazepin-2-ofle Sr 25 ~3-(2(R)-Isobutyl-3(S)-hYdOXYh I -oxo-4-phenoxybuty1)amilQ-7-CffOro 1 -methyl-S 25fluorophenyl)-2,3 -dihydro-' H-i ,4-be-nzodiazepifl-2-0flC 3-(2(R)-Methyl-3(S)-hYdOXYL 1 -axo-4-cyclohexyQXYbutYl) amino-i -xethyl-5-phetiyl-2.3- dlhydro-IH-I,4-benzodiazepin-2-oflC Isobutyl. -3 (S)-hydroxyl-lI 2,3-dihydro-lH-1I,4-benzodiazepil-2-Ole; 3 -(2(R)-Methyl-3 (S)-hydroxyl- 1 oxo-4-phezacxybutyI)8Imlo-7-ch 1 0rO-l -ncthyl-5 -phenyl- 2,3-dihydra- 1H-1,4-benzdiazepifl-2-0flC 25/05/W.,.11525.iL'A 4 -174- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:29 FAX j44a59 1588 CALLINAIN LAWRIE MELB AUS 4 PATENT OFFICE 3-(2(R)-Lsobuty1-3(S)-hydrOxyJ-1 -oxo-4-pbenoxybuty1)8flifl&7-hliOro- 1 2,3-dihydro- 1H- 1,4-benzodiazepin-2-one; 3 -(2(R)-Benzyl-3(S)-hydrOxyl-l1 oxo -4-cyclohexyloxybutY1)flio-7-chOrO 1 phcnyi-2,3-dihydro- 1H- 1,4-becnzodiazcpin-2-0flC 3-(2(R)-CyclopentyhnethY-3(S)-hYdrxyV 1 -oxo-4-oyclohcxyloxybuty1)BmiDnO-7chOY0'I methyl-5-phenyl-2,3-dihydro-IL 1 ,4-benzodiazepin-2-one; 3-(2(R)-Isobutyl-3 (S)-hydroxyl-l1 oxo4-cyclohexyloxybutyl)axninO-7-cblor~o 4 -methyl-S phenyl-2,3 -dihydro- IH- I ,4-benizodiazepin-2-ofle; fee. 3 -(2(R)-Isopropyl-3 (.S)-hydroxyl-1 -oxo-4-cyclohexyloxybuty)8mifcfl-7-chlOrO-l1-mnethyl-5- :60 15 pheny1-2,3-dihydro- 1H 1,4-belzodi8zoPifl 2 -one,- 9 3-(2(Rl)-Methoxy-3($-hYdrOXYb 1 -oxo-4-(4-trifluorornethybenfl~yoxy)bUtYl)8flinO- 7 cbloro-1 -methy1-5-pheny1-2,3 -dihydrC-H&I 1,4-benzodiazepin-2 -one; 0 20 3-(2%R)Methy1-3(S-hydroxy1-1 -oxoA4-(2,4-difluOrobflzy1OXY)bUty)8f-lif& 7 -coTo-l1 mnethyl-5-pbenyl-2,3-dihydIod1Hb 1 ,4-bcnzodiazepin-2-ole; .00 3-(2(R)-Vinyl-3 (S)-hydroxyl-l1 oxoA4-benzyloxybutyJ)amifl&70hOro-I 2,3 -dihydro-lI11-1 ,4-benzodiazepin-2-OlC; r 3-(2(R)-Methy-3(S)-hYc1IOXYb I -oxo-4-cyclohcxyloxYbUty)&lifO- 7 -chlOrO 1 phenyl-2,3-dihydro-1H- 1,4-benzodiazepin-2-0fl0 3 -(2(R)-Isohutyl-3 (S)-hydioxyl-1 -oxo-5- phenylpentyl)amino-l1-metbyl-5-phenyl- 2 3 dihydio-IH-1 ,4-benodiazepin-2-one; 3-(2(R)-Jsobuty1-3(S)1YdToxy[ I -oxc-3 cyclopropylpropyl)aniino- 1-methyl-5-pheflyl-2,3- dihydro-1IH-1 ,4-benzodiazepin-2-one; SS*I 2525.dhms,I 175 -175- COMS ID No: SBMI-01882249 Received by IF Australia: Time 11:50 Date 2005-11-03 111'05 11:29 FAX 61 3 9859 1588 CALLINAIN LAWRIE MELB AITS -4 PATENT OFFICE 10j071 3-(2(R)-Isobutyl-3 (S)-hydroxyl- 1 -oxo-heptyl)arnino- 1 -methyl-5-phenyl- 2 3 -dibydro- 1H- 1 ,4-benzodiazepin-2-one; 3-{R)-(2(R)-Isobutyl-3(5)-hydroxyl-J -oxo-hcptyl)axnino- 1 -methyl-5-phenyl-2,3 -dihydro- 1 ,4-benzdiazepin-2-olC; 3-(S)-(2(R)-Isobutyl-3 (.)-hyvdroxyl-lI-oxo-heptyl)amino-1 -miethyl-5-pbenyl-2,3-dihydro- 1H- 1,4-benzodiazepin-2-one; 3 -(2(R)-Isobuty1-3(S)-hydroxyl- I -oxo-nonyl)axnino- I -methyl-5 -phenyl-2,3 -dihydro- Il- I ,4-benzodiazepin-2-one; 3-(2(R)-Isobutyl-3 (ST-hydroxyl-l1-oxo-hexyl)arnino-l1-methyl-5-phenyl-2, 3-dihydro-lIH- I ,4-benzodiazepin-2-one; 3 -(2(R)-Isobutyl-3 (5)-hydroxyl-l1-oxo-4- phenylbutyl)amnino-lI-mcthyl-5-pbenyl-2,3- dihydro-1H-1 ,4-benodiazepin-2-one; 3-(2(R)-Methyl-3 (5)-hydroxyl-lI-oxo-5- phenylpentyl)amino-l1-methyl-5-phenyl-2,3- 20dihydro.-1H-1,4-benzodiazepil-2-OflC; 3-(2(R)-Metbyl-3 (S)-hydroxyl- I -oxo-6- phenylhexyl)amino- 1 -methyl-5-phenyl-2,3 clihydro-l 1-,4-b enzcidiazepin-2-one; 3-(2(R)-Isobutyl-3(S)-hydOXyl- 1-oxo-butyl)amino-l1-methyl-5-phenyl-2,3 -dihydro- lH- 1 .4-benzodiazepin-2-OflC; 3-(2(R)-Isobutyl-3($-ydrOXyl- 1-oxo-octyl)aino-l1-methyl-5-phenyl-2,3-dihydro- 1H- I ,4-benzodiazepinu-2-one; 3-(2(R)-Methyl-3 (S)-hydroxyl- 1-oxo-heptyl)amnino- I-methyl-5-phenyl-2,3 -dihydro- iN- 1 ,4-benzodiazepin-2-one; 25109,05ftI isli.d .176 -176- COMS ID No: SBMI-01882249 Received by IP Australia: Time (I-tm) 11:50 Date 2005-11-03 03/11 '05. A1:29 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB AITS PATENT OFFICE 141072 3-(2(R)-Methyl-3 (S)-hydroxyl-l1-oxo-3- phenylpropyl)afinl-1-methyl-5-phenyl-2,3 dihydro-1H-1 ,4-bcnzodiszepin-2-one; 3-(2(R)-Methyl-3(S)-hYdoxyl 1 -oxo-5,5-dimethy1-hexy1)amil1-methyJ-5-phenyl-2,3- dihydro- LH- 1 ,4-benzodiazepifl-2-ole; 3-(2(R)-Methy-3(S)-hYdroyW(Y-I-oxo-hexyl)amiflo- 1-xnethyl-5-pheuyl-2,3-dihydrO- IH- 1,4- benzocliazepin-2-one; 3-(2(R)-Metby1-3(S)-hydroxyl-l1 oxo-3-(4-propoXyphel)PTopy1)3mifl1-methyl-5- pbenyl-2,3-dihydrO- LH- 1,4-benzodiazepin-2-one; 3 -(2-(R)-cyclopropylxnethyl-3 -(S)-hydroxyl-l1 oxohepTtylamino-5-(2-flUOtophefll naethyl-2,3-dihydro-1H-1 ,4-benzodiazepin-2-ole; 3 -(2-(R)-cyclopropYlmthY-3-GS)-hYdrOXY1-l1-oxoheptyl)axnino-5-(azaan-l -yI)-l -methyl- 2,3-dihydro- 1H- 1,4-benzodiazepin-2-one; 3-(2-(R)-cyclopropylmethY1-5-(3 ,5-difl-uorophenly)-3(S)-hYdOXYl 1 -oxopernyl)arnino- 1- methyl-5-{pyridn-2-yI)-2,3-dihydrotl-iH-,4-benzodiazepin-2-one,; 3 -(2-(R)-cyc1opropylmethyl-3 -(S)-hydroxyl- I -oxopentyl)amino- I -methyl-5-(4- chlorophenyl)-2,3-dihydro- 1 H-I ,4-benzodiuzepin-2-one; 3-(2-(R)-cyclopropymethy-3-(S)-hYdOXYl -oxohepty1)amino-5-(4-methOXYPheflY1I methyl-2,3-dihydro- 1H-I ,4-benzodiazepin-2-one; 3-{24(R)-tycloprOPylhflthY-3 -(.S)-hydroxyl-1 -oxohepty1)amidno-5-(4-met1OXYPhtfl)l- methyl-2,3-dihydro-
11-1 ,4-benxodiazepin-2-OlC; 3-S-4ccoetl2(R-ylpoymty--(5)-hydroxyl-1 -oxobutyl)anino- 1- methy1-5-pheny1-2,3-dihYdr&-IHU ,4-benzodiazepil-2-0he; 25i0105 .ag1 2S2S.1isJ 77 -177- COMS ID No: SBMI-01882249 Received by IP Australia: Tine (I-tm) 11:50 Date 2005-11-03 03/11 '05 11:29 FAX 61 3 9859 1588 CALLINAN LAWRIE MKELB AITS 4# PATENT OFFICE 0073 3-(S)-(2-(R)--cyclopropylxnethyl-3-(S)-hYdrOXYI -oxohept-6-eny)anfo- 1 phenyi-2,3 -dibydro- I 1,4-benzodiazepin-2-one; 3-(2-(R)-cyolopropyhnethyl-3-(S)-hYdroxyl-l -oxolaept-6-enyl)amino-l1-rnethyl-5-(4- trifluorometbyl-phcnyl)-2,3 -diliydro-1 H-I ,4-benzodiazepin-2-one; 3-(S)-(2-(R)-cyclopropylmethyl-5-(3 ,5-dinaethyiisoxazO1-4-y1)-3-(S)-hYdX0XYk- 1- oxopentyl)amfflo- 1 -methyl-5-phenyl-2,3-dihydra-I H-i ,4-benzodiazepin-2-one; 3-(2-(R)-cyclopropyhynethy-3-S)-hYdIOXYh1 -oxoheptyl)amino-7-chloro- I phenyl-2,3-dihydro-1 H-i ,4-benzodiazcpin-2-one; V. 3-(2-(R)-cyclopropyhnethyl-3 -(S)-hydroxyl- I -oxoheptyl)anaino- 1 -methyl-(,pyridin-2-yl)- 2,3-dibydro-1H-1 ,4 benzodiazepin-2-one; 3 -cyclopropyhnethyl-3 -hydroxyl-l1-oxoheptyl)amino-5-(4-fluorophieyl)- 1- methyl-2,3-dihydro-lH-l ,4-benzodiazepina-2-one; -(2-{R)-cyolopropylmethy.-3 -(S)-hydroxyl-l1-oxoheptyl)aniino-1 -methyl-5-(4- trifouoromethylphenyD-2,3-dihYdrO- 1 H-I ,4-benzodiazepin-2-one; 3-5ccoetl2()ccoroynty--S-yrxl I -oxopentyl)anuino- 1 (pyridin-2-yI)-2,3 -dihydro- 1 H-i ,4-benzodiazcpin-2-ofle; 25 3-2()iobt)-3-S-yrxl -xhpyamn- Inethyl-5-(4- trifluoromethylphenyl)-2,3 -dihydro- 1 H-i ,4-benzodiazepin-2-one; 3-(S)-(2-(R)-cyC1lOpfOpyklCthy1-3-(S)-hydoxylV 1 -oxo-5-(thiophen-2-yI)amino- J pheuyl-2,3-dihydro- 1H-i ,4-benzodiazepin-2-onc; 3-(S)-(2-(R)-cyclopropYlmethY1-5-(uhraf-2-Y1)3 -(S)-hydroxyl- 1 -oxopentyi)anino- 1 inethyl-5-phenyl-2,3-dihydro- 1H-I ,4-benzodiazepin-2-one; -17 8- COMS ID No: SBMI-01882249 Received by IP Australia: Time (1-tm) 11:50 Date 2005-11-03 03/11 '05 11:30 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB AUS PATENT OFFICE 19j074 3-5ccoetl2()ccorplnty--S-yrxl I -oxopentyl)aniino- 5 4 fluorophenyl)-i -methyl-2,3-dihydro- I H-i ,4-benzodiazein-2-one; 3-(S)-(2-(R)-vyclopropyllnethyl-5-(3 ,5-difluorophenyl)-3 -(S)-hydroxy- 1 -oxopentyl)ammno- 1 -iethyl-5-phenyl-2,3-dihydro- IN-I,4-benzodiazepin-2-one; 3-{S)-(3-(S)-hydroxy-2-(R)-(thiOphel-2-Y1)metbYl- I -oxoheptyl)arnino- I 2,3-dihydro-1H-1 ,4-beazodiazepin-2-vne; 3-(S)-(2-(R)-cycopropylrmethyl-3-(S-hydOXYI- I 2,3-dihydro- I H-I ,4-benzodi azcpin-2-vone;, 3-(2-(R)-cyciopropyhnethYl-3-(S)-hydroxyi- I -oxoheptyl)ainino-7-m phenyl-2,3-diliydro- 1H-i ,4-benzodiazepin-2-one; 3 -(S)-(2-(R)-cycobutyhnethyi-3-(S)-hydrOXYl- 1 -oxoheptyl)amnino- 1 -muethyl-5-phenyl-2, 3 dihydro-iH-1I,4-benzodiazepin-2-onc; 3-(S)-(2-(R)-(3,5-difluorobel)-3 -(.S)-hydroxyl- I -oxoheptyl) amino-1I -methyl-5 -phenyl- 2,3-dihydro-IH-1,4-benzodiazepin-2-0nC; 3-(S)-(2-(R)-(furan-2-yI)methyl-3 -(5)-hydroxyl-1 ~2,3 -diihydro- 1H-i ,4-benzodiazepin-2-one; 3-(2-(R)-cyclopropyknethyl-3 -(5)-hydroxyl-i -ox6-5-phenylpentyl)aino- (pyridin-2-yl)-2,3 -dihydro- 1 ,4-bcnzodiuzein-2-one; 3-2()iobtl3()hdoy--xoetlann--4furpey) -tnethyl-2,3 dihydro- 1 H-i,4-benzodiazepin-2-afle; 3 -(2-(R).-iso-butyl-3-(S)-hydroxyl- I -oxohepty1)unino-5-(4-fluOrophelYl)- 1 -miethyl-2,3 dihydro- IH-I ,4-benzodiazepin-2-one;, -179- COMS ID No: SBMI-01 882249 Received by IP Australia: Time 11.50 Date 2005-11-03 0S3./11'0&LA1:10 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB AUS PATENT OFFICE 10]075 3-(2-(R)-cycOpropylnthY1-3-(S)-hYdrOKYh I -oxo-5-phenylpentyl)amino-l phenyl-2,3-dihydro-1H-l ,4-benzodiazepin-2-one; 3-2()ccorphpty--frn2y)3()hdoy- -oxopentyl)anino-I (4-tritluorometylphel)-2,3 -dihydro-lIH-i ,4-benzodiazepin-2-one; 3-(5-cyclopenty-2-(R)-CyCloprOpyhlmethy-3-(S)-hYdrOXYl-l -oxopentyl)amino- 1 (4-trifluorornethylphenyl)-2,3-dhYdO- IH-i ,4-benzodiazepin-2 -one; 3(-R)ccorpymty- -()hdoy- -oocy)mn-rnethyl-5-(4- trifluoromethylphenyl)-2,3 -diihydro-1 H-I ,4-benzodiazpin-2-ot1C; 3-(2-(R)-cyclopropynethy1-3-%S-bydrOXYt- 1-oxononyl)arnina-1 -methyi-5-(4- trifluorometbylphenyl)-2,3-dihYdto- 1II- 1,4-benzodiazepin-2-one; 3 -(2-(R)-cyclopropylmethyl-3-(S)-hydoXYl- I -oxobeptyl)amio-l -methyl-5-(4- trifluorornethyl(pyridin-2-y))-Z, 3 -dhydro- 1H-i ,4-benzodiazepin-2-one; :3 3(2(R)cydobuty1methY1-3 -hydoxyl- 1 -oxoheptyl)aznino- 1 -rnethyl-5 tnifluoromethylpheflyl)-2,3-dibydrO- 1lH-i ,4-benzodiazepin-2-One; 3-(2-(R)-eyclopentylmethYl-3-(S-hYdroXYl- 1 -ox oheptyl) amino-i1 -rnethyl-5 trifluorornethylphenyl)-2,3-dihydro-lH-i 1,4-benzodiazepin-2-one; 3 -(2-(R)-cyloprcpylmtethyl- 3 -(S)-hydroxy1- I -oxoheptyl)urnino- 1 -niethyl-5-{4-methyb2- pyridiyl)-2,3 -diliydro-1 14-i ,4-benzodiazepir'-2-Ofle; 3 -cyclopropylnethy-3-S) -hydroxyl-1I -oxoheptyahino- 1 -miethyl- 5-(4-methyl-2- pyridyl)-2,3 -dihydro- I H-i ,4-benzocliazepin-2-one; 3-(2-(R)-cyc0PTOPYbrnethY-3 -GS}'hYdIoxyl-l1 -oxobutyl)amino-1I -methyl-5 trifluoromnethyipbenyI)-Z, 3 -dihydro- I H-i ,4-ben~zodiazepin-2-ofle; ,5i0105.mI~fl.C 93S. 0 -1~80- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-1 1-03 03/11 '05 11:30 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB AITS PATENT OFFICE 14076 3-(S)-(2-(R)-(3-butenyl)-3-59-hydrOXyl-i -vxoheptyl)ainino- I -noethyl-5-phenyl-2,3 dihydro- 1H-l,4-beazodiazepin-2-one; 3-(5)-(2-(R)-(3-methylbutyl)3 -(59-hydroxyl-1 -oxoheptyl)amino -1I-methyl-5-phenyl-2,3 dihydro- I1H- 1,4-benzodiazepin-2-one; 3 -(S)-(2-(R)-ethy1-3-($)-hydroxy1- I -oxoheptyl)anuno-1 -methyl-5-jphenyl-2,3 -dihydro- 1 H-i ,4-benzdiazepin-2-one; 3-(5)(2-(R)-propyl-3 -(5)-hydroxyl- 1 -oxoheptyl)wnioo-i -methyl-5-phenyi-2,3 -dihydro- 1 ,4-benzodiazepin-2-one; 3-(S)-(2-(R)-buty1-3-(S)-hycdroxyl-l1-oxoheptyl)ainino-l1-rnethyl-5-phenyl-2,3 -dihydro- iN- 1 ,4-benzodiazepin-2-one; 3-(4-($-amino-3-(R)-hydroxyl-2-(R)-mCtbyI- I-oxo-5-phenylpeutyl)aniino-7-chloro-S-( 2 fluorophenyl)- I -methyl-2,3 -dihydro-i H-i ,4-benzodiazepin-2-one; 20 3-(4-(S)-(tert-butoxycarbOry1lamflo-3(R)-hYdrlxyl-2KR)-meffiyl-l1-oxo-$- *0 phenylpentyl)aaino-7-c~oro-5-(2-flUc~fOPhenl)Y -inethyl-2,3 -dihydro- I- 1,4- benzodiazepin-2-otie; oxopropy1)axnino -7-chioro- 5-(2-fiUOrophefl)- -methyl-2,3 -dihydro- 1 Fl- 1,4- 25 benzodiazepin-2-one;,
34-3 -hydroxyl-2-(R)-znethyl- I -oo3-(yrUdn2()ylpoy)a~i--hoo5 (2-fluorophenyl)-lI-methyl-2,3-dihydro- IHF-i,4-benzodiazepin-2-onc; 3 -(4-benzyloxy-3 -(R)-hYdIOXY-2(R)-4so-ptpyk- 1 -oxobutyl-axnino-7-chloro- 1 -methyl-5 phenyl-2,3 -dihydro- 1 H- 1,4-benzodiazepin-2-one; 2-(4-(5)-amnino- 3 -(S)-hydroxyl-2-(S)-methYl-l1 oxo-5-phenylpenty)arnino-7-ChOrO- 5 flourophenyl)-i -methyl-2,3 -dihydro- 1 H-i 1,4-b enzodiazepin-2-one; COMS IDNo: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:30 FAX 61 3 9859 1588. CALLINAN LAWRIE MELB AUlS PATENT OFFICE 10JU77 2-4()(etbtxeabnlrio3(~yrxl2()mty- phenylpent1)amino-7-cor5-( 2 -fluoXophel)l I -methyl-2,3-dihydrc'- 1 H-i A- benzodiazepin-2-one; 3-(2-(R)-cyc-jopropy1l8t'hY1-3 -(S)-hydroxyl-1 -oxoheptyl)amino- I -mcthyl-5-(thiazol-2-yl)- 2,3-dixydxo-1H-1 ,4-benzodiazepin-2-DC; 3-(2-(R)-cyclcopropyhlmethy1-3-(S)-hYdroxy[- 1 -oxoheptyl)amnino- 1 -cyclopropylmethyl 5 (thiazol-2-yl)-2,3-dihydrQ 4 H-i ,4benodiazepin-2-0.De; 3-(2-(R)-cyC1OprpYlmetYl-3(S$tYdrfxYl -oxoheptyl)aznino- I -cyclopropylmethyl-5-( 4 trifluoromethylphcnyl)-2,3 -dihydro-l H-1I,4-benzodiazepin-2-oflC; 3-(2-(R)-cYcloPropylmehY13-(S)hYdroxYl-1 -oxoheptyl)amino-lI-benzyl-5-(4- 0*e* trifluoromethylphenyl)-2,3-dihYdIQ
111-1 ,4-bcnodiazepin-2-Qne; 3-(2-(R)-cycloprOpylmethy-3-GS}.hYdI0xyI-l1-oxoheptyl)amino-l1-(3-phenoxybenzyl)-5-( 4 trifluoronethy-phenl1)-2,3dhYdrO- 1H-i ,4-benzcdi azeptn-2-one; 3-(2-(R)-cycIopropYflmethYL-3-S)-hYdOXYI-l-oxohepty)amiino-l1-(3 -pyridinylmethyl)- 5 (4-trifluoromethy1-pbel)-2,3-dihYdO- 11-1 ,4-benzodiazepin-2-OflC; 3-(2-(S)-cycloprpylflethy-3-R)1YdVXYl-I-oxoheptyl)amino-l1-methyl-5-(4- trjfluorojnethylphenyl)-2,3dihydroH-I -,4-bcnzodi azepin-2-one;
303-(2-(5)-cycloprOpylmthYL-3-(R)-hylroxyl- -oxoheptyl)amino-i -methyl-5-(4- trifluoromethylphenyl)-2,3-dihycfro-lH-i ,4-benizodzepi-2-ofle 3-(2-(R)-cyC10prOPYflmethYlN3 -4)-hydroxyl- 1-oxoheptyl)amino-l1-methyl-S trifluoromethylpheny1)-2,3-dihYdrQiH-1,4-benzodiazepn-2-OlC; -182- COMS IDNo: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 V~tL)-05 11:31 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB AUS 4 PATENT OFFICE tMj078 3-(2-(S)-cyr-lopropylmethyl-3-(s)-hYdOXYi-l -oxoheptyl)arnino- I-methyl-5-(4- trifluoromediylpheiyl)-2,3-dihydrO- I H-i ,4-bcnzodi azepin-2-one; 3-(2-(R)-cyclnpmopylmethy1-3-(SfrhydroKY1-3-(S)-mnethYl-l -oxoheptyl)anaino- 1 (4-trifluoromethyl-pbenyl)-2,3-dihydro-l H-i ,4-benzodiazepin-2-OflC; 3-(2-(R)-cyclopropylmethyl-3 -(S)-hydroxyl- 1 -oxohteptyl)amino- 1 methyl-2.3 -clihydro- 1 R- 1,4-b enzodiazepin-2 -one; 3-(2-(R)-cyclopropyknehtyl-3 -(S)-hydroxyl-I -oxoheptyl)amino-lI-benzyl-5-methyl-2,3- dihydo-I H-i ,4-benzodiazepin-2-one; 3-(3-(S)-acetoxy-2-(R)-iso-butyl-l -oxoheptyl)amino-5-(4-fluorOPhoflYl)- 1-methyl-2,3- 15 dihyclro-lIH-i ,4-benzodiaz.epin-2-oflC; 3-(gS)(5.cycopenty1.2(R)cycopropYltetY-3-(5)-mCthOXt 1 -oxopentyl)amino- 1- methyl-5-pheuyl-2,3-dihydro-lft I,4-benzodiazepin-2-ole; 20 1-(I-hydroxypentyl)ylOhexaflecrbOXYlic acid(5-(4-fluorophenyl)--inthYl-2-OXO- 2 1 3 dihydro-Ilu-I ,4-benzodiazepin-3 -yI)annide; 3-(2-(R)-cyclopropyhfnethyl-3-(S)-hYdrOXYl- -oxohepty1)amino-5-methyl- 5 H 711- dibenzo[b,d]Eazepin-6-one; 3-(2-(R)-cyclopropylnethyl-3-(S)-hYdrOXYV 1 -oxooctyl)amino-5-methyL5SH, 711 dibenzo[b,d] azepin-6-one; 3 -(2-(R)-cyclopropylmncthyl- 3 -(S)-hydroxyl- I-oxononyl)amino-5-methyl-5H, 7 W- dibenzo[b,djazepifl-6-0fl0 3-2()ccorplehlS frn2y)3()hdoy--oxopentyl)aniino-5-tnethyl- 5H,711-dibeflZ0[b,d]azepin-6--one; 25/Oj5ei1 Cf5. l II11 -183- COMS ID No: SBMI-01882249 Received by IP Australia: lime 11:50 Date 2005-11-03 03/11 '05 11:31 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB AUS 4 PATENT OFFICE IJUTS 3-(2-(R)-cyclopropylmethyl-3-%S-hyrOXyl-l1-oxoheptyl)amino-5-cyclopeiityl- 1-methyl- 2,3-dihydro-1 H-i ,4-benzodiazepin-2-one;, 3-(2-(R)-cyelopropylmethyl-3 -(S)-hydrexyl- I -oxoheptyl)aMino-5-benzyl- 1 -methyl-2,3 dihydro- I 1-1,4-benzodiazepin-2-one; 3-(2-(R)-eyclopropylmetbyl-3 -(S)-hydroxyl- I -oxoheptyl)anaino-5-benzyl- 1 -butyl-2,3- dihydro-1I H-I ,4-benzodiazepin-2-one; 3-(2-(R)-cyclopropylmethyl-3 -(S)-hydr-oxyl-lI-oxoheptyl)anino-5-cycloheptyl-l1-methyl 2,3-dihydro- I H-i ,4-benzodiazepin-2-one; 3-(2-(R)-cyeloropylmetby]-3 -(S)-hydroxyl-1 -oxoheptyflano-1I-benzyl-cycloheptyl-2-,3 H-i ,4-benzodliazepin-2-ofle; 3-(-(R-cylapopyfl~th~-3 (S-hycloxyl-1 -oxoheptyl)amnino- 1-butyl-5 -cycloheptyl-2,3- dihydro-IH-1 ,4-benzoDdiazepin-2-one; 3-(2-(R)-cyclopropyhnethyl-3 -($)-hydroxyl- 1 -oxoheptyl)axnino- 1 20 (4-trifluoromethylphenyl)-2,3-dihiydro-1 H-i ,4-benzodiazepin-2-one; 3-(2-(R)-cyclopnopy1-mehyl-3 .S)-hydxoxyl-l1-oxoheptyl)amino-l1-(3 -pyridinylmcthyl)-S- (2-tluorophcnyl)-2,3 -dihydro- 111- 1,4-benzodiazepin-2 -one; 3 -(2-%S-cycopropymthy-3 hYdoxyI- 1. -oxopentyl) amino- 1 -pyridynyhnethyl)- (4-lrifluoromethylphelyl)-2,3-dihydo-H' 1-1 ,4-benzodiazepin-2-one; 3 (R)-cyclopropylmthyl-3-S)-tydroxyl-l1-oxohepty])amina-1 dibutylamino)-2,3-dihydro- IH-1 ,4-benzodiazepin-2-oae;, 3-(2-(R)-oyclopropylmethYi-3 -(S)-hydroxyl-l1-oxobeptyl)ainio-l1-n-butyl- 5-t-butyl-2,3 dihydro- 1H-i ,4-benzodiazepin-2-one; 25/0lU/Q5,B M1!S2S co~s1I4 -184- COMS ID No: SBMI-01882249 Received by IP Australia: Time (1-Pm) 11:50 Date 2005-11-03 03/11 '05 11:31 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB AUS PATENT OFFICE 04080 3-(24(R)-cyclopropylmethyl-3-(S)-hydroxYl- I -oxoheptyl)mnc-1I -(2-oxo-3 ,3- dhnethylbutyl)-5-n-butyl-2,3-dihYdro-1Hl- 1 ,4-benzodiazepin-2 -one; 3-(2-(R)-cyclopropylmthy-3-S)-hydrOXYl-lI-oxoheptyl)anito-1 -benzyl-5-t-butyl-2,3- dihydro-1 H-I ,4-benzodiazepin-2-one;, 3-(2-(R)-cyclopropyhnethy-3-(S)-bYdroxyb- I -oxoheptyl)amino-1 2,3-dihydro-1H-1 ,4-benzodiazcpin-2-one; 3-(2-{R)-IsobutyI-3-%S-hydrOXYl-l1-oxoheptyl)amino-l1-methyl-5-homopiperidino-2,3- dihydro- 1H-i ,4-benzodiazepin-2-one; 3-(2-(R)-cyclopropylmethyl- 1,3 -cioxoheptyl)arnino- 1 -methyl-5-(4-trifluoromethylpheliyl)- 2,3-dihydro-1H-1 ,4-benzodiazepin-2-onc; and 1 -pentylcyclohexanecarboxylic acid (5-(4-fluorophcnyl)- 1 -methyl-2-oxo-2,3-dihydro-1 H- 1 ,4-benzodiazepin-3-y1) amnide. 9. A compound of Formula (Ig) Hs 0 N ,W-X-Y-Z *OH 0 NNR3 R R 3 (Ig) wherein: Q 1 is 0 1 -C 6 alkyl substituted with 0-3 Ria; C 2 -C 6 alkenyl substituted with 0-3 RI&; C 2 -C 6 alkynyl substituted with 0-3 R18; C 3 -C10 cycloalkyl substituted with 0-3 Rib; C 3 -CIO carbocycle substituted withi 0-3 Rib; ~5'Ot/Ot±12523. IR S COMS IDNo:SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005.-11-03 03/11 '05 11:31 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB AUS PATENT OFFICE 10081 aryl substituted with 0-3 Rib; or 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 Rlb; R l a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR 1 4 C1, F, Br, I, NR 15 R 16 CF 3 C 3 -C 10 carbocycle substituted with 0-3 Rib; aryl substituted with 0-3 Rib; and 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle .is substituted with 0-3 R 1 b; Rib, at each occurrence, is independently selected from H, OH, C1, F, Br, I, CN, NO2, 15 NR 15 R 1 6 CF 3 acetyl, SCH3, S(-O)CH3, S(=0)2CH3, CI-C6 alkyl, C 1 -C4 alkoxy, C 1 -C 4 haloalkyl, Ci-C4 haloalkoxy, CI-C4 haloalkyl-S-, and (Ci-C 6 alkyl)-O- C(O0)-; R 5 is OR 14 S 20 C 1 -C6 alkyl substituted with 0-3 C-C 6 alkenyl substituted with 0-3 RSb; or C 2 -C6 alkynyl substituted with 0-3 R 5 B is H, methyl, ethyl, propyl, butyl, or C 2 -C4 alkenyl; alternatively, R 5 and RSB may be combined to form a C 4 -C 7 cycloalkyl ring; R 5b at each occurrence, is independently selected from: H, methyl, ethyl, propyl, butyl, CF3, OR 14 C1, F B, B 0, NR 15 R 16 C3-C7 cycloalkyl substituted with 0-3 R 5 c; C 3 -C 7 carbocycle substituted with 0-3 RSC; phenyl substituted with 0-3 R 5 c; and 25/01/05 .1ll82- clnim,.185 -186- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:32 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB AUS -4 PATENT OFFICE 1082 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 RSc; R 5c at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR 15 R1 6 CF 3 acetyl, SCH 3 S(=O)CH3, S(=0) 2 CH 3 CI-C 4 alkyl, CI-C3 alkoxy, C 1 -C2 haloalkyl, and CI-C 2 haloalkoxy; W is a bond; X is a bond; Y is a bond; Z is H, CI-C4 alkyl substituted with 0-2 R 12 15 C2-C4 alkenyl substituted with 0-2 R12; C 2 -C 4 alkynyl substituted with 0-2 R 12 aryl substituted with 0-4 R 1 2b; C 3 -C 6 carbocycle substituted with 0-4 R 1 2b; or 5 to 6 membered heterocycle containing I to 4 heteroatoms selected from nitrogen, 20 oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R 1 2b; R 1 t at each occurrence, is independently selected from H, NR 1 8 R 19 C(=O)R 17 C(=)OR 17 C(--O)NR 18 R 1 9 S(=0) 2 NRl 8 R 19 CF 3 Ci-C6 alkyl substituted with 0-1 R 1 1 a; phenyl substituted with 0-3 R 1 lb; C 3 -C6 carbocycle substituted with 0-3 R 1 1 b or to 7 membered heterocycle containing to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R11b; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl; l2523.L;m,17 -187- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 3/11 '05 11:32 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB AUS 4 PATENT OFFICE 141063 R1a, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Cl, F, NR' 5 RI 6 CF 3 phenyl substituted with 0-3 R 1 b; C 3 -Cs carbocycle substituted with 0-3 R11b; or 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R 1 1b; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimnidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl; R11b, at each occurrence, is independently selected from H, OH, Cl, F, NR 15 R' 6 CF 3 ,o acetyl, SCH 3 S(=O)CH 3 S(=0) 2 CH 3 methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, CI-C2 haloalkyl, and C1-C2 haloalkoxy; *9 R 12 at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, N02, NR 1 5 R 1 6 -C(=O)NR' 5 R' 6 CF 3 acetyl, SCH3, S(=O)CH 3 S(O)2CH3, 01-06 alkyl, C 1 -C4 alkoxy, C1-C4 haloalkyl, C-C4 haloalkoxy, and C 1 -C 4 haloalkyl-S-; aryl substituted with 0-4 R12b; 20 C3-Cl carbocycle substituted with 0-4 RJ2b; or to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered beterocycle is substituted with 0-3 R12b; R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, N02, NR 15 R 16 CE 3 acetyl, SCH3, S(=0)CH3, S(=O) 2 0H 3 01-06 alkyl, C-C4 alkoxy, C1-C4 haloalkyl, CI-C4 haloalkoxy, and C1-C4 haloalkyl-S-; R 1 3 at each occurrence, is independently selected from H, OH, C-C alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO 2 NR 1 5 R 1 6 and CF 3 15/01I5.a I2525.CIIms. Ill -188- COMS ID No SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:32 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB AUS PATENT OFFICE 1g084 R 14 at each occurrence, is independently selected from H, phenyl, benzyl, C 1 -C 4 alkyl, and C 2 -C 4 alkoxyalkyl; R 15 at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; R 16 at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, phenethyl, CH 3 CH2C(-O)-, CH 3 CH 3 CH 2 CH 3 CH 3 CH 2 and CH3S(O-)2-; R 17 is H, phenyl, benzyl, CI-C4 alkyl, or C 2 -C4 alkoxyalkyl; R18, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and R 1 9 at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, and butyl- 10. A compound of Claim 9, wherein: Q 1 is CL-C 6 alkyl substituted with 0-3 Rla; C 2 -C6 alkenyl substituted with 0-3 R 1 a; C 2 -C 6 alkynyl substituted with 0-3 Rla; C 3 -C 6 cycloalkyl substituted with 0-3 Rlb; phenyl substituted with 0-3 Rib; or 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 1 b; R 1a at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, OR 14 Cl, F, Br, I, NR 15 R' 6 CF 3 C 3 -C 6 carbocycle substituted with 0-3 Rlb; l210/05, 1 2525.cl t, I89 -189- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11.50 Date 2005-11-03 03/11 '05 11:32 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB AUS 4 PATENT OFFICE 141085 phenyl substituted with 0-3 Rib; and to 6 membered heterocycle containing 1 to 4 heteroatomTns selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 RIb; Rib, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO 2 NR 15 R' 6 CF 3 acetyl, SCH3, S(=0)CH 3 S(=O) 2 CH 3 methyl, ethyl, propy), butyl, methoxy, ethoxy, propoxy, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, (methyl)OC(-O)-, (ethyl)OC(=O)-, (propyl)OC(=0O)-, and (butyl)OC(=0O)-; is OR 1 4 C 1 -C 4 alkyl substituted with 0-1 Rb; C 2 -C 4 alkenyl substituted with 0-1 R5b; or C 2 -C 4 alkynyl substituted with 0-1 R%; S 1R 5 a is H, methyl, ethyl, propyl, or butyl; alternatively, R 5 and R5a may be combined to form a cyclobatyl, cyclopentyl, cyclohexyl, or cycloheptyl ring; at each occurrence, is independently selected from: H, methyl, ethyl, propyl, butyl, CF 3 OR' 4 Cl, F, NR 1 5 R' 6 C3-07 cycloalky] substituted with 0-3 RSC; ***C3-C7 carbocycle substituted with 0-3 25 phenyl substituted with 0-3 R5c; 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 R5C; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyriminidinyl, triazinyl, furany], thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl; at each occurrence, is independently selected from H, OH, Cl, F, NRI 5 R 1 6 CF 3 acetyl, SCH3, S(=O)CH 3 S(=0) 2 CH 3 methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and 01-02 haloalkoxy; 215/DhgS/ I.clam.ch s.190 -190- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:33 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB AUS PATENT OFFICE t0o 8 W is a bond; X is a bond; Y is a bond; Z is H, Ci-C 4 alkyl substituted with 0-2 R12; C2-C4 alkenyl substituted with 0-2 R 12 C 2 -C 4 alkynyl substituted with 0-2 R 12 aryl substituted with 0-4 R 12 b; C3-C6 carbocycle substituted with 0-4 R12b; or to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R12b; 15 R 11 at each occurrence, is independently selected from SH, NRl 8 R 19 CF 3 C 1 -C 4 alkyl substituted with 0-1 R 11 a; phenyl substituted with 0-3 Rllb; C3-C6 carbocycle substituted with 0-3 R 1 lb; or 20 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, **oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R 1 lb; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidiny), homopiperidinyl, pyrazolyl, imidazolyl, 25 oxazolyl, isoxazolyl, and tetrazolyl; Rl 1 a at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Cl, F, NR 15 R 6 CF 3 phenyl substituted with 0-3 R lb; C3-C6 carbocycle substituted with 0-3 R 1 lb; or 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 1 lb; wherein said 5 to 7 membered heterocycle is I05.arl2525 sleil".l s -191- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:33 FAX 61 3 9859 1588 CALLINAN LAWRIE HELB AUS PATENT OFFICE 1I087 selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl; Rllb, at each occurrence, is independently selected from H, OH, Cl, F, NR 15 R 16 CF 3 methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C 1 -C2 haloalkyl, and Cl-C 2 haloalkoxy; R' 2 at each occurrence, is independently selected from H, OH, Cl, F, Br, NR 15 R 16 C(=O)NR 15 R 1 6 CF 3 acetyl, SCH 3 S(=O)CH 3 S(=0) 2 CH 3 methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C 1 -C 2 haloalkyl, and CI-C 2 haloalkoxy; phenyl substituted with 0-4 R12b; C 3 -C 6 carbocycle substituted with 0-4 R12b; or 5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, 5. 1 oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R12b; Rl2b, at each occurrence, is independently selected from H, OH, Cl, F, Br, NR 1 5 R 1 6 CF 3 acetyl, SCH3, S()CH 3 S(=0) 2 CH 3 methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, CI-C 2 haloalkyl, and Cj-C 2 haloalkoxy; R 13 at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Cl, F, Br, CN, NR 1 5 R 1 6 and CF 3 R 14 at each occurrence, is independently selected from H, phenyl, benzyl, methyl, ethyl, propyl, and butyl; R 15 at each occurrence, is independently selected from H, methyl, ethyl, propyl, or butyl; R 1 6 at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; 2S/bBIDS.O1atl3255ls.19f -192- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 9311 '05 11:33 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB AUS PATENT OFFICE 101088 18, at each occurrence, is independently selected from H, methyl, ethiyl, propy1, butyl, phenyl, benzyl and, phenethyl; and R 19 at each occurrence, is independently selected from H, OH, methyl, ethyl, p'ropyl, butyl, phenyl, benzyl and, phenethyl. 11. A compound of Claim 10, wherein: Q 1 is -Gil 3 -CH 2 CH 3 -CH 2 CH 2 CH 3 -CH 2 CH 2 CH2CH3, -CH 2 CH 2 CH 2 CE 2 CH3, -CH 2 CHZCHZCH 2 CH2CII3, -CH(CH 3 2 -CH(CH 3 )CI-kCH3, -CH 2 CH(CH 3 2 -CH 2 C(GH 3 3 -CE 3 -CH 2 CF 3 -CH 2 CH2CF3, -CH 2 CH 2 CH 2 CF 3 -CH=-CH 2 -CHZCH=C-2, -CH1 2 C(CH 3 )=CH2, -CH 2 CH=-C(CH 3 2 -CH 2 CH 2 CI-CH 2 -CH 2 CH 2 C(CH 3 )=CH 2 -CH 2 CH 2 CH=C(CH 3 )z, cis-CH 2 CH-CH(CH3), cis-CH 2 CH 2 CIPCH(C113), trans-CH2CH=CH(CH3) tran-CH 2 CH 2 CH=CH(CH3); -CH 2 C7-CH, -CH 2 C' C(CH 3 cyclopropyl-, cyclobutyl-, cyclopentyl-, cyclohexyl-, cyclopropyl-CH2-, cyclobaityl- CU 2 cyclopentyl-C112-. cyolohexyl-CH2-, cyclopropyl-CH2CH2-, cyclobutyl- CH 2 CH2-, cyclopentyl-CH 2 CH2-, cyclohexyl-CH2CH2-, phenyl-, 2-F-phenyl-, 3-F-phenyl-, 4-F-phenyl-, 4-methoxyphenyl-,A-ethoxyphenyl-, 4-propoxyphenyl-, phenyl-CH2-, (2-F-phenyl)CH2-, (3-F.-phenyl)C112-, (4-F-pb)enyl)CH2-, (2-Cl-phenyl)CH2-. (3-Cl-phenyl)CH2-, (4-C1-phcayl)CU 2 (2,3-diF-phenyl)CH 2 (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)CHz-, (2,5-diCl-pheny1)CH2-, (2,6-diCl-phenyl)QH2-, (3 ,4-diCl-phenyl)CH2-, (3 ,5-diCl-phcenyl)CH2-, -193- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 43/11 '05 11:33 FAX 81 3 9859 1588 CALLINAN LAWRIE MELB AUlS 4PATENT OFFICE 0d089 (3-F-4-Cl-paenyl)C112-. (3-F-5-C1-phcnyl)CH2-, (3-CI-4-F-phenylI)CH2-, 2-fur-anyl-CH2-, 3 -furanyl-C112-, 2-thienyl-CH2-, 3-thienyl-CH2-, 2-pyridy-C112-, 3-pyridyl-CH2-, 4-pyridyl-CH2-, 1 -imidazolyl -CH 2 -,2-oxazolyl-CH2-, 4-oxazolyl-C.H2-, 5-.oxazolyl-CH2-, 3-isoxazolyl-CH2-, 4-isoxawzlyl-QH2-, 5-isoxazoly]-CH-2-, phenyl-CH2CH2-, (2-F-phenyl)CH2CH2-, (3-F-phenyl)CH2CH2-, (4-F-phenyl)CH2CH2-, (2-CI-phenyl)CH2CH2-, (3-C1-phenyl)CH 2 CH2-, (4-C1-phenyl)CH42CH2-, (2,3-diF-phenyl)CH 2 CH2-, (2,4-diF-phenyl)CH2CH2-, 15 (2,5-diF-phenyl)CH 2 CH2-, (2,6-diF-phenyl)CH 2 CH2-, (3 ,4-diF-phenyl)CH 2 CH2-, (3 ,5-diF-phenyl)CH 2 CH2-, (2,3-diCl-phenyl)CH2CH2-, (2,4-diCl-phenyl)CII2CH2-, (2,5-diCbpheny)CH2C-2-, (2,641 C1-phenyl)CH2CH2-, 0 ,4-diCl-pheny)C-2CH2-, (3 ,5-diCl-pheDyl)CH2CH2-, 20 (3-F-4-C1-phenyl)CH12CH2-, (3-F-5-CI-phcayl)CHi2CH2-; *.furany1i-CH21CH2-, thienyl-CH2CH2-, pyridyl-CH2CH-, 1 -ixnidazolyJ-CH21CH2-, oxazolyl-CH2CI{2-, isoxazolyl-CH2CH2-, 3,5-ditnethylisoXazo-4-Y-CH2CH2r phenyl-propyl-; a benzyl-CE(NB2)-, benzy1-CH(NHC(=O)-O-tBU)-, henzyioxy..CH 2 pyrrolidin-2-yl-, or a...oxcronly~oii-2y- R 5 is -Gil 3 -CH 2 CH 3 -CI- 2 CH 2 CH 3 -CH(CH 3 h2, -CH 2 CH 2 CII 2 CH3, -CH(CH 3 )CI- 2 CHj, -CH 2 CH(CHJ)2, -CH 2 C(CH 3 )3, -CH 2 CH 2 CII 2 CH2CH3, -CH(CH 3 )CE 2 CH2CH3, -CH 2 CH(CH 3 )CH 2 CH3, -CH 2 CHZCH(CH3)2, -CH(CII 2 CHt)2, -CFh, -CH 2 CF 3 -CH 2 CH 2 GF 3 -GH 2 CU 2 CH 2 CF3, -CH 2 CH 2 CH 2 CJ-1 2 CF3, -CH--CH2, -CH 2 C1-lCH2, -CH2CH 2 CIH=CH2, -CH=CHCH3, cis-CH 2 CHi=CH.(CH3), trans-CH 2 CW4ZH(CH3), 2 5 1
08105.Bt Il32SbiUL 194 -194- COMS IDNo. SBMI-01882249 Received by IP Australia: Time (1-fm) 11:50 Date 2005-11-03 03/11 '05 11:34 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB AUS 4# PATENT OFFICE 14j090 trans-CH 2 CH-CH(C 6 H5), -CH 2 CH=C(CH 3 cis-CH 2 CH=CHCH 2 CH3, trans- CH 2 CH-CHCH 2 CH 3 cis-CH 2 CH 2 CH=CH(CH3), trans-CH 2 CH 2 CIF-CH(CH3), trans- CH 2 -Cm-CH, -CH 2 C=-CH, -CH 2 C=-C(CH3), -CH 2 C=C(C 6 H 5 -CH 2 Cil 2 GZ-fl{, -CI- 2 CH 2 G-=C(CH 3 -CH 2 CH 2 -CH 2 CH 2 CH 2 C=CH, -CH 2 CH 2 CilzC-C(CH3), -CH 2 CH 2 ,CH 2 Ga-C(C 6 oyclopropyl-CH2-, cyclobutyl-CH2-, cyclopentyl-CH2-, cyclohexyl-CH2-, (2-CH 3 -cyclopropyl)C112-, (3 -C8 3 -cyclobutyl)C112-, cyolopropyl-CH2CH2-, cyclobutyl-CH2CH2-, cyclopentyl-CH2CH2-, cyclohexyl-CH2CH2-, (2-C11 3 -cyclopropyl)CH2CH2-, (3-CH 3 -cyclobutyl)CH2CH2-. phenyl-CIH2-, (2-F-phenyl)CH2-, (3-F-phenyl)CH2-, (4-F-phenyl)CH2-. (3 ,5-diF-phenyl)CH2-, 2-fturayl-CH2-. 3-fuiranyl-CH2-, 2-thienyl- 000 Gi 2 3-thienyl-CH2-, 2-pyridyl-CH2-, 3 -pyridyl-ClH-, 4-oxazolyl-CE2-, 5-oxazoly1-CH2-, 3-isoxazolyl-C-2-, 4-isoxazoly1-CH2-, 5-isoxazolyl-CH2-, phenyl-CH 2 CH2-, (2-F-phenyl)CH2CH2-, (3 -F-phenyl)CH 2 CH2-, (4-F-phenyl)C- 2 CH2-, furanyl-CH2CH2-, thienyl-CH2CH2-, pyridyl-CH12CH2-, 1 -iridazolyl-GH2CH2-. oxazolyl-CH2CH2-, isoxazolyl-CH2CH2-; methoxy, ethoxy, propoxy, o uoy R 5 a is H; alternatively, R 5 and R 5 a may be combined to form cyclopentyl, cyclohexyl, or c-ycloheptyl; W is abond;, X is a bond; 25/GVttV512' 25.11la-L 195 -195- COMS ID No: SBMI-1 882249 Received by 1PAustralia: Time 11:50 Date 2005-11-03 03/11 '05 11:34 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB AUS PATENT OFFICE U4091 Y is a bond; Z is H, methyl, ethyl, n-propyl, i-propyl,.n-b utyl, i-butyl, s-butyl, t-buryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2-F-phenyl, 3-F-phnyl, 4-E-pbenyl, 2-Cl-pheiyl, 3-C 1-phenyl, 4-CI-phenyl, 2,3-diE-phenyl, 2,4-diF-phenyl, 2,6-diF-phenyl, 3,4-diF-phenyl, 3 2,3-diCi-phenyl, 2,4-diCi-phenyl, 2,5-di0-phenyl, 2,6-diCi-phenyl, 3 ,4-diCl-phenyl, 3 -F-4-CI-phenyl, 3-F-5-CL-phenyl, 3 -CI-4-F-phenyl, 2-MeG-pb enyl, 3-MeO-phenyl, 4-MeO-phenyl, 2-Me-phenyl, 3 -Me-phenyl, 4-Me- :0 15 phenyl, 2-MeS-phenyl, 3-MeS-phenyl, 4-MeS-phenyl, 2-CF3O-phenyl, 3-CF 3 O- C.,l furanyl, thienyl, pyridyl, 2-Me-pyridyl, 3-Me-pyridyl, 4-Me-pyridyl, l-irnidazoly1, oxazolyl, isoxazolyl, l-benzimidazolyl, morpholino, N-piperinyl, phenylC-,2- -hlpCh2-,(34CH2- (-lDChenlCH (4-Cl-phenyl)CH2-, (2,3- S diIF-phenyl)GH2-, *a 25 (2,4-diF-phenyl)CH2-, *off: (2,6-diF-phenyl)CH2-, (3A4-diF-phenyl)CH2-, (3,5-diF-phenyl)CH2-, (2,3-diCl-phenyl)CH2-, (2,4-diCl-phenyl)CH2-, (2,5-diCI-phenyl)CH2-, :.*too.(2,6-diCl-phenyl)CH2-, (3 ,4-diCI-phenyl)CH2-, (3 ,5-diCl-pheflyl)CH2-, (3-E-4-CI-phentyl)C112-, (3-F-5-CI-phenyl)CH2-, (3-CI-4-E-pheny)CF12-, (2-MeO-phenyl)CH2-, (3-MeQ-phenyl)CH2-, (4-MeO-phenyD)CH2-, (2-PhO-phenyl)CH2-, (3-PhO-phenyl)CH2-, (4-PhO-phenyl)C112-, (2-Me-phenyl)CH2-, (3 -Me-phenyl)CH2-, (4-Me>-phenyl)CE2-, (2-MeS-phenyl)CHa-, (3-MeS-phcnyl)CH2-, 4-MCS-pbenyl)CH2-, (2-CF 3 O-phenyl)CH2-, (3-CF 3 O-pbentyl)CH2-, -196- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03 03/11 '05 11:34 FAX 61 3 9859 1588 CALLINAN LAWELE MELB ALIS 4+ PATENT OFFICE 10J092 (4-CF3O-phenyl)CH 2 (fiurunyl)CH2-, (tbienyl)CH 2 (pyridyl)CH2-, (2-MIe-pyridyl)CkI2-, (3-Me-pyridyl)CH2-, (4-Me-pyridyl)C.H2-, (1 -imidazoly1)CH2-, (oxezolyl)CH2-, (isoxazoly1)CH2-, (1- benzimidazol)CE2-, (cyclopropyl)CH2-, (cyclobutyl)CH 2 (cyclopentyl)CH2-. (cyclohexyl)CH2-, (morpholino)CH2-, (N-pipridinyl)CH2-, phenyl-CH 2 CH 2 (pheny1)2CHCH42-, (2-F-phenyl)CH 2 GH2-, (3-F-phenyl)CH 2 CH2-, (4-F-phenyl)CH2CH2-, (2-C1-phenyl)CH2CH2-, (3-C1-phenyl)CH2CH2-, (4-C1-phenyl)CH2CH2-, (2,3-diF-phenyl)CH2CI{2-, (2,4-diF-phenyl)CH2CH2-, (2,5-diF-phenyI)CH2CH2-, (2,6-diF-phenyl)GI{ 2 CH 2 (3 ,4-d~iF-phenyl)CH 2 CH2-, (3 ,5-diF-phenyl)CH 2 CH 2 (2,3-diCl-phenyl)CH2CH2-, (2,4-diC1-pheny1)CH2CH2-, (2,5-diCl-phenyl)C-2CH2-, (2,6-diCl-phenyl)CH 2 CH 2 (3,4-diCI-phenyl)CH2CH2-, (3,5-diCl-phenyl)CH 2 C112-. (3 -F-4-CI-pbenyl)CH2CH2-, (3-F-5-Cl-plaenyl)CH2CH2-, (3 -G1-4-F-plienyl)CI-20H2-, (2-MeO-phenyl)CH2CH2-, (3-MeO-pheny1)CH2GH2-, (4-MeO-phenyi)CH2CH2-, (2-Me-phenyl)CH2CR2-, (3-Me-pheuyl)CH2CH2-, (4-Me-phenyl)C1I 2 CH2-, (2-MeS-phenyl)CH 2 (3-MeS-phenyl)CH2CH2-, (4-MeS-phenyl)CH 2 CHi2-, (2-CF 3 O-phenyl)CH 2 CH2-, (3-CF 3 O-phenyl)CH2CH2-, (4-CF 3 O-phenyl)CI2C-2-, (furanyl)CH 2 C-2- 25 (4-Me-pyridyl)CH 2 CH 2 (imaidazoly1)CH2CH2-, (oxazoly)C-2C-2-, (isoxazolyl)CH2CM2-, (benzimidazolyl)CH2CI{2-,(cyclopropy)CH2 CH2-, (oyclobutyl)CH 2 CH 2 ,(CYclopentyl)CH2CH2'. (cyclohexyl)CH 2 CH2- ,(morpholino)C.H 2 CH2-, Or (N-PiPridimnyl)CH2CH2-; R 1 1 at each occurrence, is independently selected from methyl, ethyl, n.-propyl, i- propyl, n-butyl, i-butyl, s-buiyl, t-butyl, phenyl, benzyl, phenethyd, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohcptyl, cyclopropybnethyl, cyclobutylmethyl, cyclopentyirnethyl, cyelohexylnaethyl, cycloheptylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, 2-F-phenyl-, 3-F-phenyl, 4-F-phenyl, 4-Ci-phenyl, 4-CH3-phenyl, 4-MeG-phenyl-, 4- CF 3 -phenyl, (4-F-phenyl)CH2-, (4-C1-phenyl)CH 2 (4-CH 3 -phe~l)CH2-, (4-CF3-phenyl)CH2-, (4-F-phenyD)CH 2 CH,-, -197- i/RO~n22.lo,9 COMS IDNo: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-1 1-03 03/11 '05 11:34 FAX 61 3 9859 1588 CALLINA.N LAWRIE MELB AUS 4+ PATENT OFFICE 4093 (4-Cl-phenyl)H 2 CH 2 (4-CH 3 -phenyl)CH 2 CH 2 3 -phenyl)CH 2 CH2-, pyridin-2-yl-, pyridin-3-yl-, 4-CF3-pyridin-2-yl-, 4-CH3-pyridin-2-yl-, tbiazol-2-yl-, azapan-1 -yl, N,N- dixuethylamino, N,N-diethylamino, NN-dipropylaaino, and N,N-dibutylamino; and R 13 at each occurrence, is independently selected from H, MeO, F, and Cl. 12. A compound, according to any one of Claims 9, 10, or 11, of Formula(1g); 0H1 OH 0 N\ @g) or a pharmaceutically acceptable salt form or prodrug thereof. 13. A compound, according to any one of Claims 9, 10, or 11, of Formula (Ih); S. *SSS S S S S S H 0 N ,W-X-Y-Z OH 0 1 3 RR (1h) or a pharmaceutically acceptable salt form or prodrug thereof. 14. A compound selected from: 3-(2-(R)-cyclopropybnethyl-3 -S)-hydroxyl-1 -oxohcptyl)asino-5-methyl- 5 -,7W dibenzo[b,d]azepin-6-one; 2 1.,UI12525.cdm. 151 -198- COMS ID No SBMI-01882249 Received by IP Australia: Time.(Hm) 11:50 Date 2005-11-03 03/11 '05 11:35 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB AL'S FAXhNT UJ"FICE ItjU94 3-(2-(R).cyclopropyhnethyl-3-(S)-hydroxyl-1 -oxooctyl)amino-5-methyJ-5H,7H- dibenzo[b,djazepin-6-one; 3-(2-(R)-cyc-lopropylmethyl-3-(S)-hydroxyl- I -oxononyl)ainino-5-lnethyl-5 1t7H- dibenzofb,djazepin-6-one; 3 -2-{R)-cyclopropynethy-5-(furan-2-y1)-3-(S)-hydnoxyl-l 5H,7J3-dibenzofb,djazepia-6-one; 2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-heptanoic acid (2-oxo-1I-(3-phenylamino- benzyl)azapan-3 .{S)-yl)amide. A compound of Claim 1 or a pharmaceutically acceptable salt form or prodrug thereof, is selected from: (2R,3 S)-2-(cyclopropylmnethyl)-3 -hydroxy-N- (1 mnethylphenyl)sulfonyl]amino~phenyl)mlethyl] -2-oxo(31-,4H,5H-benzo[fl 1,4- diazaperhydroepin-3 -yl)}heptanamide; S)-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl- I -oxoheptyl)anaino-5-(2- diethylaminoethy)-6,7-dibydro-5H-dibezoazepi-6-ole; 4 7-(R,S)-(2-(R)-Cyclopropynethy-3-(S)-hydroxy-l1-oxoheptyl)ainino-5-(3- liydroxypropyl)-6,7-dihydro-5H-dibelzoazepil- 6 -one, 7-(RS)-(2-(R)-Cyclopropylmethyl-3-(S)-hYdroXYl-lI-oxoheptyl)azno-5--benzyl-6,7- diliydro-5H-dibenzoazepin-6-ofle; 6-(2-(R)-cyclopropylmethyl-3 -(S)-hydroxyl- 1 -oxoheptyl)atnino- 1 ,4-dibenz~yl-hexahydro- 5H-1 6-(2-(R)-cyclopropylmethyl-3 -(S)-hydroxy- 1 -oxohetptyl)amino-4-benzy] 1 cblorophenyl)sulfonyll- -hexahydro-5H- 1,4-diazepin-5 -one; 231/0 8M0 i25 23.00Mm 99 -199- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-1 1-03 03/11 '05 11:35 FAX 61 3 9859 1588 CALLINAN LAWRIE MELB AUS PATENT OFFICE t9095 6-(2-(R)-cyclopopylmethyl-3-(S)-hydroxy- -oxopentyl)amino-4-bezyl- 1 chlorophenyl)sulfouyl]- -hexahydro-5H-1 (2R,3 S)-2-(cyelopropylmethyl)-N-( 1-f [3 -(4-fh1orophenoxy)phenyl] ethYl J-2- oxo(3 H,4HH-benzO [fazaperhydroepin-3-yl))- 3 -hydroxyheptanamfide; (2R,3 S)-2-(cyclopropylmethyl)-3 -hydxoxy-N-12-oxo-l -benzyl(3,4{,5H- benzo[f]azaperhydrOepil3-yl)heptanlide. 16. A pharmaceutical composition comprising a compound of any one of Claims 1 to and a pharmaceutically acceptable carrier. 17. A method for the treatment of Alzheirer's Disease comprising administering to a host in need of such reatment a therapeutically effective amount of a compound of any one of Clais Ilto 18. A compound of claim 1, substantially as hereinbefore described in any one of the Examples. DATED this 2 nd day of November, 2005 S.. BRISTOLMYERS SQUIBB PHARMA COMrANY By their Patent Attorneys: CALLINAN LAWRIE A A I 0/I I/05,on12523Wcirms.2 00 -200- COMS ID No: SBMI-01882249 Received by IP Australia: Time 11:50 Date 2005-11-03
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EP1212306A2 (en) 2002-06-12
AU7479700A (en) 2001-04-17
CN1399634A (en) 2003-02-26
MXPA02001813A (en) 2004-03-19
CA2377221A1 (en) 2001-03-22
BR0014269A (en) 2002-07-02
IL147774A0 (en) 2002-08-14

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