AU2007200149A1 - Vanilloid receptor ligands and their use in treatments - Google Patents

Description

-1-

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

Name of Applicant/s: Actual Inventor/s: Amgen Inc.

Yunxin Y. Bo and Ning Chen and Partha P. Chakrabarti and Elizabeth M. Doherty and Christopher H. Fotsch and Nianhe Han and Qingyian Liu and Mark Henry Norman and Xianghong Wang and Jiawang Zhu and Michael G. Kelly Address for Service is: SHELSTON IP Margaret Street SYDNEY NSW 2000 CCN: 3710000352 Telephone No: Facsimile No.

(02) 97771111 (02) 9241 4666 Attorney Code: SW Invention Title: VANILLOID RECEPTOR LIGANDS AND THEIR USE IN

TREATMENTS

Details of Original Application No. 2002364549 dated 10 Dec 2002 The following statement is a full description of this invention, including the best method of performing it known to me/us:- File: 42646AUP01 501066921 1.DOC/5844 la- O VANILLOID RECEPTOR LIGANDS AND THEIR USE IN TREATMENTS SThe present application is a divisional application of Australian Application No.2002364549, which is incorporated in its entirety herein by reference.

This application claims the benefit of U.S. Provisional Application Nos.

ON 60/339,161 filed December 10, 2001, 60/344,737, filed December 21, 2001, 60/383,331, Sfiled May 22, 2002 and 60/402,422, filed August 8, 2002, which are hereby incorporated Oby reference.

Background The vanilloid receptor 1 (VR1) is the molecular target of capsaicin, the active ingredient in hot peppers. Julius et al. reported the molecular cloning of VR (Caterina et al., 1997). VRI is a non-selective cation channel which is activated or sensitized by a series of different stimuli including capsaicin and resiniferatoxin (exogenous activators), heat acid stimulation and products of lipid bilayer metabolism, anandamide (Premkumar et al., 2000, Szabo et al., 2000, Gauldie et al., 2001, Olah et al., 2001) and lipoxygenase metabolites (Hwang et al., 2000). VR1 is highly expressed in primary sensory neurons (Caterina et al., 1997) in rats, mice and humans (Onozawa et al., 2000, Mezey et al., 2000, Helliwell et al., 1998, Cortright et al., 2001). These sensory neurons innervate many visceral organs including the dermis, bones, bladder, gastrointestinal tract and lungs; VR1 is also expressed in other neuronal and non-neuronal tissues including but not limited to, CNS nuclei, kidney, stomach and T-cells (Nozawa et al., 2001, Yiangou et al., 2001, Birder et al., 2001). Presumably expression in these various cells and organs may contribute to their basic properties such as cellular signaling and cell division.

Prior to the molecular cloning of VRI, experimentation with capsaicin indicated the presence of a capsaicin sensitive receptor, which could increase the activity of sensory neurons in humans, rats and mice (Holzer, 1991; Dray, 1992, Szallasi and Blumberg 1996, 1999). The results of acute activation by capsaicin in humans was pain at injection site and in other species increased behavioral sensitivity to sensory stimuli (Szallasi and Blumberg, 1999). Capsaicin application to the skin in humans causes a painful reaction characterized not only by the perception of heat and pain at the site of administration but also by a wider area of hyperalgesia and allodynia, two characteristic symptoms of the human -2condition of neuropathic pain (Holzer, 1991). Taken together, it seems likely that increased activity of VR plays a significant role in the establishment and maintenance of pain conditions. Topical or intradermal injection of capsaicin has also been shown to produce localized vasodilation and edema production (Szallasi and Blumberg 1999, Singh et al., 2001). This evidence indicates that capsaicin through it's activation of VR1 can regulate afferent and efferent function of sensory nerves. Sensory nerve involvement in diseases could therefore be modified by molecules which effect the function of the vanilloid receptor to increase or decrease the activity of'sensory nerves.

VR1 gene knockout mice have been shown to have reduced sensory sensitivity to thermal and acid stimuli (Caterina et al., 2000)). This supports the concept that VR1 contributes not only to generation of pain responses via thermal, acid or capsaicin stimuli) but also to the maintenance of basal activity of sensory nerves. This evidence agrees with studies demonstrating capsaicin sensitive nerve involvement in disease. Primary sensory nerves in humans and other species can be made inactive by continued capsaicin stimulation. This paradigm causes receptor activation induced desensitization of the primary sensory nerve such reduction in sensory nerve activity in vivo makes subjects less sensitive to subsequent painful stimuli. In this regard both capsaicin and resinferatoxin (exogenous activators of VR1), produce desensitization and they have been used for many proof of concept studies in in vivo models of disease (Holzer, 1991, Dray 1992, Szallasi and Blumberg 1999).

VR1 agonists or antagonists have use as analgesics for the treatment of pain of various genesis or aetiology, for example acute, inflammatory and neuropathic pain, dental pain and headache, particularly vascular headache such as migraine, cluster headache and mixed vascular syndromes as well as nonvascular, tension headache. They are also useful as anti-inflammatory agents for the treatment of inflammatory diseases or conditions, for example the treatment of arthritis and rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders uvetis), inflammatory or unstable bladder disorders cystitis and urinary incontinence), psoriasis and skin complaints with inflammatory components, as well as other chronic inflammatory conditions.

-3- They are, in particular, useful in the treatment of inflammatory pain and associated hyperalgesia and allodynia. They are also useful in the treatment of neuropathic pain and associated hyperalgesia and allodynia, e.g. trigeminal or herpetic neuralgia, diabetic neuropathy pain, causalgia, sympathetically maintained pain and deafferentation syndromes such as brachial plexus avulsion.

They are also indicated for the use in the prophylactic or curative treatment of asthma, of epithelial tissue damage or dysfunction, e.g. spontaneous lesions, of herpes simplex, and in the control of disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular e.g. for treating wounds, bums, allergic skin reactions, pruritis and vitiligo, for the prophylactic or curative treatment of gastrointestinal disorders such as gastric ulceration, duodenal ulcers, inflammatory bowel disease and diarrhea, gastric lesions induced by necrotising agents, for example ethanol or chemotherapeutic agents, hair growth, for the treatment of vasomotor or allergic rhinitis and for the treatment of bronchial disorders or bladder disorders, such as bladder hyper-reflexia.

Bibliography Birder-LA. Kanai-AJ. de-Groat-WC. Kiss-S. Nealen-ML. Burke-NE. Dineley- KE. Watkins-S. Reynolds-IJ. Caterina-MJ. (2001) Vanilloid receptor expression suggests a sensory role for urinary bladder epithelial cells. PNAS 98: 23: 13396- 13401.

Caterina, Schumacher, Tominaga, Rosen, Levine, and Julius, D, (1997). The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389: 816-824.

Caterina-MJ. Leffler-A. Malmberg-AB. Martin-WJ. Trafton-J. Petersen-Zeitz KR. Koltzenburg-M. Basbaum-AI. Julius-D (2000) Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science-(WASH-DC). 288: 5464:306-313.

Cortright-DN. Crandall-M. Sanchez-JF. Zou-T. Krause-JE.

White-G (2001) The tissue distribution and functional characterization of human VR1. Biochemical and Biophysical Research Communications 281: 5: 1183- 1189 Dray, (1992). Therapeutic potential of capsaicin-like molecules. Life Sciences 51: 1759-1765.

Gauldie-SD. McQueen-DS. Pertwee-R. Chessell-IP. (2001) Anandamide activates peripheral nociceptors in normal and arthritic rat knee joints. British Journal of Pharmacology 132: 3: 617-621.

Helliwell-RJA. McLatchie-LM. Clarke-M. Winter-J. Bevan-S.

McIntyre-P (1998) Capsaicin sensitivity is associated with expression of the vanilloid (capsaicin) receptor (VRI) mRNA in adult rat sensory ganglia. Neuroscience Lett. 250: 3: 177-180.

Holzer, P. (1991) Capsaicin: Cellular targets, Mechanisms of Action and selectivity for thin sensory neurons. Pharmacological reviews 43: 2: 143-201 Hwang-SW. Cho-H. Kwak-J. Lee-SY. Kang-CJ. Jung-J. Cho-S.

Min-KH. Suh-YG. Kim-D. Oh-U. (2000) Direct activation of capsaicin receptors by products of lipoxygenases: Endogenous capsaicin-like substances.

PNAS 97: 11: 6155-6160.

Mezey-E. Toth-ZE. Cortright-DN. Arzubi-MK. Krause-JE. Elde-R.

Guo-A. Blumberg-PM. Szallasi-A (2000) Distribution of mRNA for vanilloid receptor subtype 1 (VR1), and VRI-like immunoreactivity, in the central nervous system of the rat and human.

PNAS 97: 7: 3655-3660.

Nozawa-Y. Nishihara-K. Yamamoto-A. Nakano-M. Ajioka-H.

Matsuura-N.(2001) Distribution and characterization of vanilloid receptors in the rat stomach. Neuroscience Letters 309: 1: 33-36.

Olah-Z. Karai-L. Iadarola-MJ. (2001) Anandamide activates vanilloid receptor 1 (VRI) at acidic pH in dorsal root ganglia neurons and cells ectopically expressing VRI. Journal of Biological Chemistry 276: 33, 31163-31170.

Onozawa-K. Nakamura-A. Tsutsumi-S. Yao-J. Ishikawa-R.

Kohama-K. (2000) Tissue distribution of capsaicin receptor in the various organs of rats. Proc. Jpn. Acad. Ser. B, Phys.-Biol. Sci. 76: 5: 68-72.

Premkumar-LS. Ahern-GP. (2000) Induction of vanilloid receptor channel activity by protein kinase C. Nature (London) 408: 6815: 985-990.

Singh-LK. Pang-X. Alexacos-N. Letourneau-R. Theoharides-TC. (1999) Acute immobilization stress triggers skin mast cell degranulation via corticotropin releasing hormone, neurotensin, and substance P: A link to neurogenic skin disorders. Brain Behav. Immun. 13: 3: 225-239.

Szallasi, A. Blumberg-PM (1996) Vanilloid receptors: New insights enhance potential as a therapeutic target. Pain 68: 195-208 Szallasi-A. Blumberg-PM. (1999) Vanilloid (capsaicin) receptors and mechanisms. Pharmacol. Rev. 51: 2: 159-211.

Szabo-T. Wang-J. Gonzalez-A. Kedei-N. Lile-J. :Treanor-J. Blumberg-PM.

(2000) Pharmacological characterization of the human vanilloid receptor type-1 Society for Neuroscience Abstracts. 26:1-2: 634.18.

Tominaga, Caterina, Malmberg, Rosen, Gilbert, Skinner, Raumann, Basbaum, and Julius, (1998). The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron 21: 531-543.

Yiangou-Y. Facer-P. Dyer-NHC. Chan-CLH. Knowles-C.

Williams-NS. Anand-P. (2001) Vanilloid receptor 1 immunoreactivity in inflamed human bowel. Lancet (North American Edition) 357: 9265: 1338-1339.

Yiangou-Y. Facer-P. Ford-A. Brady-C. Wiseman-O. Fowler-CJ.

Anand-P. (2001) Capsaicin receptor VR I and ATP-gated ion channel P2X3 in human urinary bladder. BJU International 87: 9: 774-779.

Wang-H. Bian-D. Zhu-D. Zajic-G. Loeloff-R. Lile-J. Wild-K. Treanor-J.

Curran-E. (2000) Inflammation-induced upregulation of VR in rat spinal cord and DRG correlates with enhanced nociceptive processing. Society for Neuroscience Abstracts 26:1-2: 632.15.

Summary The present invention comprises a new class of compounds useful in the treatment of diseases, such as vanilloid-receptor-mediated diseases and other maladies, such as inflammatory or neuropathic pain and diseases involving sensory nerve function such as asthma, rheumatoid arthritis, osteoarthritis, inflammatory bowel disorders, urinary incontinence, migraine and psoriasis. In particular, the compounds of the invention are useful for the treatment of acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, bums, allergic skin reactions, pruritis, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders. Analogously, the invention also comprises pharmaceutical compositions comprising the compounds, methods for the treatment of vanilloid-receptor-mediated diseases, such as inflammatory or neuropathic pain, asthma, rheumatoid arthritis, osteoarthritis, inflammatory bowel disorders, urinary incontinence, migraine and psoriasis diseases, using the compounds and compositions of the invention, and intermediates and processes useful for the preparation of the compounds of the invention.

The compounds of the invention are represented by the following general structure

R

3 RI, AY R4

R

2 or a pharmaceutically acceptable salt thereof, wherein A, R 2

R

3

R

4 X and Y 2 5 are defined below.

The foregoing merely summarizes certain aspects of the invention and is not intended, nor should it be construed, as limiting the invention in any way. All patents, patent applications and other publications recited herein are hereby incorporated by reference in their entirety.

-7- Detailed Description One aspect of the current invention relates to compounds having the general structure: wherein: R' is

R

6

R

7 R8

R

9 or a naphthyl or saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the naphthyl, heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from R 5

R

6 and R 7

R

2 is H, hydroxy, halo, Ci.

6 alkyl substituted by 0, 1 or 2 substituents selected from R 1 0 or a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents-i ndependently- seleeted-from-R-5 or R' and R 2 together are

R

3 is H or C.

4 alkyl; or R' and R 3 together are _L2 'Lv~ R is n or

R

4 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the heterocycle and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from Ci.

9 alkyl, C 1 -4haloalkyl, halo, nitro, cyano, -OR 6 alkyl, -O-C1-4haloalkyl, -O-Ci.

6 alkylNR'Ra, -O-C 1 6 alkylORa, -O-Ci 6 alkylC(=O)ORa, -NRaRa, -NRa-C .4haloalkyl, -NRa-C 6 alkylNRR a, -9- -NRa-C 1 6 alkyl0R', -C(=0)C 1 6 alkyl, -C(=0)0C 1 6 alkyl, -0C(=0)CI- 6 alkyl, n C(=0)NRaC,.

6 alkyl and -NR'C(=0)C 1 6 alkyl; or R is l-membered bicyclic ring comprising fused 6-membered rings, containing 0, 1, 2, 3 or 4 N atoms with the remainder being carbon atoms, with at least one of the 6-membered rings being aromatic, wherein the carbon atoms are substituted by H, halo, OR', f 4 1'a a

C

1 6 alkyl and C 1 3 haloalkyl; and saturated carbon atoms may be additionally substituted by except that when R' is 4-chiorophenyl, 3-bromophenyl, 3-nitrophenyl, 2-nitro-3-chlorophenyl, 3 ,4-methylenedioxyphenyl, C) 3-methyithiophenyl or 2,3,4-methoxyphenyl, then R 4 is not phenyl substituted by 1 or 2 substituents selected from halo and Cl-4alkyI; and R1 and R 4 are not both 3,4-methylenedioxyphenyl; and when R1 is 4-trifluoromethyiphenyl, then R 4 is not pyridinyl, 2-methyl-4-aminoquinolinyl or 3,3-dimethyl- 1,3-dihydro-indol-2on-6-yl;

R

5 is independently, at each instance, H, C 1 9 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -0C 1 6 alkyl, -0-C 1 4 haloalkyl, -0-C 6 alkylNRaRa, -0-C 1 6 alky]0R', -NRaRa, -NR aC, 4 haloalkyl, -NR aC -(alkylNR'R a or -NR aC 1 6 alkylOR a; or R 5 is a sat 'urated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from 0, N and S; R 6is independently, at each instance, H, C 1 9 galkyl, C 1 -4haloalkyl, halo, nitro, cyano, -OCI 1 6 alkyl, -0-C 1 4 haloalkyl, -0-CI- 6 alkylNRaR', .0-CI- 6 alkyl0Ra -NRaR a, -NR aC ihaloalkyl, -NRa-CI- 6 alky1NRaR' or -NR aC i 6 alky1OR a; or Qand R 6 together are a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the carbon atoms of the bridge are substituted by 0, 1, 2 or 3 substituents selected from halo, C 1 6 alkyl, -0CI.

6 alkyI, -NR'CI-6alkyl, -CI- 6 alkyl0R' and

C,.

4 salky]NRaRa, and the available N atoms of the bridge are substituted by Ra,

-C

1 6 alkylOR aor CI- 6 alkylNRaRa; R 7 is independently, at each instance, H, C,.

9 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -0CI 6 alkyI, -0-C 1 4 haloalkyl, -0-C 1 6 alkylNRaRa, -07CI.

6 alkyl0Ra, -NRaR a, 1 4 haloalkyl, -NR aC 1 6 alkylNRaR' or -NRa-C I 6 alkylORa; 10 R 8 is independently, at each instance, H, C 1 9 alkyl, CI- 4 haloalkyl, halo, nitro, cyano, -OCI, 6 alkyl, -0-C 1 4 haloalkyl, -0-C 1 6 alkyl NRa Ra, -0-C 1 6al kylOR', -NRaRa, -NRa-C 1 -4haloalkyl, -Na'CI-alky]a R a or -NRa-Cv.

6 alkyl0Ra; orR7 and R 8together are a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater "than 2, wherein the carbon atoms of the bridge are substituted by 0, 1, 2 or 3 substituents selected from halo, C,.

6 alkyl, -0-C 1 6 alkyl, -NR'Ci- 6 alkyI, -Ci_6alkyl0R' and

CI-

6 alkylNRaR', and the available N atoms of the bridge are substituted by Ra,

-CI

6 alkylOR'or CI 6 alkylNRaRa;

R

9 is independently, at each instance, H, C 1 9 alkyl, Ci.

4 haloalkyl, halo, n itro, cyano, -0C 1 6 alkyl, -0-C 1 4haloalkyl, -0-C 1 .salkylNRaRa, -0-C 1 xalkyl0Ra -NR aR a, -NR aC 1 -hal oalkyl, -NRaC 1 6a1 kyINR aR a or -NRa-C I -6a1 kyloR'; R 1 0 is independently, at each instance, H, Cl-galkyl, -CI.

3 alkyl0R',

C

1 -4haloalkyl, halo, nitro; cyano, 4 haloalkyl, -0-C 1 6 alkyl NRa -0-C 1 6 al kylOR a, -0-Cj 6 alkylC(=0)OR a, -NRaR', -NRa-C 1 4 haloalkyl, -NRa-CI- 6 alkylNRaRa, -NRa'-C 16 a1kylOR', -C(=0)CI.

6 alkyl, -C(=0)0C 1 6 alkyl, -OC(=0)C 1 6 a1 kyl, -C(=0)NR aC, kyl or 1 6 alkyl; R" is independently, at each instance, H, Cl-galkyl, -CI.

3 alkyl0Ra

C

1 4 haloalky], halo, nitro, cyano, 1 6alkyl, -0-C 1 4 haloalkyl, -0-C 1 6 alkylNR -O-C 6 alkylR', -0-C 1 6 a1kylORa, -0-CI- 6 alkylC(=O0R -NR2R a, -NR aC 1- 4 haloal kyl, -NRa-C 1 6 alkyl NR aR a, -NR aC 1 6a1kylORa, -C(=0)CI- 6 a1 kyl, -C(=0)0C 1 6 a1 kyl, -OC(=0)C 1 6 a1kyl, -C(=0)NR aC 1 6 alkyl or -NR aC(=0)C 1- 6 alkyl; or R1 0 and R" together are a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the each of the carbon atoms in the bridge is substituted by H, -0Ra, -CI- 6 alkyl0R', -C 1 6 alkyl, -N Raa -CI- 6 alkylNRaRa, C(=0)0Ra, -C(=0)NR aR a, -C 1 3 a1 kylC(=0)ORa, -C 1 3 alkylC(=0)NR aR a, _OCr(=0)C 1 6 alkyl, -NR aC(=0)C 1 6 alkyl, -C 1 3 alkylOC(=0)C 1 6 alkyl or -C 1 .ialkylNR aC(=0)C 1- 6 a1 kyl, and any nitrogen atoms in the bridge are substituted by H, 6 alkyl0Ra, -1I1I-

-C

1 6 alkyI, -C 1 6 alkyINRaRa, -C 1 3 alkylC(=O)OR a, -C jalkylC(=0)NR aR', n -C 1 3 alkylOC(0O)Ci 6 alkyI, -C 1 3 alkylNR C(=0)CI- 6 alkyI, -C(=0)Rc or

-CI-

3 alky]R'; wherein if Rio, R' 2 R' and R' are all H, then R''1 is not -0-C 1 6 alkyINRaRa or -0-C 1 6 a1 kylORa; 1' 2 is independently, at each instance, H, Cl- 9 alkyI, Ct 3 alkylOR a,

C

1 4 haloalkyl, halo, nitro, cyano, -S(0),C 1 6 alkyl, -0-Cl-4haloalkyl, -0-C 1 6 alkylNRRa, -0-C 1 6 alkyl0R', -0-C 6al kylC(=0)OR a, -N aR', -NR a 14 haloal kyl, -NRl a_.C 1 6 a1kyiNRaR', -NRa-CI-6al kylOR a, -C(=0)CI-6alkyl, -C(=0)0C 1 -6aJ kyl, -OC(=O)C 1 6a1 kyl, -C(=0)NR'C 1 6alkyl or -NRaC(=0)CI.

6 alkyl; or R"1 and R 1 2 together are a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and. S with the remaining atoms being carbon, so long as the combination of 0.and S atoms is not greater than 2, wherein the each of the carbon atoms in the bridge is substituted by H, -OR Ct- 6 alkyl0Ra, Ct 6 alkyl, -NRaR,, -CI- 6 alkylN RaRa -C(=O)ORa, -C(=0)NRaRa, -CI- 3 alkylC(=0)ORa, -C 1 3 alkylC(=0)NR aR a, -OC(=0)C 1 6 alkyl, -NR aC(=0)C 1 6 alkyl, -C 1 3 alkylOC(=0)C I 6 alkyl or -C 1 3 alkyINRaC(=0)Ci 6 alkyl, and any nitrogen atoms in the bridge are substituted by H, -CI.

6 alkylOR,

-C

1 6 alkyI, -C 1 6 alkyINRaRa, alkylC(=O)ORa, -C 1 3 alkylC(=0)NRaR

-C

1 3 alkylOC(=0)C, 6 alkyl, 3 alkylNRaC(=O)C ,.6alkyl, -C(=0)Rc or 3 alkylRc; when R1 is 4-C,.

6 alkylphenyl or 2,4-dimethylphenyl, then R" is Cl-galkyl,

C,

4 haloalkyl, halo, nitro, cyano, 6 alkyl, -0-C 1 4 haloalkyl, 6 alkylNR aR', -0-Ci 6 alkylR', -0-CI- 6 alkylOR a, -0C 6 alkylCQ..0)ORa, _pNRa Ra, NRa.CI 4 haloal kyl, -NRa-C,.

6 alkylNR aR a, -NR'aC ,-salkyI0R', -C(=0)CI.

6 alkyl, -C(=0)OCI.

6 alkyl, -OC(=0)C,-6alkyl, 6 alkyl or -NRaC(=0)CI- 6 alkyl; or R1 0 and R" together are -L 3 -NRa-, respectively, or respectively; or R" and R 1 2 are -NRa-L 3 -L 3 _NRa_, -0-0i- or or R "is -NRaRb; or R 4 is lO-membered bicyclic ring comprising fused 6-membered rings, containing 0, 1, 2, 3 or 4 N atoms with the remainder being carbon atoms, 3 0 with at least one of the 6-membered rings being aromatic, wherein the carbon atoms are substituted by H, halo, OR', NRaR', CI- 6 alkyl and C,- 3 haloalkyl; and saturated carbon atoms may be additionally substituted by or R 4 is a saturated 12 or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the carbon atoms of the heterocycle and bridge are substituted by 1, 2 or 3 substituents independently selected from.

C

29 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -OR a, -S(=0)nC 1 6 alkyl, -0-Ci 4 haloalkyl, -0-C I 6 alkylNRaRa, -0-C 1 6 alkylORa, -0-C 1 6 alkylC(=0)ORa -NR aR', -NR aC -haloalkyI, -NRa-C 1 6 alkylNRaR a, -NRaC 1 6alkylORa, -C(=0)C 1 -6alkyI, -C(=0)0C 1 6 alkyl, -OC(=0)C 1 6 a1 kyl, -C(=0)NR'C 1 6alkyl and -N\RC(0O)C 6 alkyI; R'1 3 is independently, at each instance, H, Cli 9 alkyl, -CI- 3 alkyl0R',

C

1 4 haloalkyl, halo, nitro, cyano, -OR a, 1 _alkyl, -0-Cf~haloalkyl, -0-CI 6 alkylNR', -0-CI- 6 alkyl0Ra, -0-C 6 alkylC(=0)0R 3 -NRaR', _NaC Aloalkyl, -NRa-Cl.

6 alkylNRaR', -NR aC 1 6 alkylOR a, -C(=0)C,1 6 alkyl, -C(=0)0C 1 6 alkyl, -OC(=0)C 1 6 alkyl, -C(=0)NR'C -6alkyl or -NR aC(=O)C, .6a1 kyl; R' is independently, at each instance, H, Cl.

9 alkyl, -CI- 3 alkyl0Ra

C

1 4haloalkyl, halo: nitro, cyano, 1 6alkyl, -0-C 1 4 haloalkyl, -0-C 1 6 alkylNR aR a, -0-C 1 6 alkylOR a, -0-C 1 6 alkylC(=O0Ra, -NR aRat -NR aC 1 4 haloal kyl, -NR aC 1 -alkyl NR aRa, NR a_.CI 6 a1kyloR a, -C(=0)C 1 6 alkyI, -C(=0)OC I.

6 alkyl, -OC(=0)C 1 6 alkyl, -C(=0)NR'C 1 6 a1 kyl or -NRaC(=O)C 1 6 a1 kyl; Ra is independently, at each instance, H, phenyl, benzyl or C 1 -6alkyI; R b is H, C 1 6 alkyl, -C(=0)CI.

6 alkyl, CI- 6 alkyl-0-Ra; R' is phenyl substituted by 0, 1 or 2 groups selected from halo,

C

1 3 haloalkyl, -OR' and NRaRa; or R' is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, 0 and S, wherein no more than 2 of the ring members are 0 or S, wherein the heterocycle is optionally fused with a phenyl ring, and the carbon atoms of the heterocycle are substituted by 0, 1 or 2 oxo groups, wherein the 13 heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents selected from halo, C 1 3 haloalkyl, -OR' and -NR aR a; L' is a bond, -CH 2

CH

2 or -CH=CH-; e 2 is NRa, 0, -CH 2 NRa-, -CH=N- or -NRaCH 2 12 is a 2- or 3-atom, saturated or unsaturated, bridge containing 1, 2 or 3 carbon atoms and 0, 1 or 2 atoms independently selected from 0, N and S, wherein the each of the carbon atoms in the bridge is substituted by H, -OR

-C

1 6 alkylOR', -C 1 6 a1 kyl, -NRaR', -C 1 6 alkylNRaRa, -C(=O)0R 3 -C(=O)NRaRa,

-C

1 3 alkyC(0O)OR -C 1 3 a1 kylC(=O)NRaRa, .0C(=0)C 1 6 alkyl,

-NR

3 C(=0)C 1 6 a1 kyl, -C 1 3 a1 kylOC(=O)C1_6alkyl or -C 1 3 al kylNR aG(=O)Ct 1 6 a1 kyl, and any nitrogen atoms in the bridge are substituted by H, -CI- 6 alkylORa,

-C

1 .6alkyl, -C 1 _6alky1NR aR a, -CI- 3 alkylC(=O)OR a, -Cl.

13 al kyIC(=0)NR aRa,

-C

1 3 alkylOC(=0)C 1 6 alkyl, -C 1 3 a1 kylNRaC(=0)Ci 6 a1 kyl, -C(=0)Rc or

-C

1 3 alkylRc; L!i is a 2- or 3-atom, saturated or unsaturated, bridge containing 1, 2 or 3 carbon atoms and 0 or I atoms independently selected from 0, N and S, wherein at least one of the carbon atoms in the bridge is substituted by -OR',

-C

1 6 alkylOR', -C 1 6 alkyl, -NRa -C 1 6 alkylNRaR', -C(=0)OC 16 alkyI, -C(=O)NRaR a, -C 1 3 alkylC(=0)OR a, -C 1 3 alkylC(=0)NR aC 1 6 alkyl, -OC(=0)C 1 6 alkyl, -NRaC(=0)C 6 alkyI, -C 1 3 alkyIOC(=0)C 1 6 alkyI or -Ci- 3 alkylNRaC(=0)Ciralkyl, and any nitrogen atoms in the bridge are substituted by H, -CI- 6 alky10R', -CI.

6 alkyl, -Ci.

6 alky]NRaR', -Ci.- 3 alkylC(=0)0R

-CI..

3 aky1C(=0)NR aR', -C 1 3 alkylOC(=0)Ci 6 alkyl, -C 13 a1 kylNR aC(=0)Ci 6 alkyl, or -C1 -3alkylRc; X is 0, S or NR'; or X and R 2 together are =N-CH=CH-, or Y is NH or 0; and n is independently, at each instance, 0, 1 or 2; with the proviso that when R1 is 4-chlorophenyl, then R 4 is not 3-methoxyphenyl.

In another embodiment, in conjunction with the novel compound embodiments above and below, R' is -14or a naphthyl or saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the naphthyl, heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from R 5

R

6 and R 7

R

2 is H, hydroxy, halo, C 1 6 alkyl substituted by 0, 1 or 2 substituents selected from R' 0

T

(CH

2 )n 8 6 R R R7 or a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from R 5

R

6 and R 7 and

R

3 is H or Cialkyl.

In another embodiment, in conjunction with the novel compound embodiments above and below, R' is

I

In another embodiment, in conjunction with the novel compound embodiments above and below, R 7 is independently, at each instance, C 2 9 alkyl or Ci.

4 haloalkyl.

In another embodiment, in conjunction with the novel compound embodiments above and below, R' is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are 0 or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from

R

5

R

6 and R.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 2 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from

R

5

R

6 and R 7 In another embodiment, in conjunction with the novel compound embodiments above and below, R 2 is

(CH

2 )n R9 R8 R6 R7 or a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from R 5

R

6 and R 7 In another embodiment, in conjunction with the novel compound embodiments above and below, R 2 is L:

I-

16- In another embodiment, in conjunction with the novel compound embodiments above and below, R 2 is a saturated or unsaturated 5- oi 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from R' R 6 and R.

In another embodiment, in conjunction with the novel compound embodiments above and below, R' and R 2 together are 6

R

L R R( R7 In another embodiment, in conjunction with the novel compound embodiments above and below, R' and R 3 together are or

R

17 In another embodiment, in conjunction with the novel compound embodiments above and below, X and R 2 together are =N-CH=CH-, =CSor =C-NRa-.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 4 is R. b R14 R1 R 13 R b is H, C 1 6 alkyI, -C(=0)C 1 6 alkyl, Cj.

6 alkyl-0-Ra; and y 2 is or Q0- In another embodiment, in conjunction with the novel compound embodiments above and below, R 4 is 3 R 1 L 3 is a 2- or 3-atom, saturated or unsaturated, bridge containing 1, 2 or 3 carbon atoms and 0 or 1 atoms independently selected from 0, N and S, wherein the each of the carbon atoms in the bridge is substituted by H, -OR a,

-CI-

6 alkyl0Ra, -C 1 6 alkyl, -NRaR', -ClfalkylNRaR', -C(=0)0Ra, -C(=0)NRlRa,

-C

1 3 alkyIC(0O)OR a, -C 1 3 alkylC(=0)NR aR a, 0OC(0)CI.

6 alkyl, -NRaC(=0)C 1 6 alkyl, -C 1 3 a1 kylOC(=O)C 1 6 alkyI Ol- -C i 3 alkylNR aC(=0)Ci 1 6 alkyl, and any nitrogen atoms in the bridge are substituted by H, -CI.

6 alkyl0Ra,

-C

1 6 alkyl, -C 1 6 a1kyiNRaRa, -C 1 3 alkyIC(=0)OR', -C 1 3 alkylC(=0)NRaR',

-C

1 3 alkylOC(=0)C 16 alkyI, -CI- 3 alkylNR aC(=O)C i- 6 alkyI, or

-C

1 3 alkyIRc; R b is H, C 1 6 alkyI, -C(=0)C 1 6 alkyl, CI.

6 alkyI-0-Ra;, and Y is -NR or 18 In another embodiment, in conjunction with the novel compound embodiments above and below, R 4 is Rio Y2 R 14L3) R13 L 3 is a 2- or 3-atom, saturated or unsaturated, bridge containing 1, 2 or 3 carbon atoms and 0, 1 or 2 atoms independently selected from 0, N and S, wherein the each of the carbon atoms in the bridge is substituted by H, -OR a,

-CI-

6 alkyl0R', -C 1 -6alkyI, -NRaRa, -CI- 6 alky]NRaR', -C(=O)ORa -C(=O)NRaRa,

-CI-

3 alkylC(=O)0R a, -CI- 3 alkylC(=0)NRa -OC(=0)CI.

6 alkyl, -NRaC(0O)C 1- 6 alkyl, 3 alkylOC(=O)C, 4 ialkyl or -C 3 alkylNRaC(=0)C, 6 alkyl, and any nitrogen atoms in the bridge are substituted by H, -CI- 6 alkyl0R', 6 alkyl, -C 1 6 alkyINR aR a, -C 3 a1 kylC(=0)ORa, -C 3 alkylC(=0)NRaRa, 3 alkylOC(=O)C1.

6 alkyl, -C 1 3 alkylNRaC(=O)C, 6 alkyl, -C(=0)Rc or -CI-3alkyIRc; Rb is H, C,.

6 alkyl, -C(=0)CI-6alkyI, C,- 6 alky-0-Ra; and y 2 is -NR bor In another embodiment, in conjunction with the novel compound embodiments above and below, R.

4 is L3 R13 L 3 is a 2- or 3-atom, saturated or unsaturated, bridge containing 1, 2 or 3 carbon atoms and 0, 1 or 2.atoms independently selected from 0, N and S, wherein the each of the carbon atoms in the bridge is substituted by H, -O 6 alkylOR', 6 alkyI, -NRaRa, -Cl.

6 alkyINRaR',.-C(=0)0Ra, -C(=0)NRaRa, 3 alkylC(=0)0R 3 -Cl 3 alkyIC(=0)NR aR a, ,(O)I 6 alkyl, -NRaC(=0)CI 6 a~kyl, 3 al kylOC(=0)C 1 .6alkyI or 3 alkylNRaC(=0)C, 6 alkyl, 19 and any nitrogen atoms in the bridge are substituted by H, -Cli 6 alkyl0R',

-C

1 6 alkyl, -CI- 6 alkyINRaR3, -C I 3 alkylC(=0)ORa, -C 1 3 alkylC(=0)NRRa,

-C

1 3 alkylOC(=O)C 1 6 alkyI, -Cj.

3 alkylNRaC(=0)CI 6 alkyl, -C(=O)Rc or

-C

1 3 alkylRc; ~R bis H, C 1 6 alkyI, -C(=0)C 1 6 alkyl, CI-alky-O-Ra; and y2 is -NR-bor In another embodiment, in conjunction with the novel compound embodiments above and below, R 4 is R11

RR

R b is H, C 1 6 alkyI, -C(=0)CI.

6 alkyl, C 16 alkyl--R a; and y2 is -NR'-or In another embodiment, in conjunction with the novel compound embodiments above and below, R. IS lO-membered bicyclic ring comprising fused 6-membered rings, containing 0, 1, 2, 3 or 4 N atoms with the remainder being carbon atoms, with at least one of the 6-membered rings being aromatic, wherein the carbon atoms are substituted by H, halo, OR a, NaRaR Ci.

6 alkyl and

C

1 3 haloalkyl; and saturated carbon atoms may be additionally substituted by =0.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 4 is R11

R

1 13 Rio is independently, at each instance, H, Cl.

9 alkyl, -CI- 3 alky]ORa,

C

1 4 haloalkyl, halo, nitro, cyano, 1 6 alkyl, -0-C 1 4 haloalkyl, -0-C 1 6 alkylNRaR -0-C 1 6 alkylOR -0-C 1 6 alkyIC(=0)ORa NRa~ -NR aC 1 4 haloalkyl, -NRa.-C 1 6 a1kyINkRaR, -NRa-C 1 6 alkylOR', -C=)I 6 alkyl, -C(=0)0C 1 6 alkyl, -OC(=0)C I 6 alkyl, -C(=0)NR'C 1 -6alkyl or -NRaC(=0)CI-6alkyl; R1" is independently, at each instance, H, Cl-galkyl,

C

1 4 haloalkyl, halo, nitro, cyano, -S(=O)nC 1 6 alkyl, -0-C 1 4 haloalkyl, -0-C 1 6 alkylNRaRa, -0-CuIalkyRc, -0-CI- 6 alkyl0R', -0-C 1 .6akylC(=0)0R .4..lNRa aWCI- 4 haloalkyI, -NR aC 1 6 alkylNR aR a, -NR aCI 6 alkyIOR a, I~falkyl, -C(=O)0C 1 6 alkyl, -OC(=O)CI-6alkyl, -C(=O)NRaCI 1 6alkyl or -NRaC@0O)CI-alkyl;

C

1 6 al kylNRaRa; R 1 2 is independently, at each instance, H, C 1 9 alkyl, -CI- 3 alkyl0R',(

C

1 4 haloalkyl, halo, nitro, cyano, 1 (alkyl, -0-C 1 4 haloalkyl, -0-CI- 6 alkylNR3Ra, 0-CI- 6 alkylORa, O-.C 6 alkylC(=0)ORa, -N.RaRa -NRa-C 1 4 haloal kyl, -NR aC 1 6 a1kyiNRa Ra, -NR aC 1 6 al kyl OR', -C(=0)C 1 6 alkyl, -C(=0)0C 1 6 a1 kyl, -OC(=0)CI- 6 alkyl, -C(=O)NRaC 1 6 alkyl or -NR aC(O)C -alkyl; R 1 3 is independently, at each instance, H, C 1 9 galkyl, -CI- 3 alkyl0R',

C

1 4 haloalkyl, halo, nitro, cyano, -OR a, -S(=0)nC 1 6 alkyl, -O-CI.

4 haloalkyl, 6 alkylNRaRa, -O-CI- 6 alkyl0R -0-C 6 alkyIC(=0)0Ra, NWl~R.a -NR aC 1- 4 haloalkyl, -NRa-C 6 alkylNR aR', -NRa-C, 6 alkylOR a, 6 alkyl, 6 alkyl, 6 alkyl, 6 alkyI or -NRaC(=0)C, 6 a1 kyl; and( Ris independently, at each instance, H, CI- 9 alkyl, 3 alkyI0Ra

C

1 4haloalkyl, halo, nitro, cyano, -S(=0)nCI- 6 alkyl, 4 haloalkyl, -0-C 1 6alkylNR aR', -0-C 6 alkylOR a, -0-C 6 alkyl C(=0)OR a, NR aR', -NR aC 1-haloalkyl, -NRa-C, .6alkyl NRa Ra, -NR aC, 6 alkyIOR', -C(=0)CI-6alkyl, 6 a1 kyl, -OC(=0)C 6 alkyl, 6 alkyl or -NRaC(=0)C,-6alkyl; wherein one of R1 0 and R 1 2 is not H.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 4 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, 0 and S, wherein no more than 2 of the ring members are 0 or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused -21phenyl ring is substituted by 0, 1, 2 or 3 substituents selected from halo, Ci4haloalkyi, -ORa and -NRaR'.

Another aspect of the invention relates to a compound having the structure:

R

9

H

R1R4

R

1

R

16 or any pharmaceutically-acceptable salt thereof, wherein: n is independently, at each instance, 0, 1 or 2.

R' is

R

6 R

R

9 8 or R' is a naphthyl substituted by 0, 1, 2 or 3 substituents independently selected from Rs; or R' is Re substituted by 1, 2 or 3 substituents independently selected from R 5

R

1 5 is, independently, in each instance, R' 1 Ci.galkyl substituted by 0, 1 or 2 substituents selected from R'O, -(CH 2 ),phenyl substituted by 0, 1, 2 or 3 substituents independently selected from R 0 i, or a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from R' 0

R'

6 is, independently, in each instance, H, halo, -NH 2 -NHCi.

3 alkyl, -N(Ci.

3 alkyl)Ci.

3 alkyl or CI.3alkyl; 22 R 4 is 141 R ;or R 4 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining a tomns being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the carbon atoms of the heterocycle and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from Cl- 9 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, oxo, -OR -S(O)WI.

6 alkyI, -OCI.-shaloalkyl, -OC 2 6 alkylNR Rd, -OC 2 .6alkylOR

-OCI

1 6 alkylC(=O)OR d, -NR dR d, -NRd CI4haloalkyl, -N 26lyN Rd -NR dC 2 6 alkylORd, 16 alky1, -C(=0)OC I.-alkyl, -OC(=O)C 1 6 alkyl, -C(=O)NR dCi.- 6 alky1 and -NR dC(=0)CI- 6 alkyl; and saturated carbon atoms may be additionally substituted by and any nitrogen at oms in the bridge are substituted by H, -CI- 6 alky]OR d, -C 1 6 alkyl, -CI' 6 alkylNRdR d' -C I.

3 alkylC(=0)ORd, -CI 3 alkylC(=O)NRdRd, 1 3 a1kylOC(=O)C 1 6 alkyl,

-CI.

3 alkylNR C(=O)C 1 6 alkyl, -C(=O)Rf or -C 1 3 al kylRf; or R. is lO-membered( bicyclic ring comprising fused 6-membered rings, containing 0, 1, 2, 3 or 4 N atoms with the remainder being carbon atom s, with at least one of the 6-membered rings being aromatic, wherein the carbon atoms are substituted by H, halo, ORU,' NRd R d C 6 al ky'l and C1 3 haloalkyl;, a nd Isaturated carbon at oms may be additionally substituted by but in no inst ance i s R 4 3, ditri fILoromethylphenyl or 3'-trifludromethyl-4-fluorophen yl;

R

5 is independently, at each instance, H, CI-5alkyl, C 14 haloailkyl halo, nitro, cyano, -OCI 1 6 alkyl, -OC 14 haloalkyl, -OC 2 6 alkyiNR CO 2 6 alky]ORd -NRdR', -,~ihaloalkyl, -NR C 2 6 alkylNRd -NRdC 2 6 alkylOR, n'aphthyl, -C0 2 (CI-6alkyl), 1 ~raIkyl), _C(=O)NRd Rd, _NdC(=O)R d _NRdC(=O)NRd R d -NR dCO 2

(C

1 6 alkyl), -C 1 salkylOR d' -C 1 6 a1 kylNR dR d' 23 -S 1 6 a1kyl), 2 NRdRd, -NR dS(=O) 2

(C

1 6 alkyI), _OC(=O)NRd R d, a phenyl ring substituted with 0, 1, 2, or 3 substituents independently selected from R1;or R 5 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from 0, N and S, substituted. with 0, 1, 2, or 3 substituents independently selected from R1 0 R 6is independently, at each instance, H, CI.

5 alkyl, Cl-4haloalkyl, halo, -0C 1 6 alkyl, -0CI 4 haloalkyl, -OC,-,alkylNR -OC 2 -6alkyl0R d, _d R d -NR dCj 4 haloal kyl, _N1Rd C 2 6 alkylNRd Rd or -NR dC 2 -6alkyl0R d ,-C 1 8 al ky]ORd,

-CI-

6 alkylNRd R d -S(CI.

6 alkyl), a phenyl ring substituted with 1, 2, or 3 substituents independently selected from R 10 or R 6 is a saturated or unsaturated or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from 0, N and S substituted with 0, 1, 2, or 3 substituents independently selected from R1 0 R 7 is independently, at each instance, 8 alkyl, Cl4haloalkyl, dd d d -NRd R d, -NRdCl~haloalkyl, -NR dC 26 alkylNR dR d, -NR dC 2 alkylOR d -CisgalkylOR d, -C 1 6 alkylNR dR dor -S(C 1 6 alkyl); or R 7is a saturated or unsaturated 4- or 5-membered ring heterocycle containing a single nitrogen atom, wherein the ring is substituted with 0, 1 or 2 substituents independently selected from halo, C 1 2 haloalkyl and C 1 3 alkyl; R 8 is independently, at each instance, H, C 1 5 alkyI, C 1 4 haloalkyl, halo, -0C 1 6 alkyl, -0C 1 4 hal oalkyl, -0C 2 6 alkylNRd R d -0C 2 6 a1 kylOR d, _NR d R d -NR dCi .haloalkyl, -NR dC 26 alkylNR R d, -NR dC 2 6 alkylOR d, -CI-alkyl0R d' -C.,alkylNR dRd, -S(C 1 6 alkyl), a phenyl ring substituted with 1, 2, or 3 substituents independently selected from R' 0 or R 8 is a saturated or unsaturated or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from 0, N and S substituted with 0, 1, 2, or 3 substituents independently selected, from R' 0.

R

9 is independently, at each instance, H, C 1 .galkyI, C 1 4 haloalkyl, dd

-OC

2 6 alkyl0R d' -NR dR d, -NR dCi.

4 haloalkyl, -NR dC 2 6 alkylN d R d or -NR C 2 -6alkyl0R -C0 2

(CI-

6 alkyl), -C(=0)(C-ralkyl), -C(=0)NRdRd, _NdC(=O)(C 1 6 alkyl), -NR dC(=0)NR dRd, _.NRdC0 2

(C

1 6 alkyl), d, -C 1 6 alkylNR dRd, -S(=0)n(C 1 6 alkyl), 2 NR dR d' 24- _Nd(02CI6ly) -OC(=O)NR dR d, a phenyl ring substituted with 0, 1, 2, or 3 substituents independently selected from R1 0 or R 9 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from 0, N and S substituted with 0, 1, 2, or 3 substituents independently selected from R 1 0 or R 9 is a saturated or unsaturated 4- or ring heterocycle containing a single nitrogen atom, wherein the ring is substituted with 0, 1 or 2 substituents independently selected from halo, C 12 haloalkyl and C 1 3 alkyl; wherein at least one of R 5 R R

R

8 and R 9 is C 1 8 alkyl, Cg..

4 haloalkyl, halo, -0CI.

4 haloalkyl,

-OC

24 6alkylNRd Rd, -OC 2 _6alkyl0R d, -NR dC, 4 haloalkyl,( -NR dC ,alkylNRd Rd, -NR dC 2 ,al kylOR', -C 1 salkyIOR d, -C 1 6 alkylNR dRd or -S (CI 6 al kyl);

R'

0 is independently, at each instance, selected from H, CI.salkyl, C, 4 haloalkyl, halo, cyano, nitro, ,salkyl), 1 s8alkyl), _C(=O)NRdRd, -C(=NR d)NR dR d, -OR d, OC(=O)(C 1 .8alkyl), _OC(=O)NRd Rd, -OC(=0)N(R d)S 2 (CI-8alkyl), -0C 2 6 alkylNRd Rd, -0C 2 6 alkyl0R d, -SR d 1 .salkyl), 2 8 alkyl), 2 NR dRd, -S 2 N(R -ga1kyl), 2 N(R d)C(=0)O(C 1 8 alkyI), -S 2 N(R d)C(=0)NR dR d, .pRd Rd, -N(R d)C(=0)(Cl galkyl), -N(R d)C(=O)0(C 1.alkyl), -N(R d)C(=0)NR dR d, -N(R d)C(=NR d)NR dR d, -N(R d)S 2 (CI galkyl), -N(R d)S(=O) 2 NR dR d, _NRd C 26 alkylNR dR d and -NR dC 2 6 alkyl0R d; or Rio is a saturated or unsaturated 6- or 7-membered monocyclic or 10- or I 1-membered bicyclic ring containing 2 or 3 atoms selected from N, 0 and S, wherein the ring is fused with 0 or 1 benzo groups and 0 or I saturated or unsaturated 6- or 7-membered heterocyclic ring containing 1, 2 or 3 atoms selected from N, 0 and S; wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 groups selected from C,.

8 alkyl, C,- 4 haloalkyl, halo, cyano, nitro, -C(=0)(C,.salkyI), -C(=0)0(C,.salkyl), -C(=0)NR dR" d C(=NRd)NR"R', -OR', 8 alkyI), -OC(=0)NR dR d, -OC(=0)N(R d)S(=0) 2 (C,.salkyl), -0C 26 alkylNRd R d, -0C 2 6 alkyl*OR d, -SR d, 8 alkyl), 2 (Cl.8alkyl), 2 NRdR 2 N(R 1 8 alkyl), 2 N(R d)C(=0)O(C 1 .salkyl), 25 2 N(R d)C(=O)NR -NR -N(R d)C(=O)(Cis-alkyl), n N(R )(=)OCialkyl), -N(R R N(Rd)(NdNdd -N(R 2 (CI-8alkyl), -N(Rd)S(=O) 2 NR R, ~C 2 -alkylNRRd and -NR dC 2 -6alky]ORd; or R 10 is C 14 alkyI substituted by 0, 1, 2 or 3 groups selected from CI- 4 haloalkyl, halo, cyano, nitro, 1 8 alkyl), -C(=O)O(C 1 -8alkyl), -C(0O)NR dR d, -C(=NR d)NR'dd, -OC(0)(C.salkyl), _OC(=O)NR dR d, d)S 2 galkyl), -0C 2 6 alkylNR dR d, -OC 2 _6alkylOR d, -SR d, -S(=O)(CI-8alkyI), 2 (CI~galkyl), 2 NR R d, 2 N(R d)C(=O)(CI .Ba1 kyl), -S 2 N(R 1 8 a1 kyl), 2 N(R d)C(=O)NR dR', -NRd R d, -N(R 8 alkyl), -N(R 1galkyI), -N(R d)C(=O)NRd -N(ROC=RdNdRd -N(R d)S 2 salkyl), -N(R d)S 2 NR R d, d C 2 6 alkyINd Rd and -NR dC2_alkylOR. d R"1 is independently, at each instance, selected from H, C,.

8 alkyl,

C,.

4 haloalkyl, halo, cyano, nitro, 8 alkyl), -C(=O)O(Cl.8alkyl), d d d d d d d -C(=O)NR R -C(=NR )NR R -OR -OC(=O)(Cj_8alkyl), -OC(=O)NR R -OC(=O)N(R d)S 2 (C,.salkyl), -OC 26 alkylNRd R d, OC 2 -641kylOR d, -SR d, -S 2 N(R 1 -8aIkyl), -S 2 alkyl), 2 N(R d)C(=O)NR R d, -NR dR d, -N(R d)C(=O)(C 1 .s8alkyI), -N(R 1 8 alkyI), -N(R d)C(=O)NRd .NRd)NR dR d, K-N(R d)S(=O) 2 (C,.galkyl), -N(R d)S(=0) 2 NR dR d, _d C 26 alkyNR dR d and -NR dC 2 -6alkylOR d; or R" ,is a saturated or unsaturated 6- or 7-membered mon-ocyclic or 10- or Il1-membered bicyclic ring containing 1, 2 or 3 atoms selected from N, 0 and S, wherein the ring is fused with 0 or 1 benzo groups and 0 or I saturated or unsaturated 6- or 7-membered heterocyclic ring containing 1, 2 or 3 atoms selected from N, 0 and S; wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ling is substituted by 0, 1, 2 or 3 groups selected from CI-8alkyl, C,- 4 haloalkyl, halo, cyano, nitro, -C(=O)(Cl.8alkyl), -C(=O)O(Cj.Balkyl), -C(=O)NR dR d, -C(=NR)NR R" d, OR', -OC(=O)(Cj~galkyl), -OC(=O)NRd R d, -OC(=O)N(R d)S 2

(C

1 .salkyl),

-OC

2 6 alky]NRiR, -0C 2 6 a1 kylOR d, -SR d, salkyl), 2

(C

1 salkyl), -26 -S(=0),NRdRd, 2 N(R 1 al kyl), 2 N(R d)C(=0)0(C 1 -ga1kyl), S(=0) 2 N(R d)C(0)NR dRd, _NIRd R d -N(R d)C(0O)(C 1 -8alkyl), -N(R d)C(=0)0(C 1-galkyI), -N(R d)C(=O)NRd Rd, -N(Rd)C(=NRd)NR dR', -N(R d)S 2 (CI-8alkyl), -N(R d)S 2 NR dR d, _d C 2 -,alky]NR dR d and -NR d CalkyI0R d; or R" is C 1 4 alkyl substituted by 0, 1, 2 or 3 groups selected from C 1 4 haloalkyl, halo, cyano,*nitro, -C(=0)(CI-8alkyl), -C(=0)O(Cj~galkyl), _C(=O)NRd Rd, -C(=NR d)Nd R d -ORd, -OC(=0)(C 1 .salkyl), -OC(=0)NRd Rd, -OC(=0)N(R d)S(=0) 2 (Ct salkyl), -OC 2 6 alkylNRd Rd, -0C 2 6al kyloR d, -SR d -S(=O)(CI-8alkyI), 2

(C

1 .salkyl), 2 NR R d -S 2 N(RdC=(C 8 akyI), -S 2 N(Rd)C(=0)0(C 1 salkyl),( 2 N(R d)C(=O)NRd Rd, -NRd R d, _N(R d)C(=O)(C'i..salkyl), -N(R d)C(=0)0(C 1 8 alkyl), N(R d)C(=0)NRd Rd, -N(R d)C(=NR d)NRd Rd, -N(R d)S(=O) 2

(C

1 8 alkyl), 2 NR dR d, _d C 2 -,alkylNRd Rd and -NR dC 2 6 alkylOR d; or Ro and R" together are a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the each of the carbon atoms in the bridge is substituted by H, C 1 galkyl, C 1 4 haloalkyl, halo, cyano, nitro, -C(=0)(Cjgalkyl), -C(=0)0(C 1 8 alkyl), -C(=0)NR dR d, _C(=NRd)NRd Rd, -OC(=0)(C 1 .galkyl), -OC(=O)NRd R d, -OC(=0)N(R d)S(=0) 2 (CI-8alkyl), -0C 2 6 alkylNR dR d,

-OC

2 6 alkyIOR -SRd 1 8 alkyl), S(=0) 2 (Cl 8 alkyl), 2 NRdRd, 2 N(R galkyl), -S 2 N(R d)C(=0)O(C 1 8 alkyl), 2 N(R d)C(=O)NRd R d -N(R 1 8 a1 kyl), -N(R d)C(=0)O(CI -8alky1), -N(R d)C(=O)NRd R d, -N(R d)C(=NR d)NR dR d, -N(R d)S 2 (CI-8a]kyl), -N(R d)S 2 NRd R d, NR C 26 alky]NR d Rd and -NR dC 2 6 alky0R d and any nitrogen atoms in the bridge are substituted by H, d~ dd

-C

1 6 alkyl0R -C 2 6 alkyl, -Cj ralkylNRdR -C 1 3 alkylC(=0)ORd,

-C

1 3 al kylC(=0)NR dR d, -C 2 3 alkylOC(=O)C 1 6 aIkyl, -C 2 3 alky1Nk dC(=0)C i-alkyl, -C(=)Rfor -C 1 3 alkylRf; R 1 2 is independently, at each instance, selected from H, C-8alkyl,

C

2 4 haloal kyl, halo, cyano, nitro, 1 salkyl), -C(=0)0(C 1 8 alkyl), _C(=O)NRd Rd, _C(=NRd)NRd Rd, -OR d, .galkyl), -OC(=O)NR dRd, 27 -OC(=O)N(R d)S(=O) 2 (CI 8 a1kyl), -0C 26 al kylNR dR d, -OC 2 .4al kylOR d, -SR' d d -S(=O)(Cj 1 8 alkyl), 2 (CI-8alkyl), 2 NR R 2 N(R d)C(=O)(Ci .salkyl), 2 N(R d)C(=O)O(C 1 .alkyI), 2 N(R d)C(=O)NRd R d, -NRd R d' N(R 1-alkyl), -N(R d)C(=O)O(Ci -8alkyl), -N(R d)C(=O)NRd R d -N(R d)C(=NR d)NR dR d, -N(R d)S(=O) 2 (Cis8alkyI), N(R d)S (0) 2 NRd R d _NRd C 26 alkylNR dR d and _NRdGC 2 6 alkylOR d; or R1 2 is a saturated or unsaturated 6- or 7-membered monocyclic or 10- or IlI-membered bicyclic ring containing 1, 2 or 3 atoms selected from N, 0 and S, wherein the ring is fused with 0 or 1 benzo groups and 0 or 1 saturated or unsaturated 6- or 7-membered heterocyclic ring containing 1, 2 or 3 atoms selected from N, 0 and S; wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 groups selected from CI-8alkyl, C,- 4 haloalkyl, halo, cyano, nitro, 1 8 alkyl), 18 alky1), _C(=O)NRd R d, C(=NR d)NRdR d' -OR d,

-OC(=O)(C

1 8 alkyl), -OC(=0)NR dR', 0OC(=O)N(R d)S(=0) 2

(C

1 8 alkyl),

-OC

2 -,alkyINR R d, -OC 2 6 alkylOR d' 1 8 galkyI), 2 (CI-8alkyl), -S 2 NR dR' -S 2 N(R 1 8 alkyl), -S 2 N(R d)C(=O)O(C 1 -8al kyl), 2 N(R d)C(=O)NR -NR dR d, -N(R d)C(=O)(Gl aalkyl), d)C=OO(C dC()Nd d R) dd -N(Rd)(=)OCialkyl), -N(R )C=ON R -N ~NR (=NR ~NR R, -N(R d)S(=0) 2

(C

1 8 a1 kyl), -N(R d)S(=O) 2 NRd R d _d C 2 6 aI kylRpd R d and -NR C26alylO d;orR 1 2 is C 1 4 alkyl substituted by 0, 1, 2 or 3 groups selected from Ci.4shaloalkyl, halo, cyano, nitro, -C(=O)(CI-8alkyl), -C(=O)O(C 1 8 alkyl), -C(=O)NRd R d, -C(=NRd )NR dR d, -OR d, -OC(=O)(CI.8alkyI), -OC(=O)NR dRd -OC(=O)N(R d)S 2

(CI-

8 alkyl), -OC 2 6 alky]NR dR d, -OC 2 -6alky1OR d, -SR d 18 galkyl), 2 (C,.salkyl), 2 NRd R d 2 N(R d 1 8 alkyl), 2 N(R d)C(=O)O(C 1galky1), -S 2 N(R d)C(=O)NRd R d -NR dR d' -N(R d)C(=O)(C 1 8 a1 kyl), -N(R d)C(=0)O(C 1 .salkyl), -N(R d)C(=0)NR dR d, -N(R)C=NR d)NR dR d' -N(R )S 2

(C

1 8 a1 kyl), -N(R d)S 2 NR dR d, _NRd C 26 alkyI NR dR d and -NR dC 26 alkylOR d; wherein if R"1 or R 1 3 is CF 3 then R 1 2 is not F; or R" and R 1 2 together are a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long 28 as the combination of 0 and S atoms is not greater than 2, wherein the each of the carbon atoms in the bridge is substituted by H, Ci.galkyl, Ci.

4 haloalkyl, halo, cyano, nitro, 1 8 alkyI), -C(=O)O(C 1 .galkyl), _C(=0)NR dR d, -C(=NRd)NRdR d, -OR d, -OC 1 8 alkyl), _OC(=O)NRd R d -OC(=O)N(Rd)S=O) 2 (Cl-galkyl), -OC,,alkyINRdRd ,O26lyO -SR, d d 8 alkyl), 2

(C

1 8 alkyl), 2 N R 2 N(R)C0(C 1 8 alkyl), -S 2 N(Rd)(OOC 8 alkyl), ~S(O)N(d)C(=0)NRd d, ._dRd dN(Rd)C(=0)(C lky N(R d)C(=0)0(C 1 .8alkyI), -N(R d)C(=O)NRR, d' N(R d)C(=NR d)NR dR d, -N(R d)S 2 (CI-8alkyI), -N(Rd)S(=O) 2 NRd Rd, _NdCakyN and( -Nd C 2 -talkyl0R d ,and any nitrogen atoms in the bridge are substituted by H,

-C

1 6 alky1OR -C 1 6 alkyI, -C I 6 alkylNRdRd, -Cl 3 alkylC(=0)ORd -C i- 3 alkylC(=O)NR dR d, -C 1 3 alkylOC(=0)C 1 6 alkyl, -C 1 3 alkylNR dC(=O)C 1-alkyl, for -C 1 3 alkylR f; R'1 3 is independently, at each instance, selected from H, C 1 .8alkyl,

C

1 4haloalkyl, halo, cyano, nitro, 1 salkyl), -C(=0)0(C 1 8 alkyl), -C(=O)NR dR d, _C(=NRd)NRd R d, -OR d, -OC(=O)(Cj_8alkyl), -OC(=O)NR dRd -OC(=0)N(R d)S 2

(C

1 galkyl), -OC 2 6 al kylNRd R d, -OC 2 6 alkylOR d, -SR d, 1 8 alkyl), 2

(C

1 8 alkyl), 2 NRd R d, -S 2 N(R d)C(=O)(CI 1-alkyl), -S 2 N(R d)C(=0)0(C 1 8 a1kyl), 2 N(R d)C(=0)NRd R d, -NRd R d, -N(R 1-alkyl), -N(R 8 -alkyl); -N(R d)C(=0)NRd R d' N(R d)C(=NRd)NRd Rd, -N(R d)S 2 (CI-8alkyl), 7N(R d)S(=0) 2 NR dR d, _NRd C 26 a~kylNR dR d and -NR dC 2 .alkyl0R d; or R 1 3 is a saturated or unsaturated 6- or 7-membered monocyclic or 10- or 1 1-membered bicyclic ring containing 1, 2 or 3 atoms selected from N, 0 and S, wherein the ing is fused with 0 or 1 benzo groups and 0 or 1 saturated or unsaturated 6- or 7-membered heterocyclic ring containing 1, 2 or 3 atoms selected from N, 0 and 5; wherein the carbon atoms of the ing are substituted by 0, 1 or 2 oxo groups, wherein the ing is substituted by 0, 1, 2 or 3 groups selected from C 1 .8alkyI, C 1 4 haloalkyl, halo, cyano, nitro, 1 8 a1 kyl), -C(=0)O(C 1 8 a1 kyl), -C(=O)NR dR', -C(=NR d)NRd R d -OR d,

-OC(=O)(C

1 8 alkyl), -OC(=0)NR RdOC0NR) 2

(C

1 8 a1 kyl), 29

-OC

2 6 a1 kylNR dR d, -OC 2 _ralkylOR.d, -S 1 .galkyl), -s 2

(C

1 8 alkyl), d d 2 NR R d, 2 N(R 1 -8alkyl), 2 N(R d)C(=O)O(C 1 .alkyl), (Rd)Cd d d, )(O 0S=) 2 N(R)(=O)NR R ,-NR R. N(Rd)C=O(C 8 alkyl), -N(R d)C(=O)O(C 1 .salkyI), -N(R d)C(=O)NRd Rd, -N(R d)C(=NRd )NR dR d, -N(R d)S(=O) 2 (Cjisalkyl), -N(R d)S(=O),NR dR d, _d C 2 -6alkylNR dR d and -RdC 2 _6alkylOR d; or 3is CI-4alkyl substituted by 0, 1, 2 or 3 groups selected from C 14 haloalkyl, halo, cyano, nitro, 1 8 alkyl), -C(=O)O(C 1 galkyl), _C(=O)NRd Rd, -C(=NR d)NRd R d, -OC(=O)(C,.salkyl), -OC(=O)NR dRd, -OC(O)NR dS(=)2(j~glky), OC 2 6 alkylNR dR d, -OC 2 -6alkyIOR d -SR d, 1 .salkyI), 2

(C

1 8 alkyI), 2 NRdR -S 2 N(R 1 8 alkyl), 2 N(R d)C(=O)O(C 1.8alkyl), 2 N(Rd)C(=O)NRd Rd, -NRd R d, -N(R 1.salkyl), -N(R d)S(=O) 2

(C

1 8 a1 kyl), -N(R d)S(=O) 2 NR dR d, _NRd C 26 al kylNR dR d and -NR dC 26 alky1ORd; R 1 4 is independently, at each instance, selected from H, CI-8alkyl,

C

1 4haloalkyl, halo, cyano, nitro, -C(=O)(Cj~galkyl), -C(=O)O(C 1 .salkyl), _C(=O)NRd Rd, _C(=NRd)NRd R d, -OR d, -OC(=O)(CI-8alkyl), -OC(=O)NR dRd, -OC(=O)N(Rd)S(=O) 2

(CI-

8 alkyl), -OC 2 6 alklN R OC 2 6alkyIORd, -SR', 8 alkyl), 2

(C

1 8 alkyl), 2 NR R d 2 N(R d)C(=O)(Ci 8 a1 kyl), 2 N(R d)C(=O)O(C 1 8 a1 kyl), 2 N(R d)C(=O)NRd Rd, Nd R d, -N(R 1-8alky1), -N(R d)C(=O)O(C i.salkyl), -N(R d)C(=O)NRdR d, -N(R d)C(=NRd)NR dR d, -N(Rd)S 2

(C

1 8 a1 kyl), -N(R d)S(=O) 2 NR dR d, Pd C 2 _6alkyINR dR d and -NR dC 2 6 alky]OR d; orR 1 4 is a saturated or unsaturated 6- or 7-membered monocyclic or 10- or IlI-membered bicyclic ring containing 1, 2 or 3 atoms selected from N, 0 and S, wherein the ring is fused with 0 or 1 benzo groups and 0 or I saturated or unsaturated 6- or 7-membered heterocyclic ring containing 1, 2 or 3 atoms selected from N, 0 and S; wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 groups selected from C 1 s8alkyl, C 1 4 haloalkyl, halo, cyano, nitro, 1 8 alkyl), -C(=O)O(CI-8alkyl), -C(=O)NR Rd, -C(=NRd )NRdRd, -ORd, -OC(=O)(Cj 18 alkyl), -OC(=O)NRdR', -OC(=O)N(Rd)S 2

(C

1 salkyl),

-OC

2 6 alkyINR dR d, -OC 2 -6al kylORd, -SR Rd, 1 salkyI), 2 (C 1 alkyI), 2 NRdR d, 2 N(R 1-8alkyl), 2 N(R d)C(=O)O(C 1 8 a1 kyl),

-S(O)

2 N(R d)C(=O)NRd R d _NRd R d -N(R 1- 8 alkyl), -N(R d)C(=O)O(CI -aI kyl), -N(R d)C(=O)NRd R d, N(R d)C(=NR d)NRd R d -N(R d)S(=O) 2 (CI-8alkyl), -N(R d)S(=O) 2 NRd R d NdC 2 6 alkyld R d and -NR dC 2 6alkylOR d; or R 1 4 is C 1 4 alkyl substituted by 0, 1, 2 or 3 groups selected from C 1 4 haloalkyl, halo, cyano, nitro, 1 .salkyl), -C(=O)O(C 1 8 aI kyl), -C(=O)NR dR d, -C(=NR d)lRd R d -OR d -OC(=O)(CI-8alkyl), -OC(=O)NRd Rd -OC(=O)N(R d)S(=O) 2 (Ci 8 a1 kyl), -0C 2 6 a1 ky]NR dRd, -OC2-6al kylOR d -SR d -S(=O)(CI-8alkyl), 2

(C

1 .salkyI), 2 NR R d 2 N(R i-galkyl), -S(=O)2N(R .Salkyl), 2 N(Rd)C(=O)NR d Rd _N~dRd' -N(R)C(=O)(CisalkyI), -N(R d)C(=O)O(C 1-alkyI), -N(R d)C(=O)NR dR d, -N(Rd)C(=NR d)NR dRd -N(R d)S 2

(C

1 salkyI), -N(R d)S 2 NRd R d ._N~1dC 2 6 alkyNR d Rd and -NR dC 2 6 alky1OR d; R d is independently, at each instance, H, phenyl, benzyl or C 1 6 alkyI; R' is a heterocycle selected from the group of thiophene, pyrrole, 1 ,3-oxazole, I ,3-thiazole, I ,3,4-oxadiazole, 1,3 ,4-thiadiazole, I ,2,3-oxadiazole, 1 ,2,3-thiadi azole, 111-1 ,2,3-tfiazole, isothiazole, 1 ,2,4-oxadiazole, 1,2,4thiadiazole, 1 ,2,3,4-oxatriazole, 1 ,2,3,4-thiatriazole, IH- 1,2,3 ,4-tetraazole, I ,2,3,5-oxatriazole, I ,2,3,5-thiatriazole, furan, i midazol- l-yl, imidazol-4-yl, 1,2,4triazol-4-yI, 1 ,2,4-triazol-5-yi, isoxazol-3-yl, isoxazol-5-yi, pyrazol-3-yl, pyrazolthiolane, pyrrolidirie, tetrahydrofuran, 4,5-dihydrothiophene, 2-pyrroline, 4,5-di hydrofuran, pyridazine, pyrimidi ne, pyrazine, I ,2,3-triazine, I ,2,4-tfi azine, I ,2,4-tiazine, 1 ,3,5-triazine, pyridine, 2H-3,4,5 ,6-tetrahydropyran, thiane, 1,2di azaperhydroine, I ,3-diazaperhydroine, piperazine, 1 ,3-oxazaperhydroine, morpholine, 1 ,3-thiazaperhydroine, 1 ,4-thiazaperhydroine, pi peridine, 2H-3,4dihydropyran, 2,3-dihydro-4H-thiin, I ,4,5,6-tetrahydropyridine, 2H-5,6- 3 0 dihydropyran, 2,3-di hydro-6H-thi in, 1 ,2,5,6-tetrahydropyridine, 3,4,5,6tetrahydropyridine, 4H-pyran, 4H-thin, I ,4-dh ydropyridine, I ,4-dithiane, 1,4dioxane, I ,4-oxathiane, I ,2-oxazoli dine, 1 ,2-thiazolidine, pyrazolidine, 1,3- -31 oxazolidine, 1 ,3-thiazolidirie, imidazolidine, I ,2,4-oxadiazolidine, 1,3,4oxadi azolidine, 1 ,2,4-thiadiazol idine, I ,3,4-thiadiazolidine, 1 ,2,4-triazolidine, 2imidazoline, 3-i midazoline, 2-pyrazoline, 4-imidazoline, 2,3-dihydroisothiazole, 4,5-dihydroisothiazole, 2,5-dihydroisoxazole, dihydroisothiazole, 2,3-dihydroisoxazole, 4,5-dihydrooxazole, 2,3dihydrooxazole, 2,5-dihydrooxazole, 4,5-dihydrothiazole, 2,3-dihydrothiazole,, 1,3 ,4-oxathi azolIi dine, I ,4,2-oxathi azol idine, 2,3-dihydro- IH- [1,2,3]triazole, 2,5-dihydro- IH-[1,2,3jtriazole, 4,5-dihydro- IH-[1,2,3]triazole, 2,3-dihydro- IH-[1I,2,4]triazole, 4,5-dihydro- 1H-[1I,2,4jtriazole, 2,3-dihydro- [1,2,4]oxadiazole, 2,5-dihydro-[ 1,2,4]oxadiazole, 4,5-dihydro-[ I 2,4]thiadiazole, 2,3-dihydro-[ 1,2,4] thidiazole, 2,5-dihydro-[ 1,2,4] thiadiazole, 4,5-dihydro-[ 1,2,4] thi adiazole, 2,5-dihydro-[ 1,2,4loxadi azole, 2,3-dihydro-[1I,2,4]oxadi azole, dihydro-Ii1,2,4]oxadiazole, 2,5-dihydro-[1 ,2,4]thiadiazole, 2,3-dihydro-I1,2,4] thiadiazole, 4,5-dihydro-E 1,2,41 thiadiazole, 2,3-dihydro-[1I,3,4]oxadiazole, 2,3dihydro-[1,3,4]thiadiazole, [1,4,2]oxathiazole, [l,3,4]oxathiazole, 1,3,5triazaperhydroi ne, I ,2,4-triazaperhydroine, 1 ,4,2-dithiazaperhydroine, 1,4,2dioxazaperhydroine, 1 ,3,5-oxadi azaperhydroine, I I ,3,4-thiadiazaperhydroine, 1 ,3,5-thiadiazaperhydroine, 1,2,5thi adiazaperhydroine, 1,3 ,4-oxadi azaperhydroi ne, 1 ,4,3-oxathi azaperhydroi ne, 1 ,4,2-oxathiazaperhydroine, 1 ,4,5,6-tetrahydropyridazine, 1,2,3,4tetrahydropynidazi ne, 1,2,3 ,6-tetrahydropyri dazine, 1,2,5 ,6-tetrah ydropyri midine, 1 ,2,3,4-tetrahydropyri midine, I ,4,5,6-tetrahydropyri midine, 1,2,3,6tetrahydropyrazine, 1 ,2,3,4-tetrahydropyrazine, 5,6-dihydro-4H-[1I,2]oxazine, 5,6di hydro-2H- [1 ,2]oxazine, 3,6-dihydro-2H-[ 1,2]oxazine, 3 ,4-dihydro-2H- [1 ,2]oxazine, 5,6-dihydro-4H-[ 1,2jthiazine, 5,6-dihydro-2H- thi azine, 3,6di hydro-2H-[ 1,2] thiazine, 3,,4-dihydro-2H-[ 1,21 thiazine, 5,67dihydro-2H- [1,3]oxazine, 5,6-dihydro-4H-i1 ,3]oxazine, 3,6-dihydro-2H-[1I,3]oxazine, 3,4dihydro-2H-[ 1,3]oxazine, 3,6-dihydro-2H-[ 1,4loxazine, 3 ,4-di hydro-2H- [1 ,4]oxazine, 5,6-dihydro-2H-[ 1,3]thiazine, 5,6-dihydro-4H-[ 1,3]thiazine, 3,6dihydro-2H- 1 ,3]thiazi ne, 3 ,4-dihydro-2H--[ 1,3]thi azine, 3,6-di hydro-2H- [1 ,4]thiazine, 3,4-di hydro-2H-[ 1,4]thi azine, 1,2,3 ,6-tetrah ydro-[.i,2,4]triazine, 1 ,2,3,4-tetrahydro-[ 1,2,4]triazine, I ,2,3,4-tetrahydro-[ 1,3 ,5]triazine, 2,3,4,5- Lf 32 tetrah ydro-[ 1,2,4]tri azine, 1 ,4,5,6-tetrahydro- tri azine, 5 ,6-di hydro- [1 ,4,2]dioxAzine, 5,6-dihydro-[ 1,4,2]dioxazine, 5,6-dihydro-[1I,4,2]dithiazine, 2,3di hydro- [1 ,4,2]dioxazine, 3,4-dihydro-2H-[ 1,3 ,4]oxadi azi ne, 3 ,6-di hydro-211- [1 ,3,4loxadiazine, 3,4-dihydro-211-[1I,3,5]oxadiazine, 3,6-dihydro-2- [1 ,3,Sloxadiazine, 5,6-dihydro-211-[1I,2,5]oxadiazine, 5,6-dihydro-4H- [1 ,2,5]oxadiazine, 3,4-dihydro-2H-[ 1,3,4]thiadiazine, 3,6-dihydro-211- [1 ,3,4]thiadiazine, 3 ,4-dihydro-2H1[I,3,5]thiadiazine, 3,6-dihydro-2H- [1 ,3,5]thi adiazine, 5,6-dihydro-2H-[ 1,2,5]thiadiazine, 5 ,6-dihydro-4H- [1 ,2,5]thiadiazine, 5,6-dihydro-2H-[ 1,2,3]oxadiazine, 3,6-dihydro-2H- [1 ,2,5]oxadiazine, 5 ,6-dihydro-4H-[1I,3,4iloxadiazine, 3,4-dihydro-211- [1 ,2,5]oxadiazine, 5,6-dihydro-2H-[ 1,2,3]thiadiazine, 3,6-dihydro-2H-C- [1 ,2,5]thi adiazine, 5,6-dihydro-4H-[1I,3,4]thiadiazine, 3 ,4-dihydro-2H- [1 ,2,5]thiadiazine, 5,6-dihydro-[1I,4,3]oxathiazine, 5,6-dihydro-[1 ,4,2]oxathiazine, 2,3-dihydro-[1I,4,3]oxathiazine, 2,3-dihydro-[ 1,4,2]oxathi azine, di hydropyridine, 1 ,6-dihydropyridine, 5,6-di hydropyri dine, 2H-pyran, 211-thiin, 3 ,6-dihydropyridine, 2,3-dihydropytidazine, 2,5-dihydropyridazine,*4,5dihydropyridazine, I ,2-dihydropyridazine, 2,3-dihydropyrimidine, di hydropyrimi dine, 5,6-dihydropyrimidine, 3,6-dihydropyrimidine, di hydropyrazine, 5 ,6-di hydropyrazi ne, 3 ,6-di hydropyrazi ne, 4,5-di hydropyrazine, 1 ,4-dihydropyrazine, 1 ,4-dithiin, 1,4-dioxin, 2H-1,2-oxazine, 611-1 ,2-oxazine, 4H- I ,2-oxazine, 2H-1 ,3-oxazine, 4H- 1,3-oxazine, 6H- 1,3-oxazine, 211-1 ,4-oxazine, 4H- 1,4-oxazine, 2H-1 ,3-thiazi ne, 21i,4-thiazine, 411-1 ,2-thi azine, 611-1,3- thiazine, 411-1 ,4-thiazine, 211-1 ,2-thiazine, 6H- 1,2-thiazine, 1 ,4-oxathiin, I ,2,3-triazine, 111,411-1,2,3-triazine, 4,5-dihydro- 1,2,3-triazine, 111,611-1,2,3triazine, 1 ,2-dihydro-1I,2,3-tri azine, 2,3-dhydro-1I,2,4-triazine, 311,6H- 1,2,4triazine, 111,611-1,2,4-triazi ne, 3 ,4-dh ydro-1I,2,4-tri azine, 1 1,4H- 1,2,4-tri azine, ,6-dihydro-1 ,2,4-triazine, 4,5-dihydro- 1,2,4-tn azine, 211,51-1,2,4-tn azine, 1,2di hydro- 1,2,4-triazine, 1 H,4H- 1,3 ,5-tniazine, I ,2-dihydro- 1,3 ,5-triazine, 1,4,2dithiazine, I ,4,2-dioxazine, 2H- 1,3,4-oxadiazine, 2H- 1,3 ,5-oxadi azine, 6H1-1,2,5oxadiazine, 4H-1I,3,4-oxadiazine, 411-1,3 ,5-oxadiazine, 4H- 1,2,5-oxadiazine, 211- 1,3,5-thiadiazine, 6H-1,2,5-thiadiazine, 4H-1,3,4-thiadiazine, 411-1,3,5thiadiazi ne, 411-1 ,2,5-thiadiazi ne, 2H- 1,3 ,4-thiadiazine, 611-1 ,3,4-thiadiazine, 6H- -33- 1,3,4-oxadiazine and 1,4,2-oxathiazine, wherein the heterocycle is optionally vicinally fused with a saturated or unsaturated 6- or 7-membered ring containing 0, 1 or 2 atoms independently selected from N, O and S; R' is phenyl substituted by 0, 1 or 2 groups selected from halo, C 1 4 alkyl,

C

1 3 haloalkyl, -ORd and -NRdRd; Or Rf is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, 0O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the carbon atoms of the heterocycle are substituted by 0, 1 or 2 oxo groups, wherein the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents selected from halo, CI- 4 alkyl, CI.

3 haloalkyl, -ORd and -NRdRd and R9 is hydrogen or -CH 3 In another embodiment, in conjunction with the novel compound embodiments above and below, R' 6 is halo, -NH 2

-NHC

1 .3alkyl,

-N(C

13 alkyl)C 1 3 alkyl or C 1 3 alkyl.

In another embodiment, in conjunction with the novel compound embodiments above and below, R' 0 is independently, at each instance, CI.galkyl,

C

1 4 haloalkyl, halo, cyano, nitro, salkyl), -C(=O)O(Cis.alkyl), -C(=O)NRdRd, -C(=NRd)NRdRd, -ORd, 8 alkyl), -OC(=O)NRdRd, RdS, d d d' d -OC(=O)NR )S=O) 2

C

1 .salkyI), -OC 26 alkylNR R ,-0C 2 6 alkylOR ,-SR, d~ dd -S(=0)(C-s8alkyl), -S(=0)21(C-8alkyl), -S(=0)2NRdRd -S(=0)2N(Rd)C(=0)(C1_salkyl), -S(=0)2N(Rd)C(=0)O(C .1alkyl), 2 N(Rd)C(=O)NRdRd, -NRdRd, 8 alkyl), alkyl), -N(Rd)C(=0)NRdRd, -N(Rd)C(=NRd)N dRd -N(Rd)S(=0) 2

(CI

8 alkyl), -N(Rd)S(=0) 2 NR"R, NRdC 2 6 alkylNRdRd and -NRd C2-6alkylORd; or R' 0 is a saturated or unsaturated 6- or 7-membered monocyclic or 10- or i1-membered bicyclic ring containing 1, 2 or 3 atoms selected from N, O and S, wherein the ring is fused with 0 or I benzo groups and 0 or 1 saturated or unsaturated 6- or 7-membered heterocyclic ring containing 1, 2 or 3 atoms selected from N, O and S; wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 groups selected from C 18 alkyl, C 1 4 haloalkyl, halo, cyano, nitro, -34 8 alkyI), -C(=O)O(C 1 8 alkyl), -C(=O)NR dR.d, -C(=NR d)NRd R d, -OR d

-OC(=O)(C

1 8 alkyl), -OC(=O)NR R d, -OC(=O)N(R d)S(=O) 2

(C

1 8 a~kyl),

-OC

2 ,alkylNRd R.d, -OC 2 6 a~kylOR d, -SR d 1 .salkyl), 2

(C

1 8 alkyI), -S 2 NRd R d -S 2 N(R d)C(=O)(C 1 _galkyl), 2 N(R d)C(=O)O(C 1 8 alkyl), 2 N(R d)C(=O)NRd R d -NRd R. d, N(Rd)C(=O)(C 1.alkyl), -N(Rd)C(=O)O(CI 1 8 alkyl), -N(Rd)C(=0)NR d R.d -N(R d)C(=NR d)Nd Rd' dS dS dd_~ 2

(C

1 8 alkyl), S(=O) 2 NR NdC 2 6 alkylNR R. and -NRd C2-akylOR d; or. R.1 0 is C 1 4 alkyl substituted by 0, 1, 2 or 3 groups selected from C 1 4 haloalkyl, halo, cyano, nitro, 8 alkyl), -C(=O)O(Cv.8alkyl), _C(=O)NRd R.d, R d -OR.d' .0C(=O)(C 1 8 alkyl), Rd Rd, -OC(=O)N(R d)S(=O) 2

(C

1 _ga1 kyl), -OC 2 6 alkylNRd R.d, -OC 2 6 alkylOR d, -SR.d, -S(=O)(CI-8alkyl), 2

(C

1 8 alkyI), 2 NR dRd 2 N(R 1 _al kyl), 2 N(R d)C(=O)O(C 1 ISalkyl), 2 N(R d)C(=O)NR dR d, -NR dR d, 8 alkyl), dd~ d* C2-alkylORd.

In another embodiment, in conjunction with the novel compound embodiments above and below, R' is R 9 In another embodiment, in conjunction with the novel compound embodiments above and below, R.

7 is CI-salkyl, halo or Ci.

4 haloalkyl.

In another embodiment, in conjunction with the novel compound embodiments above and below, R' is naphthyl substituted by 0, 1, 2 or 3 substituents independently selected from R In another embodiment, in conjunction with the novel compound embodiments above and below, R' is R' substituted by 0, 1, 2 or 3 substituents independently selected from R 5 35 In another embodiment, in conjunction with the novel compound embodiments above and below, R' is R~ substituted by 1, 2 or 3 substituents independently selected from R 5 In another embodiment, in conjunction with the novel compound embodiments above and below, R 4 is R 13 In another embodiment, in conjunction with the novel compound embodiments above and below, R 1 0 and R"1 together are a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the each of the carbon atoms in the bridge is substituted by H, CI-8alkyl, C 14 haloalkyI, halo, cyano, nitro, 18 alkyl), -C(=O)O(C 1 .galkyl), -C(=O)NR dR d, _C(=NRd)NRd R d, -OR d 1 _alkyl), _OC(=O)NRd R d _OC(=O)N(R d)S(=O) 2 (C 8 a1 kyl),

-OC

2 6 alkylNR dR d' -OC 2 -6alky[OR d' -SR d' 1 8 alkyl), 2 salkyl), 2 NR dR d, 2 N(Rd)C(=O)(C i 8 alkyl), 2 N(R d)C(=O)O(C 1 8 alkyl), -S 2 N(Rd)C(=0)NR Rd -NRdRd -N(Rd)C(=O)(C 1 .galkyl), -N(R d)C(=O)O(C 1 -salkyl), -N(R d)C(=O)NRd R d -N(Rd)C(=NR d)NR d R d -N(Rd)S(=O) 2

(C

1 8 a1 kyl), -N(R d)S(=O) 2 NRd R d _d C 2 6 alkyNd Rd and -NR dC 2 _6alkyIOR d, and any nitrogen atoms in the bridge are substituted by H, -CI-6alkylOR -C 1 6 alkyl, -CI- 6 alky]NR R -Ci.

3 alkylC(=O)OR,

-C

1 3 alkylC(=O)NRd R d, -C 1 3 alkylOC(=O)C 1 6 alkyl, -C 1 3 a1kyINR dC(=O)C 1 6 alkyl, -C(=O)Rf or -C 1 3 alkylRf; or IR" and R 1 2 together are a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the each of the carbon atoms in the bridge is substituted by H, =0, C 1 8 alkyl, C 1 4 haloalkyl, halo, cyano, nitro, 8 alkyl), -36- -C(=0)0(CI-8alkyl), -C(=O)NR R d, -C(=NR )NRd Rd, -OR d, 8 alkyl), -OC(=0)NR dR d, -OC(=0)N(R d)S(=O) 2 8 a1 kyl), -OC 2 6 alkyINRdR d'

-OC

2 6 alkylOR -SR 1 .galkyl), 2 (C1_8alkyI), 2 NRR.d, 2 N(R 1 .sal kyl), 2 N(R 8 a1 kyl), 2 N(R d)C(=O)NRd R d "R"Rd 8 alkyl), -akl,- d NR C=dN d' -N(Rd)S(=0) 2 (C,-8alky1), -N(R d)S(=0) 2 NR R d, -NR C 2 -6alky]NR dR d and -NR dC 2 6 alkylOR d, and any nitrogen atoms in the bridge are substituted by H, d, -C 6 alkyl 6 alkyld R d -C 1 3 alkyIC(=O)OR d, -C 3 alkylC(=0)NRd -C 3 alkylOC(=0)C, .6alkyl, 3 alkylNR dC(=0)C, 6 alkyl, -C(=O)Rf or 3 alkylRf.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 4 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the carbon atoms of the heterocycle and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C1.

9 alkyl, C,.

4 haloalkyl, halo, nitro, cyano, oxo, -OR 6 alkyl, -OCI.

4 haloalkyl, -OC 2 6 alkylNR R

-OC

2 6 alkylOR d, -0C,.

6 alky1C(=0)0Rd, -NR dR d, _NRdC, -haloalkyl, -NRd C 2 6 alkylNR dR d, -NR dC 2 -6alkylOR d, -C(=0)CI.

6 alkyI, 6 alkyl, 6 a1 kyl, -CQ=0)NR dC 1-al kyl and -NR 6 a1 kyl; and saturated carbon atoms may be additionally substituted by and any nitrogen atoms in the bridge are substituted by H, 6 alkylOR d, 6 alkyl, 6 alkylNR dR d, 3 alkylC(=O)0R d, 3 alkylC(=O)NRd -C1-3~alkyl0C(=O)C1- 6 alkyl, -C 3 alkylNR dC(=0)CI 6 alkyl, -C(=0)Rf or -C.

3 a1 kyiRf.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 4 Is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms -37being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the heterocycle and bridge are substituted by 1, 2 or 3 substituents independently selected from C.

9 alkyl, Ci.

4 haloalkyl, halo, nitro, cyano, oxo, -ORd, -S(=0)nCj.6alkyl, -OC 1 -4haloalkyl, -OC 2 6 alkylNRdRd,

-OC

2 6 alkylORd, -OCi.

6 alkylC(=O)ORd, -NdRd, -NRdCi.

4 haloalkyl, -NRdC 2 6 alkylNRdRd, NRdC 2 .6alkylORd, -C(=O)Ci .alkyl, -C(=O)OCI.

6 alkyl, -OC(=O)Ci.

6 alkyl, -C(=O)NRdC 1 i-alkyl and -NRdC(=O)CI.

6 alkyl; and saturated carbon atoms may be additionally substituted by and any nitrogen atoms in the bridge are substituted by H, -CialkylORd, -Ci-6alkyl, -Cl.

6 alkylNRR d

-C

1 .3alkylC(=O)ORd, -C 3 alkylC(=O)NRdRd, 3 alkylOC(=O)Ci.6alkyl,

-CI.

3 alkylNRdC(=0)CI 6alkyl, or -C I 3 alkylR.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 4 is 10-membered bicyclic ring comprising fused 6-membered rings, containing 0, 1, 2, 3 or 4 N atoms with the remainder being carbon atoms, with at least one of the 6-membered rings being aromatic, wherein the carbon atoms are substituted by H, halo, ORd, NRdRd, Cc 6 alkyl and Ci.

3 haloalkyl; and saturated carbon atoms may be additionally substituted by =0.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 4 is 10-membered bicyclic ring comprising fused 6-membered rings, containing 1, 2, 3 or 4 N atoms with the remainder being carbon atoms, with at least one of the 6-membered rings being aromatic, wherein the carbon atoms are substituted by H, halo, ORd, NRdRd, C 1 i.alkyl and Ci.

3 haloalkyl; and saturated carbon atoms may be additionally substituted by =0.

Another aspect of the invention relates to a compound having the structure: R9

R'

6 or any pharmaceutically-acceptable salt thereof, wherein: n is independently, at each instance, 0, 1 or 2; -38o is independently, at each instance, 0, 1, 2 or 3; Yis NH, O or S; R' is 6R

R

R

9 or R' is a naphthyl substituted by 0, 1, 2 or 3 substituents independently selected from R 5 or R' is R' substituted by 1, 2 or 3 substituents independently selected from R 5

R'

5 is, independently, in each instance, R' 1 Ci.salkyl substituted by 0, 1 or 2 substituents selected from R' 1

-(CH

2 )nphenyl substituted by 0, 1, 2 or 3 substituents independently selected from R 1 0 or a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, 0 and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from R' 0

R'

6 is, independently, in each instance, H, halo, -NH 2

-NHC

1 3 alkyl, -N(Ci.3alkyl)Ci.

3 alkyl or Cl.

3 alkyl;

R

4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C 1 .salkyl, Cl- 4 haloalkyl, halo, cyano, nitro, -C(=O)OR n -C(=0)NR m

R

m

-C(=NR

m

)NR

m

R

m

-OR

m

-OC(=O)R

n

-OC(=O)NR

m

R

m -OC(=0)N(R m 2

R

n

-OC

2 6 alkylNR m

R

m

-OC

2 6 alkylOR m

-SR

m 2 2

NR

m

R

m 2

N(R

m

)C(=O)R

n 2

N(R

m

)C(=O)OR

n 2

N(R

m

)C(=O)NR

m

R

m

-NR

m

R

m

-N(R

m

)C(=O)R

n

-N(R

m -39-

-N(R

m )C(=0)NR m

-N(R

m

)C(=NR

m

)NR

m

-N(R

m )S 2

R',

-N(R

m 2

NR

m

R

m

-NR

M

C

2 -6alkyINR m

-NR

m

C

2 6 a1 kylQ0R m -C(=O)ORs, -C(=O)rNRs' .C(=NRn)NRnRs -OC(=0)NRnR', OC(=O)N(R m )S 2 Rs, -OC 26 alkyI..]ZrRs, -OC 2 6 al kylOR', -SRs, 2 2 NRnR', 2 N(Rrn)C(=0)R', 2 N(Rr)C(=O)0Rs, 2 N(Rrn)C(=O)NRnR', -NRrnR', -N(Rrn)C(=O)R', -N(Rr)C(=0)0Rs, -N(Rrn)C(=0)NRnRs, -N(Rrn)C(=NRn)NRnR', -N(Rr)S(=0) 2 Rs, -N(Rrn)S(=O) 2 NRnR', -NRrnC 2 _alkyINRnRs, -Nm26akl~ and C,- 4 alkyI substituted by 1 or 2 groups selected from C 1 2 haloalkyl,_halo, cyano, nitro, n, -C(=O)QR n, -C(=O)NR m

R

m

-C(=NR

m

)NR

m

R

m -OR m

-OC(=O)N(R

m )S 2

-OC

2 -6alkylNR m

R

m

-OC

26 alkylOR', -S n, 2 -S 2

NR

m

R',

2

N(R

m n, 2

N(R

m 2

N(R

m

)C(=O)NR

m

R',

-NR

m

-N(R

m n, -N(R m

)C(=O)NR

m

R

m

-N(R

m

)C(=NR-)NR

m

R

m 2 R n, -N(R m 2

NR

m

R

m

-NR

m

C

2 6 a1 kyINR m

R

m

-NR

m

C

2 _6alkylOR', -C(=O)ORs, -C(=O)NRrnR', -C(=NRn)NRnR', -ORs, -OC(=O)Rs, -OC(=O)NRnW,, 2 Rs, -0C 2 6 a1 kylNRrnRs, -OC 26 alkylORs, -S -S(=P)Rs, -S 2 Rs, -S 2 NRnR', 2 N(Rr)C(=0)Rs, -S 2 N(Rn)C(=O)ORS, -s 2 N(Rrn)C(=0)NRnRs, -NRrnRs, -N(Rrn)C(=O)Rs, -N(Rrn)C(=O)ORs, -N(Rr)G(=0)NRnR', -N(Rrn)C(=NjRn)NRnRs -N(Rrn)S(=O) 2 Rs, -N(Rrn)S(=0) 2 NRnRs, -NRrnC 2 6 alkylNRrnRs, -NRrnC 2 alkylORs; and the ing and bridge carbon atoms are substituted with 0, 1 or 2 0 groups; but in no instance is R 4 3,5-ditrifluoromethyiphenyl or 3-tn fluorometh yl-4-fl uorophenyl; R 5 is independently, at each instance, H, CI-sal 'kyI, C14haloalkyl, halo, nitro, cyano, -OC 1 -6alkyl, -0CI- 4 haloalkyl, -OC 2 6 alkylNRdR', .OC,_,alkyIORd, -NR -NR'C,- 4 haloalkyI, -NRd C 2 6 akylNRdRd, -NR dC 26 alkyIOR d, naphthyl, -C0 2 (C,-.5a1 kyl), 1 6 alkyl), _C(=O)NRd NRdC(0C)R d -NR C(=O)NRd R d, -NRd C0 2 6 alkyl), -CIs8alkylOR d, -CI- 6 alkylNR dR' 1 6 alkyl), 2 NR dR d, _Nd OC(=O)NRd a phenyl ring substituted with 0, 1, 2, or 3 substituents independently selected from Ri;or R 5 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from 0, N and S, substituted with 0, 1, 2, or 3 substituents independently selected from R1 0 R 6 is independently, at each instance, H, C 1 5 alkyl, C 1 -4haloalky1, halo, -0C 1 4 salkyl, -OC 1 -4haloal kyl, -0C 2 -6alkylNR dR d, -OC 2 6 alky10R d' .4Rd R d -NR dC, 1 4 haloalkyl, -NRdC 26 alkylNR dR' or _N C2i .alkyl -I8~yOR'

-CI.

6 alkylNR dR d, -S(C 1 6 alkyl), a phenyl ring substituted with 1, 2, or 3 substituents independently selected from R O; or R 6is a saturated or unsaturated or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from 0, N and S substituted with 0, 1, 2, or 3 substituents independently selected from R1 0 R 7 is independently, at each instance, H, C 1 8 alkyl, C 1 4 haloalkyl, d d. d halo, O-0 6 alkyl, -OCI-4haloalkyl, -0C 2 6 alkylNR R -0C 2 -6alkyl0R -NR R d, -NRdCC 1 .haloalkyl, -NR dC 26 alky1NR dR', -NR dC 2 6alkyl0R d' -Ci-galkylOR d, -C 1 6 alkylNR d Rd or -S(C 1 6 alkyl); or R 7is a saturated or unsaturated 4- or 5-membered ring heterocycle containing a single nitrogen atom, wherein the ring is substituted with 0, 1 or 2 substituents independently selected from halo, C 1 2 haloalkyl ahd'C 1 3 alkyl; R 8 is in dependently, at each instance, H, CI-5alkyl, C 1 4haloalkyl, halo, d dd dd -NR dCi 4 haloalkyl, -NR dC 2 6 alkyl NRd R d, -NR dC 2 6 alkylOR d, -CI-8alkyl0R d'

-CI.

6 alkylNR dR d, -S(C 1 -alkyl), a phenyl ring substituted with 1, 2, *or 3 substituents independently selected from R1 0 or Rg is a saturated or unsaturated or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from 0, N and S substituted with 0, 1, 2, or 3 substituents independently selected from R1 0 R 9 is independently, at each instance, H, C 1 8 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -0CI.

6 alkyl, -0CI.

4 haloalkyl, -0C 2 6 alkyl NRd R d

-OC

2 6 alkylOR, d'NR dR d, -NRdCi.haloalkyl, -NR dC 2 6 alkylNR dR dor -NR C 2 -6alkyI0R -C0 2

(CI-

6 alkyl), 1 4 6alkyl), -C(=0)NR R NR -6alkyI), PNRdC(=O)NR dR d _NRdCO (C 6 alkyl),

-C

1 salkylOR d, 6 alkylNR dR d' -S(=O)n(C 1 6 alkyl), 2 NRd R d -NR dS(=0) 2

(C

1 6 alkyl), -OC(=0)NR dR d or a -(CRqR q) 0 phenyi wherein the phenyl is substituted with 0, 1, 2, or 3 substituents independently selected from R' 0 or R 9 is -(CR'Rq) 0 ,Het wherein Het is a satu .rated or unsaturated -41or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from 0, N and S substituted with 0, 1, 2, or 3 substituents independently selected from R1 0 or R 9 is a saturated or unsaturated 4- or ring heterocycle containing a single nitrogen atom, wherein the ring is substituted with 0, 1 or 2 substituents independently selected from halo,

C

1 2 haloalkyl and C 1 3 alkyl; wherein at least one of R' and R 9 is C 1 salkyl, C 1 4 haloalkyI, halo, -OCI-.

4 haloalkyl, -OC 2 -6alkylNRd R d -OC.6lkyRd' -NR dCI 4 haloalkyl, -NR dC 26 alkylNR dRd, -NR C 2 ,~akylOR', -Ci.galkylOR d, -CI 6 alkylNR dR dor -S(C I 6 alkyI); R1 0 is independently, at each instance, selected from H, CI-8alkyl,.

C

1 4 haloalkyl, halo, cyano, nitro, 8 alkyl), 1 .galkyl), -C(=O)NR dR d, _C(=NRd)NR R d, -OR d, -OC(=0)(Cj~galkyl), -OC(=O)NR dR.d, -OC(=O)N(R d)S 2

(C

1 galkyl), -OC 2 -6alkylNRd R d, -0C 2 6 a1 kylOR d, -SR d, 1 .salkyl), 2

(C

1 8 alkyl), 2 NRd R d 2 N(R d)C(=O)(CI .salkyl), 2 N(R d)C(=0)O(C 1 8 a1 kyl), 2 N(R d)C(=O)NR dR.d, -NR dR. d, N(R 1 -8al kyl), -N(R 8 a1 kyl), )C(=0)NR dR.d, -N(Rd)C(=NR d)NR dR d, -N(R.d)S 2

(C

1 .salkyl), -N(R d)S(=O) 2 NRd R d -N.RdC 26 alkylNRd R.d and NdC 2 6alkylORd or R' 0 is a saturated or unsaturated 6- or 7-membered monocyclic or 10- or 1I-membered bicyclic ring containing 1, 2 or 3 atoms selected from N, 0 and S, wherein the ring is fused with 0 or I benzo groups and 0 or I saturated or unsaturated 6- or 7-membered heterocyclic ring containing 1, 2 or 3 atoms selected from N, 0 and S; wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 groups selected from CI-8alkyl, C 1 -4haloalkyl, halo, cyano, nitro, 8 alkyl), -C(=O)O(CjSalkyl), _C(=O)NRd R d -C(=NR d)NR dR -OR d 8 a1 kyl), -0C(=O)NR dR d, -0C(=O)N(R d)S(=O) 2 (CI-8alkyl),

-OC

2 6 alkylNR dR.d' -0C 2 6 alkylOR d' -SR d, 18 a1 kyl), -S=0 .(I 8 alkyl), 2 NRd R d, 2 N(R 1-8alkyl), 2 N(R d)C(=O)O(Cl .alkyl), 2 N(R d)C(=O)NRd R d -NR dR d, -N(Rd)C(=O)(Ci -galkyl), -N(Rd)C(=O)O(C 1 8 a1 kyl), -N(R d)C(=O)NRd R d, N(R d)C(=NRd)NRd R', -N(R d)S 2

(C

1 8 a1 kyl), -N(R d)S 2 NR d Rd, _NRd C 2 6al kylNR dR d and -42 C26alylO d;or Rio is C1 4 alkyl substituted by 0, 1, 2 or 3 groups selected from C 1 4 haloalkyl, halo, cyano, nitro, 1 8 alkyl), -C(=O)O(C 1 .8alkyl), -C(=O)NRdRd, -C(=NR d)NRd -OR d, -OC(=O)(C,..galkyl), -OC(=O)NR dR d, -OC(=O)N(R d)S(=O) 2 (CI-8alkyl), -OC 2 -,alkylNR dR', -OC 2 -6alkylOR d, -SRd d 1 8 alkyI), -S(=O)2(C 1 8 alkyI), R 2 N(R -8alkyI), 2 N(R d)C(=O)O(Ct 8 a1 kyl),

-S(O)

2 N(R d)C(=O)NRd R d -NR dR d, -N(R d)C(=O)(C 1 .galkyl), -N(R -alky1), -N(R d)C(=O)NRd R d, -N(R d)C(=NRd )NR dRd, -N(R d)S 2

(C

1 8 alkyl), -N(R d)S(=O) 2 NR dR d dC 26 alky]NR dR dand -NR d CalkyOR d;( R d is independently, at each instance, H, phenyl, benzyl or C 1 6 alkyI; R' is a heterocycle selected from the group of thiophene, pyrrole, I ,3-oxazole, I ,3-thiazole, 1 ,3,4-oxadiazole, I ,3,4-thi adi azole, 1 ,2,3-oxadiazole, I ,2,3-thiadiazole, IH-1I,2,3-triazole, isothiazole, I ,2,4-oxadiazole, 1,2,4thiadiazole, I ,2,3,4-oxat'riazole, I ,2,3,4-thiatriazole, I1I,2,3,4-tetraazole, 1 ,2,3,5-oxatriazole, 1 ,2,3,5-thiatriazole, furan, inndazol-yl, i midazo]4-yl, 1,2,4tn azol-4-yl, I ,2,4-triazol-5-yI, isoxazol-3-yI, isoxazol-5-yl, pyrazol-3-yl, pyrazolthiolane, pyrrolidine, tetrahydrofuran, 4,5-dihydrothiophene, 2-pyrroline, pyridazine, pyrimidine, pyrazine, I ,2,3-triazine, 1 ,2,4-triazine, 1,2,4-triazine, 1,3,5-triazine, pyridine, 2H-3,4,5,6-tetrahydropyran, thiane, 1,2diazaperh ydroi ne, 1 ,3-di azaperhydroi ne, pi perazine, 1 ,3-oxazaperhydroine,' morpholine, 1 ,3-thiazaperhydroi ne, 1 ,4-thi azaperhydroi ne, pi peridine, 2H-3 ,4dihydropyran, 2,3-dihydro-4H-thiin, 1 ,4,5,6-tetrahydropyridi ne, 2H-5,6dihydropyran, 2,3-di hydro-6H-thiin, I ,2,5,6-tetrahydropyri dine, 3,4,5,6tetrahydropyridi ne, 4H-pyran, 4H-thi in, I ,4-dihydropyridine, I ,4-dithiane, 1,4dioxane, I ,4-oxathiane, 1 ,2-oxazolidine, I ,2-thiazolidine, pyrazolidine, 1,3oxazolidine, I ,3-thiazoildine, imidazolidine, 1 ,2,4-Oxadiazolidine, 1,3,4oxadi azolidi ne, 1 ,2,4-thi adiazoli1dine, I ,3,4-thiadiazolidine, 1 ,2,4-triazolidine, 2imidazoline, 3-i midazoline, 2-pyrazoline, 4-imidazoline, 2,3-dihydroisothiazole, 4,5-di hydroisoxazole, 4,5-di hydroisothiazole, 2,5-di hydroisoxazole, dihydroisothiazole, 2,3-dihydroisoxazole, 4,54-dihydrooxazole, 2,3dihydrooxazole, 2,5-dihydrooxazole, 4,5-dihydrothiazole, 2,3-dihydrothiazole,,.

43 hydrothiazole, I ,3,4-oxathi azol idine, 1, 4,2-oxathiazolidine, 2,3-dihydro- 11± [1 ,2,3]triazole, 2,5-dihydro- IH-[ 1,2,3]triazole, 4,5-dihydro-I-I-[1 ,2,3]triazole, 2,3-dihydro-lfH-[1I,2,4]triazole, 4,5-dihydro- 1H-[1I,2,4)triazole, 2,3-dihydro- [1 ,2,4]oxadiazole, 2,5-dihydro-Il ,2,4]oxadiazole, 4,5-di hydro-[ 1,2,4]thiadiazole, 2,3-dihydro-[ 1,2,4] thidiazole, 2,5-dihydro-[ 1,2,4] thi adiazole, 4,5-dihydro-[ 1,2,4] thiadi azole, 2,5-dihydro-[1I,2,4]oxadiazole, 2,3-dihydro-[ 1,2,4]oxadiazole, dihydro-[1I,2,4]oxadiazole, 2,5-dihydro-[1I,2,4]thiadiazole, 2,3-dihydro-[ 1,2,4] thiadiazole, 4,5-dihydro-[ 1,2,41 thiadiazole, 2,3-dihydro-[ 1,3,4]oxadiazole, 2,3di hydro-[1I,3,4]thiadiazole, [1 ,4,21oxathiazole, [1 ,3,4]oxathiazole, 1,3,5triazaperhydroine, I ,2,4-tri azaperhydroine, 1 ,4,2-dithiazaperhydroine, 1,4,2dioxazaperhydroine, 1,3,5 -oxadiazaperhydroi ne, I I ,3,4-thiadiazaperhydroine, 1 ,3,5-thiadiazaperhydroine, 1,2,5thi adi azaperhydroi ne, 1,3 ,4-oxadi azaperhydroine, 1 ,4,3-oxathiazaperhydroine, 1,4,2-ox athi azaperhydroi ne, 1,4,5 ,6-tetrahydropyridazine, 1,2,3,4tetrahydropyridazi ne, 1,2,3 ,6-tetrah ydropyri dazine, 1,2,5 ,6-tetrahydropyri mi dine, 1 ,2,3,4-tetrahydropyrimidine, 1,4,5 ,6-tetrahydropyri midine, 1,2,3,6tetrahydropyrazine, 1,2,3 ,4-tetrahydropyrazine, 5,6-dihydro-4H-[ 1,2]oxazine, 5,6dihydro-2H-[1 ,2]oxazine, 3,6-dihydro-2H-[ 1,2]oxazine, 3 ,4-di hydrQ.-2H- [1 ,2]oxazine, 5,6-di hydro-4H-[ 1,2]thiazine, 5 ,6-dihydro-2H-[ 1,2] thiazine, 3,6- 2 0 dihydro-2H-[ 1,2] thiazine, 3,4-dihydro-2H-[ 1,2] thiazine, 5,6-dihydro-2H- [1 ,3]oxazine, 5,6-dihydro-4H-[ 1,3]oxazine, 3,6-dihydro-2H-[1I,3]oxazine, 3,4dihydro-2H-[1I,3]oxazine, 3,6-dihydro-2H-[ 1,4]oxazine, 3,4-dihydro-2H- [1 ,4]oxazine, 5,6-dihydro-2H-[1 ,3]thiazine, 5,6-dihydro-4H-[1,3]thiazine, 3,6di hydro-2H-[ 1,3]thiazine, 3,4-dihydro-2H-( 1,3]thiazine, 3,6-di hydro-2H4- [1 ,4]thiazine, 3 ,4-dihydro-2H-[ 1,4]thiazine, 1 ,2,3,6-tetrahydro-[ I,2,4]triazine, 1,2,3,4-tetrahydro-[1,2,4]triazine, 1,2,3,4-tetrahydro-[1,3,5]triazine, 2,3,4,5tetrahydro-[1I,2,4]triazine, 1 ,4,5,6-tetrahydro-[1I,2,4]triazine, 5 ,6-di hydro- [1 ,4,2]dioxazine, 5,6-dihydro-[1I,4,2]dioxazine, 5,6-di hydro-[ 1,4,2]dithiazine, 2,3dihydro-[1I,4,2]dioxazine, 3,4-di hydro-2H-[1I,3,4]oxadi azine, 3 ,6-dihydro-2H- [1 ,3,4]oxadiazi ne, 3 ,4-dihydro-2H-[1I,3,5]oxadiazi ne, 3,6-dihydro-2H- [1,3 ,Sloxadiazine, 5 ,6-di hydro-2H-[1I,2,5]oxadiazine, 5,6-dihydro-4H- [1 ,2,5]oxadiazi ne, 3,4-di hydro-2H-[1I,3,4jthi adiazine, 3 ,6-dihydro-2H- -44 [1 ,3,4lthi adiazine, 3,4-dihydro-2H-[1I,3,5]thiadiazine, 3 ,6-dihydro-2H- 111,3 ,5]thiadiazine, 5,6-dihydro-2H-[ 1,2,5]thiadiazine, 5,6-dihydro-4H- [1 ,2,5]thiadiazine, 5 ,6-dihydro-2--[ 1,2,3loxadiazi ne, 3,6-dihydro-2H- [1 ,2,5]oxadiazine, 5,6-dihydro-4H-[ 1,3,4]oxadiazine, 3,4-dihydro-2H- [1 ,2,5]oxadiazine, 5,6-dihydro-2H-[ 1,2,3lthiadiazine, 3,6-dihydro-2H- [1 ,2,'5]thiadiazine, 5,6-dihydro-4H-[1I,3,4]thiadiazinie, 3,4-dihydro-2H- [1 ,2,'5]thiadiazine, 5,6-dihydro-[ 1,4,3loxathiazine, 5,6-dihydro-[ I,4,2]oxathiazine, 2,3-dihydro-[ 1,4,3]oxathiazine, 2,3-dihydro-[ 1,4,2]oxathiazine, dihydropyridine, I ,6-dihydropyridine, 5,6-dihydropyridine, 2H-pyran,-2H-thiin, 3,6-di hydropyridine, 2,3-dihydropyridazine, 2,5-dihydropyr-idazine, dihydropyridazine, 1 ,2-dihydropyridazine, 2,3-dihydropyri midi ne, dihydropyrimidine, 5,6-dihydropyrimidine, 3,6-dihydropyrimidine, di hydropyrazi ne, 5 ,6-dihydropyrazine, 3 ,6-di hydropyrazine, 4,5-di hydropyrazi ne, I ,4-di hydropyrazine, 1 ,4-dithiin, 1,4-dioxin, 2H- 1,2-oxazine, 6H- 1,2-oxazine, 4H- 1 ,2-oxazine, 2H- 1,3-oxazine, 41-1,3-oxazine, 6H- 1,3-oxazine, 2H-1I,4-oxazine, 4H- 1,4-oxazine, 2H- 1,3-thi azine, 2H-1I,4-thi azine, 4H-1I,2-thi azine, 6H- 1,3thiazine, 4H-1I,4-thiazine, 2H- 1,2-thiazine, 6H-1 ,2-thiazine, I ,4-oxathiin, I ,2,3-triazine, IH,4H- 1,2,3-triazine, 4,5-dihydro- 1,2,3-triazine, I H,6H- 1,2,3triazine, 1 ,2-dihydro-1I,2,3-triazine, 2,3-dihydro- 1,2,4-triazine, 3H,6H- 1,2,4triazine, 1H,6H- 1,2,4-triazine, 3 ,4-dihydro-1I,2,4-triazine, IH,4H-1I,2,4-triazine, 5,6-dihydro-1 ,2,4-triazine, 4,5-dihydro-1I,2,4-triazine, 2H,5H- 1,2,4-triazine, 1,2-( dihydro-1I,2,4-triazine, 1 H,4H- 1,3,5-triazine, I ,2-dihydro-1I,3,5-tri azine, 1,4,2dithiazine, I ,4,2-dioxazine, 2H- 1,3,4-oxadiazine, 2H- 1,3,5-oxadiazine, 611-1,2,5oxadiazine, 4H- 1,3 ,4-oxadiazine, 4H- 1,3,5-oxadiazine, 4H-1I,2,5-oxadiazine, 2H1- 1,3,5-thiadiazine, 6H-1,2,5-thiadiazine, 411-1 ,3,4-thiadiazine, 4H-1 thi adiazine, 4H-1I,2,5-thiadi azine, 2H- 1,3,4-thiadiazine, 6H- 1,3 ,4-thiadi azine, 6H- 1 ,3,4-oxadiazi ne and I ,4,2-oxathi azi ne, wherein the heterocycle is optionally vicinally fused with a saturated or unsaturated 6- or 7-membered ring containing 0, 1 or 2 atoms independently selected from N, 0 and S; Rf is phenyl substituted by 0, 1 or 2 groups selected from halo,C C 1 -alkyl,

C

1 3 haloalkyl, -OR dand -NR dR d; or Rf is a saturated or unsaturated 5- or 6-meinbered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, 0 and S, wherein no more than 2 of the ring members are 0 or S wherein the heterocycle is optionally fused with a phenyl ring, and the carbon atoms of the heterocycle are substituted by 0, 1 or 2 oxo groups, wherein the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents selected from halo, C 1 4alkyl, C 1 3 haloalkyl, -OR' and _NdRd; R1, is hydrogen or C3 R' is independently at each instance H orR; R. is independently at each instance C 1 .galkyl, phenyl or benzyl; R. is independently in each instance H, C 1 -4alkyl, CI-4haloalkyI, halo, cyano, nitro, -C(=0)0R n, -C(=0)NR m

-C(=NR

m

)NR

m

-OR'

m -OC(0)NR m -0C(=O)N(R m 2 R n, -0C 2 -6alkyl NR m

R'

1 -0C 2 6 a1 kylOR, -SR' m 2 2

NR

m -S 2

N(R

m n, 2

N(R

m -S 2 N(Rn)C(=O)NRnRmn,

-NR

m n, -N(R m

-N(R

m

)C(=O)NR'R

m

-N(R

m

)C(=NR-)NR

m

R

m

-N(R

m 2

-N(R

m )S 2

NR

m

R

m

-NR

m

C

26 a1 kylNR m

R

m or -NR'C 2 6 alkylOR m and Rs is R n substituted by 0, 1, 2 or 3 substituents independently selected from R In another embodiment, in conjunction with the novel compound embodiments above and below, Y is NiH.

In another embodiment, in conjunction with the novel compound embodiments above and below, Y is 0.

In another embodiment, in conjunction with the novel compound embodiments above and below, Y is S.

In another embodiment, in conjunction with the novel compound embodiments above and below, R1 is -46- C In another embodiment, in conjunction with the novel compound embodiments above and below, R 7 is CI.salkyl, halo or Ci.

4 haloalkyl.

In another embodiment, in conjunction with the novel compound embodiments above and below, R' is a naphthyl substituted by 0, 1, 2 or 3 substituents independently selected from R 5 In another embodiment, in conjunction with the novel compound Sembodiments above and below, R' is Re substituted by 1, 2 or 3 substituents independently selected from R 5 In another embodiment, in conjunction with the novel compound embodiments above and below, R' 5 is -(CH 2 )nphenyl substituted by 0, 1, 2 or 3 C substituents independently selected from R' 0 In another embodiment, in conjunction with the novel compound embodiments above and below, R' 5 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from R' 0 In another embodiment, in conjunction with the novel compound embodiments above and below, R 1 5 is C 1 .galkyl substituted by 0, 1 or 2 substituents selected from R 1 0 In another embodiment, in conjunction with the novel compound embodiments above and below, R 5 is selected from C.galkyl, C 1 4 haloalkyl, halo, cyano, nitro, 8 alkyl), -C(=O)O(C 1 .salkyl), -C(=O)NRdRd, -C(=NRd)NRdRd, -ORd, -OC(=0)(Ci.8alkyl), -OC(=O)NRdRd, -OC(=O)N(Rd)S(=0) 2 (C -8alkyl), -OC 2 6 alkylNRdRd, -OC 2 -alkylORd, -SRd, .salkyl), 2 (C t.alkyl), 2 NRdRd, 2 N(Rd)C(=0)(C -8alkyl), 2 N(Rd)C(=O)O(C 1 _8alkyl), 2 N(Rd)C(=O)NRdR d -NRdR d -N(Rd)C(=O)(Ci .alkyl), -N(Rd)C(=O)O(Cisalkyl), -N(Rd)C(=O)NRdR d -N(Rd)C(=NRdNRdR d -N(Rd)S(=O) 2

(C

1 alkyl), -N(Rd)S(=0)2NRdRd, -NRdC 2 6 alkylNRdR d and -NRdC 2 -6alkylORd; or R' 1 is a saturated or unsaturated 6- or 7-membered -47 monocyclic or 10- or.1 -membered bicyclic ring containing 1, 2 or 3 atoms selected from N, 0 and S, wherein the ring is fused with 0 or 1 benzo groups and 0 or 1 saturated or unsaturated 6- or 7-membered heterocyclic ring containing 1, 2 or 3 atoms selected from N, 0 and S; wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 groups selected from C 1 .salkyl, CI-4haloalkyl, halo, cyano, nitro, 8 alkyl), -C(=0)O(C 1 salkyl), -C(=O)NR Rd, -C(=NR )NR Rd OR

-OC(=O)(C

1 .salkyl), _OC(=O)NRd R d -OC(=O)N(R d)S(=O) 2

(C

1 8 alkyl),

-OC

26 alkylNR dR d, -OC 2 6 alkyIOR d, -SR d, 1 8 alkyl), -S 2

(C

1 8 alkyl), 2 NRd R d -S(=O0) 2 N(R 1 .alkyl), 2 N(R d)C(=O)O(C 1 .alkyl), 2 N(R d)C(=O)NRd R d, -NRd R d, -N(R 1 -alkyl), -N(R d)C(=O)O(C 1 .8alkyl), -N(Rd)C(=O)NRd R d -N(R d)C(=NR d)NRdRd, -N(Rd)S(=O) 2

(C

1 8 a1 kyl), -N(R d)S(=O) 2 NR dR d, .d C 26 al kyINR dRd and -Nd C 2 _6alkylOR d; or R 10 is C 14 alkyl substituted by 0, 1, 2 or 3 groups selected from CI.

4 haloalkyl, halo, cyano, nitro, 1 .galkyl), -C(=O)O(C 1 8 alkyl), _C(=NRd )NR dR', -OR d, 8 alkyl), -OC(=O)NRd Rd, -OC(=O)N(R d)S(=O) 2

(C

1 8 alkyl), -0C 2 6 alkylNR dR d, -OC 2 6 alkyIO-Rd, -SR d, d d -S(=O)(CI.salkyl), 2 (Ci_ 8 alkyl), 2 NR R -S 2 N(R d)C(=O)(C 1 -8alkyl), -S 2 N(R d)C(=O)O(C 1 8 a1 kyl), d)C(=O)NRd R d Nd R d' -N(R 1.8alkyI), -N(R d)C(=O)O(C 1 .salkyl), -N(R d)C(=O)NRdR d, -N(R d)C(=NRd)NRd R d 2 salkyl), -N(R d)S(=O) 2 NRd Rd, .iPRd C 26 alkylNR d Rd and -NR dC 2 6 alkylOR'.

In another embodiment, in conjunction with the novel compound 2 5 embodiments above and below, R 16is, independently, in each instance, halo,

-NH

2

-NHC

1 3 alkyl, -N(C 1 3 alkyl)C 1 3 alkyI or Ci- 3 alkyI.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 4 is an unsaturated 6-membered ring containing 0 atoms selected from 0, N and S that is vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, -48- 1, 2 or 3 substituents independently selected from C,- 8 alkyl, C 1 4 haloalkyl, halo, cyano, ni tro, n, -C(=O)OR n, -C(=O)NR m

-C(=NR

m

)NR

m

-OR'

m -OC(=O)R n, -OC(=O)NR m

R

m

-OC(=O)N(R

m 2 R n, -OC 2 6 alkylNR'Rrn,

-OC

2 -6alkylOR', n, -S 2 2

NR

m

R

m 2

N(R

m -S 2

N(R

m 2

N(R

m

)C(=O)NR

m

R

m

-NR

m R -N(R m n, -N(R m

-N(R

m -N(Rrf)C(=NR m

)NR

m

R

m

-N(R

m )S(=O0) 2

-N(R

m 2

NR

m

R

m

-NR

m

C

2 6 alkyINR m

R

m

-NR

m

C

2 6 alkylOR', C(=O)ORs, -C(=O)NRnR', -C(=NRrn)NRrnRs, .iRs, OC(=O)Rs, -OC(=O)NRnRs, -OC(=O)N(Rrn)S(=O) 2 Rs, -OC 2 _6alkylNR ~Rs, -OC 2 6 alkyIORs, -SRs, -S(=O)Rs, 2 -S 2 NRnRS, 2 N(Rrn)C(=O)Rs, 2 N(Rrn)C(=O)ORs, -S 2 N(Rrn)C(=O)NRnRS, 44IRrRs, -N(Rrn)C(=O)Rs, -NCRr)C(=O)ORs, -N(Rrn)C(=O)NRnRs, -N(Rrn)C(=NRn)NRrnR', -N(Rrn)S(=O) 2 Rs, -N(Rrn)S(=O) 2 NR'R', -NR m

C

2 6 a1 kylNRnRs, -NRnC 2 6 alkylORs and C 1 4 alkyl substituted by I or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro,

-C(=O)NR

m

R

m

-C(=NR

m

)NR

m

R

m -ORm,

-OC(=O)NR

m

R

m

-OC(=O)N(R

m )S -OC 26 al kylNR m

R

m -OCi~alkylOR m

-SR

m -S 2 RU -S 2

NR

m

R

m 2

N(R

m 2

N(R

m 2 N(Rm)C(=O)NR m

-NR

m

R

m

-N(R

m

-N(R

m )C(=O)NR R,

-N(R

m

)C(=NR

m

)NR"'R

m

-N(R

m 2

-N(R

m )S(=O0) 2

NR

m

R

m

-NR

m

C

2 6 alkylNR m -NR MC 2 6 al ky]OR, ~(OOs -C(=O)NRnRs, -C(=NRrn)NRrnRs, OW, .0C(=o)Rs, -OC(=O)NRrnR,

-OC(=O)N(R

m )S 2 Rs, -OC 2 6 alkylNRnR', -OC1.

6 alkylOR', 2 2 NRnR', 2 N(Rrn)C(=O)Rs, 2 N(Rrn)C(=O)ORs, -S 2 N(Rrn)C(=O)NRnRS, -NRrnRs, N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRnR', -N(Rrn)C(=NRn)NRnR', -N(Rrn)S(=0) 2 Rs, -N(Rrn)S(=O) 2 NRrnRs, -NRnC 2 -6alkylNRnR', -NRn, C 2 6 alkylOR'; and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 4 is a saturated or unsaturated 5- or 6-membered ing containing 1, 2 or 3 atoms selected from 0, N and S that is vicinally fused -49 with a saturated or unsaturated 3- or 4-atom bridge containing 0 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from CI-8alkyI,

C

1 4haloalky1, halo, cyano, nitro, -C(=0)OR n, -C(=O)NR m

R',

-C(=NR

m

)NR

m

-OR'

m -OC(=O)R -OC(=O)NR m

R,

-OC(=O)N(R

m 2 Rn, -0C 2 6 a1 kylNR m

-OC

2 6 a1 kylOR m

-SR

m -S 2 2

NR

m 2

N(R

m 2

N(R

m

)C(=O)OR,

-S 2 N(Rm)C(=O)NR m

-NR

m

R

m

-N(R

m

-N(R

m

-N(R-)C(=O)NR

m 2 R n,

-N(R

m 2

NR

m

-NR

m

C

2 _6aIkyINR m

-NR

m

C

2 _6alkyIOR., -C(=O)ORs, -C(0)PRRs, -C(NRn)PRRs, -ORs, -OC(=O)R S -OC(=O)NRnR', -OC(0)N(R m )S 2 Rs, -0C 2 6 alkylNRnRs, -OC 2 6 alkylORs, -SRs, -s 2 -S 2 NRnRs, 2 N(Rrn)C(=O)R', -S 2 N(Rrn)C(=O)ORs, -S 2 N(Rm)C(=O)NRnRs, -NRrnR', -N(Rrn)C(=O)R', -N(Rr)C(=O)0Rs, -N(Rrn)G(=O)NRnR', -N(Rrn)C(=NRn)NRmlR',

-N(R

m )S 2 Rs, -N(R m )S 2 NRnRs, -NRrnC2,alkyNRnR', -NR m

C

2 -6alkylORs and C 14 alkyl substituted by I or 2 groups selected from CI- 2 haloalkyl,: halo, cyano, ni tro, n, -C(=O)OR n, -C(=O)NR m

R

m -C(=NRn)NR m Rml, -OR m -OC(=O)R n, -OC(=O)NR m

R

m

-OC(=O)N(R

m )S 2 R n, -OC 2 -6alkylNR m

R

m

-OC

26 alkylOR', -SR m 2 2

NR

m

R',

-S 2

N(R

m -S 2

N(R

m 2

N(R

m

)C(=O)NR

m

R',

-NR

m

-N(R

m n, -N(R m )C(=O)OR n, -N(R m

)C(=O)NR

m

-N(R

m

)C(=NR

m

)NR

m

R

m

-N(R

m 2 -N(Rm)S 2

NR

m

R',

-NR

M

C

2 6 aIkyINR m

R

m

-NR

m

C

2 6 a1 kyl OR m C(0)ORs, -C(=O)NRnR', .C(=NRn)NR n Rs, -ORs, -OC(=O)NRnRs, 2

-OC

2 6 alkylNR m

-OC

2 6 alkylORs, -SRs, -s 2 Rs, -S 2 NRnRs, -S 2 N(Rrn)C(=O)RS, -S(=O),N(Rrn)C(=O)ORs, -S 2 N(Rrn)C(=0)NRnRs, .MWrRs -N(Rrn)C(=O)Rs, -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRnR', -N(Rrn)C(=NRrn)NRnRs, -N(R m )S 2 Rs, -N(Rrn)S(=O) 2 NRnR', -NRrnC 2 6 alkylNRrnRs, -NRnC 26 alkyIORs; and the ring and 50 bridge carbon atoms are substituted with 0, 1 or 2 =0 groups; but in no instance is R 4 3,5-ditri fiuoromethyl phen yl or 3-trifi uorometh yl -4-fluorophenyl.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 4 is a saturated or unsaturated 6-membered ring containing 0 atoms selected from 0, N and S that is vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from CI-8alkyl, C,- 4 haloalkyl, halo, cyano, nitro, -C(=O)NR m

-C(=NR

m

)NR

m

-OR'

m -OC(0)NR m

R

m -OC(=0)N(R m )S 2 R n, -OC 2 6 alky]NR'R', -0C 2 6 alkylOR m

-SR

m 2 R n, 2 NRnRml, 2

N(R

m 2 N(R 2

N(R

m )C(=0)NR m

R

m

-NR

m

R

m

-N(R

m n, -N(R m )C(=0)0R n, -N(Rm')C(=0)NR m

R

m

-N(R-)C(=NR-)NR

m -N(R )S 2

-N(R

m 2

NR

m

-NR

m

C

2 6 aI kylNR m

-NR

m

C

2 6 aI kylOR m -C(=0)0R -C(=0)NRnR', -C(=Rn)N4TRn -0C(=0)NRR', -OC(=0)N(R

M

)S 2 Rs, -0C 2 6 a1 kyINRRs, -0C 2 6 alkyl0R', 2 2 NRmR', 2 N(Rrn)C(=0)R', -S 2 N(Rrn)C(=0)ORS, 2 N(Rrn)C(=0)NRnRs, -NRnRs, -N(Rr )C(=0)ORs, -N(Rrn)C(=0)NRnR', -N(Rrn)C(=NRrn)NRrnR', -N(R m )S 2 Rs, -N(Rrn)S(=O) 2 NRnR', -NR m

C

2 6 alkylNRrnRs, -NRnC 2 6alkyl0R' and C 1 4alkyl substituted by 1 or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=0)NR m1

-C(=NR

m

)NR

m

R

m

-OR'

m -0C(=0)R, -OC(=0)NR-R m -OC(=0)N(R m )S 2 -0C 2 6 alky]NR m -0C 2 6 a1 ky1ORmI,

-SR-

m 2 R 2

NR

m

R

m 2

N(R

m 2

N(R

m -S 2

N(R"

1 )C(=0)NR m

R

m

-NR

m

R

m

-N(R

m

-N(R

m )C(=0)NR m

-N(R

m

)C(=NR

m

)NR

m

R

m -N(Rm)S 2

-N(R

m )S 2

NR

m

R',

-NR

M

C

2 6 alkylNR m

-NR

m

C

2 -6alkylOR m -C(=0)0Rs, -C(=0)NRnR', -C(=NRrn)NRnR', 0C()RS, -OC(=0)NRnR', -OC(=0)N(Rn)S(=0) 2 Rs, -0C 2 6 alkylNRnRs, -0C 2 6 alky]OR', -SRs, -S(=O)Rs -51 -S 2 Rs, 2 NTRRs, -S(=O0) 2 N(Rr)C(=0)Rs, -S 2 N(Rn)C(=O)ORS, 2 N(Rn)C(=O)NRnR', -N4RnRs, N(Rr)C(0O)Rs, -N(Rr)C(=0)0Rs, ~~N(Rr)C(=0)NRnR', -N(Rrn)C(=NRn)NRrnR5, -NQR m )S 2 Rs, -N(Rrn)S(=0) 2 NRnR', NRnC 2 6 alkylft4I'rn, -NR m

C

24 salkylOR'; and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups; but in no instance is

R

4 3,5-ditrifluoromethyiphenyl or 3-trifluoromethyl-4-fluorophenyl.

In another embodiment, in conjunction with the novel compound embodiments above and below, R i a saturated or unsaturated 5- or 6-membered ring containing 1, 2 or 3 atoms selected from 0, N and S that is vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from Cl-galkyI,

C

1 4 haloalkyl, halo, cyano, nitro, -C(=O)NR m

R

m

-OR-

m -OC(=0)NR-~R m -OC(=0)N(R m 2

-OC

2 6 alkylNR m -0C 2 6 alkylOR', -S 2 2

NR-R

m -S 2

N(R

m n, -S 2

N(R

m -S 2

N(R

m )C(=0)NR m

-NR

m

-N(R

m

-N(R

m )C(=0)NR m

-N(R

m

)C(=NR

m

)NR

m

-N(R

m 2 R

-N(R

M

2

NR

m Rml, -NR

M

C

2 6 alkylNR m

R

m

-NR

M

C

2 6 alkylOR m .C(0)F -C(=0)ORs, C(=0)NRl'R' -C(=NRn)NRm~R', -ORS8 .0C(0)Rs -0C(=0)NRnR', =OC(=0)N(Rn)S(=O) 2 Rs, OC 2 6 al kyl N.RrnR, OC 2 6 al kyloRs, -SRS, -S 2 .5 (o) 2 NRmRn' 2

N(R

m -S 2

N(R

m )C(=0)0R 5 2

N(R

m )C(=0)NR m -NRr'Rs, -N(Rrn)C(=O)R',

-N(R

m )C(=0)0R 5

-N(R

m

)C(=NR

m

)NR

m

R',

-N(Rm 1 5

-N(R

m )S 2

NR

m

-NR

m

C

26 aI kylNRnRS, -NR m

C

26 alkylOR' and C 14 alkyl substituted by I or 2 groups selected from Ci.

2 haloalkyl, halo, cyano, nitro, -C(=0)NR m Rm 1

-C(=NR

m

)NR

m

R

m

-OR

m -0C(=O)NR m RlX -OC(=0)N(R m 2 R n, -OC 2 6 alkyl NR m

R

m

-OC

26 alkylOR m

-SR

m n, 2 2

NR

m -S 2

N(R

m -S 2 N(R')C(=O)0R 2

N(R

m

)C(=)NR

m

R

m

-NR

m

R

m

-N(R

tm n, -N(R tm )C(=O)0R n, -N(R tm

)C(=O)NR

m

R

m -52-

-N(R

m

)C(=NR

m

)NR

m

R

m

-N(R

m 2 RO, 2

NR

m

R

m

-NR

m

C

2 6 alkylNR m

R

m

-NR

M

C

2 .(alkyl OR m -C(=O)ORs, -C(=O)NRnR', -ORs, OCQ..O)NRrnRs OC(=O)N(Rn)S(=O) 2 Rs, -OC 2 6 alkylNRnRs, -OC 2 6al ky] ORS, -SRs, -S (=O)Rs, 2 Rs, -S(O) 2 N-RnRs, 2

N(R

m 2

N(R

m )C(=O)0Rs, 2

N(R

m

)C(=O)NR

m Rs, 4pNRnR' N(Rr)C(=O)Rs, -N(R m )C(=O)0R 5 -N(Rm)C(=O)NR m

-N(R

m

)C(=NR

m

)NR

m

-N(R

m 2

R',

-N(R

m 2

NR

m

-NR

m

C

2 6 alkylNRnRs, -NRnC 2 6 alkylOR'; and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups; but in no instance is R 4 3,5-ditrifluoromethyiphenyl or 3-trifluoromethylA4-fluorophenyl.( In another embodiment, in conjunction with the novel compound embodiments above And below, R 9 is H.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 9 is independently, at each instance, C 1 -galkyI,

C

1 4 haloalkyl, halo, nitro, cyano, -OCI 1 6 aikyl, -OCI.

4 haloalkyl, -OC 2 16alkylNR dRd

-OC

2 6alky]OR d, -NR dR d, -NRdC,-haloalkyl, -NR dC 2 -6alkylNR dR dor -NRd C 2 6 alkylOR d, _C0 2

(CI-

6 alkyl), 1 6 alkyl), -C(=O)NRd R d _NRdC(=O)(C 1 6 alkyl), _NRdC(=O)NR dR d, -NR dCO 2

(CI.

6 alkyl), -CI-8alkylOR d dd d -0C(=O)NRdRd.

In another embodiment, in conjunction'with' the novel compound embodiments above and below, R 9 is a -(CR qR q),,phenyl wherein the phenyl is substituted with 0, 1, 2, or,3 substituents independently selected from R' 0 In another embodiment, in conjunction with the novel compound embodiments above and below, R9 is -(CRqRq) 0 Het wherein Het is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from 0, N and S substituted with 0, 1, 2, or 3 substituents independently selected from R' 0 or R 9 is a saturated or unsaturated 4- or 5-membered ring heterocycle containing a single nitrogen atom, wherein the ring is substituted with 0, 1 or 2 substituents independently selected from halo, C 1 2 haloalkyl and CI.

3 alkyl.

Another aspect of the invention relates to a compound having the structure: -53or any pharmaceutically-acceptable salt thereof, wherein: YisOorS; n is independently, at each instance, 0, 1 or 2.

R' is

R

6

R

R

9 or R' is a naphthyl substituted by 0, 1, 2 or 3 substituents independently selected from or R' is R i substituted by 1, 2 or 3 substituents independently selected from R 5

R

15 is, independently, in each instance, R 1 0 Cl-galkyl substituted by 0, 1 or 2 substituents selected from RI 0

-(CH

2 ),phenyl substituted.by 0, 1, 2 or 3 substituents independently selected from R' 1 or a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, the heterocycle and bridge being substituted by 0, 1, 2 or 3 substituents independently selected from

R

16 is, independently, in each instance, H, halo, -NH 2

-NHC

1 3 alkyl, -N(Ci.

3 alkyl)CI.

3 alkyl, -OCi_ 3 alkyl, -Ci.

2 haloalkyl, -OC 1 i 2 haloalkyl or Ci.

3 alkyl; 54 R~Rio R14 R12 R R3 wherein when R' is bromophenyl, methyiphenyl or trifluoromethylphenyl, R 4 is not trifluoromethylphenyl'or trifluoromethylhalop .henyl; or k4 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from 0, N and S, so long as the combination of 0 and S atoms is not greater than( 2, wherein each of the carbon atoms of the heterocycle is substituted by H, h_

C

19 galkyl, C 1 4 haloalkyl, halo, cyano, oxo, -OR 6 alkyl, -OC14haloal kyl, -OC 2 6 alkylNR R h, _OC 2 6 alkyIOR.h, -OCI 6 a1 ky]C(=O)OR h, -NR hR h, -NR hC 1 4 haloalkyl, -NR hC 2 6 alkylNRhR h, -NRh 2 alkylOR h,

-C(=O)C

1 6 a1 kyl, -C(=O)OCa.

6 alkyl, -OC(=O)C 1 6 a1 kyl, -C(=O)NRhd .I 6 alkyl or -NRhC=OCi 6 alkyl; And saturated carbon atoms may be additionally substituted by and each of the available nitrogen atoms in the heterocycle are substituted by H I-6lklOh,-C 1 6 alkYl, -CI- 6 alkylNR hR h, _C, 3 alkyC(=O)OR.h,

-CI-

3 alkylC(=O)NR 3 alkylOC(=O)C 1 6 alkyl, 1'i alkylINRhC=),akl or -C 1 3 alkylRj; or R 4 is an 10- or 1 1-membered bicyclic ring, containing 0, 1, 2, 3 or 4 N atoms and 0, 1 or 2 atoms selected fro m S and 0 with the remainder being carbon atoms, wherein each of the carbon atoms of the ring is substituted by H, CI.

9 alkyl, C 1 4 haloalkyl, halo, cyano, oxo, -OR h,

-S(O)WI.

6 alkyl, -OCI 1 4 haloalkyl, -OC 26 alkylNR hR h, -OC 2 6 alkylOR h

-OCI.

6 alkyIC(=O)0R h, _NRh _NRhC I 4 haloalkyl, -NR hC 2 6 alkyINRh R h -NRh C 2 6 alkylOR h, -C(=O)C 1 6 alkyl, -C(=O)OC 1 6 alkyl, -OC(=O)C 1 6 alkyl, -C(=0)NR hC 1.

6 alkyl or -NR hC(=O)C 1-alkyl; and saturated carbon atoms may be additionally substituted by and any available nitrogen atoms in the ring are substituted by H, -CI- 6 alkyl0R h, CI 6 alkyl, -Ci.alkyINRh Rh,

-C

1 3 alkylC(=O)OR h, -C 1 3 alkylC(=O)NR hR.h, -C 1 3 alkylOC(=O)C 1 6 alkyl,

-C

1 3 alkyINR hC(=O)CI -6a1 kyl, or -CI- 3 alkylRj;

R

5 is independently, at each instance, H, CI-5alkyI, C,- 4 haloalkyl, halo, nitro, -OC 1 6 alkyl, -OCI- 4 haloalkyl, -0C 2 6 alkylNR hR', -OC 2 -6alkylOR h, -N R R h -NR hCI4haloalkyI, _NRh C 24 ialkylNR hR', -NR hC 2 ,alkylOR h, naphthyl, -C0 2

(C

1 6 a1 kyl), 1 6 al kyl), _C(=O)NRh Rh, -NRhC(=O)R h _NhC(=O)NRhR h -NRhCO 2 (CI-6al kyl), -C 1 .salkylOR h q 6alkyINR hR h, -S(=O)n(C 1 6 alkyl), 2 NR hR h, _NRhS(=O) 2 (CI-6alkyl), -OC(=O)NR hR h, a phenyl ring substituted with 0, 1, 2, or 3 substituents independently selected from R 0;or R 5 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from 0, N and S, substituted with 0, 1, 2, or 3 substituents independently selected from Rio;

R

6 is independently, at each instance, H, C 1 5 alkyl, C 1 4 haloalkyl, halo, -0CI 6 a1 kyl, -0C 1 4 haloalkyl, -0C 2 6al kyl NRh Rh, -0C 2 6 alkyl0R h, -NRh, -NRh Ci 4 haloalkyl, -NR C 2 6 alky INRh Rh or -NR hC 2 6 alkylOR h, -CI-8alkylOR, -Ci.,alkylNRh -S(C 1 6 alkyl), a phenyl ring substituted with 1, 2, or 3 substituents independently selected from Rio; or R 6 is a saturated or unsaturated or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from 0, N and S substituted with 0, 1, 2, or 3 substituents independently selected from Rio; R 7 is independently, at each instance, H, CI-8alkyl, C,4haloalkyl,.

h h h _h R h -NRhCl- 4 haloalkyl, -NR C -,alkyINRh -NR C 2 &6alkylOR h,

-CI.

8 a~kylOR h, -C 1 6 alkyINR hR hor -S(C 1 -6alkyl); or R 7is a saturated or unsaturated 4- or 5-membered ring heterocycle containing a single nitrogen atom, wherein the ring is substituted with 0, 1 or 2 substituents independently selected from halo, CI- 2 haloalkyl and CI- 3 alkyl;

R

8 is independently, at each instance, H, C 1 salkyl, C 1 4haloalkyI, halo,

-OCI.

6 alkyl, -OCI 1 4 haloalkyl, -OC 26 alkylNRh Rh, -0C 2 -6alkyl0R h, -~RRh, -NR hC 1 haloalkyI, -NR hC 2 6 alkyl NRh R h, -NR hC 2 6 alkylOR h, -CI-8alkylOR h, -Ci.

6 alkylNR hR h, -S(CI.

6 alkyl), a phenyl ring substituted with 1, 2, or 3 substituents independently selected from R1 0 or R 8 is a saturated or unsaturated or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from 0, N and S substituted with 0, 1, 2, or 3 substituents Independently selected from R' 0 -56-

R

9 is independently, at each instance, H, CI-8alkyl, C 1 4 haloalkyI, halo, nitro, -OCI 1 6 alkyl, -0CI .4haloalkyl, -OC 2 6 alk ylNhRhI

-OC

2 -6alkylOR h, -NIR -NR hC ,haloAlkyl, -NR hC 2 _6alkylNR R hor _NRhC 26 alkyloR h -C0 2 (Cl.

6 alkyl), 6 alkyl), _C(=O)NRh Rh, -NR hC(=O)(C 1 6 alkyl), -NR C(=O)NR hR', -NR hCO 2

(C

1 .alky1), -CI-8alkylOR h, -Ci 1 6 alkyINRh R h, -S=),Cakl,-(02RR' -NrR hS(..O) 2

(CI.

6 alkyl), -OC(=O)NR hR h, a phenyl ring substituted with 0, 1, 2, or 3 substituents independently selected from R' 0 or R 9 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from 0, N and S substituted wit~h 0, 1, 2, or 3 substituents( tO 6 7 8 independently selected from R10; wherein at least one of R R R R and R 9 is Ct- 8 alkyl, C]l4haloalkyl, halo, -OC 1 -4haloalkyl,

-OC

2 _6alkylNR hR h, -0C 24 ialkyl0R h, -NRhCi.

4 haloalkyl, _N~h C 2 ,alkylNR hR h, -NRhC 2 6 alkyl0R h, -C 1 .salkylOR h, -CI- 6 alkylNRh R' or -S(C 1 6 alkyI); or R9 is a saturated or unsaturated 4- or 5-membered ring heterocycle containing. a single nitrogen atom, wherein the ring is substituted with 0, 1 or 2 substituents independently selected from halo,

C,-

2 haloalkyl and CI- 3 aikyl; R1 0 is independently, at each instance, selected from H, Cl-galkyl,

C

1 4 haloalkyl, halo, cyano, nitro, -C(0O)(C 1 salkyl), -C(=0)O(Cf- 8 alkyI),.

-C(=0)NR hR h, _C(=NRh)NRh Rh, -OR h, -OC(=0)(C 1 salkyl), _OC(=O)NRh Rh, -OC(=O)N(R h)S(=0) 2 (CI-8alkyl), -OC 2 6 alkylNRh -OC 2 6 alkyl0R h, -SR h, h h -S(=0O)(C 1 salkyl), 2

(C

1 .galkyl), 2 NR R 2 N(R h)C(=0)(C 1 -galkyl), 2 N(R h)C(=O)0(C 1 -8alkyI), 2 N(Rh)C(=0)NR hR h, -N~Rh' -N(R h)C(0)(C 1-alkyl), -N(R h)C(=0)0(iC 1.alkyl), -N(R h)C(=0)NRh R h, _N(Rh)C(=NRh)NRh Rh, -N(Rh)S(=O) 2

(C

1 8 a1 kyl), -N(R h)S (0)NRR h -N'26~yN and -NR hC 2 6 alkylORh; or R1 is a saturated or unsaturated 6- or 7-membered monocyclic or 10- or 1 1-membered bicyclic ring containing 1 or 2 3 0 atoms selected from N, 0 and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 57 and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 groups selected from CI-SalkyI,C C 1 4 haloalkyl, halo, cyano, nitro, 1 8 alkyl), -C(=O)O(C 1 .gal kyl), -C(=O)NR hR h, _C(=NRh)h Rh, -OR', -OC(=O)(CI-8alkyl), -OC(=O)NRh R h, -OC(=O)N(R h)S(=O) 2 (C 1 -galkyl),

-OC

2 6 alkylNRh Rh, -OC 2 6 alkyIOR', -SR h, 1

(I

8 alky1), 2 (C 8 alkyl), -S 2 NRhR h, 2 N(R h)C(=O)(C 1 8 al kyl), -S 2 N(R h)C(=O)O(C 1 -8alkyl), 2 N(R h)C(=O)NR R h, -NR hR h, -N(R h)C(=O)(Cis-alky1), -N(R h)C(=O)O(C 1 _alkyl), -N(R h)C(=O)NR hR h, -N(R h)C(=NR h)NR hR', -N(R h)S 2 (Cz-8alkyl), -N(R h)S(=O) 2 NR hR h, -NRh C 2 6 alkylNRh R hand -NR hC 2 -alky]OR h; or R1 is C 1 4 alkyl substituted by 0, 1, 2 or 3 groups selected from C 1 4 haloalkyl, halo, cyano, nitro, 1 .galkyI), _C(=O)NR hR h, -C(=NR ,)NRh R h, -OR h, -OC(=O)(C 1 .galkyl), -OC(=O)NRh Rh, -OC(=O)N(R h)S 2

(C

1 .salkyl), -0C 2 6 al kyl NRh Rh, -OC 2 6 alkylOR h, -S Rh, 8 alkyl), 2

(C

1 .salkyI), 2 NRhR h, 2 N(R h)C(=O)(Ci 1-al kyl), -S 2 N(R h)C(=O)O(C 1 8 alkyl), 2 N(R h)C(_O)NRh -NRh R h, -N(R I -al kyl), -N(R h)C(=0)O(C 1_8alkyl), -N(R h)C(=O)NR hR h, -N(R )C(=NR h)NRh Rh, -N(R h)S 2

(C

1 .salkyl), -N(R h)S(=O) 2 NR hR h, -NRhC 2 6 a1 kylNR h Rh and -NR hC 2 6 alkylOR h R" is independently, at each instance, selected from H, CI-8alkyl,

C

1 4 haloalkyl, halo, cyano, nitro, 1 .galkyl), -C(=O)O(C 1 salkyl), -C(=O)NR hR h, -C(=NR h)NR'R h, -OR h, -OC(=O)(CI- 8 alkyl), -OC(=O)NRh Rh, -OC(=O)N(R h)S(=O) 2 (Ci~galkyl), -OC 2 6 alkylNRh Rh, -OC 2 6 alkylOR h, -SR h 1 8 alkyl), 2

(C

1 .salkyl), 2 NR R h 2 N(R 1 .a1 kyl), -S 2 N(R h)C(=O)O(C 1-galkyl), 2 N(R h)C(=O)NRhR h, NRhR h -N(R 1 8 a1 kyl), -N(R h)C(=O)O(C 1 .salkyl), -N(Rh)C(=O)NRh Rh, -N(R h)C(=NRh )NR R', -N(R h)S 2

(C

1 8 a1 kyl), -N(R h)S(O) 2 NRh Rh, I-NR'C 2 6 a1 kyl NRh Rh and -NR hC 2 6 alkylOR h; or R 11is a saturated or unsaturated 6- or 7-membered monocyclic or 10- or 11 -membered bicyclic ring containing 1, 2 or 3 atoms selected from N, 0 and S, wherein the ring is fused with 0.or I benzo 58 groups and 0 or I saturated or unsaturated 6- or 7-membered heterocyclic ring containing 1, 2 or 3 atoms selected from N, 0 and S; wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 groups selected from Ci-salkyl, C 1 4haloalkyl, halo, cyano, nitro, 8 alkyl), -C(=O)O(Cjgalkyl), -C(=O)NRhR .C(=NRh )NRhRh ORh,

-OC(=O)(CI-

8 alkyl), -OC(=O)NRh R -OC(=O)N(R h)S(=O) 2 (CI-8al kyl),

-OC

2 6 alky1NR hR h, -OC 24 ialkylOR h, -SR h, 1 8 alkyl), 2

(C

1 8 alkyl), -S 2 NRhRh, -(ON()CO)(Ci 8 a1 kyl), -S 2 N(Rh)(OOC g-alkyl), 2 N(R h)C(=O)NR hR h, -NR R h, -N(R h)C(=O)(Ci -8alkyl), -N(R h)C(=O)O(C 1-8alkyl), -N(R h)C(=O)NRh R h* -N(Rh)C(=NRh)NR hR', -N(R h)S 2

(C

1 8 a1 kyl),' -N(R h)S 2 N~h R h _h C 2 6 alkylR h and -NR hC 2 6 alkylOR h; or R' 1IS C 14 alkyl substituted by 0, 1, 2 or 3 groups selected from C 1 4 haloalkyl, halo, cyano, nitro, 1 8 alkyl), -C(=O)O(Cj~galkyl), -C(=O)NR hR', -C(=NRh)NRh Rh, -OR h -OC(=O)(C 1 .salkyl), -OC(=O)NR hRh, -OC(=O)N(R h)S(=O) 2 (C1-sa1 kyl), -OC 2 6 alkylNRhR h oC 26 alkyloRh -S R', 1 salkyl), 2

(C

1 8 alkyl), 2 NRhRh, 2 N(R h)C(=O)(Ci -8alkyI), -S 2 N(R h)C(=O)O(C 1 _alkyly, 2 N(Rh)(=O)NR R I N R N(R )(=)(8alkyl), h)(OOC 8ly) N(R h)C (=O)NR hkh, -N(R h)C(=NRh )NRhR h, -N(Rh)S(=O) 2 (CI-8alkyl), N(R h)S(=0) 2 NRh R h _NRh C 2 6 alkylNR hR h and -NR h C2alkylOR h; R'1 2 is independently, at each instance, selected from H, C 18 galkyI,

C

1 4 haloalkyl, halo, cyano, nitro, -C(=O)O(C 1 8 alkyl), -C(=O)NR Rh, _C(=NRh )NR h Rh, -OR h, -OC(=O)(C 1 salkyl), -OC(=O)NR hR', -OC(=O)N(R h)S(=O) 2 (Cj~galkyl), -OC 2 6alkylNR hR", -0C 2 6 alkylOR h,-SR h h h -S(=O)(CI-8alkyl), 2

(C

1 8 alkyl), 2 NR R 2 N(R h)C(=O)(Ci 8 alkyl), 2 N(R h)C(=O)O(CI .galkyl), 2 N(R h)C(=O)NR hR h, -NR hR h, -N(R h)C(=O)(Ci .8alkyl), -N(R h)C(=O)O(C 1.8alkyI), -N(R h)C(=O)NRh Rh, -N(R h)C(=Rh)pR h Rh, -N(R h)S(=O) 2 (C,.saI kyl), -N(Rh)S (0) 2 NR hRh, .t4Rh C 2 6 alkylNRhR h and -NR hC 2 6 alkylOR h; or R 12is a saturated or unsaturated 6- or 7-membered monocyclic or 10- or I 1-membered bicyclic ring containing 1, 2 or 3 59 atoms selected from N, 0 and S, wherein the ring is fused with 0 or 1 benzo groups and 0 or 1 saturated or unsaturated 6- or 7-membered heterocyclic ring containing 1, 2 or 3 atoms selected from N, 0 and S; wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 groups selected from CI-8alkyl, C 1 4 haloalkyl, halo, cyano, nitro, 1 8 alkyl), -C(=0)0(CI-8alkyI), -C(=O)NR hR h, c(=N.Rh)NRh Rh, -OR h, .salkyl), -OC(=O)NR hR h, -OC(=O)N(R h)S 2 (C 1 8 a1kyl),

-OC

2 6 alky]NR hR", -OC 2 6 alkylOR h, 8 alkyl), -S 2

(C

1 .galkyl), 2 NR hR', 2 N(R 8 alkyI), 2 N(R h)C(=0)O(C1-alky1), 2 N(R h)C(=O)NRh R h, -NR R h, -N(R h)C(=0)(Cl _alkyI), -N(R .salkyl), -N(R h)C(;=O)NRh Rh, -N(R h)C(=NR h)NR.h Rh, -N(R h)S(=O) 2 (Cts8alkyl), N(R h)S(=O) 2 NR hR h,._N~C 2 6 alkylN{~h R' and -NR h C2_alkyIOR h; or R 12 is C,- 4 alkyl substituted by 0, 1, 2 or 3 groups selected from CI.

4 haloalkyl, halo, cyano, nitro, -C(=O)O(CI- 8 akyl), _C(=O)NRh Rh, -C(=NRh)NR hR h, 8 alkyl), .0C(=)NR hR', -OC(=O)N(R h)S 2 (CI-8alkyI), -OC 2 6 alkylNR h Rh, -OC 2 -6alkyl0R -SRh, h h .salkyl), 2 (C ,.salkyl), 2 NR R, 2 N(R 8 a1 kyl), 2 N(R h)C(=0)O(C 1 .salkyl), 2 N(R h)C(=0)NR hR h, .INpI -N(R h)C(=O)(C 1 .sal kyl), -N(R 1-alkyl), -N(R h)C(=O)NR h Rh, -N(R h)C(=NR h)NR hR h, -N(R h)S(=O) 2 (Ci 1-alkyl), -N(R h)S(=O) 2 NR hR h, _N C26lNR hR h and -Nh C2.akyl0R h; R 1 3 is independently, at each instance, selected from H, C,.

8 alkyI,

C

1 4 haloalkyl, halo, cyano, nitro, 1 8 a1ky]), .8alkyI), -C(=O)NR hR h, _C(=NRh)NRh Rh, -OR h -OC(=0)(Cl.8alkyl), -OC(=O)NR R h, h .8alkyI), 2 (Cj_ 8 al kyl), 2

NR"R",

-S 2 N(R h)C(=O)(Cl.

8 a1 kyl), -S 2 N(R 8 a1 kyl), -S 2 N(R h)C(=O)NR R h, -NRhR h, N(R h)C(0)(C 1 .salkyl), -N(R .sal kyl), -N(R h)C(=0)NR hR h, N(R h)C(=NR h)NRh R h -N(R h)S 2

(C

1 salkyl), -N(Rh)S(=O) 2 Nkh Rh, -NhC 2 -6alkylNh Rh and _N~4h C 2 6 alkylOR h; or R 1 3 is a saturated or unsaturated 6- or 7-membered monocyclic or 10- or I 1-membered bicyclic ring containing 1, 2 or 3 atoms selected from N, 0 and S, wherein the ring is fused with 0 or 1 benzo groups and 0 or 1 saturated or unsaturated 6- or 7-membered heterocyclic ring containing 1, 2 or 3 atoms, selected from N, 0 and S; wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 groups selected from CI-salkyl, C,- 4 haloalkyl, halo, cyano, nitro, 1 .galkyl), -C(=O)O(CI.8alkyl), Ob

-OC(=O)(C

1 .galkyl), -OC(=0)NR -OC(=O)N(R 2 .galkyl), h h -S 2 NR R h, 2 N(R h)C(=O)(C 1 8 al kyl), 2 N(R h)C(=O)0(C 1 8 al kyl), 2 N(Rh)C(=O)NR -NRh R h, -N(R h)C(=O)(C 1 .galkyl),.

h)(=OO(C -8lkl),-N( h)(=ONRh h, h C=RhN Rh -N(R h)S(=0) 2

(C

1 8 alkyl), -N(Rh)S(=0) 2 NR R h, -NRh 2 alkylNRhR h and -NR hC 2 6 alkylOR h; or R 13IS Ci- 4 alkyl substituted by 0, 1, 2 or 3 groups selected from Ci- 4 haloalkyl, halo, cyano, nitro, 1 8 alkyI), -C(=O)O(C 1 8 alkyl), -C(=O)NR hR', -C(=NRh)NR R h, -OR h, -OC(=O)(C 1 8 alkyl), 'OC(=0)NR hR4, -OC(=O)N(R h)S 2 (C,.sa~kyI), -OC 2 6 alkylNR hR h, -0C 2 -6alkyIOR', -SRh, -S(=0)(CI-8alkyl), 2

(C

18 alkyl), 2 N hRI 2 N(R 1 .alkyl), 2 N(R h)C(=O)O(C 1-alkyI), 2 N(R h)C(=0)NR hR h, -NR"R h, -N(R 1 .salkyl), -N(R h)C(=O)O(C 1 8 a1 kyl), -N(R h)C(=O)NRh R h, -N(R h)C(=NRh)NR'R h, -N(R h)S 2

(C

1 gal kyl), -N(Rh)S (O) 2 Nh Rh,_ h 2kYIRh R and -NR hC 2 6 alkyIORh; R 1 4 is independently, at each instance, selected from H, C 1 8 alkyl,

C

1 4 haloalkyl, halo, cyano, nitro, 1 salkyl), -C(=O)O(C 1 .salkyl), R h C(=Nh )NR hRh, -OC(=0)(C 1 8 a1 kyl), -OC(=O)NR hR h, -OC(=O)N(R h)S(=O) 2

(CI

1 8 alkyl), -OC 2 6 alkylNR hR h, -OC 2 ,alkyl0R h, -SR h 1 .salkyI), 2

(C

1 .8alkyl), 2 NR R h 2 N(R" 1 .alkyl), 2 N(R 1 .salkyl), 2 N(R h)C(=O)NR hR h, _RhR', -N(R 18 alkyl), -N(R h)C(=O)0(Cis.alkyl), -N(R h)C(0)NR R h, -N(R h)C(=NRh)NRhR h, -N(Rh)S (0 2 (C 1 .gal kyl), -N(R h)S 2 NRhRh, -1PRhC 26 alkyl NR hR h and 61 -NRhC 2 6 alkylORh'; or R 14is a saturated or unsaturated 6- or 7-membered monocyclic or 10- or 11 -membered bicyclic ing containing 1 or 2 atoms selected from N, 0 and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atomn bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 groups selected from C,.

8 alkyl, C 1 4 haloalkyl, halo, cyano, nitro, 1 8 a1 kyl), -C(=0)O(C 1 8 alkyl), -C(=0)NRhRh, C(=NR1)NRhR h -OR',

-OC(=O)(C

1 sa~kyl), -0C(=O)NR hR h, -OC(=0)N(R h)S 2 salkyl),

-OC

2 -6alkylNRhR h, -OC 2 ,alkylOR', -SR h, 8 alkyl), 2 8 alkyl), 2 NRhR h, 2 N(R 1salkyl), 2 N(R 8 alkyI), 2 N(R h)C(=0)NR hR h -NRh R h, -N(R 8 alkyl), -N(R h)C(=O)0(C 1-alkyl), -N(R h)C(=0)NRh -N(Rh)C(=NR h)NR R', -N(R h)S 2 (CI-8alkyl), -N(Rh)S(=0) 2 NR -NR!C 26 alkylNR R hand -Nh C 2 6 alkylR. h; or R 14is CI- 4 alkyl substituted by 0, 1, 2 or 3 groups selected from C,-4haloalkyl, halo, cyano, nitro, 8 alkyl), -C(0)NR:R -C(=NRh )NR R h, -OR h, -OC(=O)(C 1 8 alkyl), -OC(=O)NRR R, -OC(=O)N(R h)S(=O) 2 (Ci 8 a1 kyl), -OC 2 6 aIkylNR hR h, -0C 2 6 a1 kylOR h, -SR', 8 alkyl), 2

(CI-

8 alkyl), 2 NRhRh, 2 N(R 1 8 alkyl), -S 2 N(R 8 a1 kyl), 2 N(R)C(=O)NR R h, -NR hR h, -N(R I -alkyl), -N(R h)C(=O)O(C 1 -alkyl), -N(R h)C(=O)NRh -N(R h)C(=NRh)NR Rh, -N(R h)S 2 8 alkyl), -N(R h)S 2 NR hR h, _NRh C 2 6 alkylN~h R h and -NRhC 2 6 alkylOR h; R h is independently, at each instance, H, phenyl, benzyl or C,- 6 alkyl, the phenyl, benzyl and C,- 6 alkyI being substituted by 0, 1, 2 or 3 substituents selected from halo, C,-4a1kyl, C 1 3 haloalkyl, -OCI 4 alkyl, -NH 2 -NHCI 4 alkyl, -N(C 14 alky1 4 alkyI; W' is a heterocycle selected from the group of thiophene, pyrrole, 1,3oxazole, 1 ,3-thiazol-5-yi, 1,3 ,4-oxadiazole, 1,3 ,4-thi adiazole, 1 ,2,3-oxadiazole, 1,2,3-thiadiazole, IH-1,2,3-triazole, isothiazole., 1,2,4-oxadiazole, 1,2,4- 62 thiadiazole, I ,2,3,4-oxatriazole, I ,2,3,4-thiatriazole, 1 H-I ,2,3,4-tetraazole, I ,2,3,5-oxatriazole, 1 ,2,3,5-thiatriazole, furan, i midazol- I-yI, imidazol-3-yl, imidazol-4-yi, I ,2,4-triazole, I ,2,4-triazole, isoxazole, pyrazol-3-yi, pyrazo]-4-yl, thiolane, pyrrolidine, tetrahydrofuran, 4,5 -dihydrothiophene, 2pyrroline, 4,5-dihydrofuran, pyridazine, pyrimidine, pyrazine, 1,2,3-triazine, 1,2,4-ri azine, I ,2,4-triazine, I ,3,5-tri azine, pyridine, 2H-3 ,4,5 ,6-tetrahydropyran, thiane, 1 ,2-diazaperhydroine, I ,3-di azaperh ydroi ne, piperazine, 1,3oxazaperhydroi ne, morpholine, I ,3-thiazaperhydroine, I ,4-thiazaperh ydroine, piperidine, 2H-3 ,4-dhydropyran, 2,3-dihydro-4H-thiin, 1,4,5,6tetrahydropyridine, 2H-5,6-dihydropyran, 2,3-dihydro-6H-thiiri, 1,2,5,6-C tetrah ydropyridine, 3,4,5 ,6-tetrabydropyridine, 4H-pyran, 4H-thiin, 1,4di hydropynidine, 1 ,4-dithiane, 1 ,4-dioxane, I ,4-oxathiane, I ,2-oxazol idine, 1,2thiazolidine, pyrazolidine, 1 ,3-oxazolidine, 1 ,3-thiazoildine, imidazolidine, 1,2,4oxadiazolidine, 1 ,3,4-oxadi azolidine, I ,2,4-thiadiazolidine, I ,3,4-thiadiazolidine, 1 ,2,4-tri azoli dine, 2-imidazolin- l-yi, 2-imidazolih-2-yi, 2-imidazolin-5-yi, 3imidazoline, 2-pyrazoline, 4-in-midazoline, 2,3-dihydroisothiazole, dihydroisoxazole, 4,5-dihydroisothiazole, 2,5-dihydroisoxazole, dihydroisothiazole, 2,3-dihydroisoxazole, 4,5-dihydrooxazole, 2,3dihydrooxazole, 2,5-dihydrooxazole, 4,5-di hydrothiazole, 2,3-dihydrothiazole,, 2,5-dihydrothiazole, I ,3,4-ox athiazol idine, I ,4,2-oxathiazolidine, 2,3-dihydro- IH- [1 ,2,3]triazole, 2,5-dihydro-lH-[1,2,3]tdazole, 4,5-dihydro- 1H-(1,2,3]triazol-1-yI,( 1H-[ 1,2,3]tfiazol-3-yl, 4,5-dihydro- IH-[1I,2,3]triazol-5-yI, 2,3dihydro- IH-[I1 ,2,4]triazole, 4,5-dihydro-1H-[ 1,2,4]triazole, 2,3-dihydro- [1 ,2,4]oxadiazole, 2,5-dihydro-[1I,2,4]oxadiazole, 4,5-dihydro-[ 1,2,4]thiadiazole, 2,3-dihydro-[ 1,2,4] thidiazole, 2,5-dihydro-[ 1,2,4] thiadiazole, 4,5-dihydro-[ 1,2,41 thiadiazole, 2,5-dihydro-[ 1,2,4]oxadi azole, 2,3-di hydro-[ 1,2,4]oxadiazole, dihydro-[1,2,4]oxadiazole, 2,5-dihydro-[1,2,4]thiadiazole, 2,3-dihydro-[1,2,4] thiadiazole, 4,5-dihydro-[ 1,2,4] thi adiazole, 2,3-dihydro-[1I,3,4]oxadiazole, 2,3dihydro-lI1,3,4]thiadiazole, [1,4,2]oxathiazole, [1,3,4]oxathiazole, 1,3,5triazaperhydroine, I ,2,4-triazaperhydroine, 1 ,4,2-dithiazaperhydroine, 1,4,2dioxazaperhydroi ne, I ,3,5-oxadi azaperhydroine, 1 ,2,5-oxadi azaperhydroi ne, I ,3,4-thi adiazaperhydroine, 1 ,3,5-thiadiazaperhydroine, 1,2,5- 63 thiadiazaperhydrointe, 1,3 ,4-oxadi azaperhydroine, I ,4,3-oxathi azaperhydroine, 1 ,4,2-oxathi azaperhydroi ne, 1 ,4,5,6-tetrah ydropyridazine, 1,2,3,4tetrahydropynidazine, 1 ,2,3,6-tetrahydropyridazi ne, 1,2,5 ,6-tetrahydropyri midine, 1,2,3 ,4-tetrahydropyrimidine, I ,4,5,6-tetrahydropyriimidine, 1,2,3,6tetrahydropyrazine, I ,2,3,4-tetrahydropyrazine, 5 ,6-dihydro-4H-[ 1,2]oxazine, 5,6dihydro-2H-[1I,2]oxazine, 3,6-dihydro-2H-[ 1,2]oxazine, 3,4-di hydro-2H- [1 ,2]oxazine, 5,6-dihydro-4H-[1I,2]thiazine, 5,6-dihydro-2H-[ 1,2] thiazine, 3,6dihydro-2H-[ 1,2] thiazine, 3 ,4-dihydro-2H-I1 thiazine, 5,6-dihydro-2H- [1 ,3]oxazine, 5,6-dihydro-4H-[ 1,3]oxazine, 3,6-dihydro-2H-[1I,3]oxazine, 3,4- ~10 di hydro-2H- III,3]oxazine, 3 ,6-d h ydro-2H-[1I,4]oxazine, 3 ,4-di hydro-2H- [1 ,4]oxazine, 5,6-dihydro-2H-[ 1,3]thiazine, 5,6-dihydro-4H-[1 ,3]thiazine, 3,6dihydro-2H- 1 ,3]tiiiazine, 3 ,4-dhydro-2H-[ 1,3]thiazine, 3,6-dihydro-2H- [1 ,4]thiazine, 3,4-dihydro-2H-[ 1,4]thiazine, 1 ,2,3,6-tetrahydro-[1I,2,4]triazine, 1 ,2,3,4-tetrahydro-[ 1,2,4]triazine, I ,2,3,4-tetrahydro-[ 1,3 ,5]tri azine, 2,3,4,5tetrahydro-[ 1,2,4]tri azine, 1 ,4,5,6-tetrahydro-[1I,2,4]triazine, 5,6-dihydro- [1 ,4,2]dioxazine, 5,6-dihydro-[1I,4,2]dioxazine, 5,6-di hydro-[1I,4,2]dithiazine, 2,3dihydro-[1I,4,2]dioxazine, 3,4-dihydro-2H- 1 ,3,4]oxadiazine, 3,6-dihydro-2H- [1 ,3,4]oxadiazine, 3,4-dihydro-2H-[ I13 ,5]oxadiazine, 3,6-dihydro-2H- [1 ,3,5]oxadiazine, 5,6-dihydro-2H-[ 1,2,5]oxadiazine, 5 ,6-dihydro-4H- [1 ,2,5]oxadiazine, 3,4-dihydro-2H-[1I,3,4]thiadiazine, 3,6-dihydro-2H- ,3,4]thiadiazine, 3,4-dihydro-2H-[ 1,3,5]thi adiazine, 3 ,6-dihydro-2H- S1 ,3,5]thiadiazine, 5,6-dihydro-2H-[ 1,2,5]thiadi azine, 5,6-dihydro-4H- [1 ,2,5]thiadiazine, 5,6-dihydro-2H-[ 1,2,3]oxadiazine, 3 ,6-dihydro-2H- [1 ,2,5]oxadiazine, 5,6-dihydro-4-1,3,4]oxadiazi ne, 3,4-dihydro-2H- [1 ,2,5]oxadiazine, 5 ,6-dihydro-2H-[1I,2,3]thiadiazine, 3 ,6-di hydro-2H- [1 ,2,5]thiadiazine, 5,6-dihydro-4H-[ 1,3 ,4]thiadi azine, 3,4-dihydro-2H- [1 ,2,5]thiadiazine, 5,6-dihydro-[1I,4,3]oxathiazine, 5,6-dihydro-[1I,4,2loxathiazine, 2,3-dihydro-[1,4,3]oxathiazine, 2,3-dihydro-[1,4,2]oxathiazine, dihydropyridine, I ,6-dihydropyridi ne, 5,6-dihydropynidine, 2H-pyran, 2H-thiin, 3,6-dihydropyridine, 2,3-dihydropyridazine, 2,5-di hydropyridazine, di hydropyridazine, I ,2-dihydropyridazine, 1 ,4-di hydropyri midin-1I-yJ, 1,4dihydropyrimidin-4-yi, I ,4-dihydropyrimidin-5-yI], 1,4-di hydropyrimidin-6-yl, -64 2,3-di hydropyri mi dine, 2,5-dihydropyrimidine, 5,6-dihydropyrimidine, 3,6di hydropyri midi ne, 4,5-dihydropyrazine, 5 ,6-di hydropyrazine, 3,6di hydropyrazinte, 4,5-di hydropyrazi ne, I ,4-di hydropyrazine, 1 ,4-dithii n, 1,4Adioxin, 211-1 ,2-oxazine, 6H-1I,2-oxazine, 4H-1I,2-oxazine, 2H- 1,3-oxazine, 4H1- 1,3-oxazine, 61-1,3-oxazine, 211-1,4-oxazine, 4H-1,4-oxazine, 2H-1,3-thiazine, 2H- 1,4-thiazine, 4H- 1,2-thiazine, 6H-1I,3-thiazine, 4H- 1,4-thiazine, 2H- ,2thiazine, 6H- 1,2-thiazine, 1 ,4-oxathiin, 2H,5H-1I,2,3-triazine, 111,411-1,2,3triazine, 4,5-dihydro- I ,2,3-triazine, 1 H,6H1-1I,2,3-triazine, I ,2-dihydro- 1,2,3triazine, 2,3-dihydro- 1,2,4-triazine, 311,61-1 ,2,4-triazine, I H,6H- 1,2,4-triazine, 3,4-dihydro-1I,2,4-triazine, 111,411-1 ,2,4-triazine, 5,6-dihydro-1I,2,4-triazine, dihydro-1I,2,4-triazine, 2H,5H-1I,2,4-triazine, I ,2-dihydro- 1,2,4-triazine, 1H,411- I ,3,5-triazine, 1 ,2-dihydro-1 ,3,5-triazine, 1 ,4,2-dithiazine, 1 ,4,2-dioxazine, 211- 1,3,4-oxadiazine, 211-1 ,3,5-oxadiazine, 611-1 ,2,5-oxadiazine, 411-1,3,4oxadiazine, 411-1 ,3,5-oxadiazine, 411-1 ,2,5-oxadiazine, 211-1 ,3,5-thi adiazine, 6H1- 1 ,2,5-thiadiazine, 411-1,3 ,4-thi adiazine, 411-1,3 ,5-thiadiazine, 411-1,2,5thiadiazine, 211-1 ,3,4-thiadiazine, 611-1,3 ,4-thiadiazine, 611-1,3,4-ox adiazine, and 1,4,2-oxathiazine, wherein the heterocycle is optionally vicinally fused with a saturated or unsaturated 6- or 7-membered ing containing 0, 1 or 2 atoms independently selected from N, 0 and S; R' is phenyl substituted by 0, 1 or 2 groups selected from halo, C,.

4 alkyl,

C

1 3 haloalkyl, -OR h and m-NR hR.h; or Ri is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, 0 and S, wherein no more than 2 of the ring members are 0 or S, wherein the heterocycle is optionally fused with a phenyl ring, and the carbon atoms of the heterocycle are* substituted by 0, 1 or 2 oxo groups, wherein the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents selected from halo, Ci.

4 alkyl, C 1 3 haloalkyl, -OR h and -NR hRh; and Rk is hydrogen or -CH 3 In another embodiment, in conjunction with the novel compound embodiments above and below, R' is In another embodiment, in conjunction with the novel compound Sembodiments above and below, R 7 is C2-6alkyl or C 1 4 haloalkyl.

In another embodiment, in conjunction with the novel compound embodiments above and below, R' is a naphthyl substituted by 0, 1, 2 or 3 substituents independently selected from R 5 In another embodiment, in conjunction with the novel compound embodiments above and below, R' is R' substituted by 1, 2'or 3 substituents independently selected from R 5 In another embodiment, in conjunction with the novel compound embodiments above and below, R' is substituted by one substituent selected from halo, C 1 .4haloalkyl and CI.salkyl, and additionally by 0, 1 or 2 substituents independently selected from R 5 In another embodiment, in conjunction with the novel compound embodiments above and below, R 1 5 is H.

In another embodiment, in conjunction with the novel compound embodiments above and below, R' 5 is R

I

C

18 alkyl substituted by 0, 1 or 2 substituents selected from R i or a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, the heterocycle and bridge being substituted by 0, 1, 2 or 3 substituents independently selected from Ro 1 or R 1 5 is -(CH 2 )nphenyl substituted by 0, 1, 2 or 3 substituents independently selected from H, Ci-salkyl, Ci 1 4 haloalkyl, halo, cyano, nitro, 1 .alkyl), -C(=0)O(Ci.galkyl), -C(=0)NRR -C(=NRh)NRhRh, -OC(=O)(C 1 .salkyl), -OC(=0)NRhR h -OC(=O)N(R h)S(=0)2(C alkyl), -OC 2 6 alkylNRhRh, -OC2.6alkylORh, -SR", 66 1 _8alkyl), 2

(C

1 .galkyl), 2 NR R h -S 2 8 a1 kyl), -S 2 N(R h)C(=O)O(C 1 8 alkyI), 2 N(Rh)C(=O)NR R h, -NR hR h, -N(R 1-8alkyJ), -N(R h)C(=O)O(Ci -8alkyl), -N(R h)C(=O)NR hR h, -N(Rh)C(=NRh)NRh Rh, -N(R h)S 2

(C

1 8 alkyl), -N(R h)S 2 NRhR', _NRh C 2 .6alk YlNRh R h -NR hC 2 6 alkylIRh and C 14 alkyl substituted by 0, 1, 2 or 3 groups selected from C I- 4 haloalkyl, halo, cyano, nitro, 1 _galkyl), -C(=O)O(C 1 .salkyl), -C(=O)NRh Rh, _C(=NRh )NRhR', -OR h, 1 -8alkyl), -OC(=O)NRhR h, hIS h h h, h -OC(=O)N(R 2

(C

1 salkyl), -OC 2 6 alkylNR RW -OC 2 .6alkylOR ,-SR, 1 .galkyl), 2

(C

1 8 alkyl), 2 NRhh, 2 N(R 1 8 a1 kyl), -S 2 N(R h)C(=O)O(C 1 .salkyl), 2 N(Rh)C(=O)NRh R h, NRhR h -N(R h)C(=O)(Ci -8alkyl), -N(Rh)C(=O)O(C,-8alkyl), -N(R h)C(=O)NR hR h, -N(R h)C(=NR h)NR hR h -N(R h)S 2

(C

1 _galkyl), -N(R h)S 2 NR hR h Nh C 2 6 alkylh R h and -NRhC 2 6 alkylORh In another embodiment, in conjunction with the novel compound embodiments above and below, R1 6 is H.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 16is halo, -NHCI 1 3 alkyl, -N(C 1 3 alkyI)C 1 3 alkyl, -0CI 3 alkyl, -C 1 2 haloalkyl, -0C 1 2 haloalkyl or C 13 a1 kyl.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 4 is 14 12 R 11 I 12 134 wherein at least one of R10, R R R" and R" is other than C 1 4 haloalkyl or halo.

In another embodiment, in conjunction with the novel compound embodiments above and below, at least one of R R' 1 R 12 ,R 1 3 and R 1 4 is -OR h or -NR R 67 In another embodiment, in conjunction with the novel compound embodiments above and below, R 4 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from 0, N and S, so long as the combination of 0 and S atoms is not greater than 2, wherein each of the carbon atoms of the heterocycle is substituted by H, C 19 galkyl, CI.

4 haloalkyl, halo, cyano, oxo, -OR h, -S(=O)nC 1 6 alkyl, -OC,_4haloalkyl, -OC 26 alkylNRhR',

-OC

2 _6alkylOR h, -0C 1 6 alkylC(=O)OR h, -NR -NR hC 1 4 haloalkyl, -NRh C 2 6 alkyINRh R h, _NRh C 2 6 alkylOR h, -C(=O)C 1 -6alkyl, -C(=O)0C 1 -6alkyl,

-OC(=O)C

1 6 alkyl, -C(=O)NR'Ci.

6 alkyl or -NR hC(=O)C 1 6 a1 kyl; and saturated carbon atoms may be additionally substituted by and any available nitrogen atoms in the heterocycle are substituted by H, -CI.

6 alkyl0Rh, -Cl-6alkyl,

-C

1 6 alkylNR hR h, -C 1 3 alkylC(=O)OR h, -C 1 3 alkylC(=O)NRh Rh,

-C

1 3 alkylOC(=O)C 1 _alkyl, -C 1 3 alkylNRhC(=O)C 1 6 alkyl, or -Ck.

3 alkylRi.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 4 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1 or 2 atoms selected from 0, N and S, wherein each of the carbon atoms of the heterocycle is substituted by H; C1.

9 alkyl,

C

1 4 haloalkyl, halo, cyano, oxo, -S(=O)nC 1 ~alkyl, -OCI 1 4 haloalkyl, hhhh h

-OC

2 6 alkylNRhR -OC 2 6 alkylORh, -OC 1 6 alkyIC(=O)OR -NRR R 4 haloalkyl, -NR hC 2 6 alkylNR h Rh, -NR hC 2 6 alkylOR h, -C(=O)C 16 alkyl, -C(=O)0C 1 6 alkyl, -OC(=O)CI- 6 alkyl, -C(=0)NR hC 1 6 alkyl or -NR hC(=O)C 1.

6 alkyl; and saturated carbon atoms may be additionally su .bstituted by and any available nitrogen atoms in the bridge are substituted by H, -C I 6 alkylORh, -C 1 6 al kyl, -C 1 6 a1 kylNR Rh, -CI- 3 alkylC(=O)ORh

-C

1 3 alkylC(=O)NR hR h, -C 1 3 alkyIOC(=O)C 16 a~kyl, -C 1 jalkylNR hC(=O)C 16 alky1, -C=)jor -C 1 3 alkylRi.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 4 is an 10- or 11l-membered bicyclic ring, containing 1, 2, 3 or 4 N atoms and 0, 1 or 2 atoms selected from S and 0 with the remainder being carbon atoms, wherein each of the carbon atoms of the ring is substituted by H, C 19 galkyl, C 1 4 haloalkyl, halo, cyano, oxo, -ORh, 68 h hh 1 .6alkyl, -0C,-4haloalkyI, -0C 2 _6alkylNR R -0C 2 6 alkyl0R

-OCI

1 6 alky]C(=0)OR h, -NR R h, -NR hC 1 haloalkyl, -NR hC 2 6 alkyINR hR', _NRh C 2 6 alkyl0R h, -C(=0)C 1 6al kyl, -C(=0)0C 1 6 alkyl, -OC(=0)C 1 6 alkyl, -C(=0)NR hC 1 6 alkyl or -NR hC(=0)C 16 alkyI; and saturated carbon atoms may be additionally substituted by and any available nitrogen atoms in the ring are substituted by H, -C 1 6 alkylORh, -C 1 6 alkyl, -C 1 6 alkylNRhRh,

-C

1 3 alkylC(=0)OR h, -C 3 alkyIC(=O)NRhR h, -C 1 3 alkylOC(=0)C 1 6 alkyl,

-C

1 3 alkylN hC(=0)CI 6 alkyl, -C(=0)Rj or -C 1 3 a1 kylRi.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 4 is an 10- or 1 1-membered bicyclic ring, containing 0, 1, 2, 3 or 4 N atoms and 0, 1 or 2 atoms selected from S and 0 with the remainder being carbon atoms, wherein at least one of the carbon atoms of the ring is substituted by Cl- 9 alkyl, C 1 4 haloalkyl, halo, cyano, oxo, -ORh, 6 a1 kyl, -0C 1 4 haloalkyl, -OC 2 6 alkylNR Rh, .oC 2 6 alkyloRh, -0CI.

6 alkyIC(=0)OR h, -NR -NR hC 1 4 haloalkyl, -NRhC 2 6 alkylNR hRh, _h C 2 6 alky0R h, -C(=0)C 1 -6alkyl, -C(=0)0C 1 6 alkyl, -OC(=0)C 1 6 alkyl, -C(=0)NR hC 1 6 alkyl or -N~hC(=o)CI6akyl.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 5 and R 9 are each independently selected from 2 0 H, C 1 4 haloalkyl, halo, nitro, -OCI 1 6 alkyl, -OCI.

4 haloalkyl, -0C 2 6 alkylNRh Rh, -0C 2 _6alkyl0R h, -NR R h, _NRhC, haloalkyl, -NR hC 26 alkylNR hR h -NR C 2 6alkyl0Rh, -C0 2

(C

1 6 a1 kyl), 6 a1 kyl), -C(=0)NRhRh,( -NR hC(=O)R h, -NRhC(=0)NR -NR h C0(CI- 6 alkyl), -Cl.

8 a~kyl0R h, hh h -OC(=O)NR R.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 6and R 8are each independently selected from H, C 1 _salkyl, C 1 4 haloalkyl, halo, -0CI.

6 alkyl, -0C 1 4 haloalkyl, -OC 2 6 alkylNR hR h,

-OC

2 6 alkyl0R h, _NRhR h, _NRhC 1 4 haloalkyl, -NR hC 2 6 alkylNRh R hor, -NR hC 26 alkylORh, -CI-8alkylOR h, -C 1 6 alkylNR hR hand -S(C 1 6 alkyl).

In another embodiment, in conjunction with the novel compound embodiments above and below, R 7 is independently, at each instance,.

69 C, 8 alkyl, C, 4 haloalkyl, -OCI 4 haloalkyl, -OC 2 6 alkyl NRh R', -0C 2 6 alkylOR h, _NR Rh, -NR"C, Ahaloal kyl, -N 26lklRhRh -NR hC 2 6 alkylOR h, -C1.

8 a1 kylOR h, a1kylNRhR h or 6 alkyl).

In another embodiment, in conjunction with the novel compound embodiments above and below, R1 0 and R 1 4 are each independently selected from H, C,.

8 alkyl, C,.

4 haloalkyl, halo, cyano, nitro, 1 8 alkyI), alkyl), -C(=O)NRhRh, _C(=4~h)4Rh -OR h, 1 galkyl), -OC(=O)NRh R h, -OC(=O)N(R h)S(=O) 2 8 alkyl), -OC 2 6 alkylNRh Rh, h hS=)C 8 hS h 2

R""

-OC

2 _6alkylOR -SR S(=O) 2 (C1.salkyl), S=)N 2 N(R 8 a1 kyl), -S 2 N(R h)C(=O)O(C 1-alkyl), -S 2 N(R h)C(=O)NR hR', -NR hR h, -N(R 1 8 alkyl), -N(R )S 2 (C,.salkyl), -N(R h)S(=O) 2 NR hR h, _NRh C 2 6 alkyINR hRh and -N4R hC 2 6alkylOR h and C 1 4 alkyl substituted by 0, 1, 2 or 3 groups selected from

C,.

4 haloalkyl, halo, cyano, nitro, 8 alkyl), -C(=O)NRh R' -C(=NRh)NRh Rh, -OR h, -OC(=O)(C1.

8 alkyl), -OC(=O)NRh Rh, -OC(=O)N(R h)S(=O) 2 (C1.

8 alkyl), -0C 2 6 alkylNR hR h, -OC 2 ,alkylOR h, -SR' 8 alkyI), 2 (C1-8alkyl), 2 NR R h 2 N(Rh)C(=O)(Ci 1 8 a1 kyl), 2 N(R)C(0O)O(C, salkyI), 2 N(Rh)C(=O)NRh R h, -NR hR h, -N(R 1-8alkyl), -N(R h)C(=O)O(C 1-alkyl), -N(Rh)C(=O)NRh R h, -N(R h)C(=NR h)NR hRh, -N(R h)S(=O) 2 8 alkyl), -N(R h)S(=O) 2 NR h _NRh C 26 alkyINR hR h and -NRhC-alkyORh In another embodiment, in conjunction with the novel compound 215 embodiments above and below, R" and R 1 3 are independently, at each instance, selected from H, C,- 8 alkyl, Cv.

4 haloalkyl, halo., cyano, nitro, 8 alkyl), 8 galkyl), -C(=O)NR hR h, -C(=NRh)NhRh 8 galkyl), -OC(=O)NR"R h, -OC(=O)N(R h)S(=O) 2 (C1_galkyl), oc 2 -(alkylNRhR h, h h()C 8 akl Nh h

-OC

2 6 alkylOR -SR O(-akl, 2 (CI-8alkyI), -=02RR 3 0 2 N(R 8 alkyl), 2 N(R h)C(=O)O(C,.g8alkyl), 2 N(R h)C(=O)NR -NRh R h, 1 8 alkyI), 1 8 a1 kyl), -N(R h)C(=O)NRh Rh, -N(R h)C(=NRh)iRh Rh, -N(R h)S 2

(C

1 8 a1 kyl), -N(Rh)S 2 NR hR h, _h C 2 6 alkyNRh R h -NR h C 2 6 akylQR hand C 14 alkyl substituted by 0, 1, 2 or 3 groups selected from

C

1 4haloalkyl, halo, cyano, nitro, 1 8 alkyl), -C(=O)O(Ci-8alkyl), -C(=O)NR hRh, _C(=NRh)NRh -OC(=O)(C 1 8 alkyl), -OC(=O)NR hR', -OC(=O)N(R h)S 2 (CI-8alkyl), -0C 2 6 alkylNR hR h, -OC 2 6 alkylOR h, -SR h, 1 8 alkyl), 2

(C

1 .salkyl), 2 NR R h 2 N(R 1 8 alkyl), -S 2 N(R h)C(=O)O(C 1 .gal kyl), 2 N(Rh)C(=O)NR hR h, -NR -N(R salkyI), h)(Nh h h)C= h h h -N(R)C(=O)O(C1.8alkyl), -N(R R,-N(R )(NR )NR Rh, -N(Rh)S 2 (CI-8alkyl), -N(R h)S 2 NRh Rh, NRh C 2 6 alkylNph R h and _NRh CalkylOR h.

In another embodiment, in conjunction. with the niovel compound embodiments above and below, R 12is independently, at each instance, selected from C 1 .8alkyl, C 1 4 haloalkyl, halo, cyano, nitro, -C(=O)O(C 1 .salkyl), -C(=O)NRhRh, -C(=NR h)NRh Rh, -OR h, _galkyl), -OC(=O)NR h Rh, -OC(=O)N(R h)S(=O) 2 (CI-8alkyl), -OC 2 6 alky1NRh Rh, -OC 2 6 aI kylOR h, -SR h h h 1 8 alkyl), 2 (Ci- 8 alkyl), 2 NR R, -S 2 N(Rh)C(=O)(C i-8al kyl), 2 N(Rh)C(=O)O(C 1 8 a1 kyl), 2 N(R h)C(=O)NRh -NR R h, -N(R h)C(=O)(Cl -alkyl), -N(R h)C(=O)O(C 1 8 alkyl), -N(R h)C(=O)NR hR h, -N(Rh)C(=NR h)NR h Rh, -N(R h)S 2 (Cts8alkyl -N(R h)S(=O),NR hR h, -NRhC 2 -6alkylNR hR h and( -NhC 2 -falky]OR h; or R 12is C 14 alkyl substituted by 0, 1, 2 or 3 groups selected from C 14 haloalkyl, halo, cyano, nitro, 1 _8alkyl), 1 salkyl), -C(=O)NRhRh, C(=NRh)NRhR h -OR h, -OC(=O)(C 1 8 alkyl), _OC(=O)NRh Rh, -OC(=O)N(R 2 (CI-8alkyl), -0C 2 6 alkyINR hR h, -OC 2 ,alkyIOR h,-SR' h h 1 -8alkYl), 2

(C

1 salkyl), 2 NR R 2 N(Rh)C(=O)(C 1 .alkyl), 2 N(R )C(=O)O(C 1 _8alkyl), 2 N(R h)C(0)NRh R h, -NR hR h, -N(R 1-8alkyl), -N(R 18 a1 kyl), -N(R h)C(=O)NR hR', -N(R h)C(Nh)NhRh, -N(R h)S(=O) 2 (CI-8alkyI) -N(R h)S(O) 2 NRh Rh, _NRh C 2 -6alkyINRhR hand -NRhC 2 6 alkylOR'.

-71- In another embodiment, in conjunction with the novel compound embodiments above and below, Y is 0.

In another embodiment, in conjunction with the novel compound embodiments above and below, Y is S.

Another aspect of the invention relates to a compound having the structure: R3 R 2

X

wherein: X is 0, S or W~; n is independently, at each instance, 0, 1 or 2; o is independently, at each instance, 0, 1, 2 or 3; Rm is independently at each instance H orR" R' is independently at each instance C 18 alkyl, phenyl or benzyl; R" is independently in each instance H, C 1 4 alkyl, Ci.

4 haloalkyl, halo, cyano, nitro, -C(=0)NR m

-C(=NRI

m

)NR

m

-OR'

m -OC(=0)NR m

R

m 2 R n, -0C 2 6 a1 kylNRlRrn,

-OC

26 alkylOR', 2 2

NR

m

R

m -S 2

N(R

m 2

N(R

m )C(=O)OR n, 2

N(R

m )C(=0)NR m

R',

-N(R

m

-N(R

m

-N(R

m

)C(=O)NR

m

R

m

-N(R

m )S 2 -N(Rml)S 2 NR R m

-NR

m

C

2 6 alkyl NR m R' or -NR m

C

2 6 alky]OR'; R' is R" substituted by 0, 1, 2 or 3 substituents independently selected from R

R

3 is H or C 14 alkyl;

R

5 is H, C 19 alkyl, C1 4 haloalkyl, halo, nitro, cyano, -OCI 1 6 alkyl, -0-C 1 4 haloalkyl, -0-C 1 6 alkylNR m -0-C 1 6 alkylOR', -NR m

R

m

-NR

m -C 14 haloalkyl, -NR m

-C

1 6 alkylNR -NR- 16 a1 kylOR m or -(CH 2 ),,Rc R 6is, independently at each isacH, Cl.

9 alkyl, C 1 4 haloalky), halo, nitro, cyano, -0C 1 6 alkyl, -0-C 1 4 haloalkyl, -0-C 1 6 alkylNR m

R',

72

-O-C

1 6 alkylOR', -NR m

R

m

-NR

m -Ci- 4 haloalkyI, -NR m

-C

1 6 alkylNR m R' or _n -NR m

-CI-

6 alkylOR';

R

8 is H, Ci.galkyl, C 1 4 haloalkyI, halo, nitro, cyano, -0CI.

6 alkyl, -0-C 4 haloalkyl, -0-C .6al kyl NR m -0-C 6 alkylOR', -NR m

R',

-NR

m -ClAhaloalkyl, -NR m

-C

1 6 alkylNR m

R

m or -NW-C 1 6 alkylOR m and R'is (CRqRq )ORO R 2 is H, -OR' m halo, C 1 3 haloalkyl or C 16 alkyl; R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C,- 8 alkyl,

C

1 4 haloalkyl, halo, cyano, nitro, -C(=O)NR m

R',

-C(=NR

m

)NR

m

R

m

-OR'

m

-OC(=O)NR

m 1 -OC(=0)N(R m -0C 2 6 al kylNR m

-OC

2 6 alkylOR', -SR m -S 2 -S 2

NR

m

R

m -S 2 2

N(R

m -s 2 N(R')C(=0)NR m

R

m

-NR"'R

m

-N(R

m

-N(R

m )C(=0)0R,

-N(R

m )C(=0)NR m

R

m

-N(R

m

)C(=NR

m

)NR

m

R

m

-N(R

m 2

R",

-N(R

m 2

NR

m

R

m

-NR

m

C

2 6 ,a1kylNR m

R

m

-NR

m

C

2 -6aIkylOR m -C(=0)Rs; -C(=0)NRnRs, -C(=NRn)NRnR OC(0O)Rs, -OC(=O)NRnR', -OC(=O)N(Rrn)S(=0) 2 Rs, -OC 2 6 alky NRrnR', OC 2 6 al kylORs, -SRS, 2 2

NR

m 2 N(Rr)C(=0)Rs, -S 2 N(R-)C(=O)0Rs, 2

N(R"')C(=O)NR

m Rs, -NR m Rs, -N(R m

-N(R

tm )C(=O)0Rs, -N(R m )C(=0)NR m

-N(R

m

)C(=NR

m

)NR

m Rs,

-N(R

m 2 Rs, -N(R m 2

NR

m Rs, -NR m C2- 6 alkylNR m

R

5

-NR

M

C

2 6 alkylORs and C 1 4alkyl substituted by 1 or 2 groups selected from C 1 2 haloalkyI, halo, 73 cyano, nitro, -C(=0)NR m

R

m

-C(=NR

m

)NR"R

m

-OR

m -OC(=0)NR m -OC(=0)N(R m )S 2 -0C 2 6 a1 kyINR m Rn,

-OC

2 -(al kyIOR m

-SR'

m -S 2 R n, 2

NR

m

R

m 2

N(R

m 2

N(R

m 2

N(R

m )C(=0)NR m

R

m

-NR

m

R

m

-N(R

m

-N(R

m n' N(R m )C(=0)NRmR m

-N(R

m

)C(=NR

m

)NR

m

-N(R

m 2 R n, -N(R m 2

NR

m

R',

-NR

m

C

2 6 alkylNR m -C(=O)0Rs, -C(=0)rNRR -C(=NRln)NRnR', -ORs, -0C(=O)Rs, -OC(=0)NRnR', -0C(=O)N(Rrn)S(=0) 2 Rs, -OC 2 6 alky1NRnR-, -0C 2 6 alkyl0Rs, S(=0) 2 Rs, 2 NRnRs 2 N(Rm)C(=0)Rs, -s S(=O),N(Rrn)C(=0)ORs, 2 N(Rrn)C(=0)NRnR', -NRrnRs, -N(Rrn)C(=O)Rs, -N(Rr)C(=0)0Rs, -N(Rrn)C(=O)NRrnRs, -N(Rrn)C(=NRrn)NRnRs, -N(Rrn)S(=0) 2 Rs, 2

NR'RS,

_NRrnC 26 alkyINR m Rs, -NRrnC 2 alkylORs and -NR

M

C

2 6 alkylOR'; and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups; R 7 is Cl.

9 )alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -0OCI.

6 al.IIkyl, 4 haloalkyl, -0-C 1 6 alkylNR m -0-C 1 6 alkyIOR m

-NR

m

-NR

m -C 14 haloalkyI, -NR m -C I 6 alkylNR m

R

m or -NW-C 1 6 al1kyIOR'; is a saturated, partially-saturated or unsaturated 6- or. 7-membered monocyclic or 10- or 11 -membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, 0 and S, so long as the combination of 0 and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from RP; RP is independently at each instance C,.8alkyl, C 1 4 haloalkyl, halo, cyano, nitro, n, -C(=0)NR m

-C(=NR

m

)NR

m

R

m

-OR

m -OC(=0)NR m

-OC(=O)N(R

m )S 2 -0C 2 6 a1 kylNR m

R',

-0C 2 6 alkylOR m 2 2

NR

m

R',

-s 2

N(R

m -S 2

N(R

tm 2

N(R

m

)C(=)NR

m

R

m

-NR

m

R

m

-N(R

tm

-N(R'

1

-N(R

tm )C(=0)NR m

R

-N(R

m

)C(=NR

m

)NR

m

R

m

-N(R

t 2

-N(R

m 2

NR

m

R

m

-NR

tm

C

2 6 alkylNR m

R

m or -NR

M

C

2 6 alkylOR m and Y is 0 or NH-; or 74 R'is R R5 R 7 N R

(CRIRI)

0 RO or (CRqRq )ORO R 2 is H, -OR' m halo, C 1 3 haloalkyl or C 1 -6alkyl; R 4 is a saturated or unsaturated 5- or 6-meinbered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected( from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 2 or 3 substituents independently selected from C 1 .salkyl,

C

1 4 haloalkyJ, halo, cyano, nitro, n, -C(=O)ORII, -C(=O)NR m

R',

-C(=NR

m

)NR

m

R

m

-OR

m -OC(=O)R -OC(=O)NR"'R,

-OC(=O)N(R

m 2 R -OC 2 6 alkylNR m

-OC

2 6 alky]OR'l, -SR' m 2 2

NR

m -S 2 2

N(R

m )C(=O)ORn, -S 2

N(R

m

)C(=O)NR

m -N(R

M

n,

-N(R

m

-N(R

m

)C(=NR

m

)NR

m

-N(R

m )S 2

R",

-N(R

m 2

NR

m

R

m

-NR

m

C

2 -6alkylNR m

-NR

m

C

2 .6al kylOR m -C(=O)Rs, -C(=O)ORs, -C(=O)NRnR', -C(=NRrn)NRrnR', OC(0)Rs -0C(=O)NRnR', -OC(=O)N(RI)S 2 Rs, -OC 2 6 alkylNRnR', -OC 2 6 alkylOR', -SRs, -S -S 2 NRrnR', 2 N(Rrn)C(=O)R', 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=O)NRnRs, -NRmIRs, -N(Rr)C(0O)Rs, -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRnR', -N(Rrn)C(=NRn)NRnR',

-N(R

m )S (0) 2 Rs, -N(Rrn)S(=O) 2 NRrnRs, -NR41flC 26 al kylNRnR', -NR m

C

2 6 aIkylORs and C 1 4 alkyl substituted by I or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=O)NR m

-C(=NR-)NR-R

m

-OR

M

-OC(=O)NR

m 2

-OC

2 6 alkylNR m R -0C 2 6 alkylOR m

-SR'

m n, 2 2

NR

m

R',

2

N(R

m -S 2

N(R

m )C(=O)OR n, 2

N(R

m

)C(=O)NR

m

R

m

-NR

m

R

m

-N(R

m

-N(R

m )C(=O)OR n, -N(Rm)C(=O)NR m

R

m 75

-N(R

m

)C(=NR

m

)NR

m

R

m

-N(R

m 2

-N(R

m 2

NR

m

R

m

-NR

m

C

2 6 a~kylNR m C(=O)ORs, -C(=O)NRnR', -C(=NRn)NRnR', -OW, .OC(=o)Rs, OC(0)NRnRS .OC(=O)N(Rrn)S(=O) 2 Rs, -OC 2 6 alkylNRnRs,

-OC

2 6 alkylOR', -SRs, -S 2 2 \RrnR', 2 N(Rrn)C(=0)Rs, 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=0)NRnR', -NRnR', -N(Rrn)C(=O)Rs, -N(Rr)C(=0)0Rs, -N(Rrn)C(=O)NRnR', -N(Rrn)C(=NRn)NRrnRs, N(R m )S 2

-N(R

m )S 2 NRnRs, -NRnC 2 6 alkyMNR', -NRrnC 2 6 alkyl0R' and -NR

M

C

2 -6alkylOR m and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups;

R

7 is C I -al kyl, C 14 haloal kyI, halo, nitro, cyan(o, -OC 1 _al kyl, -0-C 1 4 haloal kyl, -0-C 6 alkyINRm', -0-CI 6 alkyl OR m

-NR

m

R

m

-NR"'-C

1 4haloalkyl, -NR m

-C

1 6 alkylNR m R' or -NR m

-C

1 6 al kyl OR'; R' is a saturated, partially-saturated or unsaturated 6- or 7-membered monocyclic or 10- or I 1-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, 0 and S, so long as the combination of 0 and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from RP; RP is independently at each instance C 1 .galkyl, C,.

4 haloalkyl, halo, cyano, nitro, -C(=O)NR m

-C(=NR"')NR

m

R

m

-OR

m -OC(0)NR m -OC(0)N(R m )S 2

-OC

2 6 alkyl NR m

R',

-0C 2 6 alkylOR', -SR' m -S 2 2

NR''

T

-S 2 2

N(R

m 2

N(R')C(=O)NR

m

R',

-NR

M

C

2 6 alkylNR1R' or -NR'C 2 6 alkylORm1; and Y isO0 or NH; or R' is 76 R 2is H, -OR' m halo, C 1 3 haloalkyl Or C 1 6 alkyl; R 4 is a saturated, partially-saturated or unsaturated 10 or I 1-membered bicyclic heterocycle containing 1, 2, 3,4 or 5 atoms selected from 0, N and S, so long as the combination of 0 and S atoms is not greater than 2, but excluding quinolin-6-yI, 4,5,6,7-tetrahydro-benzo[blthiophen-2-yl, benzothiazol-( 2-yI, 2,3-dihydro-benzo[I,4]dioxin-6-yI, wherein the heterocycle is substituted by 0, 1, 2 or 3 substituents independently selected from Cl.

9 alkyI, oxo, C 14 haloalkyl, halo, nitro, cyano, -OR

M

6 alkyl, -O-C 1 4 haloalkyl, -O-C 1 6 alkylNR m

R',

-0-C 1 6al kyl OR, -NR m

-C

1 4 haloal kyl, -NR m

-C

1 6 alkylNR m

R',

-NR'-C 1 6 alkylOR', -C(=O)C 1 6 alkyl, talkyl, -C(=O)NR'Cl- 6 alkyl,

-NR

m C(=O)C 1 -6alkyl .C(0)ORs, -C(=O)NRrnRs, -C(=NRrn)NRrnR', -ORFs, -OC(=O)Rs, -OC(=O)NRnR', -OC(=O)N(R m )S 2 Rs, -OC 2 6 al kylNRrnRs,

-OC

26 alkylOR', -SRs, -S(0)Rs, 2 NRrnRs, -S 2 N(Rrn)C(=O)R', -S 2 N(Rrn)C(=O)ORS, -S 2 N(Rrn)C(=O)NRnRs, -NRrnRs, -N(Rr)C(=O)Rs, -N(Rr)C(=O)0Rs, -N(Rrn)C(=O)NRnR', -N(Rrn)C(=NRrn)NRnR', N(Rmn)S(=0) 2 Rs, -N(Rrn)S(=O) 2 NRnR', -NRrnC 2 6 alkylNRrnR', -NRrnC 2 6 akyl0R' and CI-4alkyl substituted by I or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, n, -C(=O)NR m

R-,

2 0

-OR

m -OC(=O)R n, -OC(=O)NR m R

M

-OC(=O)N(R

m 2 -0C 2 6 alkylNR m

R

m

-OC

2 6 alkylOR', -SR m -S 2 -S 2

NR

m

R

m -s 2

N(R

m 2

N(R

m 2

N(R

m m

R

m

-N(R

m

-N(R

m

-N(R

m

)C(=O)NR

m

R

m

-N(R

m

)C(=NR

m

)NR

m

R

m

-N(R

m 2 R

-N(R

m 2 NRm', -C(0)ORs, -C(=O)NRm~Rs, -C(=NRrn)NRnR', -ORs, -OC(=O)Rs, -OC(=O)NRnRs, -OC(=O)N(Rm)S(=O) 2

-OC

2 6 alkyl NR m

R',

-OC

2 6 alkyIOR', 2 Rs, 2 NRmnRs, -S 2 N(Rrn)C(=O)Rs, -s 2 N(R')C(=0)0Rs, 2 N(Rrn)C(=O)NRnR', 77 -NRrnR', -N(Rr)C(=O)ORs, -N(Rrn)C(=O)NRnR', -N(Rrn)C(=NRn)NRnR', -N(Rrn)S(=O) 2

-N(R

m )S 2 NRnRS, -NRnC 2 6 alky]NRnR', -NRrnC 2 alkylORs and -NR m

C

2 -6alkylOR'; wherein R 4 is not 2-aminocarborylmethyl-2,3-dihydro-benzo[ 1,4]dioxin-8-yl, 2-cyanomethyl- 2,3-dihydro-benzo[1I,4]dioxin-8-yl, quinolin-3-yl, 3H-quinazolin-4-on-3-yl, benzo[1I,3]dioxol-5-yl, 3,3-dimethyl- 1,3-dihydro-indol-2-on-6-yI or 4,4-di methyl- 3,4-dihydro- LH-quinolin-2-on-7-yl;.

R 7 is C 1 .salkyl, C 1 5 haloalkyl, I or Br* R 9 is H, Cl- 9 alkyI, C 1 4 haloalkyl, halo, nitro, cyano, -OCI 1 6 alkyl, -O-C 1 4 haloalkyl, -0-C 1 6 alkylNR m

-O-C

1 6 alkylOR', -NR m

-NR

m

-C

1 4 haloalkyl,

-NR

m -C I 6 al kylNR"'R m

-NR

m -C I 6 alkyIOR m or -(CH 2

R

9 is independently, at each instance, H, Cl- 9 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -0CI 6 alkyl, 4 haloalkyl, -0-C 6 alkyNR m

R

m 6 alkylOR m

-NR

m

-NR

m

-C

1 shaloalkyl, -NR m

-C

1 -,6alkylNR m R' or

-NR

m

-CI-

6 alkyOR m Y is NH; and Z is CR 8 or N;or Ris R 2 is C,-6alkyl substituted by 1, 2 or 3 substituents selected from

C,.

4 haloalkyl, halo, cyano, nitro, n, -C(=0)NR m

R

m

-OR

m -OC(=O)R -OC(=O)NRmlR,

-OC(=O)N(R

m )S 2 -0C 2 6 a1kylNR m

-OC

2 6 alkylOR m

-SR

m -S 2 R -S 2

NR

m 2

N(R

m 2

N(R

m )C(=0)0R, -S 2

N(R

m

)C(=O)NR

m

-NR

m

-N(R

m

-N(R

m

-N(R

m )C(=0)NR m

R

m

-N(R

m

)C(=NR

m

)NR

m

-N(R

m )S(=0h2R',

-N(R

m )S 2 NRIRn, -NRm~C 2 6 alkylNRnR or -NR'C 2 6 aI kyIOR m or

I

-78- R 2is 2 ),phenyl, wherein the phenyl is substituted by 0, 1, 2 or 3 _n substituents independently selected from Ci-salkyl, C 1 4 haloalkyl, halo, cyano, nitro, n, -C(=O)NR m

-C(=NR

m

)NR

m

R

m

-OR

m

-OC(=O)NR

m

-OC(=O)N(R

m 2 R -OC 2 (al kylNR m

R

m -0C 2 6 alkylOR', -SR m 2 2

NR

m

R

m 2

N(R

m -S 2

N(R

m m

)C(=O)NR

m

R',

-NR

m

-N(R

m

-N(R

m

)C(=O)NR

m

R',

-N(R

m

)C(=NR

m

)NR

m

R

m -N(Rm')S 2 Rn, -N(R m 2

NR

m

R

m

-NR

M

C

2 6 alkyINR m

R

m

-NR

m

C

26 alkylOR m -C(=O)ORs, -C(=O)NRnR', -C(=NRn)NRRs, -ORs, OC(=O)Rs, .OC(=O)NRnRs -OC(=O)N(Rn)S(=O) 2 Rs, OC 2 6 al kylNRrnRs, -0C 2 6 a1 kylORs, -SRs, -S(=O)Rs, -S (=O)2Rs, 2 NRrnR', -S 2

N(R

m

O)

2

N(R

m )C(=O)0Rs, -S 2

N(R

m

)C(=O)NR

m Rs, -NRrnRS, .N(R)C(0O)Rs, -N(R m )C(=O)0Rs,

-N(R

m

)C(=O)NR

m Rs, -N(R m

)C(=NR

m

)NR

m

-N(R

m 2 Rs,

-N(R

m 2

NR

m -Nm26lyNm' -NR

M

C

2 6 alkylORs and C,- 4 alkyl substituted by 1 or 2 groups selected from CI.

2 haloalkyl, halo, cyano, nitro,

-C(=O)NR

m

R

m

-C(=NR

m

)NR

m

R

m

-OR

m

-OC(=O)R,

-OC(=O)NR

m

R

m

-OC(=O)N(R

m 2 R -0C 2 6 alkylNR m

R

m

-OC

2 6 alkylOR~

-SR

m -S 2 2 NR-R-, 2

N(R

m 2

N(R

m )C(=O)OR n, -S 2

N(R

m

)C(=O)NR

m R -NR'R',

-N(R

m

-N(R

m

-N(R

m

)C(=O)NR

m

R",

-N(R

m

)C(=NR

m

)NR

m

R

m

-N(R

1 2 R n, -N(R m )S 2

NR

m

R

m

-NR

m

C

2 6 alkylNR m

R

m -C(=O)ORs, -C(=O)NR m

-C(=NR

m

)NR-R

5 .OC(=O)Rs, .OC(=O)N~R 5 ks -OC(=O)N(R m )S 2 Rs, -OC 2 6 alkyI NR m

R',

-OC

2 6 alkylORs, 2 Rs, =O) 2

NR

m

R',

-s 2 N(Rrn)C(=O)RS, -S 2 N(Rrn)C(=O)ORs, -S 2 N(Rrn)C(=O)NRnR, -NRrnRs, -N(Rrn)C(=O)Rs, -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRnR',

-N(R

m

)C(=NR

m

)NR

m Rs, -N(R

M

)S 2 Rs, -N(R m )S 2

NR

m Rs,

-NR

m

C

2 6 alkylNR m Rs, -NR

M

C

2 6 alkylOR 5 and -NR m

C

2 6 alkylOR m or R 2 IS 2 0 r, wherein R' is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, 0 and S, wherein no more than 2 of the ring members are 0 or S, 79 wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from CI-salkyl, CI- 4 haloalkyl, halo, cyano, nitro, -C(=O)OR

-C(=O)NR

m

-C(=NR

m

)NR

m

R

m

-OR

m -OC(=O)R n, -OC(=O)NR m

R

m

-OC(=O)N(R

m 2

-OC

2 6 a~kylNR m -0C 2 6 alkylOR m

-SR

m 2 2

NR

m 2

N(R

m 2 N(Rm')C(=O)OR, 2

N(R

m

)C(=O)NR

m

"R

m

-NR

m

R

m

-N(R

m

-N(R

m

)C(=O)OR,

-N(Rn m

)C(=O)NR

m

R

m -N(Rrn)C(=NRn)NRnRr, -N(R m 2

R,

-N(Rn m )S 2

NR

m R'm, -NR m

C

2 _6alkylNR m

R

m

-NR

m

C

2 -6alky1OR m -C(=O)Rs, -C(=O)ORs, -C(=O)NRnR', -C(=NRrn)NRrnRs, OC(0)Rs, -OC(=O)NRnR', -OC(=O)N(Rrn)S(=O) 2 Rs, oc 2 6 alkylrNRs, -OC 2 6 alkylOR', -SRs, -S 2 -S 2 NRnRS, S(=O) 2 N(Rr)C(--)Rs, -S 2 N(Rrn)C(=O)ORs, -s 2 N(Rm)C(=O)NRnRs, -NRrnRS, -N(Rrn)C(=O)Rs,

-N(R

m )C(=O)0R 5 -N(Rrn)C(=O)NRnRs, -N(Rrn)C(=NRn)NRnR',

-N(R

m )S 2 Rs, -N(rRr)S(=0) 2 NRnRs, -RnC 2 -alkylN4IRnRs, -NRrC 2 6 alkylOR' and C 1 4 alkyl substituted by I or 2 groups selected from C 1 2 haloalkyl, halo, cyano, ni tro, -C(=O)NR m R -C(=NR m

-OR-

m -OC(0)NRR m

-OC(=O)N(R

m

)S(O)

2 R n, -OC 2 6 alkylNR m

R'

m -0C 2 6 alkylOR', -SR m -S 2 -S 2

NR

m

R',

2 2

N(R

m )C(=O)OR n, 2

N(R

m

)C(=O)NR

m Rm',

-NR

m -N(Rm 1

-N(R

m

)C(=O)NR

m

R',

-N(R

m

)C(=NR

m

)NR

m

R

m

-N(R

m 2

-N(R

m 2

NR

m

R

m

-NR

m

C

2 6 aI kyINR m

R

m -C(=O)ORs, -C(=O)NRnR', -C(=NRn)NRnRs, 0W, .OC(0O)Rs, OC(=O)NRnRs -OC(=O)N(R m )S 2 R, -OC 2 6 alkylNRnRs,

-OC

2 6 alkylORs, -SRs, 2 Rs, 2

NR

m

R$,

-S 2 N(Rrn)C(=O)Rs, -S 2 N(Rrn)C(=0O)ORs, 2 N(Rrn)C(=0)NRnRs, -NRrnR', -N(Rrn)C(=O)Rs, -N(Rrn)C(=O)ORs, -N(R')C(=O)NRnR', -N(Rm)C(=NRn)NRmlR', -N(R m )S 2 Rs, -N(R m )S 2 NR'~Rs, _NRnC 26 alkylNRnR', -NRnC 2 6 alkylORs and -NR

M

C

2 6 alkylOk m R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N. and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected 80 from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C 1 -alkyl,

CI-

4 haloal kyl, halo, cyano, ni tro, -C(=O)R 1 m m

-C(=NR

m

)NR

m

R

m

-OR

m -OC(=O)R n, -OC(=O)NR m R

-OC(=-O)N(R

m 2 -0C 2 6 alkylNR m

R

m

-OC

2 -raIkylOR m

-SR'

m

-S(=O)R

1 2

R

1 2

NR

m

R

m 2

N(R

m n, -S 2

N(R

m )C(=0)ORn, 2

N(R

m

)C(=O)NR'R

m

-NR

m

-N(R

m

)C(=O)R

1

-N(R

m )C(=O)0R 1 -N(Rrn)C(=O)NRmRn, -N(R m

)C(=NR

m

)NR

m

R

m

-N(R

m 2 R n

-N(R

m 2

NR

m

-NR'C

2 6 alkylNR m

R

m

-NR

m

C

2 6 a1 kylO.R, -C(=O)ORs, .C(0)NRnRS -C(=NRn)rNRsR .0C(=O)Rs, -0C(=O)NR.nR', -OC(=O)N(R m )S 2 Rs, -OC 2 -6a~kylNRnR', -OC 2 -6alkylOR', -SRs, -S(0)RS' 2 2 NRnR', 2 N(Rrn)C(=0)Rs,.

2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=O)NRnR', -NRrnR', -N(Rrn)C(=O)R', -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRnR', -N(Rrn)C(=NRn)NRnRs,

-N(R

m )S 2 Rs, -N(Rrn)S(=0) 2 NRnRs, -NR nIC 2 6 a1 kylNRnR', -NRnC 26 alkylOR' and C 1 4 alkyl' substituted by 1 or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, n, -C(=O)0R 0

-C(-O)NR

m

-C(=NR

m

)NR'R

m

-OR',

-OC(=O)R

1

-OC(=O)NR

m

R

m

-OC(=O)N(R

m -0C 2 4 alkylNR m

R

m

-OC

26 alyIOR' m

-SR

m

-S(=O)R

1 2 2

NR

m

R

m 2

N(R

m -S 2

N(R

m )C(=O)0R n, 2

N(R

m

)C(=O)NR'R

m

-N(R

m

)C(=NR

m

)NR

m

-N(R

m 2

R

1

-N(R

m 2

NR

m

R

m

-NR

M

C

2 6 alkylNR m

R

m -C(=O)ORs, -C(=0)NRnR', -C(=NRn)NRnR', -ORW, -OC(=0)Rs, -OC(=O)NRnR', -OC(=O)N(Rn)S(=O) 2

-OC

2 6 aI kylNRnRs,

-OC

2 6 alkylORs, 2 2 NRnR', -S 2 N(Rrn)C(=0)RS, -S 2 N(Rm 1 )C(=O)ORs, -S 2 N(Rm 1 )C(=0)NRnR', -NRrnR', -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)N~1RmRs, -N(Rm 1 )C(=NRm 1 )NW~mRs, -N(Rrn)S(=O) 2 Rs, -N(R m )S 2 NRnRs, -NRnC 2 6 alkylNRm 1 Rs, -NRnC 2 6 alkylORs and -NR

M

C

2 -6alkyl0R', and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups; R 7 is C 2 .8alkyI, C 1 5 haloalkyl, 1, Br;.

-81-

R

9 is independently, at each instance, H, C 1 9 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -0C 1 6alkyl, -0-C 1 4 haloalkyl, -0-C 1 6 alkylNR m

R',

-O-C

1 -6alkylOR', -NkR' m

-NR

m

-C

1 4 haloalkyl, -NR m

-C

1 6 alkylNR m or

-NR

m

-C

1 Y is NH-;and Z is CR or N;or R'is R 6

F

3 C R 2 is H, -OR

M

Cl, C 1 3 haloalkyl Or C 1 6 alkyl;

R

4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms, selected from 0, N and S, so long as the combination of 0 and S atoms is not greater than 1, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from Cl-galkyl, C 1 -4haloalkyl, halo, cyano,. nitro, -C(=0)NR m

-C(=NR

m

)NR

m

R

m -OR n, -OC(=O)Rn, -OC(=O)NR m

R',

2

-QC

2 6alkylOR-, -SR m 2 R 2

NR

m -S 2 N(Rm)C(=O)R -S(=O0) 2

N(R

m

)C(=O)OR,

2 N(Rn)C(=O)NR m Rml, -NR R m -N(Rml)C(=O)R -N(R tm

)C(=O)OR,

~-N(R

t

)C(=O)NR"'R

m

-N(R

m

)C(=NR')NR

m

R

m

-N(R

m )S 2

R",

-N(R

m 2

NR

m

R

m

-NR

tm

C

2 -6alkylNR m

R

m

-NR

tm

C

2 6 alkylOR m -C(=O)Rs, -C(=O)ORs, C(=O)NRnRs, -C(=NRrn)NRrnRs, -0C(=0)Rs, -OC(=O)NRrnRs, -OC(=O)N(Rrn)S(=O) 2 Rs, -0C 2 _6alkylNRnRs, -OC 2 6 alkyl0Rs, -SRs, 2 Rs, 2 NRnR', 2 N(Rrn)C(=O)Rs, 2 N(Rr)C(=O)ORs, -S 2 N(Rrn)C(=O)NRnRs, 4-pRrn's -N(Rr)C(0O)Rs, -N(Rr)C(=O)0Rs', -N(Rrn)C(=0)NRnRs, -N(R m

)C(=NR

m )NRm

T

Rs, -N(Rr)S(=iO) 2 Rs, 2 NRrnRs, -NRnC 2 6 alkylNRnRs, -NR _C 2 alkyI0R and Cj'i 4 alkyl substituted by 1 or 2 .groups selected from C 1 2 haloalkyl, halo, cya'no,*nitrO, -C(=0)NWR m

-C(=NR

m

)NR

m

R

m

-OR

m -OC( O)R, -OC(=0)NR m

R

m -OC(=O)N(Rm)S 2 R, -OC 2 _al kylNrR m

R

m

-OC

2 6 alkylOk t m 82

-SR

m n- S(=0) 2 -S 2

NR

m

R

m -S 2

N(R

m )CQ=0)R n, 2

N(R

m )C(=0)OR n, 2

N(R

m

)C(=O)NR

m

R

m

-NR

m

R',

-N(R

m

-N(R

m

-N(R

m

-N(R

m

)C(=NR

M

)NR

m

R

m n, -N(R m 2

-N(R

m 2

NR'R

m

-NR

m

C

2 6 alkylNR m C(=0)ORS, -C(0)NRnR', -C(=NRn)NRnR', -ORs, -0C(=O)Rs, .0C(0)rNRsR' -OC(=0)N(Rrn)S(=0) 2 RS, -0C 2 6 alkyNR m Rs, -0C 2 -6alkyl0R', SR', -S 2 RS, 2 NRnR', 2 N(Rrn)C(=O)R', 2 N(Rr)C(=0)ORs, 2 N(Rrn)C(=O)NRnR', -NRrnRs, N(Rr)C(=0)Rs, -N(Rr)C(=0)0Rs, -N(Rr)C(=0)NRnR', -N(Rrn)C(=NRrn)NRrnRs, -N(Rrn)S(=0) 2 Rs, -N(R m )S 2 NRnRS,( -NRrnC 2 alkylNRnR', -NRrnC 2 4 salkyI0R' and -NR m

C

2 6 alkyIOR m wherein R 4 is not unsubstituted phenyl; R 9 is independently, at each instance, H, Cl- 9 alkyl, CI-4haloalkyl, halo, nitro, cyano, -OCI 6 alkyl, -0-C 1 Ahaloalkyl, -0-C 16 alkylNR m Rn, -0-Cl 1 ralkylOR m

-NR

m

R

m -NRn-C 14 haloalkyl, -NR m

-C

16 alkylNR m R' or

-NR

m

-C

1 6 alkylOR m Y is NH; and ZisCR 8 or N.

In another embodiment, in conjunction with the novel compound embodiments above and below, 80, wherein: R' is R6

R

8 (C q ql)ORO R 2 is H, -OR m halo, C 1 3 haloalkyl or C 1 6 alkyl; R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon,.so long-as the.

combination of 0 and S atoms is not greater than 2, wherein the ring and bridge 83 are substituted by 0, 1, 2 or 3 substituents independently selected from CI- 8 alkyl,

C

1 -4haloalkyl, halo, cyano, nitro, -C(=O)NR m

R',

-C(=NR

m

)NR

m

R

m

-OR'

m -OC(=O)R n, -OC(=O)NR m

R',

-OC(=O)N(R

m )S 2 -0C 2 6 alkylNR m

-OC

26 al ky]OR m -S 2 -S 2

NR

m

R

m 2 -S 2 N(R 2

N(R

m

)C(=O)NR

m

-NR

m

-N(R

m

-N(R

m

-N(R

m

)C(=O)NR

m

-N(R

m

)C(=NR

m

)NR

m

R

m

-N(R

m 2

R',

-N(R

m )S 2

NR

m

R

m

-NR

M

C

2 6 alkylNRm 7

R

m

-NR

M

C

2 6 alkylOR m -C(=O)Rs, -C(=O)ORs, -C(=O)NRnR', -C(4=R"l)NRm~s, .ORs, -OC(=O)R -OC(=O)NRnRs, OC(0)N(Rn)S(=O) 2 Rs, -OC 2 6 alkyl NRnRs, -OC 2 .6al kylORs, -SRs, -S 2

-S(O)

2 N4 1 m Rs 2

N(R

m )C(=0)Rs, 2

N(R

m )C(=O)0Rs, -s 2

N(R

m

)C(=O)NR

m Rs, -{R m Rs, -N(R m )C(=O)Rs,

-N(R

m )C(=0)0Rs, -N(R m

)C(=O)NR

m Rs, -N(R m

)C(=NR

m

)NR

m Rs,.

-N(R

m )S 2 Rs, -N(R m )S 2

NR

m Rs, -NR'C 2 6 alkyl NR m Rs, -NR

M

C

2 6 al kylORs and C 1 4 alkyl substituted by 1 or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=O)NR m

R"

m -C(=NRm

T

)NR"nRr, -OR m -0C(=O)R -OC(=O)NR m -OC(=O)N(RMhS(=O) 2

R

0 -0C 2 6 al kylNRIRrn,

-OC

26 alkylOR', -SR' m n, 2 2

NR

m

R

m 2

N(R

m -S 2

N(R

m 2

N(R

m

)C(=O)NR

m

R

m

-NR

m

R

m

-N(R

tm n, -N(R m

-N(R

m

)C(=O)NR

m Rm 1

-N(R

m

)C(=NR

m

)NR

m Rm, -N(R m 2

-N(R

m )S 2 NRnRI,

-NR

M

C

2 6 ,alkylNR m -C(=O)0R 5

-C(=NR

m

)NR

m Rs, -ORs, -OG(0)NR m Rs, -OC(0)N(R

M

2 Rs, -0C 2 6 alkylN.flRrnR

-OC

2 -6alkylOR', 2 -S 2 NRnRS, -S 2

N(R

m -S 2

N(R

m )C(=O)0Rs, -S 2 N(Rrn)C(=O)NRnRs, N(R)C(0)0R 5

-N(R-)C(=O)NR-R

5

-N(R

m

)C(=NR

m

)NR

m

-N(R

m )S 2

-N(R

m 2

NR

m

R',

-NR

M

C

2 6 alkylNR m

-NR

m

C

26 alkylOR 5 and -NR m

C

2 6 a1 kylOR m and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups; R 7 is Cl- 9 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -OCI- 6 alkyl, 4 haloalkyl, -O-C 1 6 a1kylNR m

R

m -0-C 6 alkylOR m

-NR

m

R

m

-NR

m

-C

1 4 haloalkyl, -NR m

-C

1 6 alkylNR.

m R' or -NR tm 6 alkylOR'; 84- R' is a saturated, partially-saturated or unsaturated 6- or 7-membered monocyclic or 10- or I 1-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, 0 and S, so long as the combination of 0 and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from RP; RP is independently at each instance C 1 8 alkyl, C 1 4 haloalkyl, halo, cyano, nitro, n, -C(=O)0R n, -C(=O)NR m

-C(=NR

m

)NR

m

-OR

m -OC(=O)R n, -OC(=O)NR m

-OC(=O)N(R

m

)S(O)

2

-OC

2 _6alkylNR m

R

m

-OC

2 -6alkyIOR', -SR' m n, 2 2

NR

m

R

m -S 2

N(R

m -S 2

N(R

m 2

N(R

m

)C(=O)NR

m

R'",C

-NR

m

-N(R

m

-N(R

m

-N(R

m

)C(=O)NR

m

R

m

-N(R

m

)C(=NR

m

)NR

m

-N(R

m 2

-N(R

m 2

NR

m

R

m

-NR

M

C

2 -6alkylNR m

R

m or -NR

M

C

2 6 aIkylOR m and Y is 0orNH.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 4 is a saturated or unsaturated 5- of 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C,.salkyI,

C

1 -4haloalkyl, halo, cyano., nitro, -C(=O)NR m

R',

-C(=NR

m

)NR

m

R

m

-OR'

m

-OC(=O)NR

m

R,

-OC(=O)N(R

m )S 2

-OC

2 -6alkylNR m

R

m

-OC

2 6 alkylOR"', -SR' m -S 2 2

NR

m

R

m 2 2

N(R

m

)C(=O)OR,

-S 2

N(R

m

)C(=O)NR

m

R

m

-NR

m

R

m

-N(R

m

-N(R

m

)C(=O)NR

m

-N(R

m

)C(=NR

m

)NR

m

-N(R

m )S 2 R

-N(R

m 2

NR

m

R

m

-NR

M

C

2 -6alkylNR m

R

m

-WN

m C 6 alkylOR m -C(=O)ORs, -C(=O)NRnRs, -C(=NR)rNRsR .OC(0)Rs, -OC(=O)NRnR', -OC(=O)N(Rrn)S(O) 2

-OC

2 6 alkylNR m Rs, -OC 2 6 alkylOR', -SRs, 2 Rs, 2 NRrnRs, 2 N(Rrn)C(=O)R', 85 -S 2 N(Rrn)C(=0)ORS, 2 N(Rrn)C(=0)NRnR', -NRrnR', N(Rr)C(0O)Rs,

-N(R

m )C(=O)0R 5 -N(Rrn)C(=0)NRnR', -N(Rrn)C(=NRn)NRnRs, -N(Rrn)S(=0) 2 -N(Rrn)S(=0) 2 NRnRs, -NR

M

C

2 -6a1kylNRnRs, -NRrnC 2 6 alky1OR' and C 14 alkyI substituted by 1 or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=O)NRmR', -C(=NRm)NR m

R

m

-OR

m

-OC(=O)NR

m

R

m -OC(=0)N(R m 2 -0C 2 6 alkylNR'R m -0C 2 6 alkylOR m

-SR

m -S -S 2 R n, -S 2

NR

m

R

m -S 2

N(R

m 2

N(R

m -S 2

N(R

m

)C(=O)NR

m

R',

-NR

m RTh -N(R m n, -N(R m

-N(R

m

)C(=Q)NR

m

R',

-N(R

m

)C(=NR-)NR

m m 2

R

0 2

NR

m

R',

-NR

m

C

2 6 alkylNR m

R

m -C(=O)ORs, -C(=O)NRnRs, -C(=NRrn)NRnRs, -OC(=O)NRnR', .OC(=O)N(Rn)S(=O) 2 Rs, -OC 2 6 alkylNRnR',

-OC

2 6 alkylOR', 2 2 NRnRs, -S 2 2 N(Rrn)C(=O)ORs -S 2 N(Rn)C(=O)NRnRS, -NRrnRs, -N(Rrn)C(=O)R's, -N(Rm)C(=0)ORs, -N(Rrn)C(=O)NRnRs, -N(Rrn)C(=NRn)NRnR', -N(R m )S 2

-N(R

m )S 2 NRnRS, -NRnC 2 6 alkylNRnR', -NR

M

C

2 4 salkylORS and -NR m

C

2 -6alkyIOR'; and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 4 is a phenyl ring that is vicinally fused with a saturated or unsaturated 3- or 4-atomn bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from CI-8alkyl,

C

1 4 haloalkyl, halo, cyano, nitro, -C(=O)OR n, -C(=O)NR m

R

m

-C(=NR

m

)NR

m Rm", -OR m -OC(=0)NRmR m -OC(=0)N(R m 2 -0C 2 6 alkylNR m

R

m -0C 2 -sa1kylOR m

-SR

m -S(0)R, 2 2

NR

m

R

m 2

N(R

m 2 2

N(R

m

)C(=O)NR

m

R

m

-NR

m1

-N(R

m

-N(R

m 3 0 -N(R m )C(=O)NR-R -N(R m

)C(=NR

m

)NR

m

-N(R

m )S 2

R,

-N(R

m 2

NR

m

R

m

-NR

m

C

2 6 alkylNR m

R

m

-NR'C

2 _6alkylOR', -C(=0)0Rs, -C(=O)NRnR', -C(=NR)NRnR' .0C(0)Rs 86 -0C(=0)NRnR-, -OC(=0)N(R m )S 2 Rs, -OC 2 6 al kyNRnRS, -OC 2 6 alkylORS, -S -S 2 2 NRnR', 2 N(Rrn)C(=O)R', 2 N(Rrn)C(=0)ORs, 2 N(Rn)C(=O)NRnR', -NRnRS -N(Rrn)C(=0)Rs, -N(Rr)C(=0)0Rs, -N(Rrn)C(=O)NRnR', -N(Rrn)C(=NRn)NRnR', -N(Rrn)S(=0) 2 N(Rr)S(=0) 2 N.RnRs -NRrnC 2 -alkyINR m -NRrnC 2 6 a~ky]OR' and C 1 4 alkyl substituted by I or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=0)NR m

R

m

-C(=NR

m

)NR

m

R

m

-O]Z

m -OC(=O)R n, -OC(=O)N(R m

)S(O)

2

-OC

2 6 alkylNR-R m -0C 2 6 alkylOR m

-SR

m n, -S 2 R n, 2 N-k m

R

m 2

N(R

m 2

N(R

m )c(=o)OR 2

N(R

m

)C(=O)NR-R,

-NR

m

-N(R

m

-N(R

m )C(=O)OR n, -N(R m

)C(=O)NR

m

R

m

-N(R

m

)C(=NR

m -N(Rm)S(=O) 2 R n -N(R

M

)S 2

NR

m

R

m

-NR

M

C

2 6 alkylNR m C(=O)ORs, C(=O)rNRsR' .C(=NRrn)NRrnRs, -OWs, .OC(=O)Rs, -OC(=O)NRnR', -OC(=0)N(Rl)S 2 R, -OC 2 6 alkylNRnR',

-OC

26 alkylORs, -SRF, 2 Rs, -S(O) 2 NRnR' -S 2 N(Rm~iC(=O)R~s, -S 2 N(Rrn)C(=O)ORs, -S 2 N(Rrn)C(=O)NRnRS, -NRrnRs, -N(Rrn)C(=O)Rs, -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRrnRs, -N(Rrn)C(=NRn)NRnR', -N(R m )S 2 R, -N(Rrn)S(=O) 2 'NRnRs, -NRnC 2 6 alkylNRnRs, -NRrnC 2 6 alkylORs and -NR m

C

2 _6alkylOR m and the bridge carbon atoms are substituted with 0, 1 or 2 =0 groups.

In another embodiment, in conjunction with the novel compound( embodiments above and below, R 7 is C 1 9 galkyl, C 1 4 haloalkyl, halo, -0CI.

6 alkyl, -0-C 1 4haloalkyl, -NR m R' or -NR m

-C

1 4 haloalkyl.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 7 is C 1 5 alkyl, CI4haloalkyl, I, Br or Cl.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 7 is tert-butyl or trifluoromethyl.

In another embodiment, in conjunction with the novel compound embodiments above and below, R' is a saturated, partially-saturated or unsaturated 6- or 7-membered monocyclic ring containing 0, 1, 2 or 3 atoms selected from N, 0 and S, so long as the combination of 0 and S atoms is not greater than 1, wherein the carbon atoms of the-ring are substituted by 0, 1 or 2 -87oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from R p In another embodiment, in conjunction with the novel compound embodiments above and below, R° is a saturated, partially-saturated or unsaturated 6-membered ring containing 0, 1, 2 or 3 N atoms, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from R

P

In another embodiment, in conjunction with the novel compound embodiments above and below, Y is 0.

In another embodiment, in conjunction with the novel compound embodiments above and below, Y is NH.

In another embodiment, in conjunction with the novel compound embodiments above and below, R' is

R

6 R7 R 5

R

7 N R R8 (CRqRI)oR or (CRqRq)oRo

R

2 is H, -OR m halo, Ci.3haloalkyl or Cl6alkyl;

R

4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from Clsalkyl,

C

1 4 haloalkyl, halo, cyano, nitro, -C(=O)NR m

R

m

-C(=NR

m

)NR

m

R

m

-OR

m

-OC(=O)NR

m

R

m

-OC(=O)N(R

m 2 -OC2-6alkylNR m

R

m

-OC

2 6 alkylOR m

-SR

m 2 2

NR

m

R

m 2

N(R

m 2

N(R

m 2

N(R

m

)C(=O)NR

m

R

m

-NR

m

R

m

-N(R

m

-N(R

m

-N(R

m

)C(=O)NR

m

R

m

-N(R

m )C(=NRm)NR m R, -N(R m 2

R",

-N(R

m 2

NR

m

R

m

-NR

m

C

2 al kylNR m

R

m

-NR

m C2.alkylOR m -C(=O)Rs, 88 -C(=0)0Rs, -C(=0)NRnR', -C(=NRrn)NRrnR', -0C(=0)Rs, -0C(=0)NRnR', OC(=0)N(Rn)S(=0) 2 Rs, -OC 2 -6alkylNR -0C 2 6 alkyI0R', -SRs, S(0)Rs, 2 Rs, 2 NRnRs 2 N(Rrn)C(=0)R', 2 N(Rrn)C(=O)0Rs, 2 N(Rrn)C(=0)NRnR', NRrnR, -N(Rrn)C(=O)R', -N(Rr)C(=0)0Rs, N(Rrn)C(=O)NRnRs -N(Rrn)C(=NRrn)NRrnRs,

-N(R

m )S 2 Rs, -N(Rrn)S(=0) 2 NRnRs, -NRrnC 2 6 alkylNRnRs, -NRnC 2 and C 1 4 alkyI substituted by 1 or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=0)NR m

-C(=NR

m

)NR

m

R

m

-OR

m

-OC(=O)NR

m

R

m -OC(=O)N(Rm 1 2 -0C 26 alkyNR m

R',

-OC

2 -6alkylOR m

-SR

m 2 2

NR

m R ',C 2 N(Rm)C(=O)R n, -S 2

N(R

m 2

N(R

m

-NR

m

-N(R

m n, -N(R m )C(=O)OR n, -N(R m

)C(=O)NR

m

R

m

-N(R

m

)C(=NR

m

)NR

m

R

m

-N(R

m 2

-N(R

m )S 2

NR

m

R

m -N R m

C

2 6 alkyINR m -C(0)ORs, -C(=O)NRnRs, R)NRnR', -ORs, -OC(=O)Rs, -OC(=O)NRnRs, -OC(=0)N(Rn)S(=O) 2

-OC

26 aIky1NRnRs, -0C 2 6 al ky]OR', 2 -S 2 NRnRS, -S 2 N(Rrn)C(=O)RS, -S 2 N(Rrn)C(=O)ORs, -S 2 N(Rrn)C(=O)NRnR', -NRrnR', -N(Rr)C(=0)ORs, -N(Rrn)C(=O)NRnRs, -N(Rrn)C(=NRn)NRnRs, -N(Rrn)S(=O) 2 -N(Rrn)S(=O) 2 NRrnR', -NRrnC 2 _alkylNRrnRs, -NRnC 26 alkylORs and -NR m

C

2 6 alkylOR m and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups; R 7 is C 1 9 )alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -OCI 1 6 alkyl, -0-C 1 4 haloalkyl, -O-C 1 _6alkylNR m -0-C 1 6 alkylOR m

-NR

m

R

m

-NR

m

-C

1 4 haloalkyl, -NR m

-C

1 -6alkyNR m R' or -NR m -C 6 alkylOR'; [C j-Salkyl,

C

1 5 haloalkyl, 1, Br or CI] R' is a saturated, partial ly-saturated or unsaturated 6- or 7-membered monocyclic or 10- or IlI-membered bicy clic ring contai ning 0, 1, 2, 3 or 4 atoms selected from N, 0 and S, so long as the combination of 0 and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0, 1 or 3 0 2 oxo groups, wherein the ring I s substituted by 0, 1, 2 or 3 substituents independently selected from RI; 89 RP is independently at each instance C 1 8 alkyl, Cl-4haloalkyl, halo, cyano, _nnitro, -C(=O)OR n, -C(=O)NR m

-C(=NR

m

-OR

m

-OC(=O)NRR

m 2 R, -OC 2 alyN m

-OC

2 6al kylOR m n, -S 2 2

NR-

1

R

m 2

N(R

m 2 2

N(R

m

)C(=O)NR

m

R

m

-NR

m

R

m

-N(R

m n, -N(R m )C(=O)OR n, -N(R m

)C(=O)NR

m

R',

-N(R

m

)C(=NR

m )NRmR m -N(Rm)S(=O) 2

-N(R

m 2

NR'R',

-NR

M

C

2 6 alkylNR m

R

m or -NR

M

C

2 6 alkylOR'; and Y is 0or NH.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C 1 8 alkyl,

C

1 .Thaloalkyl, halo,,cyano, nitro, n, C(=0)OR n, -C(=O)NR m

R',

-C(=NR

m

)NR

m

R

m

-OR

m

-OC(=O)NR

m

R',

-OC(=O)N(R

m 2 R -OC 2 6 akyNR m -0C 2 6 alkylOR', -SR' m -S 2 R n, 2

NR

m 2 N (R m )C(=0)R 0 -S 2 -S 2

N(R

m )C(=0)NR m Rm t -NRrnRr, -N(R'ThC(=O)OR',

-N(R

m

)C(=O)NR

m

-N(R

m

)C(=NR

m

)NR

m

R

m

-N(R

m 2

R,

-N(R

m 2

NR

m

R

m

-NR'"C

2 6 al kyl NR m

R

m

-NR

m

C

2 6 alkylOR m -C(=O)ORs, C(=)NRnRs, -C(=NRm)NR m -OC(=O)Rr 5

-OC(=O)NR

m Rs, -OC(=O)N(Rrn)S(=O) 2 Rs, OC 2 6 al kylNR m Rs, -OC 2 -fal kylOR', -SRs, 2 Rs, 2

NR

m Rs, -S 2 N(RmI)C(=O)R', -s 2

N(R

t )C(=O)0Rs, -s 2

N(R

tm )C(=0)NR m Rs, -Nms -N(R m

-N(R

m

)C(=O)OR

5

-N(R

tm

)C(=O)NR

m

-N(R

m

)C(=NR

m

)NR

m Rs,

-N(R

m 2 Rs, -N(R m 2

NR

m Rs, -R M

C

2 6 al kylNR m

-NR

m

C

2 6 a1 kylORs and C 1 4 alkyl substituted by 1 or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=O)NR m

-C(NW)NR"

m

-OR'

m -OC(=O)R n, -OC(=O)NR m

-OC(=O)N(R

m )S 2 -0C 2 6 a1 kyINR m

R

m

-OC

2 6al kylOR m

-SR'

m -S 2 -S 2

NR

m

R

m 2

N(R

m 2

N(R

m 2

N(R

m )C(=0)NR m

R',

-N(R

m

-N(R

m

-N(R

m )C(=0O)NR m

R',

-N(R

m

)C(=NR

m

-N(R

m 2

-N(R

m 2

NR

m

R',

-NR

m

C

2 6 alkylNR m

R

m -C(=0)ORs, -C(=O)NRnR', -C(=R)NRnRs -ORs, -0C(=0)Rs, .0C(=0)NRnRs, -OC(0)N(R m )S (0) 2 Rs, C 2 6 a~kylrNRRS -0C 26 alkyl0R', -SRs, 2 2 NRrnRs, 2 N(Rrn)C(=0)R', 2 N(Rr)C(=o)0Rs, 2 N(Rrn)C(=0)NRnR', -NRrnRs, -N(Rr)C(=0)ORs, N(Rr)C(=0)NR'Rn' -N(Rrn)C(=NRrn)NRnRs, -N(Rrn)S(=0) 2

-N(R

m )S 2 NRnRS, -NRrnC 2 6 alkylNRrnR', -NRnC 2 6 alkylORs and -NR tm

C

2 6 alkyIOR'; and the ring and bridge carbon atoms are substituted'with 0, 1 or 2 =0 groups.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 4is a phenyl ring that is vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from Ci-galkyl,

C

1 4 haloaI kyl, halo, cyano, ni tro, n, -C(=0)NR m

R',

-C(=NR-)NR-R

m

-OR-

m -0C(=0)R n, -OC(=0)NR m

R-,

-0C(=0)N(R m 2 R -0C 2 6 alkylNR-R', -0C 2 6 a1 ky[OR, -SR' m -S 2 R n, 2

NR

m

R

m 2 2

N(R

m 2

N(R

m )C(=0)NR m

R

m

-NR

m

R

m

-N(R

m )C(=0)0R,

-N(R

m )C(=0)NR m

-N(R

m

)C(=NR

m

)NR

m

-N(R

m 2

R",

-N(R

m 2 NR-R', -NR m

C

2 6 alkyl NR m

-NR

m

C

2 _6al kylOR m -C(=O)0Rs, -C(=0)NRnR', -C(=NRrn)NRrnR', OC(0)Rs, -0 C(=0)NRmIRs, -0C(=0)N(Rn)S(=0) 2 -0C 2 .6alkyl NRrnR, OC 2 6 al kyloRs, -SRs, -S(=0)R 5 2 2 NRm 1 Rs, -S 2

N(R

m -S 2

N(R

m )C(=0)0Rs, 2

N(R

m

)C(=O)NR

m

-NR

m Rs, 3 0 -N(R m

)C(=NR

m

)NR

m

R',

-N(R

m 2

-N(R

m 2

NR

m

-NR

m

C

2 _6alkylNR m Rs, -NRnC 26 alkyl0RS and C 1 4alkyl substituted by I or 2 groups selected from C 1 2 haloalkyl, halo;, -91cyano, nitro, -C(=O)NR Rn, -C(=NR m

)NR

m

-OR

m

-OC(=O)NR

m

R

m

-OC(=O)N(R

m 2 R n, -OC 2 4 3 alkyINR m

-OC

2 -6al kylOR m -S 2 2

NR

m

R

m 2

N(R

m n, 2

N(R

m 2

N(R')C(=O)NR

m

R',

-NR

m

-N(R

m )C(=O)OR n, -N(R m

)C(=O)NR

m

R

m

-N(R

m

)C(=NR

m

)NR

m

R

m

-N(R

m )S 2 R n, -N(R m )S 2

NR

m

R',

-NR

m

C

2 6 alkylNR m

R

m C(=O)ORs, -C(=O)NR m

-C(=NR

m

)NR

m

R',

-ORs, -OC(=O)Rs, -OC(0)NR m Rs, -OC(=O)N(R m 2

-OC

2 6 alkylNR'R',

-OC

26 alkylOR', S(0O)Rs, 5 2

NR

m Rs, -S 2 N(Rrn)C(=O)RS, 2

N(R

m )C(=O)0Rs, -S 2

N(R

m

)C(=O)NR

m

R',

-NRrnRs, -N(Rrn)C(=-O)Rs, -N(Rrn)C(=O)ORs, -N(Rr)C(=O)NRnRs,

-N(R

m

)C(=NR

m

)NR

m Rs, -N(R m 2 Rs, -N(R m 2

NR

m Rs,

-NR

m

C

2 6 ,alkylNR m Rs, -NR m

C

2 .6alkylOR' and -NR

M

C

2 6 alkylOR m and the bridge carbon atoms are substituted with 0, 1 or 2 =0O groups.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 7 is C 1 9 alkyl, C 14 haloalkyl, halo, -0CI.

6 alkyl, -0-C 1 4 haloalkyl, -NR m

R

m or -NW-C 14 haloalkyl.

In another embodiment, in conjunction with the novel compound embodime~nts above and below, R 7 is C 15 alkyl, C 1 4 haloalkyI, I, Br or Cl.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 7 is tert-butyl or trifluoromethyl.

In another embodiment, in conjunction with the novel compound embodiments above and below, R' is a saturated, partially-saturated or unsaturated 6- or 7-membered monocyclic ring containing 0, 1, 2 or 3 atoms selected from N, 0 and S, so long as the combination of 0 and S atoms is not greater than 1, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from RP.

In another embodiment, in conjunction with the novel compound embodiments above and below, R' is a saturated, partially-saturated or unsaturated 6-membered ring containing 0, 1, 2 or 3 N atoms, wherein the carbon -92atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from RP.

In another embodiment, in conjunction with the novel compound embodiments above and below, Y is 0.

In another embodiment, in conjunction with the novel compound embodiments above and below, Y is NH.

In another embodiment, in conjunction with the novel compound embodiments above and below, R1 is z R 2 is H, -OR m halo, C 1 3 haloalkyl or C 16 alkyl; R 4 is a saturated, partially-saturated or unsaturated 10 or I I1-membered bicyclic heterocycle containing 1, 2, 3, 4 or 5 atoms selected from 0, N and S, so long as the combination of 0 and S atoms is not greater than 2, but excluding quinolin-6-yl, 4,5 ,6,7-tetrahydro-benzo[blthiophen-2-yl, benzothiazol- 2-yl, 2,3-dihydro-benzo[1,4]dioxin-6-yl, wherein the heterocycle is substituted by 0, 1, 2 or 3 substituents independently selected from C 1 9 galkyl, oxo, C 1 4 haloalkyl, halo, nitro, cyano, -OR' m -S(=O)nC 16 alkyl, -O-C14haloalkyl, -O-C 16 alkylNR m

R

m

-O-C

1 6 alkylOR', -NR m

R

m

-NR

m

-C

14 haloalkyl, -NR m

-C

1 6 alkyINR"'R m

-NR

m

-C

1 6 alkylOR', -C(=O)C 1 6al kyl, -OC(=O)C 1 6 alkyl, -C(=O)NR'C 1 4 alkyl,

-NR

m 6 alkyl -C(=O)ORs, -C(=O)rNRs -C(=NR )NRnR', .OC(=O)NRnRS, -OC(=O)N(R m )S 2 Rs, -0C 2 6 alkylNR m

R',

-OC

26 alkyIOR', 2 Rs, S(0) 2 NRnRs, 2 N(Rrn)C(=0)Rs,.-S 2 N(Rrn)C(=0)ORS, -S 2

N(R'

t )C(=0)NRnRs,

-NR

M

-N(Rr)C(=0)0Rs, -NR)(ON's -N(Rml)C(=NRrn)NRrnRs, -N(Rr)S(=0) 2 Rs, -N(Rrn)S(=0) 2 NRnRs, -NRnC 2 6 alkylNRnR', -NRnC 26 a~kylORs and C 1 4alkyl substituted by 1 or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=O)NR m

R

m n,

-C(=NR

m

)NR

m

-OR'

m

-OC(=O)NR

m

R',

-93

-OC(=O)N(R

m 2 -0C 2 6 alkylNR m

-OC

2 -falkylOR', -SR' m -S 2 R -S 2 NR'R', 2

N(R

m 2

N(R

m )C(=O)OR -S 2

N(R

m

)C(=O)NR

m -N(Rn)C(=O)ORn,

-N(R

m

')C(=O)NR

m Rn m -N(Rn)C(=NR")NR m

-N(R

m )S 2

R",

-N(Rrn)S(=O) 2 NRlR m -C(=O)ORs, -C(=O)NRnR', -C(=NRn)NRnR', -ORF, OC(=O)RS, -OC(=O)NR'nR', -OC(=O)N(Rrn)S(=O) 2

-OC

2 6al kyINRnR', -0C 2 6 a1 kylORs, -SRs, -S 2 2

NR

m

R',

-S 2

N(R

m -S 2

N(R

m )C(=O)0R s, -s 2

N(R

m

)C(=O)NR

m

R',

-NR

m Rs, -N(R m

-N(R

m )C(=O)0Rs, -N(R m

)C(=O)NR

m Rs,

-N(R

m

)C(=R

m

)NR

m

-N(R

m 2 Rs, -N(R m 2

NR

m

R',

-NRnC 2 6 alkyINR m Rs, -NRnC 2 -6alkyIORs and -NR m

C

2 -6alkyIOR m wherein R 4 is not 2-aminocarbonylmethyl-2,3-dihydro-benzo[1 ,4ldioxin-8-yl, 2-cyanomethyl- 2,3-dihydro-benzo[ 1,4]dioxin-8-yl, quinolin-3-yl, 3H-quinazolin-4-on-3-yl, benzo[1I,3]dioxol-5-yI, 3,3-di methyl-I ,3-dihydro-indol-2-on-6-yI or 4,4-dimethyl- 3,4-dihydro-IH-quinolin-2-on-7-yl; R 7 is C 1 .salkyl, C 1 5 haloalkyI, I or Br;

R

9 is H, C 19 galkyl, CI- 4 haloalkyl, halo, nitro, cyano,*-OCI 16 alkyl, -0-C 1 Ahaloalkyl, -0-C 1 6 akylNR m -0-CI-6a1 kyl0R m -NRrlRrn,

-NR

m

-C

1 4 haloalkyl, -NR m

-C

1 6 alkylNR m R' or -NR m

-C

1 -6alkyI0R m Y is NH; and Z is CR 8 or N.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 4 is a heterocycle selected from indole, 3H1indole, benzo[blfuran, benzothiophene, IH-i ndazole, benzimidazole, benzthiazole, IH-benzotriazole, 7-quinoli ne, 8-quinoline, 1,2,3,4tetrahydroquinoline, isoquinoline, cinnoline, phthalazine, quinazoline and quinoxaline,. wherein the heterocycle is substituted by 0, 1, 2 or 3 substituents independently selected from C 1 9 alkyl, OXO, Ci; 4 haloalkyl, halo, nitro, cyano,

-OR

m 6 a1 kyl, -0-C 1 4 haloalkyl, -0-C 1 6 alkylNR m -0-C 6 alkylOR',

-NR

m

R

m -NRn-C 1 4 haloal kyl, -NR m

-C

1 6 al kylNR m

-NR

m

-C

1 6 alkylOR',

-C(=O)C

1 6 a] kyl, -OC(=0)CI.

6 alkyl, -C(=0)NR m

C

1 6 alkyl, -NR m C(=0)C 1 6 alkyl -C(=O)0Rs, -C(0)NRRs, -C(=NR m

)NR

m -0Rs, -OC(=0)Rs, -94 -OC(=O)NRnRs, -OC(=O)N(Rrn)S(=O) 2

-OC

2 -6aIky NRrnRS, -OC 2 -6al kylOR', -SRs, 2 Rs, S(0) 2 rNRs' -S 2 N(Rrn)C(=O)RS, -S(=Oh2N(Rrn)C(=O)ORs, 2 N(Rrn)C(=O)NR Rs, -NRFIRs, N(Rrn)C(=O)Rs, -N(Rr)C(=O)ORs, -N(Rrn)C(=O)NRnRs, -N(Rrn)C(=NRn)NRrnRs,

-N(R

m )S 2 Rs, -N(Rrn)S(=O) 2 NRnR', -NR m

C

2 6al kyl NRrRs, -NRrnC 2 6 alkylOR' and Ci.

4 alkyl substituted by I or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=-O)NR m

-C(=NR

m

)NR

m

-OR

m

-OC(=O)R,

-OC(=O)NR

m

R

m

-OC(=O)N(R

m 2

-OC

26 al kylNR m R -OC 2 6al kyIOR m

-SR

m n, 2 R n, 2

NR

m -S 2

N(R

m -S 2

N(R

m -S 2

N(R

m

)C(=O)NR

m

-N(R

m -N(Rm~)C(=O)ORn, -N(R m

)C(=O)NR

m

R

m

-N(R

m

)C(=NR

m

)NR

m

R

m

-N(R

m 2 R n, -N(Rm t 2

NR

m -C(=O)ORs, -C(=O)NRRs, -C(=NRrn)NRrnR', -0Rs, -OC(=O)Rs, -OC(=O)NRnR', -OC(=O)N(Rrn)S(=O) 2

R,

-OC

2 -6alkyINRnRs, -OC 2 6 alkylORs, 2 Rs, 2 NRnRs, -s 2 N(Rrn)C(=O)Rs, -S 2 N(Rrn)C(=O)ORs, -S 2 N(Rrn)C(=O)NRnRS, -NRrnRs, -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRnRs, -N(Rrn)C(=NRn)NRnR', -N(R m )S (=O2Rs, -N(Rr)S(O0) 2 NRnRs, -NRrnC2 6 alkylNRnR', -NRnC 2 6 alkylORS and -NR

M

C

2 -6alkylOR'..

In another embodiment, in conjunctio n with the novel compound embodiments above and below, R 4 is a heterocycle selected from 6-indole, 7indole, 6-3H-indole, 7-3H--indole, 6-benzo[blfuran, 7-benzo[blfuran, 6benzothiophene, 7-benzothiophene, 6- 1H-indazole, 7- 11-indazole, benzimidazole, benzthiazole, 1 H-benzotriazole, 7-quinoline, 8-quinoline, 7- 1 ,2,3,4-tetrahydroquinoli ne, 8-1,2,3 ,4-tetrahydroquinoline, isoquinolin-7-yl, isoquinolin-8-yi, 7-cinnoline, 8-cinnoline, phthalazine, 7-quinazoline, 8quinazoline and quinoxaline, wherein the heterocycle is substituted by 0, 1, 2 or 3 substituents independently selected from Cl- 9 alkyl, oxo, C 1 4 haloalkyl, halo, nitro, cyano, -OR' m -S(=O)nC 1 6 alky1, -0-Cl 4 haloalkyl, -0-C 1 6 a~kyl NR m

R',

-0-C 1 6 alkylOR m

-NR

m

-NR

m

-C

1 Ahaloal kyl, -NR m

-C

1 6 alkylNR m

R',

-NR

m

-C

1 6 a1 kylOR m -C(=O)Cj_6alkyl, 6 a1 kyl, -C(=O)NR m

C

1 6 alkyl,

-NR

m 6 a1 kyl -C(0)ORs, -C(=0)NRnR', -C(=NRrn)NRrnR', .0C(0)Rs, -OC(O)NRRs, 0C(0)N(Rn)S(=0) 2 -0C 2 6 a] kylNRR', 95

-OC

2 -6alkylOR', -S 2 2 NRnRs, 2 N(Rrn)C(=O)R', 2 N(Rrn)C(=O)ORs, -S 2 N(Rn)C(=O)NRnRS, -NRrnRS, -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NR'nR', -N(Rrn)C(=NRrn)NRrnRs, -N(Rrn)S(=O) 2 Rs, -N(R m )S (=O),NRnRS, -NRnC 2 6 alky1NRrnR', -NR m

C

2 .alkylOR' and C, -alkyl substituted by 1 or 2 groups selected from C,- 2 haloalkyl, halo, cyano, nitro, -C(=O)NR m

R

m -C(=NRn)NR'Rrn, -OR m -OC(=O)NRnR,

-OC(=O)N(R

m 2

-OC

2 6 alkyNR m

-OC

2 6 alkylOR', -SR m 2 R n, 2

NR

m 2

N(R

m n, 2

N(R

m 2

N(R-)C(=O)NR-R

m

-N(R

m

)C(=O)R

0

-N(R

m

)C(=O)OR,

-N(Rrn)C(=O)NR'R m -N(Rrn)C(=NRn)NRnR, -N(R m )S 2

R,

-N(R

m 2

NR

m

R

m C(=O)ORs, -C(=O)NRnR', -C(=NRrn)NRnRs, -ORs, -OC(=O)Rrs, -OC(=O)NRnR', -OC(=O)N(Rrn)S(=O) 2

-OC

2 6 al kylNRnRs,

-OC

2 -6alkylOR', SRs, 2 Rs, 2 NRrnR', 2 N(Rm)C(=O)Rs, 2 N(Rrn)C(=O)ORs, 2 N(R')C(=O)NRnRs, -NRrnRs, -N(Rr)C(=O)ORs, -N(Rrn)C(=O)NRnRs, -N(Rrn)C(=NRrn)NRnR', -N(Rml)S 2 Rs, -N(R m )S 2 NRnRS,

-NR

m

C

2 6al kyINR m Rs, -NR m

C

2 -6al kylORs and -NR m

C

2 6 alkylOR'.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 9 is C 19 ,alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -0CI.

6 alkyl, -0-C 1 4 haloalkyl, -O-C 1 6 alkylNR m

R

m -0-C 16 alkylOR m

-NR

m

R

m

-NR

m -CI-4haloalkyl, -NR m

-C

1 6 alkylNR or -NRrn-C1.

6 alkylORml.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 9 is H.

In another embodiment, in conjunction with the novel compound embodiments above and below, Z is CR 8 In another embodiment, in conjunction with the novel compound embodiments above and below, Z is N.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 7 is tert-butyl or trifluoromethyl.

In another embodiment, in conjunction with the novel compound embodiments above and below, R' is 96 R 2 is C 1 .6alkyl substituted by 1, 2 or 3 substituents selected from C, 4 haloal kyl, halo, cyano, nitro, n, -C(=O)OR n, -C(=O)NR m R n,

-C(=NR

m

)NR

m

R

m

-OR'

m -OC(=Q)R 7OC(=O)NR'R m

-QC(=O)N.(R

m )S 2

-OC

2 -6alkylNR m

-OC

2 6 alkylOR'., -SR' m -S(4JO)R 2 Rn, -S(=O0) 2

NR

m

R

m -S 2

N(R

m -s 2

N(R

m n,( 2

N(R

m

)C(=O)NR

m

-NR'R

m

-N(R

m

-N(R

m

-N(R

m

)C(=O)NR

m

R

m -N(Rn)C(=NR m

)NR

m

R

m

-N(R

m 2

R",

-N(R

m 2

NR

m

-NR

M

C

2 -6alkyINR m R' and -NR m

C

2 6 alkylOR m; or R is (CRqRq) 0

R

9

RA

R8 R 6

A

6 ;or R 2 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, 0 and S, wherein( no more than 2 of the ring members are 0 or S, wherein the heterocycle is optionally fused with a phienyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from R 5 R 6 and R 7 R 4 is a saturated or unsaturated S- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently $elected from CI-8alkyl, C,-4haloalkyl, halo, cyano, nitro, -C(=O)NR m

.R

m -C(=NRn)NR-lRrn, -OR m

-OC(=O)NR

m

R

m I 97 -0C(=0)N(R m )S(=0h2R", -0C 2 6 akyNRm'R m -0C 2 6 alkylOR', -SW

T

n-S 2 2 NR-R-, 2

N(R

m

)C(=O)R

T

2

N(R

m 2

N(R

m )C(=O)NR' -NR m

-N(R

m

-N(R

m

)C(=O)OR

T

-N(R

m

)C(=O)NR

m

-N(R

M

)C(=NR

m

)NR

m

-N(R

m 2

R

T

-N(R

m 2

NR

m

-NR

m

C

26 alkyINR m

-NR

m

C

2 .6alkylOR m -C(=0)Rs, -G(=O)ORs, .C(0)NRnRS -C(=NRn)rNRsR' .ORs, -OC(=O)NRnRs, -OC(=O)N(R m )S 2 Rs, -0C 2 6 alkyM'rRs, -0C 2 6 alkyOR', r- -SRs, .S(=O)Rs S(=O) 2 Rs, 2 NRnRs 2 N(Rrn)C(=O)Rs, 2 N(Rrn)C(=0)ORs, 2 N(Rrn)C(=O)NRnRs, -NRrnRS, -N(Rrn)C(=0)Rs, -N(Rr)C(=O)0Rs, -N(Rr)C(=0)NRnR', -N(Rrn)C(=NRn)NRnRS, -N(Rrn)S(=0) 2 2 NRnRs, -NR

M

C

2 6 alkylNRrnIZ,,-NRrnCu-alkyl0Rs and C,- 4 alkyl substituted by I or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=O)R

T

-C(=0)ORn -C(=O)NR m

C(=NR')NR

m

-OR

m

-OC(=O)R

T

-OC(=O)NR-R-

T

-OC(=O)N(R

m )S 2

-OC

2 -6alkylNR m

R

m

-OC

26 alkylOR m

-SR

m

-S(=O)R

T

2 Rn, 2

NR

m

R

m 2

N(R

m n, 2 N(R)C(=0)0R n, -S 2 N(Rm)C(=O)NR m

R

m -NR -N(R m n, -N(R m

-N(R

m

)C(=O)NR

m

R',

-N(R

m

)C(=NR

m

)NR

m

R

m -N(R

T

2

R

T

-N(R

m )S 2

NR

m

R',

-NR

M

C

2 6 aIkylNR m

R

m C(0)ORs, .C(=O)Np~rn's -C(=NRrn)NRnR', -0C(=0)Rs, -OC(=0)NRnRs .OC(=0)N(Rn)S(=0) 2 Rs, -0C 2 6 alkyiNRnRs, -0C 2 _6alkyI0R', S(0)Rs, 2 Rs, 2 NRnR', 2 N(Rrn)C(=0)Rs, 2 N(Rr)C(=0)0Rs, 2 N(Rrn)C(=0)NRRs, -NRrnRs, -N(Rr)C(=0)Rs, -N(Rr)C(=0)ORs, -N(Rr)C(=)rNRsR' -N(Rm)C(=NR m

)NR

m Rs, -N(Rrn)S(=O) 2

-N(R

m )S 2 NRnR',

-NR

m

C

2 6 alkyINR m -NRm

T

C

26 alkyIORs and -NR tm

C

26 (alkyIOR m and the ring and bridge carbon atoms are substituted with 0, 1. or 2 =0 groups; R 7 is C 2 8 alkyl, C 1 5 haloalkyl, 1, Br; R 9 is independently, at each instance, H, Cl- 9 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -OC 1 6 al kyl, -0-C 14 haloalkyl, -0-C 1 6 alkylNR'R', -0-C 1 6 alkylOR', -NR

T

-NR

m

-C

1 4 haloalkyl, -NR m

-C

1 6 alky]NR m R' or

-NR

M

-C

1 6 alkylOR m Y is NHl; and -98- Z is CR 8 or N.

in another embodiment, in conjunction with the novel compound embodiments above and below, R 2 is C 16 alkyl substituted by 1, 2 or 3 substituents selected from C 14 haloalkyl, halo, cyano, nitro, n,

-C(=O)NR

m Rm 1

-C(=NR

m

)NR

m

R

m

-OR

m m C) OC(=O)N(Rr)S 2 -0C 2 6 a1 kylNR m

R

m -0C 2 6 a1 kylOR m

-SR

m 2 R 2

NR

m 2

N(R

m m

)C(=O)OR,

2

N(R')C(=O)NR

m

-NR

m

R

m

-N(R

m

-N(R

m

-N(R

m f)C(=O)NR m

R

m

-N(R

m

)C(=NR

m

)NR

m 2

R'

-N(R

m 2

NR

m

R

m

-NR

m

C

2 6 alkylNR m

R

m and NR m

C

2 6 alkyiOR m In another embodiment, in conjunction with the* novel compound embodiments above and below, R 2 is 2 0 )phen'yl, wherein the phenyl is substituted by 0, 2 or 3 substituents independently selected from C 1 8 alkyl, C 1 4 haloalkyl, halo, cyano, nitro, -C(=O)ORn, -C(=O)NR m

R

m

-OR

m -OC(=O)Rn, -OC(=O:)NR m Rm 1

-OC(=O)N(R

m 2 R -0C 2 6 alkylNR m

R

m

-OC

2 6 al kylOR m

-SR'

m -S 2 2

NR

M

R

m -S 2

N(R

m -s 2

N(R

m

)C(=O)OR,

2

N(R

m )C(=O)NR m

R

1

-NR

m

R

m

-N(R

m

-N(R

m

-N(R

m

)C(=O)NR

m

R

m

-N(R

m

)C(=NR

m

)NR

m

R

m

-N(R

m 2

R',

2 NR-R-, -NR

M

C

2 6 a1 kyl NR m

-NR

M

C

2 6 a1 kyIOR, -C(=O)ORs, -C(=O)NRnR', -C(=NRrn)NRnRs, .OC(=O)Rs, -OC(=O)NRnRs, -OC(=O)N(Rrn)S(=O) 2

-OC

2 6 alkylNRrnR5, .OC 2 6 alkyl ORS, -SRs, 2

R

5 -S 2

NR

m 2

N(R

m )C(=O)Rs, 2

N(R

tm )C(=O)0R 5 2

N(R

m

)C(=O)NR

m -4TRrR', -N(R m )C(=O)Rs,

-N(R

m )C(=O)0R 5 -N(Rrn)C(=O)NRrnRs, -N(Rrn)C(=NRrn)NRrnR',

-N(R

m )S 2 Rs, -N(R m )S 2

NR

m

-NR

m

C

2 6 alkyl NRrnRS, -NR

M

C 2 6 alkyIOR' and Ci.-salkyl substituted by I or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=O)NR m

R

m

-C(=NR

m

)NR

m R -OR m

-OC(=O)NR

m

R

m

-OC(=O)N(R

m 2

-OC

2 6 alkylNR m

R

m -0C 2 6 alkylOR m

-SR

m n, 2 2

NR

m

R

m -S 2 -S 2

N(R

tm -S 2

N(R

m

)C(=O)NR

m

R

m

-NR

m

R

m

-N(R

m

-N(R

m )C(=O)NRmR m 99

-N(R

m

)C(=NR

m

)NR

m Rm, -N(R m 2 2

NR

m k m

-NR

M

C

2 6 al kylNR m -C(=O)ORs, -C(=O)NRnR', -C(=NRrn)NRnR', -ORs, -OC(=O)NRrnR', -OC(=O)N(Rrn)S(=O) 2

-OC

2 6 alkylNRnRs,

-OC

2 6 al kylORs, 2 Rs, 2

NR

m Rs, -S 2

N(R

m 2

N(R

m )C(=O)0Rs, 2

N(R

m m

R

-NR

m

-N(R

m

N(R

m )C(0)0R 5

-N(R

m

)C(=O)NR

m

R',

-N(R

m

)C(=NR

m

)NR

m N(Rr)S(=0) 2 Rs, .N(Rrn)S(=O) 2 NRnRs,

-NR

m

C

2 6 alkyNR m Rs, -NR m

C

2 6 alkyIORs and -NR

M

C

2 -6alkylOR'.

In another embodiment, in conjunction with the novel compound embodiments above and below, R2 is wherein R' is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, 0 and S, wherein no more than 2 of the ring members are 0 or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from Cl-galkyl, C 1 4 haloalkyl, halo, cyano, ni tro, -C(=0)NR m

R

m

-C(=NR

m

)NR

m

-OR

m

-OC(=O)NR

m 2 R n, -0C 2 6 a1 kyl NR.

M

R',

-0C 2 6 a1 kylOR m

-SR'

m n, 2 2

NR

m

R

m

'S(O)

2

N(R

m 2

N(R

m 2

N(R

m

)C(=O)NR

m

-NR

m

R

m

-N(R

m

-N(R

m

-N(R

m )C(=0)NR m

R',

-N(R

m

)C(=NR

m

)NR

m

-N(R

m 2 R n, -N(R m 2

NR

m

R

m

-NR

M

C

2 6 a1 kylNR R'M, -NR m

C

2 6 alkylOR m C(=0)ORS

-C(=O)NR

m

-C(=NR

m

)NR

m

-OC(=O)R

5

-OC(=O)NR

m

R

5

-OC(=O)N(R

m )S 2

-OC

2 6 al kylNR m -0C 2 6 alkylOR', 2 -S 2

NR

m Rs, -S 2

N(R

tm 2

N(R

m )C(=O)0R 5 -S 2 N(Rrn)C(=0)NRnRS, -NR m

-N(R

m

)C(=O)R

5 -N(Rr)C(0O)ORs,

-N(R

m )C(=0)NR m m

R

5

N(R

m 2

R',

-N(R

m )S 2

NR

m Rs, NRrnC 2 .alkylNRnRs, -NR m

C

2 6 alkylORs and Ci 4 alkyl substituted by 1 or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=O)NRnR, -C(=NRm)NR m

R

m

-OR'

m

-OC(=O)R,

-OC(=O)NR

m

R

m -OC(=O)N(Rm)S(=O) 2 R n, -OC 2 6 al kylNR m Rm

T

-OC

2 6 al kylOR m

-SR

M

-s 2 R -S 2

NR

m

R

m -S (=O0) 2

N(R

m -100- 2 N(RrI)C(=O)ORfl, 2

N(R

m

-NR

m

R',

.N(R

m

-N(R

m

-N(R

m )C(=O)NRlR',

-N(R

m

)C(=NR

m

)NR

m

-N(R

m 2 -N(Rrn)S(=O) 2 NRnRn,

-NR

m

C

2 -6alkylNR m -C(=O)ORs, -C(=O)NRnRs, -C(=NRn)NRnRs, -ORs, .OC(z:O)Rs, -OC(=O)NRnRs, -OC(=O)N(Rn)S(=O) 2 Rs, -OC 2 6 alkyINRnRs,

-OC

2 6 alkylORs, -SRs, 2 Rs, 2 NRnRs, 2 N(Rrn)C(=O)R', -S 2 N(Rrn)C(=O)ORs, -S 2 N(Rrn)C(=O)NRnRS, -NRrnRs, -N(Rrn)C(=O)Rs, -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRnRs, -N(Rrn)C(=NRn)NRnRs, -N(Rrn)S(=O) 2 Rs, -N(Rrn)S(=O) 2 NRnR', -NRnC 2 alkyINRnR', -NRrnC 2 6 alkylORs and -NR

M

C

26 alkylOR m In'another embodiment, in conjunction with the* novel compound embodiments above and below, R 4 is a phenyl ring that is vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C 1 .salkyl,

CI-

4 haloAlkyI, halo, cyano, nitro, -C(=O)0R n, -C(=O)NR-RT,

-C(=NR

m

)NR

m

-OR

m -OC(=0)R 0

-OC(=O)NR

m

R',

-0C(=0)N(R m 2 R -0C 2 6 alkylNR m

R

m

-OC

2 6 alkylOR', -SR' m 2 -S 2

NR

m

R

m 2

N(R

m 2

N(R

m -S 2

N(R

m )C(=0)NR m

R

m

-NR

m

R

m

-N(R

m

-N(R

m

-N(R

m )C(=0)NR m

R

m

-N(R

m

)C(=NR

m

)NR

m

-N(R

m )S 2

R,

-N(R

m )S 2

NR

m

-NR

m

C

2 6 alkylNR m

R

m

-NR

m

C

2 6 alkylOR', .C(0)NPRnRs, -C(=NRrn)NRrnRs, -ORs, .0C(=0)Rs, -OC(0)NRnRs, OC(=0)N(R m )S 2 Rs, 0C 2 6 akyNRnRs, bC 2 6 al kyloRs, -SRs, -S(0)Rs -S 2 Rs, -S 2 NRnR', 2 N(Rrn)C(=0)Rs, -S 2 N(Rn)C(=O)ORs, -S 2 N(Rrn)C(=0)NRnRS, -N4RnRs, -N(Rrn)C(=O)Rs, -N(Rr)C(=0)0Rs, -N(Rr)C(=0)NRnR', -N(Rrn)C(=NRn)NRnRs, -N(Rrn)S(=0) 2 Rs, -N(R m )S 2 NRnRs, -NR m

C

2 6 a1 kylNRnRS, -NRrnC 2 6 alkyl0R' and C 1 4 alkyI substituted by 1 or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=0)0R n, -C(=O)NR m

R

m

-C(=NR

m

)NR

m

R

m

-OR

m

-OC(=O)NR

m

R

m

-OC(=O)N(R

m 2

-OC

2 6 a~kylNR m

R

m 101

-OC

26 alkylOR', -SQ 2 2

NR

m

R',

-S 2

N(R

m 2

N(R

m -S 2

N(R

m )C(=0)NR m

R~

-N(R

m

-N(R

m )C(=0)NR m

R

m

-N(R

m

)C(=NR

m

)NR

m

R

m 2 -N(Rrn)S(=0) 2 NRnR'l,

-NR

m

C

2 6 alky]NR m

R

m and -NR

M

C

2 6 alkylOR'; and the bridge carbon atoms are substituted with 0, 1 or 2 =0 groups.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 7 is tert-butyl or trifluoromethyl.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 9 is H.

In another embodiment, in conjunction with the novel compound 8 embodiments above and below, Z is CR.

In another embodiment, in conjunction with the novel compound embodiments above and below, Z is N.

In another embodiment, in conjunction with the novel compound embodiments above and below, R, is R 6

F

3 0 t R' is H, -OR m Cl, C 1 3 haloalkyl or C1- 6 alkyl; R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 2 0 3 atoms selected from 0, N and S, so long as the combination of 0 and S atoms is not greater than 2, wherein the ing is substituted by 0, 1, 2 or 3 substituents independently selected from CI.

8 alkyl, C 1 4 haloalkyl, halo, cyano, nitro, -C(=0)NR m

R

m

-C(=NR

m )NrRRm, -OR, n- -OC(=0)N R m 2 R n, -OC 26 al kylOR"', -SRI", 2

R",

-S 2 NR-R-, -S 2 n, -S 2 -S 2 -N(Rml)C(=0)R n, m

-N(R

m )S 2

R'

-N(Rnl)S(=O) 2 NRnlR, -NR"'C 26 al kylNR m

-NR

m

C

26 a~kylOR m 102 -C(=O)ORs, C(Q-)NRnRS -C(=NRrn)NRrnR', -OCQ=O)Rs, -OC(=O)NRnR', -OC(=O)N(Rrn)S(=O) 2

-OC

2 6 al kyl NRrnR, -OC 2 -6alkylOR', -S Rs, -S 2 Rs, -S 2 NRnRS, -S 2 N(Rrn)C(=O)RS, 2 N(Rrn)C(=O)ORs, -s 2 N(Rrn)C(=O)NRnRS, -NRrnRs, -N(R n,)C(=O)RW, -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRrnRs, -N(Rr)C(4TNR)rNRsR -N(Rrn)S(=O) 2 Rs, -N(Rrn)S(=O) 2 NRrnR', -NRnC 2 -6alky1NRrnR', NRrnC 2 alkylORs and C 1 ._4alkyl substituted by 1 or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=O)NR m

-C(=NR

m

)NR'R

m

-OR

m

-OC(=O)NR

m

R

m

-OC(=O)N(R

m 2 -0C 2 6 alkylNR"'R', -0C 2 6 alkylOR m

-SR

m n, 2 R n, 2 NRm''R, 2

N(R

m 2 2

N(R

m

)C(=O)NR

m

-NR

m

R',

-N(Rrn)C(=NRn)NR'Rn, -N(R m 2 R n, -N(R m )S 2

NR

m

R

m

-NR

m C2alkylN t m

R'

1 and -NR

M

C

2 -6alkylOR m wherein R 4 is not unsubstituted phenyl;

R

9 is independently, at each instance, H, Cl- 9 alkyl, C 1 4 haloalkyI, halo, nitro, cyano, -0C 1 6 alkyl, -0-C 14 haloalkyl, -0-C 1 6 alkylNR m

R

m 6 alkylOR m

-NR

m 4 haloalkyl, -NR m

-CI-

6 alkylNR m

R

m or

-NR

m 6al kylOR m Y is NE-;and Z is CR 8 or N.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 4 is a saturated or unsaturated 5- or 6-membered ring containing 1, 2 or 3 atoms selected from 0, N and S, so long as the combination of 0 and S atoms is not greater than 1, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from Cl-galkyl, C, 4 haloalkyl, halo, cyano, nitro, -C(=0)NR m

-C(=NR

m

)NR

m

-OC(=O)N(R

m )S(O0) 2 -0C 2 6 a~kylOR m

-SR

m -S 2 -S 2

NR

m

R

m -S 2

N(R

m n, 2

N(R

m )C(=0)0Rn, 3 0 -s 2

N(R

m )C(=0)NR m

R

m

-NR-R

m

-N(R

m

-N(R

m )C(=O)0R,

-N(R

m )C(=0)NR m

-N(R

m

)C(=NR

m

)NR

m

R

m

-N(R

m 2

R',

-N(R

m 2

NR

m

R

m

-NR

m

C

2 6 a1 kylNR m

-NR

m

C

2 6 alkylOR', 103 -C(=O)ORs, C(=O)NRrnRs -C(=NRn)NRnR', -OC(=O)R -OC(=O)NRnRs, -OC(=O)N(R m 2

-OC

2 6 alkyl NRrnRs, -0C 2 6 al kylOR', -SRs, -S 2 -S(=O0) 2 NRrnRs, 2

N(R

m )C(=O)Rs, 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=O)NRnRs, -NRrnRs, N(Rrn)CQ=O)Rs, -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRnR', -N(Rrn)C(=NRrn)NRnRs, -N(Rrn)S(=O) 2 -N(Rrn)S(=O) 2 N RRs, -NRrnC 2 6 alky1NRrRs, -NRnC 2 6 alkylORs and C 1 4 alkyl substituted by I or 2 groups selected from CI- 2 haloalkyl, halo, cyano, nitro, -C(=O)NR m

R

m

-C(=NR

m

)NR

m

R

m

-OR

m

-OC(=O)R,

-OC(=O)NRmR', 2

-OC

2 -6alkylNR m

R

m

-OC

2 6 alkylORn,

-SR-

m 2 R 2

NR

m 2

N(R

m 2 N(R')C(=O)OR n, 2

N(R

m

)C(=O)NR

m

-NR

m

R',

-N(R

m

-N(R

m )C(=O)OR n, -N(Rrn)C(=O)NR'Rm,

-N(R

m

)C(=NR

m

)NR

m

R

m

-N(R

m 2 R n, -N(R m 2

NR

m

R

m

-NR

M

C

2 .6alky]NR m R' and -NR m

C

2 6 alkylOR m In another embodiment, in conjunction with the novel compound embodiments above and below, Z is CR 8 In another embodiment, in conjunction with the novel compound embodiments above and below, Z is N.

Another aspect of the invention relates to a compound having the structure: R 3 R 3 R2H x wherein: X isO0, S or NR'; n is independently, at each instance, 0, 1 or 2; o is independently, at each instance, 0, 1, 2 or 3; R' is independently at each instance H or R n; R n is independently at each instance C 1 .salkyl, phenyl1 or benzyl; Rq is independently in each instance H, C 1 4 alkyI, CI- 4 haloalkyl, halo, cyano, nitro, n, -C(=O)NR m

R

m

-C(=NR

m

)NR

m

-OR

m -OC(=O)R -OC(=O)NR m Rm, -OC(=O)N(R m 2 Rn, -OC 2 6 alkylNR m

R

m -104- -0C 2 .6alkyI0R', -SR m n, 2 Rn, 2

NR

m

R

m -S 2

N(R

m 2 2

N(R

m

-NR

m

R

m

-N(R

m

-N(R

m

-N(R

m )C(=0)NR m

R,

-N(R

m

)C(=NR

m

)NR

m

-N(R

m 2

-N(R

m 2

NR

m

R',

-NR

m

C

2 6 alkylNR m R' or -NRrnC 2 6 alkyl0Rn; R' is R' substituted by 0, 1, 2 or 3 substituents independently selected from R R 3 is Hor C 4 alkyl; R 5 is H, Cl.

9 alkyl, C 1 -4haloalkyl, halo, nitro,- cyano, -0C 1 6 ailkyl, -0-c 14 haloalkyl, -0-C 6 alkyINR m

R

m -0-C 1 6 alkylOR', -NR m

R',

-NR

m

-C

1 -4haloaI kyl, -NR m

-C

1 6 al kylNR m

R

m

-NR

m

-C

1 6 a1 kyl0R'i, or -(CH 2 ).Rc R 6is, independently at each instance, H, Cl-galkyl, C 1 -4haloalkyl, halo, nitro, cyano, -0C 1 -6alkyl, -0-C 1 4 haloalkyl, -0-C 1 i 6 alkyNR m

R

m -0-C 6 al kylOR m

-NR

m

-NR

m

-C

1 4 haloalkyl, -NR m

-C

1 6 a1 kylNR m

R

m or

-NR

m

-C

16 alkylOR';

R

8 is H, C 1 ,)alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -0C 1 -6alkyl, -0-C 1 4 haloalkyl, -0-C 16 alkylNR m

R

m -0-C 6 alkylOR m

-NR

m

R

m

-NR

m

-CI.

4 haloalkyl, -NR m

-C

1 6 alkylNR m R' or -NR m

-C

1 6 alkylOR m and R' is

R

6

R

8 (CRqRq) 0

RO

R 2is H, -O11 m halo, C 1 3 haloalkyl Or C 1 6 alkyl; R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than wherein the inig and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from CI-8alkyl,

C

14 hal .oalkyl, halo, cyano, nitro, n' -c(=0)0R n, 105

-C(=NR

M

)NR

m

R'

m

-OR

m -OC(=O)R n, -OC(=O)NR m

R',

2 R n, -0C 2 6 a1 kylNR m

R

m

-OC

2 6 alkylOR m

-SR

m 2 2

NR

m

R

m 2

N(R

m 2

N(R

m

)C(=O)OR,

-S(=O0) 2

N(R

m

)C(=O)NR

m

R

m

-NR

m -N(Rm)C(=O)Rn, -N(R m -N(R n)C(=NR m -N(Rml)S(=O) 2

R',

-N(R

m )S 2

NR

m

R

m

-NR

M

C

26 a~kylNR m

R

m

-NR

M

C

2 -6alky1OR m -C(=O)ORs, -C(=O)NRnR', -C(=NRrn)NRrnR', -OC(=O)Rs, -OC(=O)NRnR', 2 Rs, -0C 2 6 a1 kylNRrnRs, -OC 2 -6alkylORs, -SRs, 2 Rs, 2

NR

m 2

N(R

m )C(=O)Rs, -S 2

N(R

m )C(=O)0R 5 -S 2 N(Rrn)C(=O)NRnRs, -NRrnRs, -N(R m

-N(R

m )C(=O)0R 5

-N(R

m )C(=O)NR n -N(R m

)C(=NR

m

)NR

m Rs,

-N(R

m 2

-N(R

m 2

NR

m

-NR'C

2 6 a~kyINR m Rs, -NR

M

C

2 6 alkylORs and C 1 4alkyI substituted by I or 2 groups selected from CI- 2 haloalkyl, halo, cyano, n itro, -C(=O)OR n, -C(=O)NR m R

M

-C(=NR

m

)NR

m

-OR

m

-OC(=O)NR

m

-OC(=O)N(R

m 2 R n, -OC 26 al kyINR m

R

m

-OC

2 6 al kylOR m

-SR

m n, 2 -S 2

NR

m

R-,

-s 2

N(R

m -s 2 N(Rm)C(=O)OR", 2

N(R

m )C(=O)NRmR m

-NR"'R

m

-N(R

m

-N(R

m

-N(R

m

C(=O)NR

m

R

m

-N(R

m

)C(=NR

m

)NR

m

R

m

-N(R

m 2 R n, -N(R m 2

NR

m

R',

-NR

m

C

2 6 alkylNR m -C(=O)0R 5 -C(=O)NRnRs, -C(=NR m

)NR

m

R',

-ORs, -OC(=O)Rs, -OC(=O)NR m Rs, -OC(=O)N(R m 2 Rs, -OC 26 al kylNRnR',

-OC

2 6 aIkylORs, -SRs, 2 -s 2

NR

m Rs, 2

N(R

m 2 N(Rrn)C(=O)ORs, -S 2 N(R n)C(=O)NR m Rs,

-NR

m Rs, -N(R m N(Rr)C(=O)ORs, .N(R m )C(0)N' m Rs

-N(R

m

)C(=NR

m

)NR

m Rs, -N(R m 2

-N(R

tm 2

NR

m

R',

-NR

m

C

2 6al kyl NR m Rs, -NR m

C

2 6 aIkylORs and -NR m

C

2 6 aI kylOR m and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups;

R

7 is C 19 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -OCI 1 6 alkyl, -0-C 1 4 haloalkyl, -0-C 1 6 alkylNR m -0-Cl.

6 alkylOR m

-NR

m

R

m

-NR

m

-C

1 4 haloalkyl, -NR m

-CI-

6 a1 kyINR m

R

m or -NR m

-C

1 6 aIkylOR m

R

0 is a saturated, partial]ly-saturated or unsaturated 6- or 7-membered monocyclic or 10- or I I-membered bicyclic ring containing 0, 1, 2, 3 or -106 4 atoms selected from N, 0 and S, so long as the combination of 0 and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from RP; RP is independently at each instance CI-8alkyl, C 1 4 haloalkyl, halo, cyano, nitro, -C(=0)OR n, -C(=0)NR m

R

m

-C(=NR

m

)NR

m

R

m

-OR

m -OC(0)NR m

R

m

-OC(=O)N(R

m

)S(O)

2

-OC

2 6 al kylNR m

R',

-OC

2 -6alkylOR m -S 2 -S 2

NR

m

R

m -S 2

N(R

m 2

N(R

m -S 2 N(Rrn)C(=O)NRnRn,

-NR

m

R

m

-N(R

m n, -N(R m )C(=O)OR n, -N(R m )C(=O)NRzWR, -N(Rrn)C(=NRftl)NRnRr, -N(R m )S(=O0) 2 Rn, -N(R

M

)W(O)

2

NR

m

R

m n,

-NR

m

C

2 6 alkyNR m

R

m or -NR m

C

2 6 a1 kylOR m and Y is 0or NHi;or R'is R 6 R7R 5 R 7 N R R8 (CR qRq )ORO or (CRqRq )ORO

R

2 is H, -OR' m halo, C 1 3 haloalkyl or C 1 6 alkyI; R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C 1 8 alkyl,

C

1 4 haloalkyl, halo, cyano, nitro, -C(=O)NR m

R',

-C(=NRn)NRnR, -OR' m -OC(=0)NRR m 2 -0C 2 6 alkylNR m

R

m

-OC

2 6 alkylOR m

-SR

m -S 2 2

NR

m -S 2 N(Rm)C(=0)R -S 2

N(R

m

)C(=O)OR,

-S 2

N(R"')C(=O)NR

m

R

m

-NR'R

m

-N(R

m

-N(R

m )C(=O)OR n -N(Rm 1

)C(=O)NR

m

R

m

-N(R')C(=NR

m

)NR

m

R

m

-N(R

m 2

R',

107

-N(R

m 2

NR

m

R

m

-NR'C

2 -6alkylNR m

R

m

-NR

M

C2- 6 alkylOR m -C(=0)Rs, -C(=O)0Rs, -C(=0)NRnR', -C(=NRrn)NRnR', .OC(=0)Rs, -0C(=0)NRnR', -OC(=0)N(Rn)S(=0) 2 Rs, -0C 2 6 al kylNRmRS, -OC 2 6 alkyIORs, -S(0)Rs -S 2 2 NRnR', 2 N(Rrn)C(=0)Rs, 2 N(Rr)C(=0)0Rs, 2 N(Rrn)C(=0)NRnRs, -NRrnRs. -N(Rr)C(=0)0Rs, -N(Rrn)C(=0)NRnR', -N(Rrn)C(=NRn)NRnRs, -N(Rr)S(=0) 2 -N(Rn)S(=0) 2 NRl'rn, -NRrnC 2 6 alkylNRnRs, 4-4RrC 26 alkyl0Rs and C 1 -4alkyl substituted by 1 or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, n, -C(=O)OR n, -C(=0)NRmR m

-C(=,NR

m

)NR

m

-OR

m

-OC(=O)NR

m

-OC(=O)N(R

m 2

-OC

2 6 alkylNR m

R

m -0C 2 6 alkylOR m

-SR'

m n, -S 2 2

NR

m Rm 1 2

N(R

m n, 2

N(R

m -S 2

N(R

m

)C(=O)NR

m

R

m -NRmlRrn, -N(R m

-N(R

m )C(=0)NR m

R

m

-N(R

m

)C(=NR

m )NRm' 1 R, -N(R m 2 R n, -N(R m 2

NR

m

R

m

-NR

m

G

26 al kylNR m

R

m -C(=O)0Rs, -C(=O)NRnRs, -C(=NRn)NRnR, -ORF, OC(=O)NRnRs, .OC(=O)N(R m )S 2 -0C 2 6 alkyl NRnR',

-OC

2 6 alkyl0Rs, 2 Rs, 2 NRnRs, 2 N(Rrn)C(=O)R', 2 N(Rr)C(=0)0Rs, 2 N(Rr)C(=0)rNRsR -NRrnRs, -N(Rr)C(=0)ORs, -N(Rrn)C(=O)NRnRs, -N(Rrn)C(=NRrn)NRnR', -N(R m )S 2 -N(Rrn)S(=0) 2 NRnR',

-NR

m

C

26 aI kylNRrnRs, -NRrnC 2 -alkylORs and -NR m

C

2 _ral kyl0R m and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups; R 7 is Cl.

9 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -OCI- 6 alkyI, -0-C 1 4 haloalkyl, -0-C.

6 alkylNR m

R

m -0-C 1 6alkyl0R', -NR m

R

m

-NR

m

-C

1 4haloalkyl, -N R m

-C

1 6 alkyINR m

R

m or -NW-C 1 6 alkylOR m R' is a saturated, partial ly-saturated or unsaturated 6- or 7-membered monocyclic or 10- or I 1-membered bicyclic ring con Itaining 0, 1, 2, 3 or 4 atoms selected from N, 0 and S, so long as the combination of 0 and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from RP; -108- RP is independently at each instance C 1 8 galkyl, C 1 4 haloalkyl, halo, cyano, nitro, -C(=O)OR n, -C(=O)NRR m

R

m

-C(=NR

m )NR R m

-OR

m -OC(=O)R n, -OC(=O)NR m

-OC(=O)N(R

m 2

-OC

2 -6alkylNR m

R

m

-OC

2 6 al kyIOR m

-SR'

m -S 2 R n, 2 NRnR m 2

N(R

m 2

N(R

m 2

N(R

m

)C(=O)NR-R,

-NR

m

R

m

-N(R

m

-N(R

T

-N(R

m

)C(=O)NR

m

R',

-N(R

m

)C(=NR

m

)NR

m

R

m 2

-N(R

m 2

NR

m

R',

-NR

m

C

2 6 alkyN

M

'R

m or -NR"'C 2 6 alkylOR m and Y is 0or NHI;or R'is

R.

2 is H, -OR' m halo, C 1 3 haloalkyl or C 1 -6alkyl; R 4 is a saturated, partially-saturated or unsaturated 10 or Il1-membered bicyclic heterocycle containing* 1,2, 3, 4 or 5 atoms selected from 0, N and S, so long as the combination of 0 and S atoms is not greater than 2, but excluding quinolin-6-yl, 4,5,6,7-tetrahydro-benzo[blthiophen-2-yl, benzothiazol- 2-yl, 2,3-dihydro-benzo[ 1,4]dioxin-6-yl, wherein the heterocycle is substituted by 0, 1, 2 or 3 substituents independently selected from Cl.

9 alkyl, oxo, C 1 -4haloalky1, halo, nitro, cyano, -OR m 1 _(alkyl, -O-C,4haloalkyl, -O-CI.

6 alkylNR m

R',

-O-C

1 _6alkylOR m

-NR

m

R

m

-NR

m -C,-4haloalkyl, -NR m -Cj- 6 alkylNR m

R

m

-NR

m

-C

1 6 alkylOR', -C(=0)CI.

6 alky), -OC(=O)C 1 6 alkyl, -C(=O)NR m

C

1 6 alkyl,

-NR-C(=O)C

1 6 alkyl -C(=O)ORs, -C(=O)NRnR', -C(=N1R)rNRsR -OW, OC(0)Rs -OC(=O)NR1'rn, .OC(=O)N(R m )S 2 Rs, -OC 2 6 aI kylNR m

R',

-OC

2 6 alkylORs, -SRs, -S(0)Rs, 2 Rs, 2 NRrnRs, 2 N(Rrn)C(=O)Rs, -S 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=O)NRnRs, -NRrnRS, -N(Rr)C(=O)Rs, -N(Rr)C(=O)ORs, -N(Rm)C(=O)NRnR', -N(Rrn)C(=NRn)NRnR', -N(R m )S 2 Rs, -N(R m )S 2 NRnRs, -NRrnC 2 6 alky]NRnRs, -NRnC 2 6 alkylOR' and C 1 4 alkyl substituted by I or 2 -109groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=O)NR m

R

m _n-C(=NR m )NRm t

R

m

-OR

m -OC(=O)Rn, -OC(=O)NR m

R',

-OC(=O)N(R

m 2 -0C 2 6 alkylNR m

R

m

-OC

2 6 alkyIOR m

-SR

m 2 2

NR

m

R

m 2

N(R

m 2 N(Rm)C(=O)OR", 2

N(R

m

)C(=O)NR

m

R

m

-N(R

t

-N(R

m

)C(=O)OR,

-N(R

m

)C(=O)NR

m -N(R"')C(=NRn)NR m

R

m

-N(R

m )S 2

R',

-N(R

m 2

NR

m

R

m -C(=O)ORs, -C(=O)NRrnR', -C(=NRrn)NRnR', OC(0O)Rs, -OC(=O)NRnR', -OC(=O)N(Rrn)S(=O) 2

-OC

2 6 alkyINRnR',

-OC

2 -6alkylORs, S(=O)Rs, 2 2

NR

m Rs, 2 -S 2

N(R

m )C(=O)0Rs, 2

N(R

m

)C(=O)NR

m

R',

-NR

m Rs, -N(R tm -N(Rm)C(=O)0Rs, N(R tm )C(0)NR m Rs,

-N(R

m

)C(=NR

m

)NR

m

-N(R

m 2

-N(R

m 2

NR

m

R',

-NR

M

C

2 6 alkylNR m -NRrnC 2 -6alkylOR 5 and -NR m

C

2 _ralkylOR m wherein R 4 is not 2-aminocarbonylmethyl-2,3-dihydro-benzo[ 1,4]dioxin-8-yl, 2-cyanomethyl- 2,3-dihydro-benzo[1,4]dioxiri-8-yI, quinolin-3-yl, 3H-quinazolin-4-on-3-yl, benzo[1I,3]dioxol-5-yl, 3,3-diniethyl- 1,3-dihydro-indol-2-on-6-yl or 4,4-di methyl- 3 ,4-dihydro- IH-quinolin-2-on-7-yi; R 7 is C 1 8 al kyl, C 1.

5 h aloal kyl, I or Br

R

9 is H, C 19 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -OCI.

6 alkyl, -O-C 1 4 haloalkyl, -0-C 1 6 alkyINR m -0-C 1 6 alky]OR m

-NR

m

-NR

m

-C

1 4 haloalkyl,

-NR

m

-C

1 6 a1kylNR m R, -NRm 1

-C

1 .6a1 kyIOR, or -(CH 2 )nRC;

R

9 is independently, at each instance, H, Cl.galkyl, C 1 4 haloalkyl, halo, nitro, cyano, -0C 1 6alkyl,.-0-C 1 4 haloalkyl, -0-C 1 6 alkylNR m

R',

-0-C 1 6 a1 kyl OR m

-NR

m

R

m

-NR"'-C

1 4 haloalkyl, -NR m

-C

1 6 alkylNR m

R

m or

-NR

tm

-C

1 6 alkylOR'; Y is NH-; and ZisCR 8or N;or R' is -110- R 2 is C 1 -6alkyl substituted by 1, 2 or 3 substituents selected from

C

1 -4haloalkyl, halo, cyano, nitro, -C(=O)OR n, -C(=O)NR m

R

m

-C(=NR

m

)NR

m -OC(=O)R n, -OC(=O)NR m

R

m 2 R -OC 2 6 al kylNR m

-OC

2 6 al kylOR m 2 -S 2

NR

m -S 2

N(R

m n, 2 2

N(R

m

)C(=O)NR"'R

m

-NR

m

-N(R

t

-N(R

m

-N(R

m

)C(=NR

m

)NR

m

R

m

-N(R

m 2

R",

-N(R

m 2

NR

m

-NR

m

C

2 6 alkyINR"'R' or -NR m

C

2 -ralkylOR'; or R' is q) 2 0 ,phenyl, wherein the phenyl is substituted by 0, 1, 2 or 3 substituents independently selected from CI-salkyI, C 1 4 haloalkyl, halo, cyano, nitro, -C(=O)NR m

R

m

-C(=NR

m

)NR

m

R

m

-OC(=O)NR

m

-OC(=O)N(R

m )S 2 R' -OC 2 6 alkyl NIR tm

R,

-OC

26 alky]OR', -SR m n, 2 2

NR

m

R',

2

N(R

T

2 N(Rrm)C(=O)OR n, 2

N(R

m

)C(=O)NR

m -NRm', n,

-N(R

m

)C(=NR

m

)NR

m

-N(R

m 2 R n, 2

NR

m

R',

-NR

m

C

2 6 alkylNR m

R

m

-NR

m

C

2 salkylOR m -C(=O)ORs,( -C(=O)NRnRs, -C(=NRrn)NRrnRs, -ORs, .OC(=O)Rs, -OC(=O)NRrnRs, -OC(=O)N(Rrn)S(=O) 2 Rs, -OC 2 6 alkyINRrnRs, -OC 2 6 alkyIORs, -S Rs, -S(=O)Rs, -S 2 Rs, 2 NRrnRs, 2 N(Rr')C(=O)Rs, 2 N(Rm)C(=O)ORs, s NRm~Rs, -N(Rm)C(=O)OR', -N(Rrn)C(=O)NRrnRs, -N(R')C(=NRn)NRH'R', -N(Rr)S(=0) 2 Rs, -N(Rm)S(=O) 2 NRrnR', -NRnC 2 6 alkyINRrnRs, -NRrnC 2 6 alkylORs and Ci.

4 alkyl substituted by 1 or 2 groups selected from CI- 2 haloalkyl, halo, cyano, nitro,

-OC(=O)NR

m 2 R n, -0C 2 6 alkylNR"'R", -OC 2 6 alkylOR m n, 2 2

NR

m

R

m 2

N(R

m -111l- -S 2

N(R

m 2

N(R

m

)C(=O)NR

m

-NR

m

R',

-N(R

m

-N(R

m

-N(R

m

)C(=O)NR

m

R',

-N(R

m

)C(=NR

m

)NR

m

-N(R

m )S 2 R n, -N(Rrn)S(=O) 2 NRnRn,

-NR'C

2 6 alkyl NR m .C(=o)oRs, -C(=O)NRnRs, -C(=NRn)NRnR', -ORs, .OC(0)Rs, -OC(=O)NRrnRs, -OC(=O)N(Rrn)S(=O) 2

-OC

2 _6alkyI NRrnR',

-OC

2 6 alkylOR', -S 2 2 NRnRs, 2 N(Rrn)C(=O)R', -S 2 N(Rrn)C(=O)ORs, -S(o) 2 N(Rrn)C(=o)rNRsR' -NRrnRs, N(Rr)C(0O)ORs, -N(Rrn)C(=O)NRnRs, -N(Rrn)C(=NRn)NRnRs, -N(Rrn)S(=O) 2 Rs, -N(R m 2

NR

m

R',

-NRrnC 2 6 alkylNRnRs, -NRrnC 2 6 alkylORs and -NR m

C

2 6 alkylOR'; or R 2 is 2.r wherein R" is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, 0 and S, wherein no more than 2 of the ring members are 0 or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from CI-8alkyI, C 1 4 haloalkyI, halo, cyano, nitro, n, -C(=0)NR m

-C(=NR')NR

m

R

m

-OR

m -OC(=O)NRnRml,

-OC(=O)N(R

m 2

-OC

2 6 alkylNR m

-OC

2 6 alkyOR', -SR' m 2 R n, 2

NR

m 2

N(R

m 2

N(R

m 2

N(R

m

)C(=O)NR

m

-NR

m

-N(R

m n, -N(R m

-N(R

m

)C(=O)NR

m

-N(R

m

)C(=NR

m

)NR

m

R

m

-N(R

m 2

R',

-N(R

m 2

NR

m

R

m

-NR

M

C

2 -6aIkylNRm'~R, -NR'C 2 6 alkylOR', -C(=O)ORs, -C(=O)NRrnRs, -C(=NRn)NRnRs, -OC(=O)Rs, -0C(=O)NRnRs, -OC(=O)N(Rrn)S(=O) 2 Rs, -OC 2 6 al kyl NRrRs, -OC 2 6 alkyIORs, -SRs, 2 Rs, 2 NRnRs, 2 N(Rrn)C(=O)R', 2 N(Rrn)C(=O)ORs, -S 2 N(Rn)C(=O)NRnR', -NRmlRs, .N(Rn)C(0O)Rs, -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRnR', -N(Rrn)C(=NRn)NRrnRs,

-N(R

m )S 2 Rs, -N(R m )S 2 NRnRS, -NR 1

C

26 aI ky]NRnRs, -NR m

C

26 alky]OR' and CI-alkyl substituted by I or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, n, -C(=O)NRm)Rrn, -C(=NR m

)NR

m

R

m

-OR

m

-OC(=O)NR

m

R

m

-OC(=O)N(R

m 2 -OC2- 6 alkyl NRmIR m

-OC

26 alkylOR m

-SR

m 2 R n, 2

NR

m

R',

-112- -S(=Oh2N(R

M

2

N(R

m )C(=O)OR n, 2

N(R

m )C(=O)NR"'Rn,

NR

m

R

m

-N(R

m n, -N(Rml)C(=O)OR n, -N(R

M

)C(=O)NR

m

R

1

-N(R

m

)C(=NR

m )NRnR m

-N(R

m 2 R n, -N(RmI)S(=O) 2 NRnRn,

-NR

m

C

2 -6alkyINR m C(=o)oRs, -C(=O)NRRs, C(44jNR)N~RmR -OC(=O)Rs, -OC(=O)NRnR', -OC(=O)N(Rn)SQO0) 2

-OC

2 6 alkylNRnRS,

-OC

24 ialkylOR', SR', 2 Rs, 2 NRrnRs, 2 N(Rrn)C(=O)R', 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=O)NRnR', -NRrnRs, -N(Rrn)C(=O)Rs, -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRnR', -N(Rrn)C(=NRn)NRnRs, -N(Rrn)S(=O0) 2 Rs, -N(Rrn)S(=O) 2 NRnRs, -NRrnC 2 6 alkyINRnR', -NRrnC 2 6 alkylORs and -NR

M

C

2 -6alkylOR m

R

4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C 18 alkyl,

C

1 -4haloalkyl, halo, cyano, nitro, -C(=0)0R n, -C(=0)NR m

R',

-C(=NR

m

-OR'

m -0C(=O)NR m R -OC(=0)N(R m 2 R -0C 2 6 alkyNR m

R

m -0C 2 -6alkyl0R', -SR' m 2 -S 2

NR

m 2

N(R

m n, -S 2

N(R

m -S(=O0) 2

N(R

m

)C(=O)NR

m

R

m

-NR

m

R

m

-N(R

m

-N(R

m

)C(=O)OR,

-N(R

m

)C(=O)NR

m

-N(R

m

)C(=NR

m

)NR

m

-N(R

m 2

R,

-N(R

m 2

NR

m -NRm 1

C

2 _6alky1NR m

R

m

-NR

m

C

2 _6alkylOR m -C(=O)Rs, -C(=O)NRrnRs, -C(=NR n,)NRrnRs, ORs, .OC(0O)Rs, -OC(=O)NRIIR-, -0C(=O)N(Rn)S(=O) 2 Rs, -OC 2 6 alkylNRm~Rs, -OC 2 6 alkylORs, -SRs, -s 2 Rs, -S 2 NRnRS, -S 2 N(Rrn)C(=0)RS., 2 N(Rrn)C(=O)ORs, -S 2 N(Rn)G(=O)NRnR-, -NRrnRs, -N(Rrn)C(=O)RS, -N(Rrn)C(=O)ORs, N(Rr)C(0)NRnRs -N(Rrn)C(=NRm)NRnR',

-N(R

m )S 2 Rs, -N(Rrn)S(=O) 2 NRnRs, -NR m

C

2 6 alky NRrnRS, -NRrnC 2 6 alkyIOR~s and C 1 4 alkyl substituted by 1 or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=O)ORn, -C(=O)NR m

R

m

-G(=NR

m

)NR

m

R

m

-OR

m

-OC(=O)R

0

-OC(=O)NR

m

R

m

-OC(=O)N(R

m 2 -0C 2 6 alkylNR m

R

m 113 -0C 2 -6alkylOR', -S 2 2

NR

m

R',

2

N(R

m -S 2 2

N(R

m )C(=0)NR m

R',

-NR

m

-N(R

m

-N(R

m )C(=0)ORn, -N(R m

)C(=O)NR

m

R

m

-N(R

M

)C(=NR

M

)NR

m

R

m -N(Rm)S(=0) 2 R n, -N(R m 2

NR

m

R

m

-NR

m

C

2 6 alkylNR m -C(=0)0Rs, -C(=0)NRnRs, -C(=NRrn)NRnRs, -0Rs, -0C(=0)Rs, .0C(=0)rNRsR' -OC(=0)N(Rrn)S(=0) 2 Rs, -O26lyNms -0C 2 6 alkyl0R', -SRs, 2 2 NRnRs, 2 N(Rrn)C(=0)Rs, -s 2 N(Rrn)C(=O0RS, -S 2 N(Rn)C(=0)NRnRs, -NRrnR', -N(Rrn)C(=O)Rs, -N(Rm)C(=0)0Rs, -N(Rr)C(=0)NRnR', -N(Rrn)C(=NRn)NR"'Rs, -N(Rrn)S(=0) 2 -N(Rrn)S(=0) 2 NRnR', -NRnC 2 6 alkylNRnRs, -NRrnC 2 alkyl0Rs and -NR m

C

26 alkylOR m and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups; R 7 is C 2 -8alkyl, C 1 5 haloalkyI, 1, Br; R 9 is independently, at each instance, H, C 19 galkyl, C 1 4 haloalkyl, halo, nitro, cyano, -OCI.

6 alkyl, -0-C 1 4 haloalkyl, -0-C 16 alkylNR m

R',

-0-CI- 6 alky]OR', -Nk m

R

m

-NR

m

-C

1 4 haloalkyl, -NR m

-C

1 6 alkylNkR m R or

-NR

m -C 16 alky OR m Y is NH; and Z is CR 8orN; or R' is

F

3

C,,

R

9 R 2 is H, -OR m Cl, C 1 3 haloalkyl or C,.

6 alkyl; R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S, so long as the combination of 0 and S atoms is not greater than 1, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from Cl-galkyl, C 14 haloalkyl, halo, cyano, nitro,

-C(=O)NR

m

R

m

-C(=NR

m

)NR

m

R

m -0C(=O)Rn, -OC(=O)NR-R m -0C(=0)N(R m 2 R n, -OC 26 al kylOR m -S -S -S 2

R',

-114- 2

NR

m

R

m 2

N(R

m

-S(O)N(

m )R 2

N(R

m

)C(=O)NR"'R

m

-NR

m

R

m

INR)(OO~

-N(R

m )C(=O)NR R m

-N(R

m

)C(=NR"

m

)NR

m

R

m

-N(R

m )S 2 Rn, -N(Rn m 2

NR

m

R

m

-NR"(C

2 _alkylNR m

R

m

-NR

m

C

2 6 a1'ylOR m C(=O)ORS, -C(=O)NRmRs, C(=N41Rn)NRrnRs, OR',.O(0R -OC(=O)NRnRs, -OC(=O)N(Rrn)S(=O) 2 Rs, -OC 2 6 alkyl -RS, -OC 2 6 al kylORs, -SRs, 2 Rs, 2 N(Rrn)C(=O)Rs, 2 N(Rrn)C(=O)ORS, 2

N(R

m

)C(=O)NR

m -NRrR', -N(Rrn) C(=O)Rs, -N(Rrn)C(=O)ORs, -N(Rr)C(=O)NRmRs, -N(Rrn)C(=NRn)NRrnR', -N(Rrn)S(=O) 2 Rs, -N(Rrn)S(=O) 2 NRnR', -NR

M

C

2 6 a1 kylNRrnRs, -NRnC 2 6 alkylORsC and C,_4alkyl substituted by I or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=O)NR m

R

m

-C(=NR

m

)NR

m

R

m

-OR

m

-OC(=O)NR

m

R

m

-OC(=O)N(R

m 2

-OC

2 6 afkylNR R m -0C 2 6 alkylOR', -S(=O0) 2 2

NR

m

R

m 2

N(R

m 2

N(R

m )C(=O)OR n, 2

N(R

m

)C(=O)NR

m

R

m

-NR

m

R

m

-N(R

m

-N(R

m -N(Rm)C(=O)NRm~Rn,

-N(R

m )C(=NRm)NR m 2 R n, -N (R m 2

NR

m

R',

-NR

M

C

2 6 alkyl NR m

R

m -C(=O)ORs, -C(=O)NRnRs, -C(=NRn)NRnR', -ORs, .0C(0)Rs, -OC(=O)NRnRs, -OC(=O)N(Rn)S(=O) 2 Rs, -OC 2 6 alkyINR m Rs,

-OC

2 6 alkylOR', 2 Rs, 2 NRnR', 2 N(Rrn)C(=O)R', 2 N(R')C(=O)ORS 2 N(Rrn)C(=O)NRnR', -NRmRs, -N(R!ThC(=O)Rs, -N(Rrn)C(=O)ORs, -N(Rr)C(O)NRnRs, -N(Rrn)C(=NRn)NRnR', -N(Rrn)S(=O)2R', -N(R m )S 2 NRnRS, -NRrnC 2 6 a~kylNRnR', -NRnC 2 6 alkylORs and -NR

M

C

2 .6alkyl OR m wherein R 4 is not unisubstituted phenyl;

R

9 is independently, at each instance, H, Cl- 9 alkyI, C 1 4 haloalkyI, halo, nitro, cyano, -OCI 6 alkyl, -0-CI- 4 haloalkyl, -0-CI 6 a1kyINR m

R

m -0-CI 6 alkylOR m

-NR

m

R

m

-NR

m

-C

1 ~haloalkyl, -NR m

-CI-

6 alkyINR m R' or

-NR

m

-C

1 6 alkylOR m Y is NIHand Z is CR 8 or N.

115- In another embodiment, in conjunction with the novel compound embodiments above and below, R IS

R

8 (CRqRq) 0

RO

R 2 is H, -OR m halo, C 1 3 haloalkyl or C 1 6 alkyl; R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C 1 8 galkyl,

C

1 4 haloalkyl, halo, cyano, nitro, -C(=0)NR m

R',

-C(=NR

m

-OR'

m

-OC(=O)N(R

m 2 R n, -OC 2 6 alkylNRm~R m -0C 2 6 alkylOR m

-SR

m 2 2

NR

m

R

m 2

N(R

m n, -S 2

N(R

m 2

N(R

m

)C(=O)NR

m

R

m

-NR

m

R

m

-N(R

m

-N(R

m

-N(R

m

)C(=O)NR

m

R

m

-N(R

m

)C(=NR

m

)NR

m

R

m -N(Rm)S 2

R',

-N(R )S 2

NR

m

-NR

m

C

2 6 alkyl NR"'R m

-NR

m

C

2 6 aI kylOR m -C(=O)ORs, -C(=O)NRrnRs, -C(=NRm)NRnR', .ORs, .OC(0)Rs, -OC(=O)NRnR', 2 Rs, -OC 2 6 alkyINRnRs, -0C 2 6 alkylOR', S(=0) 2 Rs, 2 NRrnR', 2 N(Rrn)C(=O)R', -S 2 N(Rm)C(=O)ORs, -S 2 N(Rrn)C(=O)NRnRs, -NRrnR', -N(Rrn)C(=O)Rs, -N(Rm~)C(=O)ORs, -N(Rr)C(0)NRnRs, -N(Rm)C(=NRrn)NRrnRs, -N(Rrn)S(=OX2R', -N(Rni)S(=O) 2 NRnRs, -NR m

C

26 aIkylNRrnRs, -NRnC 2 6 alkylORs and C 1 4 alkyl substituted by I or 2 groups selected from C 1 2 haloalkyI, halo, cyano, nitro, -C(=O)OR n, -C(=O)NR m

R

m

-C(=NR

m

)NR

m

R

m

-OR

m -0C(=O)R n, -OC(=O)NR m

R

m -OC(=0)N(R m 2

-OC

2 6 alkyl NR'n R m -0C 2 6 alkylOR m

-SR

m n, 2 R n, 2

NR

m

R

m -S 2

N(R

m n, 2

N(R

m 2

N(R

m )C(=0)NR m

R

m 116- -N1R m

R

m -N(Rml)C(=O)R n, -N(R m n' N(R m )C(=O)NRmlR',

-N(R

m )C(=NRn')NR m

R

m

-N(R

m 2

-N(R

m )S 2

NR

m

R

m

-NR

m

C

2 6 alkyINR m

R

m -C(=0O)ORS, -C(=O)NRnRs, -C(=NRrn)NRrnRs, -0C(=O)NRnR', -OC(=O)N(Rrn)S(=0) 2 Rs, -0C 2 6 alkylNRnR',

-OC

26 alky10R', -S -S 2 Rs, -S 2 NRnRS, -S 2 .N(Rn)C(=O)RS, -S 2 N(Rrn)C(=0)ORS, 2 N(Rrn)C(=O)NRnR',

-NR

m Rs, -N(Rr)C(=O)0Rs, -N(Rrn)C(=O)NRnR', -N(Rrn)C(=NRn)NR"nR', -N(Rr)S(=0) 2 Rs, -N(Rrn)S(=0) 2 NRnR', -NRrnC 2 6 alkyINR"nR', -NRnC 2 6alkylOR' and -NR m

C

2 6 alkylOR m and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups;( R 7 is C 19 alkyl, C 14 haloalkyl, halo, nitro, cyano, -0C 1 -6alkyI, -0-C 14 haloalkyl, -0-C 1 6 alkyINR m

R

m -0-C 16 alkylOR', -NR m

R

m

-NR

m

-CI-

4 haloal kyl, -NR m -C 16 alkylNR m R' or -NR m

-C

1 6 alkyIOR'; R' is a saturated, parti ally- saturated or unsaturated 6- or 7-membered monocyclic or 10- or IlI-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, 0 and S, so long as the combination of 0 and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from RP; RP is independently at each instance C 18 Salkyl, C 1 4 haloalkyl, halo, cyano, nitro, -C(=0)0R n, -C(=0)NR m

-C(=NR

m

)NR

m

-OR-

m -OC(=0)NR m -0C(=O)N(R m 2 R n, -OC 2 6 alkylNR m Rn m -0C 2 6 alkylOR', -SR' m 2 R n, 2

NR

m

R',

2

N(R

m n' n, -S 2

N(R

m )C(=0)NR m

R',

-N(R n, -N(R m n' N(R m )C(=)NRmRm,

-N(R

m

)C(=NR

m

)NR

m

-N(R

m 2

-N(R

m 2

NR

m

R',

-NR

m

C

26 alkyINR m R' or -NR m

C

2 6 alkylOR'; and Y is 0or NiH.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms 117selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C 1 8 alkyl,

C,-

4 haloalkyl, halo, cyano, nitro, n, -C(=0)NR m

R',

-C(=NR

m

)NR

m

-OR

m -OC(=O)NRnR

-OC(=O)N(R

m 2 -0C 2 6 alkylNR'R', -OC 2 -(alkyOR', -SR m -S 2 2

NR

m -S 2

N(R

m 2

N(R

m -S 2

N(R

m )C(=0)NR m

R

m

-NR

m

R

m

-N(R

m

-N(R

m )C(=O)NR -N(R m

)C(=NR

m

)NR

m

R

m

-N(R

m 2

R',

-N(R

m 2

NR

m

-NR

M

C

2 6 alkylNR"R m

-NR

M

C

2 -6alkylOR m -C(=0)0Rs, -C(=O)NRnR', -C(=NRn)NRnRs, .ORs, -OC(=0)Rf', -0C(=O)NRnR', -OC(=O)N(R m )S 2 Rs, -OC 2 6 alkyI NRnRS, -OC 2 6 al kylORs, -S 2 -s 2

NR

m 2

N(R

m -S 2 N(Rrn)C(=0)ORS, -S 2

N(R

m )C(=0)NR m NRrnRS -N(R m )C(=0)Rs,

-N(R

m )C(=0)0R 5

-N(R

m

)C(=O)NR

m -N(Rrn)C(=NRn)NRnR', -N(Rrn)S(=0) 2 Rs, -N(Rrn)S(=o) 2 NRnRs, -NRnC 2 6 alkylNRnR', -N'26aklR and C 1 4 alkyl substituted by 1 or 2 groups selected from CI- 2 haloalkyl, halo, cyano, nitro, -C(=O)OR n, -C(=0)NR m

-C(=NR

m

)NR

m

R

m

-OR

m -0C(=0)R n, -OC(0)NRR m

-OC(=O)N(R

m 2 R n, -OC 2 -6aIkylNR m

R

m -0C 2 6 alkylOR m

-SR

m 2

R

1 2

NR

m

R

m 2

N(R

m 2 N(Rm)C(=O)OR n, 2

N(R

m

)C(=O)NR

m

R',

-NR

m

-N(R

m -N(Rm 1 )C(=0)NR m

R

m

-N(R

m

)C(=N-R')NR

m

R

m

-N(R

m )S 2

-N(R

m )S 2

NR

m

R

m

-NR

M

C

2 6 aI kyl NR m

R

m -C(=0)0R 5 -C(=O)NRnR', -C(=NR m )N RrRs, -ORs, -OC(0)NR m

-OC(=O)N(R

m 2

-OC

2 6 alkylNR m Rs,

-OC

26 alkylO 5 2 2 NR'Rs, -S 2 N(Rm)C(=0)0R 5 -S 2

N(R

m

)C(=O)NR

m

R',

-NR

m

-N(R

m

-N(R

m )C(0)0R 5

-N(R

m

)C(=O)NR

m

R',

-N(R

m

)C(=NR

m

)NR

m

-N(R

m 2

-N(R

m 2

NR

m

R',

-NR

M

C

26 a~kyNR m

-NR

m C2- 6 alkylOR 5 and -NR m

C

2 6 alkylOR m and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups.

118- In another embodiment, in conjunction with the novel compound embodiments above and below, R 4 is a phenyl ing that is vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ing and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from CI-salkyl,

C

14 haloalkyl, halo, cyano, nitro, -C(=0)NR m

R',

-C(=NR

m

)NR

m

-OR

m

-OC(=O)NR',

-OC(=O)N(R

m 2

-OC

2 6 alkylNR m

R

m -0C 2 6 alkylOR m

-SR

m 2 2

NR

m -S 2

N(R

m 2

N(R

m 2

N(R

m

)C(=O)NR

m

R

m -NRmlRrn, -N(R m

-N(R

m -N(Rrn)C(=O)NR'Rn, -N(R m

)C(=NR-)NR

m

R

m

-N(R

m 2

R',

-N(R

m 2

NR

m

R

m

-NR

M

C

2 6 alkylNR m

-NR

m

C

2 6 alkylORn, -C(=O)ORs, C(0)NRnRs, -C(=NRn)rNRsR' -OC(=O)NRrnRs, -OC(=O)N(Rrn)S(=O) 2

-OC

2 6 alkylNRnRs, -OC 2 6 alkylORs, -SRs, 2 Rs, 2 NRnRs 2 N(Rm)C(=O)Rs, -S(=Oh2N(Rrn)C(=O)ORs, -S 2 N(Rrn)C(=O)NRnRS, -NjRn~s, -N(Rr)C(0O)Rs, -N(Rr)C(=O)ORs, -N(Rm)C(=O)NRmlR', -N(Rrn)C(=NRm)NRnR', -N(Rrn)S(=O) 2 Rs, -N(Rrn)S(=O) 2 NRnR', -NRMC 2 6 atkylNRRs, -NRrnC 2 6 alkylOR' and C, 4 alkyl substituted by I or 2 groups selected from CI 2 haloalkyl, halo, cyano, nitro, -C(=O)NR m

R

m -C(=NRm)NR m RTh -OR m -OC(=O)R n, -OC(=O)NR m Rm, -OC(=O)N(R m 2

-OC

2 -6alkylNR m

R

m

-OC

26 alkylOR', -SR m n, 2 2

NR

m

R

m -S 2

N(R

m 2

N(R

tm -S 2

N(R"')C(=O)NR

m

R

m

-NR"'R

m

-N(R

m

-N(R

m

-N(R

m

)C(=O)NR

m

R

m

-N(R

m

)C(=NR

m

)NR

m

-N(R

m 2 R n, -N(R m 2

NR

m

R

m

-NR

m

C

2 6 alkylNR m

R

m -C(=O)ORs, -C(=O)NRrnR', -C(=NRrn)NRrnR', -OC(=O)NRrnR', -OC(=O)N(Rrn)S(=O) 2

-OC

2 6 alkylNRnR',

-OC

2 _(alkylOR', 2 RS, 2 NRnR', 2 N(Rrn)C(=O)R', 2 N(Rrn)C(=O)ORs, 2 N(Rm)C(=O)NRm t

R',

-NRrnR', -N(Rr)C(0O)ORs, -N(Rr)C(=O)NI&Rs, N(Rrn)C(=NRrn)NRrnR', -N(Rm)S(=O) 2 -N(R 2 NRnR', 119- -NRmC 2 6 alkylNRmRs, -NRmC 2 .6alkylORs and -NR m

C

2 6 alkylOR m and the bridge carbon atoms are substituted with 0, 1 or 2 =0 groups.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 7 is Ci.9alkyl, Ci.

4 haloalkyl, halo, -OCI.

6 alkyl,

-O-CI

4 haloalkyl, -NR"R m or -NR"-Ci-4haloalkyl.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 7 is Ci.salkyl, C 1 4 haloalkyl, I, Br or Cl.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 7 is tert-butyl or trifluoromethyl.

In another embodiment, in conjunction with the novel compound embodiments above and below, Ro is a saturated, partially-saturated or unsaturated 6- or 7-membered monocyclic ring containing 0, 1, 2 or 3 atoms selected from N, O and S, so long as the combination of O and S atoms is not greater than 1, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from R

P

In another embodiment, in conjunction with the novel compound embodiments above and below, R° is a saturated, partially-saturated or unsaturated 6-membered ring containing 0, 1, 2 or 3 N atoms, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from R

P

In another embodiment, in conjunction with the novel compound embodiments above and below, Y is O.

In another embodiment, in conjunction with the novel compound embodiments above and below, Y is NH.

In another embodiment, in conjunction with the novel compound embodiments above and below, R' is 120 R 2 is H, -OR' m halo, C 1 3 haioalkyl or C 1 6 alkyI; R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from CJ-8alkyI,

C

1 4 haloalkyl, halo, cyano, nitro, -C(=0)NR m

R',

-C(=NRn m

)NR

m

R

m

-OR

m -OC(=0)R -OC(=O)NR m R

-OC(=O)N(R

m 2 R n, -0C 2 6 alkylNR m

R

m

-OC

2 6 alkylOR', -SR m 2 R n, 2

NR

m

R

m -S 2

N(R

m n, -S 2

N(R

m )C(=O)OR n 2

N(R

m

)C(=O)NR

m

R

m

-NR

m

-N(R

m

-N(R

m

-N(R

m

)C(=O)NR

m

R

m

-N(R

m )C(=NRm)NR m

R

m

-N(R

m 2

R",

-N(R

m 2

NR

m

R

m

-NR'C

2 -6a~kylNR m

R

m

-NR

m

C

26 alkylOR m -C(=O)ORs, -C(=O)NR-Rs, -C(=NRn)NRrnRs, -ORs, OC(0)Rs, -OC(=O)NRnR', -0C(=O)N(Rn)S(=O) 2

-OC

2 6 alkylrNRsR' -OC 2 6 alkylOR', -SRs, 2 2 NR"nR', 2 N(Rrn)C(=O)Rs, 2 N(Rrn)C(=O)ORs, 2 N(Rml)C(=O)NRnRs, -NRrnRs, -N(Rr)C(0O)Rs, -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRnR', -NR)(NmNms -N(Rrn)S(=O) 2 Rs, -N(Rrn)S(=O) 2 NRnRs, -NR m

C

2 6 alkylNR m Rs, -NRnC 2 6 alkylOR' and C 1 4alkyI substituted by I or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=O)OR n, -C(=O)NR m

R

m

-C(=NR

m

)NR

m

R

m

-OR

m 2

-OC

26 al kyl NR m

R

m

-OC

26 alkylOR m

-SR'

m n, 2 R n, 2

NR

m

R

m 2 -S 2

N(R

m )C(=O)OR n, -S 2

N(R

m

)C(=O)NR

m

R

m

-NR

m

R

m

-N(R

m -N(Rm)C(=0)NR m

R

m

-N(R

m

)C(=NR

m

)NR

m

R

m

-N(R

m 2

-N(R

m 2

NR

m

R',

-NR

m

C

2 6 alky]NR m

R

m -C(=O)ORs, -C(=O)NRnRS, -C(=NR')NRnRs -ORs, -OC(0)NRnRs -OC(=O)N(Rrn)S(=O) 2

-OC

2 6 alkylNR m

R',

-OC

2 6 alkylOR', 2 2 NRnR', 2 N(Rrn)C(=O)Rs, 2 N(Rml)C(=O)ORs, 2 N(Rm)C(=O)NRnRs, -N(Rml)C(=O)Rs, -N(Rrn)C(=O)OR S, -N(Rrn)C(=O)NRnR', 121 -N(Rrn)C(=NRn)NRnRs, -N(R m )S 2 Rs, -N(Rrn)S(=O) 2 NRnR',

-NR

M

C

2 .(,alky1NR m RS, -NRnC 2 6 alkyI0RS and -NR

M

C

2 6alkyl0R m and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups; R 7 is C 1 9 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -OCI- 6 a~kyl, $-0-C 1 4 haloalkyl, -0-C 1 _6alkylNR m

R

m -0-Ci.

6 alkyIOR m

-NR

m

R

m

-NR

m

-C

1 4 haloalkyl, -NR m

-C

1 6 alkylNR m

R

m or -NR m

-C

1 6alkylOR m fC s8alkyI,

C

1 5 haloalkyl, 1, Br or CI1 R' is a saturated, partially-saturated or unsaturated 6- or 7-membered monocyclic or 10- or I 1-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, 0 and S, so long as the combination of 0 and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from RP; RI is independently at each instance C 1 8 alkyl, CI.

4 haloalkyl, halo, cyano, nitro, n' -C(=O)NR m

R

m -C(=NRn)NRnRm, -ORm -0C(=0)R n, -OC(=O)NR m

R

m -OC(=0)N(R m 2

-OC

2 6 alkylNR m

R

m -0C 2 -6alkyl0R m

-SR

m 2 2 NRm'~R, -S 2

N(R

m -S 2

N(R

m -s 2

N(R

m )C(=0)NR m

R',

-NR

m

R

m

-N(R

m )C(=0)R 1

-N(R

m )C(=0)0R 1

-N(R

m )C(=0)NR m

R

m 2 0 -N(R m

)C(=NR-)NR-"R

m

-N(R

m 2

-N(R

m 2

NR

m

R

m

-NR

m

C

2 6 aI kylNR m R' or -NR

M

C

2 6 a1 kylOR m and Y is 0or NE.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from Cl.salkyl,

C

14 haloalkyl, halo, cyano, nitro, -C(=0)NR m

R',

-C(=NR

m

)NR

m

-OR

m -OC(=0)NR m R -0C(=O)N(R m 2

-OC

2 6 alkylNR m

R

m

-OC

2 6 alkylOR', -SR m -S(=0)Rn, -122- -S 2 -S 2

NR

m

R

m 2

N(R

m 2 -S 2

N(R

m )C(=0)NR m

-NR

m

-N(R

m

-N(R

m -N(Rrn)C(=0)NRmRrn, N(R m )C(=NRn)NRnRml, -N(R m 2

R',

-N(R

m 2

NR

m

R

m -NRnC 2 6 alkylNR m

-NR

m

C

2 6 al kylOR m -C(=0)0Rs, -C(=0)NRnR', -C(NR m m .OC(0)Rs -OC(=-O)NRnR', -OC(=0)N(R m )S 2 Rs, -0C 2 6 al kyINRrnR, -OC 2 6 alkyIORS, -SRs, S(=0) 2 Rs, -S 2 NRnRs, 2 N(Rr)C(=O)Rs, 2 N(Rr)C(=0)0Rs, -S 2 N(Rnl)C(=0)NRnR', -NRrnRs, -N(Rr)C(=0)Rs, -N(Rr)C(=0)0Rs, -N(Rrn)C(=O)NRnR', -N(Rrn)C(=NRn)NRnRs, -N(Rr)S(=0) 2 N(Rr)S(=O) 2 NRnRs, -NRrnC 2 -(alkylNRnRs, -NR m

C

2 6 a1 kylORs and C 1 4 alkyl substituted by I or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=0)NR m

-C(=NR

m

)NR

m

-OR'

m -OG(=0)NR m

-OC(=O)N(R

m 2 -0C 2 -6alkyl NR m

R',

-OC

26 alkylOR', -SR m 2 2

NR

m

R',

2

N(R

m 2

N(R

m 2

N(R

m )C(=0)NR m

R

m

-NR

m

-N(R

m

-N(R

m )C(=0)OR n, -N(R m )C(=0)NR m

R',

-N(R

m

)C(=NR

m

)NR

m

R

m

-N(R

m 2 R n, -N(R m 2

NR

m

R

m

NR

m

C

2 6 alkyNR m

R

m -C(=0)0Rs, -C(=O)NRrnRs, -C(=NR)NRnRs, .0C(=O)Rs, -OC(=O)NRnR', -OCQ=0)N(Rrn)S(=0) 2 Rs, -0C2zalkylNRm1rRs,

-OC

2 6 alkylORs, 2 Rs, 2 NRrnRs, 2 2 N(Rr)C(=0)0Rs, -S 2 N(Rrn)C(=0)NRnRS, -NRrnR', -N(Rr)C(=0)Rs, -N(Rr)C(=O)0Rs, -N(Rrn)C(=O)NRnR', -N(Rrn)C(=NRn)NRnRs, -N(Rrn)S(=O) 2 Rs, -N(Rrn)S(=O) 2 NRnRs, -NRrnC 2 _alkylNRnRs, -NRrnC 2 6 alkylORS and -NR m

C

2 6 alkylOR m and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups.

Inanotheembodiment,iojnctonunt-he owihel.cmonve.comoun.._ embodiments above and below, R 4is a phenyl ring that is vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from Cl, 8 alkyl,,

CI.

4 haloalky], halo, cyano, nitro, -C(=0)NR m

R

m 123

-C(=NR

m )NRMR"', -OR m -OC(=O)Rn, -OC(=O)NR m

R

m

-OC(=O)N(R

m 2 -0C 2 6 alkylNR m

R

m -0C 2 6 alkylOR m

-SR

m -S 2 -S 2

NR

m 2

N(R

m 2

N(R

m -S 2

N(R

m

)C(=O)NR"'R

m

-NR

m

-N(R

m

-N(R

m

)C(=O)OR,

-N(Rmn)C(=O)NRnRm, -N(R m

)C(=NR

M

)NR

m

N(R

m 2 R

-N(R

m 2

NR'R

m

-NR

m

C

26 alkyNR m

R

m

-NR

m

C

2 6 alkylOR', -C(=O)ORs, -C(=O)N.41Rrn, C(=NflRm)NRnR' -OC(=O)Rs, -0C(=O)NRnRs, -OC(=O)N(Rm')S 2

-OC

2 6 alkylNRnR', -OC 2 6 al kylORs, 2 2

NR

m Rs, 2

N(R

m -S 2

N(R

m )C(=O)0Rs, 2

N(R

m

)C(=O)NR

m Rs, -NRrnRs, -N(R n,)C(=O)Rs,

-N(R

m )C(=O)0Rs, -N(R m

)C(=O)NR

m -N(Rr)C(=NlR)rNRsR'

-N(R

m 2 Rs, -N(R m 2

NR

m Rs, -NRnC 2 6 alky]~NRs -NRrnC 26 alkylORs and C 14 alkyl substituted by I or 2 groups selected from CI- 2 haloalkyl, halo, cyano, nitro, -C(=O)OR n, -C(=O)NR m

R

m

-C(=NR

m

)NR

m

R

m

-OR

m -OC(=O)R n, -OC(=O)NR m

R

m

-OC(=O)N(R

m 2

-OC

2 6 alkylNR m

R

m

-OC

2 6 alkylOR', -SR m n' 2 2

NR

m

R

m -S 2

N(R

m n, -S 2

N(R

tm 2

N(R

m

)C(=O)NR

m

R',

-NR'Rrn, -N(R tm

-N(R

tm

-N(R

m

)C(=O)NR

m

R

m

-N(R

m

)C(=NR

m

)NR

m

R

m

-N(R

m 2

-N(R

m 2

NR

m

R

m

-NR

m

C

2 6 alky]NR m

R

m -C(=O)ORs, C(O)rNRsR -C(=NR m

)NR

m

R',

-OC(=O)Rs, -OC(=O)NR m Rs, 2

-OC

2 6 alkylNR m Rs, -0C 2 6 alkyOR', 5 2

NR

m Rs, 2

N(R

m S(=0) 2 N(Rrn)C(=O)ORs, 2

N(R

m

)C(=O)NR

m Rs,

-NR

m

-N(R

m

-N(R

t )C(=O)0R 5 -N(Rm)C(=O)NR m

R',

-N(R

m

)C(=NR)NR

m

-N(R

m 2

-N(R

m )S 2

NR

m Rs,

-NR

m

C

2 6 a~kyNR m

-NR

tm

C

2 6 alkylOR' and -NR m

C

2 6 alkylOR m and the bridge carbon atoms are substituted with 0, 1 or 2 =0 groups.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 7 is Cl.

9 alkyl, C 14 haloalkyl, halo, -OCI 1 6 alkyl, -O-CI.-shaloalkyl, -NR m

R

m or -NR m

-C

1 4 haloalkyl.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 7 is C 1 .salkyl, C,- 4 haloalkyl, 1, Br or Cl.

124- In another embodiment, in conjunction with the novel compound embodiments above and below, R 7 is tert-butyl or trifluoromethyl.

In another embodiment, in conjunction with the novel compound embodiments above and below, RO is a saturated, partially-saturated or unsaturated 6- or 7-membered monocyclic ring containing 0, 1, 2 or 3 atoms selected from N, O and S, so long as the combination of O and S atoms is not greater than 1, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from R

P

In another embodiment, in conjunction with the novel compound embodiments above and below, Ro is a saturated, partially-saturated or unsaturated 6-membered ring containing 0, 1, 2 or 3 N atoms, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from R

P

In another embodiment, in conjunction with the novel compound embodiments above and below, Y is O.

In another embodiment, in conjunction with the novel compound embodiments above and below, Y is NH.

In another embodiment, in conjunction with the novel compound embodiments above and below, R' is

R

6 R

R

2 is H, -OR m halo, Cl_ 3 haloalkyl or C 1 6 alkyl;

R

4 is a saturated, partially-saturated or unsaturated 10 or 11-membered bicyclic heterocycle containing 1, 2, 3, 4 or 5 atoms selected from 0, N and S, so long as the combination of O and S atoms is not greater than 2, but excluding quinolin-6-yl, 4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl, benzothiazol- 2-yl, 2,3-dihydro-benzo[1,4]dioxin-6-yl, wherein the heterocycle is substituted by 0, 1, 2 or 3 substituents independently selected from Cl- 9 alkyl, oxo, C 1 4 haloalkyl, 125 halo, nitro, cyano, -OR m 1 6 alkyl, -O-C 1 4 haloalkyl, -O-C 1 6 aikylNR m

R',

-0-C 6 alkylOR m

-NR

m

R

m

-NR

m

-C

1 4 haloalkyl, -NR m 6 alkyINR m

R

m

-NR

m

-CI.

6 alkylOR m

-C(=O)C

1 6 alkyl, -OC(=0)CI- 6 a~kyl, -C(=O)NR m

C

1 6 alkyl,

-NR'C(=O)CI-

6 a1 kyl -C(=O)0Rs, C(=)NRmRS, -C=~)Nm OC(=O)Rs, -OC(=O)NRnR', -OC(=O)N(Rrn)S(=O) 2

-OC

26 a1 kylNRnRs,

-OC

2 6 alkylOR', S(=0) 2 R, 2 rPRnRs 2 N(Rrn)C(=O)ORS, 2 N(Rrn)C(=O)NRnR', -NRrnR', -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRnR', -N(Rrn)C(=NRrn)NkRmRs, -N(R m )S 2 Rs, -N(Rrn)S(=O) 2 NRnR', -NRnC 26 alkylNRnR', -NRnC 26 alkyIORs and C 1 4 alkyl substituted by 1 or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=O)NR m

R

m

-C(=NR

m

)NR

m

-OR'

m

-OC(=O)NR

m

R',

-S 2 2

NR

m 2

N(R

m -s 2

N(R

m 2

N(R

m

)C(=O)NR

m

-N(R

m

-N(R

m )C(=O)OR

-N(R

m

)C(=O)NR

m

-N(R

m

)C(=NR

m

)NR

m

R

m

-N(R

m 2

R',

-N(R

m )S 2

NR

m

R

m -C(=O)ORs, -C(0)NRnRs, -C(=NRn)NRnRS, -ORs, -OC(=O)Rs, -0C(=O)NRnR', -OC(=O)N(Rm)S 2 Rs, -0C 2 6 alky NR n'RS,

-OC

26 a~kyIOR', .SRs, -S(0)Rs, 2 2 NRnR', -S 2 N(Rrn)C(=O)RS, 2 N(Rm)C(=O)ORs, -S 2 N(Rrn)C(=O)NRnRS, -NRmlRS, -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRnRs, -N(Rrn)C(=NRn)NRnR', -N(R m )S 2 Rs, N(R m )S 2 NRrRS, -NRnC 2 6 alkyNRnRs, -NRnC 2 6 alkyIOR' and -NR m

C

2 6 alkylOR'; wherein R 4 is not 2-aminocarbonylrnethyl-2,3-dihydro-benzo[1I,4]dioxin-8-yl, 2-cyanomethyl- 2,3-dihydro-benzo[ 1,4]dioxin-8-yl, quinolin-3-yl, 3H-quinazoliri-4-on-3-yi, benzo[1 ,3]dioxol-5-yI, 3,3-dimethyl-1 ,3-dihydro-indol-2-on-6-yI or 4,4-dimethyl- 3,4-dihydro- IH-quinolin-2-on-7-yl; R 7is C 1 .8alkyI, Cl-shaloalkyI, I or Br;

R

9 is H, C 1 9 galkyl, Ca- 4 haloalkyI, halo, nitro, cyano, -OCI.

6 alkyl,

-O-C

1 4 haloalkyl, -O-C 1 6 alkylNR m

-O-C

1 6 alkylOR'", -NR m

R',

-NR

m

-CI-

4 haloalkyl, -NR"'-C 1 6 a1kylNR m R' or -NR m 6 alkylOR'; Y is NH; and 126 Z is CR 8 or N.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 4 is a heterocycle selected from indole, 3Hindole, benzo[b]furan, benzothiophene, IH-indazole, benzimidazole, benzthiazole, IH-benzotfiazole, 7-quinoline, 8-quinoline, 1,2,3,4tetrahydroquinoline, isoqui noline, cinnoline, phthalazine, quinazoline and quinoxaline, wherein the heterocycle is substituted by 0, 1, 2 or 3 substituents independently selected from Cl- 9 alkyl, oxo, C 14 haloalkyl, halo, nitro, cyano,

-OR

m 1 6 alkyl, -0-C 1 4 haloalkyl, -O-C 1 6 alkylNR m -0-C 6 alkylOR',

-NR

m

R

m

-NR

m

-C

1 4 haloalkyl, -NR m -Ci- 6 alkylNR m

R

m

-NR

m

-C

1 6 alkylOR m

-C(=O)CI.

6 alkyl, -OC(=0)C 1 6 alkyl, -C(=0)NR m

C,.

6 alkyl, -NR m C(=0)C 1 6 alkyl C(0)oRs, -C(=0)NRnR', -C(=NRrn)NR'nR', -0Rs, -0C(=0)R, -OC(=0)NRnR', -OC(=O)N(R m )S 2

-OC

26 alkyl NRrnR, OC 2 6 alkylORs, -S -S 2 Rs, -s 2 NRnRs, 2 N(Rrn)C(=0)R', 2 N(Rr)C(=0)0Rs, -S 2 N(Rn)C(=O)NRnRs, -NRrnRs, -N(Rrn)C(=O)Rs, -N(Rr)C(=O)0Rs, -N(Rr)C(=0)NRnRs, -N(Rr)C(NRn)rNRsR -N(Rn m )S 2 Rs, -N(R m )S 2 NR"nRS, -NR"C 2 6 alkylNRnRs, -NRmrC 2 6 alkylORs and C 14 alkyl substituted by 1 or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=0)NR m

R

m

-C(=NR

m

)NR

m

R

m

-OR

m

-OC(=O)NR

m 2 -0C 2 6 a1 kyINR m

R

m

-OC

2 6 alkylORm 1

-SR

m -S 2 2

NR

m 2

N(R

m 2

N(R

m 2 N(Rn)C(=O)NR"Rn, -N(R m

-N(R

m )C(=O)OR n, -N(R m

)C(=O)NR

m

R

m -N(Rm 1

)C(=NR

m

)NR

m

R

m

-N(R

m 2

-N(R

m )S 2

NR

m

R

m -C(=0)0Rs, C(0)NRnRS -C(=NRm)NRrnR', -ORs, -OC(=O)Rs, -OC(=O)NRnRs, OC(=O)N(Rrn)S(=O) 2 Rs,

-OC

2 6 alkylNRnRs, -OC 26 alkylOR', 2 Rs, 2 NRnRs,

S(=O)

2 N(Rr)C(=O)Rs, 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=O)NRnRs, -NRrnRs, -N(Rr)C(=O)Rs, -N(Rm)C(=O)ORs, -N(Rrn)C(=O)NRnRs, -N(Rrn)C(=NRrn)NRrnR', -N(Rrn)S(=0) 2 Rs, -N(Rrn)S(=O) 2 NRnRs, -NRrnC 2 6 alkylNRrnR', -NRnC 2 6 alkylOR' and -NRinC 2 6 alkyl OR m In another embodiment, in conjunction with the novel compound embodiments above and below, R 4 is a heterocycle selected from 6-indole, 7-

I

127 indole, 6-3H-indole, 7-3H-indole, 6-benzo[b]furan, 7-benzo[bjfuran, 6benzothiophene, 7-benzothiophene, 6-11 H-indlazole, 7- 111-indazole, benzimidazole, benzthi azole, I H-benzotiazole, 7-quinoline, 8-quinoline, 7- 1,2,3 ,4-tetrahydroquinoline, 8-1,2,3 ,4-tetrahydroquinoline, isoquinolin-7-yl, isoquinolin-8-yl, 7-cinnoline, 8-cinnoline, phthalazine, 7-quinazoline, 8quinazoline and quinoxaline, wherein the heterocycle is substituted by 0, 1, 2 or 3 substituents independently selected from C 1 9 alkyl, OXO, C 1 4 haloalkyl, halo, nitro, cyano, -OR' m -S(=O)nC 1 6 alkyl, -0-C 1 4 haloalkyl, -0-C 1 6 alkylNR m

R

m 6 alkyOR', -NR m

R

m

-NR

m -C 1 4 haloalkyl, -NR m

-C

1 6 a1kylNR m

R

m

-NR

m -C1 6 alkylOR', -C(=O)CI-6alkyl, -OC(=O)C 1 6 alkyl, -C(=O)NR m

C

1 6 alkyl,

-NR

m C(=0)C 1 6 alkyl .C(0)ORs, -C(=O)NRnRs, -C(=NRn)NRnRs, -0Rs, -OC(=O)Rs, -0C(=0)NRnRs, 0OC(=O)N(Rn)S(=O) 2 R, -OC 2 6 alkyINRnRs, -0C 2 6 alkylORs, -SRs, 2 2 N.RrRs, -S 2 N(Rrn)C(=O)Rs, 2 N(Rrn)C(=O)ORs, -S 2 N(Rn)C(=O)NRnR', -NRrnRs, -NCRr)C(=0)Rs, -N(Rr)C(=0)ORs, -N(Rr)C(=0)NRwRs, -N(Rrn)C(=NRrn)NRnRs, -N(Rrn)S(=O) 2 Rs, 2 NRnR', -NRnC 26 alky1NRrnR', -NRnC 26 alky]0R' and C 1 4 alkyl substituted by 1 or 2 groups selected from C 12 haloalkyl, halo, cyano, nitro, -C(=0)NR m

R',

-C(=NRn)NRmlRrn, -OR' m

-OC(=O)NR

m R -0C(=0)N(R m 2

-OC

26 alkylNR m

-OC

2 6 alkyl0R', -SR m 2 -s 2

NR

m 2

N(R

tm 2

N(R

tm 2

N(R

m )C(=0)NR m

-N(R

m

-N(R

t

-N(R

tm

)C(=O)NR

m

-N(R

m

)C(=NR

m

)NR

m

-N(R

m )S 2

R',

-N(R

m )S 2

NR

m

R

m -C(=O)0Rs, -C(=0)NRnRs, -C(=NRrn)NRrnR', -0RFs, -0C(=O)Rs, -OC(=0)NRnR', -OC(=O)N(R m )S 2 Rs, -OC 2 6 al kyl NRrnRS, -0C 2 6 alkyl0Rs, 2 Rs, 2 NRrnR', -S 2 N(Rrn)C(=0)Rs, 2 N(RI")C(=O)ORs, -S 2 N(Rn)C(=0)NRnR', -NRrnR', -N(Rr)C(=o)ORs, -N(Rr)C(=0)NRnR', -N(Rrn)C(=NRn)NRnRs, -N(Rrn)S(=O) 2 Rs, -N(Rrn)S(=O) 2 rNRsR'

-NR

M

C

2 6 alkyINR m

-NR

m

C

2 6 a1 kylORs and -NR m

C

2 6 alkylOR m In another embodiment, in conjunction with the novel compound embodiments above and below, R 9 is Cl- 9 alkyl, C 1 4 haloaikyl, halo, nitro, cyano, 128 -0C 1 6 alkyl, -0-C 4 haloalkyl, -0-C 1 6 alkylNR m -0-Ci 1 ,alkyl0R', -NR m

R',

-NR'-C

1 AhaloalkyI, -NR m

-C

1 6 alky]NR m R' or -NR m

-C

1 6 alkyl0R'.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 9 is H.

In another embodiment, in conjunction with the novel compound 8 embodiments above and below, Z is CR.

In another embodiment, in conjunction with the novel compound embodiments above and below, Z is N.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 7 is tert-butyl or trifluoromethyl.

In another embodiment, in conjunction with the novel compound embodiments above and below, R' is R 9 R 2 is C,- 6 alkyl substituted by 1, 2 or 3 substituents selected from

CI-

4 haloalkyl, halo, cyano, nitro, n, -C(=0)NR m

R',

-C(=NR

m )NRn'R m

-OR

m -0C(=0)R n' -OC(=O)NR m

R',

-OC(=0)N(R m 2

-OC

2 6 alkylNR m

R

m -0C 2 6 alkylORn, -SR m -S(=0)Rn, -S 2 2 NR'R', 2

N(R

m 2

N(R

m )C(=O)0R, -S 2

N(R

m )C(=O)NRmR m

-NR

m

R

m

-N(R

m n, -N(R m -N(R-)C(=0)NR m

R

m

-N(R

m

)C(=NR

m

)NR

m

R

m

-N(R"

1 2 Rn,

-N(R

m 2

NR

m

R

m

-NR

m

C

2 6 alkylNR m and -NR

M

C

2 6 alkylOR m or R 2is (CR R q) 0

R

8 R R 6 R 6 ;or 129- R 2 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, 0 and S, wherein no more than 2 of the ring members are 0 or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from R R 6 and R; R 4is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C 1 8 alkyl,

C

1 -4haloalkyl, halo, cyano, nitro, n, -C(=0)NR m

R',

-C(=NR

m

)NR

m

R

m

-OR

m -OC(=O)Rn, -OC(=O)NR m

R',

-0C(=0)N(R m 2 Rn, -0C 2 6 alkylNR m -0C 2 6 alkylOR m

-SR'

m 2 2

NR

m 2 2

N(R

m 2

N(R

m

)C(=O)NR

m

R

m

-NR

m

-N(R

m

-N(R

m

)C(=O)OR,

-N(R

m

)C(=O)NR

m

R

m

-N(R

m

)C(=NR

m

)NR

m

R

m -N(Rm)S(=O) 2

R,

-N(R

m 2

NR

m

R

m

-NR

m

C

2 6 alkylNR m

-NR

M

C

2 6 alkylOR m -C(=O)ORs, -C(=0)NRnR', -C(=NRrn)NRrnRs, .OC(0O)Rs, -OC(=0)NRnR', -OC(=O)N(Rrn)S(=0) 2

-OC

2 6 alkylNRnRs, -0C 2 6 alkyl0R', -SRs, -S(0)Rs, -S 2 Rs, 2 NRrnRs, 2 N(Rlm)C(=0)Rs, -S 2 N(Rrn)C(=O)ORS, -S 2 N(Rrn)C(=O)NRnRs, -PRnRs, -N(Rrl)C(=O)R', -N(Rrn)C(=O)ORs, -N(Rml)C(=O)NRrnRs, -N(Rm)C(=NRm)NRnRs, -N(Rrn)S(=O) 2 Rs, -N(Rm)S 2 NRm~Rs, -NR m

C

2 tal kyl NRrnR', -NR

M

C

2 6 alkyl ORS and C 1 4 alkyI substituted by 1 or 2 groups selected from CI- 2 haloalkyl, halo, cyano, nitro, -C(=O)NR m

-C(=NR

m

)NR

m

-OR

m -OC(0)NR m

R

m -OC(0)N(R m )S 2 R n, -0C 2 6 al kylNR'R 1

-OC

2 -6alkylOR m

-SR'

m 2 R n, 2 t4R m

R

m -S 2

N(R

m 2

N(R

m 2

N(R

m

)C(=O)NR

m

R

m

-NR

m

R

m

-N(R

m

-N(R

m

-N(R')C(=O)NR

m

R

m

-N(R

m )C(=NRm)NR m

-N(R

m 2 R n, -N(R m 2

NR

m

R

m

-NR

m

C

2 6 alkylNR'R m C(0)ORs, -C(=0)NR m Rs, -C(=NR l)NRrnR', 130 -0Rs, -0C(=0)Rs, -0C(=O)NRnR', -OC(=0)N(R m )S 2

-OC

2 6 alkylNRnRs, -0C 2 6 al kylORs, -SRs, -S 2 Rs, -s 2

NR

m Rs, 2

N(R

m 2 N(Rm)C(0)0R 5 2

N(R

m )C(=0)NR m Rs, -NRrnR', -N(R m

-N(R

m )C(=0)0R 5

-N(R

m

)C(=O)NR

m Rs,

-N(R-)C(=NR-)NR

m Rs, -N(R

M

2

-N(R

m 2

NR

m Rs,

-NR

M

C

2 -(al kylNR m Rs, -NR m

C

2 6 alkyIORs and -NR

M

C

26 alkylORn, and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups; R 7 is C 2 8 alkyl, C 15 haloalkyl, I, Br; R 9 is independently, at each instance, H, C 1 9 alkyl, C 1 4 haloalkyI, halo, nitro, cyano, -OC 1 6 alkyl, -0-C 1 4 haloalkyl, -0-C 16 alkylNR m

R',

-0-C 1 6 alkyl0R', -NR m

R

m

-NR

m

-C

14 haloalkyl, -NR m -Cl 1 6 alky]NR m

R

m or

-NR

m

-C

1 6 akylOR m Y is NH; and Z is CR 8or N.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 2 is C 16 alkyl substituted by 1, 2 or 3 substituents selected from C 1 4 haloalkyl, halo, cyano, nitro, -C(=0)NR m

R

m

-C(=NR

m

)NR

m

-OR

m -0C(=0)Rn, -OC(=0)NR m

R

m -OC(=0)N(R m 2

-OC

2 6 alkylNR m

-OC

2 6 alkylOR m 2 2

NR-R

m 2

N(R

m 2

N(R

m 2

N(R

m )C(=0)NR m

R

m

-N(R

m n, -N(R m m

-N(R

m

)C(=NR

m

)NR

m

-N(R

m 2

R",

-N(R

m )S 2

NR

m

R

m

-NR

m

C

2 6 al kylNRnR and -NR'C 2 6 aIkylOR m In another embodiment, in conjunction with the novel compound embodiments above and below, R 2 is 2 )phenyl, wherein the phenyl is substituted by 0, 1, 2 or 3 substituents independently selected from C 1 .galkyl, C 1 4 haloalkyl, halo, cyano, nitro, -C(=0)NR m

R

m -C(=NRrn)NRnR m

-OR

m -OC(=0)NRnRn, -OC(=0)N(R m 2

-OC

26 alkylNR m

R

m

-OC

26 alkylOR m 2 Rn, -S(=0)NR m 2 Nki.. n' 2 2 N(Rm)C(=0)NR"R m

-NR'"R

m

-N(R

m n' -N(R m

-N(R

m )C(=0)NR m

-N(R

m

)C(=NR

m

)NR

m

R

m

-N(R

m 2 Rn, 131 2

NR

m -NR m

C

2 6 alkylNR m

-NR

m

C

2 6 a~kylOR m -C(=O)Rs, -C(=O)ORs, -C(=O)NRnRs, -C(=NRn)NRm~Rs, ORs, -OC(=O)Rs, -OC(=O)NRnR', 0C(=O)N(R m )S 2 Rs, -0C 2 -6a1 kyINRnRS, -OC 2 6 aIkyJORS, -Ss -S 2 2

NR

m 2

N(R

m )C(=O)Rs, 2

N(R

m

)C(=O)OR

5 -S 2

N(R

m

)C(=O)NR

m 4RrnRs -N(R m

-N(R

m )C(=O)0Rs, -N(R m

)C(=O)NR

m

-N(R

m

)C(=NR

m

)NR

m

R',

-N(R

m )S 2

-N(R

m )S 2

NR

m

-NR

m

C

2 6 al kylNRnRs, -NR m

C

2 6 alkylOR' and C I 4 alkyl substi tuted by I or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=NR m

)NR

m

R

m

-OR

m

-OC(=O)NR-R

m 2 Rn, -OC 2 6 alkylNR m

R

m

-OC

2 6 alkylOR m

-SR

m n, 2 2

NR

m

R',

-S 2

N(R

m n, 2

N(R

m )C(=O)OR n, 2

N(R

m

)C(=O)NR

m

R

m

-NR

m

R

m

-N(R

m

-N(R

m )C(=O)OR n, -N(R m

)C(=O)NR

m

R

m

-N(R

m

)C(=NR

m

)NR

m

-N(R

m )S 2 R n, -N(Rm)S 2

NR

m

R

m

-NR

1

_C

2 6 alkyNR-R, -C(=O)ORs, -C(=O)rNRsR -C(=N4Rrn)NRnRs -OC(=O)Rs, 0OC(=O)NRnRs -OC(=O)N(Rrn)S(=O) 2

-OC

2 6 alkylNRmR',

-OC

2 6 alkylOR', S(=O) 2 Rs, 2

NR

m Rs, 2 2

N(R

m )C(=O)0R 5 -S 2

N(R

m

)C(=O)NR

m

R',

-NR

m

-N(R

m

-N(R

m )C(=O)0Rs, -N(Rm)C(=O)NR m

R',

-N(R

m

)C(=NR-)NR

m Rs, 2 2

NR

m

R',

-NR

m

C

2 6 alkyl{RnR', -NR m

C

2 6 a~kyIORs and -NR m

C

2 6 a1 ky OR m In another embodiment, in conjunction with the novel compound embodiments above and below, R 2is 2 wherein R' is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, 0 and S, wherein no more than 2 of the ring members are 0 or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from C 1 .8alkyl, C 1 4 haloalkyl, halo, cyano, nitro, n, -C(=O)NR m

-C(=NR

m

)NR

m

-OR'

m

-OC(=O)NR-R

m 2 -0C 2 6 alkylNR m

R',

-OC

2 6 alky]OR', -SR' m 2 2

NR

m

R',

-s 2

N(R

m -s 2 n, -S 2

N(R

m

)C(=O)NR

m

R',

132

-NR

m

-N(R

m

-N(R

m

-N(R

m

)C(=O)NR

m

R',

-N(R

m

)C(=NR

m

)NR

m

R

m

-N(R

m )S 2

-N(R

m )S 2

NR

m

R

m

-NR

m

C

2 6 alkylNR m

R

m

-NR

M

C

26 alkyIOR m -C(=O)OR -C(=O)NRrnRs, -C(=NRrn)NRrnR', .OC(0O)Rs, .OC(0)NRnRs, 2 Rs, -OC 2 6 alkylNRnR', -OC 2 6 alkyIOR', -SRs, -S(=o)Rs, 2 Rs, -S 2 NRnRs, -S 2 N(Rrn)C(=O)Rs, 2 N(Rrn)C(=O)ORs, -S 2 N(Rm)C(=O)NRnRS, -NRrnRs, -N(Rrn)C(=O)OR, -N(Rrn)C(=O)NRnR', -N(Rrn)C(=NRn)NRnR', -N(Rrn)S(=O) 2 Rs, -N(Rrn)S(=O) 2 NRnR', -NR m

C

2 6 alky NRrnRS, -NR m

C

2 6 al kyl ORS and C 1 4 alkyI substituted by I or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro,

-C(=O)NR

m

R

m

-C(=NR

m

)NR

m

-OR

m -OC(=O)NRm t

R

m -OC(=O)N(R 2 -0C 2 6 a1 kylNR m

R

m

-OC

2 6 alkylOR m

-SR

m n, 2 2

NR

m 2

N(R

m -S 2

N(R

m -S 2

N(R

m

)C(=O)NR

m

R

m

-NR

m

R

m

N(R

m -N(Rm')C(=O)OR n, -N(R m

)C(=O)NR

m

R

m

-N(R

m

)C(=NR

m

)NR

m

R

m

-N(R

m 2 R n, -N(R m )S 2 NR n'R m

-NR

m

C

2 6 alkyINR m C(=O)ORs, -C(=O)NRnRs, -C(=NRrn)NRrnR', -OC(=O)R5, -OC(=O)NRnRs, -OC(=O)N(Rrn)S(=O) 2

OC

2 6 alkylN41RnRs, -0C 2 6 al kylORs, -SRs, -S -S 2 Rs, -s 2 NRnRS, 2

N(R

m 2

N(R

m )C(=O)0Rs, 2

N(R

m

)C(=O)NR

m Rs, -NRrnR', -N(Rrn)C(=O)Rs, -N(R m )C(=O)0Rs, -N(Rrn)C(=O)NRnRs,

-N(R

m

)C(=NR

m

)NR

m Rs, -N(R m 2 -N(Rrn)S(=O) 2 NRnR',

-NR

m

C

2 6 aI kylNRnRs, -NRmC 2 6 al kylORs and -NR

M

C

2 6 aI kyl OR m In another embodiment, in conjunction with the novel compound embodiments above and below, R 4 is a phenyl ring that is vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from CI-8alkyl,

C

1 4 haloalkyI, halo, cyano, nitro, n, -C(=O)NR m

R

m

-C(=NR

m )NRm' 1 t

-OR

m -OC(=O)R n, -OC(=O)NR m

R',

-OC(=O)N(R

m 2

-OC

2 6 alkyNR m

R

m

-OC

2 6 al kyIOR m

-SR

m 133 -S 2 2

NR

m -S 2

N(R

m -s 2

N(R

m )C(=0O)0R", 2

N(R

m

)C(=O)NR

m

-NR

m

-N(R

m

-N(R

m )C(=0)0R,

-N(R

m

)C(=O)NR

m

R

m

-N(R

m

)C(=NR

m

)NR

m -N(Rm)S(=0) 2

R',

-N(R

m 2

NR

m

-NR

m

C

2 6 alky]NR m

R

m -NRrfC 2 -6alkylOR m -C(=0)0Rs, -C(=O)NRnRs, -C(=NRn)rNRsR .ORS, .OC(=0)Rs, -OC(=0)NRnR', OC(=0)N(R m )S 2 Rs, -0C 2 6 a1 kyl NRrRs, -0C 26 alkyl0R', -SRs, 2 2 NRnRs, -S 2 N(Rrn)C(=O)RS, -S 2 N(Rrn)C(=0)ORS, 2 N(Rrn)C(=O)NRnRs, -NRrnR', -N(Rrn)C(=O)R', -N(Rr)C(=0)0Rs, -N(Rrn)C(=0)NR"Rs, -N(Rrn)C(=NRn)NRnRs,

-N(R

m )S 2 Rs, -N(R m )S 2 NRnRs, -NR m

C

2 6 aI kylNRrnRs, -NRnC 2 6 alkyl0Rs and C 1 4 alkyl substituted by 1 or 2 groups selected from C 12 haloalkyI, halo, cyano, nitro, n, -C(=0)NR m

R

m

-C(=NR

m

)NR

m

R

m

-OR

m -OC(=O)R n, -OC(=O)NR'R m

-OC(=O)N(R

m )S 2 -0C 2 6 al kylNR m

R

m -0C 2 6 a1 kylOR m -S -s 2 2

NR

m

R

m -S 2 -S 2

N(R

m -S 2

N(R

m

)C(=O)NR

m

R',

-NR

m Rm

T

-N(R

m

-N(R

m )C(=O)OR n, -N(R m

)C(=O)NR

m

R

m

-N(R

m

)C(=NR

m

)NR

m

R

m

-N(R

m 2

-N(R

m )S 2

NR

m

-NR

M

C

2 6 alkylNR m

R

m and -NR m

C

2 6 alkylOR m and the bridge carbon atoms are substituted with 0, 1 or 2 =0 groups.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 7 is tert-butyl or trifluoromethyl.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 9 is H.

In another embodiment, in conjunction with the novel compound embodiments above and below, Z is CR8 In another embodiment, in conjunction with the novel compound embodiments above and below, Z is N.

In another embodiment, in conjunction with the novel compound embodiments above and below, R' is -134-

F

3

C)W

Ris H,-OR m Cl, C 1 3 haloalkyl or CI 6 alkyl; 4 R is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from C 1 8 alkyl, C 1 4 haloalkyl, halo, cyano, nitro, -C(=0)NR m

-C(=NR')NR

m -OC(=0)NR m

R',

-OC(=O)N(R

m 2

-OC

26 al kylOR m -S 2

R",

2

NR

m -S 2

N(R

m 2 2 N(RmI)C(=0)NRnRr, -NR m

-N(R

m

-N(R

m

-N(R')C(=O)NR

m

R

m

-N(R

m

)C(=NR

m

)NR

m

R

M

-N(R

m )S 2

R',

-N(Rrn)S(=0) 2 NRnRml, -NR

M

C

26 aI kylNR m

R

m

-NR

M

C

2 6alkyl0R m C(=0)Rs, -C(=0)0Rs, -C(=O)NRrnR', -C(=NRrn)NRrnR', -OC(=O)R -0C(=0)NRnR', -OC(=0)N(Rrn)S(=0) 2

-OC

2 6 alkylNRnR', -OC 2 6 alkylORs, 2 Rs, 2 NRnR', 2 N(Rrn)C(=O)Rs, 2 N(Rr)C(=0)0Rs, 2 N(R')C(=O)NRmR', -NRrnRS -N(Rnl)C(=0)Rs, -N(Rm~)C(=0)ORs, -N(Rnl)C(=O)NRnR', -N(RmI)C(=NRrn)NRrnRs, -N(Rrn)S(=O)2Rs, -N(Rrn)S(=O) 2

-NR

M

C

2 6 aI kylNR m Rs, -NRnC 2 6 alkyl0Rs( and C 1 4 alkyl substituted by I or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=0)NR m

R

m

-C(=NR

m

)NR

m

R

m

-OR

m

-OC(=O)R,

-OC(=O)NR

m R 2 R n, -0C 2 6 alkylNR m

R

m

-OC

2 6 alkylOR m

-SR

m 2 R 2

NR

m 2

N(R

m 2

N(R

m )C(=O)OR n, 2 N(Rm 1

)C(=O)NR

m Rm 1

-NR

m

R

m n, -N(Rm)C(=O)OR n, -N(R m

)C(=O)NR

m

R

m -N(Rrn)C(=NRm)NRnRm -N(R m 2 R n, -N(R m 2

NR

m

R

m

-NR

m

C

2 6 alkylNR m

R

m and -NR

M

C

2 6 alkylOR m wherein R 4 is not unsubstituted phenyl; 135

R

9 is independently, at each instance, H, C 1 9 galkyl, C 1 4 haloalkyl, halo, nitro, cyano, -0C 1 6 alkyl, -0-C 1 4 haloalkyl, -0-C 1 6 alkylNR m

R',

-0-C 1 6 alkylOR"', -NR m

R

m

-NR

m

-C

14 haloalkyl, -NR m 6 alkylNR m R' or

-NR

m

-C

1 6 a1 kylOR m Y is NH-;and Z is CR 8 or N.

In another embodiment, in conjunction with the novel compound embodiments above and below, R 4 is a saturated or unsaturated 5- or 6-membered ring containing 1, 2 or 3 atoms selected from 0, N and S, so long as the combination of 0 and S atoms is not greater than 1, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from C 1 8 alkyl,C C 1 4 haloalkyl, halo, cyano, nitro, -C(=0)NR m

R

m -C(=NR-l)NRnRr, -OR -OC(=O)R,

-OC(=O)NR

m -0C(=O)N(R m 2

-OC

2 6 alkyIOR-, 2 2 NRnR, 2 N(Rrn)C(=O)R', 2 -S 2

N(R

m )C(=0)NR m

-NR

m

-N(R

m -N(Rrm)C(=0)OW',

-N(R

m 2

NR"'R

m

-NR

M

C

24 6alkylNR m

R

m

-NR

M

C

2 6 alkylOR', -C(=O)0Rs, -C(=NRrm)NRnRs, -0Rs, -OC(=0)R -OC(=O)NRrnR', -OC(=O)N(R m )S 2 Rs, -0C 2 6 alkyl NRrnRS, -0C 2 6 al kyloRs, -SRs, 2 Rs, 2

NR

m 2

N(R

m )C(=0)Rs, 2 N(R')C(=O)0Rs, 2

N(R

m )C(=0)NWR 5 R, 4-pR m Rs, -N(R m )C(=0)Rs,

-N(R

m )C(=O)0R 5 N(Rr)C(0)NRnRs, m )NRm 1 Rs,

-N(R

m 2

-N(R

m 2

NR

m

-NR

M

C

2 6 a~ky]NR m Rs, -NR m

C

2 6 alkyIOR' and C 1 -4alkyI substituted by 1 or 2 groups selected from CI 2 haloalkyl, halo, cyano, nitro, -C(=0)NR m

-C(=NR

m

)NR

m

-OR

m -0C(=O)N(R m 2 R n, -OC 2 6 alky1NR m

-OC

2 6 alkylOR m 2 R n, 2

NWR

m R, 2 2 2 N(Rm)C(=O)NR m

-NR

1

R',

-N(R

m

-N(R

m -N(Rrn)C(=NRn)NRnR, 2

-N(R

m 2

NR

m

R',

-NR

M

C

2 6 alkylNR m

R

m and -NR m

C

2 6 a~kylOR m -136- In another embodiment, in conjunction with the novel compound 8 embodiments above and below, Z is CR.

In another embodiment, in conjunction with the novel compound embodiments above and below, Z is N.

Another aspect of the invention relates to a method of treating acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, bums, allergic skin reactions, pruritis, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders, comprising the step of administering a compound having the structure: R R4 R R 3 R4

R

1 4 R

R

2 X or R 2

X

wherein: R' is

R

6 R R

R

8

R

9 or a naphthyl or saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein 137no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the naphthyl, heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from R 5

R

6 and R 7

R

2 is H, hydroxy, halo, Ci.

6 alkyl substituted by 0, 1 or 2 substituents selected from R 1 0 or a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from R 5

R

6 and R 7 or R' and R 2 together are

R

6 R

R

R and R together are

R

7

R

3 is H or CI.4alkyl; or R1 and R3 together are

R

4 is 138 R14" .1 12 13 R ;or R 4 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atomn bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the carbon atoms of the heterocycle and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from Cl- 9 alkyl, CI-4haloalkyl, halo, nitro, cyano, -OR', 6alkyl, -0-C 1 4 haloalkyl, -0-C 1 6 a1 kylNRaRa, -0-C 1 6 alkylOR', -0-c I.

6 alkylC(=0)OR a, -NR aR', -NR 3

-C

1 4 haloalkyl, -NR 3 -C 1 6 alkyI NRaR', _NaC16lyO' -C(=0)CI- 6 alkyl, -C(=O)0C 1 6 alkyi, -OC(=0)C 1 6 alkyl, -C(=0)NR aC 1 6 alkyl and -NaC(0)C 6 alkyl; or R 4 is lO-membered bicyclic ring comprising fused 6-membered rings, containing 0, 1, 2, 3 or 4 N atoms with the remainder being carbon atoms, with at least one of the 6-membered rings being aromatic, wherein the carbon atoms are substituted by H, halo, OR', NRaR.

C,-

6 alkyl and C~I-haloalkyl; and saturated carbon atoms may be additionally substituted by =0;

R

5 is independently, at each instance, H, Cl.

9 alkyl, C 14 haloalkyl, halo, nitro, cyano, -0C 1 6 alkyl, -0-Cl 4 haloalkyl, -0-C 6 alkylNRaRa, -0-C 1 6 alky]OR', -NR aR. -NR 3

-C

1 4 haloalkyl, -NRa-CI- 6 alky]NRaR'or -NR 3

-C

1 6 alkylOR'; or R 5 iS a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from 0, N and S; R 6 is independently, at each instance, H, C 1 9 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -0C 1 6 alkyl, -0-C 1 4 haloalkyl, -0-C 1 6 alkylNRaR a, -0-C 1 6 a1 kyloRa, _NRa Ra, NRa-CI- 4 haloalkyl, -NRa-CI- 6 alky]NRaRa or -NRa-CI- 6 alkylOR'; or R and R 6 together are a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the 139 carbon atoms of the bridge are substituted by 0, 1, 2 or 3 substituents selected from halo, C 1 6 alkyl, -OC 1 6 alkyl, -NR'C 1 6 alkyl, -C 1 6 alky]OR' and

CI-

6 alkyINRaRa, and the available N atoms of the bridge are substituted by R',

-C

1 6 alkylOR 3 or C 1 6 a~ky]NR 3

R

3 R 7 is independently, at each instance, H, C 1 9 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -OC, 6 alkyl, -0-C 1 4 haloalkyl, 6 alkylNR 3 -0-C 6 alkylOR 3 .4NRa Ra, -NR 3 4 haloalkyl, -NR 3

-C

1 6 alkylNR aR a or -NRa-C, 6 alkylOR';

R

8 is independently, at each instance, H, Cl- 9 alkyl, C,- 4 haloalkyl, halo, nitro, cyano, -OCI.

6 alkyl, -0-C 4 haloalkyl, -0-C 1 6 alkylNR 3 R a, -0-C 6 alkylOR', -NRaR a, _NRa..C 4 haloalkyl, -NRa-C 1 6 alkylNRaR' or -NRa-C 1.

6 alkyl0R'; or R 7 and R 8 together are a saturated or unsaturated 3- or 4-atomn bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the carbon atoms of the bridge are substituted by 0, 1, 2 or 3 substituents selected from halo, CI- 6 alkyl, 6 alkyl, -NRaCI- 6 alkyl, 6 alkyl0Ra and

C,-

6 alkylNR 3 and the available N atoms of the bridge are substituted by R', 6 alkylOR or C, 6 alkylNR 3

R;

R

9 is independently, at each instance, H, C 1 9 )alkyl, C,- 4 haloalkyl, halo, nitro, cyano, -0CI 1 6 al kyl, 4 haloalkyl, -0-C 1 6 alkylNR 3 -0-C -alky]0R', -NRaR a, 4 haloalkyl, -NR 3 6 alkylNR 3 R' or _NR aC 1 6 alkylOR'; R1 0 is independently, at each instance, H, Cl- 9 alkyl, 3 alkylOR 3

C,-

4 haloalkyl, halo, nitro, cyano, 6 alkyl, -0-C 1 4 haloalkyl, -0C 6 alkylNRR, 6 a1kylOR', -0-C 6 alkylC(=0)ORa, -NR aR', -NRa-Ci-4haloal kyl, -NRa-C .6a1 kyiNR a Ra, -NR -C 6 a1 kylOR', -C(=0)C 1 .6a1kyl, 6alkyl, -OC(=0)CI.

6 a1 kyl, 6 alkyl or -NRaC(=0)C,.

6 alkyl; R"1 is independently, at each instance, H, C 1 9 alkyl, 3 alkyOR, Ci- 4 haloalkyl, halo, nitro, cyano, 6 alkyl, 4 haloalkyli .6alkylNR aR', 6 alkyR', 6 a1kylOR a, 6 alkylC(=O)0R 3 -NRa Ra, -NRa-C 1 4 haloalkyl, -NR aC, 6 alkyl NRaR', -N7R-C,.

6 alkylOR', 6 a1 kyl, 6 alkyl, 6 a1 kyl, -C(=O)NR'C 6 alkyl or -NRaC(=O)C I 6 al kyl; or R 1 0 and R 1 together are a saturated or unsaturated 3- or 140 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the each of the carbon atoms in the bridge is substituted by H, -CI- 6 alkyl0R', -C 1 6 alkyl, -NRaRa, -CI 6 alky1NaRa, -C(=0)0Ra, _C(=0)NRa -C I 3 alkylC(=0)0R a, _Ci1.

3 alkyiC(=0)NR aR a, OC(=0)C 1 6 alkyl, -NRaC(=0)CI- 6 alkyl, -C 1 3 alkylOC(=0)C 1 6 alkyl or -C 1 3 alkylNR aC(=0)Ci 6 alkyI, and any nitrogen atoms in the bridge are substituted by H, -Ci.

6 alkyIOR',

-C

1 6 alkyl, -CI- 6 alkylNR aR', -CI- 3 alkylC(=0)0R a, -CI- 3 alkyIC(=0)NRaR a -C 13 alkylOC(=0)C: 6 a1kyl, -CI 3 alkylNRaC(=0)C 6 aikyl, -C(=0)Rc or 0 2 13 4I

-CI-

3 alkylRc; wherein if R1 R R and R are all H, then R1 is not 6 alkyNRaR a or CI- 6 alky10R a; R' is independently, at each instance, H, C 1 9 alkyl, -CI..

3 alkyl0Ra

C

1 4haloalkyl, halo, nitro, cyano, -OR a, -S(=0)nC 1 6 alkyl, -0-C 1 4 haloalkyl, -0-CI- 6 alkylNRaR', -0-C I.

6 alkylORa, -0-C I 6 alkyIC(=0)ORa, -NRaRa,

-NW-C

1 4 haloal kyl, -NRa-C 1 6 alkylNRaR', -NR aC 1 6 a1kyloR a, C(0)C, 6 alkyI, -C(=0)0C 1 6 a1 kyl, -OC(=0)CI.

6 a1 kyl, -C(=0)NR aC 1 -6alkyl or -NRaC(=0)C 1.

6 al kyl; or R 11and R 12together are a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the each of the carbon atoms in the bridge is substituted by H, -ORa, -CI- 6 alkyl0Ra, -C,-6alkyl, -NRaR', -CI.

6 alkylNRaR -C(=0)0Ra, -C(=O)NRaR', -C 1 3 alkylC(=0)ORa, -C 1 3 alkylC(=O)NR aR a, -OC(=0)C 1 6 alkyl, -NRaC(=0)C 16 alkyI, -C 1 3 a1 kylOC(=0)C, 6 alkyl or -C 1 3 alkylNRaC(=O)CI 6 alkyI, and any nitrogen atoms in the bridge are substituted by H, -Cv.

6 alkyl0Ra -C 1 6alkyl, -Cli 6 alkylNRaR', -C 1 3 a1 kylC(=O)ORa, -C~I.

3 alkylC(=O)NR aR a,

-C

1 3 alkylOC(=0)CI- 6 alkyl, -C 1 3 a1kyINRaC(=0)Ci 6 a1 kyl, -C(=0)Rc or

-CI-

3 alkylRc; R'1 3 is independently, at each instance, H, C 1 9 alkyl, -C 1 3 alkyIOR',

C

1 4 haloalkyl, halo, nitro, cyano, -0R3, -S(=0)nC 16 (alkyl, -O-C 1 4 haloalkyl, -0-CI- 6 alkylNRaRa, -OC 6 a1 kylORa, -0-C 1 6 a1 kyIC(=0)OR a, -NR aR', -NRaEC 1 4 haloal kyl, -NRa-Cf- 6 a1 kylNRaR a, -NRa-C 1 6 a1 kylOR a, 6 a1kyl, 141

-C(=O)OC

1 6 alkyl, -OC(=O)CI- 6 a~kyl, -C(=O)NR'Ci.

6 alkyl or -NRC(O)C-alkyl; 1' 4 is independently, at each instance, H, Ci- 9 alkyl, -Ct.

3 alkylORa,

C

1 4 haloalkyl, halo, nitro, cyano, 1 6 alkyl, -0-C 1 4 haloalkyl, -0-CI- 6 alky1NR R -0-CI- 6 alky]OR -O-Ci- 6 alkylC(=O)ORa, _N.RaR',

-N-I.C

1 ~haloalkyl, -NRa.C 1 6 alkylNRaR', -NR aC 1 6 alky10Ra, -C(=0)CI.

6 alkyl, -C(=0)0C 1 6 a1 kyl, -OC(=0)C 1 6 a1 kyl, -C(=0)NRaC 1 6 a1 kyl or NR aC(=0)C 1 6 a1 kyl; R a is independently, at each instance, H, phenyl, benzyl orC 1 6 alkyl; RC' is phenyl substituted by 0, 1 or 2 groups selected from halo,

C

1 3 haloalkyl, -OR' and -NRaR or Rc is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, 0 and S, wherein no more than 2 of the ring members are 0 or S, wherein the heterocycle is optionally fused with a phenyl ring, and the carbon atoms of the heterocycle are substituted by 0, 1 or 2 oxo groups, wherein the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents selected from halo, C 1 3 haloalkyl, -OR' and -NRaRa; Ll is a bond, -CH 2

CH

2 or -CH=CH-; L 2is NR a, 0, -CH 2 NRa-, -CH=N- or N CH- X is 0, S or NR'; or X and R 2 together are =N-CH=CH-, or =C-NRa~ Y is NH or 0; and n is independently, at each instance, 0, 1 or 2; with the proviso that when R' is 4-chiorophenyl, then R 4 is not 3-methoxyphenyl.

In another embodiment, in conjunction with the method of treatment embodiments above and below, R1 is -142or a naphthyl or saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the naphthyl, heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from R 5

R

6 and R 7

R

2 is H, hydroxy, halo, C 1 6 alkyl substituted by 0, 1 or 2 substituents selected from R 1 0 R9

R

R8 R6 x-

R

7 or a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from R 5

R

6 and R 7 and

R

3 is H or C 1 -4alkyl.

In another embodiment, in conjunction with the method of treatment embodiments above and below, R' is

R

6

R

9

R

9 In another embodiment, in conjunction with the method of treatment embodiments above and below, R 7 is independently, at each instance, C2- 9 alkyl or

CI.

4 haloalkyl.

In another embodiment, in conjunction with the method of treatment embodiments above and below, R' is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the 143heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from

R

5

R

6 and R 7 In another embodiment, in conjunction with the method of treatment embodiments above and below, R 2 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from

R

5 R and R.

In another embodiment, in conjunction with the method of treatment embodiments above and below, R 2 is

T

(CH

2 )n

R

9

R

R

7 or a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from R 5

R

6 and R 7 In another embodiment, in conjunction with the method of treatment embodiments above and below, R 2 is 144- In another embodiment, in conjunction with the method of treatment embodiments above and below, R 2 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from

R

5

R

6 and R 7 In another embodiment, in conjunction with the method of treatment embodiments above and below, R 1 and R 2 together are

K

R R

R

In another embodiment, in conjunction with the method of treatment embodiments above and below, R' and R 3 together are

R

6 R

R

In another embodiment, in conjunction with the method of treatment embodiments above and below, X and R 2 together are =N-CH=CH-, or In another embodiment, in conjunction with the method of treatment embodiments above and below, R 4 is 145 R13 R.b is H, C 1 6 alkyI, -C(=0)C 1 6 alkyl, CI- 6 alkyl-0-Ra; and Y 2 is or In another embodiment, in conjunction with the method of treatment embodiments above and below, R 4 is 3 R 1 12 is a 2- or 3-atom, saturated or unsaturated, bridge containing 1, 2 or 3 carbon atoms and 0 or I atoms independently selected from 0, N and S, wherein the each of the carbon atoms in the bridge is substituted by H, -OR a,

-C

1 6 alkylORa, -CI- 6 alkyl, -NRa -C 1 6 alkylNRaR', -C(=0)0R a, -C(=0)NR aRa,

-C

1 3 alkylC(=0)ORa, -C I- 3 alkylC(=0)NRaR a, -OC(=O)CI- 6 alkyl, -NRj'a(=O)C 1 6 alkyI, -C 1 3 alkylOC(=0)C 1 6 alkyI or -C 1 3 alkylNR 3 6 alkyI, and any nitrogen atoms in the bridge are substituted by H, -CI- 6 alkyI0Ra,

-C

1 6 alkyI, -C 1 6 alkylNR aR a, -C I-alkylC(=0)OR a, -C 1 3 alkylC(=0)NRaRa,

-C

1 3 alkyIOC(=0)C 1 6 alkyJ, -C 1 3 alkylNRaC(=0)Ci 6 alkyl, or

-C

1 3 alkyIR'; R b is CI-6alkyl, -C(=0)CI- 6 alkyI, Ci- 6 alkyl--R a and y2 is -NRb_ or In another embodiment, in conjunction with the method of treatment embodiments above and below, R 4 is -146- Rio Y2 L 3 is a 2- or 3-atom, saturated or unsaturated, bridge containing 1, 2 or 3 carbon atoms and 0, 1 or 2 atoms independently selected from 0, N and S, wherein the each of the carbon atoms in the bidge is substituted by H, -OR',

-CI-

6 alkyl0R', -C 1 6 alkyl, -NRaRa, -CI- 6 alkylNR aR a, -C(=0)0R a, C(0O)NRaR', -Cl 3 alkylC(=0)OR a, -C I 3 alkylC(=0)NRaRa, -OC(=0)CI- 6 alkyl, -NaC(=0)C 1 6 alkyl, 3 alkylOC(=0)C 16 alkyl or -C 1 3 alkylNR aC(=0)C 1 6 alkyl, and any nitrogen atoms in the bridge are substituted by H, -CI- 6 -C 16 alky1, -C 1 6 alkylNRaRa, -C 1 3 alkylC(=0)ORa,

-C

1 3 alkylC(=0)NRa~

-C

1 3 a1 kylOC(=0)C1- 6 alkyl, -C 1 3 alkylNRaC(=0)C1- 6 alkyl, or

-C

1 4 3alkylR'; R b is H, C 1 6 alkyl, -C(=0)C 1 6 alkyl, CI- 6 alkyl-o-Ra; and Y' is-NR- or In another embodiment, in conjunction with the method of treatment embodiments above and below, R 4 is R 14 Y y2) 1 3 L 3 is a 2- or 3-atom, saturated or unsaturated, bridge containing 1, 2 or 3 carbon atoms and 0, 1 or 2 atoms independently selected from 0, N and S, wherein the each of the carbon atoms in the bridge is substituted by H, -0Ra, -Ci.

6 alkyl0R', -C 1 6 alkyl, -NRaRa, -CI.

6 alkylNR -C(0)Ra, -C(=0)NRaR

-C

1 3 akylC(0O)OR -C 1 3 a1 kyiC(=0)NRaRa, -OC(=0)C 1 6 alkyl, -NR'C(=0)CI 6 alkyl, -C 1 3 a1 kyl0C(=0)C 1 6 a1kyl or -C 1 3 alkylNRaC(=0)Ci 6 alkyl, and any nitrogen atoms in the bridge are substituted by H, -CI- 6 alkyl0R',

-C

1 6 alkyl, -C 16 a1 kyINR 3

-C

1 3 alkyIC(=0)ORa, -C 1 3 a1 kyIC(=0)N RaR', 147

-C

1 3 alkylOC(=O)Ci_6alkyl, -C 1 3 alkyINR 3 C(=0)Ci 6 alkyl, -C(=0)Rc or _n -CI- 3 alky]R'; Rb Is H, C 16 alkyl, -C(=0)C 1 6 alkyl, CI- 6 alkyl-0-Ra; and Y 2 is -NR b_ or In another embodiment, in conjunction with the method of treatment embodiments above and below, R 4 141 R R R Rb R 1 3 R b is H, C 1 6 alkyI, -C(=O)C 1 6 alkyl, C,- 6 a~kyl-0-R'; and Y 2 is or In another embodiment, in conjunction with the method of treatment embodiments above and below, R 4 is L-membered bicyclic: ring comprising fused 6-membered rings, containing 0, 1, 2, 3 or 4 N atoms with the remainder being carbon atoms, with at least one of the 6-membered rings being aromatic, wherein the carbon atoms are substituted by H, halo, OR', NR aR', C 1 6 alkyl and

C

1 3 haloalkyl; and saturated carbon atoms may be additionally substituted by =0.

In another embodiment, in conjunction with the method of treatment embodiments above and below, R 4 is R 11 R14 R12 R 13 R1 0 is independently, at each instance, H, Cl-galkyl, -CI- 3 alkylOR',

C

1 4 haloalkyl, halo, nitro, cyano, -S(=0)nCI-6alkyl, -0-C 1 4 haloalkyI, -O-C1-alkylNRaR', -o-c i 6 alkylORa, iOC1 6 alkylC(z=0)ORa, -NRaR a, -NRa-Cl.

4 haloaI kyl, -NRaC, 6 a1kyINRaRa, -NaC 6 alkylORa, -C(0)CI- 6 a1 kyl, 6 a1 kyl, -OC(=O)C 1 6 alkyl, 1 ~a,-alkyl or -NRaC(=0)CI- 6 alkyl; -148- R"1 is independently, at each instance, H, C I.

9 alkyl, -CI- 3 alkyl0R3,

C

1 4 haloalkyl, halo, nitro, cyano, 1 6 alkyl, -0-C 1 4 haloalkyl, -0-C 1 6 al kYINRa Ra, 6 alkylRC, 6 alkyIOR', -0-CL 6 alkylC(=0)OR a, -NR2Ra .4 .a 1 haloalkyl, -Na~, 6 alkylNRaR',~~, 6 a1 kylORa, 6 alkyl. -C(=O)0C 1 6 alkyl, 6 alkyl, -C(=O)NR aC 6 alky1 or -NRaC(=O)CI- 6 alkyl;

C,.

6 alkylNRaR a; 12a R is independently, at each instance, H, C 19 galkyl, 3 alkyIORa C, 1 4 haloalkyl, halo, nitro, cyano, -OR a, -S(=0)nC 1 6 alkyl, 4 haloalkyl, 6 alkylNR aR a, 6 alkyIOR a, -0-Ci 6 alkyIC(=0)ORa, -NR aRa, -NRa-C, 4 haloalkyl, -NRa-C,- 6 al kyiNR aR', -N 1 6 alkylORa, 6 alkyl, 6 alkyl, -OC(=0)C 6 alkyI, -C(=0)NR'Cl-6alkyl or -NRaC(=0)C,- 6 alkyl; R 1 3 is independently, at each instance, H, C, 9 galkyl, 3 alkyl0R', C 1 4 haloalkyl, halo, nitro, cyano, -OR a, -S(=0)n 1

C,

6 alkyl, 4 haloalkyl, -0-C 6 al kyiNRaRa, -0-C 6 alkylOR a, -0-C1_ 6 alkyl C(=0)OR a, -NR aR',

-NR

3 4 haloalkyl, -NR aC, .6a1 kyiNR aR', -NR aCI 6 alkylOR a, 6 alkyI, 6 alkyl, -OC(=0)C 6 a1 kyl, 6 alkyl or -NR aCQ..)C alkyl; and R 1 4 is independently, at each instance, H, Cl-qalkyl, 3 aikyl0R',

C

1 4 haloalkyl, halo, nitro, cyano, -OR a, ,salkyl, -0-C 4 haloalkyl, -0-C 6 alkylNRaRa, -0C 6 alkyl0R', 6 alkylC(=O0Ra, -NR Ra, NR aC, -4haloalkyI, -NRa-C, 6 alkylNRaRa, -NR aC, 6 alkylORa, -C(=0)CI-6alkyl, -C(=0)0C 1 6 alkyl, -OC(=0)CI- 6 alkyl, -C(=0)NRaC, 6 alkyl or -NR aC(=0)C 6 alkyI; wherein one of R1 0 and R 1 2 Is not H.

In another embodiment, in conjunction with the method of treatment embodiments above, R 4 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, 0 and S, wherein no more than 2 of the ring members are 0 or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents selected from halo,

C,.

4 haloalkyl, -OR' and -NRaR'.

-149- Another aspect of the invention relates to a method of treating acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, bums, allergic skin reactions, pruritis, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders, comprising the step of administering a compound according to compound description embodiments above--each seperately and alternatively.

Another aspect of the invention involves a method of treating acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, 2 0 cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritis, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, 150 bronchial disorders or bladder disorders, comprising the step of administering a compound having the structure:

R

3

R

2

X

wherein: X is0, Sor NR m n is independently, at each instance, 0, 1 or 2; o is independently, at each instance, 0, 1, 2 or 3; R' is independently at each instance H or R( R n i s i ndependentl y at each i nstance C I.

8 alkyl, phenyl or benzyl; R is independently in each instance H, C 1 4 alkyl, C 1 4 haloalkyl, halo, cyano, nitro, -C(=0)NRnR m

-C(=NR

m

)NR

m

R

m

-OR

m -OC(=O)R n, -OC(=O)NR m

R

m

-OC(=O)N(R

m 2

-OC

2 6 alkyNR m

R

m

-OC

26 alkylOR m 2 R 2

NR

m

R,

2

N(R

m 2

N(R

m 2 N(Rrn)C(=0)NRnR

-NR

m

R

m

-N(R

m n, -N(R m )C(=0)OR -N(Rm)C(=O)NR m

R

m

-N(R

m

)C(=NR

m

)NR"

m RR, -N(Rm)S(=O) 2 -N(Rn)S 2

NR

m

R

m

-NR

m

C

2 6 alkylNR m

R

m or -NR m

C

2 6 alkylOR'; R' is R' substituted by 0, 1, 2 or 3 substituents independently selected from R q R 3 is Hor C.

4 alkyl; R 5 is H, C 19 galkyl, CI- 4 haloalkyl, halo, nitro, cyano, -OCI 1 6 alkyI,

-O-C

1 -4haloalkyl, -0-C 16 alkylNR m

R

m -0C, 6 alkylOR', -N1R m

R

m

-NR

m

-C

1 4 haloalkyl, -NR m

-C

1 6 alkylNR m

R

m

-NR

m

-C

1 6 alkylOR

M

or -(CH 2 R 6is, independently at each instance, H, Cl- 9 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -0CI 6 alkyl, -0-CI- 4 haloalkyl, -0-C 1 6 alkylNR m

R',

-0-C 16 alkylOR m

-NR

m

R

m

-NR

m

-C

1 4 haloalkyl, -NR m

-C

1 6 a1 kylNR m R' or

-NR

m -C 6 alkylOR m

R

8 is H, CI.

9 alkyl, CI- 4 haloalkyl, halo, nitro, cyano, -OCI 1 6 alkyl, -0-C 1 4 haloal kyl, -0-C 16 alkylNR m

R

m -0-C 1 6 alkylOR m

-NR

m

R

m

-NR

m

-C

1 4 haloalkyl, -NR m

-C

1 6 alkyINR m

R

m or -NR m

-C

1 6 alkylOR m and 151 R' is

R

8 (CRqRq )ORO R 2 is H, -OR' m halo, C 13 haloalkyl or C,- 6 alkyl; R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C 1 .galkyl,

C

1 -4haloalkyl, halo, cyano, nitro, n, -C(=0)OR n, -C(=0)NR m

R',

-C(=NR

m

)NR

m

R

m

-OR'

m

-OC(=O)NR

m

R'~

-OC(=O)N(R

m 2

-OC

2 6 al kylNR m

-OC

26 al kylOR m

-SR'

m -S 2 -S 2

NR

m

R

m -S 2

N(R

m -S 2

N(R

m -S 2

N(R

m )C(=O)NR m

-NR

m

R

m

-N(R

m n, -N(R m

-N(R-)C(=O)NR

m

R

m

-N(R-)C(=NR

m

)NR-R

m

-N(R

m 2

R",

-N(R

m 2

NR

m

-NR

m

C

2 6 alkylNR m

-NR

m

C

2 6 alkylOR m -C(=O)ORs, -C(=0)NRrnR', C(=NRn)NRnRs, -ORs, -OC(=O)Rs, -OC(=O)NRnRs, -OC(=O)N(R m )S 2 Rs, -OC 2 6 al kyl NRrnRs, -OC 2 6 alkyl ORS, -SRs, -S(=0)R 5 2 Rs, 2 NRnRS 2

N(R

m )C(=0)Rs, -s 2 N(R-)C(=O)0Rs, -S 2

N(R

m

)C(=O)NR

m

-NR

m Rs, -N(R m

-N(R

tm )C(=0)0R 5 -N(Rr)C(0O)NRnRs, -N(R m

)C(=NR

m

)NR

m Rs,

-N(R

m )S 2

-N(R

m )S 2

NR

m Rs, -N1RmC 2 6 al kyl NR m

-NR

m

C

2 6 alkylOR' and C 1 4 alkyl substituted by I or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=O)OR n, -C(=O)NR m R m -C(=NqRin)N1R 1

-OR

m -OC(=O)R n, 2 R n, -OC 2 6 alkylNR m

R

m

-OC

2 6 alkylOR', -SRm 1 2 2

NR

m

R',

-S 2

N(R

m -S 2

N(R

m 2

N(R

m )C(=0)NR m

R',

-NR

m

-N(R

m

-N(R

m

-N(R

m

)C(=O)NR

m

R',

152 -N(Rrn)C(=NRn)NRnRml, -N(R m 2

-N(R

m 2

NR

m

R

m

-NR

m

C

2 6 aIkyINR m

R

m -C(=O)0Rs, C(=0)NRnR', -C(=NRn)NRnRs, -0C(=0)Rs, -OC(=O)NRnR', -OC(=0)N(Rrn)S(=0) 2 -O26lyNms -0C 2 6 alkylOR', 2 Rs, 2 NRnR', -S 2 N(Rrn)C(=0)RS, 2 N(Rrn)C(=0)ORs, 2 N(Rrn)C(=0)NRnR', -NRrnRs, -N(Rr)C(=0)0Rs, N(Rr)C(=0)NRnRs, -N(Rrn)C(=NRn)NRrnR', -N(Rrn)S(=0) 2 -N(Rrn)S(=0) 2 NRnRs, -NRnC 2 6 alkylNRrnR', -NRrnC 2 .aky0Rs and -NR m

C

2 _6alkyl0R m and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups;

R.

7 is Cl- 9 alkyl, C,- 4 haloalkyl, halo, nitro, cyano, -OCI 1 6 alkyI, 4 haloalkyl, -0-C 1 6 a1 kylNR m

R

m -0-CI- 6 a1 kylOR m

-NR

m

R

m

-NR

m 4 haloal kyl, -NR m 6 alkylNR m

R

m or -NR m 6alkylOR m

R

0 is a saturated, partial ly-saturated or unsaturated 6- or 7-membered monocyclic or 10- or 1 1-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, 0 and S, so long as the combination of 0 and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from RP; RP is independently at each instance CI-8alkyl, C 1 4 haloalkyl, halo, cyano, nitro, -C(=0)NR m

-C(=NR

m

)NR

m R -OR m -0C(=0)NR m -OC(=0)N(R m )S 2 R n, -0C 2 6al kyl NR m

R

m

-OC

26 alkylOR', n, 2 R n, 2

NR

m

R

m -S 2

N(R

m n, -S 2

N(R

m )C(=0)0R n, 2

N(R

m )C(=0)NRR',

-NR

m

-N(R

m n, -N(R m )C(=0)NR m

R

m

-N(R-)C(=NR-)NR

m

R

m

-N(R

m 2 R n, -N(R m 2

NR

m

R',

-NR

m

C

2 6 alkyINR m R' or -NR m

C

2 6 alky]OR m and Y isO0 or NH; or R'is 153

(&CRI)

0 RO or (6RqRq 0 R 2 is H, -OR' m halo, C 1 3 haloalkyl or CI- 6 alkyI; R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C 1 .8alkyl,

C

14 haloalkyl, halo, cyano, nitro, n, -C(=0)NR m

R

m

-C(=NR

m

)NR

m

-OR-

m

-OC(=O)NR

m

R,

-OC(=O)N(R

m 2

-OC

2 -(alkylNR m

-OC

26 alky]OR', -SR' m 2 2

NR

m

R

m 2

N(R

m 2

N(R

m )C(=O)0R, 2

N(R

m

)C(=O)NR

m

-N~

m

R

t fl -N(R m

-N(R

m

-N(R

m

)C(=O)NR

m

R

m

-N(R

m

)C(=NR

m

)NR

m

-N(R

m 2

R',

2

NR-R

m

-NR

M

C

2 6 alkylNR m

R

m

-NWIC

2 6 alkylORn, -C(=O)Rs, -C(=O)ORs, -C(=O)NRnRs, -C(=NPRn)NRnRs -0Rs, -OC(=O)Rs, -OC(=O)NRrnR', -OC(=O)N(Rrn)S(=O) 2 Rs, -0C 2 6 a1 kyl NRrnR, -OC 2 6 ,alkylOR', 2 2 NRnR', 2 N(Rrn)C(=O)Rs, 2

N(R

m )C(=O)0R 5 2 N(Rrn)C(=O)NRnR', -NRrnRS, -N(Rrn)C(=O)R', -N(Rr)C(=O)ORs, -N(Rrn)C(=O)NR'lRs, -N(R')C(=NRn)NRnR',

-N(R

m )S 2

-N(R

m )S 2 NRnRs, -NR m

C

2 6 a1 kyl NRRs, -NRrnC 2 6 alkylOR' and Ci.

4 alkyl substituted by I or 2 groups selected from CI- 2 haloalkyl, halo, cyano, nitro, -C(=O)NR m

R

m

-C(=NR

m

)NR

m

R

m

-OR

m -OC(=O)R n, -OC(=O)NR m

R

m

-OC(=O)N(R

m 2

-OC

26 al kylNR m

R

m

-OC

2 6 alkylOR m

-SR

m n, 2 R n, 2

NR

m

R

m 2

N(R

m n, 2

N(R

m 2

N(R

m

)G(=O)NR

m

R',

-NR

m

R

m

-N(R

m n, -N(R m

-N(R

m )C(=0)NR m

R',

-N(R ')C(=NR m

)NR

m

R

m

-N(R

m 2 R n, -N(Rn)S(=O) 2

NR"'R

m -154- Ct -NR m

C

2 6 alkylNR m -C(=0)0Rs, -C(=0)NRnR', -C(=NR m

)NR

m

R',

n -OW, -OC(=O)NRnR', -OC(=O)N(RtDS(=O)2R', -OC 2 6 alkyINRnRs, -0C 2 6 a~kyl0Rs, -SRs, S(=O)Rs, 2 2 NRrnR', -s 2 N(Rrn)C(=0)R', 2 N(Rr)C(=0)0Rs, 2 N(Rrn)C(=0)NRnRs,

-NR

m Rs, -N(Rr)C(=0)0Rs, -N(Rr)C(=0)NR'R', -N(Rrn)C(=NRn)NRnR', -N(Rrn)S(=0) 2 Rs, -N(Rr)S(=0) 2 NRnR', -NRnC 2 6 alkylNRnR', -NRrnC 2 6 alkyl0Rs and -NR'C 2 -6alkyl0R m and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups; Ris Cl.

9 alkyl, C 1 4haloalkyl, halo, nitro, cyano, -0CI.

6 alkyl, -0-C 1 4 haloalkyl, -0-C 1 6 alkylNR m

R

m -0-C 1 6 alkyl0R m

-NR

m

R

m

-NR

m

-C

1 4 haloalkyl, -NR m

-C

1 6 alkyINR m

R

m or -NW-C 1 6 alkylOR m R' is a saturated, partial ly-saturated or unsaturated 6- or 7-membered monocyclic or 10- or 11l-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, 0 and S, so long as the combination of 0 and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from RP; RP is independently at each instance C 1 8 alkyl, C,.

4 haloalkyl, halo, cyano, nitro, -C(=O)NR m

-C(=NR

m

)NR

m

R

m

-OR'

m -OC(0)NR-R-, 2 -0C 2 6 alkylNR m

R',

-OC

26 alkylOR', -SR m 2 2

NR

m

R',

-S 2

N(R

m 2

N(R

m )C(=0)NR m

R

m

-NR

m

-N(R

m

-N(R

m )C(=0)0R n, -N(R m )C(=0)NR m

R',

-N(R

m

)C(=NR

m

)NR

m

-N(R

m )S 2

-N(R

m )S 2

NR

m Rm",

-NR

m

C

26 alky]NR m

R

m or -NR

M

C

26 alkylOR'; and Y is 0or NH; or R' is 155 R 2is H, -OR' m halo, C 1 3 haloalkyl or C 1 6 alkyl; R 4 is a saturated, partial ly-saturated or unsaturated 10 or I 1-membered bicyclic heterocycle containing 1, 2, 3, 4 or 5 atoms selected from 0, N and S, so long as the combination of 0 and S atoms is not greater than 2, but excluding quinol in-6-yl, 4,5,6,7-tetrahydro-benzofblthiophen-2-yl, benzothiazo!- 2-yl, 2,3-dihydro-benzo[1,4]dioxin-6-yl, wherein the heterocycle is substituted by 0, 1, 2 or 3 substituents independently selected from Cl.

9 alkyl, oxo, CI4haloalkyl, halo, nitro, cyano, -OR' m 6 alkyl, -O-C 1 4 haloalkyl, -O-C 1 6 alkylNR m

R',

-0-C 1 6 alkylOR', -NR R m

-NR

m

-C

1 4 haloalkyl, -NR m

-C

1 6 alkylNR m

R',

-NR

m

-C

1 6 alkylOR', -C(=O)C 1 6alkyl, -OC(=O)C 1 6alkyl, -C(=O)NR'C 1 6 alkyl,

-NR-C(=O)C

1 6 alkyl -C(=O)ORs, -C(=O)NRrnRs, -C(=NRrn)NRrnRs, -OC(=O)Rs, -OC(=O)NRnlR', -OC(=O)N(Rrn)S(=0) 2

-OC

2 6 alkyl NRnRS,

-OC

2 6 alkyIOR', -SRs, -S(0) 2 Rs, 2 NRrnR', 2 N(Rrn)C(=O)R', 2 N(Rr)C(=0)ORs, 2 N(R-u)C(=O)NRnR, -NRmIRs, -N(Rml)C(=0)0Rs, -N(Rml)C(=0)NRnRs, -N(Rrn)C(=NRn")NRnRs, -N(Rrn)S(=0) 2 Rs, -N(Rrn)S(=0) 2 NRnR', -NRnC 2 6 alky!NRnR', -NRrnC 2 alkyl0Rs and C 14 alkyl substituted by I or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, n, -C(=0)NR m

R',

-C(=NR

m

)NR

m

-OR

m -OC(=0)NR m

R

m -0C(=O)N(R m 2

-OC

2 6 alkylNR m

-OC

2 6 alkylOR m

-SR

m 2 2

NR

m 2

N(R

m n, 2

N(R

m )C(=0)0R 0 -S 2

N(R

m )C(=0)NR m

-N(R

m n, -N(R m m

R

m

-N(R

m

)C(=NR

m

)NR

m 2 R

-N(R

m )S 2

NR

m

R

m -C(=0)ORs, -C(=O)NRnR', -C(=NRn)NRnR', 0C(0)Rs -0C(=O)NRnR', 2 -0C 2 6 alkylNR'R', -0C 2 6 alkylOR', 2 Rs, 2 NRrnR', 2 2 N(Rrn)C(=O)0Rs, 2 N(Rrn)C(=0)NRnR', -NRmlRS, -N(Rr)C(=0)0Rs, -N(Rr)C(=0)NRnR', -N(Rml)C(=NRm)NRnRs, -N(RlmhS(=O) 2 -N(Rrn)S(=O) 2 NRnR', -NRrnC 2 6 alkylNRnRs, -NRrnC 2 6 a~kyIORSand -NR m

C

2 6 alky]0R wherein R 4 is not 2-aminocarbonyl met hyl -2,3 -di h ydro-benzo[ I ,4]dioxi1n-8-yl, 2-cyanomethyl- 2,3-dihydro-benzo[1 ,4]dioxin-8-yl, quinolin-3-yi, 3H-quinazolin-4-on-3-yi, 156 benzo[ 1,3]dioxol-5-yI, 3 ,3-di methyl-i ,3-di hydro-i ndol-2-on-6-yl or 4,4-dimethyl- 3,4-di h ydro- I-I-qui nol in-2-on-7-yl;

R

7 is Cl-galkyl, Ci-shaloalkyl, I or Br

R

9 is H, Cl- 9 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -OCI 1 6 alkyl, 4 haloalkyl, -0-C 1 6 alkylNR m -0-C 1 6 alkylOR m

-NR

m

R

m

-NR

m

-C

1 4 haloalkyl,

-NR

m

-C

1 6 alkylNR m

R

m

-NR

m

-C

1 6 alkylOR"', or -(CH 2 ),nRc;

R

9 is independently, at each instance, H, C 1 9 alkyl, C 1 4 haloalkyl, halo, ni tro, cyano, -OCI 6 alkyl, -0-C 1 4 haloalkyl, -0-C 1 6 al kylNR m

R',

-0-CI.

6 alkylOR', -NR m

-NW-CI-

4 haloalkyl, -NR m

-C

1 6 alkylNR m R' or

-NR

m -C 1 6 alkylOR'; Y is NH-; and Z is CR 8 or N; or R' is

R

9 R 2 is C 1 6 alkyl substituted by 1, 2 or 3 substituents selected from

C

1 4 haloalkyl, halo, cyano, nitro, -C(=0)NR m

R',

-C(=NR

m

)NWR

m R, -OR' m -OC(=0)NR m

R',

-OC(=0)N(R m 2

-OC

2 6 alkylNR m

R

m -0C 2 ~alkyl0R', -SR' m 2 R 2

NR

m 2

N(R

m 2

N(R

m )C(=O)0R, 2

N(R

m )C(=0)NR m

R

m -NR-lRrn, -N(R m )C(=0)0R,

-N(R

m )C(=0)Nk m

R

m

-N(R

m

)C(=NR

m

)NR

m

-N(R

m )S 2

R",

-N(R

m 2

NR

m

R

m

-NR

m

C

26 alkylNk m R' or -NR m

C

2 6 alkylOR'; or R 2 is q) 2 )ophenyl, wherein the phenyl is substituted by 0, 1, 2 or 3 substi tuents independently selected from C 1 .Salkyl, C 1 4 haloal kyl, halo, cyano, nitro, -C(=0)NR m

-C(=NR

m

)NR

m

R

m

-OR

m -OC(=0)R n, -OC(=0)NR m

R

m

-OC(=O)N(R

m 2 R n, -OC 2 6 al kylNR m

R

m -0C 26 al kylOR m

-SR

m 2 -S 2

NR

m R 2

N(R

m n, 2

N(R

m 2

N(R

m )C(=0)NR m

R',

157

-NR

m

-N(R

m

-N(R

m

-N(R

m

)C(=O)NR

m

R,

-N(R

m

)C(=NR

m

)NR

m

-N(R

m 2

-N(R

m )S 2

NR'R',

-NR

M

C

26 al kyl NR m

R

m

-NR

m

C

2 6 aI kyl OR, -C(=O)ORs, -C(=O)NRnR', -C(=NRrn)NRnR', .ORs, -OC(=O)NRnR', -OC(=O)N(Rrn)S(=O) 2 Rs, -OC 2 6 alkylNRnR', -OC 2 6 al kylORs, SR', S(=O)Rs, -S 2 -S 2

NR

m Rs, 2 N(Rrn)C(=O)R', -s 2

N(R

m )C(=O)0R 5 -S 2

N(R

m

)C(=O)NR

m NRmnRS -N(Rr)C(0O)Rs, -N(Rr)C(0O)ORs,

-N(R

m

)C(=O)NR

m Rs, -N(R m

)C(=NR

m

)NR

m Rs, -N(R m )S 2

R',

-N(R

m )S 2

NR

m

-NR

M

C

2 6 aIkyINR m

-NR

m

C

2 6 alkylOR 5 and C 1 4 alkyl substituted by 1 or 2 groups selected from C,- 2 haloalkyl, halo, cyano, nitro, -C(=O)OR n, -C(=O)NR m

R

m

-C(=NR

m

)NR

m

R

m

-OR

m

-OC(=O)NR

m

R

m

-OC(=O)N(R

m 2 R n, -0C 2 6 alkyl NR m

R

m

-OC

2 6 alkyl OR m 2 2

NR

m

R

m 2

N(R

m 2 N(Rm)C(=O)OR", -S 2

N(R

m

)C(=O)NR

m

R

m

-NR

m

R

m

-N(R

tm n' -N(R m)C(=O)NR m

R

M

-N(R

m

)C(=NR

m

)NR"'R

m 2

-N(R

m 2

NR

m

R

m

-NR

m

C

26 alkylNR R -C(=O)NRnWs -C(4=4Pi)NRnRs -ORs, -OC(=O)Rs, .OC(=O)rNRsR" .0C(=o)N(Rn)s(=0) 2 Rs, -0C 2 6 alkyNR m Rs,

-OC

2 -6alkylOR', 2 Rs, 2

NR

m

R',

-S 2 N(RImhC(=O)RS, 2 N(Rrn)C(=O)ORs, 2

N(R

t m

)C(O)N

m

R

-NRrnR', -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRnR', N(Rr)S(=O) 2 Rs, -N(Rrn)S(=O) 2 NRnR',

-NR

M

C

2 6 a1 kyINR m R, -NRmC 26 aIkylORs and -NR m

C

2 6 a] kylOR m or R' is -(C(Rq) 2 0 wherein R' is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, 0 and S, wherein no more than 2 of the ring members are 0 or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from CI-8alky], C 1 4 haloalkyl, halo, cyano, nitro, 3 0 -C(=O)NR m

R

m

-C(=NR

m

)NR

m

R

m -Ok~n7-OC(=O)R', -OC(=O)NR'R m

-OC(=O)N(R

m 2

-OC

2 6 al kylNR m

R

m

-OC

2 6 al kylORfl, 2 2

NR

m

R

m 2

N(R

m 2

N(R

m 158 2 N(R')C(=O)NR'Rrn, -NRm'"R, -N(Rm)C(=O)OR, -N 2

-NR'C

2 6 akyINR m

-NR'"C

2 6 al kylOR'", -C(=O)ORs, -C(=O)NRrnR', -C(=NRrn)NRrnRs, OR', -OC(=O)NRnR', -OC(=O)N(Rn)S(=O) 2

-OC

2 -(alkyINRnR', -OC 2 6 alkylOR', -S 2 -S 2 NRnRS, -S 2 N(Rrn)C(=O)R', 2 N(Rrn)C(=O)ORs, -S 2 N(Rrn)C(=O)NRnRS, -NRrnR', -N(Rrn)C(=O)R', -N(Rrn)C(=O)ORs, -N(Rnl)C(=O)NRnR', -N(Rrn)C(=NRn)NRnR', -N(Rrn)S(=O) 2 R-s, 2 NRnR', -NRnC 2 6 alkyNRnRs, -NRmrC 26 alkylORs and C 14 alkyl substituted by I or 2 groups selected from C 12 haloalkyl, halo, cyano, ni tro, -C(=O)OR n, 2 R, -OC 2 6 alkylNRnR', 2 N(R'hC(=O)R n, 2 n, 2

M,

-NRm 1 -N(Rrn)C(=O)NR'Rn,

-NR'"C

2 -(alkylNR'"R', -C(=O)ORs, -C(=O)NRnR', -C(=NRn)NRnR',

-OC

2 .6alkyIOR', 2 Rs, 2 NRnR', 2 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=O)NRnR', -NRrnRs, -N(Rrn)C(=O)Rs, -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRnR', -N(Rrn)C(=NRn)NRrnR', -N(R n)S(=O) 2 -N(Rrn)S(=O) 2 NRrnR', -NRnC 26 alkyINRmR', -NRnC 2 6 alkyIORs and -NR'"C 26 al kyl OR'"; R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom, bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C 1 8 alkyl,

C

14 haloalkyl, halo, cyano, nitro, n, -C(=O)OR n, m -OC(=O)R n, 2 R -OC 2 6 alkylNR'"R', -OC 2 6 alkylOR', 159- 2 R n, -S 2

NR

m -S 2 n, 2

N(R

m 2

N(R

m )C(=0)NRn m

R

m

-NR

m

R

m

-N(R

m n, -N(R m

-N(R

m )C(=0)NR

M

R -N(R')C(=NR m

)NR

m

R

m

-N(R

m )S 2

R'

-N(R

m )S 2 NRmlRrn, -NR m

C

2 _raIkylNR m

R

m -NRmIC 26 al kylOR m C(=0)Rs, -C(=0)0Rs, -C(=0)rNRsR' .C(=NR)NRlR' -0C(=0)NRnR', -OC(=0)N(R m )S 2 -0C 2 6 alky NRrnRs, -OC 2 6 al kyl ORS, 2 Rs, 2

NR

m Rs, 2

N(R

m )C(=0)Rs, 2

N(R

m )C(=O)0R 5 -S 2

N(R

m )C(=0)NR m -NRrnRS, -N(R m

-N(R

m )C(=0)0Rs, -N(R m )C(=0)NR-Rs, -N(R m

)C(=NR

m

)NR

m

R',

-N(R

m 2 Rs, 2 N-RnR, -NR m

C

26 aI kylNRrnR', -NR m

C

2 6 alkylOR' and C 1 4 alkyl substituted by 1 or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, n, -C(=O)NR m

R

m -C(=NR n')NR m

R

m

-OR

m -OC(=O)R n, -OC(=O)NR'R m

-OC(=O)N(R

m 2

-OC

26 al kyl NR m

R',

-OC

26 a1kyIOR m h -S 2 -S 2

NR

m

R

m -S 2

N(R

m 2 -S 2

N(R

m

)C(=O)NR

m 1

-NR

m

R

m -N(RThC(=O)R", -N(R m

-N(R

m

)C(=O)NR

m

R

m

-N(R

m

)C(=NR

m )NR"R, -N(R m )S 2

-N(R

m )S 2

NR

m

R

m

-NR

m

C

2 6 alkylNR m

R

m

C(=O)NRP

m

-C(=NR

m )NRnRs, -ORs, .0C(=O)Rs, -OC(=O)NR m

-OC(=O)N(R

m 2 Rs, -OC 2 6 al kylNR m

R',

-0C 2 6 alkylOR', S(=O) 2 2

NR

m

R',

2 N(Rrn)C(=O)R', -S 2 N(R')C(=0)ORS, 2

N(R

m

)C(=O)NR

m Rs, -NRrnRs, -N(R m

-N(R

m )C(=0)0Rs, -N(R m )C(=0)NR m Rs,

-N(R

m

)C(=NR

m

)NR

m Rs, -N(R m )S 2

-N(R

m 2

NR

m

R',

-NR

m

C

2 6 alkyINR m

R

5

-NR

m

C

2 -6alkyIORs and -NR m

C

2 6 alkylOR m and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups; R 7 IS C 2 -galkyl, C 15 haloalkyl, I, Br;

R

9 is independently, at each instance, H, Cl.

9 alkyl, C 1 4 haloalkyI, halo, nitro, cyano, 1 CI 6 alkyl, -0-C 1 4 haloalkyl, -0-C 1 6 al kylNR m

R',

-0-C 6 a1 kylOR m

-NR

m

R

m

-NR

m

-C

1 4 haloalkyl, -NR m

-C

1 6 a1 kylNR m

R

m or

-NR

m

-C

1 6 alkylOR m Y is NH; and Z is CR 8 or N; or -160- R'I s

R

6

R

9

R

2 is H, -OR m Cl, C 1 3 haloalkyl or C 1 6 alky!;

R

4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S, so long as the combination of 0 and S atoms is not greater than 1, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from C 1 8 alkyl, C 1 4 haloalkyl, halo, cyano, nitro,

-C(=O)NR

m

-C(=NR

m

)NR

m

R

m

-OC(=O)NR

m

R',

-0C(=O)N(R m 2

-OC

26 alkylOR', -SR' m 2 Rn, 2

NR

m 2

N(R

m 2

N(R

m )C(=O)OR -S 2

N(R

m

)C(=O)NR

m

-NR

m

R

m

-N(R

m n,

-N(R

m

)C(=O)NR

m

-N(R

m

)C(=NR

m

)NR

m1

-N(R

m 2

R,

-N(R

m 2

NR

m

-NR

M

C

2 6 alkylNR m

R

m

-NR

m

C

2 6 alkylOR m -C(=O)ORs, -C(=O)NRrnR', -C(=NRm)NRmIR -OC(=O)R -0C(=O)NRnRs, -OC(=O)N(R m )S 2 Rs, OC 2 6 alkylrNRsg -OC 2 -6aIkyl ORs, -SRs, 2 Rs, 2 NRrnRs, 2 N(Rm)C(=O)R', -S 2 N(R')C(=O)ORs, 2 N(Rrn)C(=0)NRnRs, -NRrnRs, -N(Rrn )C(0O)Rs, -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRnR', -N(Rrn)C(=NRrn)NRnR',( -N(Rrn)S(=O) 2 -N(Rm)S 2 NRnRs, -NRrnC 2 6 alkylNRnRs, -NRrnC 2 6 alky]OR' and C 14 alkyl substituted by 1 or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=O)NR m

-C(=NR

m

)NR

m

-OR-

m

-OC(=O)NR

m

R

m

-OC(=O)N(R

m 2 Rn, -OC 2 6 alkylNR m

R

m

-OC

2 6 alkylOR', -S R m -S 2 -S 2

NR

m 2

N(R

m -S 2

N(R

m 2

N(R

m

)C(=O)NR

m

-NR

m

R

m

-N(R

m n, -N(R m

-N(R

m

)C(=O)NR

m

R

m

-N(R

m

)C(=NR

m

)NR

m

R

m

-N(R

m )S 2 Rn, -N(R m )S 2

NR

m

R

m

-NR

m

C

2 6 aI kyl NR m R'n, -C(0)ORs, -C(=O)NRnRs, -C(=NkRm)NRnRs, -OC(=O)Rs, -OC(=O)NR'flRs, -OC(=O)N(R m 2

-OC

2 6 alkyINRnRs, -161 -OC2.

6 alkylORs, -SRs, -S(=O)R s 2

R

s 2

NR

m

R',

2

N(R

m 2

N(R

m

)C(=O)OR

s 2

N(R

m

)C(=O)NR

m

RS,

-NR

m

-N(R

m

)C(=O)R

S

-N(R

m

)C(=O)OR

s

-N(R

m

)C(=O)NR"'R

S

-N(R')C(=NRm)NRmR, -N(R m 2 R, -N(R m 2

NR

m

R

5

-NR

m C2-6alkylNR m

R

s

-NR

m C2.6alkylOR' and -NR m

C

2 -6alkylOR m wherein R 4 is not unsubstituted phenyl;

R

7 is C2-,alkyl, C 1 .shaloalkyl, I or Br;

R

9 is independently, at each instance, H, Ci.

9 alkyl, Ci- 4 haloalkyl, halo, nitro, cyano, -OCI.6alkyl, -O-C 1

I

4 haloalkyl, -O-Cl.6alkylNR m

R

m -O-Ci.calkylOR m

-NR

m

R

m

-NR

m

-C.

1 4 haloalkyl, -NR m

-C

1 6 alkylNR m

R

m or

-NR

m -Ci-6alkylOR m Y is NH; and Z is CR 8 or N.

Another aspect of the invention involves a method of treating acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, bums, allergic skin reactions, pruritis, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders, comprising the step of administering a compound having the structure: 162 wherein: X is0, S orNR'; n is independently, at each instance, 0, 1 or 2; o is independently, at each instance, 0, 1, 2 or 3; R' is independently at each instance H orR; R n is independently at each instance CI 8 alkyl, phenyl or benzyl; R is independently in each instance H, C 1 4 alkyl, C 1 4 haloalkyl, halo, cyano, nitro, -C(=O)NR m

-C(=NR

m

)NR

m

-OR

m

-OC(=O)N(R

m 2 R n, -OC 2 6 alkyINR m

R',

-OC

26 alkylOR', -SR' m n, 2 2

NR

m 2

N(R

m -S 2

N(R

m 2

N(R

m

)C(=O)NR

m

R',

-NR

m

-N(R

m

-N(R

m )C(=O)OR n, -N(R m

)C(=O)NR

m

R',

-N(R

m

)C(=NR

m

)NR

m

-N(R

m )S 2 Rn, -N(R m )S 2

NR

m

R

m

-NR

m

C

2 6 alkylNR m

R

m or -NR m

C

2 6 alkylOR'; R' is R' substituted by 0, 1, 2 or 3 substituents independently selected from Rq R 3 is H Or C 1 4 alkyl; R 5 is H, C 1 9 )alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -OCI 1 6 alky!,

-O-C

14 haloal kyl, -0-C 6 alkylNR m -0-C 1 6 alkylOR", -NR m

R

m

-NR

m

-C

1 4 haloalkyl, -NR m

-CI.

6 alkylNR m

R

m

-NR

m

-C

1 _6alkylOR m or -(CH 2 )nRc R 6 is, independently at each instance, H, C 1 9 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -0CI 6 alkyl, -0-C 1 4 haloalkyl, -0-C 1 6 alkylNR m

R

m -0-C 6 alkylOR', -NR'R m

-NR

m

-C

1 4 haloalkyl, -NR m -C 1 6 alkylNR m

R

m or

-NR

1 6 alkylR m R 8 is H, C 1 9 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -OCI 1 6 alkyl, -0-C 1 4 haloalkyl, -OC 16 alkylNR m

R

m

-OC

1 6 alkylOR m

-NR

m

R

m

-NR

m

-C

1 1 haloalkyl, -NR m

-C

1 6 alkylNR m R' or -NR m

-C

1 6 alkylOR m and R Is 163 (&Rq 0 Ro R 2 is H, -OR' m halo, C 1 3 haloalkyl or C 1 6 alkyl; R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, IN and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from CI-8alkyl,

C

1 4 haloalkyl, halo, cyano, nitro, -C(=O)OR n, -C(=O)NRnR m

-C(=NR

m

)NR

m

R

m

-OR

m -OC(=O)R n, -OC(=O)NR m

R

m

-OC(=O)N(R

m 2

-OC

2 6 alkyNR m

-OC

2 6 alkyIOR', -SR' m 2 2

NR

m

R

m -S 2

N(R

m 2 N(Rm~)C(=O)OR, 2

N(R

m

)C(=O)NR

m

R

m

-NR

m

R

m

-N(R

m -N(Rr t )C(=O)0R,

-N(R

m

)C(=O)NR

m

R

m

-N(R

m

)C(=NR

m

)NR

m

R

m

-N(R

m 2

R",

-N(R

m 2

NR

m

R

m

-NR

M

C

2 6 alkylNR m

R

m

-NR

m

C

2 6 alkylOR m -C(=0)Rs, -C(=O)ORs, -C(=0)NRnR', -C(=NRrl)NRrnRs, -OC(=O)NRnRs, -OC(=O)N(Rn)S(=O) 2

-OC

26 alkylNRmlRs, -OC 2 6 alkylOR', -SRs, 2 2 NRmR', 2 N(Rrn)C(=O)Rs, 2 N(Rm)C(=O)ORs, -S 2 N(Rrn)C(=O)NRnRS, -NpRnR's -N(Rrn)C(=O)R', -N(Rr)C(=O)ORs, -N(Rm)C(=O)NRnR', -N(Rrn)C(=NRn)NRnRs, -N(Rrn)S(=O) 2 Rs, -N(Rrn)S(=O) 2 NRrnR-, -NR

M

C

2 6 alkyl NRrnRs, -NR.

M

C

2 6 aI kylORs and C 14 alkyl substituted by I or 2 groups selected from C 1 2 haloalkyl, halo, cyano, ni tro, n, -C(=O)OR n, -C(=O)NR m -C(=NRm)NRmRrn, -OR m -OC(=O)R n, -OC(0)NR m

R

m

-OC(=O)N(R

m

)S(O)

2 R n, -OC 2 6 al kylNR m

R',

-OC

26 alkylOR', -SR' m 2 2

NR

m

R

m 2

N(R

m n, 2

N(R

m 2

N(R

m )C(=0)NR m

R

m

-NR

m

R

m

-N(R

m

-N(R

m

-N(R

m

)C(=O)NR

m

R

m

-N(R

m

)C(=NR

m

)NR

m

R

m

-N(R

m 2 R n, -N(R m 2

NR

m

R

m -164-

-NR

m

C

2 -6alkylNR m -C(=0)ORs, C(=0)NRnRs, -C(=NRrn)NRmRs, -0Rs, -OC(=O)Rs, OC(0)NRnRs, -OC(=0)N(R m )S 2 Rs, -0C 2 6 aI kylNRrnRs, -0C 2 6 alkyI0R', 2 2

N-RR',

2 N(Rrn)C(=0)R', 2 N(Rr)C(=O)0Rs, 2 N(Rn)C(=)NRnR',

-NR

m -N(Rr)C(=0)0Rs, -N(Rrn)C(=O)NRnR', -N(Rrn)C(=NRn)NRnR', -N(Rrn)S(=0) 2 -N(Rr)S(=0h2NRnR', -NRrnC 2 6 alkylNRnRS, -NRrnC 2 6 alkyl0RS and -NR m

C

2 6 alkylOR m and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups; R 7 is C 1 9 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -0CI.

6 alkyl, -0-C 1 4 haloalkyl, -0-C 1 6 akylNR m

R

m

-O-C

1 6 (alkylOR m

-NR

m

R

m

-NR

m -C,~haloalkyl, -NR m -C 1 6 alkylNR m or -NR m

-C

1 _ialkylOR m

R

0 is a saturated, partially-saturated or unsaturated 6- or 7-membered monocyclic or 10- or 1 I1-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, 0 and S, so long as the combination of 0 and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from RP; RP is independently at each instance C 1 8 alkyl, CI- 4 haloalkyl, halo, cyano, nitro, -C(=0)NR m

R

m

-C(=NR

m

)NR

m

-OR'

m -OC(=0)NR-R m -0C(=0)N(R m 2 R n, -0C 2 6 a1 kyl NR'"R m

-OC

26 alkylOR', 2 2

NR

m

R',

-S 2

N(R

m 2

N(R

m 2

N(R

m )C(=0)NR m

-N(R

m

)C(=NR

m

)NR

m

-N(R

m 2 R n, -N(R m )S 2

NR

m

R

m

-NR

m

C

2 6 alky]NR m

R

m or -NR m

C

2 6 alkylOR m and Y is 0or NH; or R' is 165

R

2 is H, -OR' m halo, C 1 3 haloalkyl or C 1 6 alkyl;

R

4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from CI.8alkyl,

C,.

4 haloalkyl, halo, cyano, nitro, n, -C(=O)NR m

R',

-C(=NR

m

)NR

m

R

m

-OR

m -OC(=O)NRmIRrn, 2

-OC

2 6 alkyNR m

-OC

2 -6alkylOR m

-SR

m 2 2

NR

m

R

m 2

N(R

m 2

N(R

m -S 2

N(R

m

)C(=O)NR

m

R

m

-NR

m

R

m

-N(R

m )C(=0)R 1

-N(R

m )C(=0)OR, -N(R-)C(=0)NR m

R

m

-N(R

m

)C(=NR

m

)NR

m

R

m

-N(R

m )S 2

R",

-N(R

m 2

NR

m

R

m

-NR

m

C

2 6 alkyINR m

R

m -NRmlC 2 6 alkylORn, -C(=O)Rs, -C(=0)ORs, -C(=O)NRrnR', -C(=NRrn)NRnR', -OC(=O)NRnR', -OC(=O)N(Rrn)S(=O) 2

-OC

2 6 alkylNR m

-OC

2 6 alkylOR', S(0)Rs, 2 2 NRnR', 2 N(Rm)C(=O)R', 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=O)NRnR', -N7RrRs, -N(Rr)C(=O)0Rs, -N(Rrn)C(=O)NR'lRs, -N(Rrn)C(=NRrn)NRrnRs,

-N(R

m )S 2 Rs, -N(R m )S 2 NRnRs, -NR m

C

2 6 alkyl N RrRs, -NR m

C

2 6 aI kylORs and C 1 4 alkyl substituted by 1 or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=0)OR n, -C(=O)NRm'R m

-C(=NR

m

)NR

m

R

m

-OR

m

-OC(=O)NR

m

R

m -OC(=O)N(Rm)S(=O) 2

-OC

2 6 alkylNR m

R

m -0C 2 6 alkylOR m

-SR

m n, 2 2

NR

m

R

m -S 2

N(R

m 2 N(Rm)C(=O)OR', 2

N(R

m

)C(=O)NR

m

R

m

-NR

m

R

m

-N(R

m

-N(R

m -N(Rm')C(=O)NR m

R

m

-N(R

m

)C(=NR

m

)NR

m

-N(R

m 2 R n, -N(R m 2

NR

m

R

m

-NTR

m

C

2 6 a1 kylNR m

R

m -C(=O)0R 5 -C(0)NrRsR -C(4NRn)~Rns, -OC(=O)Rs, -OC(=O)NRnRs, -OC(=O)N(Rrn)S(=O) 2

-OC

2 6 alkyIN m Rs, -0C 2 6 alkylORs, -SRs, 2 Rs, 2

NR

m Rs, 2

N(R

m 2

N(R

m )C(=O)0Rs, 2

N(R

m

)C(=O)NR

m Rs,

-NR

m -N(Rr)C(0)Rs, -N(Rr)CQ.0)ORs, -N(R')C(=0)NRnR', 166 -N(Rrn)C(=NRn)NRnR', -N(R m )S 2 Rs, -N(Rrn)S(=0) 2 NRnR', -NRrnC 26 alkylNRnR', NRnC 2 6 alkyl0RS and -NR m

C

2 6 alkyl0R'; and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups; R 7 is C 19 alkyl, C,-4haloalkyl, halo, nitro, cyano, -OCI 1 6 alkyl, -0-C 1 4 haloalkyl, -0-C 1 6 alkyNR m

R

m -0-C 1 6 alkyIOR m

-NR

m

R

m

-NR

m

-C

1

I.

4 haloalkyl, -NR tm -C 16 a1 kyINR m R' or -NR m -C I -alkyl0R';

R

0 is a saturated, partially-saturated or unsaturated 6- or 7-membered monocyclic or 10- or I 1-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, 0 and S, so long as the combination of 0 and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from RP; RI is independently at each instance C 1 8 alkyl, CI- 4 haloalkyl, halo, cyano, ni tro, n, -C(=0)0R n, -C(=0)NR m

-C(=NR

m

)NR

m

R

m

-OR

m 2 -0C 2 6 al kyl NR'',

-OC

2 .(alkylOR', -SR' m 2 2

NR

m Rn, 2

N(R

m 2

N(R

m 2

N(R

m )C(=0)NR m

R',

-NR'Rrn, -N(R m n, -N(R m

-N(R

m )C(=0)NR m

R',

*N(R

m

)C(=NR

m

)NR

m

R

m

-N(R

m )S 2 2

NR

m

R',

-NR

m

C

2 6 alkylNR m R' or -NR m

C

2 6 alkyOR m and Y is 0Oor NH; or R' is R 6 2 R is H, -OR' m halo, C,.

3 haloalkyl or C 1 6 alkyl; R 4 is a saturated, partially-saturated or unsaturated 10 or 1 1-membered bicyclic heterocycle containing 1, 2, 3, 4 or 5 atoms selected from 0, N and S, so long as the combination of 0 and S atoms is not greater than 2, but excluding quinolin-6-yl, 4,5,6,7-tetrah ydro -ben zofb] th iophen yl, benzothiazol- 167 2-yl, 2,3-dihydro-benzo[1,4]dioxiri-6-yI, wherein the heterocycle is substituted by 0, 1, 2 or 3 substituents independently selected from C 19 galkyl, oxo, C 1 4 haloalkyl, halo, nitro, cyano, -OR' m

-S(=O),IC

1 6 a1 kyl, -0-C 1 4 haloal kyl, -0-C 6 alkylNR m

R',

-O-CI_6alkylOR-, -NR m

-C

1 4 haloalkyl, -NR m

-C

1 6 alkylNR m

R',

-NR

m

-C

1 6 alkylOR', -C(=O)C 1 6 alkyI, -OC(=O)C 1 6 alkyl, -C(=O)NR'C 1 6 alkyl,

-NR

m

C(=O)C

1 6 a1 kyl -C(0)ORs, -C(=O)NRnRs, -C(=NRrn)NRrnR', -ORs, -OC(=O)Rs, -OC(=O)NRnR', -OC(=O)N(Rrn)S(=O) 2

-OC

2 6 alkylNRnRs,

-OC

26 al kyl ORS, -SRs, 2 -S 2

NR

m Rs, -S 2

N(R

m -S 2

N(R

t )C(=O)0R 5 2

N(R

m

)C(=O)NR

m

R',

-NR-Rs, -N(R-)C(=O)0R 5 N(R f)C(=O)NRrnRs

-N(R

m )C(=NR )NR m

-N(R

m )S 2

-N(R

m )S 2

NR

m Rs,

-NR

m

C

2 6 alkyINR m Rs, -NR m

C

2 6 alkylORs and Ci 4 alkyl substituted by I or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=O)NR m

R,

-C(=NR

m

)NR

m

-OR'

m

-OC(=O)NRR'

-OC(=O)N(R

m 2 -0C 2 6 alkyINR m

R

m -0C 2 6 alkylOR m 2 2

NR

m

R

m 2 N(Rrl)C(=O)Rn, 2 N(R' 2 N(Rml)C(=O)NR'Rrn, -N(R m

-N(R

m

)C(=O)OR,

-N(R

m

)C(=O)NR

m

-N(R

m

)C(=NR

m

)NR

m Rn,, -N(R 2 R n 2

NR

m

R

m -C(=O)ORs, -C(=O)NR m -C(=NRm")NR m Rg, -ORs, OC(=O)Rs, -OC(=O)NR m

R

5 -OC(=0)N(Rm)S(=O) 2

-OC

2 6 a~kyiNR m

R

5

-OC

2 6 alkyIORs, 2 2

NR

m Rs, 2

N(R

m 2

N(R

m

)C(=O)OR

5 2

N(R

m

)C(=O)NR

m Rs, -NRrnRS, -N(R m

-N(R

m )C(=O)ORs, -N(Rn)C(=O)N4Imrn,

-N(R

m

)C(=NR

m

)NR

m Rs, -N(R m 2 Rs, N(Rrn)S(=O) 2 NRnRs -N R

M

C

2 6 akyINR m

-NR

M

C

2 6 alkyIORs and -NR'C 2 6 alkylOR m wherein R 4 is not 2-aminocarbonylmethyl-2,3-dihydro-benzo[ 1,4]dioxin-8-yl, 2-cyanomethyl- 2,3-dihydro-benzo[1 ,4]dioxin-8-yl, quinolin-3-yl, 311-quinazolin-4-on-3-yl, benzo[1 ,3]dioxol-5-yl, 3,3-dimethyl-1I,3-dihydro-indol-2-on-6-yl or 4,4-dimethyl- 3,4-di hydro- 1H-quinolin-2-on-7-yl; R 7 is C 1 8 alkyl, C 1 5 haloalkyI, I or Br 168

R

9 is H, Ci.

9 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -OC 1 6 alkyl, -0-Cl-4haloalkyl, -0-C 1 6 alkylNR m -0-C 1 6 alkylOR', -NR m

-NR

m

-C

1 4 haloal kyl,

-NR

m

-C

1 6 alkylNkR m R, -NR m

-C

1 6 alkyI0R', or -(CH 2 )nRc;

R

9 is independently, at each instance, H, C 1 9 alkyl, CI-4haloalkyi, halo, nitro, cyano, -0C 1 6 alkyl, -0-C 1 4 haloalkyl, -0-C 1 6 alkylNR m

R

m

-O-C

1 6 alkylOR', -NR m

R

m

-NR

m

-C

1 4 haloalkyl, -NR m

-C

1 6alkylNR m R' or

-NR

m

-C

1 6 ,alkylOR m Y is NH; and Z is CR 8orN; or R' is R 2 IS C 1 6 alkyl substituted by 1, 2 or 3 substituents selected from

C

1 4 haloalkyl, halo, cyano, nitro, -C(=0)OR n, -C(=0)NR m

R',

-C(=NRm)NRn m

R

m

-OR

m -OC(=0)NR m

R

m -OC(=0)N(Rm)S(=0) 2

-OC

2 6 alkylNR m

R

m

-OC

2 6 alkylOR m

-SR

m -S 2 -S 2

NR

m

R

m -s 2

N(R

m 2

N(R

m -S 2

N(R

m )C(=0)NR'R m

-NR

m

-N(R

m -N(R')C(=0)NR m

-N(R

m

)C(=NR

m

)NR

m 2

R',

-N(R

m 2 NRm~Rrn, -NR m

C

2 -6alkyNR m

R

m or -NR m

C

2 6 alkylOR m or R 2 is q) 2 0 ,phenyl, wherein the phenyl is substituted by 0, 1, 2 or 3 substituents independently selected from C 1 .salkyl, C 1 4 haloalkyl, halo, cyano, nitro, n, -C(=O)NR m

-C(=NR

m

)NR

m

-OR'

m -OC(=0)NR m

R

m

-OC(=O)N(R

m )S 2

-OC

2 6 al kyl NR m

R',

-0C 2 6 alkylOR m

-SR'

m 2 2

NR-R

m 2 2

N(R

m )C(=O)OR n, 2

N(R

m

)C(=O)NR

m

R

m

-NR'R

m

-N(R

m n, -N(R m

-N(R

m )C(=0)NR m

R

m

-N(R

m

)C(=NR

m

)NR

m

R

m

-N(R

m 2

-N(R

m 2

NR

m

R

m

-NR

m

C

2 6 aI kylNR m

-NR'C

2 6 alkylOR', -C(=O)ORs, 169 -C(=O)NRnR', -C(=NRn)NRnR', .OC(=O)Rs, -OC(=O)NRnR',

-OC(=O)N(R

m )S 2 Rs, -OC 2 6 alkylNRnRs, -OC 2 6 al kylORs, -SRs, -S(=O)Rs, -S 2 2 NRnRs, -S 2

N(R

m -S 2

N(R

m )C(=O)0R 5 2

N(R

m

)C(=O)NR

m

-NR

m -N(Rm)C(=O)Rs, -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRnRs, -N(R m

)C(=NR

m

)NR

m

-N(R

t 2 Rs,

-N(R

m )S 2 NRnRS, -NR m

C

2 6 aIkyiNR m RS, -NR m

C

2 6 alkylORs and C 1 4 alkyl subsituted by I or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro,

-C(=O)NR

m

-C(=NR

m

)NR

m

R

m

-OR

m

-OC(=O)R,

-OC(=O)NR

m

R

m

-OC(=O)N(R

m 2

-OC

2 6 alky]NR"'R m

-OC

26 alkylOR', -S R m n, -S 2 -S 2

NR

m -s 2

N(R

m -s 2

N(R

m -S 2

N(R

m

)C(=O)NR

m

-NR

m

R

m

-N(R

m

-N(R

m )C(=O)OR n, -N(R m

)C(=O)NR

m

R

m

-N(R

m

)C(=NR

m

)NR

m

R

m

-N(R

m 2 R n, -N(R m 2

NR

m

R

m

-NR

m

C

2 6 aI ky]NR m -C(=O)0R 5

-C(=O)NR

m Rs, -C(=NR m

)NR

m

R',

-ORs, -OC(=O)Rs, -OC(=O)NR-Rs, -OC(=O)N(R m 2

-OC

2 6 alkylNRnR',

-OC

2 .(alkylOR', 2 Rs, 2

NR

m

R',

2

N(R

m 2 N(Rr)C(0O)ORs, 2 N(Rrn)C(=O)NRnR', -NRrnRs, -N(R m

-N(R

m )C(=O)0R 5

-N(R

m

)C(=O)NR

m

R',

-N(R

m

)C(=NR

m )NR"Rs, -N(Rm)S(=O) 2 Rs, -N(R m 2 NRnRs,

-NR

M

C

2 6 alkyINR m Rs, -NR m

C

2 6 alky]OR 5 and -NR m

C

2 -6alkylOR'; or R 2is q) 2 wherein R' is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, 0 and S, wherein no more than 2 of the ring members are 0 or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from C 1 8 alkyl, C 1 4 haloalkyl, halo, cyano, nitro, -C(=O)NRmRn, -C(=NR m

)NR

m

R

m

-OR

m

-OC(=O)NR-

m rl, -0C(=O)N(R m 2

-OC

2 6 alkyINR R m

-OC

2 6 alkylOR m

-SR'

m 2 R n, 2

NR

m

R

m 2

N(R

m 2

N(R

m 2

N(R

m

)C(=O)NR

m

R

m

-TNR

m nRn, -N(R m n, -N(R m

-N(R

m

)C(=O)NR

m

-N(R

m

)C(=NR

m )NR R'11, -N(R m 2 R

-N(R

m 2

NR

m

R

m -NRm~C 2 6 a~kyl NRm"R m

-NR

m

C

2 6 a1 kylOR m -170- -C(=O)ORs, -C(=O)NRnR', -C(=NRn)NRnR', .OC(0O)Rs, -OC(=O)NRnRs, 2

-OC

2 6 al kylNRnRs, -OC 2 6 al kyl ORS, -S 2 -S(=O),NRrnR', 2 N(Rrn)C(=O)Rs, -S 2

N(R

m )C(=O)0Rs, 2 N(RrI)C(=O)NRnR', -NRrnRs, -N(Rrn)C(=O)Rs, N(Rm)C(=O)ORs, -N(R m

)C(=O)NR

m -N(Rrn)C(=NRn)NRnR', -N(Rrn)S(=O) 2

-N(R

m 2

NR

m Rs, NRnC 2 -akyl4RnRs -NR m

C

2 6 a1 kylORs and C 1 4 alkyl substituted by 1 or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=O)NR m

R

m -C(=NRm)NR m

R

m

-OR

m

-OC(=O)NR

m

-OC(=O)N(R

m )S 2

-OC

2 6 alkyNR m

R

m

-OC

2 -6alkylOR m 2 2

NR-R-,(

-s 2

N(R

m 2

N(R

m -S 2

N(R"')C(=O)NR

m

R

m

-N-R

m

R

m

-N(R

m

-N(R

m

-N(R

m

)C(=O)NR

m

R

m -N(Rrn)C(=NRn)NRmRr, -N(R m 2 R n, -N(R m )S 2

NR

m

R

m

-NR

m

C

2 ,calkylNR m

R

m -C(0)Rs, -C(=O)NR m

-C(=NR

m

)NR

m

R',

-ORs, -OC(=O)NR m

-OC(=O)N(R

m 2

-OC

2 6 alkylNR m Rs,

-OC

26 alkylORs, -SRs S(=O) 2 Rs, 2 NRnR', 2

N(R

m 2

N(R

m )C(=O)0Rs, 2

N(R

m

)C(=O)NR

m

R',

-NR

m Rs, -N(Rrn)C(=O)ORs, -N(R m

)C(=O)NR

m

R',

-N(R

m

)C(=NR

m

)NR

m

-N(R

m )S 2 -N(Rrn)S(=O) 2 NRrnRs,

-NR

M

C

2 6 alkyNR m Rs, -NR

M

C

2 .cialkyIOR 5 and -NR m

C

2 6 alkylOR'; R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturat~ed or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C 1 8 alkyI,

C

14 haloalkyl, halo, cyano, nitro,

-C(=NR

m

)NR

m -OR n, -OC(=O)NR'R',

-OC(=O)N(R

m 2 R n, -0C 2 6 a1 kyINR m -0C 2 6 alkylOR', -SR' m 2 R 2

NR

m 2

N(R

m 2

N(R

m )C(=O)0R 2

N(R

m

)C(=O)NR

m

-NR

m

-N(R

m -N(Rrn)C(=0)NR m m )NRm"R m

-N(R

m 2 R 171

-N(R

m )S 2 NR'R', -NR m

C

2 6 al kyl NR R m

-NR"C

2 6 aIkylOR m -C(=0)ORs, -C(=0)NRnR', -C(=NRrn)NRrnR', .0C(=o)Rs -OC(=O)NR'nR', -OC(=O)N(R m )S 2 -0C 2 6 al kylNRmrRs, -0C 2 6 alkyl0Rs, -SRs, 2 2 NjjRnR' 2 N(Rrn)C(=0)R', -S 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=O)NRnRs, .NRrnRS, -N(Rrn)C(=O)Rs, -N(Rrn)C(=O)ORS, -N(Rrn)C(=0)NRnRs, -N(Rrn)C(=NRrn)NRnRs, -N(Rrn)S(=O) 2 N(Rrn)S(=O) 2 NRnRs, -NR

M

C

2 -6alkylNRrnRs, -NRC 2 6 al kylORs and C,.

4 alkyl substituted by I or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=O)NRmRm, -C(=NR m

)NR

m

R

m

-OR

m n, -OC(=O)NR-R m

-OC(=O)N(R

m 2

-OC

2 6 alkyNR m

R

m -0C 2 6 alkylOR', 2 2

NR

m

R

m -S 2

N(R

m n, 2

N(R

m )C(=O)OR n, 2 N(Rm~)C(=O)NR m

R

m

-NR

m

R

m

-N(R

m

-N(R

m

)C(=O)NR

m

R

m

-N(R

m )C(=NRm)NR m Rm, -N(Rm

T

)S 2

-N(R

m 2

NR

m

R

m

-NR

m

C

2 6 alkylNR-R m -C(=0)ORs, -C(=NRn)NRnR, -ORs, OC(=O)Rs, -OC(=O)NRnRs, -OC(=O)N(Rrn)S(=O) 2

-OC

26 alkylTRrnR',

-OC

26 alky1OR', -SRs, 2 2 NRrnR', 2 N(Rrn)C(=O)Rs, 2 N(Rr)C(=0)0Rs, 2

N(R

m )C(=O)NRnRs, -NRrnR', -N(Rrn)C(=O)Rs, -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRnR', -N(Rrn)C(=NRrn)NRnR', -N(Rrn)S(=O) 2 Rs, -N(Rrn)S(=0) 2 NRnR', -NRrnC 2 -6alkylNRrnRs, -NR m

C

2 6 alkyIORs and -NR m

C

2 -6alkyl0R', and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups; R 7 is C 2 -8alkyl, Cl- 5 haloalkyl, I, Br;

R

9 is independently, at each instance, Cl- 9 alkyl, C 14 haloalkyl, halo, nitro, cyano, -OCI 16 alkyl, -O-C 14 haloalkyl, -O-C 1 6 alkyNR m

R',

-0-C 1 6 al kylOR m

-NR

m

-NR

m

-C

1 4 haloal kyl, -NR m

-C

1 6 alkylNR m R' or

-NR

m

-C

1 6 a1 kyl0Rm; Y is NH; and Z is CR 8 or N; or R' is 172 R 2 is H, -OR m Cl, C 1 3 haloalkyl or C 1 6 alkyI; R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S, so long as the combination of 0 and S atoms is not greater than 1, wherein the ing is substituted by 0, 1, 2 or 3 substituents independently selected from C 1 .8alkyl, C 1 4 haloalkyI, halo, cyano, nitro,

-C(=O)NR

m

-C(=NR

m

)NR

m

R

m -ORfl, -OC(=O)NR m 2

-OC

2 6 alkylOR"', -S -S 2

R,

-S 2

NR

m 2

N(R

m 2

N(R

m 2

N(R

m -NRm

T

R

m

-N(R

m

-N(R

m

)C(=O)OR,

-N(R

m

)C(=O)NR"'R

m -N (R m

)C(=NR

m

)NR

m

R

m

-N(R

m )S 2 R

-N(R

m )S 2

NR

m

R

m

-NR

m

C

2 6 alkyl NR m

R

m -NR

M

C

2 6 aIkylOR', -C(=O)ORs, -C(=O)NRnR', -C(=NRm)NRmlRs, OR', .OC(0)R -OC(=O)NRnR', -OC(=O)N(R m )S 2 Rs, -OC 2 6 al kylNRrnRs, -OC 26 alkyIOR', 2 Rs, 2 NRnRs 2 N(Rm)C(=O)Rs, 2 N(Rm~)C(=O)NRnR', NRrnRs -N -N(RuI)C(=O)ORs, N(Rr)C(=O)N41mrn, -N(Rrn)C(=NRrn)NRn"R',

-N(R

m )S 2 Rs, -N(R m )S 2 NRnRS, -NR m

C

2 -6alkylNR m -NRnC 2 6alkylOR' and C 1 -4alkyl substituted by 1 or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=O)NR m

R

m -C(=NR"')Nk m

R

m

-OR

m

-OC(=O)NR

m

-OC(=O)N(R

m 2

-OC

2 6 alkylNR m

-OC

26 al kylOR m -SRWn, n, 2 2

NR

m 2

N(R

m -S 2

N(R

m 2 N(Rm)C(=O)NRmRm, -NR

T

"R

m

-N(R

m

-N(R

m

)C(=O)NR

m

R

m

-N(R

m

)C(=NR

m

)NR

m

-N(R

m )S 2 -N(Rm)S(=O) 2

NR

m

R

m

-NR

m

C

2 6 alkylNR m

R

m -C(=O)ORs, R'R, -C(=NR-l)NRrmRs, -ORs, -OC(=O)Rs, -OC(=O)NRmRs, 2

-OC

2 6 alkylNRnR', -0C 2 6 alkylOR', 2 Rs, 2 NRrnR', 173- 2 N(Rm)C(=O)R, 2 N(Rm)C(=O)ORs, 2 N(Rm)C(=O)NRmR

S

-NRmRs, -N(Rm)C(=O)R s -N(Rm)C(=O)OR

S

-N(Rm)C(=O)NRmRs, -N(Rm)C(=NRm)NRmRs, -N(Rm)S(=0) 2

R

S

-N(R

m 2 NRmR

S

-NR

m

C

2 6 alkylNRmR

S

-NR

m

C

2 -6alkylORs and -NR m

C

2 -6alkylOR m wherein R 4 is 0 5 not unsubstituted phenyl;

R

7 is C2-6alkyl, Ci.shaloalkyl, I or Br; n R 9 is independently, at each instance, H, Cl_9alkyl, C-.

4 haloalkyl, halo, nitro, cyano, -OCI.

6 alkyl, -O-C 1 4 haloalkyl, -O-CI.

6 alkylNR m

R',

S-O-C-6alkylOR m

-NR

m

R

m

-NR

m -C-4haloalkyl, -NR m

-CI.

6 alkylNR m

R

m or -NR"-Ci 6 alkylOR m Y is NH; and Z is CR 8 or N.

Another aspect of the invention involves a pharmaceutical composition comprising a compound according to any of the above embodiments and a pharmaceutically-acceptable diluent or carrier.

Another aspect of the invention involves the use of any of the above compound embodiments as a medicament.

Another aspect of the invention relates to the use of a compound according the any one of the above embodiments in the manufacture of a medicament for the treatment of acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, bums, allergic skin reactions, pruritis, vitiligo, general gastrointestinal disorders, gastric ulceration, -174duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders.

Another aspect of the invention relates to the manufacture of a medicament for the treatment of acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and nonvascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritis, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders, wherein the medicament contains a compound having the structure:

R

3 RYY R4

R

2

X

wherein: X is O, S or NR m n is independently, at each instance, 0, 1 or 2; o is independently, at each instance, 0, 1, 2 or 3; Rm is independently at each instance H or R"; R" is independently at each instance Ci-.alkyl, phenyl or benzyl; R' is independently in each instance H, CI.

4 alkyl, Ci- 4 haloalkyl, halo, cyano, nitro, -C(=0)NR m

R

m -C(=NRm)NR m

R

m

-OR

m

-OC(=O)NR

m

R

m

-OC(=O)N(R

m 2 -OC2.

6 alkylNR m

R

m -OC26alkylOR'", 2 2

NRR

m 2

N(R

m )C(=0)R n 2

N(R

m )C(=0)OR n 2

N(R

m

)C(=O)NR

m

R

m 175

-NR

t

-N(R

m

-N(R

m )C(=0)NR m

R',

-N(R

m )C(=NRn m

)NR

M

R

m

-N(R

m 2 Rn, -N(R m )S 2 NRnR',

-NR

m

C

26 alkylNR m

R

m or -NR m

C

2 6 alkylOR m R' is R' substituted by 0, 1, 2 or 3 substituents independently selected from R q; R 3 is H or CI- 4 alkyl; R 5 is H, Cl-galkyl, G 1 4 haloalkyl, halo, nitro, cyano, -0CI-alkyl, -0C 1 4 haloalkyl, -0-C 1 6 alkyINR m -0-C 1 6 alkylOR m

-NR

m

R

m

-NR

m -Cl 4 ha1 oal kyl, -N R m

-C

1 6alkylNR m

-NR

m

-C

1 6 a1 kylOR m or -(CH 2 )nRc R 6 is, independently at each instance, H, Cl- 9 alkyl, CI.

4 haloalkyl, halo, nitro, cyano, -0CI.

6 alkyl, -0-C 1 4haloalkyl, -0-C 1 6 alkylN R m

R',

-O-C

1 -6alkyl0R', -NR m

-NR

m

-CI-

4 haloalkyl, -NR m

-C

1 6 alkylNR m R' or

-NR

m

-C

1 6 al kylOR m R 8 is H, Cl- 9 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -0C 1 -,alkyl, -0-C 1 4 haloalkyl, -0-C 1 6 alkylNR m

R

m -0-C 1 6 aIkylOR m

-NR

m

R

m

-NW-C

14 haloalkyl, -NR m

-C

1 6 alkylNR m R' or -NR m

-C

1 6 alkylOR m and R' is

R

7

R

(CR R )ORO R 2 is H, -OR m halo, C 1 3 haloalkyl or C 1 -6alkyl; R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ing and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from CI-8alkyl,

CI-

4 haloalkyl, halo, cyano, nitro, n, -C(=0)0R n, -C(=0)NR m

R

m

-C(=NR

m

)NR

m

R

m

-OR'

m -OC(=0)R -OC(=0)NR m

R,

-0C(=0)N(R m 2 -0C 2 6 alkylNR m

R

m -0C 2 6 a1 kylOR m

-SR

m -S(=0)Rn, 176 2 -S 2

NR

m -S 2

N(R

m 2

N(R

m 2

N(R

M

)C(=0)NR m

R

m

-NR

m

R

m

-N(R

m

-N(R

M

)C(=0)OR, -N(R')C(=0)NR m

R

m

-N(R

m

)C(=NR

m

)NR

m

R

m 2 R

-N(R

M

2

NR

m

-NR

M

C

2 6 alkyI NR m

-NR

m

C

2 _6alkyIOR m -C(=0)0Rs, -C(=0)NRnRS, -C(=NRn)NRrnRS, .ORs, .OC(=O)NRnRS, .0C(=0)N(Rn)S(=0) 2 Rs, -0C 2 6 akyNRnRS, -0C 2 6 -S 2 Rs, 2 NRnR', 2 N(Rrn)C(=0)Rs, 2 N(Rr)C(=0)0Rs, -S 2 N(Rrn)C(=0)NRnRs, -NRrnRS, -N(Rr)C(=0)Rs, -N(Rr)C(=0)0Rs, -N(Rr)C(=0)rNRsR' -N(Rrn)C(=NRn)NRnRs, -N(Rrn)S(=0) 2 -N(Rrn)S(=0) 2 NRnRs, -NRrnC2 6 alkyINRrnR', -NRrnC 2 and C,- 4 alkyl substituted by I or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=O)NRnRl -C(=NR m

)NR

m

R

m

-OR'

m -OC(=0)NRm'R m 2 R n, -OC 2 6 alkylNR m

R-,

-OC

26 alkyIOR m 2 2 NR'R 2 2

N(R

m )C(=O)0Rn, 2

N(R

m

)C(=O)NR

m

R

m

-NR

m

-N(R

m -N(Rm)C(=O)OR n, -N(R m

)C(=O)NR

m

R

m

-N(R

m

)C(=NR

m

)NR

m

-N(R

m )S 2 -N(Rm)S 2

NR

m

R

m

-NR

m

C

2 6 alkylNR m

R

m -C(=O)0Rs, -C(0)NRRs, -C(=NRn)NRnRs, .0Rs, -0C(=0)Rs, -OC(0)NRnRs, -0C(=O)N(Rrn)S@=0) 2 Rs, -0C 2 6 alkyINRnRs,

-OC

2 6 alkyl0R', 2 Rs, 2 NRnR', 2 N(Rrn)C(=O)Rs, 2 N(Rr)C(=0)ORs, 2 N(Rrn)C(=O)NRnRs, -NRrnRs, -N(Rr)C(=0)Rs, -N(Rr)C(=0)0Rs, -N(Rnl)C(=O)NRnR', -N(Rrn)C(=NRn)NRrnR', -N(R m )S 2 Rs, -N(R m )S 2 NRnRs, -NRnC 2 6 alkylNRnRs, -NRrnC 2 6 alkyI0Rs and -NR m

C

2 6 alkyl0R'; and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups; R 7 is C 1 9 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -OCIcsalkyl, -0-C 4 haloal kyl, -0-C 1 6 alkylNR m

R

m -0-C 16 alkyl OR m

-NR

m

R

m

-NR

m

-C

1 4 haloaI kyl, -NR m -C 16 alkylNR m R' or -NR m

-C

1 6alkyl0R m R' is a saturated, partial ly-saturated or unsaturated 6- or 7-membered monocyclic or 10- or I 1-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, 0 and S, so long as the combination of 0 and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0, 1 or 177 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from RI; RP is independently at each instance CI-8alkyl, C 1 4 haloalkyl, halo, cyano, nitro, -C(=O)NRnR, -C(=NR m

-OR

m

-OC(=O)NR

m

-OC(=O)N(R

m 2

-OC

2 6 alkyl NR m

R',

-OC.

6 alkylOR m 2 R n, 2

NR

m

R',

-S 2

N(R

m 2

N(R

m )C(=O)OR n, -s 2

N(R

m

)C(=O)NR

m

R',

-NM

m

R

m

-N(R

m n, -N(R m )C(=O)OR n, -N(R m

)C(=O)NR

m

R

m

-N(R

m

)C(=NR

m

)NR

m

R

m

-N(R

m 2 -N(Rm)S 2

NR

m

R',

-NR

m

C

26 alkylNR m

R

m or -NR n'C 2 6 alky]OR'; and Y is 0 or NH; or R' is R 7R 5 R 7 N R (CRqRq )ORO or (CRqRq )ORO R 2 is H, -OR' m halo, C 1 3 haloalkyl or C 1 6 alkyl; R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from CI-salkyl, Cl.4haloalkyl, halo, cyano, nitro, -C(=0)NR m

R

m

-C(=NR

m

)NR

m

-OR

m

-OC(=O)NR

m R -OC(=0)N(R m 2

-OC

2 6 alkylNR m

-OC

26 alkylOR', 2 2

NR

m

R

m 2

N(R

m 2

N(R

m 2

N(R

m

)C(=O)NR

m Rm

T

-NR

m

R

m

-N(R

m n, -N(R m

-N(R')C(=O)NR

m

R

m

-N(R

m

)C(=NR

m

)NR

m

-N(R

m 2 R

-N(R

m 2

NR

m

-NR

m

C

2 6 alkylNR m

R

m

-NR

m

C

2 6 aI kylOR m -C(=O)Rs, -C(=0)ORs, -C(=O)NRmRs, -C(=NRrn)NRnRs, .OC(0)Rs, -178 -0C(=0)NRnR', -OC(0)N(Rn)S(O) 2

-OC

2 6 alkylNRrnR', -0C 2 6 a1 kylORs, -SRs, -S 2 RS, -S 2 NRnR', 2 N(Rrn)C(=0)Rs, 2 N(Rr)C(=0)0Rs, 2 N(Rrn)C(=0)NRnR', NRrnRS -N(Rr)C(=0)Rs, -N(Rrn)C(0)N{IRrn -N(Rml)C(=NRn)NRnRS

-N(R

m )S 2 Rs, -N(Rrn)S(=0) 2 NRnR', -4R

M

C

26 al kylNRnRs, -NR m

C

2 6 a1 kylORs and C 1 4 alkyI substituted by 1 or 2 groups selected from CI.

2 haloalkyl, halo, cyano, nitro, -C(=0)NR m

R

m

-C(=NR

m

)NR

m

R

m

-OR

m

-OC(=O)NR

m

R

m

-OC(=O)N(R

m 2 -0C 2 6 alkylNR m

R',

-0C 2 6 a1 kylOR m

-SR

m -S 2 -S 2 NRmR', 2 -S 2

N(R

m 2

N(R

m

)C(=O)NR

m

R

m -NRm~Rrn, -N(R m

-N(R

m

)C(=O)NR

m

R

m

-N(R

m

)C(=NR

m

)NR

m

R

m

-N(R

m 2 R n, -N(R m )S 2

NR

m

R

m

-NR

m

C

2 6 alkylNR m -C(=0)ORs, -C(=OlN4R m

-C(=NR

m

)NR

m Rs, -ORs, -OC(=O)Rs, .OC(=O)NR m Rs, -OC(=O)N(R m 2 Rs, -0C 2 6 alkylNRnRs,

-OC

2 6 alkylOR', S(O) 2 2

NR

m Rs, -S 2

N(R

m -s 2 N(Rrn)C(=O)ORS, -S 2

N(R

m

)C(=O)NR

m Rs,

-NR

m Rs, -N(R m

-N(R

m )C(=O)0Rs, -NR)(ON''

-N(R

m

)C(=NR

m

)NR

m

-N(R

m 2

-N(R

m )S 2

NR

m

R',

-NR

M

C

2 6 alkylNR m

-NR

M

C

2 6 alkylOR' and -NR

M

C

2 6 alkylOR m and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups; R 7 is C 19 galkyl, C 1 4 haloalkyl, halo, nitro, cyano, -OCI.Galkyl,

-O-C

1 ~haloalkyl, 6 alkylNR m 6 alkyIOR', -NR m

R',

-NR

m

-C

1 4 haloalkyl, -NR m 6 al kylNR m R' or -NR m 6 a1 kylOR m R' is a saturated, parti alIly- saturated or unsaturated 6- or 7-membered monocyclic or 10- or IlI-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, 0 and S, so long as the combination of 0 and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from RP; RP is independently at each instance C,.salkyl, CI- 4 haloalkyl, halo, cyano, nitro, -C(=O)0R n' -C(=0)NR m

-C(=NR

m

)NR

m

-OR-

m -OC(=0)NR m R, -0C(=0)N(R m 2 -0C 26 al kylNR m

R

m 179-

-OC

2 6 alkyIOR', -SR m 2 Rn, -S(=O),NR m

R

m 2

N(R

m -S 2 N(Rm~)C(=O)OR n, 2

N(R

m

)C(=O)NR

m

R

m

-NR

m

R

m

-N(R

m

-N(R

m )C(=O)ORn, -N(R m

)C(=O)NR

m

R

m -N(Rrn)C(=NRn)NRmlRn, -N(R m )S 2 Rn, 2

NR

m

R',

-NR

m

C

2 6 alkyINR m

R

m or -NR m

C

2 6 alkylOR'; and Y is 0 or NH; or R' is

R

6 R 2is H, -OR m halo, C 1 3 haloalkyl or C 1 6 alkyl; R 4 is a saturated, partially-saturated or unsaturated 10 or 1 1-membered bicyclic heterocycle containing 1, 2, 3, 4 or 5 atoms selected from 0, N and S, so long as the combination of 0 and S atoms is not greater than 2, but excluding quinol in-6-yl, 4,5 ,6,7-tetrahydro-benzollb]thiophen-2-yl, benzothiazol- 2-yl, 2,3-dihydro-benzo[1,4]dioxin-6-yl, wherein the heterocycle is substituted by 0, 1, 2 or 3 substituents independently selected from C 19 galkyl, oxo, C 14 haloalkyl, halo, nitro, cyano, -OR m 1 6 alkyl, -0-C 1 4haloalkyl, -0-C 1 6 a~kylNR m

R',

-0-C 1 6 alkylOR', -NR m

-NR

m

-C

1 4 haloalkyl, -NR m

-C

1 6 alkylNR m

R

m

-NR

m

-C

1 6 alkyl0R'~, -C(=O)C 1 6 alkyl, -OC(=O)Cz.

6 alkyl, -C(=O)NR'C.

6 a1 kyl,

-NR

m

C(=O)C

1 6 alkyl -C(=O)ORs, -C(=O)NRnRs, -C(=NRn)NRnRs, .OC(=O)NRnRs, -OC(=0)N(Rrn)S(=0) 2 Rs, -OC 26 alkylNRnRs,

-OC

2 6 alkylORs, -S -S 2 Rs, 2 NRrnR', 2 N(Rrn)C(=O)R', 2 N(Rrn)C(=O)ORs, -S 2 N(Rrn)C(=O)NR'Rs, -NRrnR', -N(Rrn)C(=O)Rs, -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRnR', -N(Rrn)C(=NRn)NRnRs, 2 -N(Rrn)S(=O) 2 NRnRs, -NRnC 26 alkylNRnRs, -NR m

C

26 alkylORs and C 14 alkyl substituted by 1 or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=O)NRmRm,

-C(=NR')NR

m

-OR'

m

-OC(=O)NR

m

-OC(=O)N(R

m 2

-OC

2 6 alkylNR m

R

m

-OC

26 al kyIOR m

-SR

m 180- 2 2

NR

m 2

N(R

m 2

N(R

m -S 2

N(R

m

)C(=O)NR

m

-N(R

m

-N(R

m

)C(=O)NR

m

-N(R

m

)C(=NR

m

)NR

m

-N(R

m )S 2

R',

-N(R

m 2

NR

m -C(=O)ORs, -C(=O)NRrnRs, -C(=NRm)NRlRs, -ORs, .0C(=O)Rs, .OC(=o)NRnRs, -OC(=O)N(Rrn)S(=O) 2

-OC

2 6 alkylNRnRs,

-OC

2 6 alkylORs, -S(0)Rs, 2 2 PRRs, -S 2 N(Rrn)C(=O)RS, 2 N(Rrn)C(=O)ORs, -S 2 N(Rrn)C(=O)NRnR', r- NRrnR', .N(Rr)C(0O)OR, -N(Rmr)C(=O)NRnRs, -N(Rrn)C(=NRrn)NRnRs, -N(R m )S 2 Rs, -N(Rrn)S(=O) 2 NRnR',

-NR

m

C

2 6 alkylNRnRs, -NRrnC 2 6 alkylORS and -NR m

C

2 6 alkylOR m wherein R 4is not 2-aminocarbonylmethyi-2,3-dihydro-benzo[1I,4]dioxin-8-yl, 2-cyanomethyl- 2,3-dihydro-benzo[ 1,4]dioxin-8-yl, quinolin-3-yl, 3H-quinazolin-4-on-3-yl, benzo[ 1,3]dioxol-5-yl, 3,3-dimethyl- 1,3-dihydro-indol-2-on-6-yl or 4,4-dimethyl- 3,4-di hydro- 1H-quinolin-2-on-7-yl; R 7 is CI-8alkyl, Cl.

5 haloalkyl, I or Br

R

9 is H, C 1 9 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -OCI 1 6 alkyl, -O-CI- 4 haloalkyl, -0-C 1 6 alkylNR m -0-C 6 alkylORn, -NR m

-NR

m

-C

1 4 haloalkyl,

-NR

m

-C

1 6 alkylNR m

-NR

m

-C

1 6 alky]OR', or -(CH 2 ),nRc;

R

9 is independently, at each instance, H, C1.

9 alkyI, CI.

4 haloalkyl, halo, nitro, cyano, -0C 1 6 alkyl, -0-C 1 4 haloalkyl, -0-C 1 6 alkylNR m

R',

-0-C 1 6 a1 kylOR m

-NR

m R -NR m

-C

1 4 haloalkyl, -NR m

-C

1 6 alkylNR m

R

m or

-NR

m

-C

1 6 alkyIOR'; Y is NH; and Z is CR 8orN; or

R

1 is R 2is CI- 6 alky1 substituted by 1, 2 or 3 substituents selected from 181

C

1 -4haloalkyl, halo, cyano, nitro, -C(=O)NR m

R',

-C(=NR

m

)NR

m

-OR-

m

-OC(=O)NR

m

R,

-OC(=O)N(R

m 2 -0C 2 6 alkylNR m

-OC

2 6 alkylOR m -S 2 2

NR

m -S 2

N(R

m 2 N(Rm)C(=O)OR~, 2

N(R

m

)C(=O)NR

m

-NR

m

R

m

-N(R

m

-N(R

m

)C(=O)OR,

-N(R

m

)C(=O)NR

m

R

m

-N(R

m

)C(=NR

m

)NR

m

-N(R

m 2

R',

-N(R

m 2

NR

m

-NR

m

C

2 -6alkyINR m

R

m or -NR m

C

2 6 a1 kyl OR m or R 2 is q) 2 0 phenyl, wherein the phenyl is substituted by 0, 1, 2 or 3 substituents independently selected from C 1 .galkyI, C 1 4 haloalkyl, halo, cyano, nitro, n, -C(=O)NR m

R

m

-C(=NR

m

)NR

m

R

m

-OW",

-OC(=O)R n, -OC(=O)NR m R, -OC(=O)N(R m 2 -0C 2 6 alkyl NR"'R m

-OC

26 akylOR m 2 R n, 2

NR

m

R

m -S 2

N(R

m 2

N(R

tm 2

N(R

m

)C(=O)NRR

m

-NR

m

R

m

-N(R

tm n, -N(R m

)C(=O)NR

m

R

m

-N(R-)C(=NR

m

)NR

m

R

m

-N(R

m 2 R n, -N(R m 2 NRm'R,

-NR

m

C

2 6 alkyNR m

-NR

m

C

2 6 alkylOR m -C(=O)ORs, -C(=O)NRmRs, -C(=NRrn)NRrnR', -ORs, -OC(=O)NR m

R',

-OC(=O)N(Rn)S(=O) 2 Rs, _OC 2 6 alkylNRnRs, -OC 2 6 alkylORs, SRs, -S 2 Rs, 2 NRnRS 2 2 N(Rrn)C(=O)ORs, -S 2 N(Rrn)C(=O)NRnRs, -NRrnRs, -N(Rrn)C(=O)Rs, -N(Rr)C(0)ORs, -N(Rrn)C(=O)NRnR', -N(Rrn)C(=NRrn)NRnRs, -N(Rrn)S(=O) 2 Rs,

-N(R

m )S 2 NRnRs, -NRm~C 26 alkylNRrnR', -NR

M

C

2 6 a1 kyl ORs and C 14 alkyl substituted by I or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, n, -C(=O)OR n, -C(=O)NR m

-C(=NR

m

)NR

m

R

m

-OR

m

-OC(=O)NR"'R

m 2

-OC

2 6 akyNRR m

-OC

2 6 alkylOR"', 2 2

NR

m

R

m 2 2 n, 2

-N(R

m

-N(R

m -N(Rrn)C(=O)NRnRn,

-N(R

m

)C(=NR"')NR

m

-N(R

m 2

-N(R

m 2

NR"'R

m

-NR

m

C

2 .GalkylNR m -C(=O)0Rs, -C(0)NR m

-C(=NR

m

)NW"R',

-OC(=O)Rs, -OC(=O)NR m 2 Rs, -OC2.

6 alkyNR m Rs,

-OC

26 alkylOR', 2 2

NR'R',

182 2 N(Rrn)C(=O)R', 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=O)NRnR', -N~RnR', -N(Rrn)C(=O)ORs. -N(Rrn)C(=O)NRnRs, -N(Rrn)C(=NRrn)NRnRs, -N(Rrn)S(=O) 2 -N(Rrn)S(=Oh2NRnR', -NRrnC 2 -(alkylNR m -NRrnC 2 6 alkylORs and -NR m

C

2 6 alkylOR'; or R 2 is 2.r wherein is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, 0 and S, wherein no more than 2 of the ring members are 0 or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from C 1 8 alkyl, C 1 4 haloalkyl, halo, cyano, nitro, -C(=0)NR m

-C(=NR"')NR

m

R

m

-OR'

m -OC(=O)R n, -OC(=O)NR m

R

m

-OC(=O)N(R

m 2

-OC

2 6 alkylNR m

-OC

2 6 alkylOR m

-SR

m 2 R 2

NR

m

R

m 2

N(R

m 2 N(Rm)C(=O)OR, 2

N(R')C(=O)NR

m

R

m

-NR

m

R

m

-N(R

m -N(Rrm)C(=O)ORn

-N(R

m

)C(=O)NR

m

R

m -N (R m )C(=NRn)NR m

R

m -N(Rm 1 )S 2

R',

-N(R

m 2

NR

m

-NR

M

C

2 6 alkylNR m

-NR

m

C

2 6 alkylOR', -C(=O)Rs, C(=O)ORs, C(=O)NRnRs, C(=NRrn)NRrnRs, OR' -0C(=0)NRnR', 2 Rs, -0C 2 -(alkylNR m Rs, oc 2 6 alkyloRs, SRs, 2 2 NRnR', 2 N(Rm)C(=O)Rs, -S 2 N(Rrn)C(=O)ORS, 2 N(Rrn)C(=O)NRnRs, -NRmfRs, -N(Rrn)C(=O)Rs, -N(Rml)C(=O)ORs, -N(Rrn)C(=O)NRnRs, -N(Rm)C(=NR')NRnRs, -N(Rrn)S(=O) 2 -N(Rrn)S(=O) 2 NRnRs, .IN'

M

C

26 al kylNRrnRs, -NR

M

C

2 6 a1 kylOR' and C 14 alkyI substituted by 1 or 2 groups selected from C 1 2 haloalkyI, halo, cyano, nitro, -C(=O)NR m Rml, -C(=NR m

)NR

m

R

m

-OR

m

-OC(=O)R

0 -OC(=O)NRmlR m

-OC(=O)N(R

m 2

-OC

2 6 alkylNR m

R

m

-OC

2 6 alkylOR m

-SR

m 2 2

NR

m Rml, 2

N(R

m 2 N(Rm 1 2

N(R

m

)C(=O)NR

m

R

m -NRnRr, -N(R m

-N(R

m

)C(=O)NR

m

R',

-N(R

m )C(=NR )NR m 2 2

NR

m

R",

-NR

m

C

2 6 alkylNR m

R

m -C(=O)ORs, -C(=O)NRnR', -C(=NRm 1

)NR

m

R',

OC(0)Rs -OC(=O)NRnRs, -OC(=O)N(R m 2 -0C2 6 alkylNRnRs,

-OC

2 6 alkylORs, SRs, 2 Rs, 2 NRrnRs, 183- -S 2 N(Rrn)C(=O)RS, -S 2 N(Rrn)C(=O)ORS, -s 2 N(Rn)C(=O)NRnR', n NRrnR', -N(Rr)C(=O)ORs, -N(Rrn)C(=O)NRnR', -N(Rrn)C(=NRn)NRrnR', 2

-N(R

m )S 2 NRnRS,

-NR

m

C

2 6 al kylNRrnR', -NR m

C

2 6al kylORs and -NR m

C

2 6 aIkylOR m R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C 1 .salkyl,

C

14 haloalkyl, halo, cyano, nitro, -C(=0)NR m

R',

-C(=NR

m

)NR

m

-OR

m

-OC(=O)NR

m

R',

-OC(=O)N(R

m 2

-OC

26 alkyNR m

R

m

-OC

2 6 alkylOR', -SR m 2 2

NR

m

R

m 2 2

N(R

m 2

N(R

m

)C(=O)NR

m

-NR

m

-N(R

m

N(R

m

)C(=O)OR,

-N(R

m

)C(=O)NR

m

R

m

-N(R

tm

)C(=NR

m

)NR

m

-N(R

m 2 R

-N(R

m 2

NR

m

R

m

-NR

M

C

2 6 aI kyl NR m

R

m

-NR

M

C

2 6 alkylOR', -C(=O)0R 5

-C(=O)N

m

-C(=NR

m

)NR

m -OC(=O)Rs,

-OC(=O)NR

m

-OC(=O)N(R

m 2

-OC

26 alkyNR m

-OC

2 6 alky1ORs, -SRs, 2 Rs, 2

NR

m Rs, 2

N(R

m 2

N(R

m )C(=O)0Rs, 2

N(R

m

)C(=O)NR

m Rs, -NR m

-N(R

tm

-N(R

m

)C(=O)OR

5

-N(R

m

)C(=O)NR

m Rs, -N(R m

)C(=NR

m

)NR

m Rs,

-N(R

m 2 Rs, -N(R m 2

NR

m NRnC 2 6 alkyINRnRs, -NR m

C

2 6 alkylOR' and C 1 4 alkyl substituted by 1 or 2 groups selected from Ci.

2 haloalkyl, halo, cyano, nitro, -C(=O)NR m

R

m

-C(=NR

m

)NR

m

-OR

m

-OC(=O)NR

m

R

m

-OC(=O)N(R

m 2 R n, -OC 2 _6a1kyl NR m R'm,

-OC

26 alkylOR m

-SR

m 2 R n, 2

NR

m

R',

2 2 N(Rm

T

2

N(R

m

)C(=O)NR

m

R,

-NR

m

R

m

-N(R

m

-N(R

m

-N(R

m

)C(=O)NR

m

R

m

-N(R-)C(=NR

m

)NR

m

-N(R

m 2

-N(R

m 2

NR

m

R

m

-NR

M

C

2 6 aikylNR m

R

m -C(0)Rs, C(0)0R 5

-C(=O)NR

m Rs, -C(=NR m

)NR

m

R',

.0C(0)RS -OC(=O)NR m

-OC(=O)N(R

m 2 -0C 2 6 alkyINR m

R',

184-

-OC

26 alkylOR', -SRs, -S(O) 2 2 NRnRs, -S 2 N(Rrn)C(=0)RS, -S 2 N(Rrn)C(=0)ORs, -S(O) 2 N(R)C(=)N4RrnRs, -NRrnR', -N(Rr)C(=0)0Rs, -N(Rr)C(=0)NRnR', -N(Rrn)C(=NRn)NRrnRs, -N(Rrn)S(=0) 2 Rs, -N(Rrn)S(=0) 2 NRnRs, -NRnC 26 alkylNRnRs, -NRrnC 2 4 alkyl0Rs and -NR m

C

2 6 alkylOR', and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups; R 7 is C 2 8 alkyI, C 1 5 haloalkyl, I, Br;

R

9 is independently, at each instance, H, Cl- 9 alkyl, C 14 haloalkyI, halo, nitro, cyano, -0C 1 6 alkyI, -0-CI- 4 haloalkyl, -0-C 1 6 alkylNR m

R',

-0-C 1 6 alkyl0R', -NR m

R

m

-NR

m

-C

1 -4haloalkyl, -NR m

-C

1 6 alkylNR m R' or

-NR

m -Cv.

6 alkyIOR'; Y is NH; and Z is CR 8 or N; or R'is

R

9 R 2 is H, -OR' m Cl, C 13 haloalkyl Or CI.

6 alkyl; R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S, so long as the combination of 0 and S atoms is not greater than 1, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected fromFr C 18 alkyl, C 14 haloalkyl, halo, cyano, nitro, -C(=0)NR m

-C(=NR

m

)NR

m

R

m -OR -0C(=0)R -OC(=0)NR-R m 2 R -OC 26 alkylOR', -S -S 2

R,

2 NRm'R m 2

N(R

m 2

N(R

m )C(=0)0R 2

N(R

m )C(=0)NR m

-NR

m

R

m

-N(R

m

-N(R

m )C(=0)0R,

-N(R

m )C(=0)NR m

-N(R

m

)C(=NR

m

)NR

m

R

m

-N(R

m )S 2 R

-N(R

m 2

NR

m

R

m

-NR

m

C

26 alky]NR n R m

-NR

m

C

2 -6alkyl0R', -C(=0)0Rs, -C(=0)NRnR', -C(=NRm)NRrnR', -OC(=0)NRnR', 2 Rs, -0C 2 6 alkylrNRsR' -0C 2 6 alkyl0R', 185 -S Rs, -S -S 2 -S 2 NRnRS, -S 2 N(Rrn)C(=O)Rs, -S 2 N(Rrn)C(=O)ORS, -S 2 N(Rrn)C(=O)NRnRs, -NJRnRs, -N(Rrn)C(=O)Rs, -N(Rr)C(=O)ORs, -N(Rrn)C(=O)NRnRs, -N(Rrn)C(=NRrn)NRnRs, -N(Rm')S 2 Rs, -N(Rrn)S(=O) 2 NRrnRs, -NRj'C 2 -(al kyl NRrnR, -NRrnC 2 6 alkylOR' and C 1 4 alkyl substituted by 1 or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=O)NRmlRn, -C(=NRn)NRm~Rrn, -OR m -OC(=O)Rn,

-OC(=O)NR

m

R

m

-OC(=O)N(R

m )S 2

-OC

26 (aI kyl NR m

R

m -0C 2 -(,a1kyl OR m

-SR

m 2 2

NR

m

R

m 2

N(R

m -S 2

N(R

m )C(=O)ORn, -S 2

N(R

m

)C(=O)NR

m

R

m

-NR

m

R

m

-N(R

tm

-N(R

tm

-N(R

tm

)C(=O)NR

m

R

m

-N(R

m

)C(=NR

m

)NR

m

-N(R

m 2

-N(R

m 2

NR

m

R

m

-NR

m

C

2 6 al kylNR m

R

m -C(0)ORs, -C(=O)NRrnRs, -C(=NRn)NRnRs, -ORs, -OC(=O)Rs, OC(=O)PRRs, -OC(=O)N(Rrn)S(=O) 2 Rs, -OC 2 6 alkylrNPRs

-OC

2 6 alkylORs, S(0)Rs, 2 Rs, 2 NRrnR', 2 N(Rrn)C(=O)Rs, 2 N(Rrn)C(=O)ORS, -S(O) 2 N(Rrn)C(.O)NRnRs, -NRrnRs, -N(Rrn)C(=O)Rs, -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRnRs, -N(Rrn)C(=NRrn)NRrnR', -N(Rrn)S(=O) 2

-N(R

m )S 2 NRnRs, -NRnC 2 6 alkylNRnRs, -NRrnC 2 .6alkylORs and -NR

M

C

2 6 alkylOR m wherein R 4 is not unsubstituted phenyl;

R

7 is C 2 6 alkyI, C,.5haloalkyl, I or Br;

R

9 is independently, at each instance, H, C 1 9 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -0C 1 6 alkyl, -0-C 1 4 haloalkyl, -0-C .6al kylNR m

R

m -0-C 1 6 a1kyIOR m

-NR

m

R

m

-NR

m

-C

1 4 haloalkyl, -NR m

-C

1 6 alkylNR m

R

m or

-NR

tm

-C

16 alkylOR m Y is NH-;and Z is CR 8or N.

Another aspect of the invention relates to the manufacture of a medicament for the treatment of acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and nonvascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints -186with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritis, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders, wherein the medicament contains a compound having the structure:

R

3

R

3 R 'Y R4

R

2

X

wherein: X is 0, S or NR"; n is independently, at each instance, 0, 1 or 2; o is independently, at each instance, 0, 1, 2 or 3; R" is independently at each instance H or R"; R" is independently at each instance Ci-.salkyl, phenyl or benzyl; R is independently in each instance H, C 1 4 alkyl, C14haloalkyl, halo, cyano, nitro, -C(=O)OR -C(=0)NR m

R

m

-C(=NR

m

)NR

m

R

m

-OR

m

-OC(=O)N(R

m 2

-OC

2 6 alkylNR m

R

m -OC2-6alkylOR m

-SR

m 2 R, 2

NR

m

R

m 2

N(R

m 2 N(R')C(=O)ORn, 2

N(R

m )C(=0)NR m

R

m

-NR

m

R

m

-N(R

m

-N(R

m

-N(R

m

)C(=O)NR

m Rm,

-N(R

m

)C(=NR

m

)NR

m

R

m

-N(R

m 2

-N(R

m 2

NR

m

R

m

-NR

m

C

2 6 alkylNR m

R

m or -NR m

C

2 -calkylOR m RS is R" substituted by 0, 1, 2 or 3 substituents independently selected from RI;

R

3 is H or C 1 4 alkyl; 187

R.

5 is H, C 1 9 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -OCI 1 6 alkyI, -0-C 1 4 haloal kyl, -0-C 6 alkyINR m R -0-C 1 6 alkylOR', -NR m

R',

-NR

m

-CI.

4 haloalkyl, -NR m -Cl.

6 alkylNR m

-NR

m

-C

1 6 alkylOR', or -(CH 2 R 6 is, independently at each instance, H, Cl-galkyl, C 1 -4haloalkyl, halo, nitro, cyano, -OC 1 -6alkyl, -0-C 1 4 haloalkyl, -0-C 1 6 alkylNR m

R',

-0-C 1 6 alkylOR', -NR m

-NR

m

-C

1 4 haloalkyl, -NR m

-C

1 -6alkylNR m R' or

-NR

m

-C

1 6 alkylOR'; R8 is H, Cl-qalkyl, C 1 4 haloalkyl, halo, nitro, cyano, -OCI 1 6 alkyl, -0-C 1 4 haloalkyl, -0-CI- 6 a1kylNR m

R

m -0-C 1 6 alky!OR m -NRnR m

-NR

m

-C

1 4 haloalkyl, -NR m

-C

1 6 a1 kylNR m R' or -NR m -CI.-salkyl0R'; and R' is R 6 (CRqRq) 0

RO

R 2is H, -OR m halo, C,- 3 haloalkyl or CI.

6 alkyl; R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from CI-8alkyl,

CI-

4 haloalkyl, halo, cyano, nitro, n, -C(=0)NR m

R',

-C(=NR

m

)NR

m

R

m

-OR'

m -OC(=O)NRnR -OC(=0)N(R m 2

-OC

2 6 alky]NR m

-OC

2 -salky1OR', -SR' m n -S 2 -S 2

NR

m

R

m 2

N(R

m -S 2

N(R

m 2

N(R

m )C(zO)NR m

R

m

-NR

m

R

m

-N(R

m -N(RrC(=O)ORn,

-N(R

m )C(=0)NR m

R

m

-N(R

m

)C(=NR

m

)NR

m

R

m -N(Rrm)S(=0) 2

R",

-N(Rm 1 2

N'R

m

R

m

-NR

m

C

2 6 alkyl NRmR m

-NR

m

C

2 6 a~kylOR m -C(=O)ORs, -C(=O)NRnR', -C(=NRrn)NRnR', -ORs, -OC(=O)NRnR', -OC(=O)N(Rrn)S(=O) 2 Rs, -OC 2 6 alkylNRmlR', -OC 2 6 alkyl0Rs, 188 -SRs, 2 2 NRwR', 2 N(Rr)C(0)Rs, 2 N(Rrn)C(=O)0Rs, 2 N(Rrn)C(=O)NRnRs, -PRrnRs, -N(Rrn)C(=0)Rs, -N(Rr)C(=O)0Rs, -N(Rrn)C(=0)NRnRs, -N(Rrn)C(=NRn)NRnR', -N(Rrn)S(=O) 2

-N(R

m )S 2 NRnRs, -NR tm

C

26 aIkylNR m -NRnC 2 6 alkyl0Rs and C 1 4 alkyl substituted by 1 or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=0)NR m

-C(=NR"')NR

m

-OR

m

-OC(=O)NR

m

R

m

-OC(=O)N(R

m )S 2 -0C 2 6 al kylNRmlRrn,

-OC

2 4salkylOR', -SR' m 2 2

NR

m

R',

2 2 2

N(R

m

)C(=O)NR

m

R',

-NR

m

-N(R

m

-N(R

m

)C(=O)NR

m

R',

-N(Rrn)C(=NRn)NRnR'l, -N(Rm 1 2

-N(R

m )S 2

NR

m

R',

-NR

m

C

2 -6alkylNR m -C(=0)0Rs, -C(=0)NRnR', -C(=NRn)NRnR', -ORs, -OC(=0)Rs, -OC(=O)NRnRs, -OC(=0)N(Rn)S(=O) 2 Rs, -OC 2 6 alkylNRnRs,

-OC

2 6 alkylORs, -SRs, 2 Rs, 2 NRnRs, -S 2 N(Rrn)C(=O)R', -S 2 N(Rrn)C(=0)ORs, -NRrnRs, -N(Rrn)C(=0)Rs, N(Rr)C(0)ORs, -N(Rrn)C(=0)NRnR', -N(Rrn)C(=N7Rr)NRrnRs, -N(Rrn)S(=O) 2 -N(Rrn)S(=0) 2 NRnR', -NRnC 2 6 alkylNRnR', -NRnC 2 6 alkylORs and -NR m

C

2 6 alkylOR m and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups; R 7 is Cl- 9 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -OC 1 6 alkyl,

-O-C

1 4 haloalkyl, -0-C 14 alkylNR m -0-C 1 6 alkylOR', -NR m

R',

-NR

m

-C

1 4 haloalkyl, -NR m 6 alkylNR m R' or -NR m

-C

1 6 alkylOR';

R

0 is a saturated, partially-saturated or unsaturated 6- or 7-membered monocyclic or 10- or 1 1-membered bicyclic ring containing 0, 1, 2, 3 or 2 5 4 atoms selected from N, 0 and S, so long as the combination of 0 and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from RP; RP is independently at each instance CI-8alkyl, C 1 4 haloalkyl, halo, cyano, 3 0 nitro, -C(=0)0R n, -C(=0)NR m

R

m

-C(=NR)NR

m

R

m

-OR

m -OC(=0)NR m -0C(=0)N(R m 2

-OC

2 6 alkyl NR m

R

m -0C 2 6 a1 kylOR m

-SR

m n' 2 2

NR

m

R

m -189- 2

N(R

m n, 2

N(R

m 2

N(R

m

)C(=O)NR

m

R',

-NR

m

-N(R

m

-N(R

m

)C(=O)NR

m

R',

-N(Rrn)C(=NR)NR t Rrn, -N(R m 2 R n, -N(R m 2

NR'R',

-NR

M

C

2 6 aI kyNR m

R

m or -NR'C 2 -6aIkylOR m and Y is 0or NHl;or R'is R 6 R 7 R 5 R 7 N R (CRqRq )ORO or (CRqRq )ORO R 2is H, -OR' m halo, C,- 3 haloalkyl or C 1 6 alkyl;

R

4 is a saturated or unsaturated 5- or 6-membered ing containing 0, 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atomn bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ing and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C 1 8 alkyl,

C

1 4 haloalkyl, halo, cyano, nitro, -C(=O)OR n, -C(=O)NR m

R',

-C(=NR

m

)NR

m

R

m

-OR

m -OC(=O)R n, -OC(=0)NR m

R

m

-OC(=O)N(R

m 2 R n, -OC 2 6 aI kyl NR m

-OC

2 6 alkylOR', -S(=O)Rn, 2

R

0 -S 2

NR

m

R

m 2 2

N(R

m 2

N(.R

m

)C(=O)NR

m

R

m

-NR

m

-N(R

m n, -N(R

M

)C(=O)0R n,

-N(R

m

)C(=O)NR

m

-N(R

m

)C(=NR

m

)NR

m

R

m

-N(R

m 2

R,

-N(R

m 2

NR

m

-NR'C

2 6 aIkyl NR m

R

m

-NR

M

C

2 6al kylOR m -C(=O)Rs, -C(=O)ORs, -C(=O)N{1Rr, -C(=NRmI)NRrnR', -0Rs, .OC(0)RS -OC(=0)NRnRs, -OC(=O)N(R m )S 2 -0C 2 6 a1 kyl NRrnRS, -0C 2 6 a1 kylORs, -S 2 Rs, -S 2

NR

m 2

N(R

m )C(=0)Rs, 2

N(R

m )C(=O)0Rs, 2

N(R

m

)C(=O)NR

m Rs, -NR m

-N(R

m )C(=O)0Rs, -N(R m

)C(=O)NR

m Rs, N(Rrn)C(=NRn)NRnRs, 2

-N(R

m )S 2 NR"'Rs, -NR m

C

2 6 a1 kylNRrnRs, -NR m

C

2 6 alkylORs and CI-4alkyl substituted by I or 2 groups selected fro M C 1 2 haloalkyl, halo, -190cyano, nitro, n, -C(=O)0R n, -C(=O)NR m

R

m -C(=NRm)NRnR, -OR m -OC(=0)R 0

-OC(=O)NR

m

R

m

-OC(=O)N(R

m 2 R n, -OC 2 -6alkylNR m

R

m

-OC

26 alkyIOR', 2 2

NR

m

R',

2

N(R

m n, 2

N(R

m -S 2

N(R

m

)C(=O)NR

m

R

m

-NR

m

R

m

-N(R

m

)C(=O)NR

m

R',

-N(R

m

)C(=NR

m

)NR

m

R

m

-N(R

tm 2 R n, -N(R tm )S(=Oh2NR m

R

m

-NR

m

C

2 6 alkyNR'R

M

-C(=O)ORS, -C(=O)NRnRs, -C(=NRrn)NRrnRs, -ORs, -OC(=0)Rs, OC(0)NRnRs, -OC(=O)N(Rrn)S(=O) 2

-OC

2 6 alkyINRnR',

-OC

2 6 alkylOR', -SRs, 2 2 NRrnRs, 2 N(Rrn)C(=O)Rs, 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=O)NRnRs,C -NRrnRs, -N(Rr)C(=O)ORs, -N(R )C(=O)NRnRs, -N(Rrn)C(=NRn)NRnR', N(Rrn)S(=O) 2 Rs, -N(R M 2 N RRs., -NRrC 2 6 alkylNRrnR', -NRrnC 2 _alky1OR' and -NR m

C

2 _6aIkylOR m and the ring and bridge carbon atoms are substituted with 0, 1 or 2.=O groups; R 7 is C,.

9 alkyl, C,- 4 haloalkyl, halo, nitro, cyano, -0C 1 6 alkyl, 4 haloalkyl, -0-C ,_salkylNR m

R

m 6alkyl0R m

-NR

m

R

m

-NR

m 4 haloalkyl, -NR m 6 al kyINR m

R

m or -NR tm -C 16 alkyI0R m R' is a saturated, partially-saturated or unsaturated 6- or 7-membered monocyclic or 10- or IlI-membered bicyclic nng containing 0, 1, 2, 3 or 4 atoms selected from N, 0 and S, so long as the combination of 0 and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from RI; RP is independently at each instance C,..salkyl, C 1 4 haloalkyl, halo, cyano, nitro, -C(=0)0R n, -C(=0)NR m

R

m

-C(=NR

m

)NR

m R, -OR' m -0C(=O)R n, -QC(=0)NR m

R

m -0C(=-O)N(R m 2

-OC

26 alkylNR m

R',

-0C 2 6 alkylOR', -SR' m 2 R n, 2

NR

m

R

m 2

N(R

m 2

N(R

m -S 2

N(R

m )C(=0)NR m

R',

-NR

m

R

m

-N(R

tm

-N(R

m )C(=0)OR n, -N(R tm

)C(=O)NR

m

R

m

-N(R

tm )C(=NRn)NRmlRn, -N(R m )S 2

-N(R

m )S 2

NR

m

R

m

-NR

m

C

2 _6alkylNR m

R

m or'-NR m

C

2 6 alkylOR m and Y is 0or NHI;or 191 R' is

R

2 s O~ m haoC 1 3 hlolkl R.

6 akl 0, R 2 s or 3 O' subaloe independenlyslec fro C 1 9 alk lkyoo ;hlak hao nis cao -a t urte, parialy-sturte orlkl uns 1 4 aturaedyI, 1 0 5 akolr t 0- 1 6 akyor 3sb t ue N~ t m ndepndetl selectedyro -N gCalkylN xo I-4hloakyl

-NW-CI-

6 alkylOR', -C(=O)CI.

6 alkyl, -OC(=O)C 1 6 alkyl, -C(=O)NR'C L 6 alkyl,

-NR

m C(0)CI- 6 alkyl -C(=O)ORs, .C(0)YRRs -C(=NRrn)NRrnRs, -ORs, .OC(0)R, -OC(=O)N1RnRs, .0C(0)N(R m )S 2 Rs, -OC 2 -6al kylNRrnRs,

-OC

2 6alkyl0Rs, 2

-S(O)

2 NRmR', -S 2 N(Rrn)C(=O)R', -S 2 N(Rrn)C(=O)ORs, -S 2 N(Rm)C(=0)NRnRS, -NRrnRS, -N(Rrn)C(=O)Rs, N(Rr)C(O)0Rs, -N(Rrn)C(=0)NRnR', -N(Rm)C(=NRn)NRnR',

-N(R

m )S 2 Rs, -N(Rrn)S(=O) 2 NRnR', -NRtmC 2 6 alkyINRnRs, -NRnC 2 6 alkyl0Rs and C 1 -4alkyl substituted by 1 or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro,

-C(=O)NR

m

R',

-C(=NR

m

)NR

m

-OR

m

-OC(=O)NR

m

R

m

-OC(=O)N(R

m )S 2 -0C 2 6 ,alkylNRm'R t

-OC

2 6 aI kylOR m

-SR

m -S -S 2 2

NR

m 2

N(R

tm -S 2

N(R

m )C(=0)ORr, 2

N(R

m )C(0)NR m

-N(R

m )C(=0)OR -N(Rtm)C(=O)NRnR m

-N(R

m m

)NR

m

-N(R

m )S 2

R',

-N(Rm)S(=O) 2 NRnR, -C(0)ORs, -C(=O)NRnRs, -C(=NRn)NRmlR', .OC(0)RS, OC(0)NRnRs,

-OC(=O)N(R

m )S 2

-OC

2 6 alkylNRnRs,

-OC

2 6 alkylOR', 2

-S(O)

2 NRnR', -192- -S 2 N(Rrn)C(=0)Rs, S(=0) 2 N(Rrn)C(=0)ORS, 2 N(Rrn)C(=0)NRnR', -NRrnRs, -N(Rr)C(=0)Rs, -N(Rr)C(=0)0Rs, -N(Rrn)C(=0)NRnRs, -N(Rrn)C(=NR"n)NRnRs, -N(R m )S 2 Rs, -N(Rrn)S(=0) 2 NRnRs, -NRrnC 2 -alkyINRnR', -NRnC 2 6 alkyl0Rs and -NR m

C

2 -6alkyl0R'; wherein R 4 is not 2-aminocarbonylmethyl-2,3-di hydro-benzo[ 1,4]dioxin-8-yl, 2-cyanomethyl- 2,3-dihydro-benzo[ 1,4]dioxin-8-yl, quinolin-3-yl, 3H-quinazolin-4-on-3-yl, benzo[ 1,3]dioxol-5-y], 3,3-dimethyl- 1,3-dihydro-indol-2-on-6-yl or 4,4-di methyl- 3,4-dihydro- LH-quinolin-2-on-7-yI; R 7 is CI- 8 alkyl, C 15 shaloalkyl, I or Br R 9 is H, Cl- 9 alkyl, CI4haloalkyI, halo, nitro, cyano, -OCI.

6 alkyl, -0-C,4haloalkyl,( -0-C 1 6 alkyNR m -0-C 16 alkylOR', -NR m

-NR

m

-C

14 haloalkyl,

-NR

m -C 6 a1 kylNR m

R

m

-NRM-~C

1 6 a1 ky]OR m or -(CH 2 )nR-;

R

9 is independently, at each instance, H, C 1 9 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -0CI 6 alkyl, -0-C 1 ~haloalkyl, -0-C 1 6 alkylNR m

R

m -0-C 1 6 alkylOR m

-NR

m

R

m

-NR

m

-CI.

4 haloalkyl, -NR m

-C

1 6 alkylNR'R' or

-NR

m

-C

1 6 alkyl0R'; Y is NH; and Z is CR 8 or N;or R'is

R

R 2is C 1 6 alkyl substituted by 1, 2 or 3 substituents selected from

C

1 4 haloaikyl, halo, cyano, nitro, -C(=0)NR m

R',

-C(=NR

m

)NR

m

R

m

-OR'

m -OC(=0)NR m

R

m -0C(=0)N(R m 2

-OC

2 6 alkylNR m -0C 2 6 alkylOR', -SR m -S 2 2

NR

m

R

m 2

N(R

m -S 2

N(R

m -S 2

N(R

m

)C(=O)NR

m

R

m

-NR

m

R

m

-N(R

m

-N(R

t

-N(R

m )C(=0)NR m

R

m

-N(R

tm

)C(=NR

m

)NR

m

-N(R

m 2

R',

-N(R

m )S 2

NR

m

R

m

-NR

m

C

2 6 a IkylNR m R' or -NR

M

C

2 6 alkyl OR m or 193 R 2 is q) 2 0 ,phenyl, wherein the phenyl is substituted by 0, 1, 2 or 3 substituents independently selected from C,.

8 alkyl, C 1 4 haloalkyl, halo, cyano, nitro, -C(=O)OR n, -C(=O)NR m

R

m -C(=NR"')NRmR m

-OR

m -OC(=O)R n, -OC(=O)NR m

-OC(=O)N(R

m 2 R n, -0C 2 6 a1 kylNR m

R

m

-OC

2 -6alkylOR m n, 2 R n, 2

NR

m 2

N(R

m 2 2

N(R

m

)C(=O)NR

m

R',

-NR

m

R

m n, -N(R m

-N(R

m

)C(=O)NR

m

R

m

-N(R

m

)C(=NR

m

)NR

m

R

m

-N(R

m 2 R, n' N(Rrn)S(=O) 2 NRnRn,

-NR

m

C

2 6 alkylNR m

R

m

-NR

m

C

2 -6alkylOR m C(=O)ORs, -C(=O)NRnRs, -C(=NRrn)NRnR', -0Rs, -OC(=O)Rs, -OC(=O)NRnRs, -OC(=O)N(Rrn)S(=O) 2

-OC

2 6al ky]NR m Rs, -OC 2 6 aI kylORs, -SRs, -S(=O)Rs, 2 -S 2 NRnRs, 2 N(Rrn)C(=O)R', 2 N(Rrn)C(=O)ORs, -S 2 N(Rnl)C(=O)NRnRS, 44lRrRs, -N(R m )C(=O)0R 5 -N(Rrn)C(=O)NRnR', -N(Rrn)C(=NRn)NRnR', -N(R m )S 2 Rs, -N(Rrn)S(=O) 2 NRnRs, -NR m

C

2 -6alkylNRnRs, -NRnC 2 6 alkyIOR' and C 1 4 alkyl substituted by I or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=O)OR -C(=-O)NR m

-C(=NR

m

)NR"'R

m

-OR

m

-OC(=O)NR

m

R

m

-OC(=O)N(R

m 2 -0C 2 6 aJ kylNR m

-OC

2 6 al kylOR m

-SR

m -s 2 2

NR

m -S 2 N(Rrl)C(=O)R, -s 2

N(R

m -S 2

N(R

m

)C(=O)NR

m

R

m

-NR

m

R

m

-N(R

m n, -N(R m

-N(R

m

)C(=O)NR

m

-N(R

m

)C(=NR

m

)NR

m

R'

t

-N(R

m 2 R, n'-N(R m )S 2

NR

m

R

m

-NR

m

C

2 6 aI kylNR'R m C(0)ORs, -C(=O)NRnR', -C(4pNRn)~Rn~s, -OW, -OC(=O)Rs, .0C(=O)NRnRs, OC(=O)N(Rrn)S(=O) 2

-OC

2 6 alkyINRnR',

-OC

26 alkylOR', -SW, 2 Rs, 2 NRnR', -S 2 N(Rrn)C(=O)R', -S 2 N(Rrn)C(=O)ORS, -S 2 N(Rrn)C(=O)NRnR', -NRrnR', -N(Rrn)C(=O)Rs, -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRnR', -N(Rrn)C(=NRrn)NRnR', -N(R m )S 2 R, -N(RrI)S 2 NRnR', -NRnC 2 6 alkylNR"'R', -NR~n C 26 alkyIORs and -NR m

C

2 6 alkylOR'; or R 2 is q) 2 )Rr, wherein Rr is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, 0 and S, wherein no more than 2. of the ring members are 0 or S, 194 wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from C 18 galkyl, C 1 4 haloalkyJ, halo, cyano, nitro,

-C(=O)NR

m

R

m

-C(=NR

m

)NR

m

-OR'

m -OC(=O)Rn, -OC(=O)NR m

R,

2 R -0C 2 6 alkylNR m

R

m

-OC

2 6 al kylOR' m

-SR'

m 2

R

0 -S 2

NR

m

R

m 2

N(R

m 2

N(R

m

)C(=O)OR,

-S 2

N(R

m

)C(=O)NR

m

R

m

-NR

m

-N(R

m

-N(R

m

)C(=O)OR,

-N(R

m

)C(=O)NR

m

R

m

-N(R

m

)C(=NR

m

)NR

m

-N(R

m 2

R",

-N(R

m 2

NR

m

R

m

-NR

m

C

2 6 alkyINR m

-NR

m

C

2 6 aI kylOR m -C(=O)Rs, -C(=O)ORs, -C(=O)NRrnR', -C(=NRrn)NRrnR', -OC(=O)Rs,( -OC(=O)NRmRs, -OC(=O)N(Rrn)S(=O) 2 Rs, -OC 2 6 al kyl NRrnR', -0C 2 6 a1 kylORs,

-S(=O)W

5 2 2

NR

m Rs, 2

N(R

m )C(=O)Rs, -S 2

N(R

m )C(=O)0R 5 -S 2

N(R

m

)C(=O)NR

m -NRrnRS, -N(R m )C(=O)Rs,

-N(R

m )C(=O)0R

-N(R

m

)C(=O)NR

m R -N R) N~ R R

-N(R

m 2

-N(R

m 2

NR

m

-NR

M

C

2 _6alkyiNR m Rs, -NR

M

C

2 6 alkylOR' and CI-4alkyl substituted by I or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=O)NR m

-C(=NR

m

)NR-R

m

-OR

m

-OC(=O)NR

m

R

m

-OC(=O)N(R

m 2 R n, -OC 2 6 alkylNR m

R

m -0C 2 6 alkylOR m 2 2

NR

m

R

m -S (=Oh2N(R m 2 N(Rm)C(=O)OR', -S 2 N(RmI)C(=O)NRnR',

-NR"'R

m

-N(R

m

-N(R

m )C(=O)OR n, -N(R m

)C(=O)NR

m

R',

-N(R

m

)C(=NR-)NR

m 2 m

S=)N

m m

-NR

m

C

2 6 a1 kylNRmlRrn, C(=O)ORs, -C(=O)NRnRs, -C(=NR m

)NR

m Rs,

-OC(=O)NR

m OC(0)N(R m )S 2 Rs, -0C 2 6 alkylNR m Rs, -0C 2 6 alkylORs, -S(=Oh2Rs, 2

NR

m Rs, 2

N(R

m 2

N(R

m )C(=O)0R 5 -S 2

N(R

m

)C(=O)NR

m

R',

-NR

m Rs, -N(R m

-N(R

m )C(=O)0R 5

-N(R

m

)C(=O)NR

m

R,

-N(R

m

)C(=NR

m

)NR

m Rs, -N(R m )S 2 Rs, -N(R m )S 2

NR

m

R

5

-NR'C

2 6 al kylNR m Rs, -NR m

C

2 6 alkylOR 5 and -NR m

C

2 -6alkyI OR m R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected 195 from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C 1 .galkyl,

C

1 4 haloal kyl, halo, cyano, nitro, -C(=O)0R n, -C(=0)NR m

R',

-OR-

m -OC(=O)R -OC(=0)NR-R, -0C(=0)N(R m 2

-OC

2 6 akylNR m

-OC

2 -6alkylOR', -SR' m -S 2 2

NR

m -S 2

N(R

m n, -S 2 -S 2

N(R

m

)C(=O)NR

m NRnR-, -N(Rrn)C(=0)NRnR, -N(R m

)C(=NR

m

)NR

m

-N(R

m )S 2

R",

-N(R

M

2

NR

m

-NR

m

C

2 -6alkylNR m

R

m

-NR

m

C

2 6 a1 kyIOR, -C(=O)0Rs, .C(0)NRnR' -C(=NRn)NRnRs, OC(0)RS, -OC(=O)NRnR', -OC(=O)N(R m )S 2

-OC

2 6 alky NRnR', -OC 2 6 alky]OR', -SR% -S 2 Rs, -S 2 NRnRS, -S 2 N(Rrn)C(=O)RS, -S 2 N(Rrn)C(=O)ORS, -S 2 N(Rn)C(=O)NRnRS, -NRrnR', -N(Rrn)C(=O)Rs, -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRnR', -N(Rr)C(NRn)NRnRs, -N(Rrn)S(=0) 2

-N(R

m )S 2 NRnRS, -NR m

C

2 6 aI kylNRnRs, -NRnC 2 6 alkylORs and C 1 4 alkyl substituted by I or 2 groups selected from C 12 haloalkyl, halo, cyano, nitro, -C(=O)NR m

-C(=-NR

m

)NR

m

-OR'

m

-OC(=O)NR

m

-OC(=O)N(R

m 2 -0C 2 6 a1 kyl NR m

R

m -0C 2 salkylOR m

-SR

m n, 2 2

NR

m

R

m n, 2

N(R

m 2

N(R

m 2

N(R

m

)C(=O)NR

m

R',

(-NRmR m

-N(R

m

-N(R

m )C(=O)0R n, -N(R m

)C(=O)NR

m R'l,

-N(R

m

)C(=NR

m

)NR

m

-N(R

m 2 R n, -N(R m )S 2

NR

m

R',

-NR

m

C

2 6 aI kyl NR m -C(=O)0Rs, C(=)NpjRnR' -C(=NRrn)NRnRs, -OWs, OC(=O)Rs, -OC(=O)NRnRs -OC(=O)N(Rn)S(=O) 2

-OC

2 6 al kylNRnRs,

-OC

26 a1 kylORs, -S -S 2 R, 2 NRrR', -S 2

N(R

m -S 2 N(Rrn)C(=0)ORs, .5 2 N(Rn)C(=O)NRnRs

-NR

m Rs, -N(R m -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRnRs,

-N(R

m

)C(=NR

m

)NR

m

-N(R

m )S 2 Rs, -N(R m 2

NR

m Ws,

-NR

m

C

26 aIkyINR m

-NR

m

C

26 alky[OR' and -NWC 26 alkylOR m and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups; R 7 iS-C 2 .salkyI, C 1 .5haloalkyl, 1, Br; 196

R

9 is independently, at each instance, H, C 19 galkyl, C 1 4 haloalkyl, halo, nitro, cyano, -0C 1 6 alkyl, -0-C 1 Ahaloalkyl, -0-C 1 6 a1 kylNR m

R',

6al kyIOR, -NR m

-NR

m -C,-4haloal kyl, -NR m

-C

1 6 alkyINR m R' or

-NR

M

6 a1 kylOR m Y is NH; and Z is CR 8 or N;or R) RIs

R

6 R' is H, -ORm Cl, C,.

3 haloalkyl or CI- 6 alkyl; R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S, so long as the combination of 0 and S atoms is not greater than 1, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from C 1 .galkyl, C,- 4 haloalkyl, halo, cyano, nitro, -C(=0)NR m

R

m

-C(=NR

m

)NR

m -OC(=O)R n' -OC(=0)NR m

R',

-OC(=O)N(R

m 2 R n, -0C 2 -6alkylOR m 2

R',

2

NR

m

R

m -S 2

N(R

m 2

N(R

m )C(=O)OR 2

N(R

m

)C(=O)NR

m

R

m

-NR

m

-N(R

m

-N(R

m

)C(=O)OR,

-N(R

m )C(=0)NR m

R

m

-N(R

m )S 2

-N(R

m )S 2

NR

T

-NR

m

C

2 6 a1 kylNR'mR", -NR

M

C

2 6 a1 kyl OR m -C(=O)Rs, -C(=O)ORs, -C(=O)rNRsR -OC(=O)Rs, -OC(=O)NRnRs, -OC(=O)N(Rn)S(=O) 2

-OC

2 -raIkyINRnR', -0C 2 6 a1 kylORs, -SRs, -S 2 -S 2 NRnRS, -S 2 N(R'l)C(=O)Rs, 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=O)NRnRs, -NRrnRS, -N(Rrn)C(=O)Rs, -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRnR', -N(Rm)C(=NRn)NRmIR', -N(Rm)S(=O) 2 Rs, -N(Rrn)S(O) 2 N1RnRs, -NRM~C 2 6 alkylNRrnR', -NRrnC 26 alkylOR and CA4alkyl substituted by I or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=O)NR m

-C(=NR"')NR

m

R

m

-OR-

m

-OC(=O)NR

m

-OC(=O)N(R

m 2 -0C 2 6 alkylNR m

-OC

2 6 alkylORM' 197

-SR-

m -S -S 2 2 NRnR m 2 2

N(R

m 2

N(R

m )C(=0)NR m

-NR

m

R',

-N(R

m

-N(R

m

-N(R

m

)C(=O)NR

m

R',

-N(R

m

)C(=NR

m

)NR

m

-N(R

m 2 R n, -N(R m )S 2

NR

m

R

m

-NR

m

C

2 6 alkylNR m -C(=0)ORs, .C(=0)rNRsR' -C(=NRrn)NRnR', -OC(=O)Rs, -0C(=0)NRnR', -OC(=0)N(R m )S 2 R, -0C 2 -6alkylNRnRS, -0C 2 6 alkyl0R', 2 Rs, 2 NRnRs, 2 N(Rrn)C(=O)Rs, 2 N(Rrn)C(=0)ORs, 2 N(Rrn)C(=0)NRnR', -NRrnR', -N(Rr)C(=0)ORs, -N(Rrn)C(=0)NR"'Rs, -N(Rrn)C(=NRn)NRnRs, -N(Rrn)S(=O) 2 -N(Rrn)S(=0) 2 NRnR', -NRnC 2 6 alkylNRnR', -NRrnC 2 alkyl0R' and -NR m

C

2 6 alkylOR m wherein R 4 is not unsubstituted phenyl; R 7 is C 2 -6alkyl, CI- 5 haloalkyl, I or Br;

R

9 is independently, at each instance, H, Cl.

9 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -0CI 6 alkyI, -0-C 1 4 haloalkyl, 6 alkylNR m

R

m -0-C 1 6 alkylOR m

-NR

m

R

m

-NR

m 4 haloalkyl, -NR m 6 a1 kylNRmR m or

-NR

m 6 a1 kylOR m Y Is NH; and Z is CR 8or N.

The compounds of this invention may have in general several asymmetric centers and are typically depicted in the form of racemic mixtures. This invention is intended to encompass racemic mixtures, partially racemic mixtures and separate enantiomers and diasteromers.

Unless otherwise specified, the following definitions apply to terms found in the specification and claims: "Capalkyl" means an alkyl group comprising from a to 03 carbon atoms in a branched, cyclical or linear relationship or any combination of the three. The alkyl groups described in this section may also contain a double or triple bond.

Examples Of C,.

6 alkyl include, but are not limited to the following: 198- "Halo" means a halogen atoms selected from F, CI, Br and I.

"Cahaloalkyl" means an alkyl group, as described above, wherein any numberat least one--of the hydrogen atoms attached to the alkyl chain are replaced by F, Cl, Br or I.

"Heterocycle" means a ring comprising at least one carbon atom and at least one other atom selected from N, O and S. Examples of heterocycles that may be found in the claims include, but are not limited to, the following: 0O 0o C ro-yoo 0 S N N N o U(NLOt 00 0) C 0 R, N 0II 0 Q S N, ~N rIN h OCN a CN

NO

C'N0

'-S

CN CN CO CX cN cc0 co

N

'I Q0Q~ KN N N NzTK C (0o and N -199- "Pharmaceutically-acceptable salt" means a salt prepared by conventional means, and are well known by those skilled in the art. The "pharmacologically acceptable salts" include basic salts of inorganic and organic acids, including but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulphonic acid, ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid, maleic acid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid and the like. When compounds of the invention include an acidic function such as a carboxy group, then suitable pharmaceutically acceptable cation pairs for the carboxy group are well known to those skilled in the art and include alkaline, alkaline earth, ammonium, quaternary ammonium cations and the like. For additional examples of "pharmacologically acceptable salts," see infra and Berge et al., J. Pharm. Sci.

66:1 (1977).

"Leaving group" generally refers to groups readily displaceable by a nucleophile, such as an amine, a thiol or an alcohol nucleophile. Such leaving groups are well known in the art. Examples of such leaving groups include, but are not limited to, N-hydroxysuccinimide, N-hydroxybenzotriazole, halides, triflates, tosylates and the like. Preferred leaving groups are indicated herein where appropriate.

"Protecting group" generally refers to groups well known in the art which are used to prevent selected reactive groups, such as carboxy, amino, hydroxy, mercapto and the like, from undergoing undesired reactions, such as nucleophilic, electrophilic, oxidation, reduction and the like. Preferred protecting groups are indicated herein where appropriate. Examples of amino protecting groups include, but are not limited to, aralkyl, substituted aralkyl, cycloalkenylalkyl and substituted cycloalkenyl alkyl, allyl, substituted allyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, silyl and the like. Examples of aralkyl include, but are not limited to, benzyl, orthomethylbenzyl, trityl and benzhydryl, which can be optionally substituted with halogen, alkyl, alkoxy, hydroxy, nitro, acylamino, acyl and the like, and salts, such as phosphonium and ammonium salts. Examples of aryl groups include phenyl, naphthyl, indanyl, anthracenyl, 9-(9-phenylfluorenyl), phenanthrenyl, durenyl and the like. Examples of cycloalkenylalkyl or substituted cycloalkylenylalkyl radicals, preferably have 6-10 carbon atoms, include, but are not limited to, cyclohexenyl -200methyl and the like. Suitable acyl, alkoxycarbonyl and aralkoxycarbonyl groups include benzyloxycarbonyl, t-butoxycarbonyl, iso-butoxycarbonyl, benzoyl, substituted benzoyl, butyryl, acetyl, tri-fluoroacetyl, tri-chloro acetyl, phthaloyl and the like. A mixture of protecting groups can be used to protect the same amino group, such as a primary amino group can be protected by both an aralkyl group and an aralkoxycarbonyl group. Amino protecting groups can also form a heterocyclic ring with the nitrogen to which they are attached, for example, 1,2-bis(methylene)benzene, phthalimidyl, succinimidyl, maleimidyl and the like and where these heterocyclic groups can further include adjoining aryl and cycloalkyl rings. In addition, the heterocyclic groups can be mono-, di- or trisubstituted, such as nitrophthalimidyl. Amino groups may also be protected against undesired reactions, such as oxidation, through the formation of an addition salt, such as hydrochloride, toluenesulfonic acid, trifluoroacetic acid and the like. Many of the amino protecting groups are also suitable for protecting carboxy, hydroxy and mercapto groups. For example, aralkyl groups. Alkyl groups are also suitable groups for protecting hydroxy and mercapto groups, such as tert-butyl.

Silyl protecting groups are silicon atoms optionally substituted by one or more alkyl, aryl and aralkyl groups. Suitable silyl protecting groups include, but are not limited to, trimethylsilyl, triethylsilyl, tri-isopropylsilyl, tertbutyldimethylsilyl, dimethylphenylsilyl, 1,2-bis(dimethylsilyl)benzene, 1,2-bis(dimethylsilyl)ethane and diphenylmethylsilyl. Silylation of an amino groups provide mono- or di-silylamino groups. Silylation of aminoalcohol compounds can lead to a N,N,O-tri-silyl derivative. Removal of the silyl function from a silyl ether function is readily accomplished by treatment with, for example, a metal hydroxide or ammonium fluoride reagent, either as a discrete reaction step or in situ during a reaction with the alcohol group. Suitable silylating agents are, for example, trimethylsilyl chloride, tert-butyl-dimethylsilyl chloride, phenyldimethylsilyl chloride, diphenylmethyl silyl chloride or their combination products with imidazole or DMF. Methods for silylation of amines and removal of silyl protecting groups are well known to those skilled in the art.

Methods of preparation of these amine derivatives from corresponding amino acids, amino acid amides or amino acid esters are also well known to those skilled -201in the art of organic chemistry including amino acid/amino acid ester or aminoalcohol chemistry.

Protecting groups are removed under conditions which will not affect the remaining portion of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis and the like. A preferred method involves removal of a protecting group, such as removal of a benzyloxycarbonyl group by hydrogenolysis utilizing palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, and the like or mixtures thereof. A tbutoxycarbonyl protecting group can be removed utilizing an inorganic or organic acid, such as HCI or trifluoroacetic acid, in a suitable solvent system, such as dioxane or methylene chloride. The resulting amino salt can readily be neutralized to yield the free amine. Carboxy protecting group, such as methyl, ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl and the like, can be removed under hydroylsis and hydrogenolysis conditions well known to those skilled in the art.

It should be noted that compounds of the invention may contain groups that may exist in tautomeric forms, such as cyclic and acyclic amidine and guanidine groups, heteroatom substituted heteroaryl groups O, S, NR), and the like, which are illustrated in the following examples: NR' U NHR' N n NHR R NHR" R NR"

Y'

NH

Y'-H

KN

nniN I' N NR'"

NHR'

RHN NHR" RN NHR" Y1 Y'H 1 I Iy OH 0 R

R'

0 0 R v R 0 OH R)[J R' -202and though one form is named, described, displayed and/or claimed herein, all the tautomeric forms are intended to be inherently included in such name, description, display and/or claim.

Prodrugs of the compounds of this invention are also contemplated by this invention. A prodrug is an active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a patient. The suitability and techniques involved in making and using prodrugs are well known by those skilled in the art. For a general discussion of prodrugs involving esters see Svensson and Tunek Drug Metabolism Reviews 165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985). Examples of a masked carboxylate anion include a variety of esters, such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl).

Amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bungaard J. Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, such as imidazole, imide, indole and the like, have been masked with Nacyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)).

Hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloan and Little, 4/11/81) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use.

-203- Experimental General Unless otherwise noted, all materials were obtained from commercial suppliers and used without further purification. All parts are by weight and temperatures are in Degrees centigrade unless otherwise indicated. All compounds showed NMR spectra consistent with their assigned structures.

Melting points were determined on a Buchi apparatus and are uncorrected. Mass spectral data was determined by electrospray ionization technique. All examples were purified to >95% purity as determined by high-performance liquid chromatography (HPLC). Unless otherwise stated, reactions were run at room temperature.

The following abbreviations are used: aq.- aqueous cond concentrated DMF N,N-dimethylformamide Et 2 0 diethyl ether EtOAc ethyl acetate EtOH ethyl alcohol h- hour min minutes MeOH methyl alcohol satd saturated THF tetrahydrofuran Example 1 I H O0N 2 E)-3-[4-(tert-Butyl)phenyl]-N-phenylprop-2-enamide. To a 10 mL glass vial was added 4 -tert-butyl-trans-cinnamic acid (200 mg, 0.98 mmol, EMKA-Chemie) followed by CH 2 C1 2 (5 mL), l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (225 mg, 1.17 mmol, Bachem) and aniline (98 uL, 100 mg, -204- 0 1.08 mmol, Aldrich). The reaction mixture was magnetically stirred at 25 °C for c, 24 h. EtOAc was added (60 mL) and the mixture washed successively with 1 N NaOH (2 x 20 mL), 1 N HCI (20 mL), water (20 mL) and satd NaCI (20 mL), dried over MgSO 4 filtered and concentrated. Recrystallization from hexane and

CH

2

CI

2 provided the title product as white crystals. MP 141 MS (ESI, pos.

ion) m/z: 280 C Example 2 N H Y N OCH 3

SOCH

3 (2E)-N-(3,4-Dimethoxyphenyl)-3-[4-(tert-butyl)phenyl]prop-2-enamide. To a 20 mL round-bottomed flask equipped with reflux condenser and drying tube was added 4-tert-butyl-trans-cinnamic acid (200 mg, 0.98 mmol, EMKA-Chemie) followed by CH 2

C

2 (5 mL), oxalyl chloride (90 uL, 130 mg, 1.03 mmol, Aldrich) and DMF (1 uL). The reaction mixture was magnetically stirred and heated at reflux for 30 min. The reaction mixture was concentrated in vacuo and the residue dissolved in acetone (2 mL). The solution was added to a mixture of 3,4dimethoxyaniline (180 mg, 1.17 mmol, Aldrich), potassium carbonate (200 mg), water (2 mL) and acetone (2 mL), magnetically stirred at 25 °C in a 10 mL glass vial. The reaction mixture was stirred at 25 OC for 16 h then diluted with EtOAc mL) and washed successively with 1 N HCI (20 mL), I N NaOH (20 mL), water (20 mL) and satd NaCI (20 mL), dried over MgSO 4 filtered and concentrated. Recrystallization from hexane and CH 2

CI

2 provided the title product as a yellow solid. MP 115-116 MS (ESI, pos. ion) m/z: 340 -205- Example 3

H

N 4OCH 3 O

OH

OH

(2E)-3-[4-(tert-Butyl)phenyl]-N-(4-hydroxy-3-methoxyphenyl)prop-2enamide.

H

2 N OCH3

OH

4-Amino-2-methoxyphenol. To a round-bottomed flask was added 4nitroguaiacol (500 mg, 3.0 mmol, Aldrich) and anhydrous EtOH (50 mL). The solution was stirred magnetically under N 2 and treated with 10% Pd on carbon (200 mg, Aldrich). The suspension was purged with H 2 and then stirred at 25 'C under 1 atm H 2 for 16 h. The suspension was purged with N 2 filtered through Celite and concentrated in vacuo to provide a dark solid. The solid was washed with 1:1 CH 2 Cl 2 :hexane and dried in vacuo to provide the title product as pale brown crystals. MS (ESI, pos. ion) m/z: 140 (2E)-3-[4-(tert-Butyl)phenyl]-N-(4-hydroxy-3-methoxyphenyl)prop-2enamide. Analogous to the procedure used to prepare Example 2, 4-amino-2methoxyphenol, Example (164 mg, 1.18 mmol) and 4-t-butyl-transcinnamic acid (200 mg, 0.98 mmol, EMKA-Chemie) provided, after recrystallization of the crude product from CH 2

CI

2 and hexane, the title product as brown crystals. MP 203-204 MS (ESI, pos. ion) m/z: 326 206 Example 4

H

(2E)-3-[4-(tert-Butyl)phenyl]-N-(2-5,6,7,8-tetrahydronaphthyl)prop-2enamide.

H

2N

"C

2-5,6,7,8-Tetrahydronaphthylaniine. To a round-bottomed flask was( added 6-amino-1,2,3,4-tetrahydronaphthalene (500 mg, 3.10 mmol, Maybridge), triethylsilane (2.50 mL, 15.5 mmol, Aldrich) and trifluoroacetic acid (5.0 mL, 66 mmol, Aldrich). The reaction mixture was magnetically stirred vigorously, at 25 for 2 h. The solvents were removed in vacuo and the residue dissolved in EtOAc (50 mL) and extracted with I N HCI (100 mL, then 50 mL). The combined aqueous acidic extract was washed with EtOAc (50 mL) then basified with 5 N NaOH, at 0 0 C, to pH 10. The mixture was extracted with CH 2

CI

2 (3 x mL), the combined organic extract washed with water (50 mL), satd NaCI (50 mL), dried over Na 2

SO

4 filtered and concentrated in vacuo to provide the title product as a brown oil. MS (ESI, pos. ion) m/lz: 148 [4-(tert-Butyl)phenyl]-N-(2-5,6,7,8-tetrahydronaphthyl)prop.2.

enamide. Analogous to the procedure used to prepare Example 2, 2-5,6,7,8tetrahydronaphthylamine, Example (173 mg, 1. 18 mmol) and 4-I-butyl trans-cinnamic acid (200 mg, 0.98 mmol, EM4KA-Chemie) provided, after purification by silica gel chromatography (4:1 hexane:EtOAc) followed by recrystallization from CH 2

CI

2 and hexane, the title product as white crystals. NIP 198-199 MIS (ESI, pos. ion) in/z: 334 -207- Example H HO Y N

N

(2E)-N-(2H,3H,4H-Benzo[3,4-el]1,4-oxazaperhydroin-6-yI)-3-[4-(tertbutyl)phenyl]prop-2-enamide.

H

H

2

NN

2H,3H,4H-Benzo[e]1,4-oxazaperhydroine-6-ylamine. To a roundbottomed flask was added 2-amino-4-nitrophenol (1.0 g, 6.5 mmol, Aldrich), potassium carbonate (1.8 g, 13 mmol), DMF (5 mL) and 1,2-dibromoethane (0.59 mL, 6.9 mmol, Aldrich). The mixture was magnetically stirred and heated in a 125 oC oil bath, under N 2 for 2.5 h. After allowing to cool to 25 C, the reaction mixture was diluted with EtOAc (100 mL), washed with 1 N NaOH (3 x mL), water (50 mL), satd NaCl (50 mL), dried over Na 2

SO

4 filtered and concentrated to provide a dark residue [MS (ESI, pos. ion) n/z: 181 The crude product was dissolved in EtOH (100 mL), the solution was purged with N 2 treated with 10% Pd on carbon (450 mg, Aldrich), purged with H 2 then magnetically stirred under 1 atm H 2 for 2 h. After purging again with Nz, the suspension was filtered through Celite and concentrated in vacuo. Purification by silica gel chromatography (95:5 CH 2

CI

2 2 M NH 3 in EtOH) provided the title product as a viscous brown oil. MS (ESI, pos. ion) mn/z: 151 (2E)-N-(2H,3H,4H-Benzo[3,4-e] 1,4-oxazaperhydroin-6-yl)-3-[4-(tertbutyl)phenyl]prop-2-enamide. Analogous to the procedure used to prepare Example 2, 2H,3H,4H-benzo[el1,4-oxazaperhydroine-6-ylamine, Example (176 mg, 1.18 mmol) and 4-t-butyl-trans-cinnamic acid (200 mg, 0.98 mmol, EMKA-Chemie) provided, after purification by silica gel chromatography (step gradient, 6:3:1 CH 2

CI

2 :hexane:EtOAc then 9:1 hexane:EtOAc) the title product as a yellow solid. MP 108-114 OC. MS (ESI, pos. ion) m/z: 337. -208- Example 6 H H NaN 0 O OO (2E)-3-[4-(tert-Butyl)phenyl]-N-(3-oxo(2H,4H-benzo[3,4-e 1,4oxazaperhydroin-6-yl))prop-2-enamide.

H

0 2 N N N O

O

6-Nitro-2H,4H-benzo[e]1,4-oxazaperhydroin-3-one. A mixture of 4-nitro- 2-aminophenol (4.6 g, 30 mmol, Aldrich), benzyltrimethylammonium chloride (6.8 g, 30 mmol, Aldrich) and solid NaHCO 3 (12.6 g, 150 mmol) in chloroform (100 mL) was magnetically stirred at 0 °C in a round-bottomed flask and treated dropwise with chloroacetyl chloride (2.9 mL, 33 mmol, Aldrich) over a period of min. After the addition was complete, the reaction mixture was stirred at 0 °C for 1 h, then at 50 °C overnight. The solvent was removed in vacuo and the residue treated with water (50 mL), collected by filtration and washed with water.

The solid was recrystallized from EtOH to provide 6-nitro-2H,4H-benzo[e] 1,4oxazaperhydroin-3-one. MS (ESI, neg. ion) m/z: 193

H

H

2 N

(N

O

6-Amino-2H,4H-benzo[e]l,4-oxazaperhydroin-3-one. To a suspension of 6-nitro-2H,4H-benzo[e]1,4-oxazaperhydroin-3-one, Example (0.50 g, 2.6 mmol) and CuCI (0.77 g, 7.8 mmol, Aldrich) in anhydrous MeOH (25 mL), magnetically stirred at 25 °C in a round-bottomed flask, was added potassium borohydride (0.98 g, 18 mmol, Aldrich) in portions. The reaction mixture was stirred at 25 °C for 0.5 h, then the solvent was removed in vacuo and the residue suspended in water (30 mL) and extracted with EtOAc (5 x 20 mL). The combined organic extracts were washed with satd NaCI, dried over Na 2

SO

4 -1 209 filtered and concentrated in vacuo to provide the title product as a brown solid.

MS (ESI, pos. ion) mn/z: 165 (2E)-3-[4-(tert-Butyl)phenyl]-N-(3-oxo(2H,4H-benzo[3,4-e] 1,4oxazaperhydroin-6-yl))prop-2-enamide. Analogous to the procedure used to prepare Example 1, 6-am ino-2H4,4H-benzo~e] I ,4-ox azaperh ydroi n-3 -one, Example (207 mg, 1.26 mmol) and 4-tert-butyl-trans-cinnamic acid (258 mg, 1.26 mmol EMKA-Chemie) provided, after recrystallization from EtOAc and hexane, the title compound as a pale yellow solid. M? 280 0 C. MS (ESI, pos. ion) nt/z: 351 Example 7 H CH3 (2E)-3-[4-(tert-Butyl)phenyl]-N-(4-methyl-3-oxo(2H-benzol3,4-e] 1,4oxazaperhydroin-6-yl))prop-2-enamide.

0 2 NN,0 4-Methyl-6-nitro-2H-benzo[e]1,4-oxazaperhydroin-3-one. A mixture of 6ni tro-2H,4H-benzo[eI 1 ,4-oxazaperhydroi n-3-one, Example (970 mg, mmol), benzyltrimethylammonium chloride (114 mg, 0.50 mmol, Aldrich) and iodomethane (0.47 m.L, 7.5 mmol, Aldrich) in CH 2

CI

2 (20 mL) was stirred magnetically in a 100 mL round-bottomed flask and treated with CsOH monohydrate (4.2 g, 25 mmol, Aldrich). The reaction mixture was stirred at 'C for I h, treated with water (5 mL) and extracted with CH 2 Cl 2 (3 x 50 mL).

The combined organic extract was washed with water (5 mL), satd NaCI (5 mL), dried over Na 2

SO

4 filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (9:1 hexane:EtOAc) to provide the title product.

MS (ESI, pos. ion) mz:z 209 1).

210

OH

3

H

2

NN

6-A mino-4-methyl-2H-benzo[e]1,4-oxazaperhydroin-3-one. To asolution of 4-methyl-6-nitro-2H-benzo[e] 1 ,4-oxazaperhydroin-3-one, Example 7(a), (700 mg, 3.4 rnmol) and NiC12j6H 2 O (400 mg, 1.7 mmol, Aldrich) in MeOll (10 mL), magnetically stirred in a 100 mL round-bottomed flask at 25T 0 was added NaBH 4 (190 mg, 5.1 mmol, Aldrich) in portions. The reaction mixture was stirred for 30 min then concentrated in vacuo. Purification by silica gel chromatography (CH 2 C1 2 IEtOAc) provided the title product. MS (ESI, pos. ion)( m/z: 179 (2E)-3-14-(tert-Butyl)phenyl]-N-(4-methyl-3-oxo(2H-benzo[3,4-eI 1,4oxazaperhydroin-6-yl))prop-2-enamide. Analogous to the procedure used to prepare Example 1, 4-tert-butyl-trans-cinnamic acid (200 mg, 1.0 mmol, EMVKA- Chemie) and 6-amino-4-methyl-2H-benzo[e] l,4-oxazaperhydroin-3-one, Example (180 mg, 1.0 mmol) provided, after purification by silica gel chromatography (4:1 CH 2

CI

2 :EtOAc), the title product as a pale yellow solid. MP 201-203 MS (ESI, pos. ion) m/z: 365 Example 8 H CH 3 (2E)-3-[4-(tert-Butyl)phenyl]-N-(4-methyl(2H,3H-benzo[3,4-e] 1,4oxazaperhyd roin-6-yl))prop-2-enamide.

To a solution of lithium aluminum hydride (2.0 mL, 2.0 mmol, 1.0 M in THF, Aldrich), magnetically stirred at 0 TC in a round-bottomed flask under N 2 was added 6-amino-4-methyl-2H-benzo[e] 1,4-oxazaperh ydroi n-3 -one, Example 7b, (180 mg, 1.0 mmol). The reaction mixture was allowed to warm to 25 0 C and stirred at that temperature for 1 h. The reaction was quenched by the dropwise addition of 20% H 2 0/THF (1.2 mL), followed by 5 N NaOH (0.2 mL). The mixture was stirred at 25 TC for 30 min, then filtered and washed with EtOAc.

-211 The filtrate was dried over Na 2

SO

4 filtered and concentrated in vacuo [MS (ESI, pos. ion) m/z: 165 Analogous to the procedure used to prepare Example 1, the crude product and 4-tert-butyl-trans-cinnamic acid provided the title compound as a pale yellow solid. MAP 186-188 TC. MIS (ESI, pos. ion) in/z: 351 Example 9

H

N0 0 N1

H

(2E)-3-[4-(tert-Butyl)phenyll-N-(3-oxo(2H,4H-benzo[e] 1,4-oxazaperhydroin- 7-yI))prop-2-enamide.

0 2 N0 aNO

H

7-Nitro-2H,4H-benzo[ejjl,4-oxazaperhydroin-3-one. Analogous to the procedure used for the preparation of 6-nitro-2H,4H-benzo[e] 1,4oxazaperhydroi n=3one,-Example-6(a),5nitro2--ami nophenoL-(.6g,3.0mmol, Aldrich) and chloroacetyl chloride (2.9 mL, .33 mmol, Aldrich) provided, after recrystallization from EtOH, 7-nitro-2H,4H-benzo[e] I,4-oxazaperhydroin-3-one.

MS (ESI, neg. ion) m/z: 193

H

2 N0 7-A mino-2H,4H-benzo[ell,4-oxazaperhydroin-3-one. A mixture of 7nitro-2H,4H-benzo[e] 1 ,4-oxazaperhydroin-3 -one, Example (970 mg, 5.0 mmol) and 10% Pd on carbon (100 mg, Aldrich) in MeOH (20 mE) was magnetically stirred in a round-bottomed flask under 1 atm H 2 for 2 h. The mixture was purged with N 2 and filtered through a pad of Celite. Concentration in vacuo provided the title product. MS (ESI, pos. ion) m/z: 165 (2E)-3-[4-(tert-Butyl)phenyl]-N-(3-oxo(2H,4H-benzo[e] 1,4oxazaperliydroin-7-yl))prop-2-enamide. Analogous to the procedure used to -212prepare Example 1, 4-tert-butyl-trans-cinnamic acid (200 mg, 1.0 mmol, EMKA- Chemie) and 7-amino-2H,4H-benzo[e]1,4-oxazaperhydroin-3-one, Example 9(b), (164 mg, 1.0 mmol) provided, after purification by silica gel chromatography (4:1

CH

2

CI

2 :EtOAc), the title product as a pale yellow solid. MP 226-227 MS (ESI, pos. ion) m/z: 351 Example

SH

O lao)

N

H (2E)-N-(2H,3H,4H-Benzo[e]1,4-oxazaperhydroin-7-yl)-3-[4-(tertbutyl)phenyl]prop-2-enamide.

To a solution of borane-THF complex (2.5 mL, 2.5 mmol ,1.0 M in THF, Aldrich), magnetically stirred at 0 oC under N 2 in a round-bottomed flask equipped with a reflux condenser, was added 7-amino-2H,4H-benzo[e]1,4oxazaperhydroin-3-one, Example (160 mg, 1.0 mmol). The reaction mixture was stirred at reflux for 2 h, then treated with EtOH (0.5 mL) and reflux continued for an additional 1 h. The mixture was treated with cond HCI (0.5 mL) and reflux continued for an additional 1 h. The solvent was removed in vacuo and the residue treated with 1 N NaOH (5 mL) and extracted with CH 2 Cl 2 (3 x mL). The combined organic extracts were washed with satd NaCI, dried over Na 2

SO

4 filtered and concentrated in vacuo to provide the crude aniline [MS (ESI, pos. ion) m/z: 151 Analogous to the procedure used to prepare Example 1, 4-tert-butyl-trans-cinnamic acid (200 mg, 1.0 mmol, EMKA-Chemie) and the crude aniline, after purification by silica gel chromatography (85:15

CH

2

CI

2 :EtOAc), provided the title product as a pale yellow solid. MP 186-188 OC. MS (ESI, pos. ion) m/z: 337 *l, 213 Example 11

H

N 1

CH

3 (2E)-3-[4-(tert-Butyl)phenyl]-N-(4-methyl-3-oxo(2H-benzo[e] 1,4oxazaperhydroin-7-yl))prop-2-enamide.

0 2 N0 4-Methyl-7-nitro-2H-benzo[e] 1,4-oxazaperhydroin-3-one. Analogous to the procedure used to prepare Example 7-nitro-2H,4H-benzo[e]l,4oxazaperhydroin-3-one, Example (970 mg, 25 mmol), benzyltrimethylammonium chloride (110 mg, 0.50 mmol, Aldrich), lodomethane (0.47 mnL, 7.5 mmol, Aldrich) and CsOH hydrate (4.2 g, 25 mmol, Aldrich), after purification by silica gel chromatography (9:1 hexane:EtOAc), provided the title product. MS (ESI, neg. ion) m/z: 207

H

2 N N

CH

3 7-Amino-4-methyl-2H-benzo[e)1,4-oxazaperhydroin-3-one. Analogous to the procedure used to prepare Example 4-methyl-7-ni tro-2H-benzo[e] 1,4oxazaperhydroin-3 -one, Example 11(a), (1.0 g, 5.0 mmol) provided, after recrystallization from EtOH, the title product. MS (ESI, pos. ion) inhz: 179 1).

(2E)-3-14-(tert-Butyl)phenyl]-N-(4-methyl-3-oxo(2H-benzole] 1,4oxazaperhydroin-7-yl))prop-2-enamide. Analogous to the procedure used to prepare Example 1, 4-tert-butyl-trans-cinnamic acid (200 mg, 1.0 mmol, EMKA- Chemie) and 7-amino-4-methyl-2H-benzo[e]1I,4-oxazaperhydroi n-3 -one, Example.lib, (164 mg, 1.0 mmol) provided, after purification by silica gel chromatography (85:15 CH 2

CI

2 :EtOAc), the ti tle product as a pale yellow solid.

MT 194-195 MS (ESI, pos. ion) mn/z: 365 214 Example 12

H

YN 0 0

N

CH

3 (2E)-3-[4-(tert-Butyl)phenyl]-N-(4-methyl(2H,3H-benzo[eI 1,4oxazaperhydroin-7-yl))prop-2-enamide.

Analogous to the procedure used for the preparation of Example 10, 7-amino-4methyl -2H-benzo le] 1,4-ox azaperhydroin-3 -one, Example 11(b), (180 mg, mmol) and 4-tert-butyl-trans-cinnamic acid (200 mg, 1.0 mmol, EM4KA-( Chemie) provided, after purification by silica gel chromatography (85:15

CH-

2

CI

2 :EtOAc), the title product as a pale yellow solid. MW 232-233 MS (ESI, pos. ion) m/z: 351 Example 13 Ethyl (2E)-3-[4-(tert-butyl)phenyllprop-2-enoylamino)-2H,3H,4Hbenzo[eI 1,4-oxazaperhydroine-2-carboxylate.

02NyN> 0 CO 2 Et Ethyl 6-nitro-2H,3H,4H-benzo[e] 1,4-oxazaperhyd roine-2-carboxylate. A solution of ethyl 2,3-dibromopropionate (4.8 mL, 33 mmol, Aldrich) in acetone mL, Aldrich) was added to a mixture of 2-amino-4-nitrophenol (4.6 g, mmol, Aldrich) in 80 mL of acetone in a 150 mL round-bottomed flask at 2 0 TC. After the addition, the mixture was stirred at 60 'C for 48 h. The solvent was removed in vacuo, and the residue was treated with water (30 mL) and extracted with CH 2

CI

2 x 50 mL). The combined organic phases were washed with satd NaCI (10 mL), dried over Na 2

SO

4 filtered and concentrated in vacuo. The -215 residue was purified by silica gel chromatography (9:1 CH 2 Cl 2 :EtOAc) to give the title product. MS (ESI, pos. ion) mz/z: 253 1).

H

H2N N 01CO 2 Et Ethyl 6-amino-211,3H,4H-benzo[e] 1 ,4-oxazaperhyd roi ne-2-ca rboxyl ate.

Analogous to the procedure used to prepare Example ethyl 6-nitro- 2H,3H,4H-benzo[eI I ,4-ox azaperhydroine-2-c arbox yl ate, Example 13(a), (1.3 g, mmol) provided the title product. MS (ESI, pos. ion) m/z: .223 Analogous to the procedure used to prepare Example 1, 4-tert-butyl -transcinnamic acid (1.3 g, 6.4 mmol, EMKA-Chemie) and ethyl 6-amino-2H,3H,4Hbenzo[e] 1,4-ox azaperhydroine-2-carboxyl ate, Example 13(b), (1.4 g, 6.4 mmol) provided, after purification by silica gel chromatography (85:15 CH 2

CI

2 :EtOAc), the title product as a pale yellow solid. M4P 207-208 MS (ESI, pos. ion) m/z: 409 Example 14 0 AI0 ,OH (tert-Butyl)phenyl-N-[2-(hydroxymethyl)(211,3H,4H-benzo[3,4e] 1,4-oxazaperhyd roin.6-yl)]prop-2-enamide.

A solution of ethyl 6- {(2E)-3-[4-(tert-butyl)phenyl] prop-2-enoyl aminio) 2H,3H,4H-benzo~e] 1,4-oxazaperhydroi ne-2-carbox yl ate, Example 13, (410 mg, 1.0 mmol) in THE (5 m.L, Aldrich), magnetically stirred in a round-bottomed flask under N 2 at 0 0 C, was treated with lithium borohydride (1.5 mL, 3.0 mmol, 2.0 M in THE, Aldrich). The reaction mixture was allowed to warmn to 25 TC, and stirred at that temperature for 3 h. The reaction was quenched by the addition of satd N1-L4Cl (5 mL), stirred for 30 min at 25 'C and extracted with EtOAc (2 x 15 mL).

The combined organic extract was washed with satd NaCI, dried over Na 2

SO

4 filtered and concentrated in vacuo. Purification by silica gel chromatography 1 -216-

CH

2

CI

2 :EtOAc) provided the title product as a pale yellow solid. MP 165- 167 0 C. MIS (ESI, pos. ion) mn/z: 367 (M+i1).

Example

HO

0 [(3S).3-(Hydroxymethyl)(2H,3H-benzofeI 1,4-dioxan-6-yI)I-3-[4-(tertc-I butyl)phenyllprop-2-enamide.

0 2 N <CHO( L~L~ H 2-[((2R)Oxiran-2-yl)mrethoxy]-5-nitrobenzaldehyde. A mixture of glycidyl tosylate (1.1 g, 5 mmol, Aldrich), (840 mgr, 5.0 mmol, Aldrich) and solid K 2 C0 3 (1.4 g, 10 mmol) in DWi (5 mL,.

Aldrich) was magnetically stirred in a round-bottomed flask at 100 'C under N 2 for 30 min. The reaction mixture was allowed to cool to 25 water (20 mL) was added, arnd the mixture was extracted wt t~ 3x3ri) h combined extracts were washed with water (2 x 20 inL), satd NaCI (10 mL), dried over Na 2

SO

4 filtered and concentrated in vacuo. Purification by silica gel chromatography (4:1 hexane:EtOAc) provided the title product. MS (ESI, pos.( ion) m/z: 224 1).

0 2 N 0

O

(b ((2S)-7-Nitro-2H,3H-benzo[e] 1,4-dioxan-2-yl)methan- 1-ol. To a solution of 2- [((2R)oxiran yl) methox y]-5 -n itrobenzaldeh yde, Example 15(a), (670 mg, mmol) in CH 2

CI

2 (10 mL), magnetically stirred in a round-bottomed flask at 0 ',was added 86% m-chloroperbenzoic acid (350 mg, 2.0 mmol, Aldrich). The reaction mixture was allowed to warm to 25 'C and stirred at that temperature for 18 h. The mixture was then diluted with CH 2

CI

2 (20 washed with Na 2

S

2

O

3 (3 mL), NaHCO 3 (3 x 5 mL), satd NaCI (3 mL), dried over Na 2

SO

4 -217filtered arnd concentrated in vacuo. The resulting residue was treated with MeOImL) and I N NaOH (6 mL) and stirred at 25 'C for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 10 m.L).

The combined organic extracts were washed with satd NaCI, dried over Na 2

SO

4 filtered and concentrated in vacuo. Purification by silica gel chromatography (3:2 hexane:EtOAc) provided the product. MS (ESI, pos. ion) m/z: 212 (Hydroxymethyl)(2H,3H-benzo[e] 1,4-dioxan-6-yl)] [4- (tert-butyl)phenyllprop-2-enamide. A mixture of ((2S)-7-nitro-2H,3Hbenzo[e] 1,4-dioxan-2-yl)methan-1I-ol, Example 15(b), (1 10 mg, 0.5 mmol) and 10% Pd on carbon (20 mg, Aldrich) in MeOH (5 mL), in a round-bottomed flask, was magnetically stirred under I atm H 2 for 2 h. The mixture was purged with

N

2 filtered through a pad of Celite and concentrated in vacuo to provide the crude aniline [MS (ESI, pos. ion) m/z: 182 Analogous to the procedure used to prepare Example 1, 4-tert-butyl-trans-cinnamic acid (102 mg, 0.5 mmol, EMKA Chemie) and the crude aniline, provided the title product as a white solid. MIP 169-171 MS (ESI, pos. ion) rn/z: 368 Example 16 0 0 [(3R)-3-(llyd roxymethyl)(2H,3H-benzo[e] 1,4-d ioxan-6-yI)]-3-[4-( tertbutyl)phenyllprop-2-enamide.

Analogous to the procedure described for Example 15, the title product was prepared starting from (S)-glycidyl tosylate (Aldrich), nitrobenzaldehyde (Aldrich) and 4-tert-butyl-trans-cinnamic acid (EMKA Chemie). MP 170-171 0 C. MS (ESI, pos. ion) rn/z: 368 Example 17

HO

-218- (2E)-N-[(2R)-2-(Hydroxymethyl)(2H,3H-benzo[3,4-e] 1,4-dioxan-6-yl)]-3-[4- (tert-butyl)phenyl]prop-2-enamide.

02N OMe

'.ZOH

(2-Methoxy-4-nitrophenyl)methan-l-ol. To a solution of 2-methoxy-4nitrobenzoic acid (2.0 g, 10 mmol, Aldrich) in THF (30 mL), magnetically stirred at 0 OC under N 2 in a round-bottomed flask equipped with a reflux condenser, was added borane-THF complex (30 mL, 30 mmol, 1.0 M in THF, Aldrich). The reaction mixture was stirred at reflux overnight. The reaction was quenched by the careful addition of MeOH (5 mL), followed by 1 N NaOH (30 mL). The mixture was extracted with EtOAc (2 x 50 mL), the combined organic extracts were washed with satd NaCI, dried over Na2SO4, filtered and concentrated in vacuo to give the product. MS (ESI, neg. ion) m/z: 182 0 2 N OMe

,O

2-Methoxy-4-nitrobenzaldehyde. A mixture of (2-methoxy-4nitrophenyl)methan-l-ol, Example 17(a), (1.6 g, 8.9 mmol) and MnO 2 (15 g, 180 mmol, Aldrich) in 1:1 hexane: CH 2

CI

2 (60 mL) was magnetically stirred at °C for 3 h. The solid was removed by filtration and washed with CH 2 C1 2 The filtrate was concentrated in vacuo and the residue was recrystallized from EtOAc and hexane to give the title product. MS (ESI, neg. ion) m/z: 180 0 2 N OH 2-Hydroxy-4-nitrobenzaldehyde. To a solution of 2-methoxy-4nitrobenzaldehyde, Example 17(b), (190 mg, 1.0 mmol) in CH 2 C2 (5 mL), magnetically stirred at -78 °C in a round-bottomed flask, was added BBr 3 (0.19 mL, 2.0 mmol, Aldrich). The reaction mixture was allowed to warm to OC and stirred at that temperature for 2 h. The reaction mixture was then cooled to -78 and treated with MeOH (5 mL). The mixture was allowed to warm to OC, stirred at that temperature for 30 min, then concentrated in vacuo. Purification -219by silica gel chromatography (3:2 hexane:EtOAc) provided 2-hydroxy-4nitrobenzaldehyde. MS (ESI, neg. ion) m/z: 166 roxymethyl)(2H,3H-benzo[3,4-e] 1,4-dioxan-6-yl)]-3- [4-(tert-butyl)phenyllprop-2-enamide. Analogous to the procedure described for Example 15, the title product was obtained as a white solid from 2-hydroxy-4nitrobenzaldehyde, Example 17(c), (S)-glycidyl tosylate (Aldrich) and 4-tertbutyl-trans-cinnamic acid (EMKA-Chemie). M4P 159-160 MS (ESI, pos.

ion) m/z: 368 Example 18 N0 0tr-uy~hnl (2E)-N-[(2S)-2-(Hydroxymethyl)(2H,3H-berizo[3,4-ell ,4-dioxan-6-yl)I-3-[4- (tet-btylpheylprop-2-enamide.

Analogous to the procedure described for Example 15, the title product was prepared starting from 2-hydrbxy-4-nitrobenzaidehyde, Example 17(c), glycidyl tosylate (Aldrich) and 4-tert-butyl-trans-cinnamic acid (EM4KA Chemie).

MP 169-170 MS (ESI, pos. ion) m/lz: 368 Example 19 H H (2E)-3-[4-(tert-Butyl)phenyl]-N-(7-1 ,2,3,4-tetrahydroqu inolyl)prop-2enamide.

H

0 2

NN

7-Nitro-1,2,3,4-tetrahydroquinoline. To a round-bottomed flask equipped with magnetic stirring was added 1,2,3,4-tetrahydroquinoline (6.3 mL, 50 mniol, -220- Aldrich) and 96% H 2 S0 4 (42 mL). The mixture was stirred until all of the amine had dissolved, then cooled to 0 °C and treated with KNO 3 (5.9 g, 59 mmol) in portions. The reaction mixture was allowed to warm to 25 oC and stirred overnight at that temperature. The mixture was then cooled to 0 oC and neutralized with solid NaOH followed by 5 N NaOH until pH 11 was reached.

The mixture was extracted with CH 2

CI

2 and the extract was dried over Na 2

SO

4 filtered and concentrated in vacuo. Purification by silica gel chromatography (8:1 hexane:EtOAc) provided 7-nitro-l,2,3,4-tetrahydroquinoline as an orange solid.

MS (ESI, pos. ion) m/z 179

H

H

2 N N

)DO

7-1,2,3,4-Tetrahydroquinolylamine. Analogous to the procedure used to prepare Example 7-nitro-l,2,3,4-tetrahydroquinoline, Example 19(a), (0.35 g, 2.0 mmol) provided the aniline as a pale gray oil. MS (ESI, pos. ion) m/z: 149 (2E)-3-[4-(tert-Butyl)phenyl]-N-(7-1,2,3,4-tetrahydroquinolyl)prop-2enamide. Analogous to the procedure used to prepare Example 1, 7-1,2,3,4tetrahydroquinolylamine, Example 19(b), (280 mg, 1.9 mmol) and 4-tert-butyltrans-cinnamic acid (0.33 g, 1.6 mmol, EMKA-Chemie) provided, after purification by silica gel chromatography (3:1 hexane:EtOAc) then recrystallization from EtOAc and hexane, the title product as a yellow solid. MP 225-227 OC. MS (ESI, pos. ion) m/z: 335 -221- Example O H CH3 (2E)-3-[4-(tert-Butyl)phenyl]-N-(1 -methyl(7-1,2,3,4-tetrahydroquinolyl))prop-2-enamide.

CH

3 0 2 N N 1-methyl-7-nitro-1,2,3,4-tetrahydroquinoline. To a solution of 7-nitro- 1,2,3,4-tetrahydro-quinoline, Example 19(a), (0.36 g, 2 mmol) in DMF (10 mL), magnetically stirred under N 2 at 0 OC in a 15 mL round-bottomed flask, was added sodium hydride (0.12 g, 3 mmol, 60% dispersion in mineral oil, Aldrich). After stirring for 10 min, the reaction mixture was treated with iodomethane (0.24 mL, 4 mmol, Aldrich) dropwise. The reaction mixture was stirred at 0 oC for 1 h, at 'C for an additional I h, then partitioned between EtOAc and satd NaCI. The aqueous layer was extracted with EtOAc (40 mL) and the combined organic extract was dried over Na 2

SO

4 filtered and concentrated in vacuo. Purification by silica gel chromatography (7:1 hexane:EtOAc) provided the product as an orange oil. MS (ESI, pos. ion) m/z: 193 (2E)-3-[4-(tert-Butyl)phenyl]-N-(1-methyl(7-1,2,3,4-tetrahydroquinolyl))prop-2-enamide. Analogous to the procedure described for Example 19, steps 1-methyl-7-nitro-1,2,3,4-tetrahydroquinoline, Example 20(a), (240 mg, 1.3 mmol) and 4-tert-butyl-trans-cinnamic acid (0.23 g, 1.1 mmol, EMKA- Chemie) provided, after purification by silica gel chromatography (4:1 hexane:EtOAc) then recrystallization from EtOAc and hexane, the title product as a yellow solid. MNIP 200-202 OC. MS (ESI, pos. ion) m/z: 349 222 Example 21 -I H

NN

H

(2E)-3-[4-(tert-Butyl)phenyl]-N-(2-oxo(6- 1,3,4-trihyd roquinolyl))prop-2enamide.

0 2N

N

(a)6-Ntro1,34-tihyroquinolin-2-one. To a round-bottomed flask equipped mml lrc)ad96% H, 2 S0 4 (8.3 mL). The mixture was stirred until all of the material was dissolved, then cooled to 0 T and. treated. with KNO 3 (1.2 g, 11.7 mmol) in portions. The reaction mixture was allowed to warm to 25 'C and stirred at that temperature overnight. The mixture was basified to pH 9 with NaOH, resulting in a precipitate. The solid was collected by filtration, washed with water and dried in vacuo at 50 'C to provide the title product as a yellow solid. MS (ESI, pos. ion) nz/z: 193 1).

H

2

N(

H

6-Amino-i ,3,4-trihyd roquinolin-2-one. Analogous to the procedure used to prepare Example 6-nitro- 1,3,4-trihydroquinolin-2-one, Example 21(a), (1.7 g, 8.9 mmol) was converted to the title product as a tan solid. MS (ESI, pos. ion) m/z: 163 (2E)-3-14-(tert-Butyl)phenyl]-N-(2-oxo(6-1 ,3,4-trihydroquinolyl))prop-2enamide. Analogous to the procedure used to prepare Example 1, 6-amino- 1,3,4-trihydroquinolin-2-one, Example 21(b), (0.68 g, 4.2 mmol) and 4-tertbutyl-trans-cinnamic acid (0.86 g, 4.2 mmol, EMKA-Chemie) provided, after recrystallization from MeGH, the title product as a pale yellow solid. MP 275- 276 T. MS (ESI, pos. ion)rin/z: 349 -223- SExample 22 c3 H H 0N O (2E)-3-[4-(tert-Butyl)phenyl]-N-(2-oxo(7-1,3,4-trihydroquinolyl))prop-2- Senamide.

O

2 N N0 NO 2 O JCO 2 Et Ethyl 3-(2,4-dinitrophenyl)prop-2-enoate. A suspension of sodium hydride g, 50 mmol, 60% dispersion in mineral oil, Aldrich) in anhydrous THF (100 mL) was magnetically stirred under N 2 at 25 OC and treated dropwise with triethyl phosphonoacetate (10 mL, 11 g, 51 mmol, Aldrich). The reaction mixture was stirred for 1 h at 25 °C then treated with 2,4-dinitrobenzaldehyde (9.0 g, 46 mmol, Aldrich) in portions. After stirring overnight at 25 the reaction was quenched by the addition of water (50 mL) and concentrated in vacuo to remove the THF. The remaining aqueous mixture was extracted with EtOAc (2 x 150 mL). The combined organic extract was washed with water (4 x 100 mL), satd NaCI (75 mL), dried over Na 2

SO

4 filtered and concentrated in vacuo.

Purification by silica gel chromatography (1:4 hexane:EtOAc) provided the title product as a dark oil.

H

HzN N O 7-Amino-l,3,4-trihydroquinolin-2-one. Ethyl 3-(2,4-dinitrophenyl)prop-2enoate, Example 22(a), (3.0 g, 11 mmol) was dissolved in glacial acetic acid (240 mL), treated with 10% Pd on carbon (2.4 g, Aldrich) and hydrogenated on a Parr shaker apparatus at 65 under 60 psi H 2 for 3 h. The reaction mixture was allowed to cool to 25 purged with N 2 filtered through Celite and the filtercake washed with acetic acid (200 mL) and EtOH (200 mL). The combined filtrate was concentrated in vacuo, then treated with 1 N NaOH (150 mL) and extracted with EtOAc (3 x 100 mL). The combined organic extract was washed with satd -224- NaCI (50 mL), dried over Na 2

SO

4 filtered and concentrated in vacuo.

Purification by silica gel chromatography (EtOAc) provided the title product as a pale yellow solid. MS (ESI, pos. ion) n/z: 163 (2E)-3-[4-(tert-Butyl)phenyl]-N-(2-oxo(7-1,3,4-trihydroquinolyl))prop-2enamide. Analogous to the procedure used to prepare Example 1, 7-amino- 1,3,4-trihydroquinolin-2-one, Example 22(b), (300 mg, 1.8 mmol) and 4-tertbutyl-trans-cinnamic acid (370 mg, 1.8 mmol, EMKA-Chemie) provided the title product as white crystals. MP 288-290 OC. MS (ESI, pos. ion) m/z: 349 Example 23

H

HN'. NOH 0 (2E)-3-[4-(tert-Butyl)phenyl]-N-(3-hydroxyphenyl)prop-2-enamide. To a round-bottomed flask equipped with magnetic stirring was added 4-tert-butyltrans-cinnamic acid (530 mg, 2.43 mmol, EMKA-Chemie), CH 2 C12 (10 mL), and DMF (10 uL, Aldrich) under N 2 The solution was treated dropwise with oxalyl chloride (3.0 mL, 6.0 mmol, 2.0 M in CH 2 C12, Aldrich) then stirred at 25 °C for 1 h. The reaction mixture was concentrated in vacuo and treated with 3aminophenol (265 mg, 2.43 mmol, Aldrich), THF (20 mL) and satd K 2 CO3 mL). The reaction mixture was stirred at 25 °C overnight, then acidified to with I N HCI. The mixture was extracted with EtOAc (2 x 30 mL), the combined organic extract was dried and concentrated in vacuo. Purification by silica gel chromatography (2:1 hexane:EtOAc) provided the title product as an oil.

MS (ESI, pos. ion) m/z: 296 -225- Example 24 N O CO 2

H

0 1 2-(3-{(2E)-3-[4-(tert-Butyl)phenyl]prop-2-enoylaminophenoxy)acetic acid.

To a round-bottomed flask equipped with magnetic stirring was added (tert-butyl)phenyl]-N-(3-hydroxyphenyl)prop-2-enamide, Example 23, (120 mg, 0.407 mmol), THF (10 mL), tert-butyl bromoacetate (60 uL, 0.407 mmol, Aldrich) and 5 N NaOH (10 mL). The reaction mixture was stirred at 25 °C overnight. The mixture was extracted with EtOAc (20 mL), the organic extract washed with water (20 mL), dried over Na 2

SO

4 filtered and concentrated in vacuo. The resulting residue was treated with trifluoroacetic acid (10 mL), stirred at 25 °C for 2 h, then concentrated in vacuo. Purification by silica gel chromatography (1:2 hexane:EtOAc) provided the title product as an off-white solid. MP 166-172 oC. MS (ESI, pos. ion) m/z: 354 Example I H 0 (2E)-3-[4-(tert-Butpyl)phenyl-N-[3-(2-hydroxyethoxy)phenylprop-2-enamide.

To a round-bottomed flask, equipped with magnetic stirring and reflux condenser, was added (2E)-3 [4-(tert-butyl)phenyl ]-N-(3-hydroxyphenyl)prop-2-enamide, Example 23, (200 mg, 0.68 mmol), THF (10 mL), 2-bromoethanol (200 uL, 2.80 mmol, Aldrich) and 5 N NaOH (10 mL). The reaction mixture was stirred at reflux for 5 h. After allowing to cool to 25 the mixture was extracted with EtOAc (20 mL). The organic extract was washed with water (20 mL), dried over Na 2

SO

4 filtered and concentrated in vacuo. Purification by silica gel chromatography (2:1 hexane:EtOAc) provided the title product as a colorless oil.

MS (ESI, pos. ion) m/z: 340 226 C Example 26

H

F--

I N O OCH3 0 (2E)-3-[4-(tert-Butyl)phenyl]-N-[3-(2-methoxyethoxy)phenyl]prop-2- CI enamide.

0 -H2NO

O

OCH

OH 3 3-(2-Methoxyethoxy)phenylamine. To a round-bottomed flask equipped with magnetic stirring was added 3-aminophenol (1.2 g, 11 mmol, Aldrich), THF mL) and sodium hydride (440 mg, 11 mmol, 60% in mineral oil, Aldrich) at 0 The reaction mixture was allowed to stir at 0 OC for 30 min, then 2bromoethyl methyl ether (1.0 mL, 11 mmol, Aldrich) was added dropwise. The reaction mixture was stirred at 25 °C overnight, then cooled to 0 °C and quenched with satd NaCI (10 mL). The mixture was extracted with EtOAc (20 mL) and the organic phase was washed with water (20 mL), dried over Na 2

SO

4 filtered and concentrated in vacuo to provide the title product. MS (ESI, pos. ion) m/z: 168 (2E)-3-[4-(tert-Butyl)phenyl]-N-[3-(2-methoxyethoxy)phenyl]prop-2enamide. Analogous to the procedure used to prepare Example 2, 3-(2methoxyethoxy)phenylamine, Example 26(a), (350 mg, 2.45 mmol) and 4-tertbutyl-trans-cinnamic acid (500 mg, 2.45 mmol, EMKA-Chemie) provided, after purification by silica gel chromatography (5:1 hexane:EtOAc), the title product as a colorless oil. MS (ESI, pos. ion) m/z: 354 -227- Example 27 oo

H

N ON 0 I~ o0 (2E)-3-[4-(tert-Butyl)penyll-N-{3-[2-(1,3-dioxobenzo[c]azolin-2yl)ethoxy]phenyl)prop-2-enamide.

0 0 2 N O N 0 2-[2-(3-Nitrophenoxy)ethyl]benzo[c]azoline-1,3-dione. To a roundbottomed flask, equipped with magnetic stirring, an addition funnel and a reflux condenser, was added 3-nitrophenol (2.0 g, 14 mmol, Fluka), triphenylphosphine (4.9 g, 19 mmol, Aldrich) and DMF (20 mL). A solution of N-[2-hydroxyethyl] phthalimide (2.7 mg, 14 mmol, Aldrich) and diethyl azodicarboxylate (3.3 g, 19 mmol, Aldrich) in DMF (20 mL) was added dropwise through the addition funnel at 25 The reaction mixture was stirred at 60 *C for 12 h. The reaction mixture was concentrated in vacuo, dissolved in EtOAc (55 mL), and washed with satd NaCI (20 mL) and water (20 mL). The organic phase was dried over Na 2

SO

4 filtered and concentrated in vacuo. Purification by silica gel chromatography (2:1 hexane:EtOAc) provided the title product. MS (ESI, pos.

ion) m/z: 313

O

H

2 N O

N

O

0 2-[2-(3-Aminophenoxy)ethyl]benzo[c]azoline-1,3-dione. In a roundbottomed flask, equipped with magnetic stirring, a solution of nitrophenoxy)ethyl]benzo[c]azoline-1,3-dione, Example 27(a), (1.9 g, 6.1 mmol) in 0.5% acetic acid in EtOAc (10 mL), under N 2 was treated with 10% Pd on carbon (500 mg, Aldrich). The suspension was purged with H 2 and stirred under 1 atm H 2 at 25 'C overnight. The suspension was purged with N 2 and filtered -228through a pad of Celite. The solvent was removed in vacuo to provide the title In product.

(2E)-3-[4-(tert-Butyl)phenyl]-N-(3- ,3-dioxobenzo[c]azolin-2yl)ethoxylphenyllprop-2-enamide. Analogous to the procedure used to prepare Example 2, 2-[2-(3-aminophenoxy)ethyl]benzoliclazoline-1,3-dione, Example 27(b), (1.7 g, 6.1 mmol) and 4-tert-butyl-trans-cinnamic acid (1.2 g, 6.0 mmol, c-i EMKA-Chemie) provided, after purification by silica gel chromatography (3:1 hexane:EtOAc), the title product as an off-white film. MIS (ESI, pos. ion) mlz: c-I 469 Example 28 (2-A minoetlioxy)p heniyl] (tert- butyl)phenyl] prop -2-enamide.

To a round-bottomed flask equipped with magnetic stirring was added Example 27, (2E)-3-[4-(tert-butyl)phenyl]-N- {3-[2-(1I,3-dioxobenzo[c]azolin-2yl)ethoxylphenyllprop-2-enamide, (856 mg, 1.83 mmol), EtOH (15 mL) and hydrazine (574 uL, 18.3 mmol, Aldrich). The reaction mixture was stirred at 'C for 2 h. The mixture was concentrated in vacuo, the residue dissolved in EtOAc (40 mL), washed with 10% K 2

C

3 (15 mL), water (15 mE), dried over Na 2

SO

4 filtered and concentrated in vacuo. Purification by silica gel( chromatography (step gradient, EtOAc followed by 1: 1 EtOAc:EtOH) provided the title product as an oil. MS (ESI, pos. ion) mlz: 339 -229- Example 29 O H

N

(2E)-3-[4-(tert-Butyl)phenyl]-N-indolin-6-ylprop-2-enamide.

tert-Butyl 6-(1-aza-2,2-diphenylvinyl)indolinecarboxylate. To a solution of benzophenone imine (0.91 g, 5.0 mmol, Aldrich) in CH 2 C1 2 (35 mL), magnetically stirred at 25 °C in a round-bottomed flask, was added a solution of 6-aminoindoline dihydrochloride (1.04 g, 5.0 mmol, Biosynth AG) in CH 2 C12 mL). The reaction mixture was stirred at 25 °C for 12 h, then diluted with

CH

2 C1 2 (30 mL), washed with water (30 mL), satd NaCI (30 mL), dried over MgSO 4 filtered and concentrated in vacuo. The crude product [MS (ESI, pos. ion) m/z: 299 was dissolved in 1,4-dioxane and treated with di-tertbutyl dicarbonate (8.0 mL, 8.0 mmol, 1.0 M in THF, Aldrich) and 5 N aq. Na 2

CO

3 mL). The reaction mixture was magnetically stirred at 25 °C until complete, then diluted with water (30 mL), and extracted with EtOAc (3 x 30 mL). The combined organic extract was washed with satd NaCI (30 mL), dried over MgSO 4 filtered and concentrated in vacuo. Purification by silica gel chromatography (4:1 hexane EtOAc) provided the title product. MS (ESI, pos.

ion) m/z: 399 O O

H

2 N NI tert-Butyl 6-aminoindolinecarboxylate. In a round-bottomed flask, a solution of tert-butyl -aza-2,2-diphenylvinyl)indolinecarboxylate, Example 29(a), (0.80 g, 2.0 mmol) in 1,4-dioxane (10 mL) was treated with 1 N aq. HCI mL). The reaction mixture was magnetically stirred overnight at 25 OC, then -230diluted with water (20 mL) and extracted with ethyl ether (30 mL). The aqueous phase was treated with 5 N NaOH (10 mL) and extracted with ethyl ether (3 x mL). The combined organic extracts were dried over MgSO 4 filtered and concentrated in vacuo. Purification by silica gel chromatography (3:2 hexane EtOAc) provided the title product. MS (ESI, pos. ion) m/z: 235 (2E)-3-[4-(tert-Butyl)phenyl]-N-indolin-6-ylprop-2-enamide. Analogous to the procedure used to prepare Example 1, tert-butyl 6-aminoindolinecarboxylate, Example 29(b), (230 mg, 1.0 mmol) and 4-tert-butyl cinnamic acid (200 mg, 1.0 mmol, EMKA-Chemie) provided, after purification by silica gel chromatography (7:3 hexane EtOAc), a crude product which was dissolved in

CH

2 C1 2 (5 mL) and treated with 4 N HCI in dioxane (5 mL, Aldrich). The reaction mixture was magnetically stirred at 25 °C for 1 h, then washed with 5 N NaOH (15 mL), satd NaCI (15 mL), dried over MgSO 4 filtered and concentrated in vacuo. Purification by silica gel chromatography (55:45 hexane EtOAc) provided the title product. MP 153-167 MS (ESI, pos. ion) m/z: 321 Example H CH3 (2E)-3-[4-(tert-Butyl)phenyl]-N-(l-methylindolin-6-yl)prop-2-enamide.

CH

3

H

2

N

1-Methylindoline-6-ylamine. To a round-bottomed flask was added 6nitroindoline (1.64 g, 10.0 mmol, Aldrich), 37% aq. formaldehyde (2.35 g, 30.0 mmol, Aldrich) and THF (40 mL). The reaction mixture was magnetically stirred at 25 oC and treated with sodium cyanoborohydride (1.89 g, 30.0 mmol, Aldrich). The reaction mixture was allowed to stir at 25 °C for 30 min, then washed with satd NazCO 3 The aqueous phase was extracted with ethyl ether, the organic phases combined and concentrated in vacuo to a residue. Analogous to the procedure of Goswami, Chowdhury, Indian J Chem, Sect B, 1997, 36 -231- 185-186, the crude residue was dissolved in tetrahydrofuran (60 mL) and added to Zn dust (0.43 g, 6.6 mmol, Aldrich) and AIC13.6H 2 0 (9.6 g, 40 mmol, Aldrich) in water (2 mL), magnetically stirred at 25 The reaction mixture was stirred at 25 °C for 16 h, then filtered. The filtrate was added to cold water (300 mL) and extracted with CH 2

CI

2 (3 x 100 mL). The combined organic extract was concentrated in vacuo to provide the title product as a brown solid. MS (ESI, pos. ion) m/z: 149 (2E)-3-[4-(tert-Butyl)phenyl]-N-(1-methylindolin-6-yl)prop-2-enamide.

Analogous to the procedure used to prepare Example 1, l-methylindoline-6ylamine, Example 30(a), (150 mg, 1.0 mmol) and 4-tert-butyl-trans-cinnaric acid (200 mg, 1.0 mmol, EMKA-Chemie) provided the title product as an amorphous yellow solid. MS (ESI, pos. ion) m/z: 335 Example 31

H

S N (2E)-N-(1-Acetyl-3,3-dimethylindolin-6-yl)-3-[4-(tert-butyl)phenyl]prop-2enamide.

O0 0 2 N NH Br N-(2-Bromo-5-nitrophenyl)acetamide. A solution of nitroaniline (43 g, 0.20 mol, Aldrich) in glacial acetic acid (1.3 magnetically stirred at 25 was treated with acetic anhydride (20 mL, 0.21 mol). The reaction mixture was allowed to stir at 25 °C overnight, then quenched by pouring into water (6 The precipitate was collected by filtration, washed with water, and dried in vacuo to provide the title product as an off white solid. MS (ESI, pos. ion) m/z: 259, 262 M+3).

-232- 0 2 N cN I O -Br N-(2-Bromo-5-nitrophenyl)-N-(2-methylprop-2-enyl)acetamide. To a flame-dried round-bottomed flask, equipped with magnetic stirring and an addition funnel, was added N-(2-bromo-5-nitrophenyl)acetamide, Example 31(a), (48 g, 0.19 mol), solid potassium carbonate (103 g, 744 mmol) and anhydrous SDMF (830 mL). The resulting solution was stirred at 25 °C and treated dropwise, through the addition funnel, with a solution of 3-bromo-2-methylpropene (38 mL, 380 mmol, Aldrich) in anhydrous DMF (100 mL) over 45 min. The reaction mixture was stirred at 25 °C overnight, then filtered and treated with satd NaHCO 3 The organic layer was removed and the aqueous layer was extracted with EtOAc (3 x 150 mL). The combined organic extracts were washed with water (4 x 70 mL), satd NaCI (70 mL), dried over MgSO 4 filtered and concentrated in vacuo to provide the title product as a golden solid. MS (ESI, pos.

ion) m/z: 313, 315 M+3).

0 2

N

1-Acetyl-3,3-dimethyl-6-nitroindoline. To a flame-dried round-bottomed flask, equipped with magnetic stirring, was added (2-methylprop-2-enyl)acetamide, Example 31(b), (55 g, 0.18 mol), tetraethylammonium chloride hydrate (30.8 g, 186 mmol, Aldrich), sodium formate (14.4 g, 212 mmol, Aldrich), sodium acetate (36.3 g, 443 mmol) and anhydrous DMF (443 mL). The resulting solution was purged with N 2 and treated with palladium (II) acetate (3.97 g, 17.7 mmol, Aldrich). The reaction mixture was stirred in an oil bath at 80 °C for 15 h, then allowed to cool to 25 °C and filtered through a pad of Celite. The Celite was washed with EtOAc and the combined filtrate was washed with satd NaHCO 3 (500 mL). The aqueous layer was extracted with EtOAc (3 x 100 mL) and the combined organic extract was washed with water (4 x 100 mL), satd NaCI (2 x 100 mL), dried over MgSO 4 i. -233filtered and concentrated in vacuo to provide 1-acetyl-3,3-dimethyl-6nitroindoline as a brown solid. MS (ESI, pos. ion) m/z: 235 (2E)-N-(1-Acetyl-3,3-dimethylindolin-6-yl)-3-[4-(tert-butyi)phenyl]prop- 2-enamide. To a solution of 1-acetyl-3,3-dimethyl-6-nitroindoline, Example 31(c), (110 mg, 0.47 mmol) in ethyl ether (3 mL), magnetically stirred in a roundbottomed flask at 0 was added tin (II) chloride dihydrate (0.67 g, 2.96 mmol, Aldrich) and cond HCI (0.3 mL). The reaction mixture was stirred at 0 "C for min, allowed to warm to 25 OC then stirred at that temperature overnight. The reaction mixture was washed with 10 N NaOH (10 mL), extracted with EtOAc and concentrated in vacuo. Analogous to the procedure used to prepare Example 1, the crude product and 4-tert-butyl-trans-cinnamic acid (92 mg, 0.45 mmol, EMKA-Chemie) provided, after purification by silica gel chromatography (2:3 hexane:EtOAc), the title product. MP 121 MS (ESI, pos. ion) m/z: 391 Example 32 H CH 3

ON

(2E)-3-[4-(tert-Butyl)phenyl]-N-(1,3,3-trimethylindolin-6-yl)prop-2-enamide.

0 2

NI

3,3-Dimethyl-6-nitroindoline. To a round-bottomed flask, equipped with magnetic stirring and a reflux condenser, was added 1-acetyl-3,3-dimethyl-6nitroindoline, Example 31(c), (1.73 g, 7.39 mmol) and EtOH (20 mL). The solution was treated with 12 N HCI (20 mL) then stirred and heated at reflux for 2 h. The reaction mixture was cooled to 0 providing a precipitate which was collected by filtration and dried in vacuo to afford the title product as an off-white solid. MS (ESI, pos. ion) m/z: 193 -234- N H2N 1,3,3-Trimethylindoline-6-ylamine. A solution of 3,3-dimethyl-6- Snitroindoline, Example 32(a), (0.23 g, 1.2 mmol) in anhydrous DMF (15 mL) was magnetically stirred at 25 °C and treated with sodium hydride (0.14 g, 3.6 mmol, 60% dispersion in mineral oil, Aldrich), followed by iodomethane S(0.17, 1.3 mmol, Aldrich). The reaction mixture was stirred at 25 °C for 3 h, then C, quenched with water (40 mL) and extracted with EtOAc (3 x 30 mL). The combined extract was concentrated in vacuo to provide a residue [MS (ESI, pos.

ion) m/z: 207 which was immediately dissolved in ethyl ether (5 mL), magnetically stirred at 0 and treated with tin (II) chloride dihydrate (1.7 g, mmol, Aldrich) and cond HCI (0.8 mL). The reaction mixture was stirred at 0 °C for 10 min, allowed to warm to 25 then stirred at that temperature overnight. The reaction mixture was washed with 10 N NaOH (20 mL) and extracted with EtOAc (3 x 50 mL). The combined extracts were concentrated in vacuo and purified by silica gel chromatography to provide the title product. MS (ESI, pos. ion) m/z: 177 (2E)-3-[4-(tert-ButyI)phenyl]-N-(1,3,3-trimethylindolin-6-yl)prop-2enamide. Analogous to the procedure used to prepare Example 1, 1,3,3trimethylindoline-6-ylamine, Example 32(b), (176 mg, 1.0 mmol) and 4-tertbutyl-trans-cinnamic acid (200 mg, 1.0 mmol, EMKA-Chemie) provided, after purification by silica gel chromatography (3:2 hexane:EtOAc), the title product.

MP 90-101 MS (ESI, pos. ion) n/z: 363 -235- SExample 33 ci SH

CH

3 ONN IWN (2E)-3-[4-(tert-Butyl)phenyl]-N-(1-methylindol-6-yl)prop-2-enamide.

0

CH

3 N H2N N 1-Methylindole-6-ylamine. To a round-bottomed flask was added 6nitroindole (0.81 g, 5.0 mmol, Aldrich) and anhydrous DMF (40 mL). The solution was stirred magnetically and treated with sodium hydride (0.40 g, mmol, 60% dispersion in mineral oil, Aldrich) followed by iodomethane (0.71 gm 10 mmol, Aldrich). Stirring was continued at 25 oC for 30 min, then the reaction mixture was quenched by the addition of water (75 mL) and extracted with EtOAc. The organic extract was concentrated in vacuo to provide a residue which was dissolved in EtOH (40 mL), treated with 10% Pd on carbon (400 mg, Aldrich), purged with H 2 and magnetically stirred under 1 atm H 2 for 4 h. The suspension was purged with N 2 filtered through a pad of Celite and concentrated in vacuo. Purification by silica gel chromatography (50:50 hexane:EtOAc) provided the aniline. MS (ESI, pos. ion) m/z: 147 (2E)-3-[4-(tert-Butyl)phenyl]-N-(1-methylindol-6-yl)prop-2-enamide.

Analogous to the procedure used to prepare Example 1, 1-methylindole-6ylamine, Example 33(a), (150 mg, 1.0 mmol) and 4-tert-butyl-trans-cinnamic acid (200 mg, 1.0 mmol), after purification by silica gel chromatography (65:35 hexane:EtOAc), provided the title product as a yellow solid. MP 95 OC. MS (ESI, pos. ion) r/z: 333 -236- Example 34

H

ON

CH

3 (2E)-3-[4-(tert-Butyl)phenyl]-N-(1-methylindol-5-yl)prop-2-enamide.

H

2

N

CH

3 1-Methylindole-5-ylamine. To a round-bottomed flask was added nitroindole (0.81 g, 5.0 mmol, Aldrich) and anhydrous DMF (40 mL). The solution was stirred magnetically and treated with sodium hydride (0.40 g, mmol, 60% dispersion in mineral oil, Aldrich) followed by iodomethane (0.71 gm 10 mmol, Aldrich). Stirring was continued at 25 °C for 30 min, then the reaction mixture was quenched by the addition of water (75 mL) and extracted with EtOAc. The organic extract was concentrated in vacuo to provide a crude residue. Analogous to.the procedure of Goswami, Chowdhury, Indian J Chem, Sect B, 1997, 36 185-186, the crude residue was dissolved in THF mL) and added to Zn dust (0.22 g, 3.3 mmol, Aldrich) and AlC1 3 "6H 2 0 (4.78 g, 19.8 mmol, Aldrich) in water (1 mL), magnetically stirred at 25 The reaction mixture was stirred at 25 °C for 16 h, then filtered. The filtrate was added to cold water (300 mL) and extracted with CH 2 C12 (3 x 100 mL). The combined organic extract was concentrated in vacuo to provide the title product.

MS (ESI, pos. ion) m/z: 147 (2E)-3-[4-(tert-Butyl)phenyl]-N-(l-methylindol-5-yl)prop-2-enamide.

Analogous to the procedure used to prepare Example 1, ylamine, Example 34(a), (150 mg, 1.0 mmol) and 4-tert-butyl-trans-cinnamic acid (200 mg, 1.0 mmol, EMKA-Chemie) provided, after purification by silica gel chromatography (65:35 hexane:EtOAc), the title product as a crystalline yellow solid. MP 171 C. MS (ESI, pos. ion) m/z: 333 -237- Example

H

Y ON

CH

3 (2E)-3-[4-(tert-Butyl)phenyl]-N-(1-methylindolin-5-yl)prop-2-enamide.

0 2

N

CH

3 l-Methyl-5-nitroindoline. To a round-bottomed flask equipped with magnetic stirring was added 5-nitroindoline (0.82, 5.0 mmol, Aldrich), iodomethane (0.71g, 5.0 mmol, Aldrich), sodium hydroxide (0.24, 6 mmol) and DMF (20 mL). The reaction mixture was stirred at 25 °C for 3 h, diluted with water (50 mL), extracted with EtOAc (3 x 40 mL) and the combined extracts were concentrated in vacuo. Purification by silica gel chromatography 97:3 hexane:EtOAc) provided the title product. MS (ESI, pos. ion) m/z: 179

H

2

N

CH

3 l-Methylindoline-5-ylamine. To a solution of Example 35(a), (0.55 g, 3.1 mmol) in ethyl ether (20 mL), magnetically stirred in a round-bottomed flask at 0 was added tin (II) chloride dihydrate (4.5 g, mmol, Aldrich) and cond HCI (2.5 mL). The reaction mixture was stirred at 0 °C for 10 min, allowed to warm to 25 °C then stirred at that temperature overnight. The reaction mixture was washed with ION NaOH (30 mL) and the aqueous phase extracted with EtOAc (3 x 20 mL). The combined organic extracts were concentrated in vacuo. Purification by silica gel chromatography (55:45 hexane:EtOAc) provided the aniline. MS (ESI, pos. ion) n/z: 149 (2E)-3-[4-(tert-Butyl)phenyl]-N-(1-methylindolin-5-yl)prop-2-enamide.

Analogous to the procedure used to prepare Example 1, ylamine, Example 35(b), (150, 1.0 mmol) and 4-tert-butyl-trans-cinnamic acid -238- (200 mg, 1.0 mmol, EMKA-Chemie) provided, after purification by silica gel chromatography (60:40 hexane:EtOAc), the title product as a crystalline yellow solid. MP 194 OC. MS (ESI, pos. ion) m/z: 335 Example 36

H

O

(2E)-N-Benzoxazol-5-yl-3-[4-(tert-butyl)phenyl]prop-2-enamide.

02N^ N 5-Nitrobenzoxazole. Following the procedure of A. R. Katritzky et al.

Heterocycles 1995, 41, 345, to a round-bottomed flask was added 2-amino-4nitrophenol (5.0 g, 32 mmol, Aldrich), trimethyl orthoformate (20 mL, 180 mmol, Aldrich) and p-toluenesulfonic acid monohydrate (300 mg, 1.6 mmol, Aldrich).

The reaction mixture was magnetically stirred in a 95 °C oil bath for I h, and then allowed to cool to 25 The mixture was cooled to 0 °C to provide a precipitate which was collected by filtration, washed with cold toluene, pentane, then dried in vacuo to afford the title product as a dark brown powder.

H2N

N

Benzoxazole-5-ylamine. Analogous to the procedure used to prepare Example 5-nitrobenzoxazole, Example 36(a), (2.4 g, 15 mmol) provided, after purification by silica gel chromatography (step gradient, 7:3 then 4.5:5.5 then 3:7 hexane:EtOAc), the title product. MS (ESI, pos. ion) m/z: 135 (2E)-N-Benzoxazol-5-yl-3-[4-(tert-butyl)phenyl]prop-2-enamide.

Analogous to the procedure used to prepare Example 1, Example 36(b), (530 mg, 4.0 mmol) and 4-tert-butyl-trans-cinnamic acid (820 mg, 4.0 mmol, EMKA-Chemie) provided, after twice being purified by silica gel chromatography (7:3 hexane:EtOAc then 1.25% MeOH in CH 2 C12), the title product as white crystals. MP 177 OC. MS (ESI, pos. ion) m/z: 321 239 Example 37

H

N

(2E)-N-Benzoxazol-6-yI-3-[4-(tert-butyl)phenyllprop-2-enamide.

H

2 N0 Nezxzl-6yaie Bezxzl--lmn.Analogous to the procedure described for the preparation of Example 36, steps 2-amino-5-nitrophenol (5.0 g, 32 mmol, Aldrich) provided the title product as a pale tan solid. MS (ESI, pos. ion) m/lz: 13 5 1).

(2E)-N-Benzoxazol-6-yl-3-[4-(tert-butyl)phenyllprop-2-enamide.

Analogous to the procedure used to prepare Example 1, benzoxazole-6-ylamine, Example 37(a), (1.8 g, 13 mmol) and 4-tert-butyl-trans-cinnamic acid (2.7 g, 13 mmol, EMKA-Chemi~e) provided, after purification by silica gel chromatography (6:4:0.2 CH 2

CI

2 :hexane:MeOH), the title product as a tan solid.

MP 147-148 0 C. MS (ESI, pos. ion) m/z: 321 1).

Example 38

H

(2E)-N-Benzo[blfuran-5-yI-3-[4-(tert-butyl)phenyllprop-2-enamide.

0 2

NCH

Methyl 2-(2-formyl-4-nitrophenoxy)acetate. To a round-bottomed flask was added a suspension of 2-hydroxy-5-nitrobenzaldehyde (10 g, 60 mmol, Aldrich) in anhydrous EtOH (180 mL). The suspension was treated with KOH (4.4 g, 66 mnmol) and heated under N 2 with magnetic stirring in a 65 0 C oil bath for 45 min. The reaction mixture was allowed to cool to 25 'C and concentrated in vacuo. Anhydrous DMIF (180 mL) was added, and the reaction flask was -240cooled in an ice bath and charged with methyl bromoacetate (10 mL, 110 mL, Aldrich). The reaction mixture was stirred for 3.5 h at 25 OC, then the solvent was removed in vacuo. Water (200 mL) was added, and the mixture was extracted with EtOAc (3 x 50 mL). The combined organic extract was washed with 1 M

H

3 P0 4 satd NaHCO 3 and satd NaCI. After drying over MgSO 4 the organic layer O was filtered and concentrated in vacuo. The residue was recrystallized from C. CH 2 C1 2 and hexane to afford the title product as a pale yellow solid. MS (ESI, Spos. ion) m/z: 240 C 0 2 N C 2 E I L g iCO 2 Et Ethyl 5-nitrobenzo[d]furan-2-carboxylate. To a 250 mL round-bottomed flask was added methyl 2-(2-formyl-4-nitrophenoxy)acetate, Example 38(a), (5.3 g, 22 mmol), EtOH (110 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (3.7 g, 24 mmol, Aldrich). The reaction mixture was magnetically stirred at 25 °C for h, then concentrated to approximately half of its volume in vacuo. After cooling the mixture in an ice bath for 20 min, a precipitate formed which was collected by filtration and washed with ice cold EtOH. The resulting pale yellow solid was dried in vacuo to provide the title product. MS (ESI, pos. ion) m/z: 253

(M+H

2 0).

02N

CO

2

H

5-Nitrobenzo[b]furan-2-carboxylic acid. To a 250 mL round-bottomed flask was added ethyl 5-nitrobenzo[d]furan-2-carboxylate, Example 38(b), (1.0 g, 4.3 mmol), EtOH (10 mL), and KOH (610 mg, 11 mmol) in 10 mL of H 2 0. The reaction mixture was stirred at 25 °C for 24 h, then treated with I M H 3 P0 4 (200 mL) and saturated with solid NaCI. The aqueous layer was extracted with EtOAc (3 x 70 mL), and the combined organic extracts were washed with satd NaCI, dried over MgSO 4 filtered and concentrated in vacuo to provide the title product as a yellowish-white powder. MS (ESI, pos. ion) m/z: 225 (M+H 2 0).

S. i -241- 02N 5-Nitrobenzofuran. To a 100 mL round-bottomed flask was added nitrobenzo[b]furan-2-carboxylic acid, Example 38(c), (860 mg, 4.2 mmol), copper (830 mg, 13 mmol, Aldrich), and quinoline (38 mL, Aldrich). The reaction flask was placed in a 185 °C oil bath and magnetically stirred for 20 min under N 2 After allowing to cool to 25 the mixture was filtered through a 1" pad of Celite. To the filtrate was added 10% aq. HCI (300 mL) and the aqueous layer was extracted with Et 2 O (3 x 100 mL). The combined ethereal layers were washed with 10% HCI (4 x 200 mL, 1 x 100 mL), satd NaHCO 3 (200 mL), and satd NaCI (100 mL), dried over MgSO 4 filtered and concentrated in vacuo.

Purification by silica gel chromatography (10:0.25 hexanes:EtOAc) provided nitrobenzofuran as a white solid.

H

2

N

Benzo[b]furan-5-ylamine. To a 150 mL round-bottomed flask was added nitrobenzofuran, Example 38(d), (270 mg, 1.7 mmol) and ethyl ether (16 mL).

The mixture was magnetically stirred at 0 °C under N 2 and treated with a solution of tin (II) chloride dihydrate (3.4 g, 15 mmol, Aldrich) in 12 M aq. HCI (2 mL).

The reaction mixture was stirred at 0 °C for 10 min, then allowed to warm to OC and stirred at that temperature for 20 h. Water and 2 N NaOH (pH 10) were added followed by Celite (10 The mixture was filtered through a pad of Celite and the filtrate extracted with EtOAc. The organic extract was washed with 2 N NaOH, satd NaCI, dried over K 2 C0 3 filtered and concentrated in vacuo to provide the title product as a pale yellow oil. MS (ESI, pos. ion) m/z: 134 (2E)-N-Benzo[b]furan-5-yl-3-[4-(tert-butyl)phenyl]prop-2-enamide.

Analogous to the procedure used to prepare Example 1, Example 38(e), (230 mg, 1.7 mmol) and 4-tert-butyl-trans-cinnamic acid (350 mg, 1.7 mmol, EMKA-Chemie) provided, after purification by silica gel chromatography (9:1 hexane:EtOAc), the title product as white crystals. MP 149- 150 OC. MS (ESI, pos. ion) m/z: 320 -242- Example 39

H

(2E)-3-[4-(tert-Butyl)phenyl]-N-(2,3-dihydrobenzo[b]furan-5-yl)prop-2enamide.

H

2

N

2,3-Dihydrobenzo[b]furan-5-ylamine. To a 150 mL round-bottomed flask was added 5-nitrobenzofuran, Example 38(d), (250 mg, 1.5 mmol), EtOAc (16 mL) and 10% Pd on carbon (33 mg, Aldrich). The suspension was stirred at °C under I atm H 2 for 24 h, then purged with N 2 filtered through Celite and concentrated in vacuo to provide the aniline as a red-brown solid. MS (ESI, pos.

ion)m/z: 136 (2E)-3-[4-(tert-Butyl)phenyl]-N-(2,3-dihydrobenzo[b]furan-5-yl)prop-2enamide. Analogous to the procedure used to prepare Example 1, 2,3- Example 39(a), (240 mg, 1.8 mmol) and 4-tertbutyl-trans-cinnamic acid (370 mg, 1.8 mmol, EMKA-Chemie) provided the crude title product. The product was purified by silica gel chromatography (9:1:0.25 hexane:EtOAc:MeOH) to provide 45 mg of the title product and additional impure fractions. The impure fractions were combined and concentrated in vacuo. The residue was dissolved in MeOH (25 mL), treated with 5 N NaOH (10 mL) and stirred for 1 h. The mixture was diluted with 5 N NaOH (100 mL) and extracted with EtOAc. The organic phase was washed with 5 N NaOH (2 5% citric acid, satd NaCI, dried over MgSO 4 filtered and concentrated in vacuo. Purification by silica gel chromatography (8:1:0.5 hexane:EtOAc: 2 M NH 3 in MeOH) provided an additional the title product as a white solid. MP 175-176 MS (ESI, pos. ion) m/z: 322 243 Example

H

NN O 0 N-(2H,3H-Benzo[3,4-e]1,4-dioxan-6-yl)-3,3-bis(4-methylphenyl)prop-2enamide.

-I

N OH

OH

0 3,3-Bis(4-methylphenyl)prop-2-enoic acid. Triethyl phosphonoacetate mL, 10 mmol, Aldrich) was added dropwise to a suspension of NaH (0.44 g, 11 mmol, 60% dispersion in mineral oil, Aldrich) in anhydrous THF (16 mL), magnetically stirred at 0 °C under Ar, in a round-bottomed flask equipped with a reflux condenser. The reaction mixture was allowed to warm to 25 °C then stirred at that temperature for 0.5 h. 4,4'-Dimethylbenzophenone (2.1 g, 10 mmol, Aldrich) was added in one portion and the reaction mixture stirred and heated at reflux for 48 h. After allowing to cool to 25 oC, the reaction mixture was quenched with H 2 0 (30 mL) and extracted with Et20 (4 x 10 mL). The combined organic extract was washed with H 2 0 (5 mL), dried over MgSO 4 filtered and concentrated in vacuo to an oily residue. The residue was dissolved in 1,4dioxane (2.5 mL), treated with H 2 0 (7 mL) and KOH (1.1 g, 20 mmol), then stirred and heated at reflux under Ar for 18 h. The reaction mixture was allowed to cool to 25 OC, diluted with H 2 0 (50 mL) and washed with Et20 (10 mL). The aqueous phase was acidified with 1 N HCI and extracted with chloroform. The combined chloroform extracts were washed with satd NaCI, dried over MgSO 4 filtered and concentrated in vacuo to provide the acid as a white solid. MS (ESI, pos. ion) m/z: 253 244 N-(2H,3H-Renzo[i3,4-eI 1,4-dioxan-6-yl)-3,3-bis(4-methylphenyl)prop-2enamide. Analogous to the procedure used to prepare Example 1, 3,3-bis(4methylphenyl)prop-2-enoic acid, Example 40(a), (0.50 g, 2.0 mmol) and 1,4benzodioxan-6-amine (0.33 g, 2.2 mmol, Aldrich) provided, after purification by silica gel chromatography (chloroformn), the title product as a yellow solid. IP 163-164 0 C. MS (ESI, pos. ion) m/z: 386 (M4-1).

Example 41

H

N. N 0C 00 (2E)-N-(2H,3H-Benzo[3,4-e] 1,4-dioxan-6-yl)-3- [4-(tert-butyl)phenyl].2methylprop-2-enamide.

,-OH

0 (2E)-3-[4-(tert-Butyl)phenyl]-2-metliylprop-2-enoic acid. Analogous to the procedure described for the preparation of Example 40, step triethyl 2phosphonopropionate (2.4 g, 10 mmol, Aldrich) and 4-tert-butylbenzaldehyde (1.6 g, 10 mmol, Aldrich) provided the title product as a yellow solid. MS (ESI, pos. ion) m/z: 219 1).

(2E)-N-(2H,3H-Benzo[3,4-e] 1,4-dioxan-6-yl)-3-[4-(tert-butyl)phenyl]-2methylprop-2-enamide. Analogous to the procedure used to prepare Example 1, (2E)-3-[4-(tert-butyl)phenyl]-2-methylprop-2-enoic acid, Example 41(a), (0.44 g, 2.0 mmol) and 1,4-benzodioxan-6-amine (0.33 g, 2.2 mmol, Aldrich) provided, after purification by silica gel chromatography (chloroform), the title product as an off-white solid. MP 157-158 0 C. MS (ESI, pos. ion) rn/z: 352 245 Example 42

H

N 0 (2E)-N-(2H,3H-Benzo[3,4-e]1,4-dioxan-6-yI)-3-[4-(tert-butyl)phenyl]-2ethylprop-2-enamide.

OH

0 (2E)-3-[4-(tert-Butyl)phenyl]-2-ethylprop-2-enoic acid. Analogous to the procedure described for the preparation of Example 40, step triethyl 2phosphonobutyrate (2.5 g, 10 mmol, Aldrich) and 4-teri-butylbenzaldehyde (1.6 g, 10 mmol, Aldrich) provided the title product as a white solid. MS (ESI, pos.

ion) m/z: 233 (2E)-N-(2H,3H-BenzoI3,4-el 1,4-dioxan-6-yI)-3-[4-(tert-butyl)phenyl]-2ethylprop-2-enamide. Analogous to the procedure used to prepare Example 1, (2E)-3-[4-(tert-butyl)phenyll-2-ethylprop-2-enoic acid, Example 42(a), (0.46 g, mnmol) and 1,4-benzodioxan-6-ami ne (0.33 g, 2.2 mmol, Aldrich) provided, after purification by silica gel chromatography (chloroform), the title product as a white solid. MIP 133-134 0 C. MS (ESI, pos. ion) m/z: 366 -246- Example 43 in

H

O

N

O

O (2E)-N-(2H,3H-Benzo[3,4-e]1,4-dioxan-6-yl)-3-(4-cyclopropylphenyl)prop-2- C enamide.

lC-

CO

2 Et Ethyl 4-cyclopropylbenzoate. To a round-bottomed flask under N 2 was added zinc dust (0.80 g, 12.5 mmol, Aldrich), cuprous chloride (1.23 g, 12.5 mmol, Aldrich) and Et20 (2 mL). The mixture was magnetically stirred and heated at reflux for 30 min. The suspension was treated with ethyl 4vinylbenzoate (0.85 g, 4.82 mmol, Apin) followed by methylene diiodide (1.68 g, 6.27 mmol, Aldrich) and reflux was continued for 24 h. The reaction mixture was allowed to cool to 25 filtered, concentrated in vacuo and purified by silica gel chromatography (9:1 hexane:EtOAc) to provide the title product. MS (ESI, pos.

ion) m/z: 191

CHO

4-Cyclopropylbenzaldehyde. Ethyl 4-cyclopropylbenzoate, Example 43(a), (316 mg, 1.66 mmol) was transferred to a round-bottomed flask and treated with lithium aluminum hydride (0.30 mL, 3.0 mmol, 1.0 M in THF, Aldrich) under N 2 The reaction mixture was magnetically stirred at 25 °C for 1 h, then quenched by the dropwise addition of H 2 0 (0.5 mL) followed by 20% aq. KOH (3 mL). The suspension was filtered and the aqueous phase extracted with EtOAc. The organic extract was concentrated in vacuo and the crude alcohol was redissolved in anhydrous CH 2

CI

2 (2 mL). In a separate round-bottomed flask, a solution of oxalyl chloride (2.0 mL, 4.0 mmol, 2.0 M in CH 2

CI

2 Aldrich) was magnetically 2 5 stirred under N 2 at -78 OC and treated dropwise with a solution of anhydrous -247dimethyl sulfoxide (4.0 mL, 56 mmol, Aldrich) in anhydrous CH 2 C1 2 (2 mL). The reaction mixture was stirred at -78 oC for 5 min then treated dropwise with the solution of crude alcohol in CH 2 C1 2 The reaction mixture was stirred an additional 5 min at -78 oC, treated with triethylamine (2.0 mL, 14 mmol), allowed to warm to 25 °C and stirred at that temperature for 1 h. The reaction was quenched by the addition of H 2 0 and the mixture was extracted with Et 2 0. The organic extract was concentrated in vacuo to provide 230 mg (95% over two steps) of the title product.

OH

0 (2E)-3-(4-Cyclopropylphenyl)prop-2-enoic acid. Analogous to the procedure described for Example 40, step 4-cyclopropylbenzaldehyde, Example 43(b), (0.23 g, 1.6 mmol) and triethyl phosphonoacetate (0.35 g, 1.6 mmol, Aldrich) provided the title product. MS (ESI, pos. ion) m/z: 189 (2E)-N-(2H,3H-Benzo[3,4-e]1,4-dioxan-6-yl)-3-(4cyclopropylphenyl)prop-2-enamide. Analogous to the procedure used to prepare Example 1, (2E)-3-(4-cyclopropylphenyl)prop-2-enoic acid, Example 43(c), (130 mg, 0.69 mmol) and 1,4-benzodioxan-6-amine (104 mg, 0.69 mmol, Aldrich) provided, after purification by silica gel chromatography (65:35 hexane:EtOAc), the title product as a clear glass. MS (ESI, pos. ion) m/z: 322 248 Example 44 'T

H

N N 0 (2E)-N-(2H,3H-BenzoI3,4-e] 1,4-dioxan-6-yl)-3-[6-(tert-butyl)(3-pyridy1)]prop-2-enamide.

a, CHO 6-(tert-Butyl)pyridine-3-carbaldehyde. Analogous to the procedure of Rybakova, et al. Zh. Org. Khim. 1995, 31(5), 670-673, pyridine-3-methanol (2.18 g, 20.0 mmol, Aldrich), trimethylacetic acid (10.2 g, 100 mmol, Aldrich), silver nitrate (0.68 gm 4.0 mmol, Aldrich), and 10% aq. sulfuric acid (20 mL) were combined in a round-bottomed flask. The reaction mixture was magnetically stirred and treated with a solution of ammonium persulfate (9.1 g, mmol, Aldrich) in H 2 0 (40 mL). Evolution of gas was observed and the reaction mixture was stirred at 25 0 C for 2 h. The reaction mixture was basified to pH 9 by the addition of aq. ammonium hydroxide then extracted with EtOAc.

The organic extract was washed with H 2 0, dried over Na 2

SO

4 filtered and concentrated in vacuo. Purification of the crude product by silica gel( chromatography (70:30 hexane:EtOAc) provided the title product. MS (ESI, pos.

ion)rn/z: 164 1).

OH

0 (2E)-3-[6-(tert-Butyl)(3-pyridyl)]prop-2-enoic acid. Analogous to the procedure described for Example 40, step 6-(iert-butyl)pyridine-3carbaldehyde, Example 44(a), (0.55 g, 3.4 mmol) and triethyl phosphonoacetate (0.76 g, 3.4 mmol, Aldrich) provided the title product. MS (ESI, pos. ion) m/z: 206 249 (2E)-N-(2H,3H-Benzo[3,4-ei 1,4-dioxan-6-yI)-3-[6-(tert-butyl)(3pyridyl)]prop-2-enamide. Analogous to ithe procedure used to prepare Example 1, [6-(tert-butyl)(3-pyn dyl)iprop-2-enoic acid, Example 44(b), (200 mg, mmcl) and 1,4-benzodioxan-6-amine (150 mg, 1.0 mmol, Aldrich) provided, after purification by silica gel chromatography (60:40 hexane:EtOAc), the title product as a clear glass. MS (ESI, pos. ion) m/z: 339 Example

H

0 "C(0 (2E)-N-(2H,311-Benzo [3,4-el 1,4-dioxan-6-yl)-3-13-(tert-butyl)phenyliprop-2enamide.

>ra

CHO

3-(tert-Butyl)benzaldehyde. To a round-bottomed flask equipped with magnetic stirring was added I1-tert-b utyl -3-meth ylbenzene (1 g, 6.8 mmol, Wiley), ammonium cerium (IV) nitrate (17.5 g, 29.7 mmol, Aldrich) And 50% aq. acetic acid (150 mL). The reaction mixture was stirred and heated at 90 0 C for 1.5 h.

The reaction mixture was allowed to cool to 25 'C and extracted with 10% EtOAc in hexane. The organic extract was concentrated in vacuo to provide the crude aldehyde.

OH

>ra 0 (2E)-3-[3-(tert-Butyl)phenyllprop-2-enoic acid. Analogous to the procedure described for Example 40, step 3-(tert-butyl)benzaldehyde, Example 45(a), (320 mg, 2.0 mmol) and triethyl phosphonoacetate (250 mg, mmol, Aldrich) provided the title product. MS (ESI, pos. ion) mlz: 205 1).

(2E)-N-(2H,3H-Benzo[3,4-el,4-dioxan-6-yl)-3-[3-(tert-butyl)phenyliprop- 2-enamide. Analogous to the procedure used to prepare Example 1, 250 (tert-butyl)phenyllprop-2-enoic acid, Example 45(b), (200 mg, 1.0 mmol) and 1,4-benzodioxan-6-amine (150 mg, 1.0 mmol, Aldrich) provided, after purification by silica gel chromatography (60:40 hexane:EtOAc), the title product.

MP 168 MS (ESI, pos. ion) m/z: 338 Example 46 F

F

F H F 0 (2E)-N-(2H,3H-Benzo[3,4-e] 1,4-dioxan-6-yl)-3-[2-fluoro-4-(trifluoromethyl)-( phenyllprop-2-enamide.

F

F

OH

F

[2-Fluoro-4-(trifluoromethyl)phenyllmethan-1-ol. To a round-bottomed flask, equipped with magnetic stirring and a reflux condenser, was added 2fluoro-4-(trifluoromethyl)benzoic acid (5.0 g, 24 mmol, ABCR) and borane-THF complex (72 mL, 72 mmol, 1.0 M in TI-F, Aldrich) at 0 'C under N 2 The reaction mixture was warmed to 65 'C and stirred at that temperature for 2 h.

The reaction mixture was allowed to cool to 25 'C and the solvent was removed( in vacuo. The resulting residue was dissolved in CH 2

CI

2 (100 mL) and washed with satd Na 2

CO

3 (100 mL). The aqueous phase was back-extracted with CI- 2 C1 2 (4 x 80 mL). The combined organic extract was washed with satd NaCI (200 mL), dried over Na 2

SO

4 filtered and concentrated in vacuo. Purification by silica gel chromatography (gradient: 0-10% EtOAc in hexane) provided the title product as a colorless oil.

F

F

F

0

F

2-Fluoro-4-(trifluoromethyl)benzaldehyde. To a solution of [2-fluoro-4- (trifluoromethyl)phenyllmethan-1-ol, Example 46(a), (4.4 g, 23 mmol) in CH 2 C1 2 -251- (100 mL) was added ground pyridinium dichromate (38.4 g, 102 mmol, Fluka).

The reaction mixture was stirred at 25 °C overnight, then filtered through Celite.

The Celite pad was washed with CH 2

C

2 (2 x 50 mL) and the combined filtrate was concentrated in vacuo. Purification by silica gel chromatography (gradient: 0-5% EtOAc in hexane) provided the title product as a white slurry.

FF

C02Me

F

Methyl (2E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoate. 2- Fluoro-4-(trifluoromethyl)benzaldehyde, Example 46(b), (900 mg, 4.7 mmol) in

CH

2

CI

2 (5 mL) was added via cannula to a solution of carbomethoxymethylene triphenylphosphorane (2.0 g, 6.1 mmol, Aldrich) in CH 2

C

2 (15 mL), magnetically stirred in a round-bottomed flask at 0 OC. The reaction mixture was allowed to warm to 25 °C and stirred at this temperature under N 2 overnight. The solvent was removed in vacuo and the crude material purified by silica gel chromatography (gradient: 0-5% EtOAc in hexane) to provide the title product as a white solid.

SF

F

F

C0 2

H

F

(2E)-3-[2-Fluoro-4-(trifluoromethyl)phenyl]prop-2-enoic acid. Methyl (2E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoate, Example 46(c), (1.6 g, 6.3 mmol) was treated with lithium hydroxide monohydrate (530 mg, 12.6 mmol, Aldrich) in wet EtOH (15 mL) and magnetically stirred in a round-bottomed flask at 25 °C overnight. The reaction mixture was acidified to pH 2 with 10% aq.

HCI and extracted with EtOAc (3 x 50 mL). The combined extracts were washed with satd NaCI (100 mL), dried over Na 2

SO

4 filtered and concentrated in vacuo to provide the acid as a white solid.

(2E)-N-(2H,3H-Benzo[3,4-e]1,4-dioxan-6-yl)-3-[2-fluoro-4- (trifluoromethyl)phenyl]prop-2-enamide. Analogous to the procedure used to prepare Example 1, (2E)-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoic 252 acid, Example 46(d), (200 mg, 0.85 mmol) and 1,4-benzodioxan-6-amine (193 mg, 1.28 mmol, Aldrich) provided, after purification by silica gel chromatography (gradient: 0-20% EtOAc in hexane) and recrystallization from EtOAc and hexane, the title product as a yellow crystalline solid. IMP 174= 175 'C.

MS (ESI, pos. ion) mlz: 368 Example 47 F

F

F

H

F (2E)-N-(2H,3H-Benzo[3,4-e]l ,4-dioxan-6-yI)-3-[2,3-difluoro-4-(trifluoromethyl)phenyllprop-2-enamide. Analogous to the procedure used to prepare Example 46, steps the title product was obtained from 2,3-difluoro-4- (trifluoromethyl )benzyl alcohol (ABCR) and 1 ,4-benzodioxan-6-armine (Aldrich) as a crystalline yellow solid. MIP 169-170 MS (ESI, pos. ion) mlz: 386 1).

Example 48 F

F

F IH N N FFF 0( (2E)-N-(2H,3H-Benzo[3,4-e]l ,4-dioxan-6-yl)-3-12,4-bis(tritluoromethyl)phenyllprop-2-enamide. Analogous to the procedure used to prepare Example 46, steps the title product was obtained from 2,4bis(trifluoromethyl)benzyl alcohol (Avocado) and l,4-benzodioxan-6-amine (Aldrich) as a crystalline yellow solid. MFP 204-205 0 C. MS (ESI, pos. ion) mlz: 418 253 Example 49 F "'F F H F 0

NN

H

(2E)-3-12-Fluoro-4-(trifluoromethyl)phenyl]-N-indol-5-ylprop-2-enamide.

Analogous to the procedure used to prepare Example 46, steps the title product was obtained from 2-fluoro-4-(ttifluoromethyl)benzoic acid (ABCR) and (Aldrich) as a crystalline yellow solid. NWP 203-205 TC. MS (ESI, pos. ion) mlz: 349 1).

Example F

F

F- N~ I Z F 0 N

H

(2E)-3-[2,3-Difluoro-4-(trifluoromethyl)phenyl-N-indol-S-ylprop-2-enamide.

Analogous to the procedure used to prepare Example 46, steps the title product was obtained from 2,3-difluoro-4-(tri fluoromethyl)benzyl alcohol (ABCR) and 5-aminoindole (Aldrich) as a crystalline yellow solid. NIP 220-222 0 C. MS (ESI, pos. ion) mlz: 367 Example 51

FEF

F H F F 0 F H (2E)-3-[2,4-Bis(trifluoromethyl)phenyl-N-indol-5-yprop.2enamide.

Analogous to the procedure used to prepare Example 46, steps the title product was obtained from 2,4-bis(trifluoromethyl)benzy] alcohol (Avocado) and 5-aminoindole (Aldrich) as a crystalline yellow solid. MIP 207-209 TC. MS (ESI, pos. ion) m/z: 399 I).

254 Example 52

H

N 0 0 F- F F N-(2H,3H-Benzo[eI 1,4-dioxan-6-yl)(2Z)-3-[4- (tert-butyl)phenyl]-34.

(trifluoromethyl)phenyllprop-2-enamide.( I CO 2 Et Ethyl 3-[4-(tert-butyl)phenyllprop-2-ynoate. To a 1 L round-bottomed flask was added (4-ter t-butyl)phenylacetylene (33.8 g, 214 mmol, GFS Chemicals) and anhydrous THF (220 mL). The solution was magnetically stirred, purged with N 2 and cooled to -78 then n-butyllithium (136 mL, 2.5 M in hexanes, Aldrich) was added slowly. After the addition was complete, the mixture was gradually warmed to 0 'C and stirred magnetically for 30 min. The reaction mixture was cooled to -78 'C again and ethyl chloroformate (28.6 m.L, 299.2 mmol, Aldrich) was added. After allowing to warm to 25 'C and stirring( overnight, the reaction was quenched with 1: 1 satd NaHCO 3 :satd NH4CI (200 mL) and extracted with Et 2 O (1000 mL). The organic phase was dried over Na 2

SO

4 filtered and concentrated in vacuo to afford a yellow oil. Purification by silica gel chromatography (gradient: EtOAc/hexane) provided ethyl 3- [4-(tert-butyl)phenyllprop-2-ynoate as a pale yellow oil. MS (ESI, pos. ion) Yn/z: 231 -255- Ethyl (2Z)-3-[4-(tert-butyl)phenyl]-3-iodoprop-2-enoate.

According to the procedure of E. Piers et al., Can. J. Chem. 1994, 72, 1816, to a 150 mL round-bottomed flask equipped with a reflux condenser and magnetic stirring was added ethyl 3-[4-(tert-butyl)phenyl]prop-2-ynoate, Example 52(a), g, 65 mmol), sodium iodide (31 g, 209 mmol, Aldrich) and glacial acetic acid (48 mL, 830 mmol). The reaction mixture was purged with N 2 and the flask immersed in a pre-heated 115 °C oil bath. The reaction mixture was magnetically stirred at 115 °C for 4 h, then allowed to cool to 25 °C and treated with H 2 0 (200 mL). The aqueous phase was extracted with Et20 (500 mL). The organic layer was washed with satd Na 2

CO

3 until the evolution of CO 2 ceased, then washed with 1 M Na 2

S

2 0 3 (100 mL), satd NaCI, dried over Na 2

SO

4 filtered, and concentrated in vacuo to provide ethyl (2Z)-3-[4-(tert-butyl)phenyl]-3-iodoprop- 2-enoate as a yellow oil. MS (ESI, pos. ion) m/z: 359

CO

2 Et

CF

3 Ethyl (2Z)-3-[4-(tert-butyl)phenyl]-3-[4-(trifluoromethyl)phenyl]prop-2enoate. To a 100 mL round-bottomed flask equipped with a reflux condenser and magnetic stirring was added ethyl (2Z)-3-[4-(tert-butyl)phenyl]-3-iodoprop-2enoate, Example 52(b), (0.75 g, 2.1 mmol), 4-trifluoromethylphenylboronic acid (0.60 g, 3.1 mmol, Aldrich), tetrakis(triphenylphosphine)palladium (0.24 g, 0.21 mmol, Aldrich), toluene (10 mL), EtOH (2 mL), and 2 M aq. Na 2

CO

3 (2 mL). The reaction mixture was magnetically stirred at 80 °C under N 2 overnight, allowed to cool to 25 OC and diluted with EtOAc (50 mL). The organic layer was separated, washed with H 2 0, satd NaCI (50 mL), dried over Na 2

SO

4 256 filtered and concentrated to afford a brown oil. Purification by silica gel chromatography (gradient: EtOAc/hexane) provided the title product as a white solid. MS (ESI, pos. ion) rn/z: 377 00~C 2

H

CF

3 (2Z)-3-[4-(tert-Butyl)phenyl]-3-[4-(trifluoromethyl)phenyllprop-2-enoic( acid. To a 50 mL round-bottomed flask equipped with a reflux condenser was added ethyl (2Z)-3-[4-(tert-butyl)phen yl]-3-[4-(trifluoromethyl)phenyl~prop-2enoate, Example 52(c), (0.74 g, 2.0 mmol), 1,4-dioxane (3 mL), KOH (0.66 g, 12 mmol) and H 2 0 (1.5 mL). The reaction mixture was heated and magnetically stirred under reflux overnight then diluted with H 2 0 (20 mL) and acidified with I N HCI. The aqueous mixture was extracted with CH 2

CI

2 (3 x 100 mL). The organic phase was dried over Na 2

SO

4 filtered and concentrated in vacuo to provide the title product as a white solid. MS (ESI, pos. ion) ni/z: 349 1).

N-(2H,3H-Benzo[e] 1,4-dioxan-6-yl)(2Z)-3-[4-(tert-butyl)phenyll-3-[4- (trifluoromethyl)phenyllprop-2-enamide.. Analogous to the procedure used to prepare Example 1, [4-(tert-butyl)phenyl] (trifluoromethyl)phenyllprop-2-enoic acid, Example 52(d), 15 g, 0.43 mmol) and 1,4-benzodioxan-6-amine (0.07 g, 0.43 mmol, Aldrich) provided, after purification by silica gel chromatography (gradient: 10%-18% EtOAc/hexane), the title product as a pale yellow solid. MP 150-15 1 MS (ESI, pos. Ion) m/z: 482 1).

257 Example 53

H

(2E)-N-(2H,3H-Benzo[e]1 ,4-dioxan-6-yI)-3-[4-(tert-butyl)p henyl].4phenylbut-2-enamide.

OEt Ethyl (2E)-3-[4-(tert-butyl)phenyl]-4-phenylbut-2-enoate. A solution of ethyl [4-(tert-butyl)phenyl ]-3-iodoprop-2-enoate, Example 52(b), (710 mg, 2.0 mmol) in anhydrous DMIF (4 mL) was added dropwise to benzylzinc bromide (12 mL, 6.0 mmol, 0.5 M solution in THF, Aldrich) magnetically stirred under Ar at 0 TC in a round-bottomed flask. The mixture was treated with bis(acetonitrile)dichloropalladium (11) (78 mg, 0.30 mmol, Aldrich) in one portion. The reaction mixture was then magnetically stirred for 16 h at 25 0

C,

diluted with Et 2 O (100 mL) and washed with IN HCI (25 mL) and satd NaCi mL). The organic phase was dried over MgSO 4 filtered and concentrated in vacuo and the residue purified by silica gel chromatography (49:1 hexane:EtOAc) to provide the title product as a colorless oil. MS (ESI, pos. ion) in/z: 323

OH

2E)-3-14-(tert-Butyl)phenyll-4-phenylbut-2-enoic acid. Ethyl [4- (tert-butyl)phenyl]-4-phenylbut-2-enoate, Example 53(a), (530 mg, 1.8 mmo]) was treated with KOH (0.22 g, 4.0 mmol), H 2 0 (4 mL) and I ,4-dioxane (2 mL), -258then magnetically stirred under reflux for 16 h. The reaction mixture was diluted with H 2 0 (50 mL), acidified with I N HCI and extracted with chloroform. The combined organic extract was washed with satd NaCI, dried over MgSO 4 filtered and concentrated in vacuo. The resulting residue was crystallized from EtOAc and hexane to provide the title product as a white solid.

(2E)-N-(2H,3H-Benzo[e] 1,4-dioxan-6-yl)-3-[4-(tert-butyl)phenyl]-4phenylbut-2-enamide. Analogous to the procedure used to prepare Example 1, (2E)-3-[4-(tert-butyl)phenyl]-4-phenylbut-2-enoic acid, Example 53(b), (250 mg, 0.85 mmol) and 1,4-benzodioxan-6-amine (140 mg, 0.93 mmol, Aldrich) provided, after purification by silica gel chromatography (chloroform), the title( product as off-white needles. MT 97-99 MS (ESI, pos. ion) m/lz: 428 Example 54 I H N~a 00$ (2E)-N-(2H,3H-Benzo[e] 1,4-dioxan-6-yl)-3-[4-(tert-butyl)phenyl]-5methylhex-2-enamide.

Analogous to the procedure used to prepare Example 53, starting from 3methylbutylzi nc bromide (Aldrich), ethyl (2Z)-3-[4-(tert-butyl)phenyl]-3iodoprop-2-enoate, Example 52(b), and 1 ,4-benzodioxan-6-amine (Aldrich), the title product was obtained as an off-white solid. MP 123 MS (ESI, pos. ion) mz/z: 394 259 Example K H N-(2H,3H-Benzo[e] 1,4-dioxan-6-yI)(2Z)-3-[4-(tert-butyl)phenyl]-3-iodoprop- 2-enamide.

OH

0 3-[4-(tert-Butyl)phenyllprop-2-ynoic acid. To a round-bottomed flask equipped with magnetic stirring and a reflux. condenser was added a solution of ethyl 3-[4-(tert-butyl)phenyllprop-2-ynoate, Example 52(a), (4.6 g, 20 mmol) in 1,4-dioxane (5 mL). The solution was treated with H 2 0 (15 mL) and KOH (2.2 g, 40 mmol) then stirred and heated at reflux under Ar for 18 h. After allowing to cool to 25 the mixture was diluted with H 2 0 (200 mL) and washed with Et 2

O

mL). The aqueous phase was separated, acidified with 1 N HG] and extracted with chloroform. The chloroform extract was washed with satd NaCI, dried over MgSO 4 filtered and concentrated in vacuo. Crystallization from EtOAc and hexane provided the title product as white needles. MS (ESI, pos. ion) m/lz: 203 K>

H

N0 N-(2H,3H-Benzo[e]1 ,4-dioxan-6-yl)-3-[4-(tert-butyl)phenyl p rop-2ynamide. Analogous to the procedure used to prepare Example 1, 3-[4-(tertbutyl)phenyl]prop-2-ynoic acid, Example 55(a), (404 mg, 2.0 inmol) and 1,4benzodioxan-6-amine (330 mg, 2.2 mmol, Aldrich) provided the title product as a white solid. MP 199 MS (ESI, pos. ion) rn/z: 336 (Mi-I).

N-(2H,3H-Benzo[e]1,4-dioxan-6-yl)(2Z)-3-[4-(tert-butyl)phenyl-3iodoprop-2-enamide. Analogous to the procedure described for the preparation 260 of Example 52(b), N-(2H,3H-benzo[eI 1,4-dioxan-6-yl)-3- [4-(tertbutyl)phenyllprop-2-ynamide, Example 55(b), (0.335 g, 1.0 mmol), sodium iodide (0.48 g, 3.2 mmol, Aldrich) and glacial acetic acid (0.73 mL) provided, after purification by silica gel chromatography (chloroform), the title product as yellow crystals. MNP 164 MIS (ESI, pos. ion) m/z: 464 Example 56 N 0

H

2

N

(2E)-N-(2H,3H-Benzo[e]1I,4.dioxan-6-yl)-3-(3-aminophenyl)-3-[4-(tertbutyl)phenyllprop-2-enamide.

Analogous to the procedure used to prepare Example 52, step 3aminophenylboronic acid (0.23 g, 1.5 mmol, Avocado) and N-(2H,3Hbenzo [ei 1,4-diox an-6-yl -[4-(tert-butyl)phenyl] -3-i odoprop-2-enamide, Example 55, (0.46 g, 1.0 mmol) provided the title product as off-white crystals.

MP 140 0 C. MS (ESI, pos. ion) in/z: 429 1).

Example 57 I H Na

CO

2 Et Ethyl (4E)-5-(N-(2H,3H-benzo[e] 1,4-dioxan-6-yI)carbamoyl)-4- [4-(tertbutyl)phenyllpent-4-enoate.

Analogously to the procedure used to prepare Example 53, step 3-ethoxy-3oxopropylzinc bromide (6.0 m.L, 3.0 mmol, 0.5 M in THE, Aldrich) and N- (2H,3H-benzo[e] I ,4-dioxan-6-yl)(2Z)-3-[4-QIert-butyl)phenyll-3-iodoprop-2enamide, Example 55, (0.46 g, 1.0 mmol) provided the title product as a pale yellow solid. MfP 104-105 MIS (ESI, pos. ion) m/lz: 438 -261- Example 58 Y O0 0 :0 o"" 3-Methoxyphenyl (2E)-3-[4-(tert-butyl)phenyl]prop-2-enoate. To a 100 mL round-bottomed flask equipped with magnetic stirring was added 4-tert-butyltrans-cinnamic acid (500 mg, 2.45 mmol, EMKA-Chemie), CH 2

CI

2 (10 mL), and DMF (10 uL) under N 2 The solution was treated dropwise with oxalyl chloride mL, 8.0 mmol, 2.0 M in CH 2

CI

2 Aldrich) then stirred at 25 'C for 1 h. The reaction mixture was concentrated in vacuo and the residue treated with 3methoxyphenol (269 uL, 2.45 mmol, Aldrich), THF (20 mL) and satd K 2

CO

3 (15 mL). The reaction mixture was stirred at 25 'C overnight, then acidified to pH 4.5 with 1 N HCI. The mixture was extracted with EtOAc (2 x 30 mL), the combined organic extract was dried and concentrated in vacuo. Purification by silica gel chromatography (5:1 hexane:EtOAc) provided the title product as a white solid. MP 83 OC. MS (ESI, pos. ion) m/z: 311 Example

H

OH 0 N-(2H,3H-Benzo[3,4-e]1,4-dioxan-6-yI)(2Z)-3-[4-(tert-butyl)phenyl]-3hydroxyprop-2-enamide.

OHI O tert-Butyl 3-[4-(tert-butyl)phenyl]-3-hydroxypropanoate. To a roundbottomed flask equipped with magnetic stirring was added N,N-diisopropylamine (10.4 mL, 74.0 mmol, Aldrich) and anhydrous THF (20 mL). The solution was stirred at -78 'C under N 2 and treated dropwise with n-butyllithium (30.0 mL, -262- 75.0 mmol, 2.5 M in hexane, Aldrich). After stirring for 10 min at -78 the reaction mixture was treated with t-butyl acetate (10.8 mL, 80.1 mmol, Aldrich).

After stirring 30 min at -78 the enolate was added via cannula to a solution of 4-t-butylbenzaldehyde (10.0 g, 61.6 mmol, Fluka) in anhydrous THF (100 mL), stirred under N 2 at -78 The reaction mixture was allowed to warm to 0 °C with stirring over 3 h, then quenched with satd NH 4 CI and concentrated in vacuo to remove the THF. The resulting mixture was diluted with satd NH 4 CI (100 mL) and extracted with Et20 (200 mL). The organic extract was washed with H 2 0 (100 mL), satd NaCI (50 mL), dried over MgSO 4 filtered and concentrated in vacuo to provide the title product as a white solid. MS (ESI, pos. ion) m/z: 261

(M+I-H

2 0).

0 0 0 tert-butyl 3-[4-(tert-butyl)phenyl]-3-oxopropanoate. tert-Butyl 3-[4-(tertbutyl)phenyl]-3-hydroxypropanoate, Example 60(a), (5.0 g, 18 mmol) was dissolved in CH 2

CI

2 (100 mL), magnetically stirred in a round-bottomed flask at 0 and treated with pyridinium chlorochromate (5.8 g, 27 mmol, Aldrich) in portions. The reaction mixture was allowed to warm to 25 °C and stirred at that temperature for 5 h. The mixture was filtered through a pad of Celite, the filtercake washed with CH 2 C1 2 (3 x 100 mL) and the combined filtrate was concentrated in vacuo. Purification by silica gel chromatography (1:1 hexane:EtOAc) provided the title product as a dark oil. MS (ESI, pos. ion) n/z: 277 N-(2H,3H-Benzo[3,4-e]1,4-dioxan-6-yl)(2Z)-3-[4-(tert-butyl)phenyl]-3hydroxyprop-2-enamide. According to the procedure of Wiseman et al., J. Org.

Chem. 1991, 56, 1713-1718, to a round-bottomed flask equipped with magnetic stirring and a reflux condenser was added tert-butyl 3-[4-(tert-butyl)phenyl]-3oxopropanoate, Example 60(b), (640 mg, 2.3 mmol), 1,4-benzodioxan-6-amine (350 mg, 2.3 mmol, Aldrich) and anhydrous toluene (20 mL). The mixture was stirred and heated at 130 °C for 2 h. Upon allowing to cool to 25 a precipitate -263was observed. Hexane (20 mL) was added to the suspension and the precipitate collected by filtration, washed with hexane (20 mL) and dried in vacuo at 60 oC to provide the title product as a pale grey solid. MP 161 MS (ESI, pos. ion) m/z: 354 Example 61

H

N O o

O

N-(2H,3H-Benzo[3,4-e]l,4-dioxan-6-yl)[7-(tert-butyl)(3-isoquinolyl)]carboxamide.

o k

OH

0 2-[(tert-Butyl)oxycarbonyl]-7-(tert-butyl)-1,2,3,4-tetrahydroisoquinoline- 3-carboxylic acid. According to the procedure of D. Ma, et al., Bioorg. Med.

Chem. Lett. 1998, 8(18), 2447-2450, to a 250 mL round-bottomed flask, equipped with magnetic stirring and reflux condenser, was added N-Boc-(p-tert-butyl)-Sphenylalanine (5.0 g, 15.6 mmol, Bachem), formaldehyde (50 mL, 37 wt. in

H

2 0, Aldrich) and cond HCI (30 mL). The reaction mixture was stirred and heated at 90 OC for 4 h. The solvents were removed in vacuo to provide 3.6 g of a residue [MS (ESI, pos. ion) m/z: 234 which was dissolved in THF (140 mL) and treated with 5% aq. K 2 CO3 (140 mL) and di-t-butyl dicarbonate (4.8 g, 22 mmol, Aldrich). The reaction mixture was stirred at 25 °C overnight, then acidified to pH 5 with 1 N HCI. The mixture was extracted with EtOAc (300 mL), the organic phase washed with satd NaCI (100 mL) and H 2 0 (120 mL), dried over Na 2

SO

4 filtered and concentrated in vacuo. Purification by silica gel chromatography (2:1 hexane:EtOAc) provided the title product. MS (ESI, pos.

ion) m/z: 334 264 N-(2H,3H-Benzo[3,4-e] 1,4-dioxan-6-yl)[7-(tert-butyl)(3-1,2,3,4tetrahydroisoquinolyl)]carboxamide hydrochloride. To a 250 mL roundbottomed flask equipped with magnetic stir-ring was added 2-[tertbutyl)oxycarbonyl]-7-(terr-butyl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, Example 61(a), (1.5 g, 4.65 mmol), DMF (15 mL), 1,4-benzodioxan-6amine (700 mg, 4.65 mmol, Aldrich), dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (1.25 g, 6.5 mmol, Aldrich) and NN-diisopropylethylamine mL, 13.95 mmol, Aldrich). The reaction mixture was stirred at 25 'C overnight then concentrated in vacuo. The residue was dissolved in EtOAc (35 mL), washed with H 2 0 (2x15 mL), dried over Na 2

SO

4 filtered and concentrated in vacuo. Purification by silica gel chromatography (3:1 hexane:EtOAc) provided a product [MS (ESI, pos. ion) mlz: 467 (M+1)J which was treated with 4.0 N HCI in 1A4 dioxane (10 mL, Aldrich) and stirred at 25 'C for 1 h. The solvent was removed in vacuo to provide the title product as the hydrochloride salt. MP 134 MS (ESI, pos. ion) mlz: 367 N-(2H,3H-Benzo[3,4-e]1,4-dioxan-6-yI)[7-(tert-butyl)(3-isoquinolyl)]carboxamide. Analogous to the procedure of E. D. Cox; T. I. Hagen; R. M.

McKernan; J. M. Cook, Med. Chern. Rest. 1995, 7 10-718, N-(2H,3Hbenzo[3 1 ,4-dioxan-6-yl)[7-(teri-butyl)(3-1 ,2,3 ,4tetrahydroisoquinolyl)]carboxamide hydrochloride, Example 61(b), was suspended in EtOAc (55 mL), washed with 10% NaHCO 3 (20 mL) and H 2 0 mL), dried over Na 2

SO

4 filtered and concentrated in vacuo. The resulting residue (80 mg, 0.22 mmol) was dissolved in toluene (10 mL) and treated with manganese dioxide (110 mg, 1.1 mmol). The reaction mixture was magnetically stirred at 70 'C under N 2 for 1.5 h, filtered through Celite and concentrated in vacuo. Purification by silica gel chromatography (8:1 hexane:EtOAc) provided the title product as a yellow solid. NP 154-157 MS (ESI, pos. ion) mlz: 363 1).

265- SExample 63 in

H

1" N-(2H,3H-Benzo[3,4-e]1,4-dioxan-6-yl)(2Z)-3-[4-(tert-butyl)phenyl]prop-2enamide.

OH

2 Z)-3-[4-(tert-Butyl)phenyl]prop-2-enoic acid. Potassium bis(trimethylsilyl)amide (6.1 mL, 3.05 mmol, 0.5 M in toluene, Aldrich) was added dropwise with stirring to a mixture of diphenylphosphonoacetic acid ethyl ester (0.98 g, 3.05 mmol, TCI-US) and 18-crown-6 (3.35 g, 12.7 mmol, Aldrich) in anhydrous THF (20 mL), magnetically stirred at -78 OC under Ar. The reaction mixture was stirred at -78 °C for 0.5 h then treated dropwise with a solution of 4tert-butylbenzaldehyde (0.42 mL, 2.54 mmol, Aldrich) in anhydrous THF (5 mL).

The mixture was stirred at -78 OC for 1 h, quenched with satd NH 4 Cl (5 mL), warmed to 25 OC, diluted with H 2 0 (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with satd NaCI, dried over MgSO 4 filtered and concentrated in vacuo to provide a brown viscous oil.

[MS (ESI, pos. ion) m/z: 233 The oil (0.83 g) was dissolved in THF mL) and MeOH (5 mL), magnetically stirred in a round-bottomed flask at OC, and treated with 1 N LiOH (10 mL). The reaction mixture was stirred at OC for 18 h, the organic solvents removed in vacuo, and the aqueous phase was washed with Et20, acidified with 10% citric acid and extracted with EtOAc (3 x mL). The combined organic extracts were dried over MgSO 4 filtered and concentrated in vacuo to provide the title product as a white solid. MS (ESI, pos.

ion) m/z: 205 266 N- (2H,3H-Benzo[3,4-e] 1 ,4-dioxan-6-yl)(2Z)-3- [4-(tert- butylI)p henyll prop- 2-enamide. Analogous to the procedure used to prepare Example 1, (tert-butyl)phenyl]prop-2-enoic acid, Example 63(a), (0.46 g, 2.3 mmol) and 1,4benzodioxan-6-amine (0.38 g, 2.58 mmol, Aldrich) provided the title product as a white solid. MP 114-116 TC. MS (ESI, pos. ion) 338 1).

Example 64 N0 N-(2H,3H-Benzo[eI 1,4-dioxan-6-yI)(2Z)-3-[4-(tert-butyl)phenyll-3-* phenylprop-2-enamide.

N-(2H,3H-Benzo[e] I ,4-dioxan-6-yl)-3-[4-(teri-butyl )phenyl]prop-2-ynamide, Example 55(b), (0.34 g, 1.0 mmol) was dissolved in anhydrous EtOAc (50 mL) in a 100 mL round-botitomed flask equipped with reflux condenser and magnetic stirring under dry nitrogen atmosphere. To this solution was added iodobenzene (0.20, g, 1.0 mmol, Aldrich) and bis(dibenzylideneacetone)palladium (0.080 g,.

0.14 mmol, Acros), followed by diethylamine (0.34 mL, 3.3 mmol, Aldrich) aiid formic acid (0.098 mL, 2.6 mmnol, Aldrich). The reaction mixture was heated under reflux for 20 h, cooled to room temperature, washed with I N HCI (2 x mL), I N NaOH (2 x 5 mL), satd NaCI (5 mL) and dried over Na 2

SO

4 The organic solution was filtered and concentrated to afford a brown oil which was purified by silica gel chromatography (20 EtOAc/hexane) to give the title compound as a pale yellow solid. MP 80-82 MS (ESI, pos. ion) m/z: 414 267 Example I H

N

(2E)-N-(21-,3H-Benzo [el 1,4-dioxan-6-yl)-3-[4-(tert-butyl)phenyl]-3phenylprop-2-enamide.

N0 N-(2H,3H-Benzo[e] 1,4-d ioxan-6-yl)-3-pbenylprop-2-ynamide. Analogous to the procedure used to prepare Example 1, phenylpropiolic acid (5.8 g, 140 mmol, Aldrich) and 1,4-benzodioxan-6-amine (6.65 g, 44 mmol, Aldrich) provided, after recrystallization from EtOAc and hexane, the title compound as a white solid. MP 132T 0 MS (ESI, pos. ion) m/z: 280 1).

(2E)-N-(2H,3H-Benzo[e]1 ,4-dioxan-6-yl)-3- [4-(tert-butyl)phenyll-3phenylprop-2-enamide. Analogous to the procedure used to prepare Example 64, 1-tert-butyl-4-iodobenzene (0.26 g,1.0 mnmol, Aldrich) and N-(2H,3Hbenzojl1,4-dioxan-6-yl )-3-phenylprop-2-ynamide, Example 65(a), (0.28 g, 1.0 mmol) provided, after recrystallization from EtOAc: and hexane, the title compound as an off-white solid. MIP 139 TC. MS (ESI, pos. ion) m/z: 414 1).

Example 66

H

N

N

(2E)-3-[4-(tert-Butyl)phenyll-N-[1-(N-metbylcarbamoyl)(1H-indazol-6yl)]prop-2-enamide. To a round-bottomed flask, equipped with a magnetic stir bar, was added 1H-i ndazol-6-yl)-3 -[4-(tert-butyl )phen yl ]prop-2-enamide, Example 155, (61 mg, 0. 19 mmol), THE (8 mL) and isocyanatomethane (54 mg, 0.96 mmol, Carbolabs). The reaction mixture was stirred at room temperature for 8 h. The reaction mixture was diluted with EtOAc (10 mL), washed with water -268- (8 mL), dried over Na 2

SO

4 filtered and concentrated in vacuo. Purification by silica gel chromatography (40:20:1 hexane:EtOAc:MeOH) provided the title product as an off-white solid. MP 208-209 MS (ESI, pos. ion) m/z: 377 Example 67 H H H N, CN N,

"N.O

(2E)-3-[4-(tert-Butyl)phenyl]-N-{4-chloro-3-[(methylamino)carbonylamino]phenyl}prop-2-enamide.

H

N*,,C(NH

Y IC (2E)-N-(3-Amino-4-chlorophenyl)-3-14-(tert-butyl)phenyllprop-2enamide. To a round-bottomed flask equipped with a magnetic stir bar, was added (2E)-3-[4-(tert-butyl)phenyl]-N-(4-chloro-3-nitrophenyl)prop-2-enamide, Example 156, (250 mg, 0.69 mmol), EtOH (8 mL), indium (800 mg, 6.9 mmol, Aldrich) and satd NH 4 CI (10 mL). The reaction mixture was stirred at reflux for 5 h. The solvents were removed in vacuo, the residue was dissolved in EtOAc mL), washed with water (20 mL), dried over Na 2

SO

4 filtered and concentrated in vacuo to yield the title product. MS (ESI, pos. ion) m/z: 329 (2E)-3-[4-(tert-Butyl)phenyl]-N-{4-chloro-3-[(methylamino)carbonylamino]phenyl}prop-2-enamide. According to the procedure used to prepare Example 66, (2E)-N-(3-amino-4-chlorophenyl)-3-[4-(tertbutyl)phenyl]prop-2-enamide, Example 67(a), (90 mg, 0.27 mmol) and isocyanatomethane (156 mg, 2.7 mmol, Carbolabs) provided, after purification by silica gel chromatography (2:1 hexane:EtOAc), the title product as an off-white 2 5 solid. MP 120-122 MS (ESI, pos. ion) m/z: 386

L-

269 Example 68

H

NN

(2E)-3-[4-(tert-Butyl)phenyl]-N-quinoxalin-6-ylprop-2-enamide.

H

2 N N Quinoxaline-6-ylamine. To a round-bottomed flask equipped with magnetic stirrng was added 4-nitro-1,2-phenylenediamine (1.0 g, 6.5 mmol, Aldrich), acetonitrile (10 mL) and glyoxal (2.2 mL, 19 mmol, 40 wt. in water, Aldrich).

The reaction mixture was allowed to stir at 50 OC for 12 h, then concentrated in vacuo to yield 1. 1 g crude 6-nitro-quinoxaline. The crude product was dissolved in methanol, treated with 10% Pd/C (10 mg, Aldrich) and stirred under H 2 (1 atm) at 25 'C overnight. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo to provide the title product. MS (ESI, pos. ion) m/lz: 146 1).

(2E)-3-[4-(tert-Butyl)phenyl]-N-quinoxalin-6.ylprop-2-enamide.

Analogous to the procedure used to prepare Example 2, 4-tert-butyl -transcinnamic acid (100 mg, 0.40 mmol, EMKA-Chemie) and quinoxaline-6-ylamine, Example 68(a), (71 mg, 0.40 mmol) provided, after purification by silica gel chromatography (1:2 hexane:EtOAc), the title product as a yellow solid. NIP 229- 230 MS (ESI, pos. ion) m/z: 332 270 Example 69 N H (2E)-N-(1-acetyl(7-1 ,2,3,4-tetrahyd roquinolyl))-3-[4-(tert-butyl)phenyllprop- 2-enamide.

0 2 N N 1-Acetyl-7-nitro- 1,2,3,4-tetrahydroquinoline. A mixture of 7-ni tro- 1,2,3,4tetrahydroquinoline, Example 19(a), (0.36 g 2.0 rnmol) and acetic anhydride mL, 37 mmol, Aldrich) in a 15 mL round-bottomed flask, was heated at reflux for 1.5 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc and 36% ammonium hydroxide. The aqueous layer was extracted with EtOAc (10 mL) and the combined organic layers were dried over Na 2

SO

4 filtered and concentrated in vacuo to give the title compound as a yellow solid. MIS (ESI, pos. ion) m/z: 221 I).

1-Acetyl-7-amino-1,2,3,4-tetrahydroquinoline. Analogous to the procedure used to prepare Example 3, step I1-acetyl-7 -nitro- 1,2,3,4-tetrahydroquinoline, Example 69(a), (0.44 g, 2.0 mnmol) was converted to the title product. MIS (ESI, pos. ion) m/lz: 191 (2E)-N-(1-acetyl(7- 1,2,3,4-tetrahyd roquinolyl))-3-[4-(tertbutyl) phenyll prop- 2-enamide. According to the procedure used to prepare Example 1, 4-tert-butyl-trans-cinnamic acid (0.41 g, 2.0 mmol, EMKA Chemnie) and 1 -acetyl -7-amino-i ,2,3,4-tetrahydroquinoline, Example 69(b), (370 mg, mmol) provided, after purification by silica gel chromatography (1:1 hexane:EtOAc), the title compound as an amorphous white solid. MS (ESI, pos.

ion) mn/z: 377 -271- Example

N

1 H S Y

N

(2E)-3-[4-(tert-Butyl)phenyl]-N-[1-(2-methoxyethyl)indol-6-yl]prop-2enamide.

To a round-bottomed flask was added, (2E)-3-[4-(tert-butyl)phenyl]-N-indol-6ylprop-2-enamide, Example 189, (320 mg, 1.0 mmol) and anhydrous DMF mL). The solution was stirred magnetically and treated with sodium hydride (0.10 g, 2.5 mmol, 60% dispersion in mineral oil, Aldrich) followed by 2bromoethyl methyl ether (140 mg, 1.0 mmol, Aldrich). Stirring was continued at 25 °C for 2 h, then the reaction mixture was quenched by the addition of water mL) and extracted with EtOAc. The organic extract was concentrated in vacuo. Purification by silica gel chromatography (60:40 hexane:EtOAc) provided the title compound as a yellow solid. MP 133 MS (ESI, pos. ion) m/z: 377 Example 71

N

O-

0- (2E)-3-[4-(tert-Buty)yl)phenyl-N-[-(2-methoxyethyl)indol-5-ylprop-2enamide.

Analogous to the procedure used to prepare Example 70, 2-bromoethyl methyl ether (140 mg, 1.0 mmol, Aldrich) and (2E)-3-[4-(tert-butyl)phenyl]-N-indol-5ylprop-2-enamide, Example 161, (320 mg, .01 mmol) provided, after purification by silica gel chromatography (65:35 hexane:EtOAc), the title compound as a pale yellow solid. MP 138 MS (ESI, pos. ion) m/z: 377 272 Example 72

OH

(2E)-3-[4-(tert-Butyl)phenyll-N-[1-(2-hydroxyethyl)indol-6-ylprop-2enamide.

H

2

NN

1-[2.(1,1,2,2-Tetramethyl-1-silapropoxy)ethyl]indole-6-ylamine.

Analogous to the procedure used to prepare Example 33, step 6-nitroindole (0.49 g, 3.0 mmol, Aldrich) and (2-bromoethoxy)-tert-butyldi methylsi lane (0.72 g, 3.0 mmol, Aldrich) provided the title product. MS (ESI, pos. ion) m/lz: 291

HS

(2E).3-[4-(tert-Butyl)phenyl]-N-{1-[2-(1,1 ,2,2-tetramethyl-1.

silapropoxy)ethyl]indol-6-yI~prop-2-enamide. Analogous to the procedure used to prepare Example 1, 4-tert-butyl-trans-cinnamic acid (200 mg, 1.0 mmol, EMKA-Chemnie) and 1,1 ,2,2-tetramethyl- 1-si lapropoxy)ethyl] indole-6ylamine, Example 72(a), (290 mg, 1.0 mnmol) provided the title product. MIS (ESI, pos. ion) m/z: 477 1).

(2E)-3-[4-(tert-Butyl)phenyll-N-[1-(2-hydroxyethyl)indol-6-yllprop-2enamide. (2E)-3-[4-(tert-Butyl)phenyll-N-1 ,2,2-tetramethyl- 1si lapropoxy)ethyl]indol-6-yilprop-2-enamide, Example 72(b), (420 mg, 273 0.88 mmol) was transferred to a round-bottomed flask and treated with tetrabutylammonium fluoride (2.0 mL, 2.0 mmol, 1.0 M in THE, Aldrich) under

N

2 The reaction mixture was magnetically stirred at 25 0 C for 2 h. The reaction mixture was diluted with water (25 mL) and extracted with EtOAc. The organic extract was concentrated in vacuo. Purification by silica gel chromatography (30:70 hexane:EtOAc) provided the title compound as a yellow solid. MP 178 MS (ESI, pos. ion) mlz: 363 Example 73 I H

OH

[4-(tert-Butyl)phenyl]-N-[1-(2-hydroxyethyl)indol-5-yllprop-2enamide.

H

2

N

K0 N I- [2-(1,1,2,2-Tetramethyl- 1-si lap ropoxy)ethyl1] indole-5- ylami ne.

According to the procedure used to prepare Example 33, step (0.49 g, 3.0 mmol, Aldrich) and (2-bromoethoxy)-tert-butyldimethylsi lane (0.72 g, 3.0 mrnol, Aldrich) provided the title product. MIS (ESI, pos. ion) m/z: 291 :101

N

(2E)-3-[4-(tert-Butyl)phenyl]-N-f 1- (1,1 tetra methyl-1 A lap ropoxy)ethyl i ndol-5-y I Iprop -2-ena mide. According to the procedure used 274 to prepare Example 1, 4-tert-butyl-trans-cinnamic acid (100 mg, 0.50 mmo], ENMKA-Chemie) and 1-112-( 1,1 ,2,2-tetramethyl-l1-silapropoxy)ethyl]indole-5ylamine, Example 73(a), (145 mg, 0.50 mmol) provided the title product. MS (ESI, pos. ion) mz/z: 477 1).

(2E)-3-[4-(tert-Butyl)phenyl]-N-[1-(2-hyd roxyethyl)indol-5-yIlprop-2enamide. According to the procedure used to prepare Example 72, step (2E)- 3-[4-(tert-butyl)phenyll-N- I 1,1 ,2,2-tetramethyl- I-si lapropoxy)ethyllindol- }prop-2-enamide, Example 73(b), (130 mg, 0.27 mmol) and tetrabutylamrnonium fluoride(1.0 mL, 1.0 mmol, 1.0 M in THF, Aldrich) provided, after purification by silica gel chromatography (30:70 hexane:EtOAc), the title compound as a pale yellow solid. MNP 182 MS (ESI, pos. ion) in/z: 363 Example 74 I H N OH

H

(2E)-3-[4-(tert-Butyl)phenyll-N-[2-(hydroxymethyl)indol-5-yllprop-2en amid e.

H

2 N ~yy~ OEt

H

Ethyl 5-aminoindole-2-carboxylate. Analogous to the procedure used to prepare Example 3, step ethyl 5-nitroi ndole-2-carboxyl ate (2.3 g, 9.9 mmol, Acros) provided the title product. MS (ES I, pos. ion) m/z: 205 1).

H

2 N

OH

H

(5-Aminoindol-2-yl)methan-1-ol. Ethyl 5-aminoindole-2-carboxylate, Example 74(a), (1.5 g, 7.3 mmol) was transferred to a round-bottomed flask and treated with lithium aluminum hydride (10 mL, 10 mmol, 1.0 M in TI-F, Aldrich) under N 2 The reaction mixture was magnetically stirred at 25 'C for 1 h, then 275 quenched by the dropwise addition of H 2 0 (0.5 mL) followed by 20% aq. KOH mL). The suspension was filtered and the aqueous phase extracted with EtOAc. The organic extract was concentrated in vacuo. Purification of the crude product by silica gel chromatography (20:80 hexane:EtOAc) provided the title product. MS (ESI, pb's. ion) m/z: 163 (2E)-3-[4-(tert-Butyl)phenyl]-N-[2-(hydroxymethyl)indol-S-yllprop-2enamide. Analogous to the procedure used to prepare Example 1, 4-tert-butyltrans-cinnamic acid (200 mg, 1.0 mmol, EMIKA-Chemie) and (5-aminoindol-2yl)methan-1-ol, Example 74(b), (160 mg, 1.0 mmol) provided, after purification by silica gel chromatography (40:60 hexane:EtOAc), the title product as a pale tan amorphous solid. MS (ESI, pos. ion) m/z: 349 1).

Example

H

N N 1 0 _C(0 (2E)-N-(2H,3H-Benzo[3,4-e] 1,4-dioxan-6-yl)-3-[6-(tert-butyl)-2-methyl(3pyridyl)]prop-2-enamid'e.

N C0 2 Et Ethyl 6- (tert-bu tyl)-2- methylpy rid ine-3-carboxylate. Analogous to the procedure used to prepare Example 44, step ethyl 2-methylnicotinate (8.3 g, mmol, Aldrich), trimethylacetic acid (26 g, 250 mmol, Aldrich), silver nitrate (1.7 g, 10 mmol, Aldrich), 10% aq. sulfuric acid (50 mL) and ammonium persulfate (23 g, 100 mmol, Aldrich) provided, after purification by silica gel chromatography (80:20 hexane:EtOAc), the title product. MS (ESI, pos. ion) rn/z: 222 1).

CHO

276 6-(tert-Butyl)-2.methylpyridine-3-carbaldehyde Analogous to the procedure used to prepare Example 43, step ethyl 6-(tert-butyl)-2methylpyridine-3-carbox y]ate, Example 75(a), (5.2 g, 23 mmol) provided the title product. MS (ESI, pos. ion) m/z: 178 1).

OH

0 [6-(tert-Butyl)-2-methyl(3-pyridyl))prop-2-enoic acid. Analogous to the procedure used to prepare Example 40, step 6-(tert-butyl)-2methylpyridine-3-carbaldehyde, Example 75(b), (3.0 g, 17 mmol) and triethyl phosphonoacetate (4.0 g, 18 mmol, Aldrich) provided the title product. MS (ESI, pos. ion) rn/z: 220 (2E)-N-(2H,3H-Benzo[3,4-e]1,4-dioxan-6-yl)-3-[6-(tert-butyl)-2-methyl(3pyridyl)]prop-2-enamide. Analogous to the procedure used to prepare Example 1, (2E)-3-[6-(tert-butyl)-2-methyl(3-pynidyl)]prop-2-enoic acid, Example (110 mg, 0.50 mmol) and 1,4-benzodioxan-6-amine (76 mg, 0.50 mmol, Aldrich) provided, after purification by silica gel chromatography (55:45 hexane:EtOAc), the title compound as a yellow amorphous solid. MS (ESI, pos. ion) nilz: 353 1).

Example 76

N

(tert- Butyl)-2-methyl(3-pyridyl)]-N-i ndol-6-ylprop-2-enamide.

Analogous to the procedure used to prepare Example 1, (2E)-3-[6-(tert-butyl)-2methyl(3-pyridyl)]prop-2-enoic acid, Example 75(c), (220 mg, 1.0 mmol) and 6aminoindole (130 mg, 1.0 mmol, Lancaster) provided, after purification by silica gel chromatography (55:45 hexane:EtOAc), the title compound as a yellow solid.

MP 182 0 C. MS (ESI, pos. ion) tn/z: 334 277 Example 77

H

(2E)-N-Benzothiazol-6-yl-3-[6-(tert-butyl)-2-methyl(3-pyridyl)]prop-2enamide.

Analogous to the procedure used to prepare Example 1, (2E)-3-[6-(tert-butyl)-2methyl(3-pyridyl)Iprop-2-enoic acid, Example 75(c), (220 mg, 1.0 mmol) and 6aminobenzothiazole (150 mg, 1.0 mmol, Lancaster) provided, after purification by silica gel chromatography (55:45 hexane:EtOAc), the title compound as a pale yellow amorphous solid. MS (ESI, pos. ion) m/z: 352 Example 78

H

N N

H

(2E)-3-[6-(tert-Butyl)-2-methyl(3-pyridyl)] -N-indol-5-ylprop-2-enamide.

Analogous to the procedure used to prepare Example 1, (2E)-3-116-(tert-butyl)-2methyl(3-pyfidyl)]prop-2-enoic acid, Example 75(c), (0.88 g, 4.0 mmol) and aminoindole (0.53 g, 4.0 mmol, Lancaster) provided, after purification by silica gel chromatography (55:45 hexane:EtOAc), the title compound as a yellow amorphous solid. MS (ESI, pos. ion) mlz: 334 Example 79

H

N. OH 0

H

(2E)-3-[6-(tert-Butyl)-2-methyl(3-pyridyl)]-N-[2-(hydroxymethyl)indol-5yllprop-2-enamide.

Analogous to the procedure used to prepare Example 1, (2E)-3-[6-(tert-butyl)-2methyl(3-pyridyl)]prop-2-enoic acid, Example 75(c), (110 mg, 0.50 mmol) and 278 (5-aminoindol-2-yl)methan-I-ol, Example 74(b), (81, 0.50 mmol) provided, after purification by silica gel chromatography (25:75 hexane:EtOAc), the title compound as a pale yellow solid. NW 213 0 C. MS (ESI, pos. ion) m/z: 364 Example

H

N N OH

H.

(2E)-3-[6-(tert-Butyl)(3-pyridyl)]-N-[2-(hydroxymethyl)indol-5-yllprop-2enamide.

Analogous to the procedure used to prepare Example 1, (2E)-3-[6-QIert-butyl)(3pyridyl)]prop-2-enoic acid, Example 44(b), (41 mg, 0.20 mmol) and aminoindol-2-yl)methan-1-ol, Example 74(b), (32 mg, 0.20 mmol) provided, after purification by silica gel chromatography (20:80 hexane:EtOAc), the title compound as a yellow amorphous solid. MS (ESI, pos. ion) m/z: 350 1).

Example 81

H

0 N

OH

(2E)-3-[6-(tert-Butyl)(3-pyridyl)]-N-[1-(2-hydroxyethyl)indol-5-yljprop-2enamide.

N

(2E)-3-[6-(tert-butyl)(3-pyridyl)]-N-{1-(2-(1,1,2,2-tetramethyl-1silapropoxy)ethyllindol-5.yl~prop-2-enamide. Analogous to the procedure used 279 to prepare Example 1, (2E)-3-[6-(tert-butyl)(3-pyridyl)]prop-2-enoic acid, Example 44(b), (41 mg, 0.20 mmol) and 1-[2-(1,1,2,2-tetramethyl-1 Example 73(a), (60 mg, 0.20 mmol) provided the title product. MS (ESI, pos. ion) m/lz: 478 1).

(2E)-3-[6-(tert-Buttyl) (3-pyridyl)]-N- (2-hyd roxyethyl)indol-5-yll prop- 2-enamide. Analogous to the procedure used to prepare Example 72, step [6-(tert-butyl)(3-pyridyl)]-N-j 1,1 ,2,2-tetrameth yl-I }prop-2-enamide, Example 81(a), (75 mg, 0.16 mnmol) and tetrabutylammonium fluoride (0.50 m.L, 0.50 mmol, 1.0 M in THF, Aldrich) provided, after purification by silica gel chromatography (20:80 hexane:EtOAc), the title compound as a yellow amorphous solid. MS (ESI, pos.

ion) nzlz: 364 1).

Example 82

FF

F IH

H

N

0 (2E)-N-Indol-6-yI-3-[2-methyl-6-(trifluoromethyl)(3-pyridyl)]prop-2enamide.

F

F

F

CHO

2-Methyl-6-(trifluoromethyl)pyridine-3-carbaldehyde. Analogous to the procedure used to prepare Example 43, step 2-rnethyl-6- (trifluoromethyl)pyridine-3-carboxylic acid (5.0 g, 24 mrnol, Oakwood) provided the title product. MS (ESI, pos. ion) rn/z: 190 -280-

FF

F

OH

0 (2E)-3-[2-Methyl-6-(trifluoromethyl)(3-pyridyl)]prop-2-enoic acid.

Analogous to the procedure used to prepare Example 40, step 2-methyl-6- (trifluoromethyl)pyridine-3-carbaldehyde Example 82(a), (3.7 g, 20 mmol) and triethyl phosphonoacetate (4.5 g, 20 mmol, Aldrich) provided the title product.

MS (ESI, pos. ion) nz/z: 232 (2E)-N-Indol-6-yl-3-[2-methyl-6-(trifluoromethyl)(3-pyridyl)]prop-2enamide. Analogous to the procedure used to prepare Example 1, methyl-6-(trif uoromethyl)(3-pyridyl)] prop-2-enoic acid, Example 82(b), (58 mg, 0.25 mmol) and 6-aminoindole (33 mg, 0.25 mmol, Lancaster) provided, after purification by silica gel chromatography (55:45 hexane:EtOAc), the title compound as a yellow solid. MP 223 MS (ESI, pos. ion) m/z: 346 Example 83

F

F

F YH N N

H

(2E)-N-Indol-5-yl-3-[2-methyl-6-(trifluoromethyl)(3-pyridyl)]prop-2enamide.

Analogous to the procedure used to prepare Example 1, (2E)-3-[2-methyl-6- (trifluoromethyl)(3-pyridyl)]prop-2-enoic acid, Example 82(b), (120 mg, 0.50 mmol) and 5-aminoindole (66 mg, 0.50 mmol, Aldrich) provided, after purification by silica gel chromatography (55:45 hexane:EtOAc), the title compound as a yellow solid. M? 231 MS (ESI, pos. ion) m/z: 346 Example 84

F

F

F

H

N-.

N N, Iazz z -281- (2E)-N-Benzothiazol-6-yl-3-[2-methyl-6-(trifltioromethyl)(3-pyridyl)]prop-2enamide.

Analogous to the procedure used to prepare Example 1, (2E)-3-[2-methyl-6- (tri fiuorometh yl )(3-pyridyl))prop-2-enoic acid, Example 82(b), (120 mg, 0.50 mmol) and 6-aminobenzothiazole (75 mg, 0.50 mmol, Lancaster) provided, after purification by silica gel chromatography (55:45 hexane:EtOAc), the title compound as a white solid. NAP 196 0 C. MS (ESI, pos. ion) m/z: 364 Example

F

F F

H

N ~Na (0)N(H3-Bno34e (2E)N-(H,3HBeno[3,-e1,4-dioxan-6-yl)-3-[2-methyl-6-(trifluoromethyl)- (3-pyridyl)Iprop-2-enamide.

Analogous to the procedure used to prepare Example 1, (2E)-3-[2-methyl-6- (trifluoromethyl)(3-pyridyl)Iprop-2-enoic acid, Example 82(b), (120 mg, 0.50 mmol) and 1,4-benzodioxan-6-amine (76 mg, 0.50 mmol, Aldrich) provided, after purification by silica gel chromatography (55:45 hexane:EtOAc), the title compound as a yellow solid. MP 186 MS (ESI, pos. ion) m/z: 365 Example 86 IH H NN 0 (2E)-3-[4-(tert-butyl)phenyll-N-[3-(hydroxymethyl)-2-oxo(7-1,3,4trihydroquinolyl)]prop-2-enamide.

0 2 N NH 2

OH

(2-Amino-4-nitrophenyl)methan-1-ol. To a solution of 4-nitroanthranilic acid (910 mg, 5.0 mmol, Aldrich) in THF (15 mE), magnetically stirred at 0 'C, was added borane-tetrahydrofuran complex (15 mL, 15 mmol, 1.0 M in THE, -282- Aldrich) dropwise. The reaction mixture was heated to reflux overnight. The mixture was then cooled to 0 °C and treated dropwise with MeOH (5 mL) followed by 1 N NaOH (30 mL). After stirring for 30 min at room temperature, the mixture was extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with satd NaCI (20 mL), dried over Na 2

SO

4 filtered and concentrated in vacuo. Purification by silica gel chromatography EtOAc/hexane) followed by recrystallization from EtOAc/hexane provided the title product. MS (ESI, pos. ion) m/z: 169 0 2 N NH 2 2-Amino-4-nitrobenzaldehyde. A mixture of 2-amino-4nitrophenyl)methan-l-ol, Example 86(a), (336 mg, 2.0 mmol) and MnO 2 (3.48 g, 40.0 mmol, Aldrich) in CH 2

CI

2 /hexane 10 mL) was stirred at room temperature for 1 h. The suspension was filtered and washed with CH 2 C12. The filtrate was concentrated in vacuo to give the crude product. MS (ESI, pos. ion) m/z: 167

H

0 2 N O

CO

2 Me Methyl 7-nitro-2-oxo-1,3,4-trihydroquinoline-3-carboxylate. A mixture of 2-amino-4-nitrobenzaldehyde, Example 86(b), (1.66 g, 10.0 mmol), dimethyl malonate (1.37 mL, 12.0 mmol, Aldrich), copper (II) acetate (100 mg, 0.5 mmol, Aldrich) and potassium acetate (99 mg, 1.0 mmol, Bayer) in acetic acid (20 mL) was stirred at 110 °C for 48 h. Most of the solvent was removed in vacuo and the resulting precipitate was collected by filtration, washed with EtOAc and dried in vacuo to give the title product. MS (ESI, pos. ion) m/z: 248 (M+1) H .H 0 2 N, N 0 0 2 N N O'NOH LOOH 3-(Hydroxymethyl)-7-nitro-1,3,4-trihydroquinolin-2-one and (7-nitro-3- 1,2,3,4-tetrahydroquinolyl)methan-l-ol. To a solution of methyl 7-nitro-2-oxo- 1,3,4-trihydroquinoline-3-carboxylate, Example 86(c), (1.23 g, 5.0 mmol) in THF 283 mL) was added LiBH 4 (12.5 m.L, 25.0 mmol, 2.0 M in TI-F, Aldrich). The reaction mixture was stirred at 40 'C for 18 h, then quenched by the careful addition of satd NH 4 CI (20 mL). The mixture was stirred at room temperature for min, then extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with satd NaCI (10 mL), dried over Na 2

SO

4 filtered and concentrated in vacuo. Purification by silica gel chromatography EtOAc/CH 2

CI

2 provided 3-(hydroxymethyl)-7-ni tro- 173,4-trihydroquinolin-2-one [MS (ESI, pos. ion) mlz: 223 and (7-nitro-3-1,2,3,4tetrahydroquinolyl)methan-1-oI [MS (ESI, pos. ion) m/z: 209 (M+1)1.

H

2 NN 0 (0 H H -A mino-3-(hydroxymethyl)-1 ,3,4-trihyd roquinolin-2-one. Analogous to the procedure used to prepare Example 3, step 3-(hydroxymethyl)-7-nitro- 1,3,4-tfihydroquinolin-2-one, Example 86(d), (66 mg, 0.30 mmol) provided, after purification by silica gel chromatography (10%.MeOHICH 2

CI

2 the title compound. MS (ESI, pos. ion) m/z: 193 (2E)-3-[4-(tert-Butyl)phenyl]-N-[3-(hyd roxymethyl)-2-oxo(7- 1,3,4trihydroquinolyl)]prop-2-enamide. Analogous to the procedure used to prepare Example 1, 4-tert-butyl-trans-cinnamic acid (67 mg, 0.33 mmol, EMKA- Chemie) and 7 -amino-3-(hydrox ymethyl)- 1,3 ,4-trihydroquinolin-2-one, Example 86(e), (52 mg, 0.27 mmol) provided, after purification by silica gel chromatography (10% MeOll/EtOAc), the title compound as a pale yellow solid.

MIP 201-203 0 C. MS (ESI, pos. ion) mlz: 379 284 Example 87

F

F H

H

F ,N

N

0 0: OH (2E)-N-[3-(Hydroxymethyl)(7-1,2,3,4-tetrahyd roqui nolyl)I-3-[4- (trifluoromethyl)phenyllprop-2-enamide.

H

H

2 N N

OH

(7-A mino-3-1 ,2,3,4-tetrahydroquinolyl)methan- 1-ol. Analogous to the procedure used to prepare Example 3, step (7-nitro-3-1,2,3,4tetrahydroquinolyl)methan-l-ol, Example 86(d), (140 mg, 0.68 mmol) provided, after purification by silica gel chromatography (10% MeOHICH 2

CI

2 the title compound. MS (ESI, pos. ion) m/z: 179 (2E)-N-[3-(Iiydroxymethyl)(7-1,2,3,4-tetrahyd roquinolyl)]-3-[4- (trifluoromethyl)phenyllprop-2-enamide. Analogous to the procedure used to prepare Example 1, trans-4-(trifluoromethyl)cinnamic acid (120 mg, 0.55 mmol, Aldrich) and (7-amino-3- 1,2,3 ,4-tetrahydroquinolyl)methan- 1 -ol, Example 87(a), (98 mg, 0.55 mmol) provided, after purification by silica gel chromatography MeOHIEtOAc), the title compound as a pale yellow solid. MP 176-179 TC.

MS (ESI, pos. ion) ml/z: 377 1).

Example 88

F

F

HI

N N

N

(2E)-N-[3-(hydroxymethyl)-1-methyl(7-1,2,3,4-tetrahyd roquinolyl)]-3-[4- (trifluoromethyl)phenyllprop-2-enamide.

A mixture of (2E)-N-[3-(hydroxymethyl)(7- 1,2,3,4-tetrahydroquinol [4- (trifluoromethyl)phenyllprop-2-enamide, Example 87, (75 mg, 0.20 mmol), iodomethane (0.014 mL, 0.22 mmol, Aldrich) and NaHCO 3 (84 mg, 1.0 mmol) in -285- DMF (1.0 mL, Aldrich) was stirred for 4 h at room temperature. Water (5 mL) was added and the mixture was extracted with EtOAc (2 x 20 mL). The combined organic phases were washed with water (5 mL), satd NaCI (5mL), dried over Na 2

SO

4 filtered and concentrated in vacuo. Purification by silica gel chromatography (60% EtOAc/CH 2

CI

2 provided the title product as a white solid.

MP 167-169 OC. MS (ESI, pos. ion) m/z: 391 Example 89

H

ON

O

0o (2E)-N-(2H,3H-Benzo[e]1,4-dioxan-6-yl)-3-[4-(tert-butyl)phenyl]-5-(1,3dioxolan-2-yl)pent-2-enamide.

Analogous to the procedure used to prepare Example 53(a), (1,3-dioxolan-2ylethyl)zinc bromide (3.0 mL, 1.5 mmol, 0.5 M THF solution, Rieke) and N- (2H,3H-benzo[e] 1,4-dioxan-6-yl)(2Z)-3-[4-(tert-butyl)phenyl]-3-iodoprop-2enamide, Example 55, (0.23 g, 0.50 mmol) provided, after purification by silica gel chromatography (gradient: 30%-35% EtOAc/hexane), the title product as an amorphous white solid. MS (ESI, pos. ion) m/z: 438 -286- Example

H

ON

N

(2E)-N-(2H,3H-Benzo[e]1,4-dioxan-6-yl)-3- [4-(tert-butyl)phenyl]-4-(3pyridyl)but-2-enamide.

SnBu 3

N

3-(Tributylstannanylmethyl)pyridine. Analogous to the procedure of Kaiser, E. M. and Petty, J. D. Synthesis 1975, 705-706, to a 50 mL roundbottomed flask equipped with magnetic stirring was added lithium diisopropylamide (5.2 mL, 10 mmol, 2.0 M in heptane/THF/ethylbenzene, Aldrich) at 0 C under nitrogen, followed by hexamethylphosphoramide (1.8 mL, mmol, Aldrich). The mixture was stirred for 15 min, then treated with a solution of 3-picoline (1.0 mL, 10 mmol, Aldrich) in THF (4 mL) over 5 min. The reaction mixture was stirred for 30 min, then a solution of tributyltin chloride (2.8 mL, 10 mmol, Aldrich) in THF (6 mL) was added. The resulting solution was gradually warmed to room temperature and concentrated in vacuo. Purification by silica gel chromatography (gradient: EtOAc/hexane) provided the title product as a colorless oil. MS (ESI, pos. ion) m/z: 382 (2E)-N-(2H,3H-Benzo[e]J1,4-dioxan-6-yl)-3-[4-(tert-butyl)phenyl]-4-(3pyridyl)but-2-enamide. To a 50 mL round-bottomed flask, equipped with magnetic stirring, was added 3-(tributylstannanylmethyl)pyridine, Example (0.37 g, 0.97 mmol), N-(2H,3H-benzo[e] ,4-dioxan-6-yI)(2Z)-3-[4-(tertbutyl)phenyl]-3-iodoprop-2-enamide, Example 55, (0.30 g, 0.65 mmol), 1methyl-2-pyrrolidinone (2.5 mL, Aldrich), and tetrakis(triphenylphosphine)palladium (75 mg, 0.06 mmol, Aldrich). The reaction mixture was stirred at 110OC overnight, then diluted with EtOAc (100 mL), washed with satd NaHCO 3 water and satd NaCI. The organic phase was dried over Na 2

SO

4 filtered and -287concentrated in vacuo. Purification by silica gel chromatography (25%-45% EtOAc/hexane) was followed by reverse phase preparative HPLC (CH 3 with 0.1%TFA). The fractions containing desired product were neutralized with NaHCO 3 The mixture was extracted with CH 2

CI

2 and the organic phase concentrated in vacuo to provide the title product as an amorphous white solid.

MS (ESI, pos. ion) m/z: 429 Example 91

H

ON

N-(2H,3H-Benzo[e]1,4-dioxan-6-yl)(2Z)-3-[4-(tert-butyl)phenyl]-4pyrrolidinylbut-2-enamide.

0 0 Methyl (2E)-3-[4-(tert-butyl)phenyl]but-2-enoate. To a 100 mL roundbottomed flask purged with N 2 was added 1-bromo-4-tert-butylbenzene (2.34 g, 11.0 mmol, Aldrich), methyl crotonate (1.08 mL, 10 mmol, Aldrich), Nmethyldicyclohexylamine (3.31 mL, 15 mmol, Aldrich), palladium acetate (0.045 g, 0.20 mmol, Aldrich), tetraethylammonium chloride (1.66 g, 10.0 mmol, Fluka), and N,N-dimethylacetamide (40 mL, Aldrich). The reaction mixture was magnetically stirred at 100 °C overnight, then allowed to cool to 25 diluted with Et20, and filtered through Celite. The solution was washed with H 2 0 (3 x), dried over MgSO 4 filtered, and concentrated in vacuo. Purification by silica gel chromatography (gradient: dichloromethane in hexane) provided the title product as a colorless oil. MS (ESI, pos. ion) nm/z: 233 .OMe -288- Methyl (2Z)-3-[4-(tert-butyl)phenyl]-4-pyrrolidinylbut-2-enoate. A ct solution of methyl (2E)-3-[4-(tert-butyl)phenyl]but-2-enoate, Example 91(a), (0.37 g, 1.6 mmol) in CC14 (15 mL), magnetically stirred in a 50 mL roundbottomed flask under N 2 was treated with N-bromosuccinimide (0.31 g, 5 1.75 mmol, Aldrich) and 2,2'-azobisisobutyronitrile (5 mg, 0.03 mmol, Aldrich).

0 The reaction mixture was magnetically stirred under reflux overnight, then I allowed to cool to 25 The solid was filtered. The filtrate was concentrated in 0vacuo to afford a yellow oil [MS (ESI, pos. ion) m/z: 311, 313 To CI a solution of the yellow oil in THF (5 mL), was added pyrrolidine (0.16 mL, 1.9 mmol, Aldrich) and N,N-diisopropylethylamine (0.33 mL, 1.9 mmol, Aldrich). The reaction mixture was magnetically stirred at room temperature overnight, then concentrated in vacuo. The residue was treated with water and extracted with dichloromethane (3 The organic phase was dried over Na 2

SO

4 filtered and concentrated in vacuo to afford a yellow oil. Purification by silica gel chromatography (gradient: 4%-20% EtOAc/hexane) provided the title product as a pale yellow oil. MS (ESI, pos. ion) m/z: 302 N-(2H,3H-Benzo[e] 1,4-dioxan-6-yl)(2Z)-3-[4-(tert-butyl)phenyl]-4pyrrolidinylbut-2-enamide. To a 50 mL round-bottomed flask charged with methyl (2Z)-3-[4-(tert-butyl)phenyl]-4-pyrrolidinylbut-2-enoate, Example 91(b), (188 mg, 0.62 mmol) was added THF (2 mL), MeOH (0.2 mL), H20 (1 mL), and lithium hydroxide monohydrate (54 mg, 1.25 mmol, Aldrich). The reaction mixture was magnetically stirred at room temperature overnight. The excess lithium hydroxide was removed by filtration. The mixture was purified by reverse phase preparative HPLC (CH 3

CN/H

2 0 with 0.1%TFA), concentrated in vacuo, then treated with an excess of HCI in Et20. Concentration in vacuo provided a pale yellow solid 0.15 g [MS (ESI, pos. ion) m/z: 288 Analogous to the procedure used to prepare Example 1, the solid (77 mg) and 1,4-benzodioxan-6amine (61 mg, 0.40 mmol, Aldrich) provided the crude title product. Purification by silica gel chromatography (gradient: 1-5% MeOH in CH 2 C12) was followed by reverse phase preparative HPLC (CH 3

CN/H

2 0 with 0.1%TFA). The fractions containing desired product were neutralized with NaHCO 3 The mixture was 289 extracted with CH 2

CI

2 and the organic phase concentrated in vacuo to provide the title product as a pale yellow oil. MS (ESI, pos. ion) m/z: 421 Example 92

NJ

(2E)-N-(2H,3H-Benzo[e] 1,4-d ioxan-6-yl)-3- [4-(tert-butyl)phenyl]-6imidazolylhex-2-enamide.

Ethyl 2 4 -(tert-butyl)phenyll-5-(1,3-dioxolan-2.yl)pent-2-enoate.

Analogous to the procedure used to prepare Example 53(a), starting from (1,3dioxolan-2-ylethyl)zinc bromide (0.5 M THF solution, 40 mL, 2Ommol, Rieke) and ethyl (2Z)-3-[4-(tert-butyl)phenyl ]-3-iodoprop-2-enoate, Example 52(b), (3.58 g, 10.0 mmol), the title product was obtained as a colorless oil. MIS (ESI, pos. ion) m/z: 333 ~-OEt Ethyl 2

E)-

3 4 .(tert-butyl)phenyl.6-oxohex-2-enoate. To a roundbottomed flask was added ethyl 2 E)-3-[4-(tert-butyl)phenyl] 1,3-dioxolan-2yl)pent-2-enoate, Example 92(a), (2.7 g, 8.1 mmol), TH-F (3 mL), and 5 N HCI (12 mL). The reaction mixture was initially stirred at room temperature for 24 h, -290then heated to 40 °C overnight. The pH was adjusted to -5-6 by the addition of NaHCO 3 and the mixture was extracted with EtOAc. The combined organic extract was dried over Na 2

SO

4 filtered, and concentrated in vacuo. Purification by silica gel chromatography EtOAc/hexane) provided the title product as a white solid. MS (ESI, pos. ion) m/z: 289 OEt 0 HO Ethyl (2E)-3-[4-(tert-butyl)phenyl]-6-hydroxyhex-2-enoate. To solution of ethyl (2E)-3-[4-(tert-butyl)phenyl]-6-oxohex-2-enoate, Example 92(b), (1.5 g, 5.3 mmol) in MeOH (18 mL), magnetically stirred at 0 C in a 100 mL roundbottomed flask, was added sodium borohydride (0.40 g, 11 mmol, Aldrich). The mixture was allowed to gradually warm up to room temperature over 2 h, then quenched with water (20 mL) and extracted with EtOAc (4 The organic extract was dried over Na 2

SO

4 filtered, and concentrated in vacuo. Purification by silica gel chromatography (15% EtOAc/hexane) provided the title product as a colorless oil in quantitative yield. MS (ESI, pos. ion) m/z: 291 OEt 0 Ethyl (2E)-3-[4-(tert-butyl)phenyl]-6-iodohex-2-enoate. To a 100 mL round-bottomed flask charged with ethyl (2E)-3-[4-(tert-butyl)phenyl]-6hydroxyhex-2-enoate, Example 92(c), (0.80 g, 2.7 mmol) and CH 2

CI

2 (10 mL) at room temperature, was added triphenylphosphine (0.87 g, 3.3 mmol, Aldrich), imidazole (0.22 g, 3.3 mmol, Aldrich), and 12 (1.2 g, 4.7 mmol, Aldrich). The reaction mixture was stirred for 2 h, filtered and concentrated in vacuo.

Purification by silica gel chromatography EtOAc/hexane) provided the title -291- Sproduct as a white semi-solid in quantitative yield. MS (ESI, pos. ion) m/z: 401 _0 t

N

0 Ethyl (2E)-3-[4-(tert-butyl)phenyl]-6-imidazolylhex-2-enoate. To a 100 mL round-bottomed flask charged with ethyl (2E)-3-[4-(tert-butyl)phenyl]-6iodohex-2-enoate, Example 92(d), (1.1 g, 2.7 mmol), imidazole (0.20 g, mmol, Aldrich), benzyltriethylammonium chloride (63 mg, 0.30 mmol, Aldrich), and CH 2

CI

2 (15 mL), stirred magnetically at room temperature, was added potassium hydroxide (50% aqueous solution, 1.5 mL). The reaction mixture was stirred at 50 C overnight, then diluted with water. The reaction mixture was extracted with CH 2 C12. The organic solution was dried over Na 2

SO

4 filtered, and concentrated in vacuo. Purification by silica gel chromatography EtOAc/hexane) provided the title product as a pale yellow oil. MS (ESI, pos. ion) m/z: 341 O 0

N

(2E)-3-[4-(tert-Butyl)phenyl]-6-imidazolylhex-2-enoic acid. To a 50 mL round-bottomed flask equipped with a reflux condenser was added ethyl (2E)-3- [4-(tert-butyl)phenyll-6-imidazolylhex-2-enoate, Example 92(e), (0.35 g, mmol), THF (6 mL) and KOH (50% aqueous solution, 1.5 mL). The reaction mixture was heated and magnetically stirred under reflux overnight, then concentrated in vacuo and acidified with glacial acetic acid to pH The aqueous mixture was extracted with CH 2 C12 and the organic phase was dried over 292 Na 2

SO

4 filtered and concentrated in vacuo. Purification by silica gel chromatography MeOHICH 2

CI

2 provided the title product as a white solid. MIS (ESI, pos. ion) m/lz: 313 (2E)-N-(2H,3H-Benzo[e] 1,4-dioxan-6-yl)-3-[4-(tert-butyl)pheiyl]-6imidazolylhex-2-enamide. Analogous to the procedure used to prepare Example 1, [4-(terT-butyl )phen yl I-6-imi dazolyl hex -2-enoi c acid, Example 92(0), (76 mg, 0.24 mmol) and 1,4-benzodioxan-6-amine (36 mg, 0.24 mmol, Aldrich) provided, after purification by silica gel chromatography MeOHICH 2

CI

2 the title product as an amorphous off-white solid. MS (ESI, pos.

ion) nz/z: 446 (M+1).C Example 93

NN

N

3-(4-tert-Butyl-phenyl)-6-imidazol-1-yI-hex-2-enoic acid benzothiazol-6ylamide. Analogous to the procedure used to prepare Example 1, (2E)-3-[4-(tertbutyl)phenylll-6-imidazolylhex-2-enoic acid, Example 92(f), (76 mg, 0.24 mmol) and 6-aminobenzothiazole (36 mg, 0.24 mmol, Lancaster) provided, after purification by silica gel chromatography MeOHICH 2

CI

2 the title compound as a white solid. MIS (ESI, pos. ion) mn/z: 445 -293- Example 94

F

F

F F H N. x N 0 (N 0O (2E)-N-(2H,3H-benzo[e]l,4-dioxan-6-yl)-3-[2-morpholin-4-yl-6- (trifluoromethyl)(3-pyridyl)]prop-2-enamide.

F

3 C

O

N0 N OH 0 2-Morpholin-4-yl-6-(trifluoromethyl)pyridine-3-carboxylic acid. To a round-bottomed flask was added 2-chloro-6-trifluoromethylnicotinic acid (2.0 g, 8.9 mmol, Matrix) and morpholine (5.0 g, 57 mmol, Aldrich). The reaction mixture was magnetically stirred at 25 'C for 48 h, then diluted with 1 N HCI (100 mL) and extracted with EtOAc (100 mL). The aqueous phase was saturated with NaCI and extracted again with EtOAc (50 mL). The combined EtOAc extracts were washed with 1 N HCI (50 mL), satd NaCI (50 mL), dried over MgSO 4 filtered and concentrated in vacuo to afford the title product as an off-white waxy solid. MS (ESI, pos. ion) m/z: 277

F

3C

Z.

NF OH

(N

O

[2-Morpholin-4-yl-6-(trifluoromethyl)-3-pyridyl]methan-1-ol. A solution of 2-morpholin-4-yl-6-(trifluoromethyl)pyridine-3-carboxylic acid, Example 94(a), (2.1 g, 7.6 mmol) in anhydrous THF (20 mL) was treated dropwise with lithium aluminum hydride (15 mL, 15 mmol, 1.0 M in THF, Aldrich) with stirring under N 2 at 25 OC. The reaction mixture was stirred at 25 'C for 1.5 h, then quenched by the dropwise addition of a 10% aqueous solution of Rochelle salt -294mL, potassium sodium tartrate, Aldrich). EtOAc (50 mL) was added and the bi-phasic mixture stirred vigorously for 2 h at 25 The mixture was diluted with water (100 mL) and the phases separated. The aqueous phase was extracted with EtOAc (2 x 75 mL), the organic phases were combined and washed with 1 N NaOH (2 x 75 mL), satd NaCI (75 mL), dried over MgSO 4 filtered and concentrated in vacuo to afford the title product as a viscous yellow oil. MS (ESI, pos. ion) m/z: 263

F

3 C

N

O

2-Morpholin-4-yl-6-(trifluoromethyl)pyridine-3-carbaldehyde. A solution of oxalyl chloride (3.6 mL, 7.2 mmol, 2.0 M in CH 2

CI

2 Aldrich) in anhydrous

CH

2 C12 (20 mL) was magnetically stirred under N 2 in an oven-dried roundbottomed flask, at -60 oC. The solution was treated dropwise with methyl sulfoxide (1.1 mL, 15 mmol, Aldrich) then stirred for 10 min. A solution of [2morpholin-4-yl-6-(trifluoromethyl)-3-pyridyl]methan-l-ol, Example 94(b), (1.7 g, 6.5 mmol) in anhydrous CH 2

C

2 (20 mL) was added via cannula, and the reaction mixture stirred at -60 °C for 15 min. Triethylamine (4.5 mL, 32 mmol, Aldrich) was added, the cooling bath was removed, and the reaction mixture allowed to warm to 25 °C and stirred at that temperature for I h. The mixture was washed with water (30 mL) and the aqueous wash was back-extracted with

CH

2 C1 2 (2 x 20 mL). The combined organic phase was washed with water mL), satd NaCI (30 mL), dried over MgSO 4 filtered and concentrated in vacuo. Purification by silica gel chromatography (9:1 hexane:EtOAc) provided the title product as a viscous yellow oil. MS (ESI, pos. ion) m/z: 261 295 (2E)-3-[2-Morpholin-4-yl-6-(trifluoromethyl)(3-pyridyl)]prop-2-enoic acid. Analogous to the procedure described for Example 40, step 2morpholin-4-yl-6-(triftiuorometh yl)pyridine-3-carbaldehyde, Example 94(c), (1.2 g, 4.6 mmol) provided the title product as a yellow solid. MIS (ESI, pos. ion) mlz: 303 (2E)-N-(211,31I-benzo[e] 1,4-dioxan-6-yl)-3- [2-morpholin-4-yl-6- (trifluoromethyl)(3-pyridyl)]prop-2-enamide. (2E)-3-[2-Morpholin-4-yl -6- (trifluoromethyl )(3-pyridyl)] prop-2-enoic acid, Example 94(d), (200 mfg, 0.66 mmol) was dissolved in anhydrous CH 2

CI

2 (10 ml) and treated with oxalyl chloride (0.36 mL, 0.72 mmol, 2.0 M in CH 2

CI

2 Aldrich) and anhydrous DMF (2 uL). The reaction mixture was stirred at reflux for 30 min, then concentrated in vacuo. The residue was dissolved in anhydrous CH 2

CI

2 (10 mL), treated with pyridine (0.27 mL, 3.5 mmol, Aldrich) and 1,4-benzodioxan76-amine (120 mg, 0.79 mmol, Aldrich) and stirred at reflux for 15 min. The reaction mixture was concentrated in vacuo and the residue dissolved in EtOAc (75 mL). The mixture was washed with I N HCI (2 x 50 mL), 1 N NaOH (50 mL), water (50 mL), satd NaCI (50 mL), dried over MgSO 4 filtered and concentrated in vacuo.

Recrystallization from EtOAc and hexane provided the title product as pale tan crystals. MP 200-201 MIS (ESI, pos. ion) mlz: 436 -296- Example

H

Br 0 (2E)-N-(2H,3H-Benzo[e]l,4-dioxan-6-yl)-3-[4-(tert-butyl)-2bromophenyl]prop-2-enamide.

Br 4-(tert-Butyl)-2-bromo-l-(bromomethyl)benzene. According to the procedure of Kikuchi, D. et al, J. Org. Chem. 1998, 63, 6023-6026, to a solution of sodium bromate (22 g, 145 mmol, Aldrich) in water (75 mL), magnetically stirred in an Erlenmeyer flask at 25 was added a solution of 4-t-butyltoluene (5.0 mL, 29 mmol, Aldrich) in acetonitrile (60 mL). The bi-phasic mixture was vigorously stirred while a solution of sodium bisulfite (15 g, 145 mmol, Baker) in water (150 mL) was added dropwise, via addition funnel, over 20 min. The reaction mixture was stirred for 6 h, then extracted with Et20 (300 mL). The organic phase was washed with satd aq. Na 2

S

2 0 3 (2 x 100 mL), satd NaCI (50 mL), dried over MgS0 4 filtered and concentrated in vacuo to afford of the title product as a pale orange oil.

Br 4-(tert-Butyl)-2-bromobenzaldehyde. According to the procedure of Mallory, et al, Tetrahedron 2001, 57, 3715-3724, a solution of sodium ethoxide (12 mL, 32 mmol, 21% in EtOH, Aldrich) in absolute EtOH (100 mL) was magnetically stirred under N 2 at 25 OC and treated with 2-nitropropane (2.9 mL, 32 mmol, Aldrich) followed by 4-(tert-butyl)-2-bromo-l-(bromomethyl)benzene, Example 95(a), (9.0 g, 29 mmol). The reaction mixture was stirred at 25 OC for h, then concentrated in vacuo to an orange solid. The solid was partitioned 297 between Et 2 O (150 mL) and water (100 mL). The layers were separated and the organic phase was washed with water (100 mL), 1 N NaGH (2 x 75 mL), satd NaCI (50 mL), dried over MgSO 4 filtered and concentrated in vacuo to afford the title product as an orange oil.

(2E)-3-[4-(tert-Butyl)-2-bromophenyllprop-2-enoic acid. Analogous to the procedure described for Example 40, step 4-(tert-butyl)-2bromobenzaldehyde, Example 95(b), (6.5 g, 27 mmol) provided the title product as a white solid. MS (ESI, pos. ion) m/z: 283, 285 M+2).

(2E)-N-(2H,3H-Benzo[e] 1,4.dioxan-6-yl)-3-[4-(tert-butyl)-2bromophenyllprop-2-enamide. Analogous to the procedure described for Example 94, step (2E)-3-[4-(tert-butyl)-2-bromophenyl~prop-2-enoic acid, Example 95(c), (3.0 g, 11I mmol) and 1,4-benzodioxan-6-amine (1.9 g, 13 mmol, Aldrich) provided, after recrystallization from CH 2

CI

2 and hexane, the title product as off-white crystals. MP 206-210 MS (ESI, pos. ion) mlz: 416, 418 M+2).

Example 96

H

N 0>

CO

2 Et 0 Ethyl 2-[(1E)-2-(N-(2H,3H-benzo[e] 1,4-dioxan-6-yI)carbamoyl)vinyl]-S-(tertbutyl)benzoate.

According to the procedure of Ma, et al, J. Org. Chem. 1999, 64, 120-125, a solution of (2E)-N-(2H,3H-benzo[e]1I,4-dioxan-6-yl)-3-[4-(tert-butyl bromophenyl]prop-2-enamide, Example 95, (200 mg, 0.48 mmol) in anhydrous EtOH (5 mL) and methyl sulfoxide (5 mL) was treated with triethylamine (0.67 mL, 0.48 mmol, Aldrich) and 1,3-bis(diphenylphosphino)propane (50 mg, 0. 12 mmol, Aldrich). The mixture was purged with a stream of carbon monoxide, then treated with palladium acetate (22 mg, 0.10 mmol, Aldrich), and stirred -298under a balloon of carbon monoxide in a 70 °C oil bath for 3 h. The reaction mixture was allowed to cool to 25 oC and partitioned between EtOAc (50 mL) and water (20 mL). The organic phase was washed with water (10 mL), satd NaCI mL), dried over MgS04, filtered and concentrated in vacuo. Purification by silica gel chromatography (step gradient, 4:1 then 3:1, hexane:EtOAc), followed 0 by recrystallization from EtOAc and hexane, provided the title product as white C crystals. MP 155 MS (ESI, pos. ion) m/z: 410 SExample 97

F

3

C

H

Br 0

H

2 E)-3-[2-Bromo-4-(trifluoromethyl)phenyl]-N-indol-5-ylprop-2-enamide.

F

3

C

CO

2

H

Br 2-Bromo-4-(trifluoromethyl)benzoic acid. To a solution of 2-bromo-1methyl-4-trifluoromethylbenzene (7.6 g, 32 mmol, ABCR) in pyridine (75 mL) was added tetraethylammonium permanganate (24 g, 96 mmol, prepared according to the procedure of Sala, et al. J. Chem. Soc., Chem. Comm. 1978, 253).

The reaction mixture was warmed to 70 °C and stirred at that temperature for h. The reaction mixture was allowed to cool to 25 °C and poured into an ice bath containing cond HCI (150 mL) and NaHSO 3 (150 The mixture turned to a clear aqueous solution and was extracted with EtOAc (4 x 200 mL). The combined extracts were washed with satd NaCI (200 mL), dried over Na 2 SO4, filtered and concentrated in vacuo to provide the title product as a white solid.

MS (ESI, neg. ion) m/z: 267

F

3 CyA

FCOH

Br 2 -Bromo-4-(trifluoromethyl)phenyl]methan-l-ol. Analogous to the procedure used to prepare Example 46, step 2-bromo-4- 299 (trifluoromethyl)benzoic acid, Example 97(a), (5.4 g, 20 mmol) provided, after purificaton by silica gel chromatography (gradient: 0-10% EtOAc in hexane), the title product as a white solid. MS neg. ion) m/z: 313 (M+acetate).

F

3 C Br 2-Bromo-4-(tritluoromethyl)benzaldehyde. Analogous to the procedure used to prepare Example 46, step [2-bromo-4- (trifluoromethyl)phenyllmethan-1-ol, Example 97(b), (4.6 g, 18 mmol) provided, after purificaton by silica gel chromatography (gradient: 0-4% EtOAc in hexane), the title product as a colorless oil.

F

3 0 lp

CO

2 Me Br Methyl (2E)-3-12-bromo-4-(triluoromethyl)phenyllprop-2-enoate.

Analogous to the procedure used to prepare Example 46, step 2-bromo-4- (trifluoromethyl)benzaldehyde, Example 97(c), (2.3 g, 8.9 mmol) and carbomethoxymethylene triphenylphosphorane (4.2 g, 12.5 mmol, Aldrich) provided, after purificaton by silica gel chromatography (gradient: 0-3% EtOAc in hexane), the title product as a white solid.

F

3 C 2

H

Br (2E)-3-12-Bromo-4-(trifluoromethyl)phenyl]prop-2-enoic acid. Analogous to the procedure used to prepare Example 46, step methyl (2E)-3-f2-bromo- 4-(trifluoromethyl)phenyl]prop-2-enoate, Example 97(d), (2.25 g, 8.9 mmol) provided the title product.

(2E)-3-[2-Bromo-4-(trifluoromethyl)phenyll-N-indol-5-ylprop-2-enamide.

Analogous to the procedure used to prepare Example 1, (2E)-3-[2-bromo-4- (tnifluoromethyl)phenyl]prop-2-enoic acid, Example 97(e), (140 mg, 0.48 mmol) and 5-aminoindole (75 mg, 0.57 mmol, Aldrich) provided, after purification by 300 silica gel chromatography (gradient: 0-25% EtOAc in hexane), the title compound as a yellow solid. MTP 205-207 MIS (ESI, pos. ion) m/z: 409 1).

Example 98

F

3

C

H

(2E)-N-Benzothiazol-6-yI-3-[2-bromo-4-(trifluoromethyl)phenyl]prop-2en amid e.

Analogous to the procedure used to prepare Example 1, (2E)'-3-[2-bfomo-4- (trifluoromethyl)phenyl]prop-2-enoic acid, Example 97(e), (140 mg, 0.47 mmol)C and 6-aminobenzothiazole (86 mg, 0.57 mmol, Lancaster) provided, after purification by silica gel chromatography (gradient: 0-30 EtOAc in hexane), the title product as an off-white solid. MP 214-2 15 0 C. MIS (ESI, pos. ion) m/z: 427 1).

Example 99

F

3

C

I H Br 0 0 (2E)-N-(2H,3H-Benzo[e] 1,4-dioxari-6-yl)-3-[2-bromo-4-(trifluoromethyl)phenyllprop-2-enamide.

Analogous to the procedure used to prepare Example 1, (2E)-3-[2-bromo-4- (trifluoromethyl)phenyllprop-2-enoic acid, Example 97(e), (140 mg, 0.47 mmol) and 1,4-benzodioxan-6-amine (86 mg, 0.57 mmol, Aldrich) provided, after puification by silica gel chromatography (gradient: 0-18 %EtOAc in hexane), the title product as an off-white solid. NIP 212-213 MIS (ESI, pos. ion) m/z: 428 1).

301 Example 100

F

3

C

H

0N

H

(2E)-N-indol-5.yl-3- [2-(6-methoxy(3-pyridy1))-4-(trifluoromethyl)phenyl]prop-2-enamide.

A mixture of (2E)-3-[2-bromo-4-(trifluoromethyl)phenyl]-N-indol-5-ylprop-2enamide, Example 97, (100 mg, 0.24 mmol), 2-methoxy-5-pyridineboronic acid mg 0.39 mmol, Digital Specialty Chemicals), tnis(dibenzylideneacetone)dipalladium(O) (22 mg, 0.024 mmol, Aldrich) and triphenylphosphine (26 mg, 0.098 mmol, Aldrich) in toluene (1.2 mL), 2.OM aqueous Na 2

CO

3 (0.4 m.L) and ethanol (0.4 mL) was stirred at 120 'C overnight. The reaction mixture was filtered through a pad of Celite and diluted with water (50 mL). The aqueous phase was extracted with EtOAc (3 x 60 mL). The combined extracts were washed with satd NaCI (100 mL), dried over Na 2

SO

4 filtered and concentrated in vacuo. Purification by silica gel chromatography (gradient: 0-20% EtOAc in hexane) provided the title product as a yellow solid. IMiP 2 19-221 TC. MS (ESI, pos. ion) m/z: 438 1).

Example 101

F

3

C.H

I H

NN

(2E)-N-Indol-5-yl-3- pyridyI)-4-(trifluoromethyl)phenyl]prop-2enamide.

Analogous to the procedure used to prepare Example 100, (2E)-3-[2-bromo-4- (ttifluoromethyl)phenyl]-N-indol-5-ylprop-2-enamide, Example 97, (120 mg, 0.29 mmol) and pyridi ne-4- boron ic acid (72 mg, 0.59 mmol, Frontier Scientific) provided, after purification by silica gel chromatography (gradient: 0-60 %EtOAc 302 in hexane), the title product as a yellow solid. MIP 229-234 MS (ESI, pos.

ion) m/lz: 408 1).

Example 102

F

3

C

H

H

(2E)-N-Indol-5-yl-3-[2-(3-pyridyl)-4-(trifluoromethyl)phenyllp rop-2enamide.

Analogous to the procedure used to prepare Example 100, (2E)-3-[2-bromo-4-( (trifluoromethyl)phenyl]-N-indol-5-ylprop-2-enamide, Example 97, (120 mg, 0.29 mmol) and pyridine-3-boronic acid (58 mg, 0.47 mmol, Frontier Scientific) provided, after purification by silica gel chromatography (gradient: 0-20 %EtOAc in hexane), the title product as a yellow solid. MP 196-197 MS (ESI, pos.

ion) rn/z: 408 1).

Example 103

F

3

C~

0

H

N

tert-Butyl E)-2-(N-indol-5-ylcarbamoyl)vinyl]-5- (tri fluoromethyl)phenyl) 1-1,2,5,6-tetrahyd ropy ridi necarboxylate.

Analogous to the procedure used to prepare Example 100, (2E)-3-[2-bromo-4- (trifluorornethyl)phenyl]-N-indol-5-ylprop-2-enamide, Example 97, (100 mg, 0.24 mmol) and 4-(4,4,5 ,5-tetramethyl-[ 1,3,2]loxaborolan-2-yl)-3 ,6-dihydro-2Hpyridine-1-carboxylic acid tert-butyl ester (130 mg, 0.42 rnmol, prepared according to the procedures of Wustrow, D. I. et al, Synthesis 1991, 993 and Ishiyama, T. et al, Org. Chemn. 1995, 60, 7508) provided, after purification by -l 303 silica gel chromatography (gradient: 0-35 %EtOAc in hexane), the title product as an amorphous yellow solid. MS (ESI, pos. ion) m/z: 512 Example 104

F

3

C

H

z N N S

H

(2E)-N-Indol-5-yl-3-[2-(1,3-thiazol-2-y)-4(trifluoromethyl)phenyllprop-2enamide.

Analogous to the procedure used to prepare Example 100, (2E)-3-[2-bromo-4- (tri tluoromethyl)phenyl]-N-indol-5-ylprop-2-enamide, Example 97, (100 mg, 0.24 mmol) and 2-tributylstannylthiazole (155 mg, 0.42 mmol, Frontier Scientific) provided, after purification by silica gel chromatography (gradient: 0-35 %EtOAc in hexane), the title product as an orange solid. NIP 203-204 MS (ESI, pos.

ion) m/z: 414 Example 105

F

3 C j H N 0 I

H

(2E)-N-Indol-5-yl-3-[2-(3-pyridylmethyl)-4-(trifluoromethyl) phenyllprop-2enamide.

A mixture of 2 E)-3-[2-bromo-4-(trifluoromethyl)phenyl I-N-i ndol-5 -ylprop-2enamide, Example 97, (110 mg, 0.27 minol), 3- (tributylstannanylmethyl)pyridine, Example 90(a), (160 mg, 0.43 mmol), tris(di benzylideneacetone)di pallIadi um(0) (24 mg, 0.027 mmol, Aldrich) and triphenylphosphine (28 mg, 0. 11 mmol, Aldrich) in I1-methyl -2-pyrroli di none mL) was stirred at 100 TC overnight. The reaction mixture was filtered through a pad of Celite and diluted with water (50 mL). The aqueous phase was extracted with EtOAc (3 x 60 mL)Q. The combined organic extracts were washed with satd NaCI (100 mL), dried over Na 2

SO

4 filtered and concentrated in vacuo.

Purification by silica gel chromatography (gradient: 0-70 EtOAc in hexane) 304 provided the title compound as an orange solid. MIP 202-203 MS (ESI, negion) m/z: 420 Example 106

F

3 C .H YN- (2E)-3-[2-(3-Pyridyl).4-(trifluoromethyl)phenyl] -N-(7-quinolyl)prop-2enamide.

F

3

C~

OMe 0 N 1,1,P Methyl (2E)-3-[2-(3-pyridyl)-4-(trifluoromethyl)phenyllprop-2-enoate. A mixture of methyl (2E)-3-[2-bromo-4-(trifluoromethyl)phenyl]prop-2-enoate, Example 97(d), (585 mg, 1.89 mmol), pyri di ne-3 -boron ic acid (950 mg, 2.8 mmol, Frontier Scientific), tri s(di benzyl ideneacetone)di pallIadi um (0) (170 mg, 0.19 mmol, Aldrich) and triphenyiphosphine (200 mng, 0.76 mmol, Aldrich) in toluene (5 1.0 M aqueous Na 2

CO

3 (2 mL) and ethanol (2 mL) was stirred at 80 'C under N 2 overnight. The reaction mixture was filtered through a pad of Celite and diluted with water (60 mL). The aqueous phase was extracted with EtOAc (3 x 60 mL). The combined organic extracts were washed with satd NaCI (100 mL), dried over Na 2

SO

4 filtered and concentrated in vacuo.

Purification by silica gel chromatography (gradient: 0-35% EtOAc in hex ane) provided the title product as a yellow solid. MS (ESI, pos. ion) m/lz: 308 17 3 C N. OH 0 (2E)-3-[2-(3-Pyridyl)-4-(trifluoromethyl)phenyl] prop-2-enoic acid. A mixture of methyl 2 E)-3-[2-(3-pyridyl)-4-(tnifluoromethyl)phenyl]prop-2-enoate, -305- Example 106(a), (540 mg, 1.8 mmol) and LiOH monohydrate (370 mg, 8.8 mmol) in wet ethanol (5 mL) was stirred at room temperature overnight. The reaction mixture was neutralized with aqueous HCI (2.0 M, 4.4 mL, 8.8 mmol) and concentrated under reduced pressure. The material was dried under vacuum at 60 °C for 4 h to provide 955 mg of the crude material, which contained LiCI as a byproduct. MS (ESI, pos. ion) m/z: 294 (2E)-3-[2-(3-Pyridyl)-4-(trifluoromethyl)phenyl]-N-(7-quinolyl)prop-2enamide. Analogous to the procedure used to prepare Example 1, pyridyl)-4-(trifluoromethyl)phenyl]prop-2-enoic acid, Example 106(b), (185 mg) and 7-aminoquinoline (64 mg, 0.44 mmol, Specs) provided, after purification by silica gel chromatography (gradient: 0-75% EtOAc in hexane), the title compound as an amorphous off-white solid. MS (ESI, pos. ion) m/z: 420 Example 107

F

3

C

H

N

N

N

(2E)-3-[2-(3-Pyridyl)-4-(trifluoromethyl)phenyl]-N-(3-quinolyl)prop-2enamide.

Analogous to the procedure used to prepare Example 1, (2E)-3-[2-(3-pyridyl)-4- (trifluoromethyl)phenyl]prop-2-enoic acid, Example 106(b), (185 mg) and 3aminoquinoline (64 mg, 0.44 mmol, Aldrich) provided, after purification by silica gel chromatography (gradient: 0-45% EtOAc in hexane), the title compound as a white solid. MP 196-199 MS (ESI, pos. ion) m/z: 420 306 Example 108

F

3

C

H

H

N~.N

(2E)-N-Indol-6-yl-3-[2-(3-pyridyl)-4-(trifluoromethyl)phenyllprop2enamide.

Analogous to the procedure used to prepare Example 1, (2E)-3-112-(3-pyridyl)-4- (trifluoromethyl)phenyl]prop-2-enoic acid, Example 106(b), (185 mg) and 6aminoindole (59 mg, 0.44 mmol, Aldrich) prov ided, after purification by silica gel( chromatography (gradient: 0-50% EtOAc in hexane), the title compound as an amorphous orange solid. MS (ESI, pos. ion) mlz: 408 1).

Example 109

H

YN 0 N-(2H,3H-Benzo[3,4-e] 1,4-dioxan-6-yl)-3- [4-(te6rt-butyl)phenyl] propanamide.

Na 0 0J (2E)-N-(2H,3H-Benzo[3,4-e] 1,4-dioxan-6-yI)-3-[4-(tert-butyl)phenyl]prop-2-enamide. A solution of 4-t-butyl-trans-cinnamic acid (500 mg, 2.45 mnmol, EMKA-Chemie) in anhydrous CH 2

CI

2 (10 mL) was magnetically stirred and treated with oxalyl chloride (0.22 mL, 2.5 mmol, Aldrich) and DMF (0.005 mL). The reaction mixture was stirred at reflux for 30 min, then concentrated in vacuo. The residue was dissolved in acetone (I mL) and added to a mixture of 1,4-benzodioxan-6-amine (370 mg, 2.45 mmol, Aldrich) and K 2 C0 3 (500 mg) in acetone (2 mL) and water (4 mL), stirred at 0 0 C. The reaction mixture was vigorously stirred at 0 'C for 30 min, then diluted with ice water mL). The resulting solid precipitate was collected by filtration and dissolved -307- Sin CH 2 C1 2 (20 mL) and Et2O (150 mL). The organic solution was washed with 1 SN HCI (3 x 75 mL), satd NaCI (50 mL), dried over MgSO 4 filtered and concentrated to afford the title product as an off-white foam. MS (ESI, pos. ion) m/z: 338 N-(2H,3H-Benzo[3,4-e]1,4-dioxan-6-yl)-3-[4-(tertbutyl)phenyl]propanamide. (2E)-N-(2H,3H-Benzo[3,4-e]1,4-dioxan-6-yl)-3-[4- S(tert-butyl)phenyl]prop-2-enamide, Example 109(a), (200 mg, 0.59 mmol) was dissolved in EtOH (25 mL), purged with N 2 treated with 10% Pd on carbon mg, Aldrich) then purged with H 2 and the suspension stirred at 25 under 1 atm H 2 for 16 hr. The suspension was purged with N 2 filtered through a pad of Celite, and concentrated in vacuo to a white foam. Purification by silica gel chromatography (45:45:10 hexane:CH 2 C1 2 :EtOAc) provided the title product as a clear glass. MS (ESI, pos. ion) nm/z: 340 General Scheme I 308

R

3 R1 1oxi dation

R

1

-M

M B(OH) 2 SnBU 3 R 3 ZnCI, BF MgBr Br

N

transition metal I 1

N

coupling

R

4 -NCO, DMF, 15000C bromination R3' R Chichibabin N R N Reaction

R'

5 R 6R 16 Br, N.r NH- 2

R'-M

Ntransition metal coupling R 3

H

P -0 N R 4 deprotection R16 R 4

-NH

2 amninoarylation

R

4 -Br aminoarylation 1. diazotization 2. dehydrohalogenation Br

R

4

-NH

2 aminoarylation 1. Tf 2 O, CH 2

CI

2 j 2. R 1

-M

transition metal coupling

R

3 P N0 Br

R

16 dehydrohalogenation P-0o 0 RA1 5 N NH P Ary(ICH 2 309 General Scheme 11 Br

Y

IN

R

1

-B(OH)

2 Pd(PPh 3 4 Na 2 00 3 1 ,2-dimethoxyethane refiux, 16 h R1

Y,

N" 14

CH

3 ReO 3

H

2 0 2

CH

2 01 2 '0-

H

yN, N.

R

4 Ph 3 P,Br 2

CH

2

CI

2 NEt 3 R1 Br

Y,

R 4

-NH

2 Pd(OAc) 2

BINAP

NaOt-Bu, toluene

OC

Example 110 4-[4-(tert-Butyl)phenyllpyridine.

To 4-bromopyridine hydrochloride (Aldrich) (8.9 g, 46 mmol) and tetrakis(triphenylphosphine)palladium(0) (Aldrich) (1.6 g, 1.4 mmol) was added 1,2-dimethoxyethane (250 mL) with stirring under nitrogen. After 20 min, a solution of Na 2

CO

3 (9.7 g in 70 m-L of water) and 4-tert-butylbenzeneboronic acid (9.8 g, 55 mmol) were added sequentially to the mixture. The reaction was stirred at reflux overnight. The reaction mixture was concentrated in vacuo to approximately 1/3 its original volume, and the mixture was extracted with EtOAc: (2 x 100 mL). The combined EtOAc layers were washed with brine, dried over Na 2

SO

4 and concentrated in vacuo. Purification by silica gel chromatography EtOAc/hexanes) gave the title compound as a white solid. MS (ESI, pos. Ion) m/lz: 212 4-[4-(tert-Butyl)phenyllpyridine 1-oxide.

To the mixture of 4-[4-(tert-butyl)phenyllpyridine (8.7 g, 41 mmol) and methyltrioxorhenium (VII) (Aldrich) (170 mg, 0.7 mmol) in a 100-mL round- -310bottomed flask was added CH 2

CI

2 (18 mL). The mixture was then treated with 12 mL of hydrogen peroxide (Aldrich) dropwise. The reaction was stirred at room temperature under nitrogen overnight. Methylene chloride and brine were then added, and the aqueous layer was extracted with CH 2 C2 (40 mL). The organic layer was dried over Na 2

SO

4 concentrated in vacuo to give the title compound as an off-white solid. MS (ESI, pos. ion) m/z: 228 Br

N

4-[4-(tert-Butyl)phenyll-2-bromopyridine.

To triphenylphosphine (Aldrich) (2.4 g, 9.1 mmol) dissolved in 10 mL of

CH

2 C12 in a 50-mL round-bottomed flask was added bromine (Aldrich) (0.43 mL, mmol). After stirring at 0 0 C for 10 min, 4-[4-(tert-butyl)phenyl]pyridine 1oxide (1.5 g, 6.5 mmol) was added dropwise, followed by Et 3 N (1.2 mL, mmol). The reaction mixture was stirred at 0° C for I h and then at room temperature overnight. Methylene chloride and brine were added, and the aqueous layer was extracted with CH 2 Cl 2 The organic layer was collected and dried over Na 2

SO

4 filtered and concentrated in vacuo. Following purification by silica gel chromatography (10:1 hexane:EtOAc), the title compound was obtained as a pale yellow oil. MS (ESI, pos. ion) m/z: 293

H

N NO 2H,3H-Benzo[e]l,4-dioxan-6-yl{4-[4-(tert-butyl)phenyl](2pyridyl)}amine.

To an oven-dried 50-mL round-bottomed flask were added 4-[4-(tertbutyl)phenyl]-2-bromopyridine (180 mg, 0.63 mmol) and 1,4-benzodioxan-6amine (Aldrich) (191 mg, 1.3 mmol), followed by anhydrous toluene (60 mL) and DMF (6 mL). Nitrogen was bubbled through the above solution via a needle for 1 h. Then palladium acetate (Aldrich) (21 mg, 0.01 mmol) and BINAP (Aldrich) -311 (59 mg, 0.01 mmol) were introduced to the reaction followed by sodium tertbutoxide (Aldrich) (170 mg, 1.8 mmol). The reaction mixture was heated in a C oil bath overnight. After cooling to room temperature, the reaction mixture was dissolved in ether, washed with brine, dried over Na 2

SO

4 and concentrated in vacuo. Following purification by silica gel chromatography (3:1 hexane:EtOAc), the title compound was obtained as a pale tan solid. MS (ESI, pos. ion) m/z: 361 MP: 162-1630 C.

Table A. The following compounds were prepared according to General Schemes I and II: -312- -313- 122 124 N M+2) N0 c~Kl F 3

C

H H 354 *123 NN? -N +1) Example 124

H

2 N N N2-(2,3-Dihydro-benzo[1 ,4]dioxin-6-yl)-pyridine-2,4-diamine.

In a 5-mL vial was added 4-amino-2-chloropyridine (Aldrich Chemical Company) (1.1 g, 8.7 mmol), 1,4-benzodioxane-6-amine (Aldrich Chemical Company) (5.3 g, 35 mmol) and copper iodide (Aldrich Chemical Company) (0.17 g, 0.87 mmol). The content was sonicated at room temperature for 5mmn and then heated in the Smith Microwave Synthesizer at 200 'C for 10 min. The residue was purified by flash chromatography (95:5 dichloromethane:2N Ni- 3 in MeGH) to give the title compound as a dark solid. MIS (ESI, pos. ion) n&z 244

H

(2,3-D ihyd ro-benzo[ 1,4]d ioxi n-6-yi)- (4-iodo-py rid in-2-y I)-amine.

Isopentyl nitrile (Aldrich Chemical Company) (3.9 mL, 29 mmol) was added to a mixture of N2-(2,3-di hydro-benzo[ 1,4]dioxin-6-yl)-pyridine-2,4-diamine (Example 2.4 g, 9.8 mmol), potassium iodide (Aldrich Chemical Company) (1.6 g, 9.8 mmol), iodine (Aldrich Chemical Company) (1.2 g, 4.9 mmol) and copper iodide (Aldrich Chemical Company) (1.9 g, 9.8 mmol) in 1,2dimethoxyethane (60 mL). The reaction mixture was heated at 60-65 0 C for Mhr.

-314- After cooling to room temperature, the insoluble materials were removed by filtration and the filtrate was diluted with EtOAc, washed with 25% aqueous 5% aqueous sodium bisulfite and then brine. The organic layer was separated, dried over Na 2

SO

4 and concentrated in vacuo. The residue was purified on a Biotage 40 M column (2.5:1 hexane:EtOAc) to give the title compound as an 0 off-white solid. MS (ESI, pos. ion) m/z: 355

H

0 0

N

0 o I I (N <N KCO (4-Benzo[1,3]dioxol-5-yl-pyridin-2-yl)-(2,3-dihydro-benzo[1,4]dioxin-6-yl)amine.

In a 5 mL vial were added (2,3-dihydro-benzo[l,4]dioxin-6-yl)-(4-iodo-pyridin-2yl)-amine (Example 75 mg, 0.2 mmol), tetrakis (triphenylphosphine) palladium (Aldrich Chemical Company) (12 mg, 0.011 mmol) and 1,2dimethoxyethane (2 mL). After stirring under nitrogen for 10 min, aqueous Na 2

CO

3 (22 mg in 0.5 mL of water) and 3,4-(methylenedioxy)phenylboronic acid (Aldrich Chemical Company) (42 mg, 0.25 mmol) were introduced. The reaction was heated in the Smith Microwave Synthesizer at 150 OC for 10 min. The residue was partitioned between EtOAc and brine. The aqueous layer was extracted with EtOAc and the combined EtOAc layer was washed with brine, dried over Na 2

SO

4 and concentrated in vacuo. Purification on a Biotage 40 S column (4:1 hexane:EtOAc) gave the title compound as a light-yellow solid. MS (ESI, pos.

ion) n/z: 349 Mp: 116.0-118.0 oC.

Example 125

/NN

0 (2,3-Dihydro-benzo[1,4]dioxin-6-yl)-[4-(4-dimethylamino-phenyl)-pyridin-2yl]-amine.

Following the same procedure described for Example 401(c), the mixture of (2,3dihydro-benzo[1,4]dioxin-6-yl)-(4-iodo-pyridin-2-yl)-amine (Example 401(b), -315mg, 0.2 mmol), tetrakis (triphenyiphosphine) palladium (Aldrich Chemical Company) (12 mg, 0.0 11 mmol), N, N-dimethylamnobenzeneboronic acid (Aldrich Chemical Company) (41 mg, 0.25 mmol) and 1,2-dimethoxyethane (2 mL) gave, after heated in the Microwave Smith Synthesizer at 150 "C for min and purification on a Biotage 40S column (1.5:1 hcxane:EtOAc), the title compound as a tan solid. MS (ESI, pos. ion) m/z: 348 Mp: 154.0-155.5 'C.

Example 126 I H (2,3-Dihydro-benzo[1l,4]dioxin-6-yl)-[4-(4-fluoro-phenyl)-pyridin-2-ylI-amine.

Following the same procedure described for Example 401 the mixture of (2,3dihydro-benzo[ 1,4]dioxin-6-yl)-(4-iodo-pyridin-2-yl)-amine (Example 401 mg, 0.2 mmol), tetrakis (triphenylphosphine) palladium (Aldrich Chemical Company) (12 mg, 0.011 mmol), 4-fluorobenzeneboronic acid (Avocado Chemical Company) (35 mg, 0.25 mmol) and 1,2-dimethoxyethane (2 mL) gave, after heated in the Microwave Smith Synthesizer at 150 0 C for 10 mmLi and purification on a Biotage 40S column (3:1 hexane:EtOAc), the title compound as an off-white solid. MIS (ESI, pos. ion) m/z: 323 Mp: 134.5-135.0 'C.

Example 127 I H F- N0 (2,3-Dihydro-benzolil,4]dioxin-6-y)-14-(3-trifluorometbyl-phenyl)-pyridin-2yI]-amine.

Following the same procedure described for Example 40 the mixture of (2,3dihydro-benzo[1I,4]dioxin-6-yl)-(4-iodo-pyridin-2-yl)-amine (Example 401 mg, 0.2 mmol), tetrakis (triphenylphosphine) palladium (Aldrich Chemical Company) (12 mg, 0.011 mmol), 3-(trifluoromethyl)phenylboronic acid (Aldrich Chemical Company) (47 mg, 0.25 mmol) and 1,2-dimethoxyethane (2 mL) gave, after heated in the Microwave Smith Synthesizer at 150 0 C for 10 min and -316purification on a Biotage 40S column (4:1 hexane:EtOAc), the title compound as a light-yellow solid. MS (ESI, pos. ion) m/z: 373 Mp: 138.9-140.5 0

C.

Example 128 S

H

N0 AN0 (4-Benzo[b] th iophen-2-yl-py rid in-2-yl)-(2,3-dihyd ro-benzo[1,4]d ioxin-6-yi)amine.

Following the same procedure described for Example 401 the mixture of (2,3dihydro-benzo[ 1,4]dioxin-6-yl)-(4-iodo-pyridin-2-yl)-amine (Example 401(b),( mg, 0.2 mmol), tetrakis (triphenylphosphine) palladium (Aldrich Chemical Company) (12 mg, 0.011 mmol), benzothiophene-2-boronic acid (Frontier Scientific, Inc.) (45 mg, 0.25 mmol) and 1,2-dimethoxyethane (2 mL) gave, after heated in the Microwave Smith Synthesizer at 150 'C for 10 min and purification on a Biotage 40S column (4:1 hexane:EtOAc), the title compound as a lightyellow solid. MS (ESI, pos. ion) 361 Mp: 154.0-154.1 0

C.

Example 129 0 -,N0 (2,3-Dihyd ro-benzo[ 1,4]d ioxi n-6-ylamino)-py rid in-4.ylI -phen yl}.

ethanone.

Following the similar procedure described for Example 401(c), the mixture of (2,3-dihydro-benzo[ 1,4]dioxin-6-yl)-(4-iodo-pyridin-2-yl)-amine (Example 401 0.73 g, 2.1 mmol), tetrakis (triphenyiphosphine) palladium (Aldrich Chemical Company) 12 g, 0. 11 mmol), 4-actylphenylboronic acid (Aldrich Chemical Company) (0.41 g, 2.5 mmol) and 1,2-dimethoxyethane (20 mL) gave, after heated at 90 'C overnight and purification on a Biotage 40M column (3:1 hexane:EtOAc), the title compound as a light-orange solid. MS (ESI, pos. ion) m/z: 347 Mp: 178.0-1 80.5 'C.

-317- Example 130

OH

H

1-{4-[2-(2,3-Dihydro-benzo[1 ,4ldioxin-6-ylamino)-pyridin-4-y]-phenyl}ethanol.

To the suspension of 1- 4-[2-(2,3-dihydro-benzo[1I,4]dioxin-6-ylamino)-pyridin- 4-yl]-phenyl}I-ethanone (Example 7, 0.19 g, 0.55 mmol) in 2 mL of MeCH was added a solution of methylamine in MeGH (Aldrich Chemical Company) (2N, 0.55mL, 1. 1 mmol). The reaction was stirred at room temperature under nitrogen overnight. NaBH 4 (Aldrich Chemical Company) (25 mg, 0.66 mmol) was then added to the reaction and it was stirred for another 5 hrs. The solvent was evaporated the residue was purified on a Biotage 40M column (97:3 dichloromethane:2N NH 3 in MeOH) to give the title compound as an off-white foam. MS (ESI, pos. ion) m/lz: 349 Mp: 55.9- 61.5 'C.

Example 131 FF F F H 0 F r-N [4-(3,5-Bis-tritluoromethyl-phenyl)-pyridin-2-y]-(2,3-dihydro-benzo[1,41dioxin-6-yi)-amine.

Following the same procedure described for Example 401 the mixture of (2,3di hydro-benzo[1I,4]dioxin-6-yI)-(4-iodo-pyridin-2-yl)-amine (Example 401 75 mg, 0.2 mmol), tetrakis (triphenylphosphine) palladium (Aldrich Chemical Company) (12 mg, 0.011 mmol), 3,5-bis(tnifluoromethyl)phenylboronic acid (Aldrich Chemical Company) (64 mg, 0.25 mmol) and 1,2-dimethoxyethane (2 miL) gave, after heated in the Microwave Smith Synthesizer at 150 'C for min and purification on a Biotage 40S column (4:1 hexane:EtOAc), the title -318compound as a light-yellow solid. MS (ESI, pos. ion) m/z: 441 Mp: 130.0- 131.5 OC.

Example 132 F HP H N r 0o (2,3-Dihydro-benzo[1,4]dioxin-6-yl)-[4-(4-trifluoromethoxy-phenyl)-pyridin- 2-yl]-amine.

Following the same procedure described for Example 401 the mixture of (2,3dihydro-benzo[l,4]dioxin-6-yl)-(4-iodo-pyridin-2-yl)-amine (Example 401 mg, 0.2 mmol), tetrakis (triphenylphosphine) palladium (Aldrich Chemical Company) (12 mg, 0.011 mmol), 4-(trifluoromethoxy)phenylboronic acid (Lancaster Synthesis Ltd.) (51 mg, 0.25 mmol) and 1,2-dimethoxyethane (2 mL) gave, after heated in the Microwave Smith Synthesizer at 150 °C for 10 min and purification on a Biotage 40S column (4:1 hexane:EtOAc), the title compound as an orange glass. MS (ESI, pos. ion) m/z: 389 Example 133

F

F

KN

4-(4-Trifluoromethyl-phenyl)-pyridine.

In a 250-mL, round-bottomed flask were added 4-bromopyridine hydrochloride (Aldrich) (4.7 g, 24 mmol), tetrakis (triphenylphosphine) palladium (Aldrich) (1.4 g, 1.2 mmol) and 1,2-dimethoxyethane (120 mL). After stirring under nitrogen for 10 min, a solution of Na 2 C0 3 (5.2 g in 30 mL of water) and 4trifluoromethylbenzeneboronic acid (5.1 g, 27 mmol) were added sequentially to the mixture. The reaction was stirred in a 90 OC oil bath overnight. The 1,2dimethoxyethane was evaporated in vacuo, and EtOAc was added to the residue.

The aqueous layer was separated and extracted with EtOAc (2 x 50 mL). The combined EtOAc extracts were washed with brine, dried over Na 2 S0 4 and concentrated in vacuo. Purification by silica gel flash chromatography using -319- EtOAc/hexanes as eluent gave the title compound as a light-tan solid. MS (ESI, pos. ion) m/z: 224

F

F

F\

N0" 4-(4-Trifluoromethyl-phenyl)-pyridine 1-oxide.

To a mixture of 4-(4-trifluoromethyl-phenyl)-pyridine (5.0 g, 22 mmol) and methyltrioxorhenium (VII) (Aldrich) (110 mg, 0.45 mmol) in a 100-mL, roundbottomed flask was added CH 2 C2 (10 mL). Hydrogen peroxide (5 mL, Aldrich) was added drop-wise, and the reaction was stirred at room temperature under N 2 for 48 h. The mixture was partitioned between CH 2 C2 and brine, and the aqueous layer was extracted with CH 2

CI

2 (40 mL). The combined organic layers were dried over Na 2

SO

4 filtered, and concentrated in vacuo to give the title compound as an off-white solid. MS (ESI, pos. ion) ni/z: 240

F

F

F

IN

2-Chloro-4- (4-trifluoromethyl-phenyl)-pyridine.

To 4-(4-trifluoromethyl-phenyl)-pyridine 1-oxide (2.4 g, 10 mmol) was added phosphorous oxychloride (12 mL) at room temperature. The reaction mixture was heated at reflux for 5 h. POC13 was removed under reduced pressure, and the residue was partitioned between EtOAc and aqueous ammonium hydroxide. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na 2

SO

4 filtered, and concentrated in vacuo. The crude material was purified by chromatography on a Biotage 40 M column (8:1 hexanes: EtOAc) to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 258.5 -320- Quinolin-3-yl- [4-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-amine.

To an oven-dried 50 mL round-bottomed flask were added 2-chloro-4- (4trifluoromethyl-phenyl)-pyridine (138 mg, 0.54 mmol) and 3-aminoquinoline (Aldrich Chemical Company) (93 mg, 0.64 mmol), followed by anhydrous toluene (45 mL). Nitrogen was bubbled through the above solution via a needle for Ih. Then palladium acetate (Aldrich Chemical Company) (18 mg, 0.08 mmol) and BINAP (Aldrich Chemical Company) (50 mg, 0.08 mmol) were added to the reaction in one portion, followed by sodium tert-butoxide (Aldrich Chemical Company) (145 mg, 1.5 mmol). The reaction mixture was heated at 90 °C overnight. After cooling to room temperature, the reaction mixture was taken up to ether, and washed with brine. The aqueous layer was extracted with ether (2x) and the combined ether layer was dried over Na 2

SO

4 and concentrated. The residue was purified on a Biotage 40 S column (2.5:1 hexane:EtOAc) to give the title compound as an off-white solid. MS (ESI, pos. ion) n/z: 366 Mp: 207.4-207.5 OC.

General Scheme III.a

R

3 R'-M R 3

R

3 Br 1 R S transition metal oxidation R 15 coupling R5 N Ris'1 N

O

R

16 16 R 16 M B(OH) 2 SnBu 3 ,6 ZnCI. BF 3 s. MgBr, etc.

R

3

R

3 chlorination R CR 4 -YH R F Y'R4

R'

Ri 6 R

R-^

R16 halogenexchange

R

3 R1 F R 4

-YH

N

R

16 321 Scheme 1II.b

H

2 N R 4

-YH

1. diazotization 2. dehydrohalogenation KR4

R--

transition metal coupling Scheme III.c P-a 0 dlehydrohalogenation

NH

P =ArylCH 2

R

3 PG01y 4 deprotection

R

3 P-0 CI R 4

-YH

R16

R

3 HO0, Y, YR4 1. Tf 2 O, CH 2

CI

2 I 2. R 1

-M

RA 5 N transition metal coupling Example 134

N

7- [4-4-Tritl uoromethyl-pbenylI)-py rid in-2-yloxy qu inolIine.

To an oven-dried, 50-mL, round-bottomed flask were added 7-hydroxyquinoline (Aldrich) (87 mg, 0.6 mmol) and DMF (1 mL). The solution was place under nitrogen, and NaH (24 mg, 0.6 mmol) was added in one portion. After stirring for min, 2-chloro-4-(4-trifluoromethy lphenyl) pyridine (Example 41 0 129 mg, inmol) was added. The reaction mixture was heated in. a 155 0 C oil bath for -322- 72 h. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and brine. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na 2

SO

4 concentrated in vacuo. The crude material was purified on a Biotage 40 S column (3:1 hexanes: EtOAc) to give the title compound as an off-white solid. MS (ESI, pos. ion) m/z: 367 Mp: 156.5-158.5 oC.

Example 135

F

F

F

OO

N

2-(3-Methoxy-phenoxy)-4-(4-trifluoromethyl-phenyl)-pyridine.

This material was prepared according to the method described in Example 2 (d) using 2-chloro-4- (4-trifluoromethyl-phenyl)-pyridine (Example 410 129 mg, mmol), 3-methoxyphenol (66 uL, 0.6 mmol), and sodium hydride (24 mg, 0.6 mmol) in DMF (1 mL). Purification on a Biotage 40S column (8:1 hexanes: EtOAc), provided the title compound as a white solid. MS (ESI, pos. ion) m/z: 346 Mp: 77.5- 79.6 OC.

Example 136 FF

NH

2 F N iI N

N

8-[4-(4-Trifluoromethyl-phenyl)-pyridin-2-yloxy]-quinolin-2-ylamine.

A mixture of 2-azido-quinolin-8-ol (0.28 g, 1.5 mmol), 2-chloro-4- (4trifluoromethyl-phenyl)-pyridine (Example 410 0.26 g, 1 mmol), and sodium hydride (64 mg, 1.6 mmol) in DMF (2 mL) was heated in a 180 oC oil bath for 48 h. The reaction mixture was then transferred to a 5-mL tube, and irradiated in the Microwave Smith Synthesizer at 250 OC for 10 min. EtOAc and brine were added, and the aqueous layer was extracted with EtOAc. Combined organic layers were dried over Na 2

SO

4 filtered, and concentrated in vacuo. The compound was purified on a Biotage 40S column (98:2 dichloromethane: MeOH) 323 followed by recrystallization from EtOAc/hexanes to give the title compound as a light-yellow shiny crystal. MS (ESI, pos. ion) m/lz: 382 Mp: 196.5- 199.5 Anal. Calcd for C 2 lH 14

F

3

N

3 0: C, 66.14; H, 3.70; N, 11.02. Found: C, 66.18; H, 3.69; N, 11.08.

Example 137

F

FN

N

0

-N

8- [4-(4-Trifl uoromethyl-p henyl)-py rid in -2-yloxyl-qu inol ine.

This material was prepared according to the method described in Example 413 using 2-chloro-4- (4-trifluoromethyl-phenyl)-pyridine (Example 410 0.16 g, 0.6 mmol1), 8-hydroxyquinoline (0.1 g, 0.7 mmol), sodium hydride (38 mg, mmol) and copper iodide (12 mg, 0.06 mmol) in DMIF (3 m.

Purification on a Biotage 40S column (3:1 hexanes: EtOAc), provided the title compound as a white solid. MIS (ESI, pos. ion) m/z: 367 Anal. Calcd for

C

21

H

13

F

3

N

2 0: C, 68.85; H, 3.58; N, 7.65. Found: C, 68.88; H, 3.59; N, 7.51.

Example 138

F

F N 0 N S [4-(4-trifluoromethyl-phenyl)-pyridin-2-yloxy]-benzotiiazole.

This material was prepared according to the method described in Example 413 using 2-chloro-4- (4-tri fl uoromethyl -phen yl)-pyri dine (Example 410 0.16 g, 0.6 mmol), 2-methyl-5-benzothiazolol (0.12 g, 0.7 mnmol), sodium hydride (38 mg, 1.0 mmol) and copper iodide (12 mg, 0.06 mmol) in DMIF (3 mL).

Purification on a Biotage 40S column (3:1 hexanes: EtOAc), provided the title compound as a white solid. MS (ESI, pos. ion) m/z: 367 Mp: 160.5-163.5 Anal. Calcd for C 20

HI

3

F

3

N

2 0S. 0.25 H120: C, 61.45; H, 3.48; N, 7.17; S, 8,20.

Found: C, 61.45; H, 3.39; N, 7.17; S, 8.31.

324 Table B. The following compounds were prepared according to General Schemes III.a, IuI.b and III.c:

MS

Example Structure (ESI, pos. ion) Metn Point 0

C

F

NH

2 F N( 246.3- 139 0 s 388 24.

F0 -325- Additional Examples Following the procedures described above, or with slight modifications thereof, and following procedures familiar to one of ordinary skill in the art, the following examples were prepared from commercially available reagents: Example Structure Melting Point Mass Spec.

number 0 C) (ESI) m/z 142 T244 343 (M+I) g HI 143 231 i (M,M+2) 144 rY N'N 159 311 (M+1) 0

OCH,

o O0-CH 145 1. N N.YOH >300 361 (M+l) 0 1 -326- 327 Example Strcture Melting Point Mass Spec.

number 0 0) (ESI) ,n/z N- ~0-108 281 (M+1) 295 1061 154 CH, 171-173 323 (M+1) H 3C 156 N, 187-190 359 (M+1) 158 339'~ 424 1 (M+1) 7203 328 Example Structure Melting Point Mass Spec.

number 0 0) (ESI) m/z 159 204 325 (M+1)

C~

~H

3

H

161 thin film 319 (M±1) 162 *K>173 326 (M+1)

:-OHHC

3 163 152 406 (M+1) 0CH 3 CH3 329 330 -331 -332number 0 0) (ESI) m/z 185 270 331 (M+1) 186 68 331 (M+1) Example Structure Melting Mass Spec.

number Point (ESI) m/z

N.N

N N 187 21 320 (M+1)

'N"

188 277 319 333 334 -335- -336- Example Structure Melting Mass Spec.

number Point (ESI) m/z 219 ~-64-71 428 (M+1) 220 0~ 100-104 415 (M+1)

-A

221 o 91-93 428 (M+1) 222 0205-206 415 (M+1)

NN

223 0 1 M( Z 78-80 444 1) U3--N 224 O 2. 89-93 444 (M+1) -337- -338- 230 t 168 432 (M+1) -339- Example Structure Melting Mass Spec.

number Point (ESI) m/z

F

F

F

H

235 amorphous 427 (M+1) 0 N' 0

H

236 0 56 499 (M+1)

NN

237 1497 (M+1) 340 341 342 343 Example Structure Melting Mass Spec.

number Point (TC) (ESI) m/z N 0 257 0 137-138 391 (M+1)

F

F

F H

H

258 N N 198-200 391 (M+1) 0O

O

Br 259 H H 171-173 402 (M+i1) 0

O

H 0<T 260 0 O 158-160 409 (M±1) O OH 261 N- N 168-170 365 (M+1) 262 H I179-180 395 (M+1) 263 Na 117-119 411 (M-I1) 0 0 OH 2 344 Example Structure Melting Mass Spec.

number Point 0 C) (ESI) rn/z Br H H 264 N 187-189 388 0 OH Br

H

265 N N154-157 402 (M+1) 0 OH

H

F

F

F6

H.

26 S 186-188 364 (M+1)

N>NH

269 l OH 134-135 409 (M+1) 0

F

N.

270 K a OMe 182-185 3 81 1) 0 H 345 Example SrcueMelting Mass Spec.

number SrcuePoint (ES I) mlz 271 171-173 395 (M-I1) 272 N Kome 101-105 369 (M+1) 0

H

273 I- a 176-178 411 (M+1) Br

NH

274 N~1aiO

M

O 196-199 392 (M+1) 275 146-148 382 (M+1) 276 4y--'231 363 (M+1) 277 161-162 367 (M+1) 346 H $-OH 278 N) H 108-110 425 (M+l) 279 H K186-187 409 (M+1) NC N

OM.

280 K N ,OM 160-162 381 (M+1)

H

3 c. H H )C UN 181 363 (M±1) 28 .z NH, amorphous 353 (M+1) Sr 0.

283 {(oil) 366 (M)

IH

284 N348 (M+I) F F 347 Example Structure Melting Mass Spec.

number Point (ESI) mlz 324 (M+1) o OMe 286 I I330 (MI1) o0 N F HeF 287 N F 382 (M+1) o C4 288 HN. 294 (M+1) 0

H

29 308 (M+1) 0 L 348 Example Structure Melting Mass Spec.

number Point (ESI) ,nlz

H

293 N 294 (M+1)

'NH

294 N ~367 (M+1) 295 N N 246-247 341 (M) 0

H

297 N233-235 341 (M)

H

H

298 e36 MI ONC 't1XOMe36(M) 349 Example Structure Melting Mass Spec.

number Point 0 C) (ES I) m/z

H

299 Na N0362 (M+1)

H

300 H376

(M)

o 8 IxIa

F

301 ~372 (M+1) 302 N' H OE18-187 391 (M+1) 0N

F

F

303 -Cl NaO 224-226 414 (M+I)

F

F

304I -231-232 331 (M+1)

H

F

FH

305 F 219-220 349 (M+1) -350- Example Structure Melting Mass Spec.

number Point C 0 C) (ES I) rnlz

F

306 NcCCS 231-232 383

F

FF

307 H- H 203-204 365 (M+1)

F

F 308 177-179 365 (M+1)

H

F

F

309 N a 226-227 384 (M+1) 310 N- 0 Amorphous 308 (M+1)

NNOO

311 jD" 150 360 (M) 0

F

NN N 312 N 211 427 (M+1) 0 351 Example Structure Melting Mass Spec.

number Point (ESI) m/z

F

F

F S I H 313 NN 78 433 (M+1)

N

314 N N N 286 350 (MI1)

F

F 315 N Amorphous 434 (M+1) 0 _a

F

F

F 316 N >rf I- 226 415 (M+1) 0__

F

F

F

HN

N N,(III 1I 317 H 219 530 (M+1)

HNYO,.,

0 'NN 318 N I-Amorphous 320 (M+1)

H

F

F

F

HN

319 N Amorphous 415 (M-I1) _0

H

-352- Example Structure Melting Mass Spec.

number Structure Point (oC) (ESI) m/z

F

320 211 349 (M+1)

F

321 N Amorphous 375 (M+1) SN^ oN

H

322 Amorphous 341 (M+I)

F

o o

H

323 N Amorphous 427 (M+1) Br,, H 324 'v 225 360 (M+1) 0 N 325 Amorphous 338 (M+1) 6 2 3 326 N N--N 275 320 (M+I) 0 o 353- 354 355 Example SrcueMelting Mass Spec.

number Point (ESI) mlz 341 0:n237-240 427 (M+1)

H

H

3420 N-a O 26-28 43 (+F

FF

346 a Lo) amorphous 447 (M+1) 3447N 202-205 423 (M+1) 0 N( -356- Example Structure Melting Mass Spec.

number Point 0 C) (EST) mlz 348 263-269 449 (M+1)

HO

273-275 451 (M+0) N

H

Ha 350 348 (M+1) 0 351 K 295 (M+I)

F

N

352 amorphous 417 (M+1)

H

0 353 308 (M+1) 354 H 354 N C1328 (M+1) 0 -6 357 Example Structure Melting Mass Spec.

number Point (TC) (ESI) mlz

F

F

H

355 1 amorphous 435 (M+1) (N 0

N

356 H319 (M+1) 357 323 (M+1) 0 358 N,323 (M+1) 0 359 HN334 (M+1) 360 3 20 1) 361 H 324 (M+1)

IOH

0 Examle trucureMeltng ass pec number Point (ES I) mlz

H

363 0 N 298 (M+1)

NN

364 H C1 385 (M+1) 365 0 1 359 (M+I) 0 IF 328

MI

366 325 (M+1) 367 IJNO35(M1 368 N315 (M+1)

I

-359- Example Structure Melting Mass Spec.

number Point C 0 C) (ESI) mlz 369 M 374 (M+1) 370 305 (M+1)

H

371 NN H387 (M+1)

NN

N, NN21(MI 373 358 3(M+1) 0 360 Example St ructure Melting Mass Spec.

number Point 0 CQ (ESI) mlz 376 N282 (M+1) 377 H315 (M+1) 378 H360 (M+1) 379 HN344 (M+1) o N -N 380 H N N O mrhous 449 1)

"IN

O 0 N~ N 0

I/

N-N

H

N

NO,

382 K-1HN 5 M1 N~0 0

CN

-361- Example Structure Melting Mass Spec.

number Point (TC) (ESI) m/z

H

384 NN 345 (M+1) 0

F

F

385 NN N 385 ~344 (M+1) 38633(M Example Structure Melting Mass Spec.

number Point (TC) (ESI) m/z 0 387. S- 247-248 327 (M+1) 0 388 HN 179-180 312 (M-I1) 362 Example Structure Melting Mass Spec.

number Point 0 CQ (ESI) m/z 389 17-8 360, 362 389 ___179182 M+2) N: 0 39 ~182-183 282 (M+1)

I,

C3 391 HN ~0 187-188 316 (M+1)

F

39 H~j0O 195-196 300 (M+1) 393 n.~201-202 350 (M+1) 363 364 -365- -366- Table. The following compounds were prepared according to General Schemes I, II or III:

MS

Example Melting Structure (ESI, pos. ion) number Point °C m/z 413 303 157

N

414 N OCH 333 amorphous N I 415 N 347 156 N

O

-367-

MS

EapeStructure (ESI, pos. ion) Melting number Point TC nvzz I H 416 -TN (C H 3 331 133 -N CH 3

H

417 N .q OCH 3 393 amorphous N

OCH

3

OCH

3 I H 418 N 342 106 N

N

H

419 Hj 360 154 N

N

H

420 N.N N 354 214

F

3

C

H

N

I I 372 (M+1) 203 422 422 ~366 26 206 -368-

MS

Example Melting Structure (ESI, pos. ion) number Point °C m/z

F

3

C

H

423 N O 373 114

IN

O

Br S H 383,385 424 N O 124 N h M+2) Additional Examples Following the procedures described above, and applying the procedure in Example 109 to the cinnamides exemplified, or with slight modifications thereof, and following procedures familiar to one of ordinary skill in the art, the following examples may be prepared from commercially available reagents: 0 0 ci 0 0 ci 0 0 ci -369- 2007200149 15 Jan 2007

-N

-371- 372 373 374 NH2 375 376 377 -378- 0 0 ci 0 0 ci 2007200149 15 Jan 2007 Ki 0. Z 4 't .7, 2007200149 15 Jan 2007

I

z- 0 z- 2007200149 15 Jan 2007 2007200149 15 Jan 2007 O zx o

"I

2007200149 15 Jan 2007

I

z.

0 0

I

2007200149 15 Jan 2007 1, 2007200149 15 Jan 2007 o o 0 0 2007200149 15 Jan 2007 Z-f 0 0 0 0 x zI zx zx z 0 0 00 0 0 0 0 00 2007200149 15 Jan 2007 o 0 So0 2007200149 15 Jan 2007 o 0 0 0 0

'-N

2007200149 15 Jan 2007 2007200149 15 Jan 2007 0 0 0 0 2007200149 15 Jan 2007 2007200149 15 Jan 2007 2007200149 15 Jan 2007 0 n_ n 0z0 0 r ZI: 0 x 0 ZI ZIlz4 00 00 0/ zx 2007200149 15 Jan 2007 U,7 oz z 0o0 0 o zzL zx zm

Z=

0 0 0 0 0 0 0 0 0

-N

2007200149 15 Jan 2007 2007200149 15 Jan 2007

(I

0 Zz 2007200149 15 Jan 2007 0 0 0 Zx 0x 0 2007200149 15 Jan 2007

K>

2007200149 15 Jan 2007 2007200149 15 Jan 2007 d0

Z

b1-- 2007200149 15 Jan 2007

NI

a -n 0

ZI

0 0 2z 0

ZI

2007200149 15 Jan 2007 C zx 0

ZI

00 22 Zz 0 2\-Z -403- The following examples may also be made using the above generic schemes and synthetic examples:

F

F NH 2 F H N KH1 N

S

F

HN

NN

S

FN

2007200149 15 Jan 2007 -405- Capsaicin-induced Ca 2 influx in primary dorsal root ganglion neurons Embryonic 19 day old (E19) dorsal root ganglia (DRG) were dissected from timed-pregnant, terminally anesthetized Sprague-Dawley rats (Charles River, Wilmington, MA) and collected in ice-cold L-15 media (Life Technologies, Grand Island, NY) containing 5% heat inactivated horse serum (Life Technologies). The DRG were then dissociated into single cell suspension using a papain dissociation system (Worthington Biochemical Corp., Freehold, NJ). The dissociated cells were pelleted at 200 x g for 5 min and re-suspended in EBSS containing 1 mg/ml ovomucoid inhibitor, 1 mg/ml ovalbumin and 0.005% DNase.

Cell suspension was centrifuged through a gradient solution containing 10 mg/ml ovomucoid inhibitor, 10 mg/ml ovalbumin at 200 x g for 6 min to remove cell debris; and filtered through a 88-Am nylon mesh (Fisher Scientific, Pittsburgh, PA) to remove any clumps. Cell number was determined with a hemocytometer and cells were seeded into poly-orithine 100 gg/ml (Sigma) and mouse laminin 1 lg/ml (Life Technologies)-coated 96-well plates at 10 x 103 cells/well in complete medium. The complete medium consists of minimal essential medium (MEM) and Ham's F12, 1:1, penicillin (100 U/ml), and streptomycin (100 Ag/ml), and nerve growth factor (lOng/ml), 10% heat inactivated horse serum (Life Technologies). The cultures were kept at 37 5% CO 2 and 100% humidity.

For controlling the growth of non-neuronal cells, 5-fluoro-2'-deoxyuridine (751M) and uridine (180pM) were included in the medium. Activation of VRI was achieved in these cellular assays using either a capsaicin stimulus (ranging from 0.01-10 M) or by an acid stimulus (addition of 30mM Hepes/Mes buffered at pH Compounds were also tested in an assay format to evaluate their agonist properties at VR1. The activation of VRI is followed as a function of cellular uptake of radioactive calcium (45Ca :Amersham CES3-2mCi).

I

-406- Capsaicin Antagonist Assay: E-19 DRG cells at 3 days in culture are incubated with serial concentrations of VR1 antagonists, in HBSS (Hanks buffered saline solution supplemented with BSA 0.1mg/ml and 1 mM Hepes at pH 7.4) for min, room temperature. Cells are then challenged with a VR1 agonist, capsaicin (500 nM), in activation buffer containing 0.1mg/ml BSA, 15 mM Hepes, pH 7.4, and 10 PCi/ml 45 Ca2+ (Amersham CES3-2mCi) in Ham's F12 for 2 min at room temperature.

Acid Antagonist Assay: Compounds are pre-incubated with E-19 DRG cells at room temperature for 2 minutes prior to addition of 4 5 Ca 2 in 30mM Hepes/Mes buffer (Final Assay pH 5) and then left for an additional 2 minutes prior to compound washout. Final concentration of 45 Ca2+ (Amersham CES3-2mCi) is /iCi/mL.

Agonist Assay: Compounds are incubated with E-19 DRG cells at room temperature for 2 minutes in the presence of 45 Ca2+ prior to compound washout.

Final 45 Ca2+ (Amersham CES3-2mCi) at Compound Washout and Analysis: Assay plates are washed using an ELX405 plate washer (Bio-Tek Instruments Inc.) immediately after functional assay. Wash 3 X with PBS, 0.1 mg/mL BSA. Aspirate between washes. Read plates using a MicroBeta Jet (Wallac Inc.). Compound activity is then calculated using appropriate computational algorithms.

4 5 Calcium 2 Assay Protocol Compounds may be assayed using Chinese Hamster Ovary cell lines stably expressing either human VRI or rat VR1 under a CMV promoter. Cells could be cultured in a Growth Medium, routinely passaged at 70% confluency using trypsin and plated in an assay plate 24 hours prior to compound evaluation.

Possible Growth Medium: DMEM, high glucose (Gibco 11965-084).

Dialyzed serum (Hyclone SH30079.03).

1X Non-Essential Amino Acids (Gibco 11140-050).

1X Glutamine-Pen-Strep (Gibco 10378-016).

Geneticin, 450pg/mL (Gibco 10131-035).

-407- Compounds could be diluted in 100% DMSO and tested for activity over several log units of concentration [40l.M-2pM]. Compounds may be further diluted in HBSS buffer (pH 7.4) 0.1 mg/mL BSA, prior to evaluation. Final DMSO concentration in assay would be Each assay plate could be controlled with a buffer only and a known antagonist compound (either capsazepine or one of the described VRI antagonists).

Activation of VR1 could be achieved in these cellular assays using either a capsaicin stimulus (ranging from 0.1-l1gM) or by an acid stimulus (addition of Hepes/Mes buffered at pH Compounds could also be tested in an assay format to evaluate their agonist properties at VRI.

Capsaicin Antagonist Assay: Compounds may be pre-incubated with cells (expressing either human or rat VRI) at room temperature for 2 minutes prior to addition of 45 Ca 2 and Capsaicin and then left for an additional 2 minutes prior to compound washout. Capsaicin (200nM) can be added in HAM's F12, 0.1 mg/mL BSA, 15 mM Hepes at pH 7.4. Final 45Ca2+ (Amersham CES3-2mCi) added could be Acid Antagonist Assay: Compounds can be pre-incubated with cells (expressing either human or rat VRI) for 2 minutes prior to addition of 45 Ca2+ in Hepes/Mes buffer (Final Assay pH 5) and then left for an additional 2 minutes prior to compound washout. Final 4 5 Ca 2 (Amersham CES3-2mCi) added could be Agonist Assay: Compounds can be incubated with cells (expressing either human or rat VR1) for 2 minutes in the presence of 45 Ca2 prior to compound washout.

Final 45 Ca (Amersham CES3-2mCi) added could be Compound Washout and Analysis: Assay plates would be washed using an ELX405 plate washer (Bio-Tek Instruments Inc.) immediately after the functional assay. One could wash 3 X with PBS, 0.1 mg/mL BSA, aspirating between washes. Plates could then be read using a MicroBeta Jet (Wallac Inc.) and compound activity calculated using appropriate computational algorithms.

Useful nucleic acid sequences and proteins may be found in U.S. Patent Nos. 6,335,180, 6, 406,908 and 6,239,267, herein incorporated by reference in their entirety.

-408- For the treatment of vanilloid-receptor-diseases, such as acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burs, allergic skin reactions, pruritis, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders, the compounds of the present invention may be administered orally, parentally, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles. The term parenteral as used herein includes, subcutaneous, intravenous, intramuscular, intrasternal, infusion techniques or intraperitoneally.

Treatment of diseases and disorders herein is intended to also include the prophylactic administration of a compound of the invention, a pharmaceutical salt thereof, or a pharmaceutical composition of either to a subject an animal, preferably a mammal, most preferably a human) believed to be in need of preventative treatment, such as, for example, pain, inflammation and the like.

The dosage regimen for treating vanilloid-receptor-mediated diseases, cancer, and/or hyperglycemia with the compounds of this invention and/or compositions of this invention is based on a variety of factors, including the type of disease, the age, weight, sex, medical condition of the patient, the severity of the condition, the route of administration, and the particular compound employed.

Thus, the dosage regimen may vary widely, but can be determined routinely using standard methods. Dosage levels of the order from about 0.01 mg to 30 mg per -409kilogram of body weight per day, preferably from about 0.1 mg to 10 mg/kg, cnmore preferably from about 0.25 mg to 1 mg/kg are useful for all methods of use disclosed herein.

The pharmaceutically active compounds of this invention can be processed in accordance with conventional methods of pharmacy to produce medicinal agents for administration to patients, including humans and other mammals.

For oral administration, the pharmaceutical composition may be in the form of, for example, a capsule, a tablet, a suspension, or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a given amount of the active ingredient. For example, these may contain an amount of active ingredient from about 1 to 2000 mg; preferably from about 1 to 500 mg, more preferably from about 5 to 150 mg. A suitable daily dose for a human or other mammal may vary widely depending on the condition of the patient and other factors, but, once again, can be determined using routine methods.

The active ingredient may also be administered by injection asa composition with suitable carriers including saline, dextrose, or water. The daily parenteral dosage regimen will be from about 0.1 to about 30 mg/kg of total body weight, preferably from about 0.1 to about 10 mg/kg, and more preferably from about 0.25 mg to 1 mg/kg.

Injectable preparations, such as sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known are using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

-410- Suppositories for rectal administration of the drug can be prepared by t' mixing the drug with a suitable non-irritating excipient such as cocoa butter and polyethylene glycols that are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.

A suitable topical dose of active ingredient of a compound of the invention is 0.1 mg to 150 mg administered one to four, preferably one or two ,I times daily. For topical administration, the active ingredient may comprise from 0.001% to 10% w/w, from 1% to 2% by weight of the formulation, although N it may comprise as much as 10% w/w, but preferably not more than 5% w/w, and more preferably from 0.1% to 1% of the formulation. Formulations suitable for topical administration include liquid or semiliquid preparations suitable for penetration through the skin liniments, lotions, ointments, creams, or pastes) and drops suitable for administration to the eye, ear, or nose.

For administration, the compounds of this invention are ordinarily combined with one or more adjuvants appropriate for the indicated route of administration. The compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, stearic acid, talc, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, acacia, gelatin, sodium alginate, polyvinyl-pyrrolidine, and/or polyvinyl alcohol, and tableted or encapsulated for conventional administration. Alternatively, the compounds of this invention may be dissolved in saline, water, polyethylene glycol, propylene glycol, ethanol, corn oil, peanut oil, cottonseed oil, sesame oil, tragacanth gum, and/or various buffers. Other adjuvants and modes of administration are well known in the pharmaceutical art. The carrier or diluent may include time delay material, such as glyceryl monostearate or glyceryl distearate alone or with a wax, or other materials well known in the art.

The pharmaceutical compositions may be made up in a solid form (including granules, powders or suppositories) or in a liquid form solutions, suspensions, or emulsions). The pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain -411conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers etc.

Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose, lactose, or starch.

Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting, sweetening, flavoring, and perfuming agents.

Compounds of the present invention can possess one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers as well as in the form of racemic or non-racemic mixtures thereof. The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, by formation of diastereoisomeric salts, by treatment with an optically active acid or base. Examples of appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and then separation of the mixture of diastereoisomers by crystallization followed by liberation of the optically active bases from these salts. A different process for separation of optical isomers involves the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers. Still another available method involves synthesis of covalent diastereoisomeric molecules by reacting compounds of the invention with an optically pure acid in an activated form or an optically pure isocyanate. The synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the enantiomerically pure compound. The optically active compounds of the invention can likewise be -412obtained by using active starting materials. These isomers may be in the form of a free acid, a free base, an ester or a salt.

Likewise, the compounds of this invention may exist as isomers, that is compounds of the same molecular formula but in which the atoms, relative to one another, are arranged differently. In particular, the alkylene substituents of the compounds of this invention, are normally and preferably arranged and inserted into the molecules as indicated in the definitions for each of these groups, being read from left to right. However, in certain cases, one skilled in the art will appreciate that it is possible to prepare compounds of this invention iri which'these substituents are reversed in orientation relative to the other atoms in the molecule. That is, the substituent to be inserted may be the same as that noted above except that it is inserted into the molecule in the reverse orientation. One skilled in the art will appreciate that these isomeric forms of the compounds of this invention are to be construed as encompassed within the scope of the present invention.

The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. The salts include, but are not limited to, the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methansulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 2-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, mesylate, and undecanoate. Also, the basic nitrogencontaining groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.

Examples of acids that may be employed to from pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, -413sulfuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid. Other examples include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases.

Also encompassed in the scope of the present invention are pharmaceutically acceptable esters of a carboxylic acid or hydroxyl containing group, including a metabolically labile ester or a prodrug form of a compound of this invention. A metabolically labile ester is one which may produce, for example, an increase in blood levels and prolong the efficacy of the corresponding non-esterified form of the compound. A prodrug form is one that is not in an active form of the molecule as administered but which becomes therapeutically active after some in vivo activity or biotransformation, such as metabolism, for example, enzymatic or hydrolytic cleavage. For a general discussion of prodrugs involving esters see Svensson and Tunek Drug Metabolism Reviews 165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985). Examples of a masked carboxylate anion include a variety of esters, such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, pmethoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl).

Amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bungaard J. Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, such as imidazole, imide, indole and the like, have been masked with Nacyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)).

Hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloan and Little, 4/11/81) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use. Esters of a compound of this invention, may include, for example, the methyl, ethyl, propyl, and butyl esters, as well as other suitable esters formed between an acidic moiety and a hydroxyl containing moiety.

Metabolically labile esters, may include, for example, methoxymethyl, ethoxymethyl, iso-propoxymethyl, a-methoxyethyl, groups such as a- ((Ci-C 4 )alkyloxy)ethyl, for example, methoxyethyl, ethoxyethyl, propoxyethyl, iso-propoxyethyl, etc.; 2-oxo-1,3-dioxolen-4-ylmethyl groups, such as -414- 2-oxo-1,3,dioxolen-4-ylmethyl, etc.; CI-C 3 alkylthiomethyl groups, for example, methylthiomethyl, ethylthiomethyl, isopropylthiomethyl, etc.; acyloxymethyl groups, for example, pivaloyloxymethyl, a-acetoxymethyl, etc.; ethoxycarbonyl- 1-methyl; or a-acyloxy-a-substituted methyl groups, for example a-acetoxyethyl.

Further, the compounds of the invention may exist as crystalline solids which can be crystallized from common solvents such as ethanol, N,N-dimethylformamide, water, or the like. Thus, crystalline forms of the compounds of the invention may exist as polymorphs, solvates and/or hydrates of the parent compounds or their pharmaceutically acceptable salts. All of such forms likewise are to be construed as falling within the scope of the invention. While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more compounds of the invention or other agents. When administered as a combination, the therapeutic agents can be formulated as separate compositions that are given at the same time or different times, or the therapeutic agents can be given as a single composition.

The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds. Variations and changes, which are obvious to one skilled in the art are intended to be within the scope and nature of the invention which are defined in the appended claims.

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

Claims (87)

1. A compound having the structure: wherein: R' is or a naphthyl or saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the naphthyl, heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3, substituents independently selected from R 5 R 6 and R 7 R 2 is H, hydroxy, halo, C 1 6 alkyl substituted by 0, 1 or 2 substituents selected from R' 0 or a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, 0 and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from R 5 R 6 and R 7 -416- or R' and R 2 together are R 6 R R R 7 R 3 is H or C 1 4 alkyl; or R' and R 3 together areC R 7 L 8rR R isN R3 ;or R 4 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from 0 N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom. bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the carbon atoms of the heterocycle and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C 19 galkyl, C 1 4 haloalkyl, halo, nitro, cyano, -OR a, -S(=O)nC 1 6 alkyl, -0-C 1 4 haloalkyl, -0-C I. 6 alky]NR aR a, -0-CI- 6 alkyI0R-a, -0-C .calkylC(=O)OR a, NRaR a, N 14 haloalkyi -NR aC, 6 a1 kylNRaRa, -NR'-C 16 aI kylORa, -C(=0)C 1 6 alkyl, -C(=0)OC 1 6 alkyl, -OC(=0)C 1 6alkyl, -C(=0)NR aCi.- 6 alkyl and -NRaC(=0)CI- 6 alkyl; or R 4 1 iS L-membered bicyclic ing* -417- comprising fused 6-membered rings, containing 0, 1, 2, 3 or 4 N atoms with the remainder being carbon atoms, with at least one of the 6-membered rings being aromatic, wherein the carbon atoms are substituted by H, halo, OR', NRaRa, CI-6alkyl and C 1 3 haloalkyl; and saturated carbon atoms may be additionally substituted by except that when R' is 4-chiorophenyl, 3-bromophenyl,

3-ni trophen yl, 2-nitro-3-chlorophen yl, 3 ,4-methylenedioxyphenyl, 3-methyithiophenyl or 2,3,4-methoxyphenyl, then R 4 is not phenyl substituted by 1 or 2 substituents selected from halo and C 1 4 alkyl; and R' and R 4 are not both 3,4-methylenedioxyphenyl; and when R1 is 4-trifluoromethylphenyl, then R 4 is not pyridlinyl, 2-methyl -4-aminoquinolinyl or 3 ,3-dimethyl- 1,3-dihydro-indol-2- on-6-yl; R 5 is independently, at each instance, H, C 1 9 galkyI, CI- 4 haloalkyl, halo, nitro, cyano, -0CI-6alkyl, -0-C 1 4 haloalkyl, -0-C 1 6 alkyl NR aRa, -0-C 1 6 alkylOR', _N1a -NR 3 -C 1 -4haloalkyl, -NR aCi 1 6 alkylNRaRa or -NRa-CI- 6 alkyOR'; or R 5 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from 0, N and S; R 6 is independently, at each instance, H, C,. 9 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -0CI 6 alkyl, -0-C 1 4 haloalkyl, -0-C 1 6 alkylNRaRa, -0-C I- 6 alkylOR 3 _N41a Ra, -NRa-CI 1 4 haloalkyl, -NRa-C I 6 alkylNRaR a or -NRa-C, 6 alkyIOR. or R and R 6 together are a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the carbon atoms of the bridge are substituted by 0, 1, 2 or 3 substituents selected from halo, C 1 6 alkyl, -OCI. 6 alkyl, -NR'C,. 6 alky1, -Ct- 6 alkyl0R a and C 1 -6alkylNR 3 and the available N atoms of the bridge are substituted by R -C 1 6 al kylOR' or C I. 6 al kyl NR aR'; R. is independently, at each instance, H, C 1 9 galkyl, C 1 -4haloalkyl, halo, nitro, cyano, -OC I. 6 alkyl, -0-C 1 4 haloalkyl, -0-C 1 6 alkylNRaRa, -0-C I 6 alkylORa, -NR R a, -NRa-C 1 4 h al oal kyl, -NRa-C 1 6 a1 kyl NR 3 R 3 or -NRa-C 1 6 alkylOR'; R 8 is independently, at each instance, H, C 1 .9alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -0C 1 6 alkyl, 4 haloalkyl, 6 alkylNR aR.a, -0-C. 6 alkyl0R', -NRaRa, -NRa .CC,. 4 haloai1kyl, -NR a-C,1 6 alkylNRR a or -NR 3 6 alkylOR'; orR7 -418- and R 8 together are a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the carbon atoms of the bridge are substituted by 0, 1, 2 or 3 substituents selected from halo, C,- 6 alkyl, -0-C 1 6 alkyl, -NR'CI-6alkyl, 6 alkylOR a and CI. 6 alkylNRaRa, and the available N atoms of the bridge 'are substituted by Ra, -C 1 _alkyl0R' or C 1 6 alky]NRaRa; R 9 is independently, at each instance, H, C 1 9 alkyl, C,- 4 haloalkyl, halo, nitro, cyano, 6 alkyl, -O-C, 4 haloalkyl, 6 alkylNR aR', -0-C -6al kylORa, -NR aRa, -NR aC, 4 haloalkyl, -NRa-C 6 alkylNRaRa or -NRa-C, 6 alkyIOR'; Rio is independently, at each instance, H, C, 9 galkyl, _Ci.. 3 alkyI0Ra, C, 4 haloalkyl, halo, nitro, cyano, -S(=0)nC],6alkyl, -0-C, 4 haloalkyl, -O-C 1 6 alkylNRaRa, -al kylORa, 6alkyIC(= O)0Ra N4,Ra -NRa-C, 4 haloalkyl, -NRa-C, 6 alkylNRaR a, _NRa.CI. 6 al kylOWa, )C -6alkyl, -C(=0)OC 6 alkyl, -OC(=0)CI. 6 alkyl, -C(=0)NTRaC 1 6 alkyl or -NR'C(=0)CI-6alkyl; R 1 is independently, at each instance, H; C 19 ,alkyl, 3 alkylORa, C1 4 haloalkyl, halo, nitro, cyano, 0 6 alkyl, -0-C 1 4 haloalkyl, 6 alkylNRaRa, -O-C 6 alkylR', 6 alkylORa, -0-C 1 6 alkylC(=0)ORa, -NRaR a, -NRaC, 4 haloalkyl, -NRa-Ci_6alkylNRaR -NR aC, _alkyloR a, ,6alkyl, 6alkyl, -OC(=0)C 6 alkyi, -C(=0)NRaC 6 alkyI or -NRaC(=0)C,. 6 alkyl; or Rio and R" together are a saturated or unsaturated 3- or

4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the each of the carbon atoms in the bridge is substituted by H, -Cf- 6 alkylOR', 6 alkyl, -NRaR a, -C, 6 alkylNRaRa, -C(0)ORa, -C(=0)NRa 3 alkylC(=0)ORa, -C 3 alkylC(=0)NR aR a. -OC(=0)CI-6alkyl, -NR C(=OC 1 6 alkyl, -C 1 3 alkylOC(=0)C 1 6 alkyl or -C 1 3 alkylNRaC(=0)CI 6 alkyl, and any nitrogen atoms in the bridge are substituted by 6 alkyI0R', ralkyl, -C, 6 alkylNRaR', 3 alkylC(=O)ORa, 3 alkyIC(=0)NRaRa 3 alkylOC(=O)C 6 alkyl, 3 a1 kylNRaC(=0)C 6 alkyl, -C(=0)Rc or -419-. -CI- 3 alky]R'; wherein if R' 0 R' 2 R' 3 and R 1 4 are allI H, then R" is not -0-CI. 6 alkylNRaR a or -0-C 6 alkylOR'; R 12is independently, at each instance, H, C 1 -galkyl, -CI. 3 alkylOR', C 1 4 haloalkyl, halo, nitro, cyano, 1 6 alkyl, -O-C I -haloalkyl, -6alkyl NRaR' -0-C 1 I 6 alky10R', -OC 6 alkylC(=O)ORa, -NR aR', -NRa-C,4haloalkyl, 6 alkyINRaR a, -NR a.C 1-6alkylOR', -C(=0)C 1 6 alkyl, -C(=0)0C 1 6 a1 kyl, -OC(=0)CI- 6 a1 kyl, -C(=O)NR'C 1 6alkyl or -NR aC(=O)Ci -alkyl; or 1 and R 1 2 together are a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the each of the carbon atoms in the bridge is substituted by H, -0Ra, -C 1 6 alkyIOR', 6 alkyl, -NRaR 6 alkylNRaRa, -C(=O)0R, -C(=0)NR 3 3 a1kyIC(=0)0R a, -C 1 3 a1kyIC(=0)NRaR a, -OC(=O)CI-6alkyl, 4.4RaC(=0)C, 6 alkyl, -CI 3 alkyl0C(=0)C, 6 alkyl or -C 3 alkylNRaC(=0)C, 6 alkyl, and any nitrogen atoms in the bridge are substituted by H, 6 alkyI0R 6 aJ kyl, -CI-6alkyINR aR a, 3 alkylC(=O)0R 3 -C 1 3 a1 kylC(=O)NR aR', 3 alkyIOC(=O)C 1 6 a1 kyl, 3 alkyINR 3 6 alkyl, or -CI- 3 alky]R' when R1 is 4-C,. 6 alkylphenyl or 2,4-dimethylphenyl, then R1 is.C, 9 alkyI, C,- 4 haloalkyl, halo, nitro, cyano, 4 haloalkyl, -0-C 1 .6a1kyINR 3 -0-C 1 6 alkylRC, -0-C 1 6 a1kyIOR', -0-C 1 6 -NRaR a, -NRa..CI-4haloalkyl, -NRaa., 6 a1 kylNRaR', -C(=0)CI. 6 alkyl, -C(=0)OCus6alkyl, -OC(=0)C 16 a1 kyl, -C(=0)NR'C 1 6 alkyl or -NRaC(=0)C 1-al kyl; or R'1 and R 11together are -L 3 -NRa-, respectively, or respecti vel y; or R"1 and R 1 2 are -NRa-L 3 -12-NRa-, or or R 12is -NRa 'or R 4is lO-membered bicyclic ring comprising fused 6-membered rings, containing 0, 1, 2, 3 or 4 N atoms with the remainder being carbon atoms, with at least one of the 6-membered rings being aromatic, wherein the carbon atoms are substituted by H, halo, ORa, NRaR CI-6alkyI and C,. 3 haloalkyl; and saturated carbon atoms may be additionally substituted by or R 4 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or 420 unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the carbon atoms of the heterocycle and bridge are substituted by 1, 2 or 3 substituents independently selected from C 29 alkyl, CA4haloalkyl, halo, nitro, cyano, -S(=0)nC, 1 6alkyl, -0-Ct-4haloalkyl, 6alky1NRaRa, -0-C 1 4 ialkylORa, _alkylC(=O)ORa, -NkRaR, -N~aC 4 haloalkyl, -NR'a.C 1 6 alkylNRaRa -NRa.C 6 alkyl, 6 alkyl, -OC(=0)C ,.oalkyl, 6al kyl and -NRaC(=0)C 6 alkyl; R'1 3 is independently, at each instance, H, C,-9alkyl; C,. 3 alkyl0R',( C, 4 haloalkyl, halo, nitro, cyano, -0-C,..Thaloalkyl, -0-C I 6 alkylNRR, -0-C 6 alkylORa, -0-Cj_6alkylC(=O)ORa, NRaR 4PNa..CI-. 4 haloalkyl, -NRa-C, 6 alkylNRa Ra, 4pNa-CI- 6 alky]ORa, 6 alkyl, 6alkyl, 6 alkyl, -C(=0)NR'C 1 6 alkyl or _Na(OC,.akl R 1 4 is independently, at each instance, H, C, 9 galkyl, 3 alkyl0R a, CA4haloalkyl, halo, nitro, cyano, 6 alkyl, -0-Ci. 4 haloalkyl, 6 al kyINR aR', -0-C 1 6 alkylOR', -0-C _6alkylC(=0)0R 3 -NkaRa, -NR 3 -CI- 4 haloalkyl, -N 1- 6 alkylNRaRa -NR'a.C 1 6 alkylORa, 6 alkyl, 6 alkyl, -OC(=0)CI- 6 alkyl, -C(=0)NR aC, 1 6 alkyl or -NR aC(=0)C, -6alkyl; Ra is independently, at each instance, H, phenyl, benzyl or C,- 6 alkyl; R b is H, C,_6alkyl,.-C(=0)CI- 6 alkyl, C,. 6 alkyl--R a; R' is'phenyl substituted by 0, 1 or 2 groups selected from halo, CI. 3 haloalkyl, -OR' and -NR aR'; or R' is a saturated or unsaturated 5- or

6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, 0 and S, wherein no more than 2 of the ring members are 0 or S, wherein the heterocycle is optionally fused with a phenyl ring, and the carbon atoms of the heterocycle are substituted by 0, 1 or 2 oxo groups, wherein the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents selected from halo, C,. 3 haloalkyl, -ORa and -NRaRa; L' is a bond, -CH 2 CH 2 or -CH=CH-;7 -421- 12 is NRa, 0, _CH 2 NRa_, -CH=N- or -NRaCH 2 L 3 is a 2- or 3-atom, saturated or unsaturated, bridge containing 1, 2 or 3 carbon atoms and 0, 1 or 2 atoms independently selected from 0, N and S, wherein the each of the carbon atoms in the bridge is substituted by H, -OR', -C I 6 alkylORa, -CQ 6 alkyl, -NRaR', -C 1 6alkyl NRaRa, -C(=0)0Ra, -C(0)NRR', -C 1 3 a1kyIC(=0)OR a, -C 1 3 a1 kylC(=O)NRaR', -OC(=0)C 1 .6a~kyl, .4PRaC(=0)CI-6alkyI, 3 a1 kyIOC(=0)C 1 6 alkyl or -C 1 3 alkylNRaC(=0)Cj. 6 a1 kyl, and any nitrogen atoms in the bridge are substituted by H, -CI- 6 alkyl0R', 6 alkyI, -C 1 6 alkylNRaR', 3 alkylC(=o)oRa, 3 alkylC(=0)NRRa, -C 3 alkyl0C(=O)CI- 6 alkyl, 3 alkyINRaC(=0)C 6 alkyl, or 3 alkyIRc; L! is a 2- or 3-atom, saturated or unsaturated, bridge containing 1, 2 or 3 carbon atoms and 0 or 1 atoms independently selected from 0, N and S, wherein at least one of the carbon atoms in the bridge is substituted by -OR -C I-alkyl0R', 6 alkyl, -NRaRa, 6 alkylNRaRa, 6alkyl, -C(=0)NRaRa, 3 alkylC(=0)0R', -C 1 3 alkylC(=0)NRaC, 1 6 alkyl, 6 alkyl, -NRaC(=0)C, 6 a1 kyl, 3 alkylOC(=0)C, 6 alkyl or 3 alkylNR aC(=O)C 1 _alkyl, and any nitrogen atoms in the bridge are substituted by H, -C 1. 6 al kyI0R. 6 alkyl, -C,-alkylNRaR 3 alkylC(=0)0Ra, -CI- 3 alkylC(=0)NRaRa, 3 a1 kylOC(=0)C, 6 alkyl, -C 1 3 alkylNRaC(=0)Cf- 6 aIkyl, -C(=0)RC or -C 1. 3 alkylRC; X is 0, S or N*Ra; or X and R 2 together are =N-CH=CH-, or =C-NRa~ Y is NH or0; and n is independently, at each instance, 0, 1 or 2; with the proviso that when R1 is 4-chlorophenyl, then R 4 is not 3-methoxyphenyl. 2. A compound according to Claim 1, wherein: R' is -422- or a naphthyl or saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the naphthyl, heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from R 5 R 6 and R 7 SR 2 is H, hydroxy, halo, CI.calkyl substituted by 0, 1 or 2 substituents selected from R 1 0 (CH 2 )n R 9 R R 6 R or a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from R 5 R 6 and R 7 and R 3 is H or CI- 4 alkyl. 3. A compound according to Claim 1, wherein R' is -423- 4. A compound according to Claim 3, wherein R 7 is independently, at each instance, C 2 9 alkyl or Ci-4haloalkyl. 5. A compound according to Claim 1, wherein R' is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from RS,.R 6 and R 7 6. A compound according to Claim 5, wherein R2 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from R 5 R 6 and R 7

7. A compound according to Claim 2, wherein R 2 is (CH 2 )n R 8 R R 7 or a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from R 5 R 6 and R 7

8. A compound according to Claim 7, wherein R 2 is -424-

9. A compound according to Claim 7, wherein R 2 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from R 5 R 6 and R 7 0 10. A compound according to Claim 2, wherein R' and R 2 together are

11. A compound according to Claim 2, wherein R' and R 3 together are 425

12. A compound according to Claim 2, wherein X and R 2together are =N-CH=CH-, or =C-NRa-.

13. A compound according to any one of Claims 2, 4, 5, 8 or 9, wherein: R 4 is R b is H, C 1 6 alkyl, -C(=O)CI- 6 alkyl, CI-6aky-O-Ra; and y 2 is -Na_ or

14. A compound according to any one of Claims 2, 4, 5, 8 or 9, wherein: .R 4 is 3 L 3 is a 2- or 3-atomn, saturated or unsaturated, bridge containing 1, 2 or 3 carbon atoms and 0 or 1 atoms independently selected from 0, N and S, wherein the each of the carbon atoms in the bridge is substituted by H, -ORa a, -C 1 6 alkyl, -NRaR a, -CI- 6 alkylNR aR a, -C(=O)OR a, -C(=0)NRaRa, -C 1 3 alkyIC(=O)ORa, -C 1 3 alkyIC(=0)NRaR', -OC(=0)C 1 6 alkyl, _NRaC(=0)C 1 _6alky1, -C 1 3 alkylOC(=0)C 1 6 alkyI or -C I- 3 alkyINRaC(=0)Cj- 6 alky1, and any nitrogen atoms in the bridge are substituted by H, -CI- 6 alkyl0R', -C 1 6 alkyl, -C 1 6 alkylNR aR', -C 1 3 alkylC(=0)OR a, -C 1 .jalkyIC(=O)NR aR', -C 1 3 alkyIOC(=O)C 1 6 a1 kyI, -I- 3 alkylNRad(=O)CI- 6 alkyl, -C(=0)Rc or -C 1 3 alkylRc; 426 R b is H, C 1 _6alkyl, -C(=0)C 1 6 ,alkyI, C,. 6 alky-O-R a and Y 2 is -NR b_ or A compound according to any one of Claims 2, 4, 5, 8 or 9, wherein: R~Rio R13 L3 is a 2- or 3-atom, saturated or unsaturated, bridge containing 1, 2 or 3 carbon atoms and 0, 1 or 2 atoms independently selected from 0, N and S, wherein the each of the carbon atoms in the bridge is substituted by H, -OR', 1 6 AIkyl0R a, -C 1 6 alkyI, -NRaR a, -C 6 a1 kyiNR a W, -C(=0)0R a, -C(=O)NR aR a -C 1 3 akylC(0O)OR -C 1 3 alkylC(=0)NRaR a, -OC(=0)C 1 6 a1kyl, -NR IaC(O)C 1 6 alkyl, -C 1 3 alkyIOC(=0)C,- 6 alkyl or -CI- 3 alkyINRaC(=O)C 1 6 alkyI, and any nitrogen atoms in the bridge are substituted by H, -CI- 6 alkyI0R', -C I-alkyI, -C 1 6 alkylNR R -C 1 3 alkyIC(=0)OR -C 1 3 alky]C(=0)NRaRa _CI 3 alkyOC(0)Ci. 6 alkyl, -C 1 3 a1 ky NR aC(=0)C 6 al kyl, -C(=O)Rc or -C 1 3 alkylRC;( R b is H, C 1 6 alkyl, -C(=0)C 1 -6alkyl, CI- 6 alkyl--R a; and y 2 is -NR b_ or

16.. A compound according to any one of Claims. 2, 4, 5, 8 or 9, wherein: R 4 is 427 L 3 is a 2- or 3-atom, saturated or unsaturated, bridge containing 1, 2 or 3 carbon atoms and 0, 1 or 2 atoms independently selected from 0, N and S, wherein the each of the carbon atoms in the bridge is substituted by H, -OR', 6alkylOR', -C 1 6 alkyl, -NRaRa, -C 1 4 alkylNRaR a, -C(=0)ORa, C(=0)NaRa 3 alkylC(=0)0R 3 3 a1 kylC(=O)NR aR', 6al kyl, -NR 2 .6alkyI, -C 1 3 alkyIOC(=0)C 1 6alkyl or -C 1 3 alkylNRaC(=O)CI. 6 alkyl, and any nitrogen atoms in the bridge are substituted by H, 6 alkyI0Ra 6 alkyl, -C 1 6 a1 kylNRaR a, 3 alkylC(=0)ORa, -C 1 3 a1 kylC(=0)NRaR', 3 a1 ky]OC(=O)CI-6al kyl, 3 alkyINRaC(=O)CI- 6 alkyl, -C(=O)Rc or 3 alkylRc; R bis H, C,. 6 alkyl, -C(=O)C 1 6 alkyl, C,-6aky1-0-Ra; and Y 2is -NR-bor

17. A compound according to any one of Claims 2, 4, 5, 8 or 9, wherein: R 4 is RR R13 R b is H, 6 alkyl, -C(=O)CI- 6 alkyl, C,. 6 alkyl-0-R 3 and y 2 is or

18. A compound according to any one of Claims 2, 4, 5, 8 or 9, wherein: R 4 is lO-membered bicyclic ring comprising fused 6-membered rings, containing 0, 1, 2, 3 or 4 N atoms with the remainder being carbon atoms, with at least one of the 6-membered rings being aromatic, wherein the carbon atoms are substituted by H, halo, ORa, NRaRa, C,. 6 alkyl and C,. 3 haloalkyl; and saturated carbon atoms may be additionally substituted by =0. 428

19. A compound according to any one of Claims 2, 4, 5, 8 or 9, wherein: R~Rio Rl R14 R12 R R3 R1 0 is independently, at each instance, H, ClIgalkyl,* -CI 3 alkylOR', C 1 4 haloalkyl, halo, nitro, cyano, 1 6 alkyl, -0-C 1 4 haloalkyl, -0- 1 6 alkylNRaRa, -0-C 1 6 a1 kylOR', -0-C,.6al kylC(-=0;)ORa -NRa, -NR a.C 1 4 haloalkyl, -NRa-C 1 4 salkyINRaR a, -N4R aC 1 6 alkyl0R', -C(=0)C 1 6 alkyl, -C(=0)0C 1 6aI kyl, -0C(=0)CI- 6 a1 kyl, -C(=0)NR'C 1 6 a1 kyl or -NR aC(=O)C, 6 alkyl; R" is independently, at each instance, H, Cl- 9 alkyl, -CI- 3 alky1ORa, C 1 4 haloalkyl, halo, nitro, cyano, 1 6 alkyl, -O-Cl~haloalkyl, -0-C 6 alky1NR-R a, -0-C 1 6alkylRc, -0-C 6 alkyloR2, -0-C 6 alkyIC(=0)0R a, -NR'aRa -NR aC 1 4 haloal kyl, -NR aC 1 -alkylNRaR', -NRa-C 1 oalkyloR2, 1 6 alky1, -C(=0)0C. 6 a1 kyl, -OC(=0)C 6 a1 kyl, -C(=0)NR aC 1 6 alkyl or -NRaC(=0)CI- 6 alkyl; C,. 6 a1 kyl NRaRa; R 12is independently, at each instance, H, Cl- 9 alkyl, -CI.. 3 alkyIOR', C 1 4 haloalkyl, halo, nitro, cyano, -OR a, 1 6alkyl, -0-C 1 4 haloalkyl, -0-C 1 6 alkylNRaRa, -0-C 6 a1 kylOR', -0-C 1 6al kylC(=0)OR -NRaR -NRa-C 1 4 haloalkyl, 4PNa..C 1 6 a1kyl NRaR', -NR'C 1 6 a1kylORa, -C(=0)C 1 6 a1kyl, -C(=0)0C 1 6 alkyl, -OC(=0)C 1 6 alkyl, -C(=0)NRaCl 16 alkyl or -NRC(0)CI-alkyl; R 3 is independently, at each instance, H, C 19 galkyl, -CI- 3 alkyI0R, C 1 4 haloal kyl, halo, nitro, cyano, 1 6 alkyI, -0-C 1 4 haloal kyl, -0-C 1 6 alkylNR aR', -0-C 1 6 a1 kylOR', -0-CI- 6 alkylC(=0)0R a, _,NRa Ra, -NR aC 1 haloal kyl, -NR aC 1 6 alkylNR aR', -NJR aCI 6 alkyIOR a, -C(=0)C 1 6 alkyl, 429 6 a1 kyl, -OC(=0)C 1 6alkyl, -C(=0)NR'C 1 ralkyl or -NRaC(=0)C 1 6 alkyl; and R' is independently, at each instance, H, Cl. 9 alkyJ, -CI. 3 alkyIORa CI- 4 haloalkyI, halo, nitro, cyano, 1 _alkyl, -0-C 1 4 haloalkyl, 0OC 1 6 alkylNRR', -o-c 6 alky]OR a, -0-C 1 _ialkylC(=0)0R a, -NRa.R', -NRa-C 1 4 haloalkyl, -N R-C .6a1 kyINRaR a, -NRa-C 1 6alky,0R a, -C(=0)C.-salkyl, -C(=0)0C 1 6 alkyI, -OC(=O)C 1 6 alkyI, -C(=0)NRaC 1 6alkyl or -NRaC(=0)CI- 6 alkyl; wherein one of R1 0 and R 1 2 is not H.

20. A compound according to any one of Claims: 2, 4, 5, 8 or 9,. wherein R 4 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, 0 and S, wherein no more than 2 of the ring members are 0 or wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents selected from halo, CI- 4 haloalkyl, -OR' and -NRaRa.

21. A compound having the structure: R9 H R R 4 or any pharmaceutically-acceptable salt thereof, wherein: n is independently, at each instance, 0, 1 or 2. R' is -430- or R' is a naphthyl substituted by 0, 1, 2 or 3 substituents independently selected from R 5 or R' is R' substituted by 1, 2 or 3 substituents independently selected from R 5 R' 5 is, independently, in each instance, R' 1 Cl.-alkyl substituted by 0, 1 or 2 substituents selected from R'O, -(CH 2 ),phenyl substituted by 0, 1, 2 or 3 substituents independently selected from or a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from R 1 0 R 16 is, independently, in each instance, H, halo, -NH 2 -NHC- 3 alkyl, 3 alkyl)CI. 3 alkyl or Ci.3alkyl; R 4 is 14 R 11 R1 ;or R 4 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the heterocycle and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from Ci. 9 alkyl, CI-4haloalkyl, halo, nitro, cyano, oxo, -ORd, -S(=0)nCI. alkyl, -OCi4haloalkyl, -OC2-6alkylNRdRd, -OC26alkylORd -OCI. 6 alkylC(=0)ORd, -NRdRd, -NRdCi4haloalkyl, -NRdC 2 -6alkylNRdRd, -NRdC 2 6 alkylORd, -C(=0)Ci. 6 alkyl, -C(=0)OCI. 6 alkyl, -OC(=O)Ci.6alkyl, -C(=0)NRdC,. 6 alkyl and -NRdC(=0)Cl_ 6 alkyl; and saturated carbon atoms may be additionally substituted by and any nitrogen atoms in the bridge are substituted by H, -C 1 alkylORd, -CI-6alkyl, -Ci 6 alkylNRdRd, -431- -C 3 alkylC(0O)OR d, -Ct. 3 alkyC(0O)NRRd -C 1 3 alkylOC(=O)CI- 6 alkyl, 3 alkylNR dC(=0)C 1. 6 alkyl, -C(=O)Rr or -C 1 3 alkylRf; or R 4 is 1O-membered bicyclic: ring comprising fused 6-membered rings, containing 0, 1, 2, 3 or 4 N atoms with the remainder being carbon atoms, with at least one of the 6-membered rings being aromatic, wherein the carbon atoms are substituted by H, halo, OR d, Ip~dRd' CI. 6 ,alkyl and C 1 3 haloalkyl; and saturated carbon atoms may be additionally substituted by but in no instance is R 4 ditrifluoromethyiphenyl or 3-trifluoromethyl-4-fluorophenyl; R 5 is independently, at each instance, H, C 1 .salkyl, C 1 4 haloalkyl, halo, nitro, cyano, -OCI. 6 alkyl, -OCt-4haloalkyl, -0C 2 6 alky]NRdRd -0C 2 6 alkylOR _NRd Rd, -NR dCl haloalkyl, -Rd C 2 -alky1lRd NR dC 26 alkyl0R d, naphthyl, -C0 2 (C 1 -6al kyl), 1 6 a~kyl), -C(=0)NRdR d, _NdCq=O)Rd, _PRdC(=0)NRd Rd, _NRdC0 2 (CI-6alkyl), -Ct-8alkyl0R d' -C 1 6 alky]NR dR d 1 6 a1kyl), -S 2 NRd R 2 (C 1 6 alkyl), -0C(=0)NR dR d, a phenyl ring substituted with 0, 1, 2, or 3 substituents independently selected from Rto0; or R 5 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from 0, N and S, substituted with 0, 1, 2, or 3 substituents independently selected from RIO; R 6is independently, at each instance, H, C 1 5 alkyl, Ct- 4 haloalkyl, halo, -oct 6 alkyl, -OCt 4 haloalkyl, -OC 2 6 alkylNR dR d, -0C 2 6 a1 kyl OR d, -PNRd Rd, -NR dCI -haloalkyl, -NR C 26 alkyl NRd R dor -NR dC 2 -6alkylOR d, _C tsalkyl0R.d, -CI-6alkylNR dR d, -S(Ct-6alkyl), a phenyl ring substituted with 1, 2, or 3 substituents independently selected foRI; or R 6is a saturated or unsaturated or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from 0, N and S substituted with 0, 1, 2, or 3 substituents independently selected from RtO; R 7 is independently, at each instance, H, Cts8alkyl, Ct- 4 haloalkyl, halo, -0CI. 6 alkyl, -OCg 4 haloalkyl, -0C 26 alkyNRdR -0C 2 6 alkyIORd _d R d' NpdC, 1 4 haloal kyl, -NRpd C 26 al kylNRd Rd, _NRd C 2 6al kyloR d, -CI. 8 alkylOR d, -C 1 -6alkylNR dR dor -S(C 1 6 alkyl); or R 7is a saturated or unsaturated 4- or 5-membered ring heterocycle containing a single nitrogen atom, wherein the ring is substituted with 0, 1 or 2 substituents independent]ly selected from halo, C 1 2 haloalkyl and C I 3 alkyl; 432 R 8 is independently, at each instance, H, C 1 5 alkyl, C 1 4 haloalkyl, halo, -OCI-6alkyl, -0CI. 4 haloalkyl, -OC 2 6 alkylNRd R d -OC 2 _6alkylOR d, _NRdR d, -NR dC 1 -haloalkyl, ,NdC-ak]RRd -NR dC 2 6 alkyIOR d, -C 1 salkylOR d, -CialkylNRd Rd, -S(C 1 I-alkyl), a phenyl ring substituted with 2, or 3 substituents independently selected from R10, or R 8is a saturated or unsaturated or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from 0, N and S substituted with 0, 1, 2, or 3 substituents independently selected from R1 0 R 9 is independently, at each instance, H, C 1 8 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -OCI 1 6 alkyl, -OC14haloalkyl, -0C 2 aialkylNR R -OC 2 6 alkyl0R d, .NR'd -NR dC' 4 haloalkyl, -NR dC 2 6 alkylNR dR.d or( _NRPd C 2 -al kylOR d' -C0 2 (CI-6alkyl), 1 6alkyI), -C(=o)NRpd R.d' -NR dC(=0)(C 1 -6alkyl), -NR dC(=O)NRd R d _N..RdC0 2 (CI 6al kyJ);, -C 1 8 alkylOR -C 16 a1 kylNR td 6 alkyl), 2 NR R, _NRdS(=o) 2 (CI- 6 alkyl), -0C(=0)NR dR d, a phenyl ring substituted with 0, 1, 2, or 3 substituents independently selected from R1 0 or R 9 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from 0, N and S substituted with 0, 1, 2, or 3 substituents independently selected from R1 0 of R 9 is a saturated or unsaturated 4- or ring heterocycle containing a single nitrogen atom, wherein the ring is substituted with 0, 1 or 2 substituents independently selected from halo, C 1 2 haloalkyl and C 1 I. 3 alkyl; wherein at least one of R 5 R. 6 R 7 R 8and R 9 is C 1 8 alkyl, C 1 -4haloalkyl, halo, -0CI. 4 haloalkyl, -OC 2 -6alkylNR dR.d' -0C 2 6 al kyloR d, -NR dC 1 4 haloalkyl, -Nd C 2 .6alkylNR dR d, -NR C 2 6 alkylOR d, C-aky .d -C 1 6 alkylNRd Rd or -S(Cus6alkyl); R.1 0 is independently, at each instance, selected from H, CI.Salkyl, C 1 4haloalkyl, halo, cyano, nitro, 1 .salkyl), ,gal kyl), -C(=NRdNd OR -O (=0)(CI-8al kyl), -OC(=O)NR Rd -OC(=O)N(R d)S(=O) 2 8 alkyl), -0C 2 6 alkylNR dR d, -OC 2 6 al]kylOR d, -SRd 1 galkyl), .s(I~alkyl), 2 NRd R d. -S 2 N(R 1 -8al kyl), -S 2 N(R d)C(=0)O(C 1 .8alkyl), 2 N(R d)C(=O)NR dR d, -NR dR d, -N(R 1.8alkyl), -433- -N(R )C(=O)O(C 1 8 galkyl), -N(R d)C(=0)NR -N(Rd)C(=NRd)NRd Rd, _n d)S 2 (C 1 8 alkyl), -N(R d)S(=O) 2 NRd R d, -NRd C 2 6 alkylNR dR d and -NR C 2 -6alkylORd; or R1 0 is a saturated or unsaturated 6- or 7-membered monocyclic or 10- or IlI-membered bicyclic ring containing 1, 2 or 3 atoms selected from N, 0 and S, wherein the ring is fused with 0 or 1 benzo groups and 0 or I saturated or unsaturated 6- or 7-membered heterocyclic ring containing 1, 2 or 3 atoms selected from N, 0 and S; wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 groups selected from CI-8alkyl, C 1 -4haloalkyl, halo, cyano, nitro, 1 8 alkyl), -C(=O)O(C 1 .sa~kyl), -C(=O)NRdRd, -C(=NRd)4R dRd, OR', -O.C(=O)(Cjs8alkyl), -OC(=O)NR dR d, -OC(=O)N(R d)S(=O) 2 (C 1 8 alkyl), -OC 2 .6alkylNRd Rd, -0C 24 salkylOR d, -SR d, 1 8 alkyI), 2 (C 1 .salkyl), -S(=O)zNRd R d, 2 N(R 1 8 a1 kyl), -S 2 N(R d)C(=O)O(C 1 8 alkyl), ~S(O)N(d)C(=0)NRd d, _NRd d, N(d)C(=O)(C 1 gly) -N(R d)C(=O)O(C 1 .a1 kyl), -N(R d )C(=O)NR dR d, N(R d)C(=NR d)NR dR d, -N(R d)S(=O) 2 (Ct-8al kyl), -N(R d)S(=O) 2 NR dR 7N~dC 2 6 a1 kylNRd Rd and -NR dC 2 6a.kylOR d; or Ri is C 1 4 alkyl substituted by 0, 1, 2 or 3 groups selected from C 1 4 haloalkyl, halo, cyano, nitro, 1 8 alkyl), -C(=O)O(C 1 8 alkyl), -C(=O)NR dR d, -C(=NR d)NR dR d, -OR d, -OC(=O)(C 1 8 alkyl), -QC(=O)NR dR d, -OC(=O)N(R d)S(=O) 2 (CI-&alkyl), -OC 2 6 alkylNRd Rd, -OC 2 .6alkylOR d, -SRd. d d 2 N(R 1 8 a1 kyl), 2 N(R 1-alkyl), -NR dR d, -N(R d)C(=O)(Cis-alkyl), -N(R d)C(=O)O(C salkyl), -N(R d)C(=O)NR dR d, -N(R )C(=NR )NRd Rd, 2 (CI-8alkyl), -N(R d)S(=O),NR R d, -NR C 2 _6alkyINR dR d and -NR d CalkylOR d; R" is independently, at each instance, selected from H, CI-8alkyl, C 1 4 haloalkyl, halo, cyano, nitro, 1 .salkyl), -C(=O)O(CI-Salkyl), -C(=O)NRdR d, -C(=NR d)NRd Rd, -OR d, -OC(=O)(C 1 8 alkyl), -OC(=O)NR dR d, -OC(=O)N(R d)S 2 (Cts8alkyl), -OC 2 6 alkylNR dR d, -OC 2 6 alkyIOR d, -SR d 1 salkyl), 2 (CI-8alkyl), 2 NRd Rd, 2 N(R 1 _8alkyl), 2 N(R d)C(=O)O(C 1 -8alkyi), 434 2 N(Rd)C(=O)NRdR d, -NR dR d, 1 -galkyl), -N(R d)C(=O)O(C -galkyl), -N(Rd)C(=O)NR dR d, -N(R d)C(=NR d)NR dRd, -N(R d)S(=O) 2 8 a1 kyl), -N(R d)S(=O) 2 NR dR d, NRd C 2 6 al kylINR dR d and -NR dC 2 _alkyIORd; or R" is a saturated or unsaturated 6- or 7-membered monocyclic or 10- or I 1-membered bicyclic ring containing 1, 2 or 3 atoms selected from N, 0 and S, wherein the ring is fused with 0 or 1 benzo groups and 0 or 1 saturated or unsaturated 6- or 7-membered heterocyclic ring containing 1, 2 or 3 atoms selected from N, 0 and S; wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 groups selected from C 1 8 alkyl, C 1 4 haloalkyl, halo, cyano, nitro,( 18 a1 kyl), -C(=O)0(C 1 salkyl), -C(=0)NRdRd, .Cpd)NRd~ R d -OC(=O)(CI- 8 alkyl), -OC(=0)NR dR d, -0C(=O)N(R d)S(=O) 2 (C 1 8 a1 kyl),. -0C 2 6 alkyINRd R d -0C 2 _6a1kylOR d, -SR d' -S(=O)(Ct-8alkyl), -S 2 (C 1 salkyl), -S 2 NRd R d 2 N(R 1 8 a1 kyl), 2 N(R d)C(=O)O(C 1 salkyl), 2 N(R d)C(=0)NR dR d, -NRdR d' -N(R 1-alkyl), -N(R d)C(=0)O(C 1 8 a1 kyl), -N(R d)C(=0)NR dR d, N(R d)C(=NR d)NRd R d -N(R d)S(=0) 2 (C 1 .8alkyl), 2 NR dR d, _NdC 26 al kylNR dR d and -NR d C2alkylOR d; or R" is C 14 alkyl substituted by 0, 1, 2'or 3 groups selected from C 1 4 haloalkyl, halo, cyano, nitro, 1 .salkyl), -C(=0)O(C 1 8 alkyl), -C(=0)NR dR d, -C(=NR d)NRd R d I OR d, 8 alkyl), -OC(=O)NR dR d, -0C(=0)N(R d)S(=0) 2 (CI- 8 alkyl), -OC 2 6 alkylNR dR. d, -0C 2 6 alkyJOR d, -SRd, -S(=O)(CI-8alkyl), 2 (C 1 8 alkyl), 2 NRd Rd' 2 N(Rd)C(=O)(C 1 8 al kyl), 2 N(R 8 alkyl), -S 2 N(Rd )C(=0)NR dR d, .NR~dR d -N(R 1 .alkyl), -N(R d)C(=0)0(C -8alky1), -N(R d)C(=0)NRd R d N(R d)NRd Rd -N(R d)S(=O) 2 (C 1 .salkyl), -N(R d)S 2 NR dR d, _Nkd C 26 al kyINTRd R d and -NR dC 2 6 alkyJOR d; or R1 and R" together are a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the each of the carbon atoms in the bridge is substituted by H, Cl-galkyl, C 1 4 haloalkyl, halo, cyano, nitro, 8 alkyl), -C(=O)0(C 1 salkyl), -C(=0)NR R ~Cz~ )NR R, -ORd .salkyl), -435- -OC(=O)NRdR', -OC(=O)N(Rd)S(=O) 2 (C 1 .8alkyl), -0C 2 6 alkylNR dRd -OC 2 6 alkylORd, -SR 1 8 a1 kyl), -S 2 (C 1 8 alkyl), 2 NR Rd, 2 N(R d)C(0O)(C 1 -alkyl), 2 N(R d)C(=O)O(C 1 8 a1 kyl), 2 N(Rd)C(=O)NRd R d, -NR dR d, -N(R d)C(=O)(Cl -alkyl), -N(Rd)C(=O)O(C -galkyl), -N(R d)C(=O)NRd R d -N(R d)C(=NR)NR dR d -N(Rd)S(=Q) 2 (CI-8alkyl), -N(Rd)S(=O0) 2 NRd R.d, -NRdC 2 6 alkylNR dR dand -NR dC 2 6 alkylOR.d and any nitrogen atoms in the bridge are substituted by H, -C 1 6 alkylORd, -C 1 6 alkyl, -CI -ialkyINR R -CI- 3 alkylC(=O)ORd -C 1 3 alkylC(=O)NRd R d, -CI- 3 alkylOC(=O)Cj_6alkyl, -C 1 3 alkylNR dC(=O)Ci 6alkyl, -C(=O)Rf or-C 1 3 alkylRf; R 1 2 is independently, at each instance, selected from H, C 1 .salkyl, C 14 haloalkyI, halo, cyano, nitro, 1 .gakyl), -C(=O)O(C 1 8 alkyl), -C(=O)NRd R. d, C(=NR d)NR dR d, -OR -OC(=O)(Cl.8alkyl), -OC(=O)NR dRd, d d 2 Calkyl), -WOC 2 I-al lkyl(0NR R ,-O 2 akORSR CkIS(=O) 2 (aly) dS=)CNOdOd, -S 2 1 8 alkyl), 2 N(R. )C=)OC-galkyl), 2 N(R d)C(=O)NR dR d, -NR R d, igal~kyl), -N(Rd)C(=O)O(C 1-alkyI), -N(R d)C(=O)NR dR.d -N(Rd)C(=R )NR dRd -N(R d)S(=O) 2 8 alkyl), -N(R d)S(=O) 2 NRd R d -N'26lyN and -NR dC 2 ,alkylOR d; or R.1 is a saturated or unsaturated 6- or 7-membered monocyclic or 10- or 1 1-membered bicyclic ring containing 1, 2 or 3 atoms selected from N, 0 and S, wherein the ring is fused with 0 or I benzo groups and 0 or I saturated or unsaturated 6- or 7-membered heterocyclic ring containing 1, 2 or 3 atoms selected from N, 0 and S; wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 groups selected from C 1 e8alkyl, C,- 4 haloalkyl, halo, cyano, nitro, 1 8 alkyI), -C(=O)O(C 1 8 alkyI), -C(=O)NRdR -C(=NR )NR. Rd, -OR -OC(=O)(CI-8alkyl), -OC(=O)NR R d, -OC(=O)N(Rd)S(=O) 2 (C 1 .salkyl), -OC 26 alkylNR dR d' -OC 2 6 alkylOR d' -SRW' 1 8 alkyl),.-S(=O) 2 (C 1 aikyl), 2 NR dR d, 2 N(R 1-8alkyl), 2 N(R d)(=O)O(Cl -alkyl), -S 2 N(R d)C(=O)Nkd R d -NR dR d, -N(R 1 8 a1 kyl), -N(R d)C(=O)O(Cis-alkyl), -N(R d)C(=Q?)NRd R d, -N(R d)C (=NR d)NRd Rd 436 -N(R d)S(=O) 2 (C 1 8 alkyl), -N(R d)S(=O) 2 NRdR d, _N~d C 26 alkylN pd R d and -NR dC 2 _6alky1OR d; or R 12is C 1 -4alkyl substituted by 0, 1, 2 or 3 groups selected from C 1 -4haloalky1, halo, cyano, nitro, -C(=O)(CI-8alkyl), -C(=O)O(CI-8alkyl), -C(=O)NR dR d, -C(=NR d)NRd Rd, -OR d, 1 8 alkyl), -OC(=O)NR dR d, -OC(=O)N(R d)S 2 (C 1 .salkyl), -OC 2 asalkylNRd Rd, -OC 2 .6alkylOR d, -SR d, 1 salkyl), -S 2 (CI-8alkyl), 2 NRdRd, 2 N(Rd)C(=O)(C 1-8alkyl), -S 2 N(R d)C(=O)O(C 1 8 alkyl), 2 N(R d)C(=O)NRd Rd, _NRdRd, -N(R 1-8alkyl), -N(R d)C(=OD)O(C I -al kyI), -N(Rd)C(=O)NRd Rd, -N(Rd)C(=NRd )NR dR d, -N(R d)S(=O) 2 (CI..galkyI), -N(R d)S(=O) 2 NRd Rd, _NdC-akyN and( -NR dC 2 -6alkylOR d; wherein if R" or R'1 3 is CF 3 then R 1 2 is not F; or R" and R 1 2 together are a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the each of the carbon atoms in the bridge is substituted by H, Clalkyl, CI- 4 haloalkyI, halo, cyano, nitro, 1 8 alkyl), -C(=O)O(Cj_8alkyI), -C(=O)NRd Rd, dd d d _Ndd -C(=NR )NR -OC 1 8 alkyl), -(ON R, -OC(=O)N(R d)SQO0) 2 (C ,..alkyl), -OC 2 6 alky]NR dR d, -OC 2 6 alkyIOR d, -SR", d d 1 .salkyI), 2 (C 1 salkyI), 2 NR R -S 1-alkyl), -S 2 N(R d)C(=O)O(C 1 .galkyl),. 2 N(Rd)C(=O)NR Rd -8dd~(d)(O(ialkyl),( -N(R d)C(=O)O(Ci -galkyl), -N(R d)C(=O)NR dR d, N(R d)C(=NR d)NRdRd, -N(R d)S(=O) 2 (Cigalkyl), -N(R d)S(=O) 2 NRd R d, -NR dC 24 ialkyINR dR d and -NR dC 2 _6alkylOR d, and any nitrogen atoms in the bridge are substituted by H, 6 alky1OR -C 1 6 alkyl, -CI- 6 alkylNR R -CI- 3 alkyIC(=O)ORd -C 1 3 alkylC(0O)NR Rd, -C j. 3 alkylOC(=-O)C 1 6 alkyI, -C 1 3 alkylNR dC(=O)Ct-6alkyl, for -C 1 3 alkyIR C; R 1 3 i s independently, at each instance, selected from H, Cl-galkyl, CI- 4 haloalkyl, halo, cyano, nitro, 1 salkyl), -C(=O)O(C 1 .galkyI), _C(=O)NRd Rd, -C(=NR d)NRdR d7 -OR d 70C(=O)(Cj_8al kyl), -OC(=O)NR dR d, 2 (C 1 .gaI kyl), -0C 2 6 aIk yNRd -OC 2 6 alkylORd -SR., 1 8 alkyl), 2 (C 1 8 alkyl), 2 NR R d, 437 -S 2 N(Rd)C(=O)O(Ci -8alkyl), 2 N(R d)C(-O)NR dR', Nd d, -N(R i.galky1), -N(R )C(=O)O(C 1 8 alkyl), -N(R d)C(=O)NRd R d -N(R d)C(=NRd)NRdRd, -N(Rd)S(=0) 2 (CI-8alkyI), -N(R d)S(=0) 2 NR R d, -NRd C 2 6 alky]NR dR. and -NRC 2 _6alky1OR ;or R is a saturated or unsaturated 6- or 7-membered monocyclic or 10- or 1 1-membered bicyclic ring containing 1, 2 or 3 atoms selected from N, 0 and S, wherein the ring is fused with 0 or I benzo C) groups and 0 or I saturated or unsaturated 6- or 7-membered heterocyclic ring containing 1, 2 or 3 atoms selected from N, 0 and S; wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 groups selected from Cl-galkyl, C 1 4 haloalkyl, halo, cyano, nitro, 1 .galkyl), -C(=O)O(Cj 18 alkyl), -C(=O)NRdR d, _C(=NRd )NR dR d, -ORd -OC(=O)(C 1 salkyI), -OC(=O)NR dR', -OC(=O)N(Rd)S 1 alkyl), -OC 2 6 alkyINR dR d, -OC 245 alkylOR d, -SR d, -S(=O)(C,.salkyl), 2 (C 1 .salkyl), 2 NR dR. d, S(=O) 2 N(R d)C(=O)(Ci -a1 kyl), 2 N(R d)C(=O)O(C 1 .8alkyl), 2 N(R d)C(=O)NRd R. d, -NR R d, N(R 1-8alkyl), -N(Rd)C(=O)O(Ci -8alkyl), -N(R d)C(=O)NRd R d, -N(R d)C(=NR d)NR dRd -N(R d)S(=0Oh(Cls8alkyl), .N(R d)S(=O) 2 NR d Rd _d C 26 alkyNR d Rd and -NR dC 2 _6alkylOR d; or R 13is C 1 4 alkyI substituted by 0, 1, 2 or 3 groups selected from C 14 haloalkyI, halo, cyano, nitro, 1 .galkyl), -C(=O)O(C 1 salkyl), _C(=O)NRd R d _C(=Nd)NdRd -OR d, 8 a1 kyl), -OC(=O)NR dR d, -OC(0O)N(R d)S(=O) 2 8 alkyl), -0C 2 6 alkylNR dR d, -0C 2 6 alkylOR d, -SRd d -S(=O)(CI-8alkyl), 2 (Cl.8alkyl), 2 NRR 2 N(Rd)C(=O)(C 1 8 a1 kyl), -S 2 N(R .galkyl 2 N(R .4pNRd 1 -8al kyl), -N(R d)C(=O)O(C 1 8 alkyl), -N(R d)C(=O)NRd R d, -N(R d)C(=NR d)NR dRd -N(R d)S(=O) 2 (C 1 8 alkyl), -N(R d)S 2 NRd R, dNRd C 2 -al kylNR dR d and R 1 4 is independently, at each instance, selected from H, C1. 8 alkyl, C 1 4 haloalkyl, halo, cyano, nitro, 1 .8alkyl), 1 .galkyl), 2 (C 1 8 alkyl), -0C 2 6 alkylNR R. -OC 2 6 alkylOR -SR., -438- .salkyl), 2 (C 1 .salkyl), 2 NRdR', -S 2 N(R 8 a1 kyl), 2 N(R d)C(=O)O(Ci -8alkyl), 2 N(Rd)C(=O)NRd -NR R d, -N(R 1.8alkyl), -N(R d)C(=O)O(C 1- 8 alkyl), -N(R d)C(=O)NR dR -N(R d)C(=NRd)NRd Rd, -N(Rd)S(=O) 2 (C 1 8 alkyl), -N(R d)S(=O) 2 NR dRd NRd C 26 alkylNR dR dand -NR dC 2 .cialkylOR d; or R'1 4 is a saturated or unsaturated 6- or 7-membered monocyclic or 10- or 11 -membered bicyclic ring containing 1, 2 or 3 atoms selected from N, 0 and S, wherein the ring is fused with 0 or I benzo groups and 0 or I saturated or unsaturated 6- or 7-membered heterocyclic ring containing 1, 2 or 3 atoms selected from N, 0 and S; wherein the carbon atoms of( the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 groups selected from C,- 8 alkyl, C 1 4 haloalkyl, halo, cyano, nitro, 1 .gaIkyl), -C(=0)O(C 1 8 alkyl), -C(=O)NR dR d' -C(=NRd)NRd R d -OR d, -OC(=0)(C 1 8 a1 kyl), -0C(=O)NR dR d, 0C0N(d)S(=0) 2 (Ci 8 alkyl), -0C,,alkylNRd R d, -OC 243 alkylOR d, -SR d, 1 8 alkyI), 2 (C 1 .salkyl), -S 2 NR dR d, 2 N(R d)C(=O)(Ci 8 a1 kyl), 2 N(R d)C(=O)0(C 8 alkyI), 2 (d)C(=O)NRdR ~N d' N(d)C(=0)(Cilky) dd=)2( d dddR-NR-aly) -N(R d)C(=0)O(C 1. 8 alkyl), -N(R d)C(=O)NRd R d, -N(R d)C(=NR d)NR dRd -N(R d)S(=O) 2 (CI-8alkyl), -N(R d)S(=O) 2 NR dR d, -NR C 26 alkylNR dR dand _N~d C 2 6alkyl0R d; or R 1 4 is C 1 4 alkyI substituted by 0, 1, 2 or 3 groups selected from C 1 4 haloalkyl, halo, cyano, nitro, -C(=O)(Cj.galkyl), -C(=0)O(CI-8alkyl),( -C(=O)NR dR d, -C(=NR d)NR dR d 70R d' -OC(=O)(CI-8alkyl), -OC(=O)NR dR, -0C(=0)N(R d)S(=0) 2 1 8 alkyl), -0C 2 6 alkylNR dR d, -OC 2 sal kylOR d, -SR d' d d -S 1 8 al kyl), 2 (C 1 *gal kyl), -S 2 NR R -S 2 N(R 1 8 alkyI), -s 2 N(R d)C(=0)0(C I 8 alkyl), 2 N(R d)C(=O)NRd R d _d R d -N(R )C(=0)(Cis -alkyl), -N(R d)C(=O)0(C 18 alkyl), -N(R d)C(=O)NRd R'd, -N(R d)C(=NR d)NR dRd -N(R d)S(=0) 2 (C 1 8 a1 kyl), -N(R d)S(=O) 2 NRd Rd, _NdC-akyN and -NR d CalkylORd R d is independently, at each instance, H, phenyl, benzyl or C 1 6 alkyl; R' is a heterocycle selected from the group ofthiophene, pyrrole, 1 ,3-oxazole, I ,3-thiazole,. I,3,4-oxadiazole, 1,3 ,4-thiadi azole, I,2 ,3-oxadi azole, -439- I ,2,3-thiadiazole, 1 H- 1,2,3-triazole, isothiazole, 1 ,2,4-oxadiazole, 1,2,4- thiadiazole, 1,2,3 ,4-oxatriazole, I ,2,3,4-thiatriazole, IH-1 ,2,3,4-tetraazole, I ,2,3,5-oxatriazole, 1 ,2,3,5-thiatriazole, furan, imidazol- l-yi, imidazol-4-yl, 1,2,4- triazol-4-yl, 1 ,2,4-triazol-5-yl, isoxazol-3-yI, isoxazol-5-yi, pyrazol-3-yl, pyrazol- 5-yI, thiol are, pyrrolidine, tetrahydrofuran, 4,5 -di hydrothiophene, 2-pyrroline, pyridazine, pyrimidine, pyrazine, 1 ,2,3-triazine, 1 ,2,4-triazine, 1,2,4-triazine, 1,3,5-tfiazine, pyridine, 2H-3,4,5,6-tetrahydropyran, thiane, 1,2- di azaperhydroine, 1 ,3-diazaperhydroine, piperazine, 1,3-ox azaperh ydroine, -morpholi ne, I ,3-thiazaperhydroine, I ,4-thi azaperhydroi ne, piperidine, 2H-3 ,4- di hydropyran, 2,3-di hydro-4H-thiin, I ,4,5,6-tetrahydropyridine, 2H-5 ,6- di hydropyran, 2,3-dihydro-6H-thiin, I ,2,5,6-tetrahydropyridine, 3,4,5,6-, tetrahydropyridine, 4H-pyran, 4H-thiin, I ,4-dihydropyridine, 1 ,4-di thi ane, 1,4- dioxane, I ,4-oxathiane, 1 ,2-oxazolidine, 1 ,2-thiazolidine, pyrazolidine, 1,3- oxazolidine, 1 ,3-thiazolidine, imidazolidine, 1 ,2,4-oxadiazolidine, 1,3,4- oxadiazolidine, 1 ,2,4-thiadiazolidine, 1,3 ,4-thiadiazolidine, 1 ,2,4-triazolidine, 2- imidazoline, 3-imidazoline, 2-pyrazoline, 4-imidazoline, 2,3-dihydroisothi azole, sox azole, 4,5-dihydroisothiazole, 2,5-dihydroisoxazole, dihydroisothiazole, 2,3-dihydroisoxazole, 4,5.-di hydrooxazole, 2,3- di hydrooxazole, 2,5-dihydrooxazole, 4,5-dihydrothiazole, 2,3 -dihydrothiazole,, 2,5-dihydrothiazole, 1,3 ,4-oxathiazolidine, 1 ,4,2-oxathiazolidine, 2,3-dihydro- 1H- [1 ,2,3]triazole, 2,5-dihydro- 1H- 1 ,2,3]triazole, 4,5-di hydro- 1H-[1 ,2,3]triazole, 2,3-dihydro- IH-[ 1,2,4]tri azole, 4,5-dihydro- IH-[ 1,2,4]triazole, 2,3-dihydro- [1 ,2,4]oxadiazole, 2,5-dihydro-[1I,2,4]oxadiazole, 4,5-dihydro-[ 1,2,4]thiadiazole, 2,3-dihydro-[ 1,2,4] thidiazole, 2,5-dihydro-[ 1,2,41 thiadiazole, 4,5-dihydro-[ 1,2,4] thiadiazole, 2,5-dihydro-[ 1,2,4]oxadiazole, 2,3-dihydro-[1I,2,4]oxadiazole, dihydro-[1,2,4]oxadiazole, 2,5-dihydro-[1 ,2,4]thiadiazole, 2,3-dihydro-I1,2,41 thiadiazole, 4,5-di hydro-[ 1,2,4] thiadiazole, 2,3-dihydro-[ I,3,4]oxadiazole, 2,3- dihydro-[1I,3,4]thiadiazole, [1i,4,2]oxathiazole, [1 ,3,4]oxathi azole, 1,3,5- tiiazaperh ydroine, I ,2,4-tiiazaperhydroine, I ,4,2-dithiazaperhydroine, 1,4,2- dioxazaperhydroine, 1 ,3,5-oxadiazaperhydroine, I 1 ,3,4-thiadiazaperhydroine, 1 ,3,5-thiadiazaperhydroine, 1,2,5- thiadi azaperh ydroine, 1,3 ,4-oxadi azaperhydroi ne, 1 ,4,3-oxathi azaperhydroi ne, 440 1 ,4,2-oxathiazaperhydroine, 1 ,4,5,6-tetrahydropyridazi ne, 1,2,3,4- tetrahydropyridazine, 1,2,3 ,6-tetrah ydropyridazi ne, 1,2,5 ,6-tetrah ydropyri mi dine, I ,2,3,4-tetrahydropyri midine, 1 ,4,5,6-tetrah ydropyrimidine, 1,2,3,6- tetrahydropyrazi ne, I ,2,3,4-tetrahydropyrazine, 5 ,6-dihydro-4H-[ I ,2]oxazine, 5,6- dihydro-2H-[1I,2]oxazine, 3 ,6-di hydro-2H-[ 1,2]oxazine, 3 ,4-dihydro-2H- [1 ,2]oxazine, 5,6-dihydro.-4H-[ 1,2]thiazine, 5,6-dihydro-2H-[ 1,21 thiazine, 3,6- N1 dihyd'ro-2H-[ 1,2] thiazine, 3,4-dihydro-2H-[ 1,2] thiazine, 5,6-dihydro-2H- [1 ,3]oxazine, 5,6-dihydro-4H-[ 1,3]oxazine, 3,6-dihydro-2H-[ 1,31oxazine, 3,4- ri dihydro-2H-[ 1,3]oxazine, 3,6-dihydro-2H-[1I,4]oxazine, 3,4-dihydro-2H- [1 ,4]oxazine, 5,6-dihydro-2H-[1I 3]thiazine, 5,6-dihydro-4H-[ I [,3]thiazine, 3,6-( di hydro-2H-[1I,3]thiazine, 3 ,4-dihydro-21-[ 1,3]thiazine, 3 ;6-dihydro-2H- [1 ,4]thiazine, 3,4-dihydro-2H-[ 1 -thiazine, I ,2,3,6-tetrahiydro-[ 1,2,4]triazine, 1 ,2,3,4-tetrahydro-[ 1,2,4]triazine, I ,2,3,4-tetrahydro-[1 ,3 ,5]triazine, 2,3,4,5-, tetrahydro-l I,2,4]triazine, I ,4,5,6-tetrahydro-[1I,2,4]triazine, 5,6-dihydro- [1 ,4,2]dioxazine, 5,6-dihydro-[1I,4,2]dioxazine, 5,6-dihydro-[1I,4,2]dithiaziie, 2,3- dihydro- [1 ,4,2]dioxazine, 3 ,4-dihydro-2H-[ 1,3,4]oxadi azine, 3 ,6-di hydro-2H- [1 ,3,4]oxadiazine, 3,4-dihydro-2H-[ 1,3,5]oxadiazine, 3,6-dihydro-211- [1 ,3,5]oxadiazine, 5 ,6-dihydro-2H-[1I,2,5]oxadiazine, 5,6-dihydro-4H- [1 ,2,5]oxadiazine, 3,4-dihydro-2H-[ 1,3,4]thi adiazine, 3,6-dihydro-2H- [1 ,3,4]thiadiazine, 3,4-dihydro-2H-[ 1,3,5lthiadiazine, 3 ,6-dihydro-2H- [1 ,3,5]thiadiazine, 5,6-dihydro-2H-[1I,2,5]thiadiazine, 5,6-dihydro-4H-( [1 ,2,5]thiadiazine, 5,6-dihydro-2H-[ 1,2,3]oxadi azine, 3 ,6-dihydro-2H- [1 ,2,5]ox adiazi ne, 5 ,6-dihydro-4H-[ 1,3,4]oxadi azine, 3 ,4-di hydro-2H- oxadiazine, 5 ,6-dihydro-2H-[ 1,2,3]thi adi azi ne, 3 ,6-dihydro-2H- [1 ,2,5]thiadiazine, 5 ,6-dihydro-4H-[1I,3,4]thiadiazine, 3,4-dihydro-2H- [1 ,2,5]thiadiazine, 5,6-dihydro-[1I,4,3]oxathiazine, 5,6'dihydro-[1 ,4,2]oxathiazine, 2,3-dihydro- 1 ,4,3]oxathiazine, 2,3-dihydro-[ 1,4,2]oxathiazine, dihydropyri dine, 1 ,6-dihydropyridine, 5,6-'dihydropyridi ne, 2H-pyran,* 2H-thiin, 3,6-dihydropyridine, 2,3-dihydropyridazine, 2,5-di hydropyridazine, dihydropyridazine, 1 ,2-dihydropyridazine, 2,3-di hydropyrimidi ne, dihydropyri midine, 5,6-dihydropyrimidine, 3,6-dihydropyrimidine, di hydropyrazine, 5,6-di hydropyrazine, 3,6-dihydropyrazi ne, 4,5- di hydropyrazine, -441- I ,4-dihydropyrazine, I ,4-dithiin, 1,4-dioxin, 2H-1I,2-oxazine, 611-1 ,2-oxazine, 411- 1 ,2-oxazine, 2H-1I,3-oxazine, 4H-1I,3-oxazine, 611-71,3-oxazine, 211-1 ,4-oxazine, 4H-1I,4-oxazine, 2H- 1,3-thiazine, 2H- 1,4-thiazine, 4H- 1,2-thiazine, 611-1,3- thiazine, 4H-1I,4-thiazine, 2H- 1,2-thiazine, 611-1 ,2-thiazine, I ,4-oxathiin, 211,511- 1 ,2,3-triazine, IH,4H-1I,2,3-triazine, 4,5-dihydro- 1,2,3-triazine, 1H,6H- 1,2,3- triazine, 1 ,2-dihydro- 1,2,3-triazine, 2,3-dihydro-1I,2,4-triazine, 3H,6H- 1,2,4- triazine, 1 H,6H- 1,2,4-tn azi ne, 3,4-dihydro- 1,2,4-triazine, 1 1,4H-1I,2,4-triazine, ,6-dihydro-1I,2,4-triazine, 4,5-dihydro-1I,2,4-triazine, 211,51-1 ,2,4-triazine, 1,2- dihydro- 1,2,4-triazine, 1H,41I,3,5-triazine, I ,2-dihydro- 1,3 ,5-triazine, 1,4,2- dithiazine, 1 ,4,2-dioxazine, 211-1 ,3,4-oxadiazine, 211-1 ,3,5-oxadiazine, 611-1,2,5- oxadi azine, 4H- 1,3 ,4-oxadiazine, 411-1,3,5 -oxadi azine, 411-1 ,2,5-oxadiazi ne, 211- I ,3,5-thiadiazine, 611-1 ,2,5-thiadiazine, 4H-1I,3,4-thiadiazine, 411-1,3,5- thiadi azine, 411-1 ,2,5-thiadiazine, 211-1 ,3,4-thiadiazine, 611-1,3 ,4-thiadiazine, 611- 1,3,4-oxadiazine and 1,4,2-oxathiazine, wherein the heterocycle is optionally vicinally fused with a saturated or unsaturated 6- or 7-membered ring containing 0, 1 or 2 atoms independently selected from N, 0 and S; Rf is phenyl substituted by 0, 1 or 2 groups selected from halo, C 1 4 alkyl, C 1 3 haloalkyl, -ORd and _N~dRd; or R~ is a saturated or unsaturated 57 or 6-membered ring heterocycle containing 1, 2 or 3 hieteroatomns independently selected from N, 0 and S, wherein no more than 2 of the ring members are 0 or S, wherein the heterocycle is optionally fused with a phenyl ring, and the carbon atoms of the heterocycle are substituted by 0, 1 or 2 oxo groups, wherein the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents selected from halo,C C 1 4 alkyl,C C 1 3 haloalkyl, -OR' and NR dRd.; and R9 is hydrogen or -CH 3

22. The compound according to Claim 21, wherein R 1 6 is halo, -NH 2 -NI 1 3 alkyl, 3 alkyl)CI- 3 alkyl or C 1 3 alkyl.

23. The compound according to Claim 21, wherein R1 0 is independently, at each instance, Cl. 8 alkyI, C14haloalkyl, halo, cyano, nitro, 1 8 alkyl), -C(=O)O(Cj~salkyI),.-C(=O)NR dR d, _C(=NRd)NRd R d, -ORd, 442 -OC(=O)(CI-8alkyl), -OC(=O)NR -OC(=O)N(Rd)S(=O) 2 (CI-8alkyl), -OC 2 6 alky1NRdR d, -OC 2 6 alkylOR d, 1 salkyl), 2 (C 1 .salkyl), 2 NR 2 N(R .salkyl), 2 N(R d)C(=O)O(C 1 8 alkyl), -S(=O0) 2 N(Rd)C(=O)NR dRd, _NRd R d -N(R 1-8alkyl), -N(R d)C(=O)O(C j galkyl), -N(R d)C(=O)NR dR d, -N(Rd)C(=NRd)NRd Rd, -N(R d)S(=O) 2 (Ci.8alkyl), -N(R d)S 2 NRd Rd, _d C 2 -akyNRd and -NR dC 2 -ralkylOR d; or R1 is a saturated or unsaturated 6- or 7-membered monocyclic or 10- or 1 1-membered bicyclic ring containing 1, 2 or 3 atoms selected from N, 0 and S, wherein the ring is fused with 0 or I benzo groups and 0 or I saturated or unsaturated 6- or 7-membered heterocyclic ring( containing 1, 2 or 3 atoms selected from N, 0 and S; wherein the icarbon 'atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 groups selected from CI-8alkyl, C 1 4 haloalkyl, halo, cyano, nitro, 1 8 a1 kyl), -C(=0)0(C 1 8 alkyl), -C(=0)NRdR d, -C(=NR d)NR dR d, -OR', -OC(=0)(CI-8alkyl), -OC(=O)NR dR d, -OC(=0)N(R 2 (C 1 salkyI), -OC 2 ,alky1NR R -0C 2 -6al kylORd, -SR, -s(0)C8alkyl), S(0(C aky) 2 NR dR d, 2 N(R 1 8 a1 kyl), 2 N(R d)C(=0)0(C 1 8 alkyl), -S 2 N(Rd )C(=0)NR dR d, _NRd Rd, -N(R 1 .alkyl), -N(R d)C(=0)0(C 1 -galkyl), -N(R d)C(=0)NR dR d, -N(Rd)C(=NR d)Nd R d -N(R d)S(=0) 2 (CI-8alkyl), -N(R d)S 2 NR dR d, _d C 26 alkylNR dR d and -NR dC 2 6 alkyIOR d; or R i01s C 1 4 al kyl s ubsti tuted by 0, 1, 2 or 3 groups sel ected( from Cj 4 haloalkyl, halo, cyano, nitro, 1 salkyl), -C(=0)0(C..salkyl), -C(=O)NRd R d, -C(=NR d)NR dR d, -OR d, -OC(=0)(CI-8alkyl), -0C(=0)NR dRd, -0C(=O)N(R d)S 2 (C 1 8 ,alkyl), -OC 2 -6alkylNRd Rd, -0C,,al kylOR d, -SR d 8 alkyI), 2 (C 1 8 alkyl), 2 NRd Rd, 2 N(Rd)C(=0)(C 1 .a1 kyl), 2 N(R d)C(=O)0(C 1 8 alkyl), 2 N(R d)C(=0)NR dR d, Ip'd d I.N(R d)C(=0)(C 1 saI kyl), -N(R d)C(=0)O(C 1 .aI kyl), -N(R d)C(=0)NRd Rd, -N(R d)C(=NRd)NRd R d -N(Rd)S ,.2CI 8 a1 kyl), -N(R d)S(=0) 2 NR dR d, _NRd C 26 aI kylNR dR d and -NR C 2 _6a1kylOR. I -443-

24. The compound according to any one of Claim 21, wherein R' is The compound according to Claim 24, wherein R 7 is Ci.salkyl, halo or Ci.4haloalkyl.

26. The compound according to Claim 21,.wherein R' is naphthyl substituted by 0, 1, 2 or 3 substituents independently selected from R 5 .0 27. The compound according to Claim 21, wherein R' is R e substituted by 0, 1, 2 or 3 substituents independently selected from R 5

28. The compound according to Claim 27, wherein R' is Re substituted by 1, 2 or 3 substituents independently selected from R 5

29. The compound according to Claim 21, wherein R 4 is The compound according to Claim 29, wherein and together are a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the each of the carbon atoms in the bridge is substituted by H, =O, Cl.galkyl, C]- 4 haloalkyl, halo, cyano, nitro, 8 alkyl), -444- 1 8 alkyl), _C(_0)NRd Rd, C(44Rd )NR dR, -OR d, -OC(=O)(C 1 .salkyl), _OC(=O)NRd Rd, -OC(=O)N(R d)S(=0) 2 (C 1 .salkyl), -OC 2 6 alkylNR dR d, -OC 2 6 alkylORd, -SRd, 1 8 alkyl), 2 (C 1 8 alkyl), 2 NRdR 2 N(R d)C(=0)(C 1 8 alkyI), 2 N(R d)C(=O)O(C 1 _8.alkyI), 2 N(Rd )C(=O)NRdRd, _NRd Rd, -N(R 1 -8alkyl), -N(R d)C(=O)O(C 1 8 al kyl), -N(R d)C(=O)NR dR d, -N(R)C(=d)Nd R d -N(R d)S(=O) 2 (C 1 galkyl), -N(R d)S(=0) 2 NR dR d, _d C 2 .,al kylNR dR d and d d -NR C 2 -6alkyl'OR anid any nitrogen atoms in the bridge are substituted by H, -CI-6alkyIOR d, -C 1 6 alkyl, -C 1 6 alkyINRd R d, -CI- 3 alkylC(=O)OR d, -Ci. 3 alkylC(=O)NR dR d, -CI. 3 alkylOC(=0)CI- 6 alkyl, -CI. 3 alkylNR dC(=0)C 1. 6 alkyl,( -C(=)Rfor -CI- 3 alkylRf; or R"1 and R 1 2 together are a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the each of the carbon atoms in the bridge is substituted by H, =0, CI .salkyl, C ,Ahaloalkyl, halo, cyano, nitro, 1 salkyl), -C(=O)0(C 1 8 alkyl), _C(=O)NRd Rd, -C(=NRd)NRdR11 :OC(=0)(C 1 salkyl), _OC(=O)NRd Rd, .0C(=o)N(R d)S(=O) 2 (CI-8alkyl), -OC 2 ,alky1NR d Rd -OC 2 6 alky10R d, -SR d, -S(=O)(CI-8alkyl), 2 (C 1 8 alkyl), 2 NRd Rd, 2 N(R 1 -8alkyl), 2 N(R d)C(=0)0(C 1 _8alkyl), 2 N(Rd)C(=O)NR dR d, _Rd N(R _sal kyl), d -N(R d)C(=O)0(C 1 8 alkyl), -N(R d)C(=O)NR dR d, -N(Rd)C(=NRd)NR dRd, -N(R d)S(=0) 2 (C 1 .saIkyl),,-N(R d)S 2 NR dR d, _RildC 26 alkylNd Rd and _d C 2 6 alkyl0R d ,and any nitrogen atoms in the bridge are substituted by H, -CI. 6 alkylOR -C 1 -,alkyl, -CI-6alkylNR R -CI- 3 alkylC(=0)0Rd -C 1 3 alkyl C(=O)NRd Rd, -C 1 3alkylOC(=O)C 16 alkyl, -C 1 3 alkyINR dC(=O)C 1- 6 alkyl, -C(=)Rfor -C 1 3 alkylR f.

31. The compound according to Claim 21, wherein R 4 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with 445 the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the carbon atoms of the heterocycle and bridge are substituted by 0, 1, 2 or 3 substituents independently selected, from Ci. 9 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, oxo, -OR d, -OCl-4haloalkyl, -OC 2 6 alkylNR dR d, -OC 2 6 a~kyl0R d, -OCI-alkyIC(=O)OR d, _Rd Rd, -N dC 1 -4haloalkyl, _f4,d C 2 6 alkyld R d _d C 2 6 alkyl0R d -C(=O)C 1 6 a1 kyl, -C(=O)OC 1 6 alkyl, -OC(=O)CI. 6 alkyl, -C(=O)NR dCi. 6 alkyl and -NR dC(=O)Cg 6 alkyl; and saturated carbon atoms may be additionally substituted d by and any nitrogen atoms in the bridge are. substituted by H, _aIkylOR -C 1 6 alkyl, -Ci- 6 alkylNRd Rd, -CI- 3 alkylC(=0)0R d, -CI 3 alky]C(=o)Nd Rd' -C 1 3 alkylOC(=0)CI 6 alkyl, -C 1 3 alkylNR dC(=O)CI 1 6 alkyl, -C(=O)Rf or -C 1 3 alkylRf.

32. The compound according to Claim 31, wherein R 4is a saturated or unsaturated 5- or 6-membered ing heterocycle containing 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the carbon atoms of the heterocycle and bridge are substituted by 1, 2 or 3 substituents independently selected from C 1 9 alkyl, C,. 4 haloalkyl, halo, nitro, cyano, oxo, -OR d, -S(=0),,C,-6alkyl, -OCI- 4 haloalkyl, -OC 2 6 alkylNR dRd, -0C 2 -6alkyl0R d' -OCI 1 6 alkylC(=0)OR d, -NP. Rd -NR dC 1 4 haloal kyl, -NR dC,-,alkylNRd R d, _N~dC 2 6 alkyloR d 1 6al kyl, -C(=0)0C 1 6 a1 kyl, -OC(=0)C 1 6 alkyl, -C(=O)NRdC 1 6 a1 kyl and -NR dC(=O)C 1 6 alkyl; and saturated carbon atoms may be additionally substituted by and any nitrogen atoms in the bridge are substituted by H, -CI. 6 alkyl0R, -C 6 alkyl, -C 1 6 alkylNRdR d, .CI- 3 alkylC(=o)OR '-I3lC=)Rd R d' -C 1 3 akylOC(=0)C 1 6alkyI, 3 alkylNRdC(=0)C 1 6 a1 kyl, -C(=0)Rf or f -C 1 3 a~kylR.

33. The compound according to Claim 21, wherein or R 4 is 1O-mernbered bicyclic ing comprising fused 6-membered rings, containing 0, 1, -446- 2, 3 or 4 N atoms with the remainder being carbon atoms, with at least one of the 6-membered rings being aromatic, wherein the carbon atoms are substituted by H, halo, ORd, NRdRd, C-ialkyl and C 1 3 haloalkyl; and saturated carbon atoms may be additionally substituted by =0.

34. The compound according to Claim 33, wherein R 4 is bicyclic ring comprising fused 6-membered rings, containing 1, 2, 3 or 4 N atoms with the remainder being carbon atoms, with at least one of the 6-membered rings being aromatic, wherein the carbon atoms are substituted by H, halo, OR NR R d Ci.6alkyl and Ci- 3 haloalkyl; and saturated carbon atoms may be additionally substituted by =0. A compound having the structure: R9 RR Y R 1 6 or any pharmaceutically-acceptable salt thereof, wherein: n is independently, at each instance, 0, 1 or 2; o is independently, at each instance, 0, 1, 2 or 3; Y is NH, O or S; R' is R6 R R9 or R' is a naphthyl substituted by 0, 1, 2 or 3 substituents independently selected from Rs; or R' is Re substituted by 1, 2 or 3 substituents independently selected from R 5 447 R1 5 is, independently, in each instance, R1 0 C 1 8 alkyl substituted by 0, 1 or 2 substituents selected from R1 0 -(CH 2 ),,phenyl substituted by 0, 1, 2 or 3 substituents independently selected from R1 0 or a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, 0 and S, wherein no more than 2 of the ring members are 0 or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently. selected from Rio R 16is, independently, in each instance, H, halo, -N}1 2 -NHCI- 3 a~kyl, -N(C 1 3 alkyl)C 1 3 alkyl or G 1 3 alkyl; R 4 is a saturated or unsaturated 5- or 6-.membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from CI. 8 alkyl, C 14 haloalkyl, halo, cyano, niitro, n, -C(=O)NR m R', -C(=NR m )NR m R m -OR m -OC(=O)NR m R m -0C(=0)N(Rm)S(=0) 2 -0C 2 6al kylNR m R m -OC 2 6 alkylOR m -SR m 2 2 NR m 2 N(R m 2 N(R m )C(=0O)0R, -S 2 N(R m )C(=0)NR m R m -NR m R m -N(R m -N(R m -N(R m )C(=0O)NR m R m -N(R m )C(=NR m )NR m R m -N(R m 2 R', -N(R m 2 NR m R m -NR M C 2 -6alkylNR m R m -NR M C 2 -6alkylQR m -C(=0)0Rs, -C(0)R}Rrn -C(=NRmr)NRrnR-, -0Rs,.-OC(=0O)Rs -OC(=0)NRnRS, -OC(=0)N(Rml)S(=0) 2 Rs, -OC 2 -6alkylNRnR', -OC 2 -SRs, 2 Rs, 2 NRnRs, 2 N(Rrn)C(=O)R, 2 N(Rrn)C(=0)ORs, -S 2 N(Rrn)C(=0)NRnRS, -N(Rrn)C(=O)R', N(Rr)C(=0)ORs, -N(Rrn)C(=O)NRrnRs, -N(Rm)C(=NRml)NRrnR', -N(R m )S 2 -N(Rrn)S(=O) 2 NRrnRs, -NR M C 2 6 alkylNR m RS, -NR M C 2 6 a1 kylORs 3 0 and C 1 -4alkyl substituted by I or 2 groups selected from C 1 2 haloalkyi, halo,. cyano, ni tro, -C(=O)NR m 'R m -C(=NR m ),NR m R m -OR m -OC(=0)NR m R M 7OC(=O)N(R m 2 -OC 2 6 alkyNR m R m I I 448 -OC 26 alkyIOR', -SR m n, 2 2 NRmR m -S 2 2 N(R m -S 2 N(R m )C(=0)NR m R', -NR m -N(R m -N(R m )C(=0)0R n, -N(R m )C(=0)NR m R', -N-(R m )C(=NR m )NR m -N(R m 2 -N(R m 2 NR m R, -NR'C 2 _6alkyNR m R m -NR m C 2 -6alkyl0R', -C(=0)0Rs, -C(=O)NRnR', -C(=NRn)NRrnR', .OC(=O)Rs, .OC(0)NRnRs -OC(=0)N(Rn)S(=O) 2 -OC 2 6 alkylNR m Rs, -OC 2 6 aikyl0R~s, -SRs, S(=0)Rs, -S 2 Rs, 2 NRnR', 2 N(Rrn)C(=0)R', 2 N(Rr)C(=0)0Rs, 2 N(Rrn)C(=0)NRnRs, -NRrnR', -N(Rr)c(0)ORs, -N(Rrn)C(=0)NRnR', -N(Rrn)C(=NRn)NRnRs, -N(Rrn)S(=0) 2 Rs -N(Rrn)S(=O) 2 NRnRs, NRnC 2 -6alkyINRnRs, -NR m C 2 6alkyl0Rs; And the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups; but in no instance is R 4 3 ,5-ditnifluoromethylphenyl or 3-trifi uorornethyl-4-fluorophenyl; R 5 is independently, at each instance, H, CI-salkyl, C 1 4haloalkyl, halo, nitro, cyano, -OCI 1 6 aikyl, -OCI- 4 haloalkyI, -OC 2 _6alkylNR dR. d, -0C 2 6 alkyl0Rd, -NR -NR dCI haloalkyl, -NR dC 2 6 alkyl NRd Rd, .Ikd C 2 6 AlkylOR. naphthyl, -CO 2 (CI-6alkyl), 1 6 alkyl), -C(=0)NRd -NRdC(=0)R d NRdC(=O)NR dR d -NWC0 2 CI_ AkYl, -C 1 8 alkylOR', -C 1 ,alkylNR R' -S(=O)n(C 1 6 a1 kyl), 2 NRd Rd, -NRdS(=0) 2 6 a1 kyl), _OC(=0)NRd R.d, a phenyl ring substituted with 0, 1, 2, or 3 substituents independently selected from R 0;or R 5 is a saturated or unsaturated 5- or 6-membered ring heterocycle( containing 1, 2 or 3 atoms selected from 0, N and S, substituted with 0, 1, 2, or 3 substituents independently selected from RIO; R 6is independently, at each instance, H, CI-Salkyl, GI. 4 haloalkyl, halo, -0C 1 -6alkyI, -0C 1 4haloalkyl, -0C 2 6 alkylNRdR -0C 2 6 alky10R -N~RdR -NdC 1 4 haloal kyl, -NRdC 2 6 alkyl NR dR d or -NR dC 26 alkyl0R d, -C 1 .salkylOR d, -Cp~talkylNRd Rd, -S(C 1 6 alkyl), a phenyl ring substituted with 1, 2, or 3 substituents independently selected from RIO or R 6 is a saturated or unsaturated or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from 0, N and S su Ibstituted with 0, 1, 2, or 3 substituents independently selected from RIO; R 7 is independently, at each instance, H, C,. 8 alkyl, C 1 4 haloalkyl, halo, -0CI. 6 alkyl, -OC 1 4 haloalk .yl, -0C 2 ,,alkylNRdR', -OC 2 -6alkylOR d 449 -NRd R d,-N 4PCdc 4 haloalkyl N ~d C2 alklNR dR d -NR dC 2 -6alkylOR d, -Ci-8alkyIOR d, -C 16 alkylNR dR dor -S(C 1 6 alkyl); or R 7is a saturated or unsaturated 4- or 5-membered ring heterocycle containing a single nitrogen atom, wherein the ring is substituted with 0, 1 or 2 substituents independently selected from halo, C 1 2 haloalkyl and C 1 3 alkyl; R 8 is independently, at each instance, H, C 1 salkyl, C 1 4haloalkyl, halo, -0C 1 6 a1 kyl, -0CI 4 haloalkyl, -0C 2 -,alkyINRd R d, -OC 2 6 alkyIORd' -NIR dR d. -NdC 1 4 haloalkyl, _N C26ly d ,.N1d C 2 6 alkylOR d .Ci-8alkylOR d, -CI- 6 alkylNR -S(C 1 6 alkyl), a phenyl ring substitut 'ed with 1, 2, or,3 substituents independently selected from Rio, or R 8 is a saturated or unsaturated or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from 0, N and S substituted with 0, 1, 2, or 3 substituents independently selected from Rio; R 9 is independently, at each instance, H, C,.salkyl, C 1 4haloalkyl, halo, nitro, cyano, -OCI 1 6 alkyI, -OCI 1 4 haloalkyl, -OC 2 6 alkylNR dR d' -OC 2 6 alkylOR d, -NR dR d, -NR dC,-4haloalkyl, -NR dC 26 alkylNR dR dor d dd -NR C 2 6 alkylOR -C0 2 (Cl. 6 alkyl),.-C(=0)(CI- 6 a1 kyl), -C(=0)NRdRd, -NR dC(=0)(C 1 6 alkyl), -NRdC(=0)NR dR d' NR dCO 2 (C al kyl), -C 1 .8alkylORd, .C. 6 lkIR, 1 alkyl), SO)Nd, _NRdS 2 (CI- 6 alkyl), -OC(=O)NR dR d or a -(CRIRI) 0 ,phenyl wherein the phenyl is substituted with 0, 1, 2, or 3 substituents independently selected from R' 0 or R 9 is -(CR qR )yet wherein Het is a saturated or unsaturated or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from 0, N and S substituted with 0, 1, 2, o r 3 substituents independently selected from R1 0 or R 9 is a saturated or unsaturated 4- or 5-membere d ring heterocycle containing a single nitrogen atom, wherein the ring is substituted with 0, 1 or 2 substituents independently selected from halo, C 1 2 haloalkyl and C,. 3 alkyl; wherein at least one of R 5 R 8 and R 9 IS C 1 8 alkyl, C 1 4 haloalkyl, halo, -0CI 4 haloalkyl, -OC 26 alkylNR dR d' -0C 2 6 a1 kylOR d, -NdC, 1 4 haloalkyl, _dC 26 alkylNR dR d -N~R dC 2 6 alkyl0R d -CisalkylOR d, -Cz- 6 alkylNRd Rd or -S(C. 1 6 alkyl); Rio is independently, at each instance, selected from H, CI-8alkyl, C 1 4 haloalkyl, halo, cyano, nitro, 1 salkyl), -C(=0)0(C 1 .salkyIl), 450 CC(O) R -OR, -OC(=0)(CI-8alkyl), -OC(=O)NR R, _n 2 (C Ialkyl), -OC 2 _alkylNR R -OC 2 .alkylOR d, -SR.,d -S(=O)(Cj~galkyl), 2 (CI-8alkyl), 2 NR dRd, 2 N(R 8 a1 kyl), -S 2 N(R 1 -alkyl), -S(=O0) 2 N(R d)C(=O)NRd R -NR dR. d, -N(R d)C(=O)(Cj 8 alkyl), -N(R d)C(=0)O(Ci 8 alkyI), -N(Rd)C(=O)NRd R d, -N(R )C(=NR d)NRd R, -N 2 (CI- 8 alkyl), -N(R 2 NR.R" NdC 26 alkyINRdR and -NRdC 2 6 alkyIORd or R' 0 is a saturated or unsaturated 6- or 7-membered monocyclic or 10- or I 1-membered bicyclic ring co ntaining 1, 2 or 3 atoms selected from N, 0 and S, wherein the ring is fused with 0 or 1 benzo groups and 0 or I saturated or unsaturated 6- or 7-membered heterocyclic ring containing 1, 2 or 3 atoms selected from N, 0 and wherein'the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 groups selected from C 1 .salkyI, C 1 4 haloalkyl, halo, cyano, nitro, galkyl), -C(=O)O(C 1 8 a1 kyl), -C(=O)NR dR d, .C(=NRd)NRd R, d'OR d, -OC(=0)(C.galkyl), -OC(=O)NR dR d, -OC(=O)N(R d)S 2 (CI 1 8alkyl), -OC 2 6 alkyl NRd R. d -OC 2 6 alkyIOR" d' SR d' 1 8 alkyl), 2 (C 1 8 alkyl), -S(O) 2 NRdR. -S 2 N(R 8 a1 kyl), -S 2 N(R")C=O)O(C 1 8 a1 kyl), 2 N(Rd)C(=O)NR R d, -NP R d, -N(R _galkyl), )C(=O)O(CI-8alkyl), )C(=O)NRd R d, -N(R d)C(=NRd)NR dRd -N(Rd)S(=O) 2 (CI-8alkyl), -N(R 2 NRd R d, _NRd C 2 6 alkylNR dRd and -NR dC 2 6 alkylOR d; or R1 0 is C 1 -4alkyl substituted by 0, 1, 2 or 3 groups selected from C,-4haloalkyl, halo, cyano, nitro, -C(=O)(CI-8alkyl), -C(=O)O(Cj~galkyl), -(R)RR -OR, -OC(=O)(C 1 .galkyl), -OC(=O)NROR, -OC(=0)N(Rd)S(=O) 2 (CI-8alkyl), -OC 2 6 alky]NRd R d -OC 2 _6alkylOR d, -SRd 1 -sal kyl), 2 (C 1 8 alkyl), -S 2 NRd R d 2 N(R d)C(=O)(C 1 8 alkyJ), -S 2 N(R d)C(=O)O(C 1 8 a1 kyl), 2 N(R )C(0O)NRd R d, -NR dR d, -N(R 1 .alkyl), -N(R d)C(=O)O(C 1 -alkyl), -N(R d)C(=O)NRd R d, -N(R d)C(=NR d)NR dRd -N(R d)S 2 (C,_salkyJ), -N(R d)S dR d, -NP C 2 6 alkylNR dR d and _N~d C2alkyOR d R.d is independently, at each -instance, H, phenyl, benzyl or C 1 6 alkyl; -451 R' is a heterocycle selected from the group of thiophene, pyrrole, I ,3-oxazole, 1,3-thi azole, 1 ,3,4-oxadiazole, 1 ,3,4-thiadiazole, 1 ,2,3-oxadiazole, 1 ,2,3-thiadiazole, IH-1I,2,3-triazole, isothiazole, I ,2,4-oxadiazole, 1,2,4- thiadiazole, 1 ,2,3,4-oxatriazole, 1 ,2,3,4-thiatriazole, I H-i ,2,3,4-tetraazole, 1 ,2,3,5-oxatriazole, 1 ,2,3,5-thiatfiazole, furan, imidazol- l-yl;, imidazol-4-yl, 1,2,4- triazol-4-yl, 1 ,2,4-tniazol-5-yl, isoxazol-3-yI, isoxazol-5-yI, pyrazol-3-yl, pyrazol- thiolane, pyrrolidine, tetrahydrofuran, 4,5-dihydrothiophene, 2-pyrroline, pyridazine, pyrimidine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,2,4-triazine, 1,3,5-triazine, pyridine, 2H-3,4,5,6-tetrahydropyran, thiane, 1,2- 10 diazaperh ydroi ne, I ,3-di azaperhydroi ne, piperazine, I ,3-oxazaperhydroine,* morpholine, I ,3-thiazaperhydroi ne, 1 ,4-thi azaperhydroine, piperi dine, 2H-3,4- di hydropyran, 2,3-dihydro-4H-thi in, 1,4,5 ,6-tetrah ydropyri dine, 2H-5 ,6- dihydropyran, 2,3-dihydro-6H1-thiin, I ,2,5,6-tetrahydropyridine, 3,4,5,6- tetrahydropyridi ne, 4H-pyran, 4H-thi in, I ,4-di hydropyridi ne, 1 ,4-di thi ane, 1,4- dioxane, I ,4-oxathiane, I ,2-oxazolidine, 1 ,2-thiazolidine, pyrazolidine, 1,3- oxazolidine, 1 ,3-thiazolidine, imidazolidine, 1,2,4-oxadiazolidine, 1,3,4- oxadiazolidine, I ,2,4-thi adiazol idine, 1,3 ,4-thiadiazolidine, 1,2,4-triazolidine, 2- imidazoline, 3-imidazoline, 2-pyrazoline, 4-imidazoline, 2,3-dihydroisothiazole, 4,5-dihydroisothiazole, 2,5-di hydroi sox azole, dihydroi sothiazole, 2,3-dihydroisoxazole, 4,5-dihydrooxazole, 2,3- dihydrooxazole, 2,5-dihydrooxazole, 4,5-di hydrothiazole, 2,3-dihydrothi azole,, I ,3,4-oxathiazol'idine, I ,4,2-oxathiazolidine, 2,3-dihydro- 1H- tr-iazole, 2,5-dihydro-IH-[1I,2,3]triazole, 4,5-dihydro-IH-[ I,2,3]triazole, 2,3-dihydro- 1H-[ 1,2,4jtriazole, 4,5-di hydro- 1H-[ 1,2,4]triazole, 2,3-dihydro- [1 ,2,4]oxadiazole, 2,5-di hydro-[ 1,2,4]oxadiazole, .4,5-dihydro-[ 1,2,4]thiadiazole, 2,3-dihydro-[ 1,2,4] thidi azole, 2,5-dihydro-[ 1,2,4] thiadiazole, 4,5-dihydro-[ 1,2,4) thiadiazole, 2,5-di hydro-[1I,2,4]oxadi azole, 2,3-di hydro-[1I,2,4]oxadi azole, di hydro- [1 ,2,4]oxadiazole, 2,5-di hydro-[ 1,2,4jthiadiazole, 2,3-dihydro-[ 1,2,4] thiadiazole, 4,5-dihydro-[1,2,4] thiadiazole, 2,3-dihydro-[1,3,4]oxadiazole, 2,3- dihydro-[1 ,3,41thiadiazole, [1,4,2]oxathiazole, [l,3,4]oxathiazole,, 1,3,5- triazaperhydroine, 1 ,2,4-triazaperhydroine, 1 ,4,2-dithiazaperhydroine, 1,4,2- dioxazaperhydroine, 1,3 ,5-oxadiazaperhydroine, 1 ,2,5-oxadi azaperhydroine, -452- 1,3 ,4-thi adiazaperhydroi ne, 1,3 ,5-thi adiazaperh ydroine, 1,2,5- thiadiazaperhydroine, 1,3 ,4-oxadiazaperhydroine, 1 ,4,3-oxathi azaperhydroi ne, I ,4,2-oxathiazaperhydroine, 1,4,5 ,6-tetrahydropyridazine, 1,2,3,4- tetrahydropyridazine, 1,2,3 ,6-tetrahydropyridazi ne, I ,2,5,6-tetrahydropyrimidine, 1 ,2,3,4-tetrahydropyrini dine, 1 ,4,5,6-tetrahydropyrimidine, 1,2,3,6- 0 tetrahydropyrazine, 1,2,3 ,4-tetrahydropyrazine, 5,6-dihydro-4H- [1 ,2]oxazine, 5,6- (Ni ~di hydro-2H-[ 1,2]oxazine, 3 ,6-di hydro-2H-[ 1,2joxazine, 3,4-di hydro-2H- [1 ,2]oxazine, 5 ,6-dihydro-411-[1I,2jthiazine, 5 ,6-dihydro-2H-[ 1,2] thiazine, 3,6- Ndihydro-2H- thi azine, 3,4-dihydro-2H-[ 1,2] thiazine, 5,6-di hydro-2H- [1 ,3]oxazine, 5 ,6-dihydro-4H-f1l,3]oxazine, 3 ,6-dihydro-2H-[ 1,3]oxazine, 3,4-( di hydro-2H-[1I,3]oxazine, 3,6-dihydro-2H-[1I,4]oxazine, 3,4-dihydro-2H- [1 ,4]oxazine, 5,6-dihydro-2H-[ 1,3llthiazine, 5 ,6-dihydro-4H-[1I,3]thiazine, 3,6- dihydro-2H-[ 1,3]thiazine, 3,4-dihydro-2H-[1I,3]thiazine, 3,6-dihydro-2H- [1 ,4]thiazine, 3,4-dihydro-2H-[1I,4]thiazine, 1 ,2,3,6-tetrahydro-[1I,2,4]triazirie, 1 ,2,3,4-tetrahydro-[ 1,2,4ltriazine, 1 ,2,3,4-tetrahydro-[1 ,3,5]triazine, 2,3,4,5- tetrahydro-f I,2,4]triazine, 1 ,4,5,6-tetrahydro-[ 1,2,4]triazine, 5,6-dihydro- [1 ,4,2]di oxazine, 5 ,6-dihydro-[1I,4,2]dioxazine, 5,6-dihydro-[1I,4,2]dithiazine, 2,3- di hydro- 1 dioxazine, -3,4-dihydro-2H- I ,3,4]oxadiazinfe, 3,6-dihydro-2H- [1 ,3,4]oxadiazine, 3,4-dihydro-2H-[1I,3,5]oxadiazine, 3,6-dihydro-2H- [1 ,3,5]oxadiazine, 5,6-dihydro-2H-[1 ,2,5]oxadi azine, 5,6-dihydro-4H- [1 ,2,5]oxadiazine, 3,4-dihydro-2H-[1 ,3,4]thiadiazine, 3,6-dihydro-2H- [1 ,3,4]thiadiazirie, 3,4-dihydro-2H-[1I,3,5]thiadiazine, 3,6-dihydro-2H- [1 ,3,5]thiadiazine, 5,6-dihydro-2H-[ 1,2,5]thiadiazirie, 5,6-dihydro-4H- [1 ,2,5]thiadiazine, 5,6-dihydro-2H-[ 1,2,3]oxadiazine, 3,6-dihydro-2H- [1 ,2,5]oxadiazine, 5,6-di hydro-4H-[1I,3,4]oxadiazine, 3,4-dihydro-2H- 1 ,2,5]oxadiazine, 5 ,6-dihydro-2H-[ 1,2,3]thiadiazine, 3,6-dihydro-2H-, [1 ,2,5]thiadiazi ne, 5 ,6-dihydro-4H-[ 1,3,4]thi adiazine, 3 ,4-dihydro-2H- [1 ,2,5]thiadiazine, 5,6-dihydro-[1I,4,3]oxathiazine, 5 ,6-dihydro-[ I,4,2]oxathiazine, 2,3-dihydro-[1 ,4,3]oxathiazine, 2,3-dihydro-[1 ,4,2]oxathiazine, dihydropyridine, 1 ,6-dihydropyfidine, 5,6-dihydropyridine, 2H-pyran, 2H-thiin, 3 ,6-dihydropyridine, 2,3-dihydropyridazine, 2,5-dihydropyndazine, dihydropyridazine, 1,2-dihydropyddazine, 2,3-dihydropyrimidine, -453- dihydropyrimidine, 5,6-dihydropyrimidine, 3,6-di hydropyn midine, dihydropyrazi ne, 5 ,6-di hydropyrazine, 3 ,6-di hydropyrazine, 1 ,4-dihydropyrazine, 1 ,4-dithiin, 1,4-dioxin, 2H-1I,2-oxazine, 6H- 1,2-oxazine, 4H- 1 ,2-oxazine, 2H- 1,3-oxazine, 4H-1I,3-oxazirie, 6H- 1,3-oxazine, 2H-1I,4-oxAzine, 4H-1 ,4-oxazine, 2H-1I,3-thiazine, 2H- 1,4-thiazine, 4H- 1,2-thiazine, 6H- 1,3- thiazine, 4H4-1,4-thiazine, 2H- 1,2-thiazine, 6H-1I,2-thiazine, 1 ,4-oxathiin, 2H4,5H4- I ,2,3-triazine, IH,4H- 1,2,3-triazine, 4,5-dihydro- 1,2,3-triazine, 1 H,6H- 1,2,3- triazine, 1 ,2-dihydro- 1,2,3-triazine, 2,3-dihydro-1I,2,4-triazine, 3H,6H-I ,2,4- triazine, 11H,6H4-1I,2,4-triazine, 3,4-dihydro-1I,2,4-triazine, 1H,4H-1 ,2,4-triazine, 5,6-dihydro-1I,2,4-triazine, 4,5-di hydro- 1,2,4-triazine, 2H,5H-1I,2,4-triazine, 1,2- dihydro-1 ,2,4-triazine, 1 H,4H- 1,3,5-triazine, I ,2-dihydro-1 ,3,5-triazine, 1,4,2- dithiazine, 1 ,4,2-dioxazine, 2H- 1,3,4-oxadiazine, 2H-1I,3,5-oxadiazine, 6H4-1,2,5- oxadiazine, 4H-1I,3,4-oxadiazine, 4H- 1,3 ,5-oxadi azine, 4H- 1,2,5-oxadiazine, 2H- 1,3,5-thiadiazine, 6H-1,2,5-tiadiazine, 4H-1,3,4-thiadiazine, 4H-1,3,5- thiadiazine, 4H- 1,2,5-thiadiazine, 2H- 1,3 ,4-thiadiazine, 6H-1I,3,4-thiadiazine, 6H- 1,3,4-oxadiazine and 1,4,2-oxathiazine, wherein the heterocycle is optionally vicinally fused with a saturated or unsaturated 6- or 7-membered ring containing 0, 1 or 2 atoms independently selected from N, 0 and S; Rf is phenyl substituted by 0, 1 or 2 groups selected from halo, C 1 4 alkyl, C 1 3 haloalkyl, -OR dand -NR d Rd; or Rf is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, 0 and S, wherein no more than 2 of the ring members are 0 or S, wherein the heterocycle is optionally fused with a phenyl ring, and the carbon atoms of the heterocycle are substituted by 0, 1 or 2 oxo groups, wherein the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents selected from halo, CI- 4 alkyl, C 1 3 haloalkyl, -OR' and -NR dR; R9 is hydrogen or C3 R M is independently at each instance H or n R n is independently at each instance CI-8alkyl, phenyl or benzyl; RI is independently in each instance H, C 1 4 alkyl, C 1 4 haloalkyl, halo, cyano, nitro, n, -C(=0)NR m R m -C(=NR m )NR m R m -OR m 7OC(=O)R n, -OC(=O)NR m R m -OC(=O)N(R m 2 Rn, -OC 2 6 alkylNR m R m -454- -OC 26 alkylOR', -S 2 2 NRmR m 2 2 N(R m 2 N(R m )C(=O)NR m R m -NRn m R m -N(R m )C(=O)OR n, -N(Rn)C(=O)NRMR m -N(R m )C(=NR')NR m -N(R m 2 R n, -N(R m 2 NR m R', -NR'C 2 -6alkylNR m R' or -NR'C 2 -6alkyIOR'; and Rs is R n substituted by 0, 1, 2 or 3 substituents independently selected from R

36. The compound according to* any one of Claim 35, wherein Y is NH.

37. The compound according to any one of Claim 35, wherein Y is 0.

38. The compound according to any one of Claim 35, wherein Y is S.

39. The compound according to any one'of Claim 35, wherein R' is The compound according to Claim 39, wherein R 7 is C 1 5 alkyl, halo or C 1 4 haloalkyl.

41. The compound according to Claim 35, wherein R1 is a naphthyl substituted by 0, 1, 2 or 3 substituents independently selected from R 5

42. The compound according to Claim 35, wherein R' is R' substituted by 1, 2 or 3 substituents independently selected from R 5 -455-

43. The compound according to Claim 35, wherein R 15 is -(CH 2 ),,phenyl substituted by 0, 1, 2 or 3 substituents independently selected from R' 0

44. The compound according to Claim 35, wherein R1 5 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, 0 and S, wherein no more than 2 of the ring members are 0 or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from R1 0 The compound according to Claim 35, wherein R 1 5 is CI-8alkyI substituted by 0, 1 or 2 substituents. selected from R' 0

46. The compound according to Claim 35, wherein R1 5 is selected from C 1 8 a1 kyl, C 14 haloal kyl, halo, cyano, nitro, 1 .salkyl), d d d d d I-al kyl), R -C(=NR )NRdRd, r0R 1 -al kyl), Rd -OC(=0)N(Rd) 2 (C igalkyI), -0C 2 6 a1 kylNRd RI -0C 2 6 alkylOR d, -SR d, -S(=O)(Cl.8alkyl), 2 (Cf. 8 alkyl), 2 NRd Rd, 2 N(R 1 .alkyl), 2 N(Rd)C(=O)O(C 1 .8alkyl), 2 N(R d)C(=O)NR dRd, -NRd R d' 1. 8 alkyl), -N(R d)C(=0)0(C 1. 8 alkyl), -N(R d)C(=0)NR dR d, N(Rd)C(=1R d )NR dR d -N(R d)S 2 (CI- 8 alkyl), -N(R d)S(=0) 2 NR dR d, _Nd C 2 _alkylNd Rd and -NR dC 2 6 alkyl0R d; or R1 is a saturated or unsaturated 6- or,7-membered monocyclic or 10- or I 1-membered bicyclic ring containing 1, 2 or 3 atoms selected from N, 0 and S, wherein the ring is fused with 0 or I benzo groups and 0 or I saturated or unsaturated 6- or 7-membered heterocyclic ring containing 1, 2 or 3 atoms selected from N, 0 and S; wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ing is substituted by 0, 1, 2 or 3 groups selected from CI-8alkyl, C 1 4 haloalkyl, halo, cyano, nitro, -C(=O)(CI-8alkyl), -C(=0)0(Cl-galkyl), -C(=0)NR dR d, _C(=NRd)NRd R d -OR d, -OC(=O)(CI-8alkyl), _0C(=0)NRd R d, -OC(=0)N(R d)S 2 (CI-8alkyl), -456- -OC 26 alkylNRdR d, -OC 2 6 ai kylOR d, -SR d, 8 ga1kyl), -S 2 (Cjsalkyl), 2 NRd R d -S 2 N(R d)C(=0)(C 1 I-al kyl), -S 2 N(Rd)C(=O)O(CI 1-alkyI), 2 N(R d)C(=O)NRd R d -NR dR d, .N(R 1 .alkyl), -N(R d)S(=O)2(CI-8alkyl), -N(R d)S(=O) 2 NRd R d _d C 2 6alk yjNd R d and -NR dC 24 salkylOR d; or R1 0 is C 1 -4alkyl substituted by 0, 1, 2 or 3 groups selected from C 1 4 haloalkyl, halo, cyano, nitro, -C(=O)(CI-8alkyl), -C(=O)O(C,.salkyl), _C(=O)NRd R d _C(=NRd)NRd R d -OR d, -OC(=O)(C 1 .galkyl), _OC(=O)NRd R d -OC(=O)N(R d)S(=O) 2 (C 1 .salkyI), -OC 2 -6alkylNR dR d, -OC 2 _6alkyIOR d, -SRd -S(=O)(CI-8alkyl), 2 (CI-8alkyI), 2 NR, 2 N(R d)C(=O)(Cis-aI kyl), 2 N(R d)C(=O)O(C 1 I 8 a1 kyl), -S(O0) 2 N(R d)C(=O)NR dR d, -NR R -N(R d)C(=O)(Cis-alkyl), -N(Rd)C(=O)O(Ci _8alkyl), -N(R d)C(=O)NR dR d, -N(R d)C(=NR d)NR dR d, d dd -NR C 2 _6alkylOR.

47. The compound according to Claim 35, wherein R 1 6 is, independently, in each instance, halo, -NH 2 -NHCI 1 3 alkyl, -N(C 1 3 alkyl)CI- 3 alkyI or C 1 3 ai kyl.

48. The compound according to Claim 35, wherein R 4 is an( unsaturated 6-membered ring containing 0 atoms selected from 0, N and S that is vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or*3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from Cl-galkyl, C 1 .4haloalkyl, halo, cyano, nitro, -C(=0)NR m -C(=NR m )NR m R m -OR m n'0-C(=O)NR-R m -OC(=0)N(R m )S 2 -0C 2 6 alkylNR m -OC 2 6 al kylOR m -S R m -S (=O)Rn, 2 2 NR'Rrn, 2 N(R m 2 N(R m )C(=O)OR, -S 2 N(R m )C(=O)NR m R m -NR m R m -N(R m -N(R m )C(=O)OR, -N(R m )C(=0)NR m -N(R m )C(=NR m )NR m -N(R m )S 2 R, 457 -N(R m 2 NR m -NR'C 2 6 a1 kyINR m -NR m C 2 6 alkylOR m -C(=O)ORs, C(=0)4RnRs -C(=NRrn)NRrnR', 0C(0)Rs -0C(=0)NRnR', -OC(=0)N(Rrn)S(=0) 2 -0C 2 6 alkylNRnR', -0C 2 6 al kylORs, -SRs, 2 2 NR m Rs, -S(=0)2N(R m S(=O) 2 N(R m )C(=0)0R 5 2 N(R m )C(=O)NR m -NR m R 5 -N(R m -N(R m )C(=0)0Rs, -N(R m )C(=0)NR m Rs, -N(R')C(NR m )N m R', -N(R m 2 Rs, -N(R m 2 NR m -NR m C 2 _6alkylNRnRs, NRnC 2 6 alkyl0R' and CI-4alkyl substituted by I or 2 groups selected from CI- 2 haloalkyl, halo, cyano, nitro, n, -C(=O)NR m R m -C(=NR m )NR m R m -OR m -OC(=O)NR m -OC(=O)N(R m 2 -OC 2 -6alkyNR m R', -OC 2 -6alkylOW m 2 2 NR m R m -S 2 N(R m 2 N(R m -S 2 N(R"')C(=O)NR m R m -NR m -N(R m -N(R m )C(=O)NR m R m -N(R m )C(=NR"')NR m -N(R m 2 -N(R M 2 NR m R m -NR m C 2 4 alkylNR m R m -NR'C 2 -6alkylOR m -C(=O)0R 5 -C(=0)NR m -C(=NR m )NR m .OW, -OC(=O)Rs,,-OC(=0)NRnR', -OC(=O)N(R m 2 -0C 2 6 alkyNRnR', -0C 2 _6alkyIORs, -s (0)Rs, -S 2 Rs, 2 NR m R 5 -S 2 N(R m -S 2 N(R m )C(=O)0R 5 2 N(R m )C(=O)NR m Rs, -NRm T Rs, -N(R m )C(=0)0Rs, -N(R-)C(=O)NR m -N(R m )C(=NR m )NR m -N(R m 2 R', -N(R m 2 NR m -NRrnC 2 _6alkylNRnRs, -NR m C 2 -6alkyl0R'; and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups.

49. The compound according to Claim 35, wherein R 4is a saturated or unsaturated 5- or 6-membered ring containing 1, 2 or 3-atoms selected from 0, N and S that is vicinally fused with a saturated or unsaturated 3- or 4-atomn bridge containing 0 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C 1 .salkyl, C 14 haloalkyl, halo, cyano, nitro, -C(=0)NRm~Rn, -C=~)Nmm -OR m -OC(=O)R n, -OC(=0)NR m R m -0OC(=0)N(Rm')S(=0) 2 -0C 2 6 aI kylN rRRm, -QC 2 6 aI kyIOR m -SR m n -458- 2 NR m R m 2 N(R m n, 2 N(R m -NR m R m -N(Rn)C(=0)OR, -N(R m )C(=O)NR m -N(R m )C(=NR m )NR m -N(R m 2 R, -N(R m 2 NR m -NR'C 2 6 alkylNR m R m -NR.'C 2 -6alkyl0R', -C(=O)ORs, .C(=0)NRnRs, -C(=NRrn)NRrnRs, -ORS, 0C(=o)RsI .OC(=O)NRnRS -OC(=O)N(Rn)S(=O) 2 -OC 2 6 alky1NRnR', -OC2z6alkylOR', -SRs, 2 RS, 2 NRnRs, S(=O) 2 N(Rr)C(=0)R', 2 N(Rr)C(=0)0Rs, 2 N(Rr)C(=0)NRnRs, -7RmRs. .N(Rr)C(=0)Rs, -N(Rr)C(=0)ORs, -N(Rrn)C(=0)NRnR', -N(Rrn)C(=NRn)NRR', -N(Rr)S(=0) 2 RS, -N(Rrn)S(=0) 2 NRnR', -NRrnC 2 _alkylNRnRs, -NRnC 2 and C,. 4 alkyl substituted by 1 or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=O)NTR m R m -C(=NR m )NR m R m -OR m -OC(=O)R n, -OC(=O)NR m 2 R n, -OCi~alkyNR m R', -OC 2 6 alkylORm, -SR m 2 2 NkR m t 2 -S 2 N(R m m )C(=O)NR m R m -NR m R m -N(R t -N(R m )C(=O)NR m R m -N(R m )C(=NRm T )NR m R m -N(R m 2 -N(R m 2 NR m R m -NR m C 2 6 a1 kylNRTR m -NR m C2' 6 alky1OR m -C(=O)NRnRS -C(=NRrn)NRrnR', .OC(=o)Rs, -OC(=O)NRnR', -OC 2 6 alky1NRrnRs, OC 2 6 alkylORs, -SRs, S(=0)Rs, 2 -s 2 NRnRS, 2 N(Rrn)C(=O)R', -S 2 N(Rrn)C(=O)ORS, 2 N(Rrn)C(=0)NRnR', 4pNRnR' -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRn'R', -N(Rrn)C(=NRrn)NRrnR', -N(Rrn)S(=0) 2 Rs, -N(Rrn)S(=O) 2 NRrnR', NRnC 2 6 alkylrNRSR' -NRrnC 2 -6alkyIOR'; and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups; but in no instance is R 4 3 ,5-dittriluoromethylphenyl or 3-tnifluoromethyl-4-fl vorophenyl. The compound according to Claim 35, wherein R 4 i sa saturated or unsaturated 6-membered ring containing 0 atoms selected from 0, N and S that is vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and 459 bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C 1 salkyl, C 14 haloalkyl, halo, cyano, nitro, -C(=O)NR m R m -C(=NR')NR'Rrn, -OR' m -OC(=O)NR"'Rn, 2 -OC 2 -6alkyNR m -0C 2 6 a1 kylOR m -S(=O0) 2 R 2 NR-R-, 2 2 N(R m )C(=O)OR, m R m -N(R m )C(=NR m 2 R", -N(R m 2 NR m -NR m C 2 _6alkylNR m -NR m C 2 _6alkylOR', -C(=O)Rs, C(=O)ORs, -C(=O)rNRsR' .C(=NRn)NRnRs -OR% .OC(=O)Rs -OC(=O)NRmW~, 2 -OC 2 6 alky1NRnRs, OC2- 6 alkylORs, -SRs, -S(=O0) 2 Rs, 2 NRnRs, 2 N(Rrn)C(=O)Rs, -S 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=O)NRnRs, -NRrnRs, -N(Rrn)C(=O)Rs, -N(Rr)C(=O)ORs, -N(Rrn)C(=O)NRnRs, -N(Rrn)C(=NRn)NRnRs. 2 2 NRnRs, -NRrnC 24 salkyINRrnR', -NRnC 2 6 alkyIORs and C 1 4 alkyl substituted by I or 2 groups selected fromr C 1 2 haloalkyl, halo, cyano, nitro, -C(=O)NR m -C(=NRm')NRTR m -OW", -OC(=O)NR m R m 2 R n, -OC 2 _6alkyl NR m R m -OC 26 alkyIOR m 2 2 NR"R m -S 2 N(Rr')C(=O)Rfl, 2 N(Rmf)C(=O)OR -S(O) 2 N(R.')C(=O)NR m R m -NR"'R m -N(R m -N(Rrn)C(=O)OR n, -N(R m )C(=O)NR"'R m -N(R m )C(=NR"')NR m -N(R m 2 Rn, -N(R m 2 NR'R"', -NR m C 2 6 alkyINR"'R", -NR m C 2 43 aI kylOR m -C(=O)ORs, -C(=O)NRnRs, -C(=NlRn)N~1RmRs, -OW, OC(=O)Rs, -OC(=O)NRnRs, -OC(=O)N(Rml)S(=O) 2 Rs, -OC 26 alkyl NR'~Rs, -0C 2 6 a1 kylORs, -SRs, -S(=O)Rs, 2 2 NRrnR', -S5(=0) 2 N(Rrn)C(0O)Rs, 2 N(R"')C(=O)ORs, 2 N(R"')C(=O)NR m R- 5 -N~lmRs, -N(Rr)C(0O)Rs, .N(R)C(0)0R 5 -N(Rm 1 -N(RIm)C(=N R)NRmlRs, -N(R m 2 R', -N(R m 2 NR"'Rs, -Nm26lyN'' -NR. mC 26 alkylOR'; and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups; but in no instance is R 4 3,5-ditrifluoromethylphenyl or 3-trifluorornethyl-4rfluorophenyl. 460

51. The compound according to Claim 35, wherein R 4 is a saturated or unsaturated 5- or 6-membered ring containing 1, 2 or 3 atoms selected from 0, N and S that is vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C 1 8 alkyl, C 1 4haloalkyl, halo, cyano, nitro, -C(=O)0R n, -C(=0)NR m -C(=NR m )NR m -OR m -OC(=0)NR m R m -0C(=0)N(R m 2 R n, -OC 24 salkylNR m -OC 2 6 alkylOR', -SR m 2 2 NR'R m S(=0) 2 N(R m 2 N(R m )C(=0)0R n, 2 N(R m )C(=0)NR m -NR m R m N(R m n, -N(R m )C(=O)0R n, -N(R m -N(R m )C(=NR m )NR m R m -N(R m 2 R 0 n, -N(R m 2 NR m R', -NR m C 26 alkyNR m R m -NR m C 2 6 alkylOR', -C(=0)ORs, -C(=O)NRnRs, -C(=NRn)NRnRs, -0Rs, OC(=0)Rs, 0C(=0)NRnRs, -0C(=O)N(Rn)S(=O) 2 Rs, -OC 2 6 aI kylNRnRs, -OC 2 6al kylOR-, -SRs, -S(=O)Rs, 2 -S 2 NRnRS, 2 N(Rrn)C(=O)R', 2 N(Rrn)C(=O)ORs, 2 N(Rrl)C(=0)NRnRs,.-NRrnR', -N(Rrn)C(=O)Rs, -N(R')C(=O)ORs, ~N(Rrn)C(=0)NRnRs, -N(Rrn)C(=NRn)NRnRs, -N(R m )S 2 R', -N(Rrn)S(=0) 2 NRnR', -NR m C 26 aIkylNR m Rs, -NRC 2 6al kylORs and C 1 4alkyl substituted by 1 or 2 groups selected from C 1 2 haloalkyI, halo, cyano, nitro, -C(=O)OR n. -C(=O)NR m -C(=NR m )NR m -OR- m -OC(=0)NR m R m -OC(=O)N(R m 2 R n, -OC 2 6 alkyNR m R m -OCZ. 6 alkylOR m -SR m 2 -S 2 NR m 2 N(R m 2 N(R m 2 N(RIn)C(=O)NRmR m -NR m R m -N(R m n, -N(R m )C(=O)OR n, -N(R m )C(=0)NR m R m -N(R m )C(=NR m )NR m Rm 1 2 R n, -N(R m 2 NRR m -NR"'C 26 al kyINR m -NR m C 2 6 alkylOR m -C(=O)0R 5 -C(=O)NR m -C(=NRrl)NRrnRs, .OC(0O)Rs, -OC(=O)NR"'Rs, 2 -OC 2 6 al kylNR m -OC 2 6 al kyIOR', -SRs, 2 Rs, -S 2 NR m Rs, -S 2 -S 2 N(R m )C(=O)OR 5 -S 2 N(R m )C(=O)NR m Rs, -NR m Rs, -N(R m -N(R m )C(=O)0R 5 -461- -N(Rrn)C(=0)NRnR', -N(Rrn)C(=NRn)NRrnR', -N(Rrn)S(=0) 2 R', -N(Rrn)S(=0) 2 NRnR', -NRrnC 2 -6alkyIN-RrnR, -NRrnC 2 alkyl0R'; and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups; but in no instance is R 4 3,5-ditrifluoromethyiphenyl or 3-trifluoromethyl-4-fluorophenyl.

52. Th opudacrigt Cam3,weenR sH 52. The compound according to Claim 35, wherein R9 IsH independently, at each instance, C 1 8 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, d d d d d -NR dCI -haloalkyl, -NRd C 2 -,alkylNR dR dor -NR dC 2 -6alky]OR d, -C0 2 (Cl-ralkyl), 1 6 alkyl), -C(=0)NR dR d, -NRdC(=0)(C 1 6 alkyl), -NR dC(=O)NR dR d, -NRd C0 2 (C 1 6 alkyl), -CI-8alkyl0R d, C-akl~ '-(O,(j6ly) 2 NRdR 1pNdS(=0)2(C i-aki) or -0C(=0)NRRd

54. The compound according to Claim 35, wherein R 9 is a -(CR qRI), 0 phenyl wherein the phenyl is substituted with 0, 1, 2, or 3 substituents independently selected from R1 0

55. The compound according to Claim 35, wherein R 9 is -(CR qR q)4 [et wherein Het is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from 0, N and S substituted with 0, 1, 2, or 3 substituents independently selected from R1 0 or R 9 is a saturated or unsaturated 4- or 5-membered ring heterocycle containing a single nitrogen atom, wherein the ring is substituted with 0, 1 or 2 substituents independently selected- from halo, C 1 2 haloalkyl and CI- 3 alkyl.

56. A compound having the structure: -462- or any pharmaceutically-acceptable salt thereof, wherein: Yis OorS; n is independently, at each instance, 0, 1 or 2. R' is 7 R Ri R8 R 9 or R' is a naphthyl substituted by 0, 1, 2 or 3 substituents independently selected from R 5 or R' is R' substituted by 1, 2 or 3 substituents independently selected from R 5 R 1 5 is, independently, in each instance, Ci.salkyl substituted by 0, 1 or 2 substituents selected from R' 1 -(CH 2 )nphenyl substituted by 0, 1, 2 or 3 substituents independently selected from R'O, or a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, the heterocycle and bridge being substituted by 0, 1, 2 or 3 substituents independently selected from R 1 0 R 1 6 is, independently, in each instance, H, halo, -NH2, -NICi.3alkyl, -N(Ci. 3 alkyl)C 1 i 3 alkyl, -OC. 3 alkyl, -Ci. 2 haloalkyl, -OCi.2haloalkyl or C. 3 alkyl; 463 R~Rio Rl R 13 wherein when R' is bromophenyl, methyiphenyl or trifluoromethylphenyl, R 4 is not trifluoromethyiphenyl or trifluoromethyihalophenyl;, or R 4 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from 0, N and S, so long as the combination of 0 and S atoms is not greater than 2, wherein each of the carbon atoms of the heterocycle is substituted by H, Cl- 9 alkyl, C,. 4 haloalkyl, halo, cyano, oxo, -OR h, 1 6 alkyl, hhh -OCI 1 4 haloalkyl, -OC 2 6 alkylNR -OC2z6alkylOR .QO 1 6 alkylC(=Q)0Rh, -NR R -NRhCi- 4 haloalkyI, -NR.G 2 6 alkylNR R -NRhC 2 .,alkylORh -C(=0)C 1 6 alkyl, -C(=0)0C 1 6 alkyl, -OC(=0)CI- 6 a1 kyl, -C(=O)NR hC 1 6 a1kyl or -NR hC(=O)C 1 6 alkyl; and saturated carbon atoms may be additionally substituted by and each of the available nitrogen atoms in the heterocycle are substituted by H, -C 1 6 alkyl0R h,9 6 alkyI, -CI- 6 alkylNRh 3 alkylC(=o)oRh, -C 1 3 alkylIC(=O)NRh Rh, C 1 3 alkylOC(=O)C 1 6 alkyl, -CI- 3 alkylNR hC(=O)Ci IfalkyI, -C(=)Rjor -C 1 3 alkyIRj; or R 4 is an 10- or 1 1-membered bicyclic ring, containing 0, 1, 2, 3 or 4 N atoms and 0, 1 or 2 atoms selected from S and 0 with the remainder being carbon atoms, wherein each of the carbon atoms of the ring is substituted by H, Cj. 9 alkyl, C 14 haloalkyI, halo, cyano, oxo, -ORh, 1 6 alkyl, -OCI. 4 haloalkyl, -OC 2 .cialkylNR Rh, -OC 2 6 alkylOR, -OC 1 -6alkylC(=O)OR h, -NR R h, -NRh~ C 4 haloalkyl, -NR hC 2 6 alkylNRR R, _NRh C 2 _6alkylOR h 16 alky1, -C(=O)0C 1 6 alkyl, -OC(=O)C 1 6 alkyl, -C(=O)NRhCi. 6 alkyl or -N4RhC(=O)Ca 1 6 alkyl; and saturated carbon atoms may be additionally substituted by and any available nitrogen atoms in the ing are substituted by H, -CI- 6 alkylOR hq -CI. 6 alkyl, -Ci. 6 ,alkylINR hR h, -C 1 3 alkylC(=O)OR h, 3 alkylC(=O)NRh Rh, 3 alkylOC(=O)C 1 6 alkyl, 3 alkylNRhC(=O)C 1 6 alkyl, -C(=O)Rj or -C 1 3 alkylRj; 464 R 5 is independently, at each instance, H, C 1 5 alkyl, C 1 4 haloalkyl, halo, hh h h h nitro, -0CI. 6 alkyl, -OCI 1 4 haloalkyl, -OC 2 6 alkylNR R -0C 2 6 alkylOR -NR R -NhC 1 .4haloalkyl, -N~hC 2 -6alky]NR h Rh, _NRh C 2 6 alkylOR h, naphthyl, -C0 2 (Cl. 6 alkyl), 1 6 alkyI), -C(=O)NR hR h, -NR hC(=O)R h, _NhC(=O)NR hR h -NR'hCO 2 (CI-6alkyl), -C 1 salkylOR h, -C 1 6 alkylNRh Rh, -S(=O)n(C 16 alkyl), 2 NR R h,_NhS(=O) 2 (CI- 6 alkyl), -OC(=O)NkhR h, a phenyl ring substituted with 0, 1, 2, or 3 substituents independently selected from R1;or R 5 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from 0, N and S, substituted with 0, 1, 2, or 3 substituents independently selected from Rio. R 6 is independently, at each instance, H, C 1 .salkyl,.C 1 4 haloalkyl, halo, -0CI 6 alkyl, -0CI. 4 halo'al kyl, -0C,,alkylNR'~, -0C 2 6 alkyl0Rh, -NR R -NPRhC 1-haloalkyl, _NRh C 2 -6alkylNRhRh or -NR hC 2 6 alkylOR h, -CI-8alkyIOR h, -CI- 6 alkylNR hR h, -S(C 1 6 alkyl), a phenyl ring substituted with 1, 2, or 3 substituentfs independefitly selected from Rio; or R 6 is a saturated or unsaturated or 6-membered ring heterocycle containing 2 or 3 atoms selected from 0, N and S substituted with 0, 1, 2, or 3 substituents independently selected from R' 0 R 7 is independently, at 'each instance, H, C 1.8alkyl, C I 4 haloalkyl, bromo, -0C 1 6 alkyl, -OC14haloalkyl, -OC 26 a~ky1NRhR h, -OC 2 -6alkylOR h -NR R h, -NR'CI- 4 haloalkyl, -NRhC 2 6 alkylNRh R h, -NRhC 2 6 alkyl0R h, -Cl-galkylOR h, CI- 6 alkyINRh Rh or -S(C 1 -alkyl); or R 7 is a saturated or( unsaturated 4- or 5-membered ring heterocycle containing a single nitrogen atom, wherein the ring is substituted with 0, 1 or 2 substituents independently selected from halo, C 1 2 haloalkyl and C 1 3 alkyl;' R 8 is independently, at each ins ta .nce, H, C, 5 alkyl, C 1 4 haloalkyl, halo, h h h h -0C 1 -6alkyl, -OC 1 4 haloalkyl, -0C 2 6 alkylNRR R, -0C 2 6 alky]0R -NR R -NR hC 14 haloalkyl, -NRh C 2 6 alkylNR'R, -NR hC 2 6 alkylOR', -CI-alkyl0Rh, CI-alky jIg4Rhb, -S(C 1 6 alkyI), a phenyl ring substituted- with 1, 2, or 3 substituents independently selected from R' 0 or R 8 is a saturated or Unsaturated or 6-membered ring heterocycle containing 1,2 or 3 atoms selected from 0, N and S substituted with 0, 1, 2, or 3 substituents independently selected from R 1 0 465 R 9 is independently, at each instance, H, C 1 8 alkyl, C 1 4haloalkyl, halo, nitro, -OC,-6alkyl, -0CI. 4 haloalkyl, -OC 2 6 alkylNRhRh, -OC 2 6 alkylORh, -NRh R h, _14RhCi 4 haloalkyl, -NR hC 2 6 alkyINR hR h or, -NRhC 2 -6aIkylORh, CO 2 (CI- 6 a1 kyl), 1 6 alkyl), -C(=O)NRhRh, -NRhC(=O)(Ci. 6 alkyl), -NRh C(=a)NRh, -NRhC0 2 (CI-6alkyl), -CI- 8 aikylOR h, -CI- 6 alkylNRh R h, 1 _6alkyI), 2 NR hR h ~Nh(=O) 2 (CI. 6 alkyl), -OC(=O)NRhR a phenyl ring substituted with 0, 1, 2, or 3 substituents independently selected from R' 0 or R 9 is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from 0, N and S substituted with 0, 1, 2, or 3 substituents 105 6 7 8 independently selected from R10; wherein at least one of R R R R and R 9 is C 1 8 alkyl, C 1 4 haloalkyl, halo, -0CI. 4 haloalkyl, -OC2- 6 a1 kylNRhRh, _6 2 al kyloRh ~Nh 1 4 aolkyi _NRh C 2 6 alkylNR R h, -NRh C 26 alkyIOR h, -CI-8alkyl0R h, -C 1 6 alkylNRR R or -S(C 1 6 alkyl); or R 9 is a saturated or unsaturated 4-.or 5-membered ring heterocycle containing a single nitrogen atom, wherein the ring is substituted with 0, 1 or 2 substituents independently. selected from halo, C 1 2 haloalkyl and C 1 3 alkyl; R1 0 is independently, at each instance, selected from H, C 1 8 alkyl, C 14 haloalkyl, halo, cyano, nitro, 8 al kyl), -C(=0)0(C.galkyl), _C(=0)NRh Rh, _C(=NRh)NRh Rh, OR h -OC(=0)(C 1 8 galkyl), -0C(=0)NR hR h, -0C(=O)N(R h)S(=0) 2 (CI-8alkyl), -OC 2 6 a~kylNRh -OC 2 -6al kylOR h, -SR h, h h -S(=0)(CI-8alkyl), 2 (C 1 .salkyl), 2 NR R -S 2 N(R 1 8 a1 kyl), 2 N(R h)C(=0)O(C 1 .alkyl), 2 N(R h)C(=O)NR R h, -NR -N(R h)C(=O)(Cisalkyl), -N(R h)C(=0)0(C 1 _8al kyl), -N(R h)C(=0)NRh Rh, N(R h)C(=NR h)NR h Rh -N(R h)S(=O) 2 (C 1 8 alkyI), -N(R h)S(=O) 2 NR -NR C 2 ,alky]NRhR h and -NR hC 2 6alkyl0R or R1 is a saturated or unsaturated 6- or 7-membered monocyclic or 10- or I 1-membered bicyclic ring containing 1 or 2 atoms selected from N, 0 and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atomn bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 I 466 and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo, groups, wherein the ring is substituted by 0, 1, 2 or 3 groups selected from C 1 .salkyl, Cz-4haloalkyl, halo, cyano, nitro, 1 .salkyI), salkyl), -C(=O)NR hRh1, R h -OR h, h hh -OC(=O)(CI-8a~kyl), -OC(=O)NR R. -OC(=O)N(R 2 (CI-8alkyl), -OC 2 ,alky]NRhR h, -0C 2 alkyIOR. -SR. 1 8 a1 kyl),-S 2 (C 1 8 alkyl), 2 Nh h, 2 N(R.h)C(=O)(C 1 8 alkyl), 2 N(R h)C(_O)O(C,8lI, 2 -NR Rh, -N(Rh)C(=O)(C 1 .salkyl), CI 8 alkyI), -N(Rh)C(=O)NRR', -NR )C(=NRh)NRhR, -N(R h)S(=O) 2 (CI-8alkyl), -N(R h)S(=O) 2 NRh Rh, _Nh C 26 alkylNR hR h and( -NRhC 2 -6alkylOR h; or R1 is C 1 4 alkyI substituted by 0, 1, 2 or 3 groups selected from C 1 4 haloalkyl, halo,'cyano, nitro, 1 8 alkyl), -C(=O)NR hR h h h h h -C(=NR )NR R -OR -OC(=O)(C 1 8 alkyl), -OC(=O)NRR R, -OC(=O)N(R h)S(=O) 2 .galkyl), -OC 2 -6alkylNR"R4, -OC 2 1aI kylOR h, -SR. -S(=O)(Cl.8alkyl), 2 8 alkyI), 2 NRh Rh, 2 N(R 1 8 a1 kyl), 2 N(R h)C(;=O)O(C 1 salkyl), -S 2 N(R h)C(=O)NR hRh, -NR hR h, -N(Rh)C(=O)(C 1 .alkyl), -N(R h)C(=O)O(C 1 .salkyl), )C(=O)NRh -N(R h)C(=NRh )NR hRh, -N(R h)S(=O) 2 .salkyl), -N(R h)S 2 NR hR. _h C 2 6 alkylNR hR.h and -NR hc(alky]OR h; R" is independently, at each instance, selected from H, CI.Salkyl,( C 1 4 haloalkyl, halo, cyano, ni tro, 1 8 alkyl), 8 alkyl), -C(=O)NRh R h, -C(=NR )NR R h, -OR h, -OC(=O)(CI..galkyl), -OC(=O)NR hR. h)S 2 (C 1 8 alkyl), -OC 26 aIkylNR"R h, -OC 2 ,alkylOR', -SR. 8 alkyl), 2 8 alkyl), 2 NR R h, 2 N(R 8 a1 kyl), 2 N(Rh)C(=O)O(C 18 a1 kyl), 2 N(R )C(0)NRh R. h, -NR. R h, -N(R 1 -alkyl), -N(R h)C(=O)O(Cl 8 a1 kyl), )C(=O)NR R h, hR h -N(R h)S(=O) 2 (C 1 8 a1 kyl), -N(R h)S 2 NRhR h, _h C 2 6 alkyINR hR h and _NhC2_alkyOR h; or R' is a saturated or unsaturated 6- or 7-membered monocyclic or 10- or 11 1-membered bicyclic ring containing 1, 2 or 3 atoms selected from N, 0 and S, wherein the ring is fused with 0 or 1 benzo 467 groups and 0 or 1 saturated or unsaturated 6- or 7-membered heterocyclic ring containing 1, 2 or 3 atoms selected from N, 0 and S; wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 groups selected from C 1 8 alkyl, CI-4haloalkyl, halo, cyano, nitro, -C(=O)(Cj.galkyl), -C(=O)O(CI-8alkyl), -C(=0)NR hR h, -C(=NRh)NRh -OR h -OC(=O)(C 1 8 alkyI), -OC(=0)NR -OC(=0O)N(Rh)S(=O) 2 (CI-8alkyl),. -OC 2 -ral kyl*NRh Rh, -OC 2 .6alkylOR h, -SR h, 1 8 alkyl), 2 (C 1 8 alkyl), h hh(O( phC=)( 2 NR 2 N(Rh)(O( 1 8 a1 kyl), -S 1 .alkyl), S(=0) 2 N(Rh)C(=0)NR -NRh R h, -N(R 1-alkyl), -N(R h)C(=0)O(Ci.- 8 alkyl), -N(R h)C(=O)NR R h, -N(R h)C(=NR h)NR R', -N(R h)S 2 (C,.galkyl), -N(R h)S(=O) 2 NR R h, -NRhC 2 alkylNR hR hand -NR hC 2 6 alkylOR h; or R11is C 14 alkyI substituted by 0, 1, 2 or 3-groups selected from C 1 4 haloalkyl, halo, cyano, nitro, -C(=O)(CI-8alkyl), -C(=O)O(Cl.8alkyl), _C(=O)NRh Rh, _C(=NRh)NRh Rh, -OC(=O)(Cjgalkyl), _OC(=O)NR hR h, -OC(=O)N(R h)S(=O) 2 (CI-8alkyl), -OC 2 6 alkylNR hR h, -0C 2 6 alkylOR h, -SR h galkyl), -S 2 .gal kyl), 2 NRhR', -S 2 N(Rh)C(=O)(Ci_8al kyl), 2 N(R .gal kyl), -S 2 N(R )C(0O)NRhR', -NR hR" hN(R h)C(0O)(Cis-alkyl), h RhC=R h h h -N(R )C(=O)O(CI-8alkyI), -N(R )C(=O)NR N()CNR)NR R, -N(R h)S(=0) 2 (C 1 8 a1 kyl), -N(Rt)S(=O) 2 NR R h, C 2 6 a~kyiNpI1Rh and -NR hG 2 -6alkylOR h; R'1 2 is independently, at each instance, selected from HI, CI- 8 alkyI, h h C,- 4 haloalkyl, halo, cyano, nitro, -C(=O)O(CI-8alkyl), R h hh h h h -C(=NRh)NR R -OR -OC(=O)(C,.galkyl), -OC(=O)NR R -OC(=O)N(R h)S(=O) 2 (CjsalkyI), -OC 26 alkylNR R h, -OC2-alkyIOR h, -SR h, -S(=O)(CI-8alkyl), 2 8 alkyl), 2 NR hRhI 2 N(R 1-alkyl), -S 2 N(R 8 alkyl), -S 2 N(R h)C(=O)NRhR h, _PRh Rh, 8 a1kyl), -N(Rh)C(=O)O(Cl galkyl), -N(R h)C(=O)NRh Rh, -N(R h)C(=NRh)NRh Rh, -N(R h)S 2 8 alkyl), -N(R h)S(=Q) 2 NR hR h, _NhC.alyN' and -NR hC 2 _6alkylOR h; or R 12 is a saturated or unsaturated 6- or 7-Membered monocyclic or 10- or I 1-membered bicyclic ring containing 1, 2 or 3 -468- atoms selected from N, 0 and S, wherein the ring is fused with 0 or. 1 benzo In groups- and 0 or 1. saturated or unsaturated 6- or 7-membered heterocyclic ring containing 1, 2 or 3 atoms selected from N, 0 and S; wherein the carbon atoms of the ring are substituted by 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 groups selected from Cl-galkyl, C 1 4 haloalkyl, halo, cyano, nitro, -C(=O)(Cj.galkyl), -C(=O)O(Ci'-8alkyl), -C(=O)NR hR h, _C(=NRh)NRh Rh, -OR h, C1 -OC(=0)(C 1 8 a1 kyl), OCO)R, -OC(=O)N(RhSO(C 1 8 a1 kyl), -OC,,alky1 OC 26 alkylOR, -SR, -S 1 salkyl), 2 (C 1 .salkyl), -s h _S sly) S(=O) 2 N(R h)C(=O)O(C 1 -8alkyl), -S(=O0) 2 N(R h)C(=O)NRh Rh, -NRhR h -N(Rh)C(=0)(CI-8alkyl), h)(ONh hC= h h -N(R )C(=O)0(C 1 -al kyl), -N(Rh)(ON R; N(Rh)( R )NR R, -N(R h)S(=0) 2 (CIs8alkyl), -N(R h)S(=0) 2 NRh R h, -NRh C 26 alkylNR hR and -NR hC 2 -6alkyl0R h; or R 12is C,. 4 alkyl substituted by 0, 1, 2 or 3 groups selected from Ci- 4 haloalky], halo, cyano, nitro, -C(=O)(CI-8alkyl), -C(=O)O(C 1 8 alkyl), -C(=O)NRh R h, -C(=NR h)NRh -OC(=O)(Clgalkyl), -OC(=O)NR hRh, -OC(=0)N(R h)S 2 (CI-8alkyl), -OC 2 -6alkylNRh R h -OC 2 -6aIkyloR h -SR h 1 .salkyl), 2 (C 1 .salkyl), 2 NRhRh, 2 N(R h)C(=O)(C 1 8 alkyl), 2 N(R 8 alkyl),' 2 N(R h)C(=O)NRh Rh, 4 pRh Rh, -N(R isalkyl), -N(R h)C(=O)O(C 1-8alkyl), -N(Rh)C(=0)NRh Rh, N(R h)C(=NR h)NR hR', -N(R h)S(=O) 2 (CI-8alkyl), -N(R h)S(=O) 2 NRh Rh, N1hC 26 alkylNR h Rh and -NRC2_alkylOR R" 3 is independently, at each instance, selected from H, CI-8alkyl, C 1 -4haloalkyl, halo, cyano, nitro, 1 Igalkyl), -C(=O)O(C 1 .salkyl), _=ONhh,_Nh hp h h C(ON R,-NR )NRh -ORh -OC(=O)(C 1 8 alkyl), -OC(=O)NR R, -OC(=O)N(R h)S(=O) 2 (C 1 8 a1 kyl), -0C 2 6 a1 kylNR hRh, -0C 2 6 a1 kylOR h, -SR h, 1 galkyl), 2 (C 1 .salkyl), 2 NRhRh, 2 N(R h)C(=O)(C 1 -galkyl), 2 N(R h)C(=O)O(C 1 8 akyl), 2 N(Rh)C(=O)NR R h,_Rh Rh, -N(R)C(=O)(CI-8alkyl), 1 -8al kyl), -N(Rh)(=O)NRhR, N()CNh)NIZhR', -N(Rh)S(=O) 2 (Cis alkyl), -N(R h)S(=O) 2 NR -NR C 26 alkylNR hR hand -NR hC 2 -6alkylOR h; or R 13is a saturated or unsaturated 6- or 7-memnbered 469 monocyclic or 10- or 1 1-membered bicyclic ring containing 1, 2 or 3 atoms selected from N, 0 and S, wherein the ring is fused with 0 or 1 benzo groups and 0 or 1 saturated or unsaturated 6- or 7-membered heterocyclic ring containing 1, 2 or 3 atoms selected from N, 0 and S; wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 groups selected from C 1 8 alkyl, CI- 4 haloalkyl, halo, cyano, nitro, -C(=O)(CI-8alkyl), -C(=O)O(CI-8alkyl), -C(=O)NR hR', -C(=NR )NRh OR h 1 ealkyl), -OC(=O)NR Rh OC(=o)N(R h)S(=O) 2 (CI. 8 alkyl), -OC 2 6 alkylNRh R; OC 2 -6alkyl0R', SRh, -S(=O)(CI-8alkyl), 2 (CI-8alkyl), 2 NRhR h, -S 2 N(R h)C(=O)(C 1 8 alkyl), -s 2 N(R .galkyl), 2 N(R h)C(=O)NRh -NR hRh, -N(R h)C(0)C 1 .alkyl), -N(R 8 alkyl), -N(Rh)C(;=0)NR R h, -N(R h)C(=NRh)qRh Rh., -N(R h)S(=0) 2 (CI-8a~kyl), -N(R h)S(=0) 2 NR R h, _NRh C 26 alkylN41h Rh and -NR hC 2 6 alkylOR h; or R 13is C 1 4 alkyl substituted by 0, 1, 2 or 3 groups selected from C 1 4 haloalkyl, halo, cyano, nitro, -C(=O)(CI-8alkyl), -C(=0)O(Cl.8alkyl), h h hh h h h -C(=O)NR -C(=NR )NR R, -OR -OC(=O)(C,.salkyl), -OC(=O)NR R -OC(=O)N(R h)S(=O) 2 (CI-8alkyl), -OC 2 -6al kylNR hR h, -0C 2 6 a1 kylOR hi _SR h, 1 galkyI), 2 (C 1 8 alkyl), 2 NRhR' 2 N(R h)C(=O)(Ci .8al kyl), 2 N(R h)C(=0)O(C 1 8 alkyl), 2 N(R h)C(=O)NRhR h, _h R h, salkyl), -N(R h)C(=0)0(Cis-alkyl), -N(R h)C(=O)NR hR h, -N(R h)C(=NR h)NR hRh, -N(R h)S(=O) 2 (C 1 .salkyl), -N(Rh)S(=O),NRhR h, _NRh C 26 alkylNR h Rh and -Nh C 2 6al kylOR h; R 1 4 is independently, at each instance, selected from H, 8 alkyl, C 1 -4haloalkyl, halo, cyano, nitro, -C(=0)(CI-8a~kyI), -C(=O)O(C 1 .salkyl), _C(=O)NRh Rh' -C(=NRh)NRh R h, -OR h, -OC(=O)(Cl.8alkyI), -OC(=O)NRh Rh, -0C(=O)N(R h)S(=O) 2 (CI-8alkyI), -OC 2 6 alkylNR hR h, -0C 2 6 alkyIOR h, -SR h 1 salkyI), 2 (C 1 sa~kyl), 2 NRh Rh, 2 N(R 1 -8alkyI), 2 N(R h)C(=0)O(C 1 8 alkyI), 2 N(R h)C(=0)NR h Rh, -NRhRh, -NRhC=)C 18 a1 kyl), -N(R h)C(=0)O(Cl 8 a1 kyl), -N(R h)C(=O)NRh Rh, -N(R h)C(=NRh )NR hR h, ~N(Rh)S(=O) 2 CI-8alkyl), -N(R 2 NR hR h, _NR hC 2 6 alkylNR hR" and 470 R h C 2 6 alkylOR h; or R 14is a saturated or unsaturated 6- or 7-membered monocyclic or 10- or 1 1-membered bicyclic ring containing 1 or 2 atoms selected from N, 0 and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 01 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 groups selected from C 1 .salkyl,*C 1 4haloalkyl, halo, cyano, nitro, 1 8 a1 kyl), -C(=0)0(C 1 .galkyl), -C(=0)NRhR h, C(=NR h)h R h -ORh, -OC(=0)(C 1 8 alkyl), -0C(=0)NRhR h, -0C(=O)N(R h)S(=O) 2 (C 1 .Balky]), -0C 2 -,alkylNR R h, -OC 2 6 alkyIOR h, -SR h, s8alkyl), 2 CI-8alkyl), 2 NR hR h, 2 N(R h)C(=O)(C 1 -8alkyl), 2 N(R 8 alkyl), 2 N(R h)C(0)NRh R h, -NRhR h, -N(R 1-alkyl), -N(R h)C(=0)0(C 1 .salkyl), -N(R )C(=O)NRh Rh, h)NR hRh, -N(Rh)S 2 (CJ salkyl), -N(R h)S(=O) 2 NR hR h, _NhC-aklRhR and -NR h C 2 6 alkyl0R h; or R 14is C 1 4 alkyl substituted by 0; 1, 2 or 3 groups selected from C 1 4haloalkyl, halo, cyAno, nitro, -C(=0)(C,.salkyl), -C(=0)NR hR h, -C(=NRh)NRhR ORh, -OC(=0)(Cj galkyl), -OC(=0)NR R hhh h -0C(=0)N(R 2 (CI-8alkyl), -0C 2 ,alkylNR R -0C 2 6 alkylOR -SR, -S(=O)(Ci~galkyl), 2 (CI.8alkyl), 2 NR Rh 2 N(Rh)C(=0)NR hR', _h R h -N(R 1 -8alkyI), -N(Rh)C(=O)0(C 1 .alkyl), -N(R h )C(=0)NR hR h, -N(R h)C(=Rh)h R h -N(R h)S 2 (C 1 8 alkyl), -N(R h)S 2 NRhR hi _RhC 2 -6akylNR h Rh and -NR ihC 2 6 alkyloR h; R h is independently, at each instance, H, phenyl, benzyl or C 1 -alkyl, the phenyl, benzyl and CI-6alkyl being substituted by 0, 1, 2 or 3 substituents selected from halo, C I-4alkyl, C 1 3 haloalkyl, -0C 1 4 Alkyl, -Nil 2 -NHIIC 1 4 alkyl, -N(C 14 a1 kyl )C 1 4 alkyl; R' is a heterocycle selected from the group of thiophene, pyrrole, 1,3- oxazole, I ,3-thiazol-5-yl, 1 ,3,4-oxadiazole, 1 ,3,4-thiadiazole, 1 ,2,3-oxadi azole, I ,2,3-thi adi azole, 1 H-i ,2,3-triazole, isothiazole, 1 ,2,4-oxadiazole, 1,2,4- -471- thiadiazole, 1,2,3 ,4-oxatriazole, I ,2,3,4-thiatriazole, IH- 1,2,3,4-tetraazole, 1 ,2,3,5-oxatriazole, I ,2,3,5-thiatriazole, furan, imidazol- l-yi, imidazol-3-yi, imidazol-4-yi, I ,2,4-triazole, 1 ,2,4-tri azole, i soxazole, pyrazol-3-yl, pyrazol-4-yi, thiolane, pyrrolidine, tetrahydrofuran, 4,5-dihydrothiophene, 2- pyrroline, 4,5-dihydrofuran, pyridazine, pyrimidine, pyrazine, 1,2,3-triazine, 1 ,2,4-triazine, 1 ,2,4-tniazine, 1 ,3,5-triazine, pyridine, 2H-3,4,5,6-tetrahydropyran, thi ane, I ,2-di azaperhydroi ne, I ,3-di azaperhydroine, piperazi ne, 1,3- oxazaperhydroine, morphol ine, I ,3-thiazaperhydroine, 1 ,4-thiazaperhydroine, piperidine, 2H-3,4-di hydropyran, 2,3-dihydro-4H-thin, 1,4,5,6- tetrahydropyridi ne, 2H-5 ,6-dihydropyran, 2,3-dihydro-6H-thi in, 1,2,5,67 tetrahydropyricline, 3,4,5 ,6-tetrahydropyni dine, 411-pyran, 4H-thiin, 1,4- dihydropyridine, I ,4-dithiane, 1,4-dioxane, I ,4-oxathi ane, 1 ,2-oxazolidine, 1,2- thiazolidine, pyrazolidine, 1 ,3-oxazolidine, I ,3-thiazolidine, imidazolidine, 1,2,4- oxadiazolidine, I ,3,4-oxadi azol idine, 1,2,4-thiadiazolidine, 1,3,4-thiadiazolidine, 1 ,2,4-triazolidine, 2-imidazolin- l-yl, 2-iniidazolin-2-yl, 2-imidazoliz-5-yI, 3- imidazoline, 2-pyrazoline, 4-imidazoline, 2,3-dihydroisothiazole, dihydroisoxazole, 4,5-dihydroisothiazole, 2,5-dihydroisoxazole, dihydroisothiazole, 2,3-dihydroisoxazole, 4,5-dihydrooxazole, 2,3- dihydrooxazole, 2,5-dihydrooxazole, 4,5-dihydrothiazole, 2,3-dihydrothiazole,, 2,5-dihydrothiazole, 1 ,3,4-oxathiazolidine, I ,4,2-oxathi azolidine, 2,3-dihydro-1 H- [1 ,2,3]triazole, 2,5-dihydro- 1H-[ 1,2,3]triazole, 4,5-dihydro- 1H-[ 1,2,3]triazol- l-yI, 4,5-dihydro-1H-[I ,2,3]triazot-3-yl, 4,5-dihydro- IH-[ 1,2,3]triazol-5-yJ, 2,3- dihydro- IH-[1I,2,4]triazole, 4,5-dihydro- IH-[1I,2,4]triazole, 2,3-dihydro- [1 ,2,4]oxadiazole, 2,5-dihydro-[1 ,2,4joxadiazole, 4,5-dihydro-[1I,2,4]thiadiazole, 2,3-dihydro-[ 1,2,4] thidiazole, 2,5-dihydro-[ 1,2,4] thi adi azole, 4,5-dihydro-[ 1,2,4] thi adiazole, 2,5-dihydro-[ I,2,4]oxadiazole, 2,3-dihydro-[1I,2,4]oxadiazole, dihydro-[ 1,2,4]oxadiazole, 2,5-dihydro-[1I,2,4]thiadiazole, 2,3-dihydro-[ 1,2,4] thiadiazole, 4,5-di hydro-[ 1,2,4] thiadiazole, 2,3-di hydro-[ 1,3,4]oxadiazole, 2,3- dihydro-[ 1,3,4]thiadiazole, [1 ,4,2]oxathiazole, [i1 ,3,4]oxathiazole, 1,3,5- tn azaperhydrol ne, 1 ,2,4-triazaperhydroine, 1 ,4,2-dithiazaperhydroine, 1,4,2- dioxazaperhydroine, 1,3 ,5-oxadiazaperhydroi ne, I 1,3,4-th iadiazaperhydroine, 1 ,3,5-thiadiazaperhydroine, 1,2,5- 472 thi adi azaperhydroi ne, 1,3 ,4-oxadiazaperhydroine, 1 ,4,3-oxathi azaperhydrol ne, I ,4,2-oxathi azaperh ydroi ne, 1,4,5 ,6-tetrahydropyridazine, 1,2,3,4- tetrahydropyri dazine, 1,2,3 ,6-tetrahydropyridazine, 1 ,2,5 ,6-tetrah ydropyrimidine, I ,2,3,4-tetrahydropyrimidine, 1 ,4,5,6-tetrahydropyri midine, 1,2,3,6- tetrahydropyrazine, 1,2,3 ,4-tetrahydropyrazine, 5 ,6-dihydro-4H-[ 1,2]oxazi ne, 5,6- di hydro-2H-[ 1,2]oxazine, 3 ,6-dihydro-2H- [1 ,2]oxazine, 3 ,4-dihydro-2H- [1 ,2]oxazine, 5 ,6-dihydro-4H-[1I,2]thiazine, 5,6-dihydro-2H-[ 1,2] thiazine, 3,6- dihydro-2H- thi azirie, 3 ,4-dihydro-2H-[ 1,2] thi azine, 5 ,6-dihydro-2H- 1,3]oxazine, 5,6-dihydro-4H-[ 1,3]oxazine, 3,6-dihydro-2H-[1I,3]oxazine, 3,4- dihydro-2H-[ I,37loxazine, 3,6-dihydro-2H-[ I,4]oxazine, 3,4-dihydroi-2H- [1 ,4]oxazine, 5,6-dihydro-2H-[ 1,3]thiazine, 5,6-dihydro-4H-[ I,3]thiazi'ne, 3,6-' dihydro-2H-[1 ,3]thi azine, 3,4-dihydro-2H-[ 1 ,3]thiazine,- 3,6-dihydro-2.H- [1 ,4]thiAzine, 3 ,4-dihydro-2H-[ 1,41thiazine, I ,2,3,6-tetrahydro-[ 1,2,4]triazine, I ,2,3,4-tetrahydro-[1I,2,4]triazine, 1,2,3 ,4-tetrahydro-[1I,3,5]triazine, 2,3,4,5- tetrahydro-[ 1,2,4]triazine, I ,4,5,6-tetrahydro-[1I,2,4]triazine, 5,6-dihydro- [1 ,4,2]dioxazine, 5,6-dihydro-[ I ,4,2]dioxazine, 5,6-di hydro-[ 1,4,2]dithiazine, 2,3- dihydro-[1I,4,2]dioxazine, 3,4-dihydro-2H-[ I,3,4]oxadiaz.i ne, 3,6-di hydro-2H-' [1 ,3,4]oxadiazine, 3 ,4-dihydro-2H-[1I,3,5]oxadiazine, 3,6-dihydro-2H- [1 ,3,5]oxadiazine, 5,6-dihydro-2H-[1I,2,5]oxadiazine, 5,16-di hydro-4H- [1 ,2,5]oxadi azine, 3,4-dihydro-2H-[1I,3,4]thi adiazi ne, 3 ,6-dihydro-2H- [1 ,3,4]thiadiazine, 3,4-dihydro-2H-[1I,3,5]thiadiazine, 3,6-dihydro-2H- [1 ,3,5]thiadiazine, 5,6-dihydro-2H-[1 ,2,5]thiadiazine, 5,6-dihydro-4H- [1 ,2,5]thiadiazine, 5,6-dihydro-2H-[1I,2,3]oxadiazine, 3 ,6-dihydro-2H- [1 ,2,5]oxadiazine, 5,6-dihydro-4H-[1 ,3,4]oxadiazine,, 3,4-di hydro-2H-' [1 ,2,5loxadi azine, 5,6-dihydro-2H-[ I,2,3]thiadi azineI 3 ,6-di hydro-2H- [1 ,2,5]thiadi azine, 5,6-dihydr'o-4H-[1I,3,4]thiadiazine, 3,4-di hydro-2H- [1 ,2,5]thiadi azine, 5,6-dihydro-[ 1,4,3]oxathi azine, 5,6-dihydro-[ 1,4,2]oxathiazine, 2,3-dihydro- 1 ,4,3]oxathiazi ne, 2,3-dihydro-[ 1,4,2]oxathiazi ne, di hydropyridine, I ,6-dihydropyridine, 5,6-di hydropyridine, 2H-pyran, 2H-thiin, 3,6-dihydropyridine, 2,3-dihydropyridazine, 2,5-dihydropyridazine, dihydropynidazine, 1 ,2-dihydropyridazine, I ,4-di hydropyrimidin- l-yl, 1,4- dihydropyn midi n-4-yi, I ,4-di hydropyn midin-5-yI 1 ,4-di hydropyrimidin-6-yi, -473- 2,3 -di hydrop yrimi dine, 2,5-di hydropyrimidine, 5,6-dihydropyrimidine, 3,6- dihydropyrimidine, 4,5-dihydropyrazine, 5,6-dihydropyrazine, 3,6- dihydropyrazine, 4,5-dihydropyrazine, I ,4-dihydropyrazine, 1 ,4-dithiin, 1,4- dioxin, 2H- 1,2-oxazine, 6H- 1,2-oxazine, 4H-1I,2-oxazine, 2H-1 ,3-oxazine, 4H- 1 ,3-oxazine, 6H- 1,3-oxazine, 2H- 1,4-oxazine, 4H- 1,4-oxazine, 2H-1I,3-thiazine, 2H-1I,4-thiazine, 4H- 1,2-thiazi ne, 6H- 1,3-thiazine, 4H-1I,4-thiazine, 2H- 1,2- thiazine, 6H- 1,2-thiazine, 1 ,4-oxathiin, 2H,5H-1I,2,3-triazine, 1 H,41- 1,2,3- triazine, 4,5-dihydro- 1,2,3-triazine, 1H,6H-1I,2,3-triazine, I ,2-dihydro- 1,2,3- triazine, 2,3-dihydro- 1,2,4-triazine, 3H,6H-1I,2,4-triazine, IH,6H-1I,2,4-triazine, 3,4-dihydro- 1,2,4-triazine, 1 H,4H- 1,2,4-triazine, 5,6-dihydro- 1,2,4-triazine, dihydro-1I,2,4-triazine, 2H,5H- 1,2,4-triazine, I ,2-dihydro- 1,2,4-triazine, I H,4H- I ,3,5-triazine, 1 ,2-dihydro- 1,3,5-tfiazine, I ,4,2-di thiazine, 1 ,4,2-dioxazine, 2H- 1 ,3,4-oxadiazi ne, 2H-1I,3,5-oxacliazine, 6H- 1,2,5-oxadiazine, 4H- 1,3,4- oxadiazine, 4H-1I,3,5-oxadiazine, 4H- 1,2,5-oxadiazine, 21I,3,5-thiadiazine, 6H- 1 ,2,5-thiadiazine, 4H-1I,3,4-thiadiazine, 4H-1,3,5-thiadiazine, 4H-1 thiadiazine, 2H-1I,3,4-thi adiazine, 6H-1I,3,4-thiadiaz ine, 6H-1I,3,4-oxadiazine, and 1,4,2-oxathiazine, wherein the heterocycle, is optionally vicinally fused with a saturated or unsaturated 6- or 7-membered ing containing 0, 1 or 2 atoms independently selected from N, 0 and S; Ri is phenyl substituted by 0, 1 or 2 groups selected from halo,,CI-4alkyl, C 1 3 haloalkyl, -OR hand -NR hR h; or Ri is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, 0 and S,.wherein no more than 2 of the ring members are 0 or S, wherein the heterocycle is optionally fused with a phenyl ring, and the carbon, atoms of the heterocycle are substituted by 0, 1 or 2 oxo groups, wherein the heterocycle or fused phenyl ring is substituted by 0, 2.or 3 substituents selected from halo, C 1 4 alkyl, C, 3 haloalkyl, -OR hand -NR hR h; and. Ris hydrogen or -CH 3

57. The compound according to Claim 56, wherein R' is -474-

58. The compound according to Claim 56, wherein R 7 is C 2 6 alkyl or Ci-4haloalkyl.

59. The compound according to Claim 56, wherein R1 is a naphthyl substituted by 0, 1, 2 or 3 substituents independently selected from R 5 The compound according to Claim 56, wherein R' is R' substituted by 1, 2 or 3 substituents independently selected from R 5

61. The compound according to Claim 60, wherein R' is substituted by one substituent selected from halo, C 1 i 4 haloalkyl and Ci.salkyl, and additionally by 0, 1 or 2 substituents independently selected from R 5

62. The compound according to Claim 56, wherein R 1 5 is H.

63. The compound according to Claim 56, wherein R' 5 is RI°, Ci. 8 alkyl substituted by 0, 1 or 2 substituents selected from R 1 0 or a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, the heterocycle and bridge being substituted by 0, 1, 2 or 3 substituents independently selected from R' 0 or R' 5 is -(CH 2 ),phenyl substituted by 0, 1, 2 or 3 substituents independently selected from H, Cis-alkyl, CI. 4 haloalkyl, halo, cyano, nitro, -C(=0)(CI.salkyl), -C(=O)O(C.s8alkyl), -C(=O)NRhR h -C(=NRh)NRhR -OC(=0)(Ct.salkyl), 475 -OC(=O)NRh R h, -OC(=O)N(R h)S(=O) 2 (CI- 8 alkyl), -OC 2 6 alkylNR hR h, -OC 26 alkylORh, -SR h, 1 salkyJ), 2 8 alkyl), -S (O) 2 NRh Rh, -S 2 N(R 1.salkyI), 2 N(R h)C(=O)O(Ci 8 alkyI), 2 N(R h)C(=O)NRhR h, -NRh R h, -N(R 1- 8 alkyl), ~N(h)C(=O)O(Ci~ly) N(h)C(=O)Nhh )C(=NRh)N h h, -N(Rh)S(=O) 2 (CI-8alkyl), -N(R h)S(=O) 2 NRh R 2,lyN R' -NRhC 2 -6alkylOR h, and C,. 4 alkyl substituted by 0, 1, 2 or 3 groups selected from C 1 4 haloalkyl, halo, cyano, nitro, 1 .salkyl), -C(=O)O(CI-8alkyl), -C(=O)NR hR h, -C(=NR )NRh Rh,.-OR"h, -OC(=O)(C,.-8alkyl), -OC(=O)NR hR', -OC(=O)N(R h)S 2 8 alkyl), -OC 2 -6atkylNRh Rh; -OC 2 -6alkylOR h, -SRh 1 8 a1 kyl), 2 (C 1 8 alkyl), -S(=Oh2NR Rt, 2 8 alkyl), -S=aNRh)(OOC 8 alkyl), 2 N(R h)C(=O)NRh Rh, -NRhR h, -N(R -alkyl), -N(R h)C(_O)O(C 1-8alkyl), -N(Rh)C(=O)NRh -N(R h)C(=NRh)NR hRh, h hh -NR C 2 -ralkyI0R".

64. The compound according to Claim .56, wherein R 1 6 is H.

65. The compound according to Claim 56, wherein R'1 6 is halo, -NHI- 1 3 alkyl, -N(C 1 3 alkyl)C 1 3 alkyl, -OCI, 3 alkyl, 2 haloalkyl, -OC, 2 haloalkyl or C,. 3 alkyl.

66. The compound according to Claim 56, wherein R 4 is Rh 131 R 1 wherein at least one of R' 0 R1 2 R 1 3 and R 1 4 is other than CA4haloalkyl or halo. 476

67. The compound according to Claim 66, wherein at least one of R' 0 R'1 2 ,R 1 3 and R 1 4 is -OR h or _NRh Rh.

68. The compound according to Claim 56, wherein R 4is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected' from 0, N and S, so long as the combination of 0 and S atoms is not greater than 2, wherein each of. the carbon atoms of the heterocycle is substituted by H, Cl. 9 alkyl, C 1 4 haloalkyl, halo,.cyano, oxo, -OR -S(=0)nCI- 6 alkyl;, -0C 1 4 haloalkyl, -OC2- 6 alkylNR hR h, -0C 2 6 alkylOR h, -0C 1 al kylC(=O)ORh, -NRh.h N'~~aoly~ C 2 6 alkylP Rh .fRhC 26 alkylORh -C(=O)CI-6alkyI, -C(=0)0C 1 6alkyl, -OC(=O)C 1 6 alkyl, _C(=O)NRh.C 1 6 alkyI or -NhC(=O)C 1 6 alkyl; and saturated carbon atoms may be additionally substituted by and any available nitrogen atoms in the heterocycle are substituted by H, -C I-alkylOR h, -C 1 6 alkyl,--C 1 6 alkylNRhRh, -C 1 3 alkylC(=O)OR h, -C 1 3 alkylC(0O)NR Rh, -C 1 .,alkylOC(=O)C 1 6 a1 kyl, -C 1 3 alkylNR hC(=0)Ci 1 6 alkyI, -C(=)RJor -Cz. 3 alkylRJ.

69. The compound according to Claim 56, wherein R 4is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1 or 2 atoms selected from 0, N and S, wherein each of the carbon atoms of the heterocycle is substituted by H, Ci.g)alkyl, C,- 4 haloalkyl, halo, cyano, oxo, -OR, 1 6 alkyI, -0CI. 4 haloalkyl, -OC 2 6 alkylNRh Rh -0C 2 6 alkylOR I hh -NR C 24 ialkylOR h, -C(=O)C 1 6 alkyl, -C(=O)0C 1 6 alkyI, -OC(=O)C 1 6 alkyl, _C(=)NRhC 1. 6 alkyl or -NR C 1OCi 6 alkyI; and saturated carbon atoms may be additionally substituted by and any available nitrogen atoms in the bridge are substituted by H, 6 alkylOR -C 1 6 alkyl, -CI.. 6 alkylNR R -C 1 3 alkylC(=O)OR h, -C 1 3 alkylC(=O)NRh -C 1 3 alkylOC(=O)CI- 6 alkyl, -CI-alklNRhC(O)C 16 alky1, or -C 1 3 alkylRj. The compound according to Claim 56, wherein R 4 is an or 1 1-membered bicyclic ring, containing 1, 2, 3 or 4 N atoms and 0, 1 or 2 atoms 477 selected from S and 0 with the remainder being carbon atoms, wherein each of the carbon atoms of the ring is substituted by H, Cl- 9 alkyI, C 1 4 haloalkyl, halo, cyano, oxo, -OR h, -S(=O),IC 1 -6alkyl, -OCI- 4 haloalkyI, -OC 26 alkylNR R' -0C 2 jal kylOR h, -0C 1 djaJkylC(=O)ORh, -NRhR', -NR'~C 1 4 h aloalkyl, -NhC 2 -ralkyINR -NR C 2 6 alkylORh, -C(=O)CI. 6 alkyl, -C(=O)OCt. 6 alkyl, -OC(=O)CI- 1 alkyl, -C(=O)NRhCi-6alkyl or -NR hC(=O)C 1 6 alkyl; and saturated carbon atoms may be additionally. substituted by and any available nitrogen atoms in the ring are substituted by H, -CI-6alkyIORh, -C 1 6 alkyl, -CI 6 alkyNRhRh, -C 1 3 alkylC(=O)OR h, -CI-alkylC(=O)NR hR h, -C 1 3 alkylOC(=O)Cj- 6 alkyl, -Ci_ alkylNR hC(=O)CI 6 alkyl, or -CI. 3 alkyRj.

71. The compound according to Claim 56, wherein R. is an or I 1-membered bicyclic ring, containing 0, 1, 2, 3 or 4 N atoms and 0, 1 or 2 atoms selected from S and 0 with the remainder being carbon atoms, wherein at least one of the carbon atoms of the ring is substituted by Cl. 9 alkyl, C 1 4 haloalkyI, halo, cyano, oxo, -OR h, -S(=O)nCI- 6 alkyl, -OC 1 -4haloalkyl, -OC 26 alkylNRhRh, -OC 2 6 alkylOR h, OCI-6alkylC(=O)OR h h R' _NhCl haloalkyl, -NRhC 2 ,alkylNRhR', -NR hC 2 6 alkyIOR h, -C(=O)C 1 6 alkyl, -C(=O)0C 1 6 alkyI, -OC(=O)C 1 6 alkyl, -C(=O)NRh Ci. 6 alkyl or -NR hC(=O)C 16 alkyl.

72. The compound according to Claim 56, wherein R 5 and R 9 are each independently selected from H, C 1 4 haloalkyl, halo, nitro, -OCI. 6 alkyl, -OCI- 4 haloalkyl, -OC 2 6 alkylNRh Rh, -OC 2 -6alky1ORh, _NIph R h -NR h CI 4 haloalkyI, -NRhC 2 -6alky]NRh Rh, -NRhC 26 al kylORh, 7-C0 2 (C 1 6 alkyl), 1 6 alkyl), _C(=O)NRh Rh, -NR hC(=O)NRh Rh, -NR'CO 2 (Cl. 6 alkyI), -Cl-salkyIOR h, -CialkylNRh Rh, 1 6 alkyl), 2 NRR Rh, I-iRhS(=0)2(C 16akyl) and _OC(=O)NRh Rh.

73. The compound according to Claim 56, wherein R 6 and R 8 are each independently selected from H, C 1 5 alkyl, C 1 4 haloalkyl, halo, -OC 16 al1kyI, -0C 1 4 haloalkyl, -OC 2 6 al kyl NRh Rh, -0C 2 -6a.1kylOR h, -NR h Rh -NR hC 1 4 haoalkyI, -478- -NR hC 2 6 alkylNR hR' or -NR hC 2 _alkylOR h, CI-alkylORh, -C,6alkylNRhR h and

74. The compound according to Claim 56, wherein R 7 is independently, at each instance, C 1 8 alkyl, C,-4haloalkyl, -0CI. 4 haloalkyl, -OC 2 6 alkyINRhRh, -OC 2 6 alkylORh .hRh h 1 4 haloalkyl, _Nh C 2 _alkyJ4Tih R h, -NRh C,,~alkyIORh, -Cl. 8 alky]OR h, -C- 6 alkylNRh Rh or 6 alkyI).

75. The compound according to Claim 56, wherein R1 0 and R 1 4 are each independently selected from H, Cl-galkyl, C 1 4 haloalkyl, halo, cyano, nitro, 1 salkyl), -C(=O)O(C 1 8 a1 kyl), -C(=O)NRhRh,.C=hI~~ O" 8 alkyl), -OC(=O)NR hRh, -OC(=O)N(R h)S(=O) 2 (C 1 I gal kyl),1 -OC 2 -6alkylNRh Rh, -OC 26 aI kylOR h, -SR h, -S(=O)(CI-8al kyl), 2 salkyl), 2 NR R h, 2 N(R 1 -8alkyl), 2 .galkyl), 2 N(R h)C(=O)NR R h -NRh -N(R h)C(=O)(Ci..salkyl);, 8 alkyl), -N(R h)C(=O)NRh )C(=NRh )NRh Rh 2 .galkyl), N(Rh)(=O) 2 NR Rh -Nh26lyN and -Nh C 2 _6alkylORh and C 14 alkyl substituted by 0, 1, 2 or 3 groups selected from CI- 4 haloalkyl, halo, cyano, nitro, -C(=O)(CI-8alkyl), _C(=O)NR hRh, -C(=NR )NRh R h, -OR h, -OC(=O)(C,.salkyl), -OC(=O)NR hRh, -OC(=O)N(R h)S(=O) 2 .gaI kyl), -0C 2 6 alkylNR hR', -OC 2 ,alkylOR', -SR', 8 alkyl), 2 .salkyl), 2 NRhR', 2 N(R 1 8 alkyl), -S 2 N(R .galkyI), 2 N(R h)C(=O)NRh'Rh, _N~Rh N(R h)C(0)(CI8ak .yl), -N(R h)C(=O)O(C 1-alkyl), -N(R h)C(=O)NR hR h, _N(R h)C(=NRh)4Rh Rh, -N(R h)S(=O) 2 8 a1 kyl), -N(R h)S 2 NRhR h _h C 2 _6alkylh R h and -NRh C 2 6 alkylOR h.

76. The compound according to Claim 56, wherei .n R11 and R'1 3 are independently, at each instance, selected from H, CI-8alkyl, C,- 4 haloalkyl, halo, cyano, nitro, -C(=O)(Cl.8alkyI), -C(=O)O(Cl. 8 alkyl), -C(=O)NR hR h -479- _C(=NRh )NR hR', -OR"h, -OC(=O)(C 1 8 alkyI), -OC(=O)NR hR h, n 2 (CI-8alkyI), -OC,-,alkyINRh -OC 2 -6alkylOR h, -SR h, h h -S 1 salkyl), 2 (C ,galkyl), 2 NR R 2 N(R -8alkyl), 2 N(Rh)C(=O)O(C 1-8alkyl), S(=O) 2 N(R h)C(=O)NR hR h, -NR"hR h, N(R)C(0O)(CI-8alkyl), -N(R h)C(=O)O(C 1 8 alkyI), -N(R h)C(=O)NR hR h, -N(Rh)C(=NRh )NRR R, -N(R h)S(=O) 2 (Cis8alkyl), -N(Rh)S(=O) 2 NR hR h, -NRhC 2 6 alkylNRh Rh, -NR hC 2 _6alkylOR hand C-aklsubstituted by0, 1, 2 or3groups selected from C14haloalkyI, halo, cyano, nitro, 1 .galkyl), -C(=O)O(CI-8alkyl), -C(=O)NR"R h, -C(=NR )NRhRh, -ORh, -OC(=O)(Cl.8alkyl), -OC(=O)NR hRh, h h -S(=0)(CI-8alkyl), 2 (C,.salkyl), 2 NR R 2 salkyI), 2 N(R h)C(=O)O(C 1 8 a1 kyl), 2 N(R h)C(=0)NR hR', -NRhR h, -N(R h)C(=0)(Cts-alkyl), -N(R 1 8 al kyl), -N(R h)C(=O)NRh Rh, -N(R h)C(=NR h)NR hR h, -N(R h)S 2 8 a1 kyl), -N(R h)S 2 NR R h, _N~hC 26 alkylNh Rh and -NRh C 2 6 alkylORh.

77. The compound according to Claim 56, wherein R'1 2 is. independently, at each instance, selected from H, C 1 .salkyI, C14haloalkyI, halo, cyano, nitro, I -alkyI), -C(=O)NR hR h, _C(=NRh )NR hR h, -ORh, 8 a1kyl), _OC(=O)NRh Rh, .OC(=O)N(Rh)S 2 (C 1 salkyl), -OC 2 ,alkylNR R h, -0C 2 6 alkyIOR h, -SR h, -S(=O)(C,.8alkyl), 2 8 alkyl), 2 NR R h, 2 N(R .salkyl), 2 N(Rh)C(=0)O(C 1 8 alkyl), 2 N(R )C(=O)NRh -NR hR', salkyl), 8 a1 kyl), -N(R h)C(=O)NR hR h, h)NR hR h -N(R h)S(=O) 2 (C 1 8 alkyl), -N(R h)S(=O) 2 NR -NRh C 26 alkylNR hR h and -NR hC 2 _6alkylOR h; or R 12is C, 4 alkyl *substituted by 0, 2 or 3 groups selected from C, 4 haloalkyl, halo, cyano, nitro, salkyl), ,.salkyl), -C(=O)NRh R h, -C(=NR )NR h Rh, -OR h -OC(=O)(CI-8alkyl), -OC(=O)NR hR', -OC(=O)N(R h)S(=O) 2 8 alkyl), -OC 26 alkyINRh R h, -OC 2 6 alkylOR h, -SRh, salkyl), 2 (Ci~galkyl), 2 N7RhR", 480 2 N(R h)C(=O)(Ci 1 8 a1 kyl), -S 2 N(R h)C(0O)O(CI i.alkyl), 2 N(R h)CQ=O)NRh R h, -NRhRh, .N(R 1 8 aikyl), -N(Rh)C(=O)O(Ci 8 alkyl), -N(R h)C(=O)NRhR h, -N(R h)C(=NRh)NRh Rh, -N(R h)S(=O) 2 (Cjisalkyl), -N(R h)S(=0) 2 NR R h, _NRh C 26 alkyINR hR h and -NRhC2alkyORh

78. The compound according to Claim 56, wherein Y is 0.

79. The compound according to Claim 56, wherein Y is S. A compound having the structure: R3 R 2 X wherein: X is 0, S or NR'; n is independently, at each instance, 0, 1 or 2; o is independently, at each instance, 0, 1, 2 or 3;. R' is independently at each instance H or Rn R" is independently at each instance C 1 .galkyl, phenyl or benzyl; Sis independently in each instance H, C 1 4 alkyl, C 1 4 haloalkyl, halo, cyano, nitro, -C(=0)NR m -C(=NR m )NR m -OR' m -OC(=O)NR m 2 R n, -OC 2 6 al kyl NR m R', -0C 2 .(,a1kylOR m -SR' m -S -S 2 R n, -S 2 NR m R m -S 2 N(R m n, -S 2 N(R')C(=O)OR n, -s 2 N(R m )C(=O)NR R -NR m -N(R m -N(R m )C(=O)OR n, -N(R m )C(=O)NR m R', -N(R m )C(=NR m )NR m -N(R m 2 -N(R m )S 2 NR m R m -NR m C 2 6 alkylNR m R' or -NR m C 2 6 alkylOR m R' is substituted by 0, 1, 2 or 3 substituents independently selected from Rq; .R 3 is Hor C. 4 alkyl; -481- R 5 is H, Cl-galkyl, C 1 -4haloalkyl, halo, nitro, cyano, -0C 1 6 alkyl, -O-Cl. 4 haloalkyl, -0-C 1 6 alkylNR m 4 akyIOR m NR m R m -NR m -CI-4haloalkyl, -NR m 6 alkylNR m -NR m -C 1 6 alkylOR m or -(CH 2 R 6is, independently at each instance, H, C 19 galkyl, C,- 4 haloalkyl, halo, nitro, cyano, -0CI-6a~kyI, -0-CI-4haloalkyl, -0-C 1 6 akyINR m RT, -0-CI-6alkylOR', -NR m -NR m 4 haloalkyl, 6 alkylNR m R' or -NR m -C 1 jalkylORT; R 8is H, Ci-galkyl, CAhaloalkyl, halo, nitro, cyano, -OCI. 6 alkyl, -0-C 4 haloalkyl, 6 alkylNR m R m -0-CI- 6 alkylOR m -NR m R m -NR M 4 haloalkyl.. -NIR m 6 alkyINR m R m or -NR m -C,_6alkyl0R m and R' is RR 6 (CRqRq) 0 RO R 2 is H, -OR' m halo, C I haloalkyl Or C 1 6 alkyl; R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom. bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C,- 8 alkyl, C,- 4 halo-alkyl, halo, cyano, nitro, n, -C(=0)0R n, -C(=0)NR m Rm, -C(=NRrn)NR'R m -OR m -0C(=O)R n, -OC(=0)NR m R m -0C(=0)N(R m 2 R n, -0C 2 6 alkylNR m R m -0C 26 al kylOR m -S n, -S 2 -S 2 NR m 2 N(R m n, -S 2 N(R m h -S 2 N(Rn)C(=O)NR m I, -NR m R m -N(R m -N(R m )C(=0)0R, -N(R )C(=0)NR-R m -N(R m )C(=NR')NR m -N(R m 2 R -N(R m )S 2 NR m -NR m C 2 4 6alkylNR m -NR m C 2 6 a1 kyl OR m -C(=0)0Rs, -C(0)rNRsR' -C(=NRn)NRnR', -0C(=O)NRnRs, 0OC(0)N(R m )S 2 Rs, -OC 2 6 a I .ky NRnRs, -C 2 6 al ky]ORS, -482- SRs, 2 Rs, 2 NRnR', 2 N(Rrn)C(=O)Rs, 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=O)NRnRs, -NRrnRs, -N(Rrn)C(=O)Rs, -N(Rrn)C(=O)ORs, -N(Rr)C(=O)NR'Rs, N(Rr)C(=1aRn)NRnRs, -N(Rrn)S(=0) 2 -N(Rrn)S(=-0) 2 NRnRs, -NRrnC 2 -6alky]NRnR' -NRnC 2 6 alky1ORs and C I. 4 alkyI substituted by I or 2 groups selected from C I 2 haloalkyl, halo, cyano, nitro, -C(=O)NR m -C(=NR m )NR m R m -OR m -OC(=O)R n, -OC(=0)NR m nR m -OC(=O)N(R m )S 2 -0C 2 -6akyNR m R', -0C 2 6 alkylOR m -SR m n- S(=0) 2 2 NRm'~R, CI-S 2 2 N(R m -S 2 N(R m )C(=O)NR m R m -NRn'R m -N(R m -N(R I)C(=O)OR -N(R m )C(=0)NR m R,( -N(R m f)C(=NR m )NR m -N(R m 2 -N(R m )S 2 NR m R m -NR M C 2 -6alkylNR m -C(=O)OWs, -C(=O).41Rr, -C(=NRn)NRnR', -0RS, -OC(=O)Rs, .0C(=O)NRnRs, -OC(=O)N(Rrn)S(=0) 2 -0C 2 6 alkylNRnRs, -0C 26 alkyl0R', -S 2 2 NRnR', -S 2 N(Rrn)G(=O)Rs, -s 2 N(Rrn)C(=O)ORS, 2 N(Rrn)C(=O)NRnR', -NRrnR', -N(Rr)C(=0)0Rs, -N(Rrn)C(=0)NRnR', -N(Rrn)C(=NRn)NRnRs, -N(Rn)S 2 -N(R m )S 2 NRnRS -NRrnC 2 6 alkylNRnR', -NRnC 26 alkylORS and -NR M C 2 .6alkylOR m and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups; R 7 is C1. 9 alkyI, C 1 4 haloalkyl, halo, nitro, cyano, -0CI. 6 alkyI, -O-C 1 4 haloalkyl, 6 alkyNR m -0-C 1 6 alkylOR m -NR m R m -NR m -Ci- 4 haloalkyl, -NR m -C 1 6 alkylNRmR m or -NR m -C 1 _salkyl0R m R' is a saturated, partially-saturated or unsaturated 6- or 7-membered monocyclic or 10- or 1 1-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, 0 and S, so long as the combination of 0 and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from RP; RI is independently at each instance C 18 alkyl,.C 1 4 haloalkyl, halo, cyano, nitro, -C(=0)0Rn, -C(=0)NR m -C(=NR)NR m R m -OR m -0C(=0)R n, -0C(=0)NR m Rm, -OC(=0)N(R m 2 -0C 2 6 a] kylNRm 1 R m -0C 2 6 alkyIOR m 2 R n' 2 NR m R m -483- 2 N(R m 2 N(R m 2 N(Rrn)C(=O)NR!Rn, -NR m -N(R m n, -N(R m -N(R m )C(=O)NR m R', -N(R m )C(=NRl)NRnRr, -N(R m 2 -N(R m 2 NR m R', -NR m C 26 alkyNR m R' or -NR m C 2 6 alkyIOR'; and Y is 0orNH; or R'is cR-6 RR 5 R 7 N R NN (CRqR(I) 0 RO or (CRqRq )ORO R 2 is H, -OR' m halo, C 13 haloalkyI or C 1 6 alkyI; R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atomrs selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 subsiituents independently selec ted from CI-alkyl, C 14 haloalkyl, halo, cyano, nitro, -C(=O)OR n, -C(=O)NR m R m -C(=NRm 1 )NR m R m -OR m -OC(=0)R -OC(=O)NRm~Rrn, Q ~OC(=O)N(Rml)S(=0) 2 -OC 2 6 alkylNR m -0C 2 6 alkylOR', -SR m -S 2 2 NR m 2 N(R m n, 2 N(Rm)C(=0)0R',- 2 N(R m )C(=0)NR m R m -NR m R m -N(R m )C(=0)OR" -N(Rm 1 )C(=O)NR-R m -N(R m )C(=NR m )NR m -N(R m 2 R", -N(R M 2 NR m R m -NR M C 26 alkylNR m -NR m C 2 6 aI kylOR m -C(=O)ORs, -C(=0)NRnR', -C(=NRn)NRrnRs, -ORs, -OC(=O)Rs, -OC(=O)NRnR', -0C(=0)N(Rn)S(=O) 2 -OC 2 6 alkyINRnR', -OC 2 6 alkylORs, -SRs, .5 (0)Rs, -S 2 R, -S 2 NRnRS, -S 2 N(Rn)C(=O)Rs, 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=O)NRnR', -WNRS -N(Rrn)CQ=O)Rs, N(Rr)C(=O)ORs, -N(Rml)C(=O)NRrnR', _N(Rrn)C(=NRn)NRrnRs, -N(Rrn)S(=O) 2 Rs, -N(Rrn)S(=O) 2 NRnR', -NR m C 26 alkylNR m -NRnC 2 6 alkylORs and Cl-4alkyl substituted by 1 or 2 groups selected from CI- 2 haloalkyl, halo, 484 cyano, nitro, -C(=0)ORn, -C(=0)NR m -C(=NR)NR m -OR' m -OC(=O)NR m -OC(=O)N(R m 2 -0C 2 6 alkylNR m R', -0C 2 6 alkyIOR', 2 2 NR m R', 2 N(R m 2 N(R m 2 N(R m )C(=O)NR m R', -NR m -N(R m -N(R m -N(R m )C(=O)NR m R', -N(R m )C(=NR m )NR m -N(R m 2 -N(R m 2 NR m R', -NR m C 2 6 alkylNR m C(=0)RS, .C(0)ORS, -C(=O)NRnRs, -C(=NRn)NRnRs, -ORFs, OC(=O)Rs,'-OC(=O)NRnR', -OC(=0)N(Rn)S(=O) 2 Rs, -0C 2 6 alky1lNRsR' -OC 2 6 alky1ORs, 2 2 NRnRs, 2 N(Rrn)C(=0)R', 2 N(Rn)C(=0)ORs, 2 N(Rrn)C(=0)NRnRs, -NRrnRs, -N(Rr)C(=0)0Rs,,-N(Rrn)C(=0)NRnR, -N(Rrn)C(=NRn)NRnR', -N(Rrn)S(=0) 2 Rs, -N(Rrn)S(=0) 2 NRnRs, -NRnC 2 _6alky1NRrnR', -t{RrC 2 6alkyl0R' and -NRmC 2 _6alkyl0R m and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups; R 7 is C 1 9 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -OCI- 6 alkyl, 4 haloalkyi, 6 alkylNR m R m 6 a1kyIOR m -NRm~R m -NR m -C 1 4haloalkyI, -NR m 6 alkylNR m R m or -NR m -C 6 alkylOR'; R 0 is a saturated, partiallIy- saturated or unsaturated 6- or 7-membered monocyclic or 10- or 1 1-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, 0 and S, so long as the combination of 0 and S atoms is not greater than 2, wherein the carbon. atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein, the ring is substituted by 0, 1, 2 or 3 substituents. independently selected from RP; RP is independently at each instance CI-8alkyI, C1 4 haloalkyl, halo, cyano, nitro, -C(=O)OR -C(=0)NR m -C(=NR m )NjZ m R m -OR m n, 2 R n, -OC 2 _6alkylNR m R m -0C 2 6 a1 kylOR m -S 2 -S 2 NR m R m -S 2 -S 2 N(R m 2 N(R m )C(=O)NR m R m -NR m R m -N(R m -N(Rr)C(=0)0Rn, -N(R m )C(=0)NR m R m 3 0 -N(R m )C(=NR m )NR m R m -N(Rrl)S(=O) 2 NR m R m -NR m C 2 6 a IkylNR m or -NR m C 2 6 aI kylOR m and Y is 0 or NH; or -485- R' is R 2 is H, -OR' m halo, C 1 3 haloalkyl or C 1 6 alkyl; R 4 is a saturated, partially-saturated or unsaturated 10 or 11I-membered bicyclic heterocycle containing 1, 2, 3, 4or 5 atoms selected from 0, N and S, so long as the combination of 0 and S atoms is not greater than 2, but excluding quinolin-6-yl, 4,5,6,7-tetrahydro-benzo[blthiophen-2-yl, benzothiazol- 2-yl, 2,3-dihydro-benzo[ I,4]dioxin-6-yl, wherein the heterocycle is substituted by 0, 1, 2 or 3 substituents independently selected from Cl- 9 alkyl, oxo, C 1 4 haloalkyl, halo, nitro, cyano, -OR' m 1 6 alkyl, -O-CI. 4 haloalkyl, -O-CI- 6 alkylNR m R', -0-C 1 6 alkylOR', -NR m -NR M -C 1 4 haloa] kyl, -NR m -C 1 6alkylNR m R, -NR m -C 1 6 alkylOR', -C(=O)CI- 6 alkyl, -OC(=0)C 1 6 alkyl, -C(=0)NR'C,-6alkyl, -NR' 1 C(=0)C 1 6 alkyl -C(0)OR, -C(0)rNRsR' -C(=NRrn)NRrnR', -0Rs, -OC(=0)Rs, -0C(=O)NRnR', -OC(=O)N(Rrn)S(=0) 2 Rs, -OC 2 -6alkylNRnR', -OC 2 6 al kylOR', -S Rs, 2 Rs, -s (=OhNRnRs, -S 2 N(Rrn)C(=0)R', -s 2 N(Rrn)C(=O)ORS, 2 N(R'~)C(=O)NRnRs -NRm~Rs, N(Rr)CQ0O)OR, -N(Rr)C(O)rNRsR' -N(Rrn)C(=NRrn)NRrnRs, -N(Rrn)S(=O) 2 Rs, -N(Rrn)S(=O) 2 NRnRs, -NRrnC 2 6 alkylNRnRs, -NRrnC2zalkyl0Rs and C 14 alkyl substituted by I or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=0)NR m R m -C(=NR m )NR m -OR' m -OC(=O)R n, -OC(=O)NR m R', -OC(=O)N(R m )S 2 -OC 2 -6a1kylNR m -0C 2 6 a1 kylOR S(=O)R, 2 R 2 -S 2 N(R m -s 2 N(R 1 2 N(R"')C(=O)NR m -N(R m -N(R m -N(R m )C(=O)NR m -N(R m )C(=NR m )NR m -N(R m )S 2 R -N(R m 2 NR m R m C(=O)Rs, -C(=O)ORs, -C(0)NRnRs -C(=NRrn)NRnR', -OC(=O)Rs, -OC(=O)NR-Rs, -OC(=O)N(Rr)S(=0) 2 -OC 2 6 alkylNRnRs, -OC 2 6 a1 kyloRs, S(=O) 2 Rs, -S (0) 2 NRnRS, -486- 2 N(Rrn)C(=0)R', -S 2 N(Rrn)C(=0)ORS, 2 N(Rrn)C(=Q)NJRnR -NRrnR', N(Rr)C(=0)ORs, -N(Rr)C(=o)rNRsR' -N(Rrn)C(=NRn)NRnR', -N(Rrn)S(=0) 2 -N(Rrn)S(=0) 2 NRnR', -NR'C 26 alkyINRrnR, NRrnC 2 alkyl0Rs and -NR M C 2 -6alkylOR'; wherein R. 4 is not 2-aminocarbonylmethyl-2,3-dihydro-benzo[ 1,4]dioxin-8-yl, 2-cyanomethyl- 2,3-dihydro-benzo[1I,4]dioxin-8-yl, quinolin-3-yi, 3H-quinazolin-4-on-3-yl, benzo[1I,3jdioxol-5-yl, 3 ,3-di methyl-i ,3-dihydro-indol-2-on-6-yI or 4,4-dimethyl- 3,4-dihydro-IH-quinolin-2-on-7-yl; 7 c-iR is C 1 .salkyI, C 1 5 haloalkyl, I or Br' R 9 is H, Cl-galkyl, C 1 4 haloalkyl, halo, nitro, cyano, -OCI 1 6 a~kyI, -0-C 1 4 haloalkyI, -0-C 1 6 alkylNR m -0-C 1 6 alkYl0R m -NR m k m -NR m -C 1 4 haloalkyl, -N R m -C 1 6 alkylNR m -NR m -CI 6alkyI0R m or -(CH 2 )nRC; R 9 is independently, at each instance, H, C 1 9 galkyl, CI- 4 haloalkyl, halo, nitro, cyano, -OC I. 6 alkyI, -0-C 1 Ahaloalkyl, -0-C 1 6 alkylNR m R m -0-C 1 6 alkylOR m -NR-R m -NR m -C 1 ~haloalkyI, -NR m -C 1 6 alkylNR m R m or -NR'-C 1 6 alkylOR m Y is NH; and Z_ is CR' or N; or R' is R 6 R R 2is C 1 -6alky1 substituted by 1, 2 or 3 substituents selected from CI- 4 haloalkyl, halo, cyano, nitro, m R', -C(=NR m )NR m -OR- m -OC(=0)NR-R, -0C(=0)N(R m b)S(=0) 2 -OC 2 6 alkylNR-R m -OC 2 6 alkylOR!, -S 2 2 NR m 2 N(R m -S 2 N(R)C(=0)0Rn, -S 2 N(R m )C(=O)NR m R m -NR m R m -N(R m -N(R m -N(R m )C(=0)NR m R m -N(R m )C(=NR m )NR m R m -N(R m )S 2 R' -N(R m )S 2 NR m -NR m C 2 -6al kyl NR-R m or -NW m C 2 6 alkylOR m or, 487 R 2 is q) 2 0 ,phenyl, wherein the phenyl is substituted by 0, 1, 2 or 3 substituents independently selected from C 1 8 alkyl, C 1 4haloalkyl, halo, cyano, nitro, -C(=O)NR m -C(=NR m )NR m -OR' m -OC(=O)R1, -OC(=O)NR m 2 -OC 2 6 alkylNR m R', -OC 26 alkylOR', 2 2 NRm 1 R m -S(=O0) 2 N(R 2 N(R m )C(=O)OR 0 2 N(Rm))C(=O)NR m Rm 1 -NR m R m -N(Rn)C(=O)OR1, -N(R m )C(=O)NR m R, -N(R m )C(=NR m )NR m R m -N(Rm 1 )S 2 R 1 -N(R m 2 NRR', -NR m C 2 6 aI kylNR m -NWC 26 alkyIOR m -C(=O)ORs, -C(=O)NRnR -C(=NRrn)NRnRs, -OC(=O)Rs, -OC(=O)NRnRs, -OC(=O)N(Rmn)S(=O) 2 Rs, -OC 2 6 alkyNRnRs, -OC 2 6 alkylORs, -SRs, S(=O)Rs, -S 2 -S(=O0) 2 NRrnRs, 2 N(Rrn)C(=O)Rs, 2 N(Rrn)C(=O)ORs, -S 2 N(Rrn)C(=O)NRnRs, 4.{RrnRS -N(Rrn)C(=O)QR',. -N(Rrn)C(=O)NRnRs, -N(Rrn)C(=NRn)NRnR', -N(Rrn)S(=O) 2 Rs, -N(Rm 1 )S 2 NRnRs, -NR m C 2 6 a1 kyINRnRs, -NRnC 26 alkylORs and CI. 4 alkyl substituted by, I or 2 groups selected from Ci. 2 haloalkyl, halo, cyano, nitro, n, -C(=O)OR 1 -C(=O)NRm' 1 R, -C(=NR m )NR m -OR 1 1 m, -OC(=O)R1, -OC(=O)NR m R1, -OC(=O)N(R m 2 R1, -OC 2 6 alkylNRnR m -OC 26 al kylOR', -SR- 1 -S n, 2 R1, 2 .NR m 2 N(Rml)C(=O)R1, 2 N(R m )C(=O)OR n, 2 N(R m )C(=O)NR m -NR 1 R m n, -N(R m -N(Rm 1 )C(=O)NR m R m -N(Rm 1 )C(=NR m )NR m R m -N(Rm t 2 R n, -N(R"1)S 2 NR"'R m -NR m C 2 6 alkylNR m -C(=O)ORs, C(=O)NRnRs -C(=NRrn)NRrnRs, -ORs, -OC(=O)Rs, -OC(=O)NRnR', -OC(=O)N(Rm 1 )S 2 -OC 2 6 alkylNRnRs, -OC 2 6 alkylOR', -SRs, S(=0) 2 Rs, -S(=O),NRnRS, -s 2 N(Rrn)C(=O)RS, 2 N(Rrn)C(=O)ORs, -S(=0O) 2 N(Rrn)C(=O)NRnR, -NRrnR', -N(Rrn)C(=O)Rs, -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)nmRs, -N(Rrn)C(=NRn)NRlRs, -N(Rr)S(=0) 2 Rs, -N(Rrn)S(=O) 2 NRm 1 Rs, -NRnC 2 6 alky]NRnRs, -NR' 1 C 2 6 a1 kylORs and -NR 1 C 2 6 alkyl OR m or R 2 is wherein R' is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, 0 and S, wherein no more than 2 of the ring members are Q or S, -488- wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from CI-8alkyI, C 1 -4haloalkyl, halo, cyano, nitro, -C(=O)0R 0 -C(=O)NR m -C(=NR m )NR m R m -OR m -OC(=O)NR m R m -OC(=O)N(R m 2 R' h -0C 2 6 alkyNR m R m -OC 2 -6alkyIOR m -SR m 2 2 NR m R m 2 N(R m O) 2 N(R m )C(=O)OR, -S(=O0) 2 N(R m )C(=O)NR m R m -NR m -N(R m -N(R m )C(=O)NR R m -N(R m )C(=NR m )NR m -N(R m 2 R', -N(R t 2 NR m -NR m C 2 _6alkylNR m R m _NR 1 ~nC 2 _6alkyiOR m -C(=O)Rs, -C(=O)ORFs, -C(=O)NRrnR', -C(=N~rn)NRrnRs, ORs, .OC(=O)Rs -OC(=O)NRnR', -OC(=O)N(Rrn)S(=O) 2 Rs, -OC 2 6 alky1NRrnRs, -OC 2 6 alkyIORs, -SRs, 2 2 NRrnR', S(=O) 2 N(Rr)C(=O)Rs, 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=O)NRnR', NRrnRS -N(Rrn)C(=O)Rs, -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRrnRs, -N(R"l)C(=NRrn)NRnRs, -N(Rrn)S(=O) 2 Rs, 2 NRrnR', -NRrnC 2 6 alkylNRrnR', -NRnC 2 6 alkylORs and C 1 4 alkyl substituted by I or 2 groups selected from C 1 2 haloalkyl, halo, cyano,- nitro, -C=O)NTR m R m -C(=NR m )NR m R m -OR m -OC(=O)NR m 2 -OC 2 6 alkylNR m R m -0C 2 6 alkylOR m 2 2 NR m R, -S 2 2 N(R m -S 2 N(Rm)C(=O)NR"'R m -NR m -N(R m -N(R m )C(=O)NR m R t X -N(R m )C(=NR m )NR m R m -N(R m 2 R n, -N(Rm)S(=O) 2 NR m R m -NR"'C 2 6 alkylNR"'R m C(0)ORs, -C(=O)rNRsR- -C(=NRn)NRnRs, OC(=O)Rs, -OC(=O)NRnRs, -OC(=O)N(Rrn)S(=O) 2 -OC 2 6 alky]NRnRs, -OC 26 alkylORs, SRs, 2 Rs, 2 NRrnRs,7 -S 2 N(Rrn)C(=O)Rs, 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=O)NRnR, -NRrnR', -N(Rr)C(0O)ORs, -N(Rrn)C(=O)NRnR', -N(Rrn)C(=NRrn)NRnRs, 2 R, -N(Rrn)S(=O)7,NRrnR', -NRnC 2 6 alkylNRnRs, -NR m C 2 6 aI kylORs and -NR m C 2 -6alkyl OR'; R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected -489- from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from CI-8alkyl, C 1 4 haloalkyl, halo, cyano, nitro, n, -C(=0)OR n, -C(=0)NR m R m -C(=NR- 1 -OR m -OC(=O)R -OC(=O)NR m R, -OC(=O)N(R m 2 -OC 2 6 akyNR m -0C 2 6 a~kylOR m -SR' m 2 2 NR m R m 2 N(R m 2 N(R m )C(=O)OR, 2 N(R m )C(=O)NR m -NR"'R m -N(R m -N(R m )C(=O)OR, -N(R m )C(=O)NR m R m -N(R m )C(=NR m )NR m -N(R m 2 R", -N(R m 2 NR m R m -NR'C 2 6 alkylNR m R m -NR m C 2 _6alkylOR m -C(=O)ORs, -C(=O)NRmRs, C(=NRn)NRrnRs, OR$, OC(0)Rs, -OC(=0)NRnR', -OC(=O)N(Rrn)S(=0) 2 -0C 2 6 alky1NRrnRs, -OC 2 6 alkyIORs, -SRs, S(=0) 2 Rs, -SQ0) 2 NRnRS 2 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=O)NRnRs,*N -N(Rr)C(0O)Rs, -N(Rr)C(=0)ORs, -N(Rrn)C(=o)NRnRs, -N(Rrn)C(=NRn)NRnRs, -N(R m )S 2 Rs, -N(Rrn)S(=0) 2 NRnRs, -NRnC 26 alkylNR m Rs, 44R m C 26 alkylORs and CI-4alkyl substituted by 1 or 2 groups* selected from Cv. 2 haloalkyl, halo, cyano, nitro, n, -C(=O)OR n, -C(=O)NR m R m -C(=NR m )NR m R m -OR m -OC(=O)NR m -OC(=-O)N(R m 2 -0O.C 2 6 alkylNR m R', -OC 26 alkylOR m -SR' m 2 2 NR m 2 N(R m 2 N(Rml)C(=O)OR n, -S 2 N(R m )C(=O)NR m R m (-NRm' 1 R, -N(R m n, -N(R m )C(=O)OR 1 -N(R m )C(=O)NR m R m -N(R m )C(=NR m )NR m R m -N(R m 2 -N(Rm)S(=O) 2 NR m R" m -NR M C 2 6 alkyINR m -C(=O)ORs, -C(=NRn)NRnR', -ORs, -OC(=O)Rs, -OC(=O)NRnR', -OC(=O)N(Rrn)S(=O) 2 -OC 2 -6alkyINRnRs, -OC 2 6 alkylOR', 2 Rs, 2 NRnRs, -S 2 N(R'l)C(=O)Rs, 2 N(Rrn)C(=O)ORS, -S 2 N(Rrn)C(=O)NRnRs, -NRrnR', -N(Rr)C(0O)Rs, .N(R)C(=O)ORs, N(Rr)C(O)rNRsR' N(Rrn)C(=NRm*)RnRs, -N(Rrn)S(=O) 2 Rs, -N(R m )S 2 NRnRS, -NRrnC 2 6 alkyINRrRs, -NRrnC 2 -6IkyIORs and -NR m C 2 6 alkylOR', and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups; k7 is C 28 alkyl, C 1 5 haloalkyl, 1, Br; 490 R 9 is independently, at each instance, H, C 1 9 alkyl, C 1 -4haloalkyl, halo, nitro, cyano, -0CI. 6 alkyI, -O-C 1 4 haloalkyl, -O-C 1 6 alkylNR m R m -0-C 1 6 alkyI OR m -NR"'R m -NR m -C 1 Ahaloalkyl, -NR'-C 1 6 alkylNR m R' or -NR"'-C 1 6 alkyIOR'; Y is NH; and Z is CR. 8 or N;or R'is R6 ClF 3 C'_ R 9 R 2 is H, -OR- m Cl, C 1 3 haloalkyI or C 1 I-alkyl; R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S, so long as the combination of 0 and S atoms is not greater than 1, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from C 1 8 alkyl, Ca. 4 haloalkyl, halo, cyano,.nitro, -C(=O)NR'R m -C(=NR')NR m -OC(=O)NR m R m -OC(=O)N(R m 2 -OC 26 alkylOR m -S n, 2 Rn, -S 2 N-R m -S 2 N(R m n, 2 N(R m 2 N(R m )C(=O)NR m R m -NR m W m -N(R m n, -N(Rml)C(=O)ORfl, -N(R m )C(=O)NR m -N(R m )C(=NR m )NR m -N(R m )S 2 -N(Rn m )S 2 NRm', -NR M C 2 6 alkylNR m -NR m C 2 -6alkylOR m -C(=O)Rs, -C(=O)ORs, -C(=O)NRnRs, -C(=NRn)NRrnR', 70.Rs, .0C(=o)Rs _OC(=O)NRrnR., OC(0)N(Rn)S(=0) 2 R, OC 2 6 alkyIlNRs, -0C 2 6 a1 kylORs, 2 Rs, -S(O) 2 N4RrRs, 2 N(Rn)C(=O)RS, -S 2 N(Rm)C(=O)ORS, 2 -NRrnRs, -N(Rrn)C(=O)Rs, -N(Rm)C(=O)ORs, -N(Rrn)C(=O)NRnR', -N(Rrn)C(=NRn)NRmIR', -N(R m )S 2 Rs, -N(Rrn)S(=O) 2 NRnR', -NR M C 2 6 a1 kylNRnR', -NRrnC 2 6 alkylOR' and C 1 4 alkyl substituted by I or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=O)NR m T -C(=NR m )NR m R m -OR m -OC(=O)R, -OC.(=O)NR m R m -OC(=Q)N(R m )S -,.OC 2 6 al kylN R-R m -0C 2 6 alkyl OR m -491- -SR m n, 2 2 NR m -(O 2 m -n 2 N(R m )C(=O)OR n, 2 N(R m -NR m R', -N(R m -N(R')C(=O)NRlRn, -N(R m )C(=NR m )NR m R m -N(R m 2 Rn, -N(R m 2 NR m R m -NR m C 2 6 alkyNR m -C(=O)ORs, -C(=O)NRnR', -C(=NRn)NRnRs, -ORs, .OC(=o)NRnRs -OC(=O)N(R m )S 2 Rs, -OC 2 6 alkylNRnR', -OC 26 alkylOR', 2 2 NRnRs 2 N(Rml)C(=O)R', 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=O)NRnRs, -NRrnRs, -N.QjR)C(=O)Rs, N(Rr)C(=.o)oRs, -N(Rrn)C(=O)NRnRs, -N(Rrn)C(= NRn)NRnRs -N(Rrn)S(=O) 2 Rs, -N(Rrn)S(=O) 2 NRnRs, -NR M C 2 6 alkylNRnRs, -NR.nC 2 6alkylORs and -NR m C 2 -6alky1OR m wherein R 4 is not unsubstituted phenyl; R 9 is independently, at each instance, H, Cl- 9 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -OCI. 6 alkyl, -O-CI. 4 haloalkyl, -O-C 1 6 alkylNR m R m -0-C 1 6a1 kylOR m -NR m R m -NR M -C 1 4 haloalkyl, -NR m -C 1 6alkylNR m R m or -NR m 6 alkylOR'; Y is NH; and Z is CR 8 or N.

81. A compound according to Claim 80, wherein: R' is R 8 (CRq Rq) ORO R 2is H, -OR m halo, C,. 3 haloalkyl or C 1 6 alkyl; R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, Wherein the ring and bridge 492 are substituted by 0, 1, 2 or 3 substituents independently selected from CI-8alkyI, C 14 haloalkyl, halo, cyano, nitro, -C(=O)ORn, -C(=-O)NR m R m -C(=NR m )NR m -OR' m -OC(=O)NR m R m 2 -OC 2 6al kyINR m -0C 2 6 alkylOR', -SR m -S(=O)Rn, 2 R n, 2 NR m 2 N(R m 2 N(R m 2 N(R m )C(=O)NR m -NRm 1 -N(R m -N(R m -N(R m )C(=O)NR m R m -N(R m )C(=NR m )NR m R m -N(R m 2 R", -N(R m 2 NR m R m -NR m C 2 -6alkylNR m R m -NR m C 2 _6a1kyIOR m -C(=O)Rs, -C(=O)ORs, -C(=0)NRnRs, -C(=NRn)NRrnRs, OW, .OC(=O)Rs, -OC(=O)NRnR-, -OC(=O)N(Rn)S(=O) 2 Rs, .OC 2 6 alkyINRmRs, *OC 2 6 alkylOR', -SWS, 2 Rs, 2 NRrnR', 2 N(Rrn)C(='O)R', -S 2 N(Rrn)C(=O)ORS, -S 2 N(Rrn)C(=O)NRnRs, NRlRs, -N(Rrn)C(=O)Rs, -N(Rr)C(=O)ORs, -N(Rrn)C(=O)NRnRs, -N(Rm)C(=NRn)NRnRs, -N(R m )S 2 Rs, -N(R m )S 2 NRnRs, -NRrnC 2 alkylrNRs R rn 2 lyl and CI. 4 alkyI substituted by I or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, n, -C(=O)OR n, -C(=O)NR m R m -C(=NR m )NR m R m -OR m -OC(=O)N(R m )S 2 -OC 2 6 alkylNR m R', -OC 26 alkylOR m -SR m -S 2 R n, -S 2 NR m W m -S 2 N(R m 2 N(R m )C(=O)OR n, 2 N(Rm)C(=O)NR m R', -NR- t RmI, -N(R m -N(R m -N(R m )C(=O)NRnR m -N(Rm)C(=NR m )NR m -N(R m 2 -N(R m 2 NR m R m -NR m C 2 6 alkylNRm', C(0)ORS, -C(=O)NPRnRs, -C(=NRrn)NRrnRs, -ORs, OC(=O)Rs, .0C(=O)NRnRs, -OC(=O)N(Rrn)S(=O) 2 -OC 2 6 alkylNRRs, -OC 2 _6a1kyloRs, SRs, S(=O) 2 Rs, 2 NRrnRs, 2 N(Rrn)C(=O)Rs, 2 N(Rrn)C(=O)ORs, -S 2 N(Rrn)C(=O)NRnR', -NRrnR', -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRlRs, -N(Rrn)C(=NRn)NRrRs, -N(R m )S 2 Rs, -N(Rrn)S(=O) 2 NRnR', -NRrnC 2 6 alkylNRrnR', -NRrnC 2 -6alkyIORs and -NR M C 2 6 alkylOR m and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups; R' is C 1 9 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -OC 1 6 alkyI, 4 haloalkyl, -0-C 1 6 a1 kylNR m R m 6 alkyIOR m -NR m R m -NR m -C 1 -4haloalkyl, -NR m 6 alkyINR m R m or -NR m -C 1 6alkylOR m 493 R' is a saturated, partially-saturated or unsaturated 6- or 7-membered monocyclic or 10- or I I1-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, 0 and S, so long as the combination of 0 and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents, independently selected from RP; RP is independently at each instance C 1 8 alkyl, C 1 4 haloalkyl, halo, cyano, nitro, n, -C(=0)NR m -C(=NR m )NR m -OR' m -OC(=O)NR m -OC(=O)N(R m 2 -OC 2 6 alkylNR m R m -0C 2 6 alkylOR', -SW tm 2 RW, 2 NR m R m 2 N(R m -S 2 N(R m 2 N(R m )C(=O)NR m R m -NR m -N(R m -N(Rr')C(=0)OR n, -N(Rn)C(=0)NR m R', -N(R m )C(=NR m )NR m R m -N(R m 2 2 NR-R-, -NR m C 2 6 alkylNR m R' or -NR m C 2 6 alkylQR m and Y is 0orNHl.

82. 'A compound according to Claim 81, wherein: R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and, bridge are substituted by 0, 1, 2 or 3 substituents independently selected from Ci.8alkyI, C 1 -4haloalkyl, halo, cyano, nitro, -C(=O)NR m -C(=NR m )NR m -OR m rOC(=O)NR-R-, -OC(=O)N(R m )S 2 -OC 2 6 alkylNR m R', -0C 2 6 a1 kylOR m n, 2 R n, -S 2 NR-R-, 2 N(R m 2 N(R m -s 2 N(R')C(=O)NR m R', -NR m -N(R m -N(R m -N(R m )C(=0)NR m R', -N(R m )C(=NR m )NR m -N(R m )S 2 R n, -N(R m )S 2 NR'R', -NR m C 2 6 alky]NR m -NR m C 2 6 alkylOR', -C(=O)0Rs, -C(=0)NRnR', -C(=NRI)NRrnRs, -OC(=O)Rs, -OC(=0)NRnRs, -OC(=0)N(Rrn)S(=0) 2 -OC 2 6 alkyMNR',~ -OC 2 6 alkylORs, 7S(=O)Rs, 494 t7 S(=0) 2 2 NPrnRs, 2 N(Rrn)C(=O)Rs, 2 N(Rrn)C(=O)0Rs, 2 N(Rrn)C(=0)NRnR', 4PNRnRs, N(Rn)C(=0)0R, -N(Rrn)C(=0)NRnR', -N(Rrn)C(=NRn)NRnR', -N(Rrn)S(=O0) 2 R', -N(Rrn)S(=O) 2 NRnR', NR'C 2 .6alkylNRnRS -NRnC 2 ralky10Rs and Cj- 4 alkyl substituted by 1 or 2 groups selected from C 1 2 haloalkyI, halo, cyano, nitro, -C(=O)NR m -C(=NR m )NR m -OR' m -OC(=O)R -OC(=O)N*R m -OC(=O)N(R m 2 R -OC 2 6 alkyINR m -0C 2 6 alkylOR', -SR m -S=O) 2 Rn, -S(=O0) 2 NR m R m 2 N(R m 2 N(R m -S 2 N(R m -N(R m )C(=O)NR m R m -N(R m )C(=NR m )NR m R m -N(R M 2 Rn, -N(R m 2 NR m R m -NR m C 2 -6a~ky]NR m R- -C(=O)ORs, -C(=O)NRnRs, -C(=N"Prn)NRnR', -0Rs, .0C(0)Rs, -OC(=0)NR m -OC(=O)N(Rrn)S(=O) 2 Rs, -OC 2 6 alkyl NRnRS, -OC 2 6 alkylOR', -SRs, 2 Rs, 2 NWrRs, 2 N(Rrn)C(=O)Rs, -s 2 N(Rrn)C(=O)ORS, -S 2 N(Rn)C(=O)NRnRs, -NRrnR', -N(R m -N(Rrn)C(=O)ORs, -NR)(ON'' -N(R m )C(=NR m )NR m -N(R m )S 2 Rs, 2 NRrnRs, -NR m C 2 6 a1 kylNRrnRs, -NR'CZ 2 6 aI kylORs and -NR m C 2 -6alkyI OR m and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups.

83. A compound according to Claim 81, wherein R 4 is a phenyl ring( that is vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C 1 .salkyl, C 1 4 haloalkyl, halo, cyano,* nitro, 'C(=O)NRlR m .C(=NR m )NR m -OR m -OC(=O)R, -OC(=0)NR m -OC(=O)N(R m )S 2 R~n, -0C 2 6 a1 kylNR m R, -0C 2 6 al kylOR m -SR- m n, 2 R, 2 NR m -S 2 N(R m 2 N(R m 2 N(R m )C(=0)NRR m -NP t R m -N(R m -N(Rrl)C(=O)ORn, -N(R tm )C(=0)NR m R', -N(R m )C(=NR m )NR m R m -N(R m 2 Rn, -N(R m 2 NR m R m 495 -NR m C 2 6 alkylNR m -N7R m C 2 6alkyl0R', -C(=0)ORs, _n C(=O)NRrnR', -C(=NRrn)NRnR', -0C(=O)Rs, -OC(=O)NRnRs, -OC(=O)N(R m )S 2 Rs, -0C 2 6 al kylNR m Rs, -0C 2 6 a1kylORs, -SRs, S(=O)R 2 2 NR m -S 2 N(Rrn)C(=0)RS, 2 N(R m )C(=0)0Rs, 2 N(Rrn)C(=O)NRnRs, -NR m Rs, -N(R m -N(R m )C(=0)0R 5 -N(R m )C(=0)NR m -N(R m )C(=NR m )NR m Rs, -N(R m 2 Rs, -N(R m 2 NR m -NR _C 2 alky1NRnlRs, -NRrnC 2 _6a~kylORS and C 1 4 alkyl substituted by 1 or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C=ORD nC=)R, -C(=O)NR m -C(=NR m )NR m -OR- m -OC(=0)N(R m 2 R n, -OC 2 6 alky NR m R m -OC 2 _6alkylOR', t m 2 NR m R m 2 N(R m n, 2 N(R m )C(=O)OR n, 2 N(R m )C(=O)NR m R m -NR m W m -N(Rm 1 n, -N(R)C(=0)0R n, -N(R m )C(=O)NR m -N(R m )C(=NR m )NR m R m -N(R m )S 2 -N(R m )S 2 NR m R m -NR m C 2 6 alkyINR-R-, -C(0)ORs, -C(0)NRnRs, -C(=NRr)rNRsR, -ORs, -OC(=0)Rs, OC(=0)NRnRs, -OC(=O)N(R m )S 2 -OC 2 6 alkylNR m R', -OC 26 aI kylORs, SRs, 2 -S 2 NR m R', 2 N(Rm 1 )C(=O)0Rs, -S 2 N(R m )C(=O)NR m Rs, -NR m Rs, -N(R tm -N(Rrn)C(=O)ORs, -N(R tm )C(=O)NR m Rs, -N(R tm )C(=NR m )NR Rs, 2 Rs, -N(R m 2 NR m R 5 -NRnC 2 _6alkyINRnR', -NR m C 24 salkyIOR' and -NR m C 2 6 alkylOR'; and the bridge carbon atomns are substituted with 0, 1 or 2 =0 groups.

84. A compound according to Claim 8 1, wherein R 7 is C I galkyl, C 1 4 haloalkyI, halo, -0CI. 6 alkyl, -O-C 1 4 haloalkyI, -NR m R m or -NR m -C 1 4haloalkyI. A compound according to Claim 81, wherein R 7 is C 1 5 alkyl, C I 4 haloalkyl,* 1, Br or Cl.

86. A compound according to Claim 8, wherein R 7 is tert-butyl or trifluoromethyl. -496-

87. A compound according to Claim 81, wherein Ro is a saturated, partially-saturated or unsaturated 6- or 7-membered monocyclic ring containing 0, 1, 2 or 3 atoms selected from N, O and S, so long as the combination of O and S atoms is not greater than 1, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from R P

88. A compound according to Claim 81, wherein RO is a saturated, partially-saturated or unsaturated 6-membered ring containing 0, 1, 2 or 3 N atoms, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from R p

89. A compound according to Claim 81, wherein Y is O. A compound according to Claim 81, wherein Y is NH.

91. A compound according to Claim 80, wherein: R' is R6 R 7 R6 R 5 R 7 N R R8 (CRqRq)oRO or (CRqRq)oRo R 2 is H, -OR m halo, Ci.3haloalkyl or C- 1 6 alkyl; R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from Ci-salkyl, L 497 C 1 4 haloalkyl, halo, cyano, nitro, -C(=0)0Rn, -C(=0)NR m R', -C(=NR m )NR m -OR' m -OC(=O)NR m R', -OC(=O)N(R M 2 -OC 26 alkylNR m -0C 2 6 a1 kylOR m -S 2 -S 2 NR m 2 N(R m 2 N(R m )C(=O)OR 2 N(Rrn)C(=O)NRnR, -NR m -N(R m -N(R m -N(R m )C(=O)NR m -N(R m )C(=NR m )NR m -N(R m 2 R", -N(R m 2 NR m -NR M C 2 6 alkylNR-R', -NR m C 2 6 alkylOR', -C(=O)ORs, -C(=O)NpRnR's -CQ.NRr)rNRsR 0C(=0)Rs, -OC(=O)NRnR', .0C(=O)N(Rn)SQ.O) 2 Rs -OC 2 6 alkylNRnR', -OC 2 -6alkylOR', -SRs, 2 2 NRnR', 2 N(Rr)C(=0O)R', 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=O)NRnR', -NRrnRS -N(Rrn)C(=O)R', N(Rrn)C(=O)ORf', -N(Rrn)C(=O)NRnR', -N(Rrn)C(..NR)NRnRs, -N(R m )S 2 Rs, -N(Rrn)S(=O) 2 NRnR', -NR m C 2 -6alkyINRnR', -NRrnC 2 -alkylORs and CI-4alkyl substituted by I or 2 groups selected from G,. 2 haloalkyl, halo, cyano, nitro, -C(z-O)NR m -C(=NR m )NR m -OR' m -OC(=0)NRmlRn, -OC(=O)N(R m )S 2 -0C 2 6 al kyl NR m R m -OC 26 alkylOR m -SR m 2 2 NR m R m -S 2 N(R m -S 2 N(R m ,S 2 N(g m )C(=O)NR m R m -NR m -N(R m -N(R m )C(=O)0R n, -N(R m )C(=O)NR m IR m -N(R-)C(=NR-)NR m R m -N(R m 2 -N(Rrn)S(=O) 2 NRnR', -NR m C 2 -6alky]NR m R m -C(=0)0Rs, -C(=0)NRnRs, -C(=NRn)NRnR', -ORs, .OC(0)Rs, -OC(=O)NRnRs, 2 Rs, -OC 2 6 alkyNRnRs, -OC 26 alkylOR', -S -S 2 Rs, -S 2 NRnRs, 2 N(Rrn)C(=O)Rs, 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=0)NRnRs, -NRrnR-, -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRnRs, -N(Rrn)C(=NRn)NRnRs, -N(R m )S 2 Rs, -N(Rrn)S(=0) 2 NRnR', -NRnC 2 6 alkylNRnRs, -NR m C 2 6 alkyIOR' and -NR m C 2 .talkylOR m and the ring and bridge carbon atomns are substituted with 0, 1 or 2 =0 groups; R 7 is C 19 galkyl, C 1 4 haloalkyl, halo, nitro, cyano, -OCI-6alkyI, -0-C 1 4 haloal kyl, 6 a1 kylNR m R m -0-C 1 6 alkyIOR', -mNR m R m -NR m -C,4haloalkyl, -NR m -C I.6a1 kylNR ~R m or -NR m -C 1 6 alkylOR m [C 1 8 alkyl, C I.-haloalkyl, I, Br or Cl] -498- R' is a saturated, partially-saturated or unsaturated 6- or 7-membered monocyclic or 10- or 11 -membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, 0 and S, so long as the combination of 0 and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1t* 2 or 3 substituents independently selected from RP; RP is independently at each instance CI-salkyl, C,- 4 haloalkyl, halo, cyano, nitro, -C(=O)NR m R m -C(=NR m )NR m R' m -OC(=O)RP, -OC(=O)NR m -OC(=O)N(R m 2 -OC 2 -6a~kyINR m R', -OC 2 _6alky]OR m -SR- m 2 2 NR m R.~ 2 N(R m n, 2 N(R m 2 N(R m )C(=O)NR m R m -NR m R m -N(R m -N(R m )C(=O)OR n, -N(R m )C(=NR m )NR m -N(R m 2 -N(R m 2 NR m -NR m C 2 -6alkylNR m R m or -NR m C 2 6 alkylOR'; and Y is 0or NH-.

92. A compound according to Claim 91, wherein R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is vicinally fused with a saturated or unsaturated 3- or 4-atom. bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C 1 .salkyl, C 1 4 haloalkyl, halo, cyano, nitro, -C(=0)NR m R m -C(=NR m )NR m -OR m -OC(=O)R, -OC(=0)NR m R m -OC(=O)N(R m 2 -OC 2 6 alkylNRTR, -0C 2 6 alky]OR"', -SR' m -S 2 R 2 NR m 2 N(R'm)C(=O)R, 2 N(R m )C(=O)OR n, 2 N(R m )C (=O)NR m -NRmlRrn, -N(R m -N(R m -N(R m )C(=O)NR m R', -N(R m )C(=NR m )NR m -N(Rm 1 )S 2 R n, -N(R m )S 2 NR"'R', 3 0 -NR M C 2 6 a1 kylNR'R', -NR m C 2 6 aI kylORm~, -C(=O)ORs -C(=NRn)NRrnR', -0C(=O)Rs, -0C(=O)NRnR, -OC(=O)N(Rn)S(=O) 2 Rs, -OC 2 6 aIkylNRnRs, -OC 2 6 alkylORs, -SRs, .S(=O)Rs, 499 2 2 NRnR', 2 N(Rrn)C(=0)R', 2 N(Rrn)C(=0)0Rs, 2 N(Rrn)C(=0)NRnRs, -N4RrnRs, -N(Rrn)C(=-O)NRrnRs -N(Rrn)C(=NRrn)NRrnRs, -N(R m )S 2 Rs, -N(R m )S 2 NRnR', -NRrnC 2 -6alkylNRrnRs, -NRrnC 2 -alkylORs and C, 4 alkyl substituted by I or 2 groups selected from C,. 2 haloalkyl, halo, cyano, nitro, -C(=O)OR -C(=0)NR m R m -C(=NR m )NR m R m -OR m -OC(=O)R, -OC(=O)NR m -OC(=O)N(R m 2 -0C 2 4 salkylNRm', -OC 2 6 alkylOR', -SR m 2 2 NR m R m 2 N(R m 2 N(R m )C(=O)0R 1 -S(=O0) 2 N(R m )C(=O)NR m -NR m R', -N(R m -N(R m )C(=O)OR n, -N(R m )C(=O)NR m R m -N(R m n)C(=NR m )NR m R m -N(R m 2 R n, -N(R m 2 NR m R m -NR m C 2 6 alkylNR m -C(=O)ORs, -C(=O)NRnRs, C(=NRn)rNRs, -OC(=O)Rs, -OC(=O)NRnR', -OC(=O)N(Rrn)S(=O) 2 OC 2 6 alkylNRnRs, -0C 26 alkyIORs, S(0)Rs, -S 2 W, 2 NRW,. 2 N(Rrn)C(=O)Rs, -S 2 N(R m -S 2 N(Rn)C(=O)NRnRs, -NRrnRs, -N(Rr)C(=O)ORs, -N(Rrn)C(=O)NRnRs N(Rrn)C(=NRn)NRnRS', -N(Rrn)S(=O) 2 -N(Rrn)S(=O) 2 NRnR', -NRrnC 2 6 a~kylNRrnRs, -NRrnC 2 .ralkylORs and -NR'C 2 6 alkylOR m and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups.

93. A compound according to Claim 91, wherein R 4 is a phenyl ring Q that is vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C 1 8 alkyl, C 1 4 haloalkyl, halo, cyano, nitro, n, -C(=NRn)NRnR'l, -OR' m -OC(=O)NR m -OC(=O)N(R m 2 -0C 2 6 alkylNR m R m -0C 2 6 alkylOR', -SR- m -S 2 R n, 2 NR m -S 2 N(R m 2 N(R m 2 N(R m )C(=O)NR m -NR m R', -N(R m -N(R m )C(=O)NR m R', -N(R m )C(=NR m )NR"'R m -N(R m )S 2 R n, 2 NR m R', 500 -NR m C 2 6 alkylNR m R m -NR M C 24 salkyIOR m -C(0)ORs, -C(=0)NRnR', -C(=NRn)rNRsR' 0C(0)Rs, -OC(=O)NRnRs, -OC(=0)N(Rrn)S(=0) 2 -OC 2 6 alkylNRnR', 0OC 2 6 alkylORs, -SWs, 2 Rs, 2 NRnR', 2 N(Rn)C(=0)Rs, 2 N(Rrn)C(=0)ORs, 2 N(Rrn)C(=0)NRnRs, f4RnRs, -N(Rr)C(=0)0Rs, -N(Rrn)C(=0)NRnR', N(Rrn)C(4=PRr)NRnRs, -N(Rrn)S(=0) 2 Rs, -N(R m )S 2 NRnR', -NRrnC 2 -alkylNRnR', -NRrnC 2 6 alkyl0Rs and C 1 4alkyl substituted by 1 or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=0)NR m Rm, -C(=NR m )NR m -OR m -OC(=O)NR m R m -OC(=0)N(R m 2 R, -0 _6 4 alkylNR m R m 0 2 6 ~yO m -SR- m -S 2 2 NW T 2 N(R m )C(=O)Rn, 2 N(R m )C(=O)OR n, 2 N(R m )C(=O)NR m R m -NR m R m -N(R m -N(Rm 1 -N(R m )C(=O)NR m R m -N(R m )C(=NR m )NR m R m -N(R m 2 R n, -N(R m )S 2 NR m R m -NR m C 2 6 alkylNR m R m C(=O)oRs -C=~)Nms -0C(=O)Rs, -OC(=O)NRnR', -OC(=0)N(Rn)S(=O) 2 -0C2' 6 alkylNRnRs, -OC 2 _6al kylOR', -SW, 0) 2 kR, 2 NR m R 2 N(Rrn)C(=O)RS, -S 2 N(R m )C(=O)0Rs, -S 2 N(R m )C(=0)NR m Rs, -NRrnRs, -N(R m -N(Rrn)C=O)ORs -N(R m )C(=O)NR m R', -N(Rrn)C(=NRrn)NRnR', -N(R m 2 Rs, -N(R m 2 NRnRs, -NR m C 2 6 alkylNR m Rs, -tPR M C 2 -6alkylORS and -NR M C 2 6 alkylOR m and the bridge( carbon atoms are substituted with 0, 1 or 2 =0 groups.

94. A compound according to Claim 91, wherein R 7 is C 19 galkyl, C 1 4 haloalkyl, halo, -OCI 1 6 alkyl, -O-C 1 4 haloalkyl, -NR m R m or -NR m -C 1 4 haloalkyl. A compound according to Claim 91, wherein R 7 is C 1 5 alkyl, C 1 4 haloalkyl, 1, Br or C1.

96. A compound according to Claim 91, wherein R 7 is tert-butyl or trifluoromethyl. -501

97. A compound according to Claim 91, wherein Ro is a saturated, partially-saturated or unsaturated 6- or 7-membered monocyclic ring containing 0, 1, 2 or 3 atoms selected from N, O and S, so long as the combination of O and S atoms is not greater than 1, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from R P

98. A compound according to Claim 91, wherein. R is a saturated, partially-saturated or unsaturated 6-membered ring containing 0, 1, 2 or 3 N atoms, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from R P

99. A compound according to Claim 91, wherein Y is O.

100. A. compound according to Claim 91, wherein Y is NH.

101. A compound according to Claim 80, wherein: R' is R 6 R Z y R 9 R 2 is H, -OR m halo, Ci. 3 haloalkyl or Cl. 6 alkyl; R 4 is a saturated, partially-saturated or unsaturated 10 or 11-membered bicyclic heterocycle containing 1, 2, 3, 4 or 5 atoms selected from 0, N and S, so long as the combination of O and S atoms is not greater than 2, but excluding quinolin-6-yl, 4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl, benzothiazol- 2-yl, 2,3-dihydro-benzo[l,4]dioxin-6-yl, wherein the heterocycle is substituted by 0, 1, 2 or 3 substituents independently selected from Cl. 9 alkyl, oxo, Ci. 4 haloalkyl, 502 halo, nitro, cyano, -OR' m 1 6 alkyl, -O-C 1 4 haloalkyI, -0-C 6 alkyNR m R', -0-C 1 6a1 kylOR m -NR m -NR m -C 14 haloal kyl, -NR m -C 1 6 alkyINRnRn, -NR m -C 1 6al kylOR m -C(=O)C 1 6 a1 kyl, -OC(=0)CI- 6 alkyI, -C(=0)NR'C 1 6 alkyl, -NR m C(=0)Cj. 6 alkyl -C(=O)ORs, -C(=O)NRnRs, C(=NRr)NRnRs, -0Rs, .OC(=O)rNRsR' -OC(=O)N(Rrn)S(=0) 2 OC 2 6 alkylrNRs, -0C 2 -6aikylOR', 2 Rs, 2 N m R R -S 2 N(Rrn)C(=O)Rs, 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=O)NRnRs, -NRrnR', N(Rrn)C(=O)RS, N(Rr)C(=0)ORs, -N(Rrn)C(=O)NRnRs, -N(Rrn)C(=NRn)NRnRs, -N(Rrn)S(=O) 2 -N(Rr)S(=O) 2 NRmR', -NRrnC 2 6 alkylNRnR', -NR'C 2 -6alkylOR' and C, -alkyI substituted by I or 2 groups selected from C,- 2 haloalkyl, halo, cyano, nitro,- -C(=O)NRmRm, -C(=NR m )NR m R m -OR m -OC(=O)R -'OC(=O)NR m R m -OC(=O)N(R m )S 2 R -0C 2 6 alkylNR m -OC 2 6 al kylOR m -S 2 -S 2 NR m R m 2 N(R m 2 N(R m )C(=0)OR, 2 N(R m )C(=O)NR"'R m -N(Rn)C(=0)R -N(R m n)C( 0)OR, -N(R m )C(=O)NR m -N(R m )C(=NR m )NR m R m -N(R m )S 2 R', -N(R m 2 NR m R m -C(=O)ORs, -C(=0)NRnlRs, -C(=NRrn)NRnR', -OC(=O)RF, OC(=O)NR-lRs, -OC(=0)N(Rrn)S(=0) 2 Rs, -OC 2 6 a~ky~NRsR' -0C 2 -6al kyORs, -SRs, 2 2 N RRs, -s 2 N(Rrn)C(=O)RS, -S 2 N(Rn)C(=O)ORs, -S 2 N(Rrn)C(=0)NRnRS, -NRrnRS, -N(Rrn)C(=O)ORs, -N(Rrn)C(=0)NRnRs, -N(Rrn)C(=NRn)NRnR', -N(Rrn)S(=O) 2 -N(Rrn)S(=0) 2 NRnRs, -NRnC 2 6 alkylNR m Rs, -NR m C 2 6 a1 kylORs and -NR m C 2 6 a! kylOR"'; wherein R 4 is not 2-aminocarbonylmethyl-2,3-dihydro-benzo[ 1,4]dioxin-8-yl, 2-cyanomethyl- 2,3-dihydro-benzo[1I,4]dioxin-8-yl, quinolin-3-yl, 3H-quinazolin-4-on-3-yl, benzo[1I,3]dioxol-5-yl, 3,3-dimethyl-1I,3-di hydro-i ndol-2-on-6-yl or 4,4-di methyl- 3,4-dihydro- LH-quinolin-2-on-7-yI; R 7 is C 18 alkyI, CI-5haloalkyl, I or Br; R 9 is H, Cl- 9 alkyl, C 1 4haloalkyl, halo, nitro, cyano, -0CI. 6 alkyl, -0-c 1 ~haloal kyl, -O-C 1 6 alkylNR m R m -0-CI 6 alkylOR m -NR6 m R m -NR'-C I 4 haloalkyl, -NIR m -C 1 6 alkylNR m R m or -NR m -C 1 6 alkyIOR m Y is NH-; and 503 Z isCR 8 or N.

201. A compound according to Claim 101, wherein R. 4 is a heterocycle selected from indole, 3H-indole, benzo[b] furan, benzothiophene, 1H-indazole, benzimidazole, benzthiazole, IH-benzotriazole, 7-quinoline, 8-quinoline, 1,2,3,4- tetrahydroquinoline, isoquinoline, cinnoline, phthalazine, quinazoline and quinoxaline, wherein the heterocycle is substituted by 0, 1,.2 or 3 substituents independently selected from Cl- 9 alkyl, oxo, C 1 4 haloalkyl, halo, nitro, cyano, -S(=O)nC 1 6ai kyl, -0-C 4 haloalkyl, -0-C 1 6 alkylNR'R', -0-C 1 .6a1 kylOR m -NR-R m -NR"'-C 1 4 haloalkyl, -NR m -C 1 6alkylNR m -NR m -C 1 6 alkylOR', -C(=O)C 1 6 alkyl, -OC(=O)CI-6alkyl, -C(=O)NR'C 1 6 alkyl, -NR m C(=O)C 1 6a1 kyl C(=O)ORs, -C(=O)NRnR', -C(=NRn)NRrnRs, -OC(=O)Rs, -OC(=O)NRnRs, -OC(=O)N(Rn)S(=0) 2 Rs, -OC 26 ralky1NR m -OC 2 _6alkylORs, -SWS, -S 2 Rs, -s 2 NRnRs, -S 2 N(Rrn)C(=0)RS, -S 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=O)NRnRs, .NRnRs, -N(Rrn)C(=0)R', -N(Rr)C(=0)ORs, -N(Rrn)C(=O)NRnRs, -N(Rrn)C(=NRn)NRrnRs, 2 RS, -N(Rrn)S(=Q) 2 NRnR', -NR M C 2 _6alkyl NRnRS, -NR m C 2 6 a4lkyIOR' and CI- 4 alkyl substituted by 1 or 2 groups selected from C 1 2 haloalkyl, halo, cyano, ni tro, n, -C(=O)NR m R m -C(=NR m -OR- m -OC(=O)N(R m 2 R n, -0C 2 6 alkylNR"'R', -OC 2 6 alkylOR', 2 2 NR m R m 2 2 N(R m 2 N(R m )C(=O)NR m R m -N(R m -N(R tm )C(=O)NR m -N(R m )C(=NR m )NR m R m -N(R tm 2 -N(R m 2 NR m R m -C(=O)0Rs,7C(0)NRWRS, -C(=NR m )NR m Rs, -ORs, -OC(=O)Rs, -OC(=O)NRnRs, -OC(=O)N(R m 2 R', -0C 2 6 a1 kylNRrnRs, OC 26 alkylORs, -SRs, -S 2 Rs, -S 2 NR"'Rs, -S 2 2 N(R"')C(=O)OR 5 2 N(R"')C(=O)NR m R', -NIR m Rs, -N(R m -N(R')C(=O)0R 5 -N(Rr)C(O)rNRs -N(R tm 2 Rs, -N(R m )S 2 NTrl'Rs., -NR'C 2 6 a~kyNR m -NR"'C 2 6 alkylORs and -NR m C 2 6 alkylOR7. 504 103. A compound according to Claim 101, wherein R 4 is a heterocycle selected from 6-indole, 7-indole, 6-3H-indole, 7-3H-indole, 6-benzo[blfuran, 7- benzo[bljfuran, 6-benzothiophene, 7-benzothiophene, 6-1H-indazole,.7-1H- indazole, benzimidazole, benzthiazole, IH-benzotriazole, 7-quinoline, 8- quinoline, 7-1 ,2,3,4-tetrahydroquinoline, 8-1 ,2,3,4-tetrahydroquinoline, isoquinolin-7-yl, isoquinolin-8-yl, 7-cinnoline, 8-cinnoline, phithalazine, 7- quinazolin'e, 8-quinazoline and quinoxaline, wherein the heterocycle is substituted by 0, 1, 2 or 3 substituents independently selected from C 1 9 alkyl, oxo, C 1 4 haloalkyI, halo, nitro, cyano, 6 alkyl, -O-C 1 4 haloalkyl, -0-C 1 6 a1 kylNR m R m -0-C 1 6 alkylOR'n, -NR m R m -NR m -C 1 4 haloalkyl,( -NR m -C 1 6 alkylNR m R m -NR m -C 1 6 alkyiOR 6 alkyl -OC(=O)C 1 6 alkyl, R m C 1 6 alkyl, -NR m C(=O)CI 6 alkyl -C(=O)OR -C(=O)NRnRs, -C(=.41Rn)NRnRs .ORs, .OC(0O)Rs, .OC(=O)rNRsR' -OC(=O)N(R m )S 2 Rs, -OC 2 6 alkylNRnR', -OC 2 6 alkylOR', 2 Rs, -S(=O0) 2 NR-Rs, 2 N(Rrn)C(=0)R', 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=O)NRnRs, -NRrnRs, _N(Rrn)C(=O)Rs, -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRnR, -N(Rrn)C(=NRn)NRnRs, -N(R m )S 2 -N(R m )S 2 NRnRs, -NR m C 2 6al kylNRnRs, -NR m C 2 6 alkylORs and C 4 alkyi substituted by 1 or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=NR m )NR m R, -Ok tm -OC(=O)Rn -OC(=O)NR M R m 2 R n, -OC 2 .6alkylNR m R m -0C 2 6 alkylOR', -SR m -S -S 2 2 NR m R m -S 2 N(R m 2 N(R m )C(=O)OR n, 2 N(R m )C(=O)NR m -N(R m h -N(R m )C(=O)0R n, -N(R m )C(=O)NR m R m -N(R tm )C(=NR m )NR m R m -N(R m 2 R n, -N(R m 2 NR m R m -C(0)ORs, -C(=O)NRm'~R, -C(=NR m )NR m Rs, .OC(=O)Rs, -OC(=O)NRmlR', -OC(=O)N(Rrn)S(=O),Rs, -OC 2 6 aI kylNR m -OC 26 alkylORs, -S(0)Rs, 2 Rs, -S 2 NRnRs, 2 N(R m -s 2 N(R m )C(=O)0Rs, 2 N(R')C(=O)NR m Rs, -NRmRs, -N(R m -N(Rr)C(=O)ORs, -N(Rrn)C(=O)NRnR', -N(R m )C(=NR m )NR m Rs, -N(R m 2 Rs, -N(R tm 2 NR m nRs, -NRnC 2 6 alkylNR m -NR m C 2 -6al kylORs and -NR m C 26 aI kylOR m 505 104. A compound according to Claim 101, wherein R 9 is Cl- 9 alkyI, C 1 4 haloalkyl, halo, nitro, cyano, -OCI 1 6 alkyl, -0-C 1 4 haloalkyl, -0-CI- 6 alkylNR m -0-C 1 6 al kylOR m -NR m R m -NRn-C 1 4 haloalkyl, -NR m -C 1 6 alkylNRm"' m or -NR m -C 1 4 alkyl0R m acrigt lam11 hri R9isH 105. A compound according to Claim 101, wherein R is HR.

10106. A compound according to Claim 101, wherein Z is CR.

10107. A compound according to Claim 101, wherein RZ is N.t-uylo trifluoromethyl. 109. A compound according to Claim 80, wherein: R' is z~- R 9 R 2 is C 1 -6alky1 substituted by 1, 2 or 3 substituents selected from C1 4 haloalkyl, halo, cyano, ni tro, -C(=0)NR m R', -OC(=O)NR m R', 2 2 2 2 m -N(R m )C(=NR m )NR m -N(R 1 2 R', 2 -NR"'C 2 6 alkyNR m 'R m and -NR m C 26 alky!OR'; or R2i 506 R8~R6 R 6 ;or R 2is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, 0 and S, wherein no more than 2 of the ing members are 0 or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from R 5 R 6 and R 7 R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atomn bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from CI-8alkyl, C 1 4 haloalkyl, halo, cyano, nitro, -C(=0)NR m R', -C(=NR m )NR m -OR m -0C(=O)Rn, -OC(=0)NR m R m -0C(=0)N(R m 2 -OC 2 6 alkylNR m R m -OC 2 6 alkylOR m 2 -S 2 NR m 2 N(R m 2 N(R m )C(=0)OR, -S 2 N(R m )C(=0)NR m -NR m -N(R m -N(R m -N(R m )C(=O)NR m -N(R m )C(=NR m )NR 1 Rm", -N(R m 2 R", -N(R m )S 2 NR m -N R m C 2 -6alkylNR m -NR m C 2 o6alky]OR', -C(=O)ORs, -C(0)NRnRs, -C(=NRrn)NRRs, -ORs, -G(=0)Rs, -OC(=O)NRnRs, 2 Rs, -OC 2 6 alkylNRnRs, -0C 2 -6alkyORs, -SRs, -S 2 Rs, -S 2 NRnRS, -s 2 N(Rrn)C(=0)RS, 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=0)NRnR', -NflRnRs, -NQRr)C(0)Rs -N(Rr)C(=0)ORs, -N(Rrn)C(=0)NR'R', -N(Rrn)C(=NRn)NRnRs, -N(R m )S 2 Rs, -N(R m )S 2 NRnRs, -NR m C 2 6 alkyINRrnRs, -NRnC 2 6 alkyIOR' and C 14 alkyl substituted by 1 or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=0)R 1 -C(=0)0Rn, -C(=0)NR m R m -C(=NR m )NR m -OR- m 507 -OC(=0)NR m 2 -OC 2 -6al kyl NR'R', -0C 2 -ralkyOR', -SR'n, 2 2 NR-R-, 2 N(R m 2 N(R m -S 2 N(R m )C(=0)NR m R', -NR m -N(R m -N(R m -N(R m )C(=0)NR m R', 2 -N(R m 2 NR m R', -NR m C 2 6 alkylNR m R m -C(=0)ORs, -C(=0)NRnR', -C(=NRn)NRnR', 0C(=o)Rs, .OC(=0)NRnR' -OC(=O)N(Rrn)S(=0) 2 OC 26 alkyl NRnR', -OC 2 6 alkyI0RS, 2 2 NRnRs 2 N(Rrn)C(=0)R', 2 N(Rrn)C(=O)0Rs, 2 N(Rrn)C(=0)NRnRs, -NR-IRs, -N(Rrn)C(=0)Rs, -N(Rr)C(=0)ORs, -N(Rrn)C(=-O)NRnR', -N(Rrn)C=NRn)NRnRs, -N(Rrn)S(=0) 2 -N(Rrn)S(=0) 2 NRnRs,, -NRnC 2 6 alkyNRnRs, -NRnC 2 -6alkyl0Rs and -NR m C 2 6 alkylOR m and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups; R 7 is C 2 8 alkyl, CI-5haloalkyl, 1, Br; R 9 is independently, at each instance, H, C 1 9 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -OCI. 6 alkyl, -0-Cj 4 haloalkyl, -0-C 1 6 alkylNR m R m -0-C 1 6 alkyl0R m -NR m -NR m -C 1 ~haloalkyl, -NR m -C 1 6 alkylNR'R m or -NR m 16 alkylOR m Y is NI-; and Zis CR 8 or N. 110. A compound according to Claim 109, wherein R 2 is C 1 -6alkyl substituted by 1, 2 or 3 substituents selected from C 1 4 haloalkyl, halo, cyano, nitro, -C(0)NRR m -C(=NR m )NR m R m -OR m -0C(=0)Rn, -OC(=0)NR m R m -0C(=0)N(R m 2 R n, -OC 2 6 alkyNRm 1 R m -0C 26 alkylOR m -SR m -S 2 -S(=O0) 2 NRmlRrn -S 2 N(R m 2 N(R m )C(=0)0R n, -S 2 N(R m )C(=O)NR m R m -NR m R m -N(R m n, -N(R m -N(R m )C(=O)NR"'R m -N(R m )C(=NR m )NR m R m -N(R m )S 2 R n, -N(R m 2 NR m R m -NR m C 2 6 alkylNR m R m and -NR m C 2 6 alkyIOR m 508 111. A compound according to Claim 109, wherein R 2is -(C(Rq) 2 ),,phenyl, wherein the phenyl is substituted by 0, 1, 2 or 3 substituents independently selected from CI.8alkyl, C 1 4 haloalkyI, halo, cyano, nitro, -C(=O)NR m -C(=NRn)NRnR, -OR m -OC(=O)R, -OC(=O)NR-R m -OC(=O)N(R m 2 R -OC 2 6 alkyNR m -OC 2 _6alkyIOR", 2 2 2 -S(=02N(Rr~l)C(=O)OR n, 2 N(R m )C(=O)NR m R m -NRnRmI, -N(R m -N(R m )C(=O)NR m R m -N(R m )C(=NR m )NR m -N(R m 2 -N(R m )S(=O0) 2 NR m R m -N_26lkl~~. -NR m C 2 6 alkyIOR"', -C(=O)ORs, -C(=O)NRnR',.-C(=NRml)NRrnRs, .0C(0)Rs -OC(=O)rNRs. -OC(=O)N(Rm)S(=O) 2 Rs, OC 2 6alkylNRnR', -OC 2 -6alkyIORs, -S (=O)Rs, 2 2 NRmlRs, 2 N(Rm~)C(=O)Rs, 2 N(Rrn)C(0)ORs, 2 N(Rm~)C(=O)NRrnRs, 44TRrRs, -N(Rr)C(0O)Rs, .N(Rr)C(0O)ORs, -N(Rm~)C(=O)NRnRs, -N(Rm~)C(=NRn)NRmW, 2 Rs, -N(R m )S 2 NRnRs, =NRm~C 26 alkylNRrnRs, -NRnC 2 -alkyORs and C Aalkyl substituted by 1 or 2 groups selected from CI. 2 haloalkyl, halo, cyano, nitro, -C(=O)OR -C(=O)NR m T -C(=NR"')NR m R m -OR m -OC(=O)R, -OC(=O)NR m -OC(=O)N(R m 2 R n, -OC 2 6 al kylNR m R m -OC 2 _6alkylOR', -SR m -S 2 -S 2 NR m R m 2 N(R m 2 N(Rrn)C(=O)OR n, -S 2 N(R m )C(=O)NR m -N(R m n, -N(R m )C(=O)OR n, -N(R m )C(=O)NR m -N(R m )C(=NR m )NR m -N(R m 2 R n, -N(R m 2 NR m R m -NR M C 2 -6alky1NR m -C(=O)ORs, -C(=O)NRnRs, -C(=NRn)NRm~R', .0C(0)Rs, OC(=O)NRnRs, -OC(=O)N(Rn)S(=O) 2 Rs, -OC 2 6 alkylNR m Rs, -OC 2 6 alkylOR', -SRs, 2 2 NR'~R', 2 N(Rrn)C(=O)Rs, 2 N(Rm~)C(=O)ORs, -S 2 N(Rrn)C(=O)NRm~Rs, -NRrnRs, -N(Rrn)C(=O)ORs, -N(Rr)C(O)NRnRs, -N(Rrn)C(=NRm)NR'~Rs -N(R m )S 2 R, 2 NRnRs, -NR M C 2 6 alkylNR m W, -NR M C 2 6 alkyIORs and -NR'C1. 6 alkyIlOR m 509 112. A compound according to Claim 109, wherein R 2 is wherein R' is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, 0 and S, wherein no more than 2 of the ring members are 0 or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from CI-8alkyl, C 1 4 haloalkyl, halo, cyano, nitro, -C(=0)0R n, -C(=O)NR m R', -C(=NR m )NR m -OR' m -OC(=O)NR m R m -OC(=O)N(R m 2 R n, -0C 2 6 alkyNR m -OC 2 6 alkylOR', -SR m 2 Rn, 2 NR m 2 N(R m 2 N(R m 2 N(R m )C(=O)NR m R m -NR m R m -N(R m -N(R m )C(=O)OR, -N(R m )C(=O)NR"'R m -N(R m )C(=NR m )NRm''R, -N(Rm 1 )S 2 R, -N(R m 2 NR m -NR m C 24 jalkylNR m R m -NR"'C 2 _6alkylOR m -C(=O)ORs, -C(0)NRnRS -C(=NRrn)NRrnR', -ORs, -OC(=O)Rs, OC(=O)NRnRs, -OC(=O)N(Rn)S(=O) 2 -OC 2 6 alkylNR m Rs, -OC 2 6 alkyIORs, 2 2 NRnR', 2 N(Rrn)C(=O)Rs, 2 N(RI'hC(=O)ORs, -S 2 N(Rrn)C(=O)NRnRs, -NRrnRs, -N(Rrn)C(=O)R', -N(Rr)C(=O)ORs, -N(Rrn)C(=O)NRnRs, -N(Rrn)C(=NRrn)NRnRs', -N(Rrn)S(=O) 2 Rs', -N(Rrn)S(=O) 2 NRnRs, -NRrnC 2 6 alkylNRrnRs, -NR m C 2 6 a1 kylORs and C 1 4 alkyl substituted by I or 2 groups selected from C 1 2 haloalkyI, halo, cyano, nitro, -C(=O)NR m R'm, -C(=NR m )NR m R m -OR' m -OC(=O)NRnRml, -OC(=O)N(R m 2 -OC 2 -6alkyJNR'R', -OC 2 .6alkylOR m -SR m n, 2 2 NR m R', -S(=Oh2N(R m 2 N(R m -S(=O0) 2 N(R m )C(=O)NR m R, -NR m Rn, -N(R m -N(R m -N(R m )C(=O)NR m R m -N(R m )C(=NR m )NR m R m -N(R m 2 -N(R m 2 NR m R', -NR'C 2 6 alkylNR m -C(=O)ORs, -C(=0)NRnRs, -C(=NRml)NRmRs, -OWs, -OCQ=O)NRnR', -OC(=O)N(Rn)S(=O) 2 -OC 2 6 alkylNRnRs, -OC 26 al kylORs, -SRs, -S 2 Rs, -S 2 NR m Rs, 2 N(R m -S 2 N(R m )C(=O)0R 5 -s 2 N(R m )C(=O)NR m Rs, -NR m -N(R m -N(R m )C(=O)0R 5 -N(R m )C(=O)NR m R', -510-- -N(Rrn)C(=NRn)NRnR', -N(R m )S 2 Rs, -N(Rrn)S(=O) 2 NRrnRs, -NR m C 2 6 al kylNRrnRs, -NRrnC 24 salkylORs and -NR m C 2 -tsa~kylOR'; 113. A compound according to Claim 109, wherein R 4 is a phenyl ring that is vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atomns is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C 1 galkyl, C 14 haloalkyl, halo, cyano, nitro, -C(=0)NR m -C(=NRni)NR m R m -OR- m -OC(=O)NRnRr, -OC(=O)N(R m )S 2 R6, -OC 2 6 a~kylNR m OC 2 -6alkyI OR m -SR- m 2 R n, 2 NR-R-, -S(O) 2 N(R m n -S 2 N(R m 2 N(R m )C(=O)NR m R m -NR m R m -N(R m n, -N(R m n' N(R m )C(=O)NRmlR', -N(R m )C(=NRm)NR m -N(Rm)S(=O) 2 R n' -N(R m 2 NR m R', -NR m C 2 6 alkylNR m -NR'"C 2 6al kyIOR m -C(=O)ORs, ~C(=-O)NRmlR', -C(=NRrn)NRrnRs. OC(=O)Rs, -OC(.=O)-NRrR', -OC(=O)N(R m )S 2 Rs, I OC 26 al kylNRrnRs, -0C 2 6 a1 kylORs, -SRs, -S(=O)Rs, 2 2 NRrnR', 2 N(Rrn)C(=O)Rs, 2 N(Rr)C(=O)0Rs 2 N(Rrn)C(=O)NRnRs, -NR m Rs, -N(R m -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRnR', -N(Rrn)C(=.1R)fNRnRs, -N(Rrn)S(=O) 2 R', -N(R m 2 NR m Rs, -NR m C 26 alkyiNR m Rs, -NRnC 2 .6alkylORs and C 14 alkyl( substituted by I or 2 groups selected from C,- 2 haloalkyl, halo, cyano, nitro, -C(=O)NRnR, -C(=NR m )NR m R m -OR m -OC(=O)NR m R m -OC(=O)N(R m )S 2 -0C 2 6 alkylNR m R m -OC 2 6al kyIOR m -s -S 2 -s 2 NR m R m -S 2 N(R' T *O)R, m 2 N(R')C(=O)NRnR, -NR m R m -N(R m -N(Rn')c(=O)OR n, -N(R m )C(=O)NR m R m -N(R m )C(=NR m )NR m R m -N(R m )S 2 -N(R m )S 2 NR m R m -NR m C 2 6 alkylNR m R m and -NR tm C 2 6 a~kylOR"'; and the bridge carbon atoms are substituted with 0, 1 or 2 =0 groups. -511 114. A compound according to Claim 109, wherein R 7 is tert-butyl or trifluoromethyl. 115. A compound according to Claim 109, wherein R 9 is H. 116.A cmpond ccoringto lai 109 whrei Z s C 8 117. A compound according to Claim 109, wherein Z is N.

10118. A compound according to Claim 10, whereinZisN R, is F 3 CtW 2Z R 2is H, -OR- m Cl, C 1 3 haloalkyl or C 1 6 alkyl; R 4 is a saturated or unsaturated 5- or 6-membered ing containing 0, 1, 2 or 3 atoms selected from 0, N and S, so long as the combination of 0 and S atoms is not greater than 2, wherein the ing is substituted by 0, 1, 2 or 3 substituents independently selected from C 1 8 alkyl, C 1 4 haloalkyl, halo, cyano, nitro, -C(=NR-)NR m -OC(=O)NR m R', -OC(=O)N(R m 2 -0C 2 6 alkylOR m -SR' m 2 R', 2 NR m R m 2 N(R m 2 N(R m 2 N(R m )C(=O)NR m R m -NR m R m -N(R m -N(R m )C(=O)OR -N(R m )C(=O)NR m R m -N(R m )C(=NR m )NR m -N(R m 2 R', -N(R m 2 NR m -NR m C 2 6 aI kylNR m R m -NRnC 2 6 alkylOR"', -C(=O)Rs, -C(=O)ORs, -C(=O)NRrnR', -C(=NRm)NRnRs, -ORs, OC(=O)Rs, -OC(=O)NRnRf, -OC(=O)N(R m )S 2 Rs, -~OC 26 al kylNRnRs, -OC 2 6 alkylORs, -SRs, -S -S 2 Rs, -S 2 NRnR', 2 N(Rrn)C(=O)R', -S 2 N(Rrn)C(=O)ORS, 2 N(R m )C(=rO)NR m RS, NRflRs, -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRnR', -N(Rrn)C(=NRn)NRnRs, 512- -N(Rrn)S(=O) 2 Rs, -N(Rrn)S(=O) 2 NRnR', -NRrnC 2 _6alkylNR m Rs, -NR M C 2 6 alkylORs and C 1 4 alkyl substituted by I or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=O)NRmlRn, -C(=NR m )NR m R m -OR m -OC(=O)Rn, -OC(=O)NR m -OC(=O)N(R M 2 -0C 2 6 alky]NR m R m -OC2. 6 alkylOR m -SR m n, 2 Rn, 2 NR m R m 2 N(R m m 2 N(Rml)C(=O)NRmR', -NR m R', -N(R m -N(R m -N(R m )C(=O)NR m R m -N(R m )C(=NR m )NR"'R m -N(R m 2 -N(R m 2 NR m R m -Nk m C 2 6 alkylNR m R' and -NR m C 26 alkylOR'; wherein R 4 is not unsubstituted phenyl;( R9 is independently, at each instance, H, C1.galkyl, C 1 4 haloalkyI, halo, nitro, cyano, -0CI. 6 alkyl, -O-C 1 4 haloalkyl, -0-C 6 alkylNR m R m -0-C 1 6al kylOR m -NR m R m -NR m -C 1 4 haloalkyl, -NR m -C 1 6 alkylNR m R m or -NR m 6 alkylOR m Y is NH; and Z is CR 8 or N. 119. A compound according to Claim 118, wherein R 4is a saturated or unsaturated 5- or 6-membered ring containing 1, 2 or 3'atoms selected from 0, N and S, so long as the combination of 0 and S atoms is not greater than 1, wherein the fing is substituted by 0, 1, 2 or 3 substituents independently selected from C 1 8 alkyl, C 14 haloalkyl, halo, cyano, nitro, -C(=0)NR m R m -C(=NR m )NR m R m -OR,( -0C(=O)NR m -0C(=O)N(R m 2 -OC 2 6 alkyIOR', -SR m -S 2 2 NR'R m -S 2 N(R m 2 N(R m )C(=O)NR m R m -NR m R m -N(R m )C(=NR m )NR m R m -N(R m )S(=Oh2R n -N(R m 2 NR m -NR m C 2 6 alkylNR"'R m -NR m C 2 6 a1 kyl OR m -C(=O)0Rs, -C(=O)NR'lRs, -C(=NRrn)NR-W, .ORs, OC(0O)Rs, -OC(=O)NRnR', -0C(=0)N(Rn)S(=O) 2 Rs, -OC 26 alkylNRrnR', -OC 2 6 alkyIORs, -S 2 Rs, 2 NRrnR', 2 N(Rrn)C(=O)R', -s 2 N(Rrn)C(=O)ORS, -S 2 N(Rn)C(=O)NRnRS, 4pNRnR' N(Rr)C(0)ORs, -513- -N(Rrn)C(=O)NRrnRs, -N(Rrn)C(=NRn)NRnR', -N(Rrn)S(=-O) 2 R', -N(R m )S 2 NRnR', -NRrnC 2 oalkylNRnR', -NRrnC 2 alkylORs and C14alkyl substituted by I or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=O)NR m R m -C(=NR m )NR m R m -OR' m -OC(=O)NR m R m -OC(=O)N(R m 2 R n, -OC 2 6 alkylNR m -0C 2 6 a1 kylOR m -SR m -S n, 2 2 NR m -S 2 N(R m 2 N(R m )C(=O)ORn, 2 N(R m )C(=O)NR m R m -NR m R m -N(R m -N(R m -N(Rrn)C(=O)NRnRl -N(R m )C(=NR m )NR m -N(R m 2 Rgn, 2 NR m R m -NRnC 2 6 alkylNR m R' and -NR m C 2 6 alkylOR'; 120.A cmpond ccoringto lai 118 whrei Z s C 8 121. A compound according to Claim 118, wherein Z is N. 122. A compound having the structure: R 3 R 3 R2H x wherein: X is 0, S or N' n is independently, at each instance, 0, 1 or 2; o is independently, at each instance, 0, 1, 2 or 3; R m is independ ently at each. instance H orR; R n is independently at each instance C 1 .galkyl, phenyl,.orbenzyl; R qis independently in each instance H, C 1 -4alky1,.C,4haloalkyl, halo, cyano, nitro, -C(=O)OR n, -C(=O)NR m -C(=NR-)NR-R m -OR m n, 2 -OC 2 -6al kyl NR m Rm', -0C 2 6 a1 kylOR m -SR m n, -s 2 R n, 2 NR m R m -s m 2 N(R m -S 2 N(R tm )C(=O)NR'Rm, -NR m R, -N(R tm -N(R tm -N(R m )C(=O)NR m R m 514 m )NR m -N(R m -N(R m 2 NR m R', -NR m C 2 6 alkylNR m or -NR m C 2 6 alkylOR'; R' is R' substituted by 0, 1, 2 or 3 substituents independently selected from R q R'isHorC 4 alkyl; R 5 is H, Cl-galkyl, C,- 4 haloalkyl, halo, nitro, cyano, -0C,-6alkyl, 4 haloal kyl, 6alkyINR-R-, 6 alkylOR m -NR m R m -NR m 4 haloalkyl, -NR m 6 alkylNR m -NR m 6 alkylOR M or -(CH 2 )nR' R 6is, independently at each instance, H, 9 alkyl, C,. 4 haloalkyl, ha lo, ni tro, cyano, -OCI 6 al kyl, -0-C 4 haloalkyl, -0-C 1 6 alkylNR m R m -0-CI- 6 alkylOR m -NRR m -NR m Ahaloalkyl, -NR m 6 alkylNR m R' or( -NR m -C~I-alkylOR'; R 8is H, C1. 9 alkyl, C,. 4 haloalkyl, halo, nitro, cyano, -OCI, 6 alkyl, 4 albalkyl, 6 akyNRnR', 6 alkyl0R m -NR m R m -NR m 4 haloalkyl, -NR m -C 6 alkylNR m R' or -NR m 6alkyl0R m and R'is R 6 (CR R O 0 RO R 2 is H, -OR' m halo, C,- 3 haloalkyl or C,- 6 alkyl; R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atomn bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 And S atoms is not greater than 2, wherein the ing and bridge are sibstiut~4y0~1,6#3 selected from CI- 8 alkyl, C,. 4 haloalkyl, halo, cyano, nitro, -C(=0)NR m R m -C(=NR m )NR m -OR m -OC(=0)NR-R -0C(=0)N(R m 2 -0C 2 6 alkylNR-R m -0C 2 6 alkylOR -SR m -S 2 -S 2 NR m 2 N(R m 2 N(R m )C(=O)0R, 515 2 N(R m )C(=0)NR m R m -NRnRn', -N(R m -N(R m )C(=0)NR m R m -N(R m )C(=NR m -N(R m 2 R', -N(R m 2 NR m Rn', -NRnC 2 6 alkylNR m R m -NR m C 2 6 aIkyIOR m -C(=0)0Rs, -C(=O)NRnR', -C(=NRrn)NRrnRs, ORs, -OC(=0)Rs, -0C(=0)NRnRs, -0C(=0)N(Rn)S(=O) 2 Rs, -OC 2 6 al kyl NRrnR', 0C 2 6 al kylORs, -SRs, 2 2 NRnR', S(=0) 2 N(R m )C(=O)Rs, 2 N(Rr)C(=0)0Rs, 2 N(R m )C(=0)NR m -NRrnR' -N(R m )C(=0)Rs, -N(R m )C(=O)0R 5 -N(R m )C(=0)NR m Rs, -N(R m )C(=NR m )NR m Rs, -N(Rrn)S(=O) 2 Rs, -N(R m 2 NR m -NR'C 2 6al kyl NR m -N]~1RC 2 6 alkylORs and C 14 alkyl substituted by 1 or 2 groups selected from C 12 haloalkyl, halo, cyano, nitro, -C(=O)NR m -C(=NR m )NR m R m -OR m -OC(=O)NR m -OC(=O)N(Rm)S(=O) 2 -OC 26 al kylNR m R', -OC 2 -6alkyIOR m -SR' m 2 Rn, 2 NR m R m -S 2 N(R m -s 2 N(R m 2 N(R m )C(=O)NR m R', -NR m R m -N(R m n, -N(R m -N(Rm')C(=O)NRnR, -N(R m )C(=NR m )NR m R m 2 -N(R m )S 2 NR m R m -NR m C 2 6 a1 kylNR M -C(0)ORs, -C(=O)NRnR', -C(=NR m )NR m R', -ORs, -OC(=O)Rs, -OC(=O)NRnR, -OC(=O)N(Rrn)S(=O) 2 Rs, -OC 2 6 alkyINRnR', -0C 2 6 alkylORs, -SRs, S(=O)Rs, 2 2 NRrnR', 2 N(Rrn)C(=O)R', -S 2 N(Rrn)C(=O)ORs, -s 2 N(Rrn)C(=O)NRnRs, -NR m -N(R m -N(R m )C(=O)0R 5 -N(R m )C(=O)NR m Rs, -N(Rrn)C(=NRrn)NRnR', -N(R M 2 Rs, -N(R m 2 NR m R', -NRnC 26 alkylNRnR', -N.R m C 26 alkylOR 5 and -NR M C 2 6 alkylOR m and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups; R 7 is C 1 9 alkyl, C14haloalkyI, halo, nitro, cyano, -OCI 16 alkyl, -O-C 1 4 haloalkYl, -0-C 1 6 alkylNR m -0-C 1 6 alkylOR', -NR m R', -NR m -C 1 4 haloalkyl, -NR m -C 1 6 alkylNR m R m or -NR m -C I- 6 alkylOR'; is a saturated, partially-saturated or unsaturated 6- or 7-membered monocyclic or 10- or 1 1-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, 0 and S, so long as the combination of 0 and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0, 1 or -516- 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from RP; RP is independently at each instance C,- 8 alkyl, C 1 -4haloalkyl, halo, cyano, nitro, n, -C(=O)OR n, -C(=O)NR m -C(=NR m )NR m -OR' m -OC(=O)N(R m 2 -0C 2 6 alkylNR m R', -OC 2 -6alkylOR', -SR m 2 2 NR m R', -S 2 N(R m 2 N(R m 2 N(R m )C(=O)NR m R m -NR m -N(R m )C(=O)ORn, -N(R m )C(=O)NRnRT, -N(Rrn)C(=NRn)NRnR', -N(R m 2 -N(R m 2 NR m R',I -NR m C 2 6 alkyINR m R m or -NR m C 2 _6alkylOR m and Y is 0or NHi;or R'is R R 5 R' N R *(CRqRq )ORO or (CRqfl )OROo R 2is H, -OR' m halo, C 1 3 haloalkyl Or CI 6 alkyl; R 4 Is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected( from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C,.salkyl, C 1 4 haloalkyl, halo, cyano, nitro, n, -C(=0)NR m R', -C(=NR m -OR m -OC(=O)NR m R m -OC(=O)N(R m )S 2 -OC 2 6 aIkyl NR m -OC 2 6 al kylOR"', -SR m -S -S 2 R n, -S 2 NR m -S 2 -S 2 N(Rm 1 2 N(R m )C(=O)NR m R m -NR m -N(R m n, -N(R tm -N(R m )C(=O)NR m R m -N(R-)C(=NR m )NR m R m -N(R m )S 2 R, -N(R m 2 NR m R m -NR m C 2 6 alkylNR"'Rm, -NR m C 2 6 a1 kylOR m -C(=O)Rs, -C(=O)ORs, -CQ.O)rNRsR' -C(=NRn)NRnR', -517- -0C(=0)NRnR', -OC(=0)N(Rrn)S(=0) 2 Rs, -0C 2 6 a1 kyl NRnRS, -0C 2 6 a1 kylORs, -SRs, S(=0)Rs, 2 Rs, 2 NRnRs, 2 N(Rrn)C(=0)R', 2 N(Rr)C(=0)0Rs, -S 2 N(Rn)C(=O)NRnRs, -1~NRRS -N(Rrn)C(=0)Rs, -N(Rr)C(=O)0Rs, -N(Rrn)C(=0)NRnRs, -N(Rrn)C(=NRn)NRrnR', -N(Rrn)S(=0) 2 Rs, -N(Rrn)S(=0) 2 NRnRs, -NRrnC 2 6 alkylNRmWR, -NR m C 2 6 alkylORs and C 1 4 alkyI substituted by 1 or 2 groups selected from Ci. 2 haloalkyl, halo, cyano, nitro, n, -C(=0)0R n' -C(=0)NR m R m -C(=NR m )NR m R m -OR" m -OC(=O)NR m R m -OC(=O)N(R m 2 R n, -OC 2 6 alkylNR m R', -OC 2 6al kyIOR m -SR m 2 2 NR m R', 2 -S 2 N(R m )C(=0)0R n, 2 N(R m )C(=0)NR m R m -NR'R m -N(R m n, -N(R m )C(=O)NR m R m -N(R m )C(=NR m )NR m -N(R m )S 2 -N(R m 2 NR m R m -NR m C 2 6 alkyNR m -C(=0)ORs, -C(=NRn)NRnRs, -OWS, -OC(=O)Rs, -0C(=0)NRnRs, -OC(=O)N(R m )S 2 Rs, -0C 2 6 al kylNRrnRs, -0C 2 6 alkyl0Rs, -S(=O 2 s IS=)N~n 2 N(Rrn)C(=O)R', -S 2 N(Rrn)C(=O)ORs, -S 2 N(Rrn)C(=O)NRnRs, -NRrnR', -N(Rr)C(=O)Rs, -N(Rrn)C(=O)ORS, -N(R M)C(=O)NRnRs, -N(Rrn)C(=NRn)NRnR', -N(Rrn)S(=O) 2 Rs, -N(Rrn)S(=-0) 2 NRnRs,. -NRnC 2 6 alkyINRnR', -NWrC 2 -6alkylORs and -NR m C 2 -6alkyIOR m and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups; R 7 is Ci-galkyl, CI- 4 haloalkyl, halo, nitro, cyano, -OCI 1 6 alkyl, -0-C 1 4 haloalkyl, -0-C 1 6 alkylNR m R m -0-C 1 6 alkylOR m -NR m R m -NR m -C 1 4 haloalkyl, -NR m -C 1 6alkylNR m R m or -NR m -C 1 6a~kyl0R m R 0 is a saturated, partially-saturated or unsaturated 6- or. 7-membered monocyclic or 10- or I I1-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, 0 and S, so long as the combination of 0 and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituen ts, independently selected from RP; RP is independently at each instance CI-8alkyI, C 1 -4haloalkyl, halo, cyano, nitro, -C(=0)NR m -C(=NR m )NR m R m -OR m -OC(=0)NR m R m -OC(=0)N(R m )S 2 R 1 -OC 2 6 alkyl NR m R m -518- -OC 2 6 alkyIOR', -S 2 2 NR m R', 2 N(R m 2 N(R m 2 N(R m )C(=O)NR m R', -N(R m -N(R m )C(=O)NR m R', -N(R m )C(=NR m )NR m R m 2 -N(R m 2 NR"'R', -NA m C 2 6 alkylNR m R' or -NR m C 2 -6alkylOR'; and Y is 0or NH;or R'is R 6 7 R 2 is H, -OR' m halo, C 1 3 haloalkyl or C 1 6 alkyl; R 4 is a saturated, partial ly-saturated or unsaturated 10 or I 1-membered bicyclic heterocycle containing 1, 2, 3, 4 or 5 atoms selected from 0, N and S, so long as. the combination of 0 and S atoms is not greater than 2, but excluding quinolin-6-yl, 4,5,6,7-tetrahydro-benzo~b]thiophen-2-yl, benzothiazol- 2-yl, 2,3-dihydro-benzo[ 1,4]dioxin-6-yl, wherein the heterocycle is substituted by 0, 1, 2 or 3 substituents independently selected from Cl- 9 alkyI, oxo, G 1 4 haoalkyl, halo, nitro, cyano, -OR' m 1 6 alkyl, -0-C 1 4 haloalkyl, -0-C 1 6 alkylNR m R', -0-Cf- 6 alkylOR', -NR m -NR m -C 1 4 haloalkyl, -NR m -C 1 6 alky]NR m -NR m -C 1 4 jalkyIOR', -C(=O)C 1 6alkyl, -OC(=O)C 1 6 alkyl, -C(=O)NR"'C 1 6 alkyl,( -NRr-C(=O)CI 6 alkyI -C(=0)0Rs, -C(=O)NRnR', -C(=NRrn)NRrnR', -ORs, -OC(=O)Rs, O)NRm~Rs, -OC(=O)N(Rrn)S(=O) 2 Rs, -OC 24 6alkylNRmRs, -OC 2 -6alkylOR', -SRs, -S(0)Rs, -S 2 R, -S 2 NR'~Rs, -S 2 N(Rrn)C(=O)Rs, -S 2 N(Rrn)C(=0)ORS, -s 2 -NRrnRs, -N(Rrn)C(=O)Rs, -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRnR', -N(Rm)C(=NRrn)NRrnRs, -N(R m )S 2 R, -N(Rm)S(=O) 2 NRmnR', -NRMnC 26 akyINRrnRs, -NR'C 2 -6alkylORs and C 1 4 alkyl substituted by 1 or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, n, -C(=O)NR m -C(=NR m )NR m -OR' m 7OC(=O)R', -0C(=O)NRmR OC(=O)N(R m 2 -OC 2 6 alkylNR m R m -0C 2 6 alkylOR"', -SR m 519 2 2 NR m 2 N(R m 2 2 N(R m -N(R m h -N(R m -N(R m )C(=O)NR m R m -N(R m )C(=NR m )NR m -N(R m 2 R', -N(R m 2 NR m R m .C(=O)NRnRS -C(=NRn)NRr, -ORs, -OC(=O)NRrnRs, -OC(=O)N(Rrn)S(=O) 2 -OC 2 6 alkyINRnRs, -OC 2 -6alkylORs,--SR', 2 Rs, -S(=O),NR m Rs, 2 N(R m 2 N(Rrn)C(=O)ORs, -S 2 N(R m )C(=O)NR m Rs, -NR m Rs, -N(R m -N(R m )C(=O)0R 5 -N(R m )C(=O)NR m R', -N(R m )C(=NR m )NR m Rs, -N(R m 2 Rs, -N(R m 2 NR m R', -NR m C 2 6 alkyINR m -NR M C 2 4 salkylOR 5 and -NR m C 2 6 alkyIOR'; wherein R 4 is not 2-aminocarbonylmethyl-2,3-dihydro-benzo[ 1,4]dioxin-8-yI, 2-cyanomethyl- 2,3-dihydro-benzo[ I,4]dioxin-8-yl, quinolin-3-yI, 3H-quinazolin-4-on-3-yl, benzo[ I ,3]dioxol-5-yl, 3,3-dimethyl- I ,3-di hydro-indol-2-on-6-yl or 4,4-dimethyl- 3 ,4-dihydro- lH-quinolin-2-on-7-yl; R 7 is C 1 8 alkyl, C 1 5 haloalkyl, I or Br R 9 is H, C 19 alkyl, C1. 4 haloalkylI halo, nitro, cyano,.-OCI-alkyl, -O-C 1 4 haloalkyl, -0-C 1 4 alkylNR m -0-CI-6~alkyI0R m -N.R m R m -NR m -C 4 haloal kyl,. -NR m -C 1 6 alkyINR m R m -NR m -C 1 I. 6 alkylQR m or -(CH 2 )nR'; R 9 is independently, at each instance, H, Cl. 9 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -0C 1 6 alkyl, -0-C 1 4 haloalkyl, -0-C 1 6 alkylNR m R m -0-C 1 6 aI kylOR m -NR m R m -NR m -C 1 Ahaloal kyl, -NR m -C 1 6a1 kylNR m R' or -NR m 6 a1 kylOR'; Y is NH; and Z is CR 8 or N; or R' is R 2 is C 1 6 alkyl substituted by 1, 2 or 3 substituents selected from 520 C 1 4 haloalkyl, halo, cyano, nitro, -C(=O)NR m R', -C(=NR m -OR' m -OC(=O)NR m -OC(=O)N(R m 2 -OC 2 -6al kylNR m -OC 2 _6alkylOR m -SR m 2 Rn, 2 NR m R m 2 N(R m 2 N(R m )C(=O)OR n -S(=O0) 2 m -NR m R m n, -N(R m -N(Rr')C(=O)NR m -N(R m )C(=NR m )NR m R m -N(R m 2 R, 2 NR"'R m -NR m C 2 -6alkylNR m R m or -NW t C 2 6 alkylOR'; 'or R 2 is q) 2 0 )phe'ny1, wherein the phenyl is substituted by 0, 1, 2 or 3 substituents independently selected from C 1 .8alkyl,. CI- 4 halo'alkyl, halo, cyano, nitro,;-C(=O)R n, -C(=O)NR m -C(=NR m )NkRT~, -OC(=O)R -OC(=O)NRPRml,'-OC(=O)N(R m 2 -0C 2 6 alkylNR m R', -OC 2 6 alkylOR m -S(=O)NR m R' 1 2 N(R m 2 N(R')C(=O)OR n, 2 N(R"')C(=O)NRn m -NR m R m -N(R m n, -N(R 1 m -N(R m )C(=NR-)NR m R m -N(R m 2 R n, -N(R m 2 NR m R m -NR m C 2 6 alkylNR m R m -NR m C 2 6 a1 kylOR m C(=O)oRs, -C(=O)NRnR', C(=NRrn)NRnRs, OC(0O)Rs, -OC(=O)NRnRs, -OC(=O)N(R m )S 2 Rs, _OC 2 _6alkyNRnR', -OC 2 _6al kylOR-, -S Rs, -S(=O)Rs, 2 2 NjRn~s, 2 N(R m 2 N(R m )C(=O)0Rs, 2 N(R m -NJRnRs, -N(R m -N(R m )C(=O)0R, -N(R m )C(=O)NR m -N(R m )C(=NR m )NR m Rs, -NQ(R)S(O0) 2 Rs, -N(R m 2 NR m Rs, -NR m C 2 _6al kylNRnRs, -NR 1 mC 2 -6akyl ORs and C 1 4 alkyl substituted by I or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=O)NR m R m -C(=NR m )NR m R -OC(=O)R, -OC(=O)NR m -OC(=O)N(R m )S 2 -OC 2 6 alkyINR m -0C 2 6 a1 kylORn, n, 2 2 NRm', -S 2 N(R m -S 2 N(Rn)C(=O)OR', 2 N(R m )C(=O)NR"R m -NR m R'm, -N(Rrn)C(=O)R n, -N(R m )C(=O)NR m R m -N(R m )C(=NR m )NR"'R m z.N(R m 2 R m )S(=0)-2NR m R m -NR m C 2 6 aI ky]NR m -C(=O)0Rs, -C(=O)NR m Rs, -C(=NRm)NR'R', -ORs, -OC(=O)Rs, -OC(=O)NR-R 5 2 RF 5 -OC 2 _taIkyINR m R', -OC 26 alkyIOR', -SRs, -S 2 Rs, -S 2 NR m Rs, 521 Ct 2 N(Rrn)C(=O)R', 2 N(Rrn)C(=O)ORs, 2 N(R m )C(=O)NR m R', NRrnR', -N(Rrn)C(=O)Rs, -N(Rr)C(=O)ORs, -N(Rrn)C(=O)NRnR', -N(Rrn)C(=NRn)NRnRs, -N(Rr)S(=0) 2 Rs, -N(Rrn)S(=O) 2 NRnRs, -NRnC 2 6 alkyNRnRs, -NRnC 2 -6alky]ORs and -NR m C 2 .ralkylOR'; or R' is wherein Rris a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, 0 and S, wherein no more than 2 of the ring members are 0 or S wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle ri or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently. selected from CI-8alkyl, C 1 4 haloalkyl, halo, cyano, nitro, n, -C(=O)NR m R m -C(=NR m )NR"'R m -OR m -OG(=O)NR m R', -OC(=O)N(R m 2 -0C 2 6 alkylNR m -0C 2 6 alkylOR', -S 2 -S 2 NR m R'n, 2 N(R m n, -S 2 N(R tm 2 N(Rm)C(=O)NR m R m -NR m R m -N(R m -N(R m )C(=O)QR, -N(R! m )C(=O)NR m R, -N(R m )C(=NR m )NR m R m -N(Rm T 2 R h -N(R m )S(=O)INR'R'm, -NR m C 2 6 alkyl NR m R m -NR'T 2 6 al kylOR m -C(=O)ORs, -C(=O)NRnRs, -C(=NRm~)NRrnR', -ORs, -OC(=O)NRnRs, -0C(=O)N(Rn)S(=O) 2 -OC 2 6 alkylNR m -OC 2 6 alkylORs, -SW, -S 2 Rs, 2 NRrnRs, 2 N(Rrn)C(=O)R', 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=O)NRnR', -NRrnRS, -N(Rrn)C(=O)R', -N(Rr)C(=O)ORs, -N(Rrn)C(=O)NRmlR', -N(Rrn)C(=NRn)NRnRs, ~~N(Rrn)S(=O) 2 N(R m )S 2 NRnRS, -NRnC 2 6 alkylNRnRs, -NRrnC 2 alkyl0Rs and C 1 4 alkyl substituted by 1 or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=O)NR m R m -C(=NR m )NR R m -OR m -OC(=O)NR m R m -OC(=O)N(R m 2 -OC 2 -ralkylNR m R m -0C 2 6 alkylOR m SR' m -S n, -S 2 2 NR', -S 2 N(R t 2 N(R tm -S 2 N(R m )C(=O)NR m R m -NR m R m -N(R m -N(R m )C(=O)OR n, -N(R tm )C(=O)NRmrRn, -N(R m )C(=NR m )NR m R m -N(R m 2 R n, -N(R m )S 2 NR m R m -NR m C 2 6 alky]NWR m -C(=O)ORs, -C(=O)NR m Rs, -C(=NRrn)NRrnR', -OWs, -OC(=O)Rs, -OC(=O)NRnRs, -OC(=O)N(R m )S 2 Rs, -OC 2 6 alkylNRnRs, -OC 2 6 alkylORs, -SW, 2 Rs, 2 NRnRs, 522 2 N(Rrn)C(=O)R', 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=O)NRnRs, NRrnR', -N(R m -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRnR', -N(Rrn)C(=NRn)NRrnRs, -N(Rrn)S(=O) 2 NRrnRs, -NRnC 2 6 alkyINRnRs, -NR m C 2 -6aIkylORs and -NR m C 2 .ralkylOR'; R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the, combination of 0 and S atoms is not greater than 2, wherein the ring and bridge 'are substituted by 0, 1, 2 or 3 substituents independently selected from C 1 galkyl, CI- 4 haloalkyl, halo, cyano, nitro, -C(=0nR, -C(=0)ORn, -C(=0)NR m R', -C(=NR m )NR m -OR m -OC(=0)NR m R m -OC(=O)N(Rml)S(=O) 2 R -OC 2 6 al kylNRmR m -0C 2 6 a1 kylOR m ,--SR m -S 2 2 NR m -s 2 N(R m -S 2 N(R m )C(=O)OR, -S 2 -NR m R m -N(R m n, -N(R m )C(=O)OR n -N(R m )C(=O)NR m R m -N(Rrn)C(=NR m )NR m R m -N(R m )S 2 R', -N(R m )S 2 NR m R m -NR m C 2 6 a1 kylNR m R -NR m C 2 6 alkylOR m -C(=O)0R 5 -C(O)NRnRs, -C(=NR m )NRm' 1 5 ORS, 0Q..O)Rs. -OC(=O)NRnRs, -OC(=O)N(Rrn)S(=O) 2 -OC 2 6 aI kylNR m -OC 2 6 alkylOR', -SRs, 2 2 N~ m 2 N(R m )C(=O)Rs, 2 N(R m )C(=O)0Rs, 2 N(R')C(=O)NR m Rs, -NR m -N(R m )C(=O)Rs, -N(R m )C(=O)0Rs, -N(R m )C(=O)NR m -NR)C=R)(m' -N(R m 2 Rs, 2 NR m Rs, -N m C 2 6al kylNR m -NR m C 2 6 alkyl ORS and C 1 4 alkyl substituted by 1 or 2 groups selected from Cv-2haloalkyl,- halo; cyano, nitro, -C(=O)NR m R m -C(=NR m )NR m R m -OR m -OC(=O)Rn, -OC(=O)NR m -OC(=O)N(R m )S 2 -OC 2 -6alkylNRmIRrn, -OC 26 alkylOR m -SRm, 2 2 NR m R', 2 N(R m n, 2 2 N(R m )C(=O)NR m R', -NR m R m -N(R m -N(R m )C(=O)ORn, -N(R m 2 -N(R m 2 NR m R m -NR m C 2 6 a1 kyl NRm~Rrn, C(0)0R 5 -C(=O)NR m Rs, -C(=NR m )NR m R 5 s, -ORs, -OC(0)R 5 -OC(0)NR R 5 2 R, -OC 2 6 al kylNR m R', 523 -OC 26 alkylOR', -S 2 Rs, 2 NRnRs, -s 2 N(Rrn)C(=0)RS, 2 N(Rr)C(=0)0Rs, 2 N(Rn)C(=O)NRnRs, -NRrnRS, -N(Rr)C(=O)Rs, -N(Rr)C(=0)0Rs, -N(Rr)C(=0)NRnRs, -N(Rrn)C(=NRn)NRnRs, -N(Rrn)S(=0) 2 -N(Rrn)S(=0) 2 NRnR', -NRnC 2 6 alkylNRnR', -NRrnC 2 6 alkyl0Rs and -NRMC 2 6 alkylOR', and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups; R 7 is C 2 .8alkyl, C 1 5 haloalkyI, I, Br; R 9 is independently, at each instance, H, Cl-galkyl, CI-4haloalkyl, halo, nitro, cyano, -0CI-6alkyl, -0-C 1 4 haloalkyI, -O-C 1 6 alkyINR m R', -0-C 1 6 a1 kylOR m -NR m -NR m -C 1 4 haloalkyl, -NR m -C 1 6 alky]NR m R' or -NR m 6 alkyIOR m Y is NH; and Z is CR 8 or N; or R' is F 3 CW R 9 R 2is H, -OR- m Cl, C 1 3 haloalkyl or C 1 -6alkyl; R 4 is a saturated or unsaturated 5- or 6-mernbered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S, so long as the combination of 0 and S atoms is not greater than 1, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from C 1 .salkyl, C 1 4 haloalkyl, halo,,cyano, nitro, -C(=O)NR m -C(=NR m )NR m R m -OR n, -0C(=0)R n, -OC(=O)NR m R m -OC(=0)N(R m 2 R -0C 2 6 a1 kylOR m -SR m -S 2 R, 2 NR m R m -S 2 -S 2 N(R m )C(=0)OR, 2 N(R')C(=0)NRmR m -NR m -N(R tm )C(=0)0R, -N(R m )C(=0)NR m -N(R m )C(=NR m )NR m -N(R tm 2 R -N(R m 2 NR m R m -NR tm C 2 6 alkylNR"'R m -NR M C 2 6 alkylOR m -C(=0)Rs, -C(=0)0Rs, C(=0)NRnR', -C(=NlRn)NRrnRs, -OC(=O)NRnR', 2 -0C 2 6 alkylNRnRs, -0C 2 6 alkyl0R', 524 2 2 NRrnR', 2 N(Rrn)C(=O)Rs 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=O)NRnRs, I~rn's -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRnR', -N(Rr)C(4INRn)rNRsR -N(Rrn)S(=O) 2 -N(Rrn)S(=O) 2 NRnR', -NRrnC 2 6 alkylNRrnRs, -NRnC 2 -6alkylOR' 5 and CI.. 4 alkyI substituted by 1 or 2 groups selected from 2 haloalkyl, halo, cyano, nitro, -C(0)NR'R m -C(=NR m )NR m R m -OR m -OC(=O)NR m R m -OC(=O)N(R m 2 -OC 2 6 alkylNR m -0C 2 6 alkylOR m -SR- m -S(=O0) 2 2 NR m R m 2 N(R m CI 2 N(R m 2 N(R m )C(=O)NR m R m -NR"'R m -N(R m -N(Rm')C(=O)ORn, -N(R m )C(=O)NR m R m -N(R m )C(=NR m )NR m R m -N(R m 2 R -N(R m 2 NR m -NR m C 2 6 alkylNR"'R m -C(=O)ORs, C(0)RRs, -C(=NRn)NRnRs, -ORF, -OC(=O)Rrs, OC(=O)rNRRs -OC(=O)N(Rrn)S(=O) 2 -OC 2 6 alkyIlNRRs, -OC 2 6 alkylORs, -SRs, 2 -S 2 NRnRs, -S 2 N(Rrn)C(=O)RS, 2 N(Rrn)C(=O)ORs, 2 N(Rn)C(=O)NRnRs, -NRrnRs, -N(Rrn)C(=O)ORs, -N(R ThC(=O)NRnRS, -N(Rrn)C(=NRn)NRnR', -N(Rrn)S(=O) 2 -N(R m )S 2 NRnRs, -NR'C 2 -6aIkylNRnRs, -NR m C 2 -6alkylORs and -NR'C 26 alkylOR m wherein R 4 is not unsubstituted pheny]; R 9 is independently, at each instance, H, Cl- 9 alkyl, C 1 4 haloalkyI, halo, nitro, cyano, -OC ,6alkyl, -0-C 1 4 haloalkyl, -0-C 1 6 alkylNR m R', -0-C 6 hlkylOR', -NR m -NR m -C 1 4 haloalkyl, -NR m -C 1 6alkylNR m R' or -NR m -C 16 alkylOR'; Y is NH; and Z is CR 8 or N. 123. A compound according to Claim 122, wherein: R'is -525- (CRqlRq) 0 RO R 2 is -OR' m halo, C 1 .3haloalkyl or C 16 alkyl; R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being'carbon, so long as the combination of 0 and S atoms is'not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C 18 galkyl, C 1 4 haloalkyl, halo, cyano, nitro, -C(=0)NR m R m -C(=NR-)NR m R m -OR m -OC(=O)NR m R', -OC(=O)N(R m 2 -OC 2 6 al kylNR m R m -OC 2 6 al kylOR m -S 2 2 NRnR'~, 2 N(Rm 1 -S 2 N(R tm -S 2 N(R m )C(=O)NR m R m -NR m R m -N(Rm 1 )C(=O)OR, -N(R m )C(=O)NR m -N(R m )C(=NR m )NR'R m -N(R m 2 R', -N(R m 2 NR m R m -NR M C 2 -6alkyl NR m R m -NR M C 2 6 alkylOR m -C(=O)Rs, -C(=O)ORs, .C(=o)pRRs, -C(=NRn)NpRm' -ORs, .OC(0O)Rs, -OC(=O)NRnR', -OC(=O)N(R m )S 2 Rs, -OC 2 6 alkyNRnRs, -OC 2 6 al kylOR', -S 2 2 NRnRs, -S 2 N(Rrn)C(=O)Rs, -S 2 N(Rrn)C(=O)ORS, -S 2 N(Rrn)C(=O)NRnRs, -NRrnRs, N(Rr)C(0O)Rs, -N(Rrn)C(=O)ORs, -N(Rml)C(=O)NRrnRs, -N(R tm )C(=NRrn)NRrnR', -N(Rrn)S(=O) 2 -N(R m )S 2 NRrnR', -Nm26lyNms -NRnC 2 6 aIkylORs and C 1 4 alkyl substituted by I or 2 groups selected from Ci. 2 haloalkyl, halo, cyano, nitro, -C(=O)NR m R m -C(=NR m )NR m R m -OR m -OC(=O)NR'R m -OC(=O)N(R m )S 2 -0C 2 .a1 kylNR m R', -OC 26 alkylOR', -SR m 2 R n, 2 NR m R m 2 -S 2 N(R tm -S 2 N(R m )C(=O)NR m R m -NR m R m -N(R tm n, -N(R m )C(=O)OR n, -N(R-)C(=O)NR m R m -N(Rml)C(=NRm)NR m l, -N(R tm 2 R -N(R m )S 2 NR m R m -526- -NR m C 2 6 alkylNR m C(=O)ORs, C(=0)NRrnRs -C(=NRn)NRnRs, -ORs, .0C(=0)RS, 0C(0)rNRsR -OC(=0)N(Rrn)S(=0) 2 -0C 2 -,alkyNRnR', -OC 2 -6alky10R', .SRs, 2 2 NRnR', 2 N(Rrn)C(=0)R', 2 N(Rr)C(=0)0Rs, 2 N(Rrn)C(=0)NRnR', -NR-Rs, -N(Rr)C(=0)Rs, -N(Rr)C(=O)0Rs, -N(Rr)C(=0)NRnRs, -N(Rrn)C(=NRn)NRnRs, -N(Rrn)S(=0) 2 -N(Rrn)S(=0) 2 NRnR', -NRrnC 24 ialkyINRnRs 7NRmfC 2 -alkylOR' and -NR M C 2 6 alkylOR m and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups; R 7 is C 1 9 alkyl, C 1 4 haloaikyl, halo, nitro, cyano, -OC 1 -6alkyl, -0-C 1 4 haloalkyi, -0-C 6 alkyINR m R m -0-C 6 alkyIOR', -NR m R', -NR m -C 1 4 haloalkyl, -NR m 6 alkylNR m R m or -NR m -C 1 6 alkylOR'; R 0 is a saturated, partially-saturated or unsaturated 6- or 7-membered monocyclic or 10- or I I-membered bicyclic ring containing 0, 1, 2, 3or 4 atoms selected from N, 0 and S, so long as the combination of 0 and S. atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by,0, 1, 2 or 3 substituents independently selected from RP; RP is independently at each instance C 1 8 alkyl, C, 4 haloalkyl, halo, cyano, ni tro, -C(=0)0R -C(=0)NR m m -OC(=0)NRnR", -OC(=0)N(R m 2 R n, -0C 2 .6a1kylNR"', -0C 2 6al kylOR m -SR' m 2 -S(=Oh2NR m R m -S 2 N(R m 2 N(R m 2 N(R m )C(=0)NR m R m -NR m R m -N(R m -N(R m -N(R m )C(=0)NR m R m -N(R m )C(=NR m )NR m R m -N(R m 2 -N(R m 2 NR'', 2 5 -NR m C 2 -6alkylNR m R' or -NR m C 2 6 alkylOR'; and Y isOorNH. 124. A compound according to Claim 123, wherein: R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms se lected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 527 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substi tuents i ndependentl y selected from C 1 _8alkyI, C 1 4 haloalkyl, halo, cyano, nitro, -C(=O)OR n, -C(=O)NR m -C(=NRft)NR m R m -OR m -OC(=O)NRnR, -OC(=O)N(R m 2 -0C 2 6 a1 kylNRIRrn, -0C 26 a1 kylOR m -SR m 2 2 NR m R', 2 N(R m -S 2 2 N(R m )C(=O)NR m R~ -NR m R m N(R m -N(R m -N(R m m R, -N(R m )C(=NR m )NR m -N(R m 2 -N(R m 2 NR m R', -NR M C 2 6 al kyiNR m -NR m C 2 6 alkylOR9, C(0)ORs -C(=O)NRnR', -C(ppRn)NRns -OC(=O)NRnR -OC(=O)N(R m )S 2 -OC 2 6alky]NRrnR', -OC 2 6 alkylORs, -S(0)Rs, 2 2 NRnR', 2 N(Rrn)C(=O)R', 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=O)NRnR', -NRrnR', .N(Rr)C(0)oRs, -N(Rrn)C(=O)NRnR', -N(Rrn)C(=NRrn)NRrnR', -N(Rrn)S(=0) 2 R', -N(Rrn)S(=O) 2 NRnR', -NR M C 2 .6alkylNR m -NRnC 2 6 al kyl OR' and Cj4alkyl substituted by 1 or 2 groups selected from CI 2 haloalkyl, halo, cyano, nitro, -C(=O)OR -C(=O)NRm~rI, -C(=NR m )NR m R m -OR m -OC(=O)R, -OC(=O)NR m R m -OC(=O)N(R m 2 -OC 26 al kylNR'R', -OC 26 alkyIOR', 2 R n, 2 NR m R m -S 2 N(Rlm)C(=O)R', 2 N(R tm 2 N(R m )C(=O)NR m R m -NR m R', -N(R m -N(R tm -N(R tm )C(=O)NR m R m -N(R m )C(=NR m )NR m R m -N(R m )S 2 -N(R m )S 2 NR m R m -NR tm C 2 6 alkylNR m R m -C(=O)ORs, -C(=O)NR m -C(=NRrn)NRrnR', -OWs, -OC(=O)Rs, -OC(=O)NRnRs, -OC(=O)N(R m )S 2 Rs, -OC 2 6 aI kylNRnRs, -OC 26 alkylOR', -SRs 2 Rs, -S(O) 2 rNRs' 2 N(Rrn)C(=O)Rs, 2 N(Rrn)C(=O)ORs, 2 N(Rn)C(=O)NRmRs, -NRrnRs, -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NR m Rs, -N(Rrn)C(=NRn)NRnRs, -N(Rrn)S(=O) 2 -N(Rm)S(=O) 2 NRnR', -NR M C 2 6 aIkylNRnRs, -NR'~C 2 alkyIORs and -NR' M C 26 al kyl OR m and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups:. -1 528 125. A compound according to Claim 123, wherein R 4 is a phenyl ring that is vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from CI-8alkyl, C 1 .4haloalkyI, halo, cyano, nitro, -C(=NR m )NR m -OR m -OC(=O)NR m -OC(=O)N(R m )SQ=O) 2 R n, -0C 2 6 a]kyINR m -OC 26 alkylOR', -SR- m -S 2 R n 2 NR m 2 N(R m -S(=O0) 2 2 N(R m )C(=O)NR m R m -N(R m -N(R m -N(R m )C(=O)NR'R m -N(R m )C(=NR m )NR m R m -N(Rra)S(=O) 2 -N(R m 2 NR m R', -NR M C 2 6 alkylNR m -NR M C 2 -6alkylOR', -C(0)ORs, -C(=O)NRnR', -C(NRrn)NRrnR' OC(0)Rs, -OC(=O)NRnRs, -OC(=O)N(Rrn)S(=O) 2 Rs, -OC 24 ialkylNRrnRs, OC 26 alkylORs, SRs, -S(=O)Rs, 2 Rs, 2 NRnR', 2 N(Rrn)C(=O)Rs, 2 N(Rrn)C(=O)ORs, -NRrnRs -N(Rr)C(=O)ORs,. -N(Rrn)C(=O)NRnRs, -N(Rrn)C(=NRn)NRrnR', -N(R m )S 2 R', -N(Rrn)S(=O) 2 NRnRs -NRrnC 2 -alky]NRnR', NRrnC 2 alky10Rs and C 1 Aaikyl substituted by I or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=O)NR m -C(=NR m )NR m R m -OR' m -OC(=O)R, -0C(=O)NRI.R, -OC(=O)N(R m 2 R n, -OC 26 alkyNR R m -OC 2 6 alkylOR',( n, 2 2 NR m 2 N(R m -S(0) 2 (R T 2 N(R m )C(=0)NR m -NqR m R m -N(R m )C(=O)OR -N(R m )C(=0)NR-R, -N(R m )C(=NR m )NR m R m -N(R m )S 2 -N(R m 2 NR"'~R, -NR m C 2 6 alkylNR m R m -C(=O)ORs, -C(o)NRnRs, -C(=NRn)NRnR', -ORs, .OC(0)Rs OC(=0)NRnRs, -OC(=O)N(Rml)S(=O) 2 Rs, -OC 2 6 alkylNRnR', -OC 2 6 aI kylORs', -SRF 5 2 Rs, 2 pRrn's -S 2 N(R m 2 N(R m )C(=O)0R 5 2 N(R m )C(=O)NR m Rs, -NRrnR', -N(R m -N(R m )C(=O)0R 5 -N(R m )C(=0)NR m R -N(R m )C(=NR m )NR m -N(R m )S 2 -N(R m 2 NR m R 5 -529- -NR'C 2 -6alkylNR m Rs, -NR m C 2 6alkylOR and -NR m C 2 -6alkylOR m and the bridge carbon atoms are substituted with 0, 1 or 2 =0 groups. 126. A compound according to Claim 123, wherein R 7 is C-i.alkyl, C 1 4haloalkyl, halo, -OCi- 6 alkyl, -O-C-4haloalkyl, -NR m R m or -NR m -Ci- 4 haloalkyl. 127. A compound according to Claim 123, wherein R 7 is Ci.salkyl, C 1 i 4 haloalkyl, I, Br or Cl. 127. A compound according to Claim 123, wherein R 7 is tert-butyl or trifluoromethyl. 129. A compound according to Claim 123, wherein RO is a saturated, partially-saturated or unsaturated 6- or 7-membered monocyclic ring containing 0, 1, 2 or 3 atoms selected from N, O and S, so long as the combination of 0 and S atoms is not greater than 1, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from R P 130. A compound according to Claim 123, wherein Ro is a saturated, partially-saturated or unsaturated 6-membered ring containing 0, 1, 2 or 3 N atoms, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from R P 131. A compound according to Claim 123, wherein Y is O. 132. A compound according to Claim 123, wherein Y is NH. 133. A compound according to Claim 122, wherein: R' is 530 (CRqRq) 0 RO or Rq Rq) 0 RO R 2is H, halo, C 1 3 haloalkyl or C 16 alkyl; R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from.0, N and S with the remaining atoms being carbon, so long as the( combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from CI- 8 alkyI, C14haloalkyl, halo, cyano, nitro, -C(=O)OR n, -C(=O)NR m R m -C(=NR-)NR m R m -OR m -OC(=O)R n, -OC(=O)NR m R m -OC(=O)N(R m )S 2 -OC 2 6 alkylNR m -OC 2 6 alkylOR', 7$Rm, -s 2 R~ 2 NR m 2 N(R m -S 2 N(R m )C(=O)OR, 2 N(R m )C(=O)NR m R m -NR m R m -N(Rrm)C(=O)ORn, -N(R m )C(=O)NR-R m -N(R-)C(=NR-)NR m R m -N(R m )S -N(R m 2 NR m R m -NR M C 2 6 alkylNR m R m -NR M C 2 -6alkylOR m C(0O)Rs, -C(=O)ORs, -C(=O)rNRs' -C(=NRrn)NRnR', -OC(=O)Rs, -OC(=O)NR-~Rs, -OC(=O)N(Rrn)S(=O) 2 -OC 2 6 al kyl NRKR, -OC 2 -6a1 kylOR',( -S 2 2 NRrnR', -S 2 N(Rrn)C(=0)Rs, -S 2 N(Rrn)C(=0)ORS, 2 N(Rrn)C(=O)NRnRs, -NRnR' -N(Rrn)C(=O)R', 2 0 -N(Rrn)C(=O)ORs, -NR)(ONms -N(Rn)C(=NRn)NRrRs, -N(Rrn)S(=O) 2 -N(Rrn)S(=O) 2 NRnR', -NR m C 2 6 aI kylNRnR', -NRrnC 2 6 alkylOR' and Ci. 4 alkyl substituted by I or 2 groups selected from CI- 2 haloalkyl, halo, cyano, nitro, -C(=O)NR m -C(=NR')NR m R m -OR m -OC(=O)NR m -OC(=O)N(R m 2 R n, -0C 2 6 a1 ky]NR m R m -OC 2 6 alkyIOR m 2 2 NR m R-, -S 2 N(R m -S 2 -s 2 N(R m -N(R m )C(=NR m )NR m Rn, -N(R m 2 R n, N(R m )S 2 NRnRn, I 9 -531 -NR m C 2 6 aIkylNR m -C(=O)0Rs, -C(=0)NRnRs, -C(=NRn)NRnRs, OC(=0)R, -OC(O)N4RnRs, -0C(=O)N(Rn)S(=O) 2 -0C 2 6 akylNRnRs, -0C 2 6 alkyl0R', -SRs, -S 2 Rs, 2 rNRsR' 2 N(Rrn)C(=0)Rs, 2 N(Rr)C(=0)0Rs, 2 N(Rrn)C(=0)NRnR', -NR m Rs, N(Rr)C(=0)Rs, -N(Rr)C(=0)0Rs, -N(Rrn)C(=0)NRnRs, -N(Rrn)C(=NRn)NRnRs, -N(Rrn)S(=0) 2 -N(Rrn)S(=0) 2 NRnRs, -NRrnC 2 6 alkyINRrnRs, -NRrnC 2 6 alky]0Rs and -NR m C 2 ~al kylOR m and the ing and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups; R 7 is C1. 9 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -OCI. 6 alkyl, -0-c I. 4 haloalkyl, -0-C 1 6 alkylNR m R m -0-C 1 _6alkylOR', -NR m R', -NR m -C 1 4haloalky1, -NR m -C 1 6 alkylNRmR m or -NR m -C 1 6 alkylOR m [C 1 .salkyl, CI-shaloalkyI, 1, Br or Cl] SR' is a saturated, partial ly-saturated or unsaturated 6- or 7-membered monocyclic or 10- or 1I1-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, 0 and S, so long as the combination of 0 and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from RP; .RP is independently at each instance C 1 .8alkyl, C 1 4 haloalkyl, halo, cyano, nitro, -C(=0)NR m R m -C(=NR m )NR m Rm, -OR m -0C(=0)NRrRn, -OC(=0)N(R m )S 2 -0C 2 tal kyINR m R m -OC 2 6al kyIOR m -S -S 2 2 NR'R', 2 N(R m -S 2 N(R m -S 2 N(R m )C(=0)NR m R m -NR m -N(R m -N(R m )C(=0)0R n, -N(Rrn)C(=0)NR'Rn, -N(R-)C(=NR-)NR m -N(R m 2 -N(R m 2 NR m R', -NR m C 2 6 alky]NR m R m or -NR m C 2 6 alkylOR'; and Y is 0 or NH. 134. A compound according to Claim 133, wherein R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is vicinally fused with a saturated or unsaturated 3- or 4-atomn bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms 532 being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C 1 8 alkyl, C 1 -4haloalkyI, halo, cyano, nitro, -C(=0)NR m R m -C(=NR m )NR m R m -ORm 1 -OC(=O)R, -OC(=O)NR-R m -OC(=O)N(R m 2 R 1 -OC 2 -6al kylNR m -OC 24 6alkyIOR', -S(=0)R 1 2 R 1 2 NR m 2 N(R m 1 2 N(R')C(=0)OR 1 2 N(R m )C(=O)NR m R m -NR m R m -N(R m )C(=O)R 1 -N(R m )CQ=O)OR", -N(R m )C(=O)NR"'R m -N(R m )C(=NR m )NR m -N(R m 2 R 1 -N(R m )S 2 NR m R m -NR m C 2 6 alky]NR-R-, -NR M C 2 -6alkylOR', -C(=0)ORs, -C(=O)NRnRs, -C(=NRrn)NRnR', ORs* -OC(=O)Rs, -0C(=O)NRnRs,( -OC(=O)N(Rrn)S(=O) 2 -OC 2 6 alkyINRRs, -OC 2 6 alkyIORs, .SRs, -S(=O)Rs, 2 -S 2 NRnRS, -s 2 N(Rrn)C(=0)Rs:, -S(=Oh2N(Rn)C(=O)ORs, -S 2 N(Rrn)C(=O)NRnRS, -NRrnRs, -N(Rrn)C(=O)Rs, -N(Rr)C(=0)0Rs, -N(Rrn)C(=O)NRnR', -N(Rrn)C(=NRrn)NRnRs, -N(Rrn)S(=O) 2 R', -N(Rrn)S(=O) 2 NRnRs, -NR M C 2 -6alkylNRrnRs, -NRnC 2 6 alkylOR' and C 1 4 a1 kyl substituted by 1 or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=O)R 1 -C(=O)OR1, -C(=O)NR m R m -C(=NR m )NR m RT, -OR 1 -OC(=O)R1 -OC(=O)NR m R m 2 R1, -0C 2 6 a1 kylNR m R m -OC 2 6 aI kylOR m -SR' m S(=O)R1, 2 2 NR m R m 2 N(Rm 1 )C(=O)R1 2 N(R m )C(=O)OR1, 2 N(R m )C(=O)NRm 1 -NR m R', -N(R m -N(Rm 1 -N(Rm 1 )C(=O)NRm 1 R m -N(R"')C(=NRm 1 )NRmR m -N(R M 2 R1, -N(R m )S 2 NRnRml, -NR m C 2 -6alkylNR m R m -C(=O)0Rs, -C(=O)rNRsR' -C(=NflRn)NRrnRs, -ORs, -0C(=O)Rs, -0C(=0)NRnRs -OC(=O)N(R 2 -OC 2 6 alkylNRrnRs, -0C 2 6 alkyl ORS, 2 Rs, 2 NRm' 1 R, 2 2 N(Rrn)C(=O)ORs, 2 N(Rm1)C(=O)NR"'R', -NRmYRS, N(Rr)C(0O)Rs, -N(Rm1)C(=O)0R 5 -N(R m )C(=O)NR m Rs, -N(R m )C(=NR m )NR m -N(Rm 1 2 Rs, -N(R m )S 2 NR m R', -NR m C 2 6 alkylNR', -NR M C 2 6 alkylORs and -NR'1C 2 6 alkyIOR'; and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups. 533 135. A compound according to Claim 133, wherein R 4 is a phenyl ring that is vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from CI-8alkyl, C 1 4 haloalkyl, halo, cyano, nitro, -C(=NR m )NR m R m -OR m -OC(=O)R, -OC(=O)NR m R m -OC(=O)N(R m )S(O) 2 -0C 2 6 alkyNRTR', -OC 2 6 alkylOR m -SR m n, 2 R n, 2 NR m 2 N(R m 2 N(R m 2 N(R m )C(=O)NR m R m -NR m R', -N(R m -N(R m -N(R m )C(=O)NR m R m -N(R m )C(=NR m )NR m 2 -N(R m 2 NR m R m -NR m C 2 6 alkyNR m -NR m C 2 -6alky1OR m C(0O)ORs, -C(=O)NRnRs, -C(=NRml)NRrnR', -ORs, 0C(0)Rs, OC(=O)N~1RmRs, -OC(=O)N(Rrn)S(=O) 2 Rs, -OC 2 -6alkylNRnRs, -OC 2 6 alkylORs, .SRs, -S (=O)Rs, 2 Rs, 2 NRnRs, 2 N(Rrn)C(=0)Rs, -S 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=:O)NRnRs, -NRrnRs, -N(Rr)C(=O)Rs, -N(Rr)C(=O)ORs, ,N(Rml)C(=O)NRnR', -N(Rrn)C(=NlRn)NRnRs, -N(Rrn)S(=O) 2 Rs, -N(Rrn)S(=O) 2 NRmIRs, -Nm26lyNm' -NRrnC 2 -alkyIORs and C 1 4 alkyI substituted by I or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, n, -C(=O)OR n, -C(=O)NR m -C(=NR m )NR m R m -OR' m -OC(=O)NR m R m -OC(=O)N(R m 2 -OC 2 6 alkylNR m R m -0C 2 6 alkylOR m -SR m 2 2 NR m 2 N(R m 2 N(R m 2 N(R m )C(=O)NR m Rm, -NR m R m -N(R m -N(R m )C(=O)NR m R m -N(R m )C(=NR')NR t R m -N(R m 2 R, -N(R m )S (=O),NR m R', -NRrnC 2 6 alky]NRnRm, C(0)ORs, -C(=O)NRnRs, C(4kRn)NRnRs, -ORs., .OC(=O)4TRrn, 0C(0)N(R m )S 2 Rs, -OC 2 6 alkylNRrnR', -OC 2 6 al kylORs, -S 2 Rs, -s 2 NR m R', 2 N(Rm)C(=O)Rs, 2 N(R m )C(=O)0R 5 2 N(Rm)C(=O)NRmR', -NR m R 5 -N(R m -N(R m )C(=O)0Rs, -N(R m )C(=O)NR m R', -N(R m )C(=NR m )NR m 2 Rs, -N(R m 2 NR m R', -534- -NRmC 2 alkylNR"R, -NR m C 2 .6alkylOR s and -NRC 2 -6alkylOR m and the bridge carbon atoms are substituted with 0, 1 or 2 =0 groups. 136. A compound according to Claim 133, wherein R 7 is Cl-9alkyl, Ci.~haloalkyl, halo, -OC-_alkyl, -O-CI-4haloalkyl, -NR m R m or -NR m -CI.4haloalkyl. 137. A compound according to Claim 133, wherein R 7 is Ci- 5 alkyl, Ci-4haloalkyl, I, Br or Cl. 138. A compound according to Claim 133, wherein R 7 is tert-butyl or trifluoromethyl. 139. A compound according to Claim 133, wherein Ro is a saturated, partially-saturated or unsaturated 6- or 7-membered monocyclic ring containing 0, 1, 2 or 3 atoms selected from N, O and S, so long as the combination of O and S atoms is not greater than 1, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1,2 or 3 substituents independently selected from R p 140. A compound according to Claim 133, wherein Ro is a saturated, partially-saturated or unsaturated 6-membered ring containing 0, 1, 2 or 3 N atoms, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from RP. 141. A compound according to Claim 133, wherein Y is O. 142. A compound according to Claim133, wherein.Y is NH. 143. A compound according to Claim 122, wherein: R' is 535 I 9 R 2 is -OR m halo, C 1 3 haloalkyl or C,. 6 alkyl; R 4 is a saturated, partially-saturated or unsaturated 10 or IlI-membered bicyclic heterocycle containing 1, 2, 3, 4 or 5 atoms, selected from 0, N and S, so long as the combination of 0 and S atoms is not greater than 2, but excluding qui nolin-6-yi, 4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl, benzothi azol- 2-yl, 2,3-dihydro-benzo [1 ,4]dioxi n-6-yl, wherein the heterocycle is substituted by 0, 1, 2 or 3 substituents independently selected from C 19 galk yl, oxo, CI-4haloalkyI, halo, nitro, cyano, -OR' m -S(=0)nC 1 6 alkyl, -0-C 1 4 haloalkyl, -O-C 1 6 alkylNR m R m -0 .I 6 alkyIOR', -NR m -NR m -C 1 4 haloalkyl, -NR M -CI 6 alkylNR m R m -NR m -C 1 6 alkylOR m -C(=O)C 1 6 a1 kyl, -OC(=0)C, 6 a1kyl, -C(=0)NR'C. 6 a1 kyl, -NR m C(=0)C 1 6 alkyl -C(=0)0R 5 C(=O)PR m Rs, -C(=NR m )NR m Rs, -OC(=0)R 5 0OC(=0)rNRsR -OC(0)N(R m 2 Rs, -OC 2 6 alkyINRrnR-, -OC 2 6 alkyl0Rs, SR', -S(70)Rs, 2 Rs, 2 R m Rs, -S 2 N(R m )C(=O)0R 5 2 N(R m )C(=O)NR m Rs, -NRrnR', N(Rr)C(0)ORs, -N(Rr')C(=-O)NRrnR', -N(R m )C(=NR m )NR m -N(R m 2 Rs, -N(R m )S(=O),NR m Rs, -NR m C 2 6 alkylNRm', -NR m C2z6alkylORs and C 1 4 alkyl substituted by I or 2 groups selected from CI- 2 haloalkyl, halo, cyano, nitro, n, -C(=O)NR m R m m )NR"'R m -OR m -OC(=O)NR m R-, -OC(=O)N(R m )S 2 -0C 2 6 alkylNR m -0C 2 6 a1 kylOR m 2 2 NR'R', 2 N(R t n, -S 2 N(R tm )C(=O)0R 0 -N(R tm )C(=0)NR m R m -N(R m )C(=Nk m )NR m R m 2 R, 2 NRnRmn, -C(=O)0Rs, -C(=O)N4R m Rs, -C(=NR m )NR m Rs, -ORs, -OC(=O)Rs, -OC(=O)NRm~R', -OC(=0)N(R m 2 Rs, -0C 2 6 a1 ky NRrnRs, -OC 2 6 alkylOR', -S 2 -SQ=O) 2 NR m R', -S 2 N(R m 7S(0) 2 N(Rrn)C(0)ORs, -S 2 N(R m )C'(=0O)NR m R', -536- .NRrnR', -N(Rrn)C(=O)Rs, -N(Rr)C(=O)0Rs, -N(Rrn)C(=0)NRnRs, -N(Rrn)C(=NRn)NRnRs, -N(Rr)S(=0) 2 -N(Rrn)S(=0) 2 NRnRs, -NRrnC 2 6 alkyINRnR', -NRrnC 2 6 akyI0Rsand -NR m C 2 _ralkyI0R'; wherein R 4 is not 2-ami nocarbon yl meth yl-2,3 -di hydro-benzo 1 dioxin- 8-yl, 2-cyanomethyl- 2,3-dihydro-benzo[1I,4]dioxin-8-yl, quinolin-3-yI, 3H-quinazolin-4-on-3-yl, benzo[ 1,3ldioxol-5-yl, 3,3-dimethyl-1I,3-dihydro-indol-2- on-6-yl or 4,4-dimethyl- 3,4-dihydro- 1H-quinolin-2-on-7-yl; R 7 is C 18 alkyl, C 15 haloalkyl, I or Br; R 9 is H, Cl- 9 alkyI, C 14 haloalkyl, halo, nitro, cyano, -OCI 1 6 alkyl, -0-C 1 1 haloalkyI, -O-Cj. 6 alkylNR m -0-C 1 6 alkyOR m -NR m -NR m 4 haloal kyl, -NR m -C 1 6 a1 kylNR m R' or -NR m -C 1 6 al kylOR'; Y is NH; and Z is CR 8 or N. 144. A compound according to Claim 143, wherein R 4 is a heterocycle selected from indole, 3H-indole, benzo[b]furan, benzothiophene, LH-indazole, benzimidazole, benzthiazole, IH-benzotriazole, 7-quinioline, 8-quinoline, 1,2,3,4- tetrahydroquinoline, isoquinoline, cinnoline, phthal azine, quinazoline and quinoxaline, wherein the heterocycle is substituted by 0, 1, 2 or 3 substituents independently selected from Cp 9 alkyl, oxo, C 14 haloalkyl, halo, nitro, cyano, -OR' m -S 1 6 a1 kyl, -0-C 1 4 haloalkyl, -0C 6 alkyINR m -0-C 1 6 alkylOR',( -NR m R m -Npm-CI- 4 haloalkyl, -NR m -C 1 6 a1 kylNR m R m -NR m -C 1 6 alkylOR', -C(=0)C 1 -6aIkyl, 6 alkyl, -C(=0)NR'C 1 6 alkyl, -NR m C(=0)C 1 6alkyl -C(0)ORS, -C(=0)NRnRs, -C(=NRrn)NRrnRs -0Rs, -OC(=O)Rs, :_0C(=0)NRnR', -OC(=0)N(R m )S 2 Rs, -0C 2 6 a1 kylNRnRs, -0C 2 -SRs, 2 2 NRnRS, S(=0) 2 N(Rrn)C(=0)Rs 2 N(Rrn)C(=0)0Rs, 2 N(Rrn)C(=0)NRnRs, -NRrnRs, N(Rr)C(0O)Rs, -N(Rrn)C(=0)NRnRs, -N(Rrn)C(=NRrn)NRrnR', -N(R M 2 Rs, -N(R m )S 2 NRnRS, -N'26lklR s -NRrnC 2 6 akylOR' and C 1 4 alkyl substituted by I or 2 groups selected from C 1 2 haloalkyl, halo, cyano, ni tro, -C(=0)NR m R m -C(=NR m )NR m R m -OR m -OC(=0)NR m -OC(=0)N(R m )S 2 -OC 2 6 alkylNR m -OC 26 alkylOR m 537 -SR' m -S 2 2 NR m 2 N(R m -s 2 2 N(R m )C(=O)NR m R m -N(R m -N(R m )C(=O)0R 0 -N(Rnl)C(=O)NRmR'h -N(R m )C(=NR m )NR m R', 2 -N(R m 2 NR m R m C(0)ORs, -C(=O)NRnR', -C(=NRrn)NRrnRs, .OC(=o)rNRsR" -OC(=O)N(Rn)S(=O) 2 Rs, -OC 26 alkylNRnRs, -OC 2 6 alkylORs, SRS 2 Rs, -S(=O),NRrnRs, 2 N(Rrn)C(=O)R', -S 2 N(Rrn)C(=O)ORs, -S 2 N(Rrn)C(=O)NRnRs, -NRmlR', N(Rr)C(0O)Rs, -N(Rrn)C(=O)ORs, -N(Rr)C(=O)rNRsR' -N(Rrn)C(=NRn)NRrnRs, -N(Rrn)S(=O) 2 Rs, -N(Rrn)S(=O) 2 NRnRs, -NRrnC 2 6 alkylNRnRs, -NRrnC 2 6 alkylOR' and -NR m C 2 6 alkylOR m 145. A compound according to Claim 143, wherein R 4 is a heterocycle selected from 6-indole, 7-indole, 6-3H-indole, 7-3H-indole, 6-benzo[blfuran, 7- benzo[blfuran, 6-benzothiophene, 7-benzothiophene, 6- 1H-indazole, 7-1H- indazole, benzimidazole, benzthiazole, 1H-benzotriazole, 7-quinoline, 8- quinoline, 7-1 ,2,3,4-tetrahydroquinoline, 8-1 ,2,3,4-tetrahydroquinoline, isoquinolin-7-yl, isoquinol in-8-yI, 7-cinnoline, 8-cinnoline, phthalazine, 7- quinazoline, 8-quinazoline and quinoxaline, wherein the heterocycle is substituted by 0, 1, 2 or 3 substituents independently selected from C 1 9 alkyl, oxo, C 1 4 haloalkyl, halo, nitro, cyano, -OR' m 16 alky1, -O-C,4haloalkyl, -0-C 6 alkyl NR m R m -0-C 1 6 alkylOR m -NR m R m -NR M -C 1 4 haloalkyl, -NR m -C 1 6 a1 kyINR m -N R m -C 1 6alkyl0R m -C(=O)C 1 6 a1 kyl, -OC(=0)CI- 6 alkyl, -C(=O)NR m C 1 6 alkyl, -NR m C(=0)C 1 6 alkyl C(=0)ORs, -C(=0)NRnR', -C(=NRr)NRrnRs -ORs, .OC(=O)Rs% 0C(=o)N4!mrn, -OC(0)N(R-)S 2 Rs, -OC 2 6 al kylNRnRs, -OC 2 6 alkyl0Rs, -S (=0)Rs, 2 -S 2 NRnRS, 2 N(Rrn)C(=O)Rs, -S 2 N(Rrn)C(=O)ORS, 2 N(Rrn)C(=O)NRnRs, -NRnRS -N(Rr)C(0)ORs, -N(Rnl)C(=O)NRnR', -N(Rrn)C(=NRn)NRnR', -N(R m )S 2 R, -N(Rrn)S(=0) 2 NRnRs, -NRrnC 2 -(alkylNR"R', -NRrnC 2 6 alkyl0Rs and CI- 4 alkyl substituted by I or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=O)NR m -C(=NR m )NR m R m -OR m -OC(=O)R -OC(=0)NR m R m -OC(=O)N(R m 2 R n, -OC 2 6 alkylNR m R m -OC 2 -538- -SR m 2 2 NR m 2 N(R m -S(=O0) 2 N(R m 2 N(R m )C(=O)NR m R m -N(R m -N(Rr')C(=O)OR -N(R m )C(=O)NR m -N(R m )C(=NR m )NR m R -N(R m 2 -N(R m 2 NR m R m C(=O)ORs, -C(=O)NRnR', -C(=NRrn)NRrnRs, OR', -OC(=O)Rs, -OC(=O)NRnR', -OC(=O)N(Rn)S(=O) 2 R', -OC 2 .6alkylNR m -OC 2 6 alkylORs, -SRs, 2 2 NRnRs, 2 N(Rrn)C(=O)R5, 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=O)NRnR', -NRrnR', -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRnRs, -N(Rrn)C(=NRn)NRnRs, -N(Rrn)S(=O) 2 Rs, -N(R nl)S(=O) 2 NRnR', -NRnC 2 6 alkylNRR', -NRrnC 2 -alkylORs and -NR m C 2 -6alkylOR m 146. A compound according to Claim 143, wherein R 9 is C 1 9 alkyl, C 1 -4haloalkyl, halo, nitro, cyano, -OCI. 6 alkyl, -O-C 1 4 haloalkyl, -0-C _6alkylN R m -0-C 1 -6alkyl0R', -NR m R m -NR m -C 1 4 haloalkyl, -NR m -C 1 ialky1NR m R' or -NW-CI. 6 alkylOR'. 147. -A compound according to Claim 143, wherein R 9 is H. 148. A compound according to Claim 143, wherein Z is CR 149. A compound according to Claim 143, wherein Z is N.( 150. A compound according to Claim 101, wherein R 7 is tert-butyl or trifluoromethyl. 151. A compound according to Claim 122, wherein: R' is 539 R 2 is C,. 6 alkyI substituted by 1, 2 or 3 substituents selected from C 1 4 haloalkyl, halo, cyano, ni tro, -C(=O)NR-R m -C(=NR m -OR m -OC(=O)R n, -OC(=O)NR'R', -OC(=O)N(R m 2 -OC 2 6 alkylNR'R', -OC 2 6 alkylOR m -SR m 2 R 2 NR m R m 2 N(R m 2 N(R m )C(=O)OR, -S 2 N(R m )C(=O)NR m R m -NR m R m -N(R m -N(R m )C(=O)OR, -N(R m )C(=O)NR m -N(R m )C(=NR m )NRR', -N(R m 2 R, -N(R m 2 NR m R m -NR m C 2 6 alkylNRnR m and -NR m C 2 .6alkylOR m or R 2is (CR R~) R 6 ;or R 2 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, 0 and S, wherein no more than 2 of the ring members are 0 or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from R 5 R 6 and R 7 R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not gr eater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from Cl-galkyI, C,- 4 haloalkyl, halo, cyano, nitro, -C(=0)NR m R', -C(=NR m )NR m R m -O1 t m -OC(=O)R -OC(=O)NR m R m -OC(=O)N(R m 2 -OC 2 6 aI kylNR m R m -OC 2 -6alky]OR m -SR' m -S 2 -S 2 NR-R m -S 2 N(R m -S 2 N(Rn)C(=O)OR, 2 N(R m )C(=O)NR m R m -NR m R m -N(R tm -N(R tm )C(=O)OR, -N(R m )C(=O)NR m R m -N(R tm )C(=NR m )NR m -N(R m )S (O) 2 R, 540 -N(R m 2 NR m -NR m C 2 -6alkylNR m -NR m C 2 .6alkyl OR m -C(=O)R 3 -C(=O)0R 3 C(=O)NR m Rs, -C(=NR m )NR m Rs, .ORs, OC(0)Rs. -OC(=O)NR m -OC(=O)N(R m 2 -0C 2 6 alkylNR m OC 26 alkylORs, -SW, -S 2 2 NR m Rs, S(=O) 2 N(R)C(0)Rs, 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=O)NRnR', 44i-NRsR -N(R m )C(=O)Rs, -N(R m )C(=O)0Rs, -N(P m )C(=O)NR m -N(R m )C(=Nk" m )NR m Rs, -N(R m 2 -N(R m 2 NR m -NRnC 2 .6alkyINR m Rs, -NRrnC 2 6 alkylORs and C 1 4 alkyl substituted by 1 or 2 groups selected from C 1 2 haloalkyI, halo, cyano, nitro, -C(=NR m )NR m Rn, -OR m -OC(=O)NR m -OC(=O)N(R m 2 Rn, -OC 2 -6alkyNR m R m ,C -0C 26 al kylOR m -SR' m 2 -S 2 NR m R', -S 2 N(R m 2 N(R m 2 N(R m )C(=O)NRnR', -NRnRm,~ -N(R m -N(Rm)C(=O)OR n, -N(R m )C(=O)NR m R m -N(R m )C(=NR m )NR m Rm, -N(R m )S 2 Rn, -N(R m )S 2 NR" m R', -NR m C 2 -6aIkylNR-R m -C(=O)0Rs, C(=O)NRnRs, -C(=NRn m )NR m Rs, -ORs, -OC(=O)Rs, -OC(='O)NR m -OC(=O)N(R m 2 -OC 2 6 alkylNR m Rs, -0C 2 6 a1 kylORs, SRs, -S 2 2 NRmRs, -S 2 N(R m n)C(=O)Rs, 2 N(R m )C(=O)0Rs, -S 2 N(R m )C(=O)NR m Rs, -NR m Rs, -N(Rrn)C(=O)Rs, -N(R m )C(=O)0Rs, -N(Rrn)C(=O)NRnRs, 2 0 -N(Rrn)C(=NRrn)NR' -N(R m 2 Rs, -N(Rr)S(=O) 2 NRnRs, -NR m C 2 6 alkylNR m Rs, -NR M C 2 -6alkylORs and -NR M C 2 6 alkylOR m and the ring( arnd bridge carbon atoms are substituted with 0, 1 or 2 =0 groups; R 7 is C 2 .Salkyl, CI.shaloalkyl, 1, Br; R 9 is independently, at each instance, H, Cl-galkyl, C 1 4 haloalkyl, halo, nitro, cyano, -0CI 6 alkyI, -0-C 4 haloalkyl, -0-C 1 6 5alky]NR m R m -O-CI.. 6 alkylORm, -NR m R m -NR m -C 1 4 haloalkyl, -NR m -C 1 6 alkylNR m R' or -NR m -C 6 alkylOR m Y is NH; and Z is CR 8or N. 152. A compound according to Claim 151, wherein R 2 is C 1 ralkyI substituted by 1, 2 or 3 substituents selected from C 1 4 haloalkyl, halo, cyano, -541 nitro, -C(=O)NR m -C(=NR m )NR m R m -OR m -OC(=O)NR m -OC(=O)N(R m 2 -OC 2 6 alkylNR m R', -OC 2 -6a~kylOR', -SR' m 2 -S 2 NR'', 2 N(R m 2 N(R m 2 N(R m )C(=O)NRnR m -NR m -N(R m -N(R m )C(=O)OR n, -N(R m -N(R m )C!(=NR m )NR m R m -N(R m 2 -N(R m 2 NR m R', -NR M C 2 6 alkylNR''~ and -NR m C 2 6 alkylOR m 153. A compound according to Claim 15 1, wherein R 2is q) 2 0 phenyl, wherein the phenyl is substituted by 0, 1, 2 or 3 substituents independently selected from CI-8alkyl, Cr, 4 haloalkyI, halo, cyano, nitro, -C(=O)NR m -C(=NR m )NR m -OR' m -OC(=O)R, -OC(=O)NR m R m -OC(=O)N(R m 2 -0C 2 6 a1 kylNR m R m -OC 2 6 alkylOR m -SR- m -S n, 2 2 NR m R m 2 N(R m 2 2 N(R m )C(=O)NR m R m -NR m R', n, n, -N(R- 1 )C(=O)NR-R m -N(R m )C!(=NR m )NR m R m -N(R m 2 N(Rml)S(=O) 2 NR m R m -NR m C 2 6al kyl NR m -NR M C 2 6 a1 kyl OR m -C(=O)ORs, -C(=O)NR m Rs, -C(=NRm 1 )NR m .OC(0)NRnRS -OC(=O)N(Rrn)S(=O) 2 Rs, -OC 26 alkyINR m Rs, OC 26 alkylORs, -SRs, 2 2 NR m Rs, 2 -S(0) 2 N(Rrn)C(0)ORs, 2 N(R m )C(=O)NR m Rs, -NR m -N(Rrn)C(=O)Rs, -N(R m )C(=O)0R 5 -N(R m )C(=O)NR m -N(R m )C(=NR m )NR m Rs, -N(R m 2 Rs, -N(Rrn)S(=O) 2 NRnRs, -NRnC 2 6 alkyINR m -NIR m C 2 6 alkyIOR 5 and C, 4 alkyl substituted by 1 or 2 groups selected from CI- 2 haloalkyl, halo, cyano, nitro, -C(=O)NR m R m -C(=NR m )NR m R m -OR m -OC(=O)R, -OC(=O)NR m R m -OC(=O)N(R m 2 R n, -OC 2 6 alkyl NR m R m -OC 2 6 al kyl OR m -SR m 2 2 NR m R m 2 N(R m )C(=O)Rn, -S 2 N(R m )C(=O)OR 2 N(R m )C(=O)NRm'R t -NR m R m -N(R tm n, -N(R m -N(R m )C(=O)NRR m -N(R m )C(=NR m )NR m R m -N(R m )S 2 -N(R m )S 2 NR m 'R m -NR M C 2 6 a1 kylNR m R m C(0)oRs, -C(=O)NR m Rs, -C(=NR m )NR m R', 542 -ORs, OC()Rs, -OC(=O)NRnRs, -OC(=O)N(Rn)S(=O) 2 -OC 2 6 alky1NRnRs, -OC 2 6 alkylOR', S(=0) 2 Rs, 2 NRnR-, 2 N(Rrn)C(=O)R', 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=O)NRnR', -NRrnRs, -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRnR', -N(Rrn)C(=NRn)NRnRs, -N(Rrn)S(=O) 2 Rs, -N(Rrn)S(=O) 2 NRnR', -NRrnC 2 6 alkylNPrnRS, -NR.nC 2 6 alkyIOR' and -NR m C 2 _6alkyIOR'. 2 q 154. A compound according to Claim 151, wherein R is 2.' wherein Rr is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently'selected from N, 0 and S, wherein no more than 2 of the ring members are 0 or S, wherein the heterocycle is. optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from CI..salkyl, C 1 4 haloalkyl, halo, cyano, nitro, n, -C(=0)ORn, -C(=O)NR m R m -C(=NR-)NR m R m -OR- m -OC(=O)NR m R -OC(=O)N(R m )S 2 -0C 2 6 a1 kylNR m R m -OC 2 6 alkylOR m -SR m -S 2 R -S 2 NR m R, 2 N(R t n- S(=0) 2 N(R m -S 2 N(R m )C(=)NR m R m -NR m -N(R m n, -N(R tm -N(R m )C(=0)NR m -N(R m )C(=NR m )NR m R, -N(R m 2 R -N(R m 2 NR m -NR m C 2 6 alkylNR m -NR tm C2-akylOR m -C(=0)0Rs, -C(=O)NRl'Rs, -C(=NRrn)NRrnR', 0C(0)Rs -OC(=0)NRnR', -OC(=O)N(Rrn)S(=0) 2 Rs, -OC 2 6 alkylNRrnRs, -0C 2 -ralkylOR', -SRs, -S 2 RS, -S 2 NRnRS, 2 O) 2 N(Rrn)C(=O)0Rs, 2 N(Rrn)C(=0)NRnR', 4.1-NRs N(Rr)C(=0)R', -N(Rr)C(=O)0Rs, -N(Rrn)C(=O)NRmxR', -N(Rrn)C(=NRn)NRnRs, -N(Rrn)S(=0) 2 -N(Rrn)S(=0) 2 NR'R', -NR m C 2 6 a1 kyiNkrnRs, 4'R tm C 26 aIky]ORs and C I 4 alkyl substituted by 1 or 2 groups selected from C 12 haloalkyl, halo, cyano, nitro, -C(=0)NR m R m m )qR m R m -OR m -OC(=O)NR m R m -OC(=O)N(R m )S 2 -OC 2 -6akylNR m R m -OC 2 6 alkylOR m -SR' m n, 2 2 NR m R m 2 N(R m -S 2 N(R tm )C(=O)ORn, -S (=O0) 2 N(R m )C(=O)NR m R M -NR m R m -N(R m -N(R m )C(=O)OR -N(R m O)NR m R m 543 -N(R m )C(=NR m )NR m -N(R m 2 -N(R m 2 NR m R', -NR m C 2 6 aI kylNR m -C(=O)ORs; -C(=NRn)NRnR', -OWs, -OC(=O)Rs, -OC(=O)NRnR', -OC(=O)N(R m )S 2 -OC 2 6 alkyINRnR', -OC 2 6 alkylOR', -S 2 2 NR'R', -S 2 N(Rrn)C(=O)RS, 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=O)NRnRs, -NRrnR', N(Rr)C(=o)oRs, -N(Rrn)C(=O)NRnR', -N(Rrn)C(=NRn)NRnR', -N(R m )S 2 -N(Rrn)S(=O) 2 NRnR', -NRrnC 2 6 alkylNRrnR', -NR m C 2 6 a1 kylORs and -NR M C 2 -6al kyIOR m 155. A compound according to Claim 151, wherein R 4 is a phenyl ring that is vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C 1 8 alkyl, C 1 4 haloalkyl, halo, cyano, nitro, -C(=0)0R n, -C(=0)NR m Rn, -C(=NRm)NR m Rm~, -OR m 0 -OC(=O)NR m -OC(=O)N(R m 2 -OC 26 alkyINR m R m -OC 26 alkylORm~, -SR m -S -S 2 R n, 2 NR m R m -s 2 N(R m 2 N(R m 2 N(R m )C(=O)NR m -NR m R', -N(R m -N(R m )C(=O)0Rn, -N(R m )C(=O)NR m R m -N(R m )C(=NR m )NR m R m -N(R m 2 R n, -N(R m 2 NR"'R m -NR M C 2 6 alkylNR m -NR M C 2 6al kylOR m -C(=O)R 5 -C(0)0R% -C(=NRn)rNRsR OC(=O)Rs, -OC(=O)NR m R', 2 -OC 2 6 alkyNR m -0C 2 6 a1 kylORs, 2 -S 2 NR m 2 N(R m -S 2 N(R m 2 N(R m )C(=O)NR m R 5 -NR m R 5 -N(R m -N(R m )C(=O)0R 5 -N(R m )C(=O)NR m -N(R m )C(=NR m )NR m -N(R m )S 2 R', -N(R m 2 NR m -NR m C 2 6 alkylNRnR', -NR M C 2 6 alkylOR 5 and C,4a~kyl substituted by I or 2 groups selected from Ca- 2 haloalkyl, halo, cyano, nitro, -C(=O)NR m -C(=NR m )NR m R m -OR' m -OC(=O)R, -OC(=-O)NR m R m -OC(=O)N(R m 2 R n, -OC 2 -lkyINR m -OC 2 .6alkylOR m -SR- m 2 R n, 2 NR m R m 2 N(R m n, 544 2 N(R m 2 N(R m )C(=0)NR m R m -NR m R m -N(R m )C(=NR m )NR m -N(R m 2 Rn, -N(R m 2 NR m R', -NR m C 2 -6alkylNR m R m and -NR m C 2 6 alkylOR'; and the bridge carbon atoms are substituted with 0, 1 or 2 =0 groups. 156. A compound according to Claim 15 1, wherein R 7 is tert-butyl or tifl uoromethyl. 157. A compound according to Claim 15 1, wherein R 9 is H.( 158.A cmpond ccoringto lai 151 whrei Z s C 8 158. A compound according to Claim 151, wherein Z is N. 160. A compound according to Claim 122, wherein: R' is F 3 C)W R' is. H, -OR m Cl, C 13 haloalkyl or C 1 6 al~kyl; R 4 is a saturated o r unsaturated-5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from C 18 alkyl, C 1 4 haloalkyl, halo, cyano, nitro, -C(=0)NR m -C(=NR")NR m -OC(=0)Rn, -OC(=0)NR m R-, -OC(=O)N(R m 2 R n, -OC 26 alkylOR m -SR m n, 2 R", -S m n, -S 2 N(R)C(=0)0R', 2 N(R m )C(=0)NR m -NR m R m -N(R m C(0R, -N(R m )C(=0)NR m -N(R-)C(=NR m )NR m R m -N(R m 2 R, 545 -N(R m 2 NR m -NR m C 2 -6alkylNR m -NP m C 2 -6alkyIOR m -C(=O)Rs, -C(=O)ORs, -C(=O)NRnR', -C(=NRn)NRrnR', .QRs, .OC(0)Rs, -OC(=O)NRnR', -OC(=O)N(R m )S 2 Rs, -OC 2 .6al kylNRrnRs, -OC 2 6 alkyIORS, -SRs, 2 Rs, 2 NRnR', -S(=O0) 2 N(Rrn)C(=O)Rs, 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=O)NRnRs, -NRrnRs, -N(Rrn)C(=O)R', -N(Rrn)C(=O)ORs, -N(Rrn)C(=-O)NRnR', -N(Rrn)C(=NRrn)NRrnRSI -N(Rrn)S(=O) 2 Rs, -N(Rrn)S(=O) 2 NRnRs, -NRrnC 2 6alkyINRnRs, -NR M C 26 alky1ORs and C 1 4 alkyl substituted by I or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=O)NR m R m -C(=NR m )NR m -OR m -OC(=O)NR m 2 -OC 2 6 alkyINR m R m -OC 2 6 alkylOR', -SR m n, 2 2 NRm' t 2 N(Rrn)C(=O)R", 2 N(R m 2 N(R m )C(=O)NR m -NR m R', -N(R m )C(=NR m )NR m R m -N(R m 2 Rn, -N(R m )S 2 NR m R', -NR m C 2 -6alky]NR m R' m and -NR tm C 2 6 alkylOR m wherein R 4 is not unsubstituted phenyl; R 9 is independently, at each instance, C 1 9 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -0C 1 6 alkyl, -0-C 1 4 haloalkyl, -0-C 1 -6alkylNR m R m -0-C 1 6 alkylOR m -NR m R m -NR m -C 1 4haloalkyl, -NR m -C 1 6 alkylNR m R m or -NR m -C 1 -6alkylOR m Y is NH; and Z is CR 8 or N. 161. A compound according to Claim 160, wherein R 4 is a saturated or unsaturated 5- or 6-membered ring containing 1, 2 or 3 atoms selected from 0, IN and S, so long as the combination of 0 and S atoms is not greater than 1, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from C 1 8alkyl, C 1 4 haloalkyl, halo, cyano, nitro, -C(=O)NR m R m -C(=NR m )NR m R tm -0C(=O)R n, -OC(=O)NR m R m -0C(=O)N(R m 2 -OC 2 6 al kyl OR m -SR m 2 2 NR m R' 2 N(R m 2 N(R m )C(=O)OR n, -S 2 N(R m )C(=O)NR m -NR m R', -N(Rm 1 n, -N(R m n' N(Rrn)C(=O)NRmR-, 546 -N(R m )C(=NR m )NR m -N(R m 2 R n, -N(R m 2 NR m R m -NR M C 2 -6alkylNR m -NR M C 2 -6aIkylOR m C(=o)oRs, -C(=O)NRnR', -C(=NRn)NRnRs, -OWs, -OC(=O)Rs, -OC(o)NRnRs, -OC(=O)N(Rrn)S(=O) 2 -OC 2 6 alkylNRnRs -OC 2 6 alkylORs, 2 Rs, 2 NRrnRs, 2 N(Rrn)C@=O)R', -S 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=O)NRnR', -NRrnR', -N(Rrn)C(=O)Rs, -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRnRs, -N(Rrn)C(=NRn)NRnRs, N(Rr)S(=o) 2 Rs, -N(Rrn)S(=O) 2 NRrnRs, -NRrnC 2 -alkylNRnRs, -NRnC 2 -6a~kylORs and CI-4alkyl substituted by 1 or 2 groups selected from Cj- 2 haloalkyl, halo, cyano, nitro, -C(=NRm')NRmR m -OR m -OC(=O)NR m Rm, -OC(=O)N(R m 2 R n, -OC 2 6 alkyINRm', -OC 2 -6aIkylOR m -SR m 2 R 2 NR m R m 2 N(R m -S 2 N(R m )C(=O)OR n, -S 2 N(Rn)C(=O)NRn m R'T -NR m R m -N(R m n, -N(R m -N(R m )C(=O)NR m R m -N(Rrn)C(=NRn)NR'Rrn, -N(R m 2 R n, -N(R m 2 NR m R', -NR m C 2 6 alky]NR m R m and -NR m C 2 6 alkylOR m 162.A cmpond ccoringto lai 160 whrei Z s C8. 162. A compound according to Claim 160, wherein Z is CR 164. A compound according to Claim 1, or a pharmaceutically- acceptable salt thereof, wherein the compounds is selected from: (2E)-3-[4-(tert-butyl)phenyl) -N-phen ylprop-2-eriamide, (2E)-N -(3,4-dimethox yp hen yl)-3- [4-(tert-butyl)phen yl ]prop-2-en ati de, (2E)-3 -[4-(tert-butyl)phenylj-N-(4-h ydrox y-3-methox yphenyl )prop-2-enamide, (2E)-3-[4-(tert-butyl)phenyl]-N-(2-5,6,7,8-tetrahydronaphthyl)prop-2-enamide, (2E)-N-(2H,3H,4H-benzo[3 I ,4-oxazaperhydroin-6-yl [4-(tert- butyl)phenyllprop-2-enamide,. [4-(tert-butyl )phen yl] -N-(3-oxo(2H,4H-benzo[3 1,4-ox azaperhydroin- 6-yl))prop-2-enamide, 547 [4-(tert-butyl)phenyl]-N-(4-methyl-3-oxo(2H-benzo[3 1,4- oxazaperhydroi n-6-yl ))prop-2-enami de, (2E)-3-[4-(tert-butyl)phenyl]-N-(4-methyl (2H,3H-benzo[3,4-e] 1,4- oxazaperhydroi n-6-yl))prop-2-enamide, (2E)-3-[4-(tert-butyl)phenyll-N-(3-oxo(2H,4H-benzo[eI 1 ,4-oxazaperhydroin-7- yl ))prop-2-enamide, (2E)-N-(2H,3H,4H-benzo[e] I,4-oxazaperhydroin-7-yl)-3-[4-(tert7 butyl)phen yl ]prop-2-enamide, (2E)-3-[4-(tert-butyl)phenyl]-N-(4-methyl -3-oxo(2H-benzo[e] 1,4- oxazaperhydroi n-7-yl))prop-2-enamide, [4-(tert-butyl)phenyl]-N-(4-methyl(2H,3H-benzo fe] I,4-oxazaperhydroin- 7-yl))prop-2-enamide, ethyl 6-f( (2E)-3-[4-(tert-butyl)phenyl I prop-2-enoyl amino)} -2H,3H,4H- benzo[e] I ,4-oxazaperhydroi ne-2-carboxyl ate, [4-(tert-butyl)phenyl]-N-[2-(h ydrox ymethyl )(2H-,3H,4H-benzo[3 1,4- oxazaperhydroin-6-yl)] prop-2-enami de, (2E)-N-[(3S)-3-(hydroxymethyl)(2H,3H-benzo[e] 1 ,4-dioxan-6-yl)]-3-[4-(tert- butyl)phenyllprop-2-enamide, (2E)-N-[(3R)-3-(hydroxymethyl)(2H,3H-benzo[e] 1 ,4-diox an-6-yl)]-3- [4-(tert- butyl)phenyl]prop-2-enamide, (2E)-N-[(2R)-2-(hydroxymethyl)(2H,3H-benzo[34e]I ,4-dioxan-6-yl butyl)phenyllprop-2-enamide, ydroxymethyl)(2H,3H-benzo[3 I ,4-dioxan-6-yl)] -3-[4-(tert- butyl)phenyl]prop-2-enami de, [4-(tert-butyl)phenyl]-N-(7- 1,2,3,4-tetrahydroquinolyl)prop-2-enamide, [4-(tert-butyl)phenyl]-N-( 1-methyl (7-1,2,3 ,4-tetrahydroquinolyl))prop-2- enamnide, (2E)-3-[4-(tert-butyl)phenyl)-N-(2-oxo(6- 1,3,4-trihydroquinolyl))prop-2-enamide, (2E)-3-[4-(tert-butyl)phenyl]-N-(2-oxo(7-.1,3,4-tn hydroquinolyl))prop-2-enamide, 4 -(tert-butyl)phenyl]-N-(3-hydroxyphenyl)prop-2-enamide, (2E)-3 -[4-(tert-butyl )phen yl]I prop-2-en oyl amino I phenox y) acetic acid, 2 E)- 3 4 -(tert-butyl)phenyl]-N-[3-(2..hydroxyethoxy)phenyllprop-2enamide, 548 (2E)-3-[4-(tert-butyl)phenyll-N-[3 -(2-methoxyethoxy)phen yI]prop-2-enamide, (2E)-3-[4-(tert-butyl)phenyl]-N- I 3-[2-(1I,3-dioxobenzo~clazolin-2- yI)ethoxylphenyl) prop-2-enamide, (2E)-N-[3-(2-Ami noethoxy)phen yl ]-3-14-(ert-butyl)phenyl]prop-2-enamide, (2E)*-3-[4-(tert-butyl)phenyl ]-N-indoli n-6-ylprop-2-enamide, [4-(tert-butyl)phen 1 -methylindolin-6-yI)prop-2-enamide, 1-Acetyl -3 ,3-dimethyli ndol in-6-yI)-3-[4-(tert-butyl )phenyl] prop-2- enamide,I .w (2E)-3-[4-(tert-butyl)phenyl]-N-(1I,3,3-trimethylindolin-6-yl)prop-2-enamide, (2E)-3-[4-(tert-butyl)phenyl]-N-( 1 -methyli ndol -6-yJ )prop-2-enami de, (2E)-3-[4-(tert-butyl)phenyl 1 -methylindol-5-yI)prop-2-enami de, (2E)-3-[4-.(tert-butyl )phenyl]-N-( 1 -methylindolin-5-yI)prop-2-enamide, (2E)-N-benzoxazol-5-yI-3-[4-(tert-butyl)phenyl]prop-2-enamide, (2E)-N-benzoxazol -6-yI-3-[4-(tert--butyl)phenyl]prop-2-enamide, (2E)-N-benzo[blfuran -5-yI-3-[4-(tert-butyl )phenyl Iprop-2-enami de, (2E)-3-[4-(tert-butyl )phenyl -di hydrobenzo[b]furan-5-yI )prop-2-en amide, N-(2H,3H-benzo[3,4-e] I ,4-dioxany-6-yI)-3,3-bis(4-methylphenyl)prop-2-enamide, (2E)-N-(2H,3H-benzo[3,4-e] I ,4-dioxan-6-yI)-3-114-(tert-butyl)phenyl]-2- methylprop-2-enamide, (2E)-N-(2H,3H-benzol3 1 ,4-dioxan-6-yI )-3-[4-(tert-butyl)phen ylI- 2 ethylprop-2-enamide,( (2E)-N-(2H,3H-benzo[3 1 ,4-dioxari-6-yI)-3-(4-c yclopropylphen yI)prop-2- enamide, (2E)-N-(2H,3H-benzo[3 I ,4-dioxan-6-yI -[6-(tert-butyl)(3 -pyridyl)] prop-2- enamide, (2E)-N-(2H,3H-benzo[3 ,4-eI I ,4-di oxan-6-yI)-3 -[3-(tert-butyl)phen yI]prop-2- enamide, (2E)-N-(2H,3H-benzo[3 I ,4-dioxan-6-yI)-3-[2-fluoro-4-(tfifl uoromethyl)- phenyllprop-2-enamide, (2E)-N-(2H,3H-benzo[3 I ,4-dioxan-6-yI)-3-[2,3-difluoro-4-(tn fi uorome thyl)- phenyl] prop-2-enamide, 549 (2E)-N-(2H,3H-benzo[3,4-e] 1 ,4-di oxan-6-yl [2,4-bi s(tri fluoromethyl phenyl]prop-2-enamide, (2E)-3-[2-fluoro-4-(tfifluoromethyl)phenyl]-N-indol-5-ylprop-2-enamide, (2E)-3-[2,3-di fiuoro-4-(tri fluoromethyl)phenyll-N-indol-5-ylprop-2-enami de, ,4-bis(tri fiuoromethyl)phenyl]-N-indol-5 -ylprop-2-enami de, N-(2H,3H-ben 'zo[e] I ,4-dioxan-6-y)(2Z)-3-14-(tert-butyl)phenyll-3-[4- (trifluoromethyl)phenyl] prop-2-enamide, (2E)-N-(2H,3H-benzo[e] 1 ,4-dioxan-6-yl)-3- [4-(tert-butyl)phen yI]-4-phen ylbut-2- enamide; (2E)-N-(2H,3H-benzo(e] I ,4-dioxan-6-yl)-3 -[4-(tert-butyl)phen yl]1 -5 -meth yl hex -2- enamide, N-(2H,3H-benzo[e] I,4-di oxan-6-yl)(2Z)-3- [4-(tert-butyl)phenyl]-3 -iodoprop-2- enamide, (2E)-N-(2H,3H-benzo[e] 1 ,4-dioxan-6-yl)-3-(3-aminophenyl)-3-[4-(tert- butyi)phenyl]prop-2-enamide, ethyl (4E)-5-(N-(2H,3H-benzo~e] 1,4-dioxan-6-yl)carbamoyl)-4-[4-(tert- butyl)phen yl ]pen t-4-enoate, 3-methoxyphenyl (2E)-3-[4-(tert-butyl)phenyl]prop-2-enoate, N-(2H,3H-benzo[3 I ,4-dioxan-6-yl)(2Z)-3-[4-(tert-butyl)phenyl]-3- hydroxyprop-2-enamide, I N-(2H,3H-benzo[3 ,4-eI I ,4-dioxan-6-yl)[7-(tert-butyl)(3-isoquinol yl)]- carboxamide, N-(2H,3H-benzo[3 I ,4-di oxan-6-yl)(2Z)-3- [4-(tert-butyl)pheriyl]prop-2- eriamide, N-(2H,3H-benzo[e] I ,4-dioxan-6-yI)(2Z)-3-[4-(tert-butyl)phenyl]-3-phenylprop-2- enamide, (2E)-N-(2H,3H-benzo[e) 1 ,4-di ox an-6-yi)-3 -[4-(tert-buty l)ph en yl )-3-phen ylIprop- 2-enamide, (2E)-3 (tert- butyl )phen yl]-N- [I (N-meth ylcarbamoyl)(I H-i ndazol prop- 2-enamide, (2E)-3-[(4-(tert-butyl)phen yl]-N- I 4-ch Ioro-3- [(methyl ami no)carbon yl amino]- phenyl lprop-2-enamide, -550 [4-(tert-butyl)phenyl] -N-quinoxalin-6-ylprop-2-enamide, 1 -acetyl 1,2,3 ,4-tetrahydroquinol yI ))-3-[4-(tert-butyl)phenyllprop-2- enamide, [4-(tert-butyl)phenyl] [1 -(2-methoxyethyl)indol -6-yI]prop-2-enamide, [4-(tert-butyl)phenyl] -N-Ill -(2-methoxyethyl )indol-5-yI]prop-2-enamide, (2E)-3-[4-(tert-butyl)phenyl] 1 -(2-hydroxyethyl)indol-6-yl] prop-2-enamide, [4-(tert-butyl)phen yII-N-( [1-(2-hydroxyethyl)i ndol-5-ylljprop-2-enamide, [4-(tert-butyl )phenyl]-N- ydroxymethyl )indol-5-yllprop-2-enamide, (2E)-N-(2H,3H-benzo[3,4-e] 1 ,4-dioxan-6-yI)-3-116-(tert-butyl)-2-methyl(3- pyridyl)]prop-2-enamide,( [6-(tert-butyl)-2-methyl(3-pyridyl -N-i ndol-6-ylprop-2-enamide, (2E)-N-benzothi azol-6-yI-3- [6-(tert-butyl)-2-methyl (3-pyri dyil prop-2-enaniide, [6-(tert-butyl)-2-methyl(3-pyfidyl)]-N-indol-5-ylprop-2-enamile, (2E)-3-[6-(tert-butyl)-2-methyl(3-pyridyl)] -N-2-(hydroxymeth yI)indol-5-yI Iprop- 2-eriamide, [6-(tert-butyl )(3-pyridyl)] -N-[2-(hydrox ymethyl)i ndol-5-yI]prop-2- enamide, (2E)-3-[6-(tert-butyl)(3-pyridyl)I-N-[ I-(2-hydroxyethyl)indol-5-YI]prop-2- enamide, (2E)-N-indoI-6-yI-3-[2-methyI-6-(trifluoromethy)(3-pyfidy)IprOP-2-enamide, 2 E)-N-indol-5-yI-3-[2-methyl-6-(trifluoromethyl)(3-pyridyl)]prop-2-enamide,( (2E)-N-benzothiazol-6-yI-3-[2-methyl-6-(trifl uoromethyl)(3-pyridyl)] prop-2- enamide, (2E)-N-(2H,3H-benzo[3 1,4-diox an-6-yi)-3-[2-methyl-6-(triflIuoromethyl pyridyl)Iprop-2-enamide, (2E)-3-[4-(tert-butyl)phenyl]-N-[3-(hydroxymethyl)-2oxo(7 1,3,4- trihydroquinol yI)Iprop-2-eriamide, (2E)-N-[3-(hydroxymethyl 1,2,3,4-tetrahydroquinolyl)]-3- [4- (trifi uoromethyl)phen yI]prop-2-enami de, (2E)-N-[3-(hydroxymethyl)-l1-methyl(7- 1,2,3 ,4-tetrahydroqui nolyl)]-3-[4- (trifluoromethyl)phenyllprop-2-enamide, I -551 (2E)-N-(2H,3H-benzo[e] 1 ,4-di oxan-6-yi)-3- [4-(tert-butyl)phenyl 1,3- dioxolan-2-yI)pent-2-enamide, (2E)-N-(2H,3H-benzo[e] I ,4-dioxan-6-yi)-3-[4-(tert-butyl)phenyl]-4-(3- pyridyl)but-2-enamide, N-(2H,3H-benzo[eI 1 ,4-dioxan-6-yI)(2Z)-3-[4-(tert-butyl)phenyl]-4- pyrrolidinylbut-2-enamide, (2E)-N-(2H,3H-benzole] 1 ,4-dioxan-6-yI)-3-[4-(tert-butyl)phenyl]-6- imidazolylhex-2-enamide, 3-(4-tert-butyl -phenyl midazol- i-yI-hex-2-erioic acid benzothiazol-6-ylamide, (2E)-N-(2H,3H-benzo~e]1I,4-dioxan-6-yI)-3 -[2-morpholin-4-yl-6- (trifluoromethyl)(3-pyridyl)]prop-2-enamide,. (2E)-N-(2H,3H-benzo[e] 1 ,4-di ox an-6-yl -[4-(tert-butyl)-2-bromophen yl Iprop- 2-enamide, ethyl IE)-2-(N-(2H,3H-benzol 1,4-dioxan-6-yI)carbamoyl)vinyl]-5-(tert- butyl)benzoate, (2E)-3-[2-Bromo-4-(tri fiuoromethyl)phen yI]-N-indol-5-ylprop-2-enamide, (2E)-N-benzothi azol -6-yI -3-12-bromo-4-(tri fl uorometh yl)phenylljprop-2-enamide, (2E)-N-(2H,3H-benzole I ,4-dioxan-6-yI)-3- [2-bromo-4-(trifluoromethyl phenyl]prop-2-enamide, (2E)-N-indol-5-yl-3-[2-(6-methoxy(3-pyri dyl))-4-(tr i fuorometh yl )phenyllprop-2- enamide, (2E)-N-indol-5-yI-3-[2-(4-pyridyl)-4-(trifl uoromethyl)phenyll prop-2-enamide, (2E)-N-indol-5-yI-3-112-(3-pyridyl)-4-(trifluoromethyl)phen yilprop-2-enamide, tert-butyl 1E)-2-(N-i ndol -5 -ylcarbamoyl) vinyl] -5 (tifluoromethyi)phenyl) 1,2,5 ,6-tetrahydropyridinecarbox yJ ate, (2E)-N-indol75-yl-3-[2-(1I,3-thiazol-2-yI)-4-(trifluoromethyl)phenyl]prop-2- enamide, (2E)-N-iridol-5-yl-3-[2-(3-pyridylmethyl)-4-(tri ifuoromethyl)phenyllprop-2- enamide, (2E)-3-[2-(3-pyridyl)-4-(tfifluoromethyl)phenyl]-N-(7-qui nolyl)prop-2-enamide, (2E)-3-[2-(3-pyridy] )-4-(trifl uoromethyl)phenylli-N-(3-quinolyl)prop-2-enamide, -552- (2E)-N-i ndol-6-yI-3-[2-(3-pyridyl)-4-(triifluoromethyl)phenyl ]prop-2-enamide, and N-(2H,3H-benzo[3 1 ,4-dioxan-6-yl)-3- [4-(tert-butyl)phenyl Ipropanamide. 165. A compound according to Claim 21, or a pharmaceutically- acceptable salt thereof, wherein the compounds is selected from: (4-benzo[ I 3]dioxol-5-yl-pyridin-2-yl)-(2,3-dihydro-benzo[ 1,4ldioxin-6-yl)- amine, (2,3-dihydro-benzo[ 1,4]dioxin-6-yl)-[4-(4-dimethylamino-phenyl)-pyridin-2-ylJ- amine, (2,3-dihydro-benzo [1 ,4]diox in-6-yl)-[4-(4-fl uoro-phenyl)-pyridin--2-yII-amine, (2,3-dihydro-benzo[1I,4]dioxin-6-yl)-[4-(3-trifluoromethyl-phenyl)-pyridin-2-yI- amine, (4-benizo[b]thiophen-2-yl-pyridin-2-yl)-(2,3-dihydro-benzo[ I,4]dioxin-6-yl)- amiine, 1- {4-(2-(2,3-dihydro-benzo[1I,4]dioxin-6-ylamino)-pyridin-4-yl]-phenyl I- ethanone, 1- (4 -[2-(2,3-dihydro-benzo[1I,4]dioxi n-6-ylamino)-pyridin-4-yli-phenyl) -ethanol, f4-(3 ,5-bis-trifluoromethyl-phenyl)-pyridin-2-yl]-(2,3-dihydro-benzo[ I,4]dioxin- 6-yi)-amine, (2,3-dihydro-benzo [I,4]dioxi n-6-yl)- 14-(4-trifluoromethoxy-phenyl)-pyridi n-2- yl)-amine, and quinolin-3-yl- [4-(4-trifluoromethyl-phenyl)-pyridin-2-yJ]-amine. 166. A compound according to Claim-56, or a pharmaceutically- acceptable salt thereof, wherein the compounds is selected from:' 7-[4-(4-trifluoromethyl-phenyl)-pynidin-2-yloxy]-quinoline, 2 -(3-methoxy-phenox y)-4-(4-tti fl uorometh yl -phenyl)-pyridine, 8-[4-(4-trifl uoromethyl-phenyl)-pyridin-2-yloxy] -quinolin-2-ylamine, 4 4 4 trifl uoromet hyl -phen yl)-pyi di n-2-ylox y] -ben zothi a~ol.2yl ami ne, N- 4 4 4 -trifluoromethyl-phenyl)-pyridin-2-yloxy]- benzothiazolz2yl acetamide, -553- 8- [4-(4-tri fluoromethyl-phenyl)-pyridin-2-yloxy -qui noline, and [4-(4-tfifl uoromethyl-phenyl )-pyridi n-2-yloxy] -benzothi azole. 167. A compound according to Claim 21, or a pharmaceutically- salt thereof, wherein the compounds is selected from: K 01 H N C" N H 554 N N F 3 G 11N F 3 C N' H N 0 0, Br H IC( 0 ,and F 3 C~ KN I 168. A compound according to Claim 1, or a pharmaceutically- acceptable salt thereof, wherein the compounds is selected from: N 0. -555- A~ CH H G. 0K. ~CH 31A 556- OH ":Y HH N N 'CH 33 U3. HA..H -H 557 o HOtC H I H CHH N_ p. H CH: 558 -559- NN -H C ON H' H CNH. .0 O' -j" Krip 3 F 2007200149 15 Jan 2007 /7 561 H N N 0 IC -N OH ~NN Br cl- 1* .sa -ii 3 HH H 562 563 564 CH. H 3 C OH 0 N- 2007200149 15 Jan 2007 U.' w w\ 000 0 0 0 0 0 0 0 0 0 0 CN LA 2007200149 15 Jan 2007 (-N 2007200149 15 Jan 2007 0 zx 0 x Z: 0 x 0 0(/ 0 0 0 0 m 2007200149 15 Jan 2007 0. 0 0 z 0 0 0 2007200149 15 Jan 2007 0\ zx 0 Zx 0 rr: 0 Zm 0 Zx ;r 2007200149 15 Jan 2007 0 0 0 1 '1 0 0 Zm 0ld 0 0 ZI 0 2007200149 15 Jan 2007 0 0= Zz o 0 2007200149 15 Jan 2007 2007200149 15 Jan 2007 0 2007200149 15 Jan 2007 2007200149 15 Jan 2007 /z 0 I0 o o 2007200149 15 Jan 2007 0 C I- 0 0 Zx z- I0 0 0 KN.. 2007200149 0 ZI z h 0 Zx 0 0 15 Jan 2007 0 2007200149 15 Jan 2007 0 2I 0 2I 0 ZI 0 0 a)w zx diz 2007200149 15 Jan 2007 0i 580 0( HN 0 ;H 0 581 -582- 583 I 2007200149 15 Jan 2007 -585- F 3 C H N S N F 3 C I N O 169. A pharmaceutical composition comprising a compound according to any one of Claims 1-168 and a pharmaceutically-acceptable diluent or carrier. 170. The use of a compound according the any one of Claims 1-168 as a medicament. N 0 the manufacture of a medicament for the treatment of acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, -586- disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or t vascular regions, wounds, bums, allergic skin reactions, pruritis, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders. N 172. The manufacture of a medicament for the treatment of acute, O inflammatory and neuropathic pain, dental pain, general headache, migraine, N cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary; gastrointestinal or vascular regions, wounds, bums, allergic skin reactions, pruritis, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders, wherein the medicament contains a compound having the structure: R 3 R 1 R 2 X wherein: X is O, S or NR m n is independently, at each instance, 0, 1 or 2; o is independently, at each instance, 0, 1, 2 or 3; R m is independently at each instance H or R"; R" is independently at each instance CI-galkyl, phenyl or benzyl; -587- Rqis independently in each instance H, C14alkyl, C 1 4haloalkyl, halo, cyano, nitro, n, -C(=O)0R n, -C(=0)NR m -C(=NR m )NRnRmI, -OR m -OC(=0)NR m -OC(=0O)N(R m 2 -OC 2 -6alky1NR m R m -0C 2 -6alkylOR m -SR' m -S 2 R n, 2 NR m R', 2 N(R m 2 N(R m )C(=O)OR 2 N(R m -NR m -N(R m )C(=O)NR m R m -N(R-)C(=NR m )NRmR m -N(R m 2 Rn, -N(R m 2 NR m -NR m C 2 6 alkylN.R m R m or -NR m C 2 Rsis R n substituted by 0, 1, 2 or 3 substituents independently selected from R q; R 3 isHorC,4alkyl; R 5 is H, Cl- 9 alkyl, C 1 4haloalkyl, halo, nitro, cyano, -0C 1 -6alkyl,- -O-C 1 4 haloalkyl, -0-C 1 6 alkylNR m R m -0-C 1 -ralkyl0R', -NR m R m -NR m 4 haloalkyl, -NR m -C 1 6 alkylNR m -NR m -C 1 6 alkylORT, or -(CH 2 )nRc R 6 is, independently at each instance, H, C1. 9 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -0C 1 6 alkyl, -0-C 1 4 haloalkyl, -0-C 1 6 alkyINR m R m -0-C 1 6 alkylOR', -NR m R m -NR m -C 1 4 haloalkyl, -NR m -C 1 6 alkylNR m R m or -NR m -C 1 6 alkyl0R m R 8 is H, C 1 9 )alkyl, C1, 4 haloalkyl, halo, nitro, cyano, -OCI 1 6 alkyl, -0-C 1 4 haloalkyl, -0-C 1 6 alkylNR m R m -0-C 1 6 alkylOR m -NR RR, -NR m -C 1 4 haloal kyl, -NR m -C 1 6 alkylNR m R' or -NR m -C 1 6 a1 kylOR m and R' is R 8 R (CRqRq) ORO R 2is H, -OR m halo, CI- 3 haloalkyl or C 1 6 alkyl; R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selec ted from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the -588- combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C 1 8 Salkyl, C14haloalkyl, halo, cyano, nitro, -C(=O)NR m R', -C(=NR m )NR m R m -OR m -OC(=O)Rn, -OC(=O)NR R" 1 '-OC(=O)N(R m 2 -OC 2 6 alkylNR m R m -OC 2 6 alkylOR m -SR' m 2 NR m R m 2 N(R m 2 2 N(R m )C(=O)NR m R m -NR"'R m -N(R m -N(R m )C(=O)NR m nR m -N(R m )C(=NR m )NR m -N(R m 2 R -N(R m 2 NR m R m -NR m C 2 6 alkylNR m R m -NR m C 2 -alkyIOR m -C(=O)Rs, -C(=0)ORs, -C(=O)NRnR', -C(=NRn)NRnRs, -ORs, OC(=0)Rs, -0C(=O)NRnR', -OC(=O)N(Rrn)S(=O) 2 -OC 2 6 alkylNRrnRs, -OC 2 -6alkylOR', -SRs, -S(=O0) 2 RS, 2 NRnR', 2 N(Rrn)C(=O)Rs, 2 N(Rrn)C(=O)ORs, S(=O) 2 N(Rrn)C(=O)NRnRs, NRrnRs, N(Rr)C(=0O)Rs, -N(Rr)C(=O)ORs, -N(Rrn)C(=O)N4lmrn, N(Rrn)C(=NJ1Rn)NRrnRs. -N(Rrn)S(=O) 2 Rs, -N(R m )S 2 NRnRs, *-NRnC 2 6alkylNRnRs, -NRnC 2 6 and C 14 alkyl substituted by 1 or 2 groups selected from C 1 2 haloalkyl, hald, cyano, nitro, -C(=O)OR n, -C(=O)NRmR m -C(=NR m )NR m R m -Ok t m -OC(=O)R n, -OC(=O)NR m -OC(=O)N(R m )S 2 R n, -OC 2 -6alkylNR m R', -OC 2 -6alkylOR', -SR m n, 2 R n, 2 NR m R-, 2 N(R m 2 N(Rml)C(=O)OR n, -S 2 N(R')C(=O)NR m R m -NR m R m -N(R m n, -N(R m )C(=O)OR n, -N(R m )C(=O)NR"'R m -N(R m )C(=NR"')NR m R m -N(R m 2 -N(R m 2 NR m R m -NR m C 2 -6alkyINR m R m -C(=O)NRnRs, -C(=NR)NRnR', -ORs, -OC(=O)Rs, -OC(=O)NRnRs, -OC(4-O)N(Rrn)S(O) 2 -OC 2 6 alkylNR m Rs, -OC 2 6 alkylOR', 2 R, -S(0) 2 NRnRs, 2 N(Rrn)C(=O)Rs, 2 N(Rrn)C(=O)ORs, 2 N(Rn)C(0)NRnRs, -NRmlR', -N(Rrn)C(=O)Rs, -N(Rr)C(0O)ORs, -N(Rrn)C(=O)NRnRs, -N(Rrn)C(=NRn)NRnR', -N(Rm T )S 2 Rs, -N(R m )S (70) 2 NRmrnR, -NRrnC 2 6 4kyINRrnRs, -NRnC 2 -6a~kylORs and -NR m C 2 6 alkylOR m and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups; -589- R 7 is C 1 9 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -0CI. 6 alkyl, -O-C 1 -4haloalkyl, -0-C 1 6 alkyINR m -0-C 1 6 a1 kylOR, -NR m R', -NR' m 4 haloalkyl, -NR m -C 1 .6alkylNR m R m or -NR m -C 1 6 alkylOR m R' is a saturated, partially-saturated or unsaturated 6- or 7-membered monocyclic or 10- or 1 1-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, 0 and S, so long as the combination of 0 and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from RP; RP is independently at each instance C 1 .salkyl, C 1 4 haloalkyl, halo, cyano, nitro, n' -C(=0)0R n' -C(=0)NR m R m -C(=NR m )NR m R m -OR m -OC(=O)N(Rm)S(=O) 2 R n' -0C 2 6 alky NR m R m -OC 26 al kylOR m -SR' m 2 R n' -S 2 NR m R', -S 2 N(R m n, -S 2 N(R m 2 N(R m )C(=O)NR t R m -NR m R m -N(R m -N(R m )C(=O)NR m R m -N(R m )C(=NR m )NR m 2 -N(R m )S 2 NR m R', -NR m C 2 6 aIkyl NR m or -NR m C 2 6 a1 ky!OR m and Y is 0Oor NH; or R' Is R, 5 R 7 N R (CRqRq) 0 flO or (CRqRq )ORO R 2 is H, -OR m halo, C 1 3 haloalkyl or C 1 6 alkyl; R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C 1 .salkyl, C-4haloalkyl, halo, cyano, nitro, -C(=O)NR m R', -590- -C(=NR m )NR M R m -OR m -OC(=O)R -OC(=O)NR m R -OC(=O)N(R m 2 -OC 2 6 a1ky]NR m -OC 2 -6alkyl0R m -SR m 7 2 2 NR m R m -S 2 N(R m 2 N(R m -N(R m )C(=O)NR m R m -N(R m )C(=NR m )NR m R m -N(R m 2 R n -N(R m 2 NR m -NR m C 2 _alkyNR m R m -NR m C 2 _6alkyOR m -C(=O)Rs, -C(=O)0R 5 -C(=0)NRnR', -C(=NRrn)NRnR', -0C(=O)R, -OC(=O)NRnR', -OC(=O)N(Rn)S(=O) 2 Rs, OC 2 6 alkyINRnRs -OC 2 -6alky1OR', -SRS, 2 RS7 2 NRnR', 2 N(Rnl)C(=O)Rs, 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=O)NRnR',- -NRrnRs, -N(R)C(0)Rs N(Rr)C(=O)ORs, -NQ(R)C(O)NRnRs, -N(Rrn)C(=NRn)NRnR', -N(Rrn)S(=0) 2 -N(Rrn)S(=O) 2 NRrnRs, -RmC 2 -6alkylf4RnRs, -NRnC 2 6 alkylORs and C 14 alkyl substituted by 1 or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=O)NR m R m -C(=NR m )NR m R m -OR m -OC(=O)Rn, -OC(=O)NR m R m -OC(=O)N(R m )S 2 -OC 2 -6alkylNR m R m -OC 2 6 alkyI0Rm, -SR m 2 2 NR m R, 2 N(R m -S tm )C(=O)OR n, 2 N(R m )C(=O)NR m R m -NR m -N(R m -N(R m -N(R m )C(=O)NR m R m -N(R m )C(=NR m )NR m R m -N(R m 2 -N(R m 2 NR m R m -NR tm C 2 6 alkylNR-R m -C(=O)ORs, C(=Q)NpRnR' -C(=NRn)NRnRs, -OC(=0)NRnRs, -0C(=0)N(Rn)S(=O) 2 -OC 26 alkylNRnRs, -0C 2 6 alkyl ORS, -SRs, -S 2 Rs, 2 NR m 2 N(R m 2 N(Rrn)C(=O)ORs, 2 N(R m )C(=0)NR m Rs, -NR m -N(R m -N(R m )C(=O)0R 5 -N(Rrn)C(=O)NRnRs, -N(R m )C(=NR-)NR m -N(R m 2 -N(R m 2 NR m Rs, -NR tm C 2 6 aI kylNR m Rs, -NR m C 2 6 alkyIOR 5 and -NR m C 2 6 alkylOR'; and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups; R 7 is C1. 9 alkyl, CI- 4 haloalkyI, halo, nitro, cyano, -OCI- 6 alkyI, -0-C 1 4 haloalkyl, -0-C 1 6 alkylNR m R m -0-C 1 6 alkylOR', -NR m R m -NR m -C 1 4 haloalkyl, -NR m -C 1 6 alkylNR m R m or -NR m -C 1 6 alkylOR m R' is a saturated, partially-saturated or unsaturated 6- or 7-membered monocyclic or 10- or 11 -membered bicyclic ring containing 0, 1, 2, 3 or -591- 4 atoms selected from N, 0 and S, so long as the combination of 0 and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents. independently selected from RP; RI is independently at each instance Cl*salkyl, C 1 4 haloalkyl, halo, cyano, nitro, -C(=0)NR m -OR m -OC(=O)NRlR'l, -OC(=O)N(R m 2 -0C 2 6 alkylNR m R', -OC 2 -6alkylOR', 2 R n, 2 NR m R m -S 2 n, 2 N(R m 2 N(R m )C(=O)NR m R', -NR m -N(R t n, -N(R tm -N(R m )C(=0)NR m R', -N(R m )C(=NR m )NR m R m -N(R m 2 R n, -N(R m 2 NR m R m -NR m C 2 6 alkylNR m R m or -NR M C 2 6 alkylOR m and Y is 0or NH; or R' is R 9 R 2 is H, -OR m halo, CI- 3 haloalkyl or CI_ 6 alkyI; R 4 is a saturated, partial ly-saturated or unsaturated 10 or I I1-membered bicyclic heterocycle containing 1, 2, 3, 4 or 5 atoms selected from 0, N and S, so long as the combination of 0 and S atoms is not greater than 2, but excluding quinolin-6-yI, 4 5,6,7-tetrahydro-benzo[blthiophen-2-yl, benzothi azol- 2-yl, 2,3-dihydro-benzo[1,4]dioxin-6-yl, wherein the heterocycle is substituted by 0, 1, 2 or 3 substituents independently selected from Cl-galkyl, oxo, CI4haloalkyl, halo, nitro, cyano, -OR m 0 ,C 1 6 alkyl, -O-C 1 4 haloalkyl, -O-C 1 6 alkylNR m R m -0-C 16 a1kylOR m -NIR m R m -NTR-C 1 4 haloal kyl, -NR m -C 1 6 a1 kylNR m R m -NR m -C 1 6 aIkylOR m -C(0)CI. 6 alkyl, -OC(=O)C 1 6 alkyl, 6 alkyl, -NR m C(=O)C 1 6 alkyl -C(0)ORS, -C(=O)NRnR', -C(=NRn)NRrnR', -OWs, 0OC(0O)rNRsR -OC(=O)N(R m )S 2 -OC 2 6 al kylNRnRs, -OC 2 6 alkylOR', -SRs Ss(0)Rs, 2 -S(0) 2 NRnRs -592- -S 2 N(Rrn)C(=O)Rs, 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=O)NRR', -NRrnRs, -N(Rrn)CQ..0)ORs, -N(R r)C(=O)NRnRs, -N(Rrn)C(=NR')NRnRs, -N(Rrn)S(=O) 2 -N(Rrn)S(=O) 2 NRR', -NRrnC2 6 alkylNRnRs, -NRnC 2 6 alkylOR' and C 1 4 alkyl substituted by 1 or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, 6 -C(=O)NR m R m -OR- m -OC(=O)Rn, -OC(=O)NR m R m -OC(=O)N(R m 2 R -0C 2 6 alkyNR m R m -OC 2 -6alkylOR', -SR m 2 R -S 2 NR m R m 2 N(R m 2 N(R m )C(=O)OR, 2 N(R m )C(=O)NR m R m -N(R 11 n, -N(R m -N(R-)C(=O)NR m -N(R m )C(=NR m -N(R m 2 R, -N(R m 2 NR m R m -C(=O)ORs, -C(=O)NRnR', -C(=NRn)NRnRs, Q -ORs, -OC(=O)Rs, -OC(=O)NRrnR', -OC(=O)N(Rrn)S(=O) 2 Rs, OC 2 6 alkylIR'RR -OC 26 a1 kylORs, 2 2 NR m R', -S 2 N(R m 2 N(R m )C(=O)ORs, 2 N(R m )C(=O)NR m R', -NR m Rs, -N(R m )C(=O)0R 5 -N(R m )C(=O)NRmRs, -N(R m )C(=NR m )NR m Rs, -N(R m )S 2 -N(R m )S 2 NR m R', -NR m C 2 _ralkyINR m -NR M C 2 6 alkylORs and -NR m C 2 -ralkyIOR'; wherein R 4 is not 2-ami nocarbonylmethyl-2,3-dihydro-benzo 1 ,4]dioxin- 8-yl, 2-cyanomethyl- 2,3-dihydro-benzo[1I,4]dioxin-8-yl, quinolin-3-yl, 3H-quinazolin-4-on-3-yI, benzo[ 1,3]loxol-5-yI, 3,3-dimethyl- 1,3-dihydro-indol-2-on-6-yI or 4,4-di methyl- 3,4-dihydro-1H-quinolin-2-on-7-yl; R 7 is CI-8alkyl, CI-shaloalkyI, I or Br R 9 is H, C 19 galkyl, C 1 -4haloalkyl, halo, nitro, cyano, -OC 16 (alkyl, -O-Cl. 4 haloalkyl, -0-C 6 a1 kyl NR m -O-C 1 6 alkyIOR', -NR m -NR m -C 1 4 haloalkyl, -NR m -C 1 6 alkylNR m R m -NR m -C 1 _6alkylOR', or -(CH 2 R 9 is independently, at each instance, H, Cl- 9 alkyl, Ci'-haloalkyl, halo, nitro, cyano, -0CI. 6 alkyl, -O-C 1 4 haloalkyl, -O-C 1 6 alkylNR m R', -0-C i.,alkyIOR -NR m R m -NR m -C 1 4 haloalkyl, -NR m -C 1 6 alkyINR m R' or -NR m -C 1 6 alkylOR'; Y is NH; and Z is CR 8 or N; or' R'is .1 -593- R 6 R 2 is C 1 -6alkyl substituted by 1, 2 or 3 -substituents selected from Cl-4haloalkyl, halo, cyano, nitro, -C(=O)0R 0 -C(=O)NR m R', -C(=NR m )NR m -OR' m -OC(=O)NR m R', ci 5 -OC(=O)N(R m 2 R 1 -OC 2 6 alkylNR m -0C 2 6 alkylOR, -SR m -S(=O)R1 2 R n, 2 NRrnRr, 2 N(R m 2 N(R m (n 2 N(Rrn)C(=O)NRmlRn, -NR m Rm1, -N(R m -N(R m )C(=O)OR1 -N(R m )C(=O)NRn m R m -N(R m )C(=NR m )NR"'Rm 1 -N(R m 2 R1 -N(R m )S 2 NR m R m -NR M C 2 6 alkylNR m R m or -NR M C 2 -6alkylOR m or R 2 is q) 2 0 ,phenyl, wherein the phenyl is substituted by 0, 1, 2 or 3 substituents independently selected from C 1 .salkyl, C 1 4 haloalkyl, halo, cyano, nitro, -C(=O)OR n, -C(=O)NR m R1', -C(=NR m )NR m R m n-7C(=O)NR'R m -OC(=O)N(Rrl)S(=O) 2 R1 -0C 2 6 alkyl NRm'", -0C 2 6 alkyIOR m 2 2 NRm1Rm1, 2 N(Rm1)C(=O)R', 2 N(R m )C(=O)OR1, -S 2 N(R m )C(=O)NRm'1R, -NR"'R m n, -N(R m m R', -N(R m )C(=NR'1')NR m -N(R m 2 2 NR'R1 -NR M C 2 -6alkylNR m -NR m C 2 _talkylORm', -C(=O)ORs, -C(=O)NRnR', -C(=NRrn)NRrnRs, -OC(=O)Rs, -OC(=O)NRnR', -OC(=O)N(Rn)S(=O) 2 -OC 2 .salky1NRrnR', -OC 2 6 alkylORs, -SRs, S(=O)Rs, 2 2 NRrnR', -S 2 N(Rrn)C(=O)Rs, -S 2 N(Rrn)C(=O)ORS, 2 N(Rrn)C(=Q -)NRnR -NRrnRs, -N(Rrn)C(=O)RS, -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRnRs, -N(Rrn)C(=NRrn)NRrnRs, -N(Rr)S(=0) 2 Rs, 2 NRmRs, -NRrnC 2 alkylNRnRs, -NRm T C 2 -ra1 k-ylORS and C 1 Aalkyl substituted by I or 2 groups selected from C 1 2 haloalkyl, halo, c yano, nitro, -C(=O)NR m Rm 1 m -OR m -OC(=O)R1, -OC(=O)NRm1Rm1, -OC(=O)N(R m 2 R n, -OC 2 6 alkyNRm1R m -OC 2 6al ky OR m -SR m -S 2 2 NR M R M (=O)ANR"')C(=Q)gn1, 594 2 2 N(R m )C(=O)NR m R m -NR m R m -N(R m -N(R m -N(R m )C(=O)NR m R m -N(R m )C(=NRm)NR m R m -N(R m 2 -N(R m 2 NR m R'h -NR M C 2 -6alkyNR m R m -C(=O)ORs, -C(=O)NRnR', -C(=NRrn)NRrnR', -ORs, -OC(=O)Rs, .0C(0)NRnRS -OC(=O)N(Rrn)S(=O) 2 Rs, OC 2 6 alkylNJrnRS, -OC 2 6 alkylOR', -SRs, -S -S 2 Rs, 2 NRnRs, 2 N(Rrn)C(=O)R', -s 2 N(Rrn)C(=O)ORS, 2 N(Rrn)C(=O)NRnRs, -NRrnRs, -NQRfl)C(=O)Rs, -N(Rr)C(=O)ORs, -N(Rrn)C(=O)NRnRs, -N(Rrn)C(=NRn)NRnRs, -N(Rrn)S(=O) 2 Rs, -N(Rn)S(=O) 2 14Rs, -NRnC 2 -6alkylNRnRs, -NRnC 2 _6alkylOR' and -NR m C 2 6 alkylOR m or R 2 is 2 0 Rr, wherein R' is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatorns i ndependently selected from N, 0 and S, wherein no more than 2 of the ring members are 0 or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents, independently selected from CI-8alkyl, C 1 4 haloalkyl, halo, cyano, nitro, -C(=O)0R -C(=0)NR m -C(=NR m )NR m -OR- m -OC(=O)NR m R m N(R' 1 )S(O) 2 R -OC 26 al kylNR m -OC 2 6 alkylOR m -SR m S( (O)R, 2 R 2 NRnRr, 2 N(R m -s 2 N4(R m )C(=O)OR, 2 N(Rm")C(=O)N-R -N(R m )C(=O)NR m -N(R m )C(=NR m )NR m R m -N(R M 2 R, -N(R m 2 NR m R m -NR m C 2 6 alkylNR m R m -NR M C 2 -6alkylOR m -C(=O)Rs, -C(=O)ORs, -C(=O)NRrnR', .C(=NRml)NRlRs, -ORs, .0C(0)Rs, -OC(=O)N(Rrn)S(O) 2 -OC 2 6 alkyNR m Rs, OC 2 6 alkyl0R 5 -SRs, 2 2 NRrnRs, 2 N(Rrn)C(=O)R', 2 N(Rr)c(=q)OR, 2 N(Rn)C(0)NRnRs, -NRrnRs, -N(Rr)C(0O)Rs, -N(Rr)C(=O)0Rs, -N(Rr)C(O)NRnRs, N(Rr)C(=NRrn)rNRsR -N(Rrn)S(=O) 2 -N(Rrn)S(=O) 2 NRnRs, -NRnC 26 alkylNR m NRnC 2 ,ky]ORS and C 14 alkyl substituted by 1 or 2 groups selected from C 1 2 haloalkyl, halo, cyano, niitro, -C(=O)NR m -C(=NR&)NR m R m -OR m -OC(=O)NR m R m -OC(=O)N(Rm)S(=O) 2 -OC 2 6 akylNR m R m -OC 2 6 alkylOR m -SR m n, 2 R n, 2 NR m R m 595 -S 2 N(R m 2 N(R m -S 2 N(R m )C(=O)NR m R n -NR m R m -N(R m -N(R m -N(R m )C(=O)NR m R', -N(R m )C(=NR n )NRmRm, -N(R m )S 2 -N(R m 2 NR m R', -NR'C 2 6 alkylNR m .C(=O)ORs, C(=O)NRnR', -C(=NRrn)NRrnR', -OWg, -OC(=O)Rs, -OC(=O)NRnR', -OC(=O)N(Rrn)S(=O) 2 -OC 24 6alkylNRnR', -OC 2 -talky]OR', 2 S(=O) 2 NRrnR', 2 N(Rrn)C(=O)R', 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=O)NRnRs, -NRrnRs, -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRnRs, -N(Rrn)C(=NRn)NRnR', -N(Rrn)S(=O) 2 Rs, -N(Rrn)S 2 NlRnRs. -NRrnC 2 6 alky]NR m -NR m C 2 6 a1 kylORs and -NR'C 2 6al kylOR m R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from CI- 8 alkyl, C, 4 haloalkyl, halo, cyano, nitro, -C(=0)NR m R', -C(=NR m )NR m R m -OR m -OC(=O)R n, -OC(=O)NR m R', -OC(=O)N(R m 2 -0C 2 6 alkylNR"'R m -OC 2 6 alkylOR', -SR' m 2 R, n' S(=O) 2 NRmIRrn, 2 N(R m n, 2 N(R m 2 N(R m )C(=O)NR m R m -NR m R m -N(R m -N(R m )C(=O)OR, -N(R m )C(=O)NR m R m -N(R m )C(=NR m -N(R m 2 R -N(R m 2 NR m R m -NR m C 2 6 alkylNR m R m -NWC 2 6 alkylOR m -C(=O)0R 5 C(=0)N~4 1 R'R -C(=NR m )NR m R, -OC(=0)R 5 -OC(=O)NR m Rs, -OC(=O)N(R m )S 2 -OC 2 6 aI kylNR m -OC 2 6 al kylOR', -SWs, -S S4=O) 2 -S 2 NRnRS, 2 N(R m )C(=0)0R 5 2 N(Rrn)C(=O)NRnR', 4pNRnR' -N(R m -N(Rr)C(=O)ORs, -N(R m )C(=O)NR m -N(Rrn)C(=NR m)NRmlR', 2 R 5 -N(R m )S 2 NR m Rs, -NR m C 2 6 a1 kyINR-R 5 -NRnC 2 6 akyIOR'. and C 1 4 alkyl substituted by 1 or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro,* C(=O)NR m R m -C(=NR m )NR m -OR m -OC(=0)NR m -OC(=O)N(R m )S 2 -OC 2 -6alky]NR m R m 596 -QC 2 _6alky1OR', 2 -S(=O0) 2 NR m R m -S 2 N(R m 2 2 N(R m )G(=O)NR m R', -NR m R m -N(R m -N(R m -N(R m )C(=O)NR m R', -N(R m )C(=NR m )NR m -N(R m 2 -N(R m 2 NR m R', -NR m C 2 6 alkyINR"'R m -C(=O)0R 3 -C(=O)PR m Rs -C(=NR m )NR m Rs, -ORs, -OC(=O)Rs, 2 -OC 2 6 alkylNR m R', -OC 26 alkylORs, -SRs, 2 Rs, -S 2 NR m Rs, 2 N(R m 2 N(R m )C(=O)0R 3 -S 2 N(R m )C(=O)NR m Rs, -NRrnR', -N(R m -N(R m )C(=O)0R 3 -N(R m )C(=O)NR. m Rs, -N(R m 2 Rs, -N(R m 2 NR m Rs, -NR m C 2 6 alkyINR m Rs, -NR m C 2 6 alkylOR' and -NR m C 2 -6alky1OR', and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups; R 7 is C 2 .salkyl, C 15 haloalkyl, 1, Br; R 9 is independently, at each instance, H, Cl- 9 alkyl, CI- 4 haloalkyl, halo, nitro, cyano, -0C 1 6 alkyl, -O-C 1 4 haloalkyl, 6 akylNR m R m -0-C 1 6 alkylOR', -NR m R m -NW-CI-. 4 al oal kyl, -NR m -C 1 6 alkylNR m R m or -NR m -C 1 6 alkylOR m Y is NH; and Z is CR 8 or N; or 2 0 R' is R 9 R 2 is H, -OQ m CI, CI. 3 haloalkyl or CI. 6 alkyl; R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S, so long as the combination of 0 and S atoms is not greater than 1, wherein the ing is substituted by 0, 1, 2 or 3 substituents independently selected from C 1 .8alkyI, C 1 4 haloalkyI, halo, cyano, nitro, 2 -OC 2 6 alky]OR', -S 1, 2 R, 597 2 NR m 2 N(R m 2 N(R m 2 N(R m )C(=O)NR m -NR m -N(R m -N(R m -N(R m )C(=O)NR m R m -N(R m )C(=NR m )NR m -N(R m 2 R', -N(R m )S 2 NR m -NR'C 2 6 a1 kylNRm', -NR M C2'sal kylOR, -C(=O)ORs, -C(=o)NRnRs, -C(=NRn)NRrnRs, ORs, -OC(=O)Rs, -OC(=O)NRnR', .0c(=o)N(Rn)S(=0) 2 Rs, -OG 2 6 5alkylNRrnR', -OG 2 -6alkylORs, -SRs, 2 Rs, 2 NRnR', 7 S(=O) 2 N(Rrn)C(=O)Rs, 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=O)NRnR', -NRnRs, -N(Rrn)C(=O)Rs, -N(Rrn)C(=O)ORs, -N(Rn,)C(=O)NRnRs, -N(Rrn)C(=NRn)NRnR', -N(Rrn)S(=O) 2 Rs, -N(Rrn)S(=O) 2 NRnRs, -NRrnC2zalkyINRrnRs, -NR m C 2 6 alkylORs and C 1 4 alkyI substituted by 1 or 2 groups selected from CI. 2 haloalkyl, halo, cyano, nitro, -C(=O)NR m R m -C(=NR m )NR'R m -OR m -OC(=O)NR m -OC(=O)N(R m 2 -OC 26 a1 kylNR m -OC 2 -6a1kyIOR m -SR m -S -S 2 R 2 N~ m R m 2 N(R m -S 2 N(R m )C(=O)ORn, 2 N(R m )C(=O)NR m R m -NqR m R m -N(R m -N(R m -N(R m )C(=O)NR m R', -N(R m )C(=NR m )NR m R m 2 R n, -N(R m )S 2 NR m R m -NR m C 2 -6alkyINR m -C(=O)ORs, C(=)NRnRS -C(=NRrn)NRnRs, .OC(0O)Rs, -OC(O)rNRs' -OC(=O)N(Rrn)S(=0) 2 Rs, -0C 2 6 a1 ky]NRmlR', -OC 26 a~kylOR', .S(0)Rs, 2 -S(O) 2 NJRn Rs, 2 N(Rrn)C(=O)R', 2 N(Rn)CQ.O)ORs, 2 N(Rrn)C(=O)NRnR', ~~NRrnRs, -N(Rml)C(=O)ORs, -N(Rrn)C(=O)NRnRs -N(Rrn)C(=NRn)NRnRs, -N(Rrn)S(=O) 2 Rs, -N(Rrn)S(=O) 2 NRnRS, -NRnC 2 6 alky]NRnR', -NRrnC 2 -alkylOR' and 7NR M C 2 -6alkylOR m wherein R 4 is not unsubstituted phenyl; R 7 is C 2 6 alkyl, C 1 5 hal oalkyl, I .or Br; R 9 is independently, at each instance, H,.Cl-galkyl, C14haloalkyl, halo, nitro, cyano, -0C 1 4 jaIkyl, -0-Ci 4 haloalkyl, -O-CI. 6 a~kyNR m R m 0OC 1 6 a1 kyIO~ m -NR m -NR m -C 1 4 haloalkyl, -NR m -C 1 -salky1NR m R m or -NR m -C 1 6 alkylOR m Y is NH; and Z is CR'or N. 598- 173. The manufacture of a medicament for the treatment of acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder N, disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyneralgesia and N, allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, bums, allergic skin reactions, pruritis, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders, wherein the medicament contains a compound having the structure: R 3 R 3 RR4 R 2 X wherein: X is O, S or NR; n is independently; at each instance, 0, 1 or 2; o is independently, at each instance, 0, 1, 2 or 3; Rm is independently at each instance H or R"; R" is independently at each instance Cl.galkyl, phenyl or benzyl; .R q is independently in each instance H, Ci- 4 alkyl, Ci4haloalkyl, halo, cyano, nitro, -C(=O)NRmR m -C(=NR m )NR m R m -OR m -OC(=O)NR m R m -OC(=O)N(R m 2 R, -OC 2 -6alkylNRR m -OC2-6alkylOR m -SR m 2 2 NR m R m S-S(=O) 2 N(R m 2 N(R m 2 N(R m )C(=O)NR m R m -NR m R m -N(R m -N(R m -N(Rm)C(=O)NR"Rm, 599 -N(R m )C(=NqR m )NR m R m -N(R m 2 R n, -N(Rm)S(=O) 2 NR m R m -NR m C 2 6 alkylNR-R' or -NR m C 2 6 alkylOR m Rs is R n substituted by 0, 1, 2 or 3 substituents independently selected from R R 3 is H or C 1 4 alkyl; R 5 is H, C,. 9 alkyl, CI. 4 haloalkyl, halo, nitro, cyano, -0CI. 6 alkyl, -0-Cl.4haloalkyl, -0-C- 6 a1 kylNR m -O-C 1 6 alkylOR m -NR m R m -NR m -C 1 Ahaloal kyl, -NR m -Cl 6 alkylNR m -NR m -C 1 6 alkyl0Rm, or -(CH 2 )nR' R 6 is, independently at each instance, H, Cl- 9 alkyl, C 1 4 haloalkyI, halo, nitro, cyano, -0CI 1 6 alkyl, -0-C 1 4 haloalkyl, -0-C 1 6 alkylNR m R m -0-C 1 6al kyl OR m -NR m -NR m -C 1 4 haloalkyl, -NR m -C 1 6 alkylNR m R' or -NR m 6 alkylOR m R 8 is H, C 1 9 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -OC 1 6 alkyl, -0-C 1 4 haloalkyl, -0-C 16 alkylNR m R m -0-C 1 6 alkylOR"', -NR m R m -NR m -C 1 -4haloalkyl, -NR m -C 1 6 alkyINR m R' or -NR m -C 1 -6alkyl0R'; and R' is R 6 R 8 (CRqRq )oRO *R 2 is H, -OR m halo, CI.. 3 haloalkyl or C 1 -6alkyl; *R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and'S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected* from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C 1 .Salkyl, C 1 4 haloalkyl, halo, cyano, nitro, -C(=0)NRR m -C(=NR m )NR m R m -OR m -OC(=0)NRR m -0C(=0)N(R m 2 -0C 2 6 alkylNR m R m -OC 2 6 akylOR m -SR- m 2 2 NR m R m S(=01 2 1N(R m S=)NR)(O0~ 600 2 N(R m )C(=0)NR m R m 4PN'R~m -N(RmI)C(=0)Rn, -N(R m -N(R m -N(R m )C(=NR m )NR m -N(R m 2 R -N(R m 2 NR m R" m -NR m C 2 .talkylNR m Rrf, -NR m C 2 6al kyIOR m C(=0)Rs, -C(=0)0Rs, -C(=0)NRnR', -C(=Rn)NRfRrn, -ORs, -OC(=0)NRnRs, -0C(=0)N(Rn)S(=0) 2 -0C 2 6 alkylNRnR', -0C 2 6 alkyl0R', 2 Rs, 2 NRnRs, 2 N(Rrn)C(=0)R', 2 N(Rr)C(=0)0Rs, 2 N(Rrn)C(=0)NRnRs, -NRrnRs, N(Rr)C(0O)Rs, -N(Rr)C(=0)QRs, -N(Rrn)C(=0)NRRs, -N(Rrn)C(=NRn)NRnRs, -N(Rrn)S(=O) 2 -N(Rrn)S(=0) 2 NRnRs, -NR m C 2 -6alkylNRnR', -NRrnC 2 6 alkyI0Rs and C 1 4 alkyl substituted by 1 or 2 groups selected from C,- 2 haloalkyl, halo, cyano, nitro, -C(=O)0R n, -C(=0)NR m R m -C(=NR m -OR m -OC(=O)NR m -OC(=O)N(R m 2 -OC 2 -6alkylNR m R', -0C 2 6 a1 kylOR m -SR' m 2 2 NTR m R', 2 N(R m n, 2 N(R m )C(=0)0R n, 2 N(R" m )C(=0)NR m R m -NR m R m -N(R m n' -N(R m )C(=O)OR n, -N(R m )C(=O)NRm 1 R m -N(R m )C(=NR m )NR m R m -N(R m 2 -N(R m )S 2 NR n'R', -NR M C 2 6 alkyINR m R m -C(=0)0Rs, -C(=NRn)NRnRs, -OWs, -OC(=O)Rs, -OC(=O)NRnR', -OC(=O)N(Rn)S(=O) 2 OC 2 6 alkylrNRs, -0C 2 6 al kylOR', .SRs, 2 2 NRnR', 2 N(Rrn)C(=O)Rs, 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=O)NRnRs, -NRrnR', -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRnRs, -N(Rrn)C(=NRn)NRnRs, NCRr)S(=0) 2 Rs, -N(Rrn)S(=0) 2 P~(rns -NR M C 2 -6alkylNRnRs, -NR m C 2 -6alkylORs and -NR M C 2 -6alkyJOR'; and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups; R 7 is C1. 9 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -0C 1 -6alkyl, -0-Cl 4 haloalkyl, -0-C 1 6 a1 kylNR m R m 1 6 alkylOR m -NR m R m -NR m -C 1 4 haloal kyl, -NR m -C 1 6alkylNR m R m or -NR m -C 1 ralkylOR m R* is a saturated, partially-saturated or unsaturated 6- or 7-membered monocyclic or 10- or 11 1-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, 0 and S, so long as the combination of 0 and S* atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0, 1 or 601 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from RP; RP is independently at each instance C 1 8 alkyl, C 1 -4haloalkyl, halo, cyano, nitro, n, -C(=O)OR n, -C(=-O)NR m -C(=NR m )NR m -OC(=O)N(R m 2 -OC 2 -6alkylNR m R m -0C 2 6 alkylOR m -SR m 2 2 NR m R', 2 N(R m 2 N(R m )C(=O)OR n, 2 N(R m )C(=O)NR m R', -NR m -N(R m -N(Rm~)C(=O)ORn, -N(R m )C(=O)NR m R m -N(R m )C(=NR m )NR m R m -N(R m )S(=O0) 2 -N(R m 2 NR m R m -NR'C 2 6 alkyINR m or -NR m C 2 6 alkylOR m and Y is 0 or NI-; or R' is R7R 5 W 7 N (C Rq Rq)RO or (CRqRq) 0 RO R 2 is H, -OR m halo, C 1 3 haloalkyl or C 1 6 alkyl; R 4 is a saturated or unsaturated 5- or 6-membered fing containing 0, 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atomn bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from CI-salkyl, C 1 4 haloalkyl, halo, cyano, nitro, n, -C(=O)OR n, -C(=O)NR m R m -OR m -OC(=O)Rn, -OC(=O)NR m R m -OC(=O)N(R m )S 2 -OC 2 6 a~kyINR m -OC 2 6 alkylOR"', 2 R 2 2 N(R m -S 2 N(R m )C(=O)OR, 2 5 2 N(R m )C(=O)NR- m -NR m R m n, -N(R m )C(=O)ORn, m R m -N(R m )C(=NRm T -N(R m 2 R", -N(Rm)S 2 NR -NR m C 2 6 alkylNR"'R m -NW m C 2 -al kylOR"', -C(=O)Rs, ~C(O)Os, C( O)N4!RnRs;--.C(NRn)NRnRs O, t.(OR. 1- 602. .1 -0C(=0)NRnRs, .0C(0)N(Rn)S(=o) 2 Rs, -OC 2 -6alkylNRnRs, OC 2 -6alky10RS, -SRs, 2 Rs, 2 NRnR', 2 N(Rrn)C(=0)Rs, 2 N(Rr)C(=0)0Rs, 2 N(Rrn)C(=0)NRnRs, -N~rn's -N(Rr)C(=0)Rs, -N(Rr)C(=0)0Rs, -N(Rrn)C(=0)NRnRs, -N(Rrn)C(=NRn)NRnRs, -N(Rrn)S(=O) 2 Rs, -N(Rrn)S(-%Q)hNRnR', -NRnC 2 6 alkyiNRnRs, -NRnC 2 6 alkyl0Rs and C 14 alkyl substituted by I or 2 groups selected from C 1 2 haloalkyl, halo, cyarlo, nitro, -C(=0)NR m R m -C(=NR m )NR m R'm, -OR m -OC(=O)Rn, -OC(=O)NR m -OC(=O)N(R m 2 R n, -OC 2 -6alky]NR m R m -OC 2 -6alky]OR m -SR m -S -S 2 2 NR m R m 2 N(R m n, 2 N(R m )C(=O)OR n, 2 N(R m )C(=O)NR m R m -NR m R m n'-N(R t -N(R m )C(=O)NR m R m -N(R m )C(=NR m )NR m R m -N(R m 2 R n, -N(R m 2 NR m R m -NR M C 2 6 alkylNR m R m -C(=O)0Rs, -C(=O)NR m -C(=NRrn)NRnRs, -OW, .OC(=O)NRnRs, -OC(=O)N(R m 2 -OC 2 -6alkylNR m Rs, -OC 2 -6alkylORs, SRs, 2 Rs, 2 NRnRs, 2 N(Rrn)C(=O)Rs, 2 N(Rr)C(=0)ORs, -S 2 N(Rrn)C(=O)NRnRS, -NRrnRs, -N(Rrn)C(=O)Rs, -N(Rr)C(=-O)0Rs, -N(Rrn)C(=O)NRnRs, -N(Rrn)C(=NRn)NRnRs, -N(Rrn)S(=O) 2 Rs, -N(Rr)S(=0) 2 NRnRs, -NR tm C 2 6 alky]NRrnR, -NRrnC 2 alkylORs and -NR m C 2 -6alky1OR'; and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups; R 7 is C 19 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -OCI 1 6 alkyl, -0-C 1 4 haloalkyl, -0-C .6al kylNR"'R m -0-C 1 6al kylOR m -NR m R m K -NR m -CI-4haloal kyl, -NR m -C 1 6 alkylNR m R m or -NR m -CI-6alkylOR m R 0 is a saturated, partial ly-saturated or unsaturated 6- or 7-membered monocyclic or 10- or 1 1-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, 0 and S, so long as the combination of 0 and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from RP; RP is independently at each instance CI-8alkyl, Cl- 4 haloalkyl, halo, cyano, nitro, -C(=0)NR m R m -C(=NR m )NR m -OR m -OC(=O)NR m OC(= )N(R7hS(=OhR n -OC-2.alkylNR m 603 -0C 2 6 alkylOR', 2 NR m R m 2 N(R m n, 2 N(R m 2 N(R m )C(=O)NR m -NR m -N(R m n, -N(R m )C(=O)OR n, m R', -N(R m )C(=NR m )NR m 2 -N(R m )S(=O0) 2 NRrnR m -NW m C 2 _6alky1NR m R m or -NR'C 2 6 alkylOR'; and Y is 0or NHI;or R' is R 2 is H, -OR m halo, CI- 3 haloalkyl or C 1 6 alkyl; R 4 is a saturated, partially-saturated or unsaturated 10 or 1 1-membered bicyclic heterocycle containing 1, 2, 3, 4 or 5 atoms selected from 0, N and S, so long as the combination of 0 and S atoms is not greater than but excluding qui nol in-6-yl, 4,5,6,7-tetrah ydro-benzo[b] thiophen-2-yl, benzothi azol- 2-yl, 2,3-dihydro-benzo[1,4]dioxin-6-yI, wherein the heterocycle is substituted by 0, 1,2 or 3 substituents independently selected from Cl-galkyI, oxo, C 1 4 haloalkyl, halo, nitro, cyano, -OR m -S(=O)nCi-(alkyl, -O-C 1 4 haloalkyl, -O-C 1 6 alkyINR m R m -0C. 6 a1kyplORm, -NR m -NR m -C 1 Ahaloalkyl, -NR m -C 1 6 alkylNR m R m -NR m -C,6al kylOR m 1 6 alkyl, -OG(=O)CI-6al kyl, -C(=O)NR'C 1 6 alkyl, -NR m C(=0)C 1 6 alkyl -C(=O)ORs, -C(=O)NRnRs, -C(=NRrn)NRnRs, OC(0O)Rs, -OC(=O)NRnRs, -OC(=O)N(Rrn)S(=O) 2 Rs, -OC 2 6 a~kylNR m Rs, -OC 2 6 alkylORs, -SRs, 2 Rs, 2 N(Rrn)C(=O)R', -S(=0)N(Rn)C(.O)ORs, 2 N(Rrn)C(=O)NRnR', -NR'IR', -N(Rrn)C(=O)Rs, -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRnlRs, -N(Rrn)C(=NRn)NRnRs, -N(Rrn)S(=O) 2 Rs, -N(Rr)SQO) 2 NRnRs, -NR'~C 2 6 alkylNRrnRs, -NR m C 2 6 alkylORs and CI- 4 alkyI substituted by 1 or 2 groups. selected from CI.2haloalkyl, halo, cyano, nitro, n, -C(=O)NR m nR m -C(=NRml)NR m -OR m -OC(=O)NR m R m -OC(=O)N(R m 2 -0C 2 6 a1 kylNR m -0C 2 6 a1 kyIOR m -604- -S(=Oh2R", 2 NR m 2 N(R m 2 N(R m )C(=O)OR, 2 N(R')C(=O)NR m -N(R m -N(R m )C(=O)OR, -N(Rrn)C(=O)NRlRrn, -N(R m )C(=NR m )NR m -N(R m 2 R', -N(Rm)S(=O) 2 NRnR, -C(=O)ORs, -C(=O)NRnRs,. 7C(=N'Mm)N',RRs, -ORs, -OC(=O)Rs, -OC(=O)NRnRs, -OC(=QO)N(Rrn)S(=O) 2 Rs, OC 2 6 alky1NRnRs, -OC 2 6 alkylQR', -SRS, S(=o)Rs, 2 Rs, 2 NRrnR', 2 N(R m -S(=O0) 2 N(Rrn)C(=O)ORs, -S(=O)2N(Rrn)C(=O)NRnRs, -NRrnRS, -N(Rrn)C(=O)ORs, -N(Rrn)Q(=O)NRrnRs, -N(Rrn)C(=NRn)NRnRs, -N(Rrn)S(=O) 2 Rs, -N(R M 2 NR m R', -NRnC 26 alkyINRnR', -NRrnC 2 -6I alky1ORs and -NR m C 2 6a~ky1OR'; wherein R 4 is not 2-aminocarbonylmethyl-2,3-dihydro-belzo[ 1,4]dioxin-8-yl, 2-cyanomethyl- 2,3-dihydro-benzo[ll,4]dioxin-8-yl, quinolin-3-yl, 3H-quinazolin-4-on-3-yl, benzo 1 ,3]dioxol-5-yl, 3 ,3-dimethyl- I ,3-dihydro-indol-2-on-6-yl or 4,4-dimethyl 3 ,4-di hydro- 1H-quinolin-2-on-7-yl; R 7 is CI-8alkyl, C 1 5 haloalkyl, I or Br R 9 is H, C 1 9 galkyl, C 1 4 haloalkyll, halo, nitro, cyano, -OC 1 -6alkyl, -O-C 1 4 haloalkyl,' -0-C 16 alkylNR m -0-C 1 6 alkylOR', -NR m R m -NR m -C 4 haloalkyl, -NR m -C 1 6 alkyINR m R m -NR"'-C 1 6alky10R', or -(CH 2 )nRC; R 9 is independently, at each instance, H, Cl. 9 alkyl, C 1 4 haloalkyl, halo, nitro, cyano, -0C 1 6 alkyl, -0-C 1 4 haloalkyl, -0-C 1 6 alkylNR m R', -0-C. 6 alkylOR', -NR m -NIR m -C 1 4haloalkyI, -NR m -C 1 6alkyI.NR m R' or -NR m -CI- 6 alkyIOR'; Y is NHl; and Z is CR 8 or N; or R' Is R 9 Ris C 1 -6alkyl substituted by 1, 2 or 3 substituents selected from e.1.. 605 C,- 4 haloalkyl, halo, cyano, nitro, -C(=O)OR n, -C(=O)NR m R', -C(=NR m )NR m nR m -OC(=O)Rn, -OC(=O)NR m R -OC(=O)N(R m 2 -OC 2 -6al kylNR m R m -OC 2 -6alkyIOR m -S 2 R 2 NR m R m -S 2 N(R m 2 2 N(R m )C(=O)NR m R m -NR m R m -N(R m -N(R m -N(R m )C(=O)NR m R m -N(R m )C(=NR m )NR'R m -N(R m 2 R', -N(R m 2 NR m R m -NR m C 2 6 alkylNR m or -NR m C 2 6 alky]OR m or R 2 is q) 2 0 phenyl, wherein the phenyl. is substi tuted by0, 1, 2or 3 substituents independently selected from CI-8alkyI, C 1 4 haloalkyl, halo, cyano, nitro, -C(=O)OR n, -C(=O)NR m R m -C(=NR m )NR m R m -OR m -OC(=O)NR m R m -OC(=O)N(R m 2 R n, -OC 2 -6alkylNR m R m -0C 2 6 alkylOR', -SR m n, 2 Rn, 2 NR m R m 2 N(R m 2 N(R m 2 N(R m )C(=O)NR m R m -NR m -N(R m -N(R m )C(=O)NTR m R', -N(R m )C(=NR m )NR m -N(R m 2 -N(R m 2 NRm'~R, -NR'C 2 6 alkylNR m -NR m C 2 6 alkyIOR m -C(=-O)ORs, -C(=O)NRnRs, -C(=NRn)NRnRs, ORs, -OC(=O)NRnRs, -OC(=O)N(Rrn)S(=O) 2 -OC 2 6 alkylNRnR', -OC 2 -6alkyIOR', -SRs, -S(=O0) 2 2 rNRsR' 2 N(Rrn)C(=O)R', 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=O)NRnRs -NRrnRs, -N(Rr)C(0O)Rs, -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRnR', -N(Rrn)C(=NRrn)NRnRs, -N(Rrn)S(=O) 2 Rs, 2 NRrnRs, -NRnC 2 -6alky]NRnRs, -NR m C 2 -6alkylORs and C 1 -4alkyl substituted by I or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=O)ORn, -C(=O)NR m -C(=NRrn)NR m R m -OR m -OC(=O)R, -OC(=O)NR m -OC(=O)N(R m 2 R n, -OC 2 -6alkylNR m -OC 2 -6alkylOR m 2 R 2 2 N(R m 2 N(R')C(=O)OR n, 2 N(R m )C(=O)NR m R m -N(R m -N(R m -N(R m )C(=NR m -N(R m 2 R n, -N(R m 2 NR m R m -NR"'C 2 6 alkylNR m R m -C(=O)NRnR', -C(=NR n )NRm~R', -ORs, -OCQ=O)R, OC(=O)NRmlR', -OC(=O)N(Rn)S(=O) 2 Rs, -OC 2 -6alkyNRnR', -OC 2 6 alky]OR',-.SRs. O)RS, 2 R 5 .S(=O)NRnRs, -606.- 2 N(Rrn)C(=O)Rs, 2 N(Rrn)C(=O)ORs, -S(=O0) 2 N(Rrn)C(=O)NRnR -NRrnR', -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRnRs, -N(Rrn)C(=NRn)NRnRs, -N(Rrn)S(=O) 2 Rs, -N(Rrn)S(=O) 2 NRnlR', -NRnC 2 -6alkylNIrnRs, -NRrnC 2 alkylOR' and -NR m C 2 -6alkylOR'; or R 2 is _(C(Rq 2 wherein R' is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, 0 and S, wherein no more than 2 of the ring members are 0 or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2.or 3 substituents independently selected from C 1 .salkyl, C 1 4 haloalkyI, halo, cyano, nitro, -C(=0)OR -C(=0O)NrR m R m -C(=NRm)NR m R m -O11 m -OC(=0)R n, -OC(=0)NR m R', -0C(-=0)N(R m 2 -0C 2 6 alkylNR m R m -OC 2 6 alkyIOR', -SR m 2 2 4R m R m 2 N(R m 2 N(R t )C(=0)0R, 2 N(R m )C(=0)NR m -NR m -N(R m -N(R m )C(=O)0R, -N(R m )C(=0)NR m R, -N(R m )C(=NR m )NR m -N(R m 2 R, -N(R m 2 NR m -NR'C 2 -6alkylNR m -NR m C 2 6 alkylOR m -C(=O)0Rs, -C(=O)NRrnRs, -C(=NRrn)NRrnRs, -ORs, -OC(=O)Rs, -OC(=0)NRnR', -OC(=0)N(Rrn)S(=0) 2 -OC 2 6 alkyNRnR', -OC 2 6 alkylORs, 2 Rs, 2 NRrnRs, 2 N(Rrn)C(=O)Rs, 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=O)NRnRs, .IPRrRs, -N(Rr)C(=0)Rs, -N(Rr)C(=0)ORs, -N(Rrn)C(=O)NRnR', -N(Rrn)C(=NRn)NRrnRs, -N(Rrn)S(=0) 2 -N(Rrn)S(=0) 2 NRnR', -NRrnC 2 -alkylNRnRs, -NRrnC 2 -alky1OR' and CI4alkyI substituted by I or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=O)0R n, -C(=0)NR m R m -C(=NR m )NR m R m -OR m -OC(=0)NR m R m -OC(=O)N(R m 2 R n, -OC 2 .falkylNR m R m -OC 2 6 alkyI0R'", -SR m 2 2 NR m R m 2 N(R m n, 2 N(R m 2 N(R m )C(=0)NR m R', -NR m -N(R t n, -N(R t -N(R tm )C(=O)NR m R m -N(R tm )C(=NRn)NRnRml, -N(R m 2 -N(R m 2 NR m R m -NR tm C 2 6 alkyNR m R m .C(0)ORs,-C(=0)NRRs *-C(=NRrn)NRrnRs,- -OW, -OC(=O)Rs, 0OC(=OflNfll' -OC(=O)N(Rmn)S(=O) 2 Rs, -OC 2 6 alkylNRrnRs, 607 2 N(Rrn)C(=O)R', 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=O)NRR', -NR'fl' N(Rr)C(=o)Rs, .N(Rr)C(0O)ORs, -N(Rrn)C(=O)NRnR', -N(Rml)C(=NRrn)NRnRs, -N(Rrn)S(=O0) 2 Rs, -N(R m )S 2 NRnRS, -NRrnC 2 -alkylNRrnRs, -NR M C 2 -6alkylORs and -NR M C 2 -6alkylOR m R 4 is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from 0, N and S with the remaining atoms being carbon, so long as the combination of 0 and S atoms is not greater than 2, wherein the ring and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from Ci.salkyl, CI-4haloalkyl, halo, cyano, nitro, n, -C(=O)0Rn, -C(=O)NR m R', -C(=NR m )NR m -OR' m -OC(=O)R n, -OC(=O)NR m R m -OC(=O)N(R m 2 R -0C 2 6 alky]NR m -OC2- 6 a1 kylOR m -SR m 2 2 NR m R m -S 2 N(R m 2 N(R m )C(=0)OR, 2 N(R m )C(=O)NR m -NR m -N(R m -N(R m )C(=O)OR, -N(R m )C(=O)NR m R m -N(R m )C(=NR m )NRmR m -N(R m )S 2 R, -N(R m 2 NR m R m -NR m C 2 6 alkyl NR m R m -NR m C 2 -6alkylOR m -C(=O)Rs, -C(=O)NRnR', -C(=NRn)rNRsR ORs, .0C(0)Rs, -OC(=O)NRnR', -OC(=O)N(R n)S(=0) 2 -OC 2 _6alkylNRnRs, -OC 2 6 alkylORs, -SRs, 2 Rs, 2 NRmlRs, 2 N(Rrn)C(=O)Rs, 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=O)NRnR', -NRmlRs, -N(Rr)C(0)Rs, -N(R m )C(=O)0R 5 -N(R m -N(Rrn)C(=NRml)NRnRs, -N(Rrn)S(=O) 2 -N(Rrn)S(=O) 2 NRnRs, -RmC 2 6alkylNrnRs, -N.RrnC 2 alkylORs_ and CI- 4 alkyl substituted by I or 2 groups selected from C 1 2 haloalkyl, halo, cyano, nitro, -C(=O)NR m -C(=NR m )NR m R m -OR m -OG(=O)R n, -OC(=O)NR m R m -OC(=O)N(R m 2 -0C 2 6 alkyNR m R m -OC 2 -6alkylOR m -SR m n, 2 -SC=O0) 2 NR m R m 2 N(R m 2 N(R m 2 N(R m )C(=O)NR'R M -NR m -N(R m -N(R m -N(R m )C(=O)NR m R', -N(R m )C(=NR m )NR m R m -N(Rml)S(=O) 2 -NR)(')Nmm -NR m C 2 6 a1 kylNR m CONrnsc(n)lns -ORS,.-O C(0)RS, -OC(0)NRnRs, -OG(=O)N(Rrn)S(=O) 2 Rs, -OC 2 6 lkylNpRn~s, 608 -OC 2 6 alky]OR', 2 Rs, -S(O) 2 NRnRs, 2 N(Rr)C(=0)Rs, 2 N(Rrn)C(0O)ORs, 2 N(Rrn)C(=O)NRnRsV -NRrnRs, -N(Rrn)C(=O)Rs, -N(Rr)C(=O)ORs, -N(Rrn)C(=O)NRR', -N(R m )C(=NR m )NR m Rs, -N(Rrn)S(=O) 2 RS, -N(Rrn)S(=O) 2 NRrnRs,. -NmC 2 6 akylNRnR' -NRrnC 2 4 alkyl0R' and -NR M C 2 -6a~kyl0R m and the ring and bridge carbon atoms are substituted with 0, 1 or 2 =0 groups; R 7 is C 2 .galkyl, C 1 5 haloalkyl, 1, Br; R 9 is independently, at each instance, H, C 19 galkyl, C 1 -4haloalkyI, halo, nitro, cyano, -OC 1 -6a~kyl, 4 haloalkyl, -0-C 1 6 alkylNR m R m -0-C -6alky]OR', -NR m -C 1 4 haloalkyl, -NR m -C 1 4 ialkylNR m R m or -NR m -C 14 salky]OR'; Y is NH; and Z is CR or N;or R' is R 9 R 2 is H, -OR- m Cl, C 1 3 haloalkyl or C 1 6 alkyl; R 4 Is a saturated or unsaturated 5- or 6-membered ring containing 0, 1, 2 or 3 atoms selected from 0, N and S, so long as the combination of 0 and S atoms is not greater than 1, wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from CI-8alkyl, C14haloalkyl, halo, cyano, nitro, -C(=O)NR m R m -C(=NR m )NR m R m -OR n, -OC(=O)R n, -OC(=-O)NR m R m -OC(=O)N(R m 2 -OC 2 6 alkylOR', -SR m 2 R, 2 NR m 2 N(R m -S 2 N(R')C(=O)OR" 2 N(R"')C(=O)NR m R m -NR m R m -N(R m t -N(R m )S(=Oh)R 2 -NR"'C 2 6 aIkylNR"'RR', -NR"'C 2 _6alkylOR m -C(=O)ORs, -C(=O)NRnRs, -C(=NRn)NRm~Rs, -ORs, OC(=O)Rs,. -0C(=Q)N]RRs, -OC(0)N(R m )S 2 Rs, -OC 2 6 alkyIN~mgs,. OC 2 6 alkyIORs, 609 S(=O) 2 Rs, -S (=O)2NRRS, SO)NR)COR, 2 N(Rrn)C(=O)ORs, 2 N(Rrn)C(=O)NRn)R', NRnRs, -N(Rrn)C(=O)Rs, -N(Rrn)C(=O)ORs, -N(Rrn)C(=O)NRmfRS, -N(Rrn)C(=NRn)NRnR', -N(Rrn)S(=O) 2 .NQ(R)S(=O) 2 NRrnRs -NR M C 2 6 aIky]NRnRs, -NR M C 2 6 alkylORs and C 1 4 alkyl substituted by I or.2 groups selected from CI- 2 haloalkyl, halo, cyano, nitro, -C(=O)NR m -C(=NR m )NR m -OR' m -OC(=O)NRm'R m 2 R n, -0C 2 6 alkylNTR m R m -OC 2 6 alkylOR', -SR m n, 2 2 NR"'R m 2 N(R m 2 2 N(R m -NR-R m n, -N(R m -N(R m )C(=O)NR m R', -N(R m )C(=NR m )NR m R m -N(R m 2 R n, -N(R m 2 NR m R', -NR m C 2 6 alkylNR m R m -C(0)ORs, -C(=O)NRnR', -C(=NRrn)NRnRs, -OC(=O)Rs, -OC(=O)NRnR', .0C(=O)N(Rrn)S(=0) 2 Rs, -OC 2 -6a~kyNR m Rs, -OC 2 -6alky1OR', 2 NRnRs, -S(=O0) 2 N(Rrn)C(=O)Rs, 2 N(Rrn)C(=O)ORs, 2 N(Rr)C(=O)NRnR', -NRrnRs, -N(Rrn)C(=O)Rs, -N(Rrn)C(=O)OR.s', 'N(Rrn)C(=O)NR-nRs,- -N(Rrn)C(=NR')NRnR', -N(Rrn)S(=O) 2 -N(Rn)S(=0) 2 PRRs, -NRrnC 2 6 alkylNRnR', -NR m C 2 -6alkylORs and -NR'C 243 alkylOR m wherein R 4 is not unsubstituted phenyl; R. 7 is C2- 6 alkyl, C 1 5 haloalkyI, I or Br; R 9 is independently, at each instance, H, Cl-galkyl, C1. 4 haloalkyl, halo, nitro, cyano, -0C 1 6 a~kyl, -O-Cl~haloalkyl, -0-C 16 alkyINR m R', -0-C 1 6 a1 kylOR m -NR" 1 -NR m -C 1 4 haloalkyl, -NR m -C 1 .6a1 kylNR m R m or -NR m -C 1 6alkylOR m n; Y is NH; and Z is CRS or N. 174. A pharmaceutical composition comprising a compo .und according to any one of Claims 1-168 and a pharmaceuticallIy-acceptable diluent or carrier.