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AU2005289881A1 - Substituted sulfonamidopropionamides and methods of use - Google Patents

Substituted sulfonamidopropionamides and methods of use Download PDF

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AU2005289881A1
AU2005289881A1 AU2005289881A AU2005289881A AU2005289881A1 AU 2005289881 A1 AU2005289881 A1 AU 2005289881A1 AU 2005289881 A AU2005289881 A AU 2005289881A AU 2005289881 A AU2005289881 A AU 2005289881A AU 2005289881 A1 AU2005289881 A1 AU 2005289881A1
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nrara
amino
sulfonyl
butanamide
tetrahydro
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AU2005289881A
Inventor
Jr. Ben C. Askew
Toshihiro Aya
Kaustav Biswas
Guolin Cai
Jian Jeffrey Chen
Christopher H. Fotsch
Nianhe Han
Jason Brooks Human
Aiwen Li
Qingyian Liu
Tanya Peterkin
Wenyuan Qian
Babak Riahi
Chester Chenguang Yuan
Jiawang Zhu
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Amgen Inc
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Amgen Inc
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/36—Sulfur atoms
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    • C07D233/20—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
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    • C07D275/06—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/68—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with nitrogen atoms directly attached in position 4
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    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

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  • Agricultural Chemicals And Associated Chemicals (AREA)

Description

WO 2006/036664 PCT/US2005/033659 SUBSTITUTED SULFONAMIDOPROPIONAMIDES AND METHODS OF USE BACKGROUND OF THE INVENTION 5 Field of the Invention This invention is in the field of pharmaceutical agents and specifically relates to compounds, compositions, uses and methods for treating inflammation-related disorders, including pain. 10 State of the Art More than two million people in the United States alone are incapacitated by chronic pain on any given day (T. Jessell & D. Kelly, Pain and Analgesia in PRINCIPLES OF NEURAL SCIENCE, third edition (E. Kandel, J. Schwartz, T. Jessell, eds., (1991)). Unfortunately, current treatments for pain are only partially effective, and many cause lifestyle 15 altering, debilitating, and/or dangerous side effects. For example, non-steroidal anti inflammatory drugs ("NSAIDs") such as aspirin, ibuprofen, and indomethacin are moderately effective against inflammatory pain but they are also renally toxic, and high doses tend to cause gastrointestinal irritation, ulceration, bleeding, increased cardiovascular risk, and confusion, Patients treated with opioids frequently experience confusion and constipation, and 20 long-term opioid use is associated with tolerance and dependence. Local anesthetics such as lidocaine and mixelitine simultaneously inhibit pain and cause loss of normal sensation. In addition, when used systemically, local anesthetics are associated with adverse cardiovascular effects. Thus, there is currently an unmet need in the treatment of chronic pain. Pain is a perception based on signals received from the environment and transmitted 25 and interpreted by the nervous system (for review, see M. Millan, Prog. Neurobiol. 57:1-164 (1999)). Noxious stimuli such as heat and touch cause specialized sensory receptors in the skin to send signals to the central nervous system ("CNS"). This process is called nociception, and the peripheral sensory neurons that mediate it are nociceptors. Depending on the strength of the signal from the nociceptor(s) and the abstraction and elaboration of that signal by the CNS, 30 a person may or may not experience a noxious stimulus as painful. When one's perception of pain is properly calibrated to the intensity of the stimulus, pain serves its intended protective function. However, certain types of tissue damage cause a phenomenon, known as hyperalgesia or pronociception, in which relatively innocuous stimuli are perceived as intensely painful because the person's pain thresholds have been lowered. Both inflammation 1 WO 2006/036664 PCT/US2005/033659 and nerve damage can induce hyperalgesia. Thus, persons afflicted with inflammatory conditions, such as sunburn, osteoarthritis, colitis, carditis, dermatitis, myositis, neuritis, inflammatory bowel disease, collagen vascular diseases (which include rheumatoid arthritis and lupus) and the like, often experience enhanced sensations of pain. Similarly, trauma, 5 surgery, amputation, abscess, causalgia, collagen vascular diseases, demyelinating diseases, trigeminal neuralgia, cancer, chronic alcoholism, stroke, thalamic pain syndrome, diabetes, herpes infections, acquired immune deficiency syndrome ("AIDS"), toxins and chemotherapy cause nerve injuries that result in pain. As the mechanisms by which nociceptors transduce external signals under normal and 10 hyperalgesic conditions become better understood, processes implicated in hyperalgesia can be targeted to inhibit the lowering of the pain threshold and thereby lessen the amount of pain experienced. Bradykinin (BK) and the related peptide, kallidin (Lys-BK) mediate the physiological actions of kinins on the cardiovascular and renal systems. However, the active peptides, BK 15 and kallidin, are quickly degraded by peptidases in the plasma and other biological fluids and by those released from a variety of cells, so that the half-life of BK in plasma is reported to be approximately 17 seconds (1). BK and kallidin are rapidly metabolized in the body by carboxypeptidase N, which removes the carboxyterminal arginine residue to generate des-Arg BK or des-Arg kallidin. Des-Arg-kallidin is among the predominant kinins in man and 20 mediate the pathophysiological actions of kinins in man. In addition to being a very potent proinflammatory peptide, des-Arg-BK or des-Arg-kallidin is known to induce vasodilation, vascular permeability, and bronchoconstriction (for review, see Regoli and Barabe, Pharmacological Rev, 32(1), 1-46 (1980)). In addition, des-Arg-BK and des-Arg-kallidin appear to be particularly important mediators of inflammation and inflammatory pain as well 25 as being involved in the maintenance thereof. There is also a considerable body of evidence implicating the overproduction of des-Arg-kallidin in conditions in which pain is a prominent feature such as septic shock, arthritis, angina, and migraine. The membrane receptors that mediate the pleiotropic actions of kinins are of two distinct classes, designated B 1 and B2. Both classes of receptors have been cloned and 30 sequenced from a variety of species, including man (Menke, et al, J. Biol. Chem. 269, 21583 21586 (1994); Hess et al, Biochem. Biophys. Res. Commun. 184, 260-268 (1992)). They are typical G protein coupled receptors having seven putative membrane spanning regions. In various tissues, BK receptors are coupled to every known second messenger. B2 receptors, which have a higher affinity for BK, appear to be the most prevalent form of bradykinin 2 WO 2006/036664 PCT/US2005/033659 receptor. Essentially all normal physiological responses and many pathophysio-logical responses to bradykinin are mediated by B2 receptors. B 1 receptors, on the other hand, have a higher affinity for des-Arg-BK compared with BK, whereas des-Arg-BK is inactive at B2 receptors. In addition, B 1 receptors are not 5 normally expressed in most tissues. Their expression is induced upon injury or tissue damage as well as in certain kinds of chronic inflammation or systemic insult (F. Marceau, et al., Immunopharmacology, 30, 1-26 (1995)). Furthermore, responses mediated by BI receptors are up-regulated from a null level following administration of bacterial lipopolysaccharide (LPS) or inflammatory cytokines in rabbits, rats, and pigs. 10 The pain-inducing properties of kinins coupled with the inducible expression of B 1 receptors make the B 1 receptor an interesting target in the development of anti-inflammatory, antinociceptive, antihyperalgesic and analgesic agents that may be directed specifically at injured tissues with minimal actions in normal tissues. Certain compounds have been described as bradykinin antagonists. WO 03/07958, 15 published 30 Jan. 2003, describes tetrahydroquinoxalines. Dihydroquinoxalinones are described in a JACS communication. Piperazine-2,3,5-triones are described in Tet. Lett., 40, 7557-7560 (1999). European application 641779, published 8 Mar. 1995, describes 3,6-dioxopiperazines as platelet aggregation inhibitors. 20 Clearly, there is a need for new, safe and effective treatments for inflammation and pain. Such agents are provided in the present invention. DETAILED DESCRIPTION OF THE INVENTION In one aspect, this invention is directed to a class of compounds useful in treating 25 inflammation and pain and having the structure of Formula (I):
R
3 Rib R1c R 4 I I R2_-SN N-R5 0 2 R1 Rla O (I) wherein: 30 R' is selected from H, cyano, -C(O)OC 1
.
8 alkyl, -C(O)OH, -C(=O)NRaRa, or -CI.alkyl substituted by 0, 1, 2, or 3 groups independently selected from R', cyano, oxo, nitro, -C(=O)Rb, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Ra, -OC(=O)NRaRa, 3 WO 2006/036664 PCT/US2005/033659 -OC(=O)N(Ra)S(=0) 2 R', -OC 2
.
6 alkylNRaRa, -OC 2 -salkylOR -SRa, -S(=O)Rb, -S(=O) 2 R ,
-S(=O)
2 NRaRa, -S(=0) 2 N(Ra)C(=O)Rb, -S(=O) 2 N(Ra)C(=O)ORa, -S(=O) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O) 2 Rb, -N(Ra)S(=O) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa and -NRaC 2
-
6 alkylORa, and 5 additionally substituted by 0, 1, 2, 3, 4, 5 or 6 atoms independently selected from Br, Cl, F and I; Ria and R are each independently, H, F, Cl, -OCH 3 , -CI- 2 alkyl or -CF3; RIc is H, -Ci-salkyl, -CI 4 haloalkyl, halo, cyano, nitro, -C(=O)Rb, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=0) 2 Rb, 10 -OC 2
.
6 alkylNRaRa, -OC 2
-
6 alkylORa, -SRa, -S(=O)Rb, -S(=0) 2 Rb, -S(=O) 2 NRaRa, -S(=0) 2 N(Ra)C(=O)R', -S(=O) 2 N(Ra)C(=O)ORb, -S(=O) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O) 2 Rb, -N(Ra)S(=O) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa, -NRaC 2
-
6 alkylORa, or -Ci- 6 alkyl substituted by 0, 1, 2 or 3 substituents selected from -CIAhaloalkyl, halo, cyano, nitro, 15 -C(=O)Rb, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)R, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=O) 2 Rb, -OC 2
-
6 alkylNRaRa, -OC 2 -salkylORa, -SRa, -S(=O)Rb, -S(=0) 2 Rb, -S(=0) 2 NRaRa, -S(=0) 2 N(Ra)C(=O)Re, -S(=0) 2 N(Ra)C(=O)ORb, -S(=0) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O) 2 Rb, -N(Ra)S(=O) 2 NRaRa, -NRaC 2
.
6 alkylNRaRa or -NRaC 2
-
6 alkylORa; 20 R2 is a saturated, partially saturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 1 1-membered bicyclic hydrocarbon ring containing 0, 1, 2, 3 or 4 atoms selected from N, 0 and S, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups and the ring is substituted by 0, 1, 2 or 3 substituents independently selected from R*, R9, C 1 ihaloalkyl, halo, cyano, nitro, -C(=0)Rb, -C(=O)ORb, -C(=0)NRaRa, -C(=NRa)NRaRa, 25 -ORa, -OC(=0)Rb, -OC(=0)NRaRa, -OC(=O)N(Ra)S(=0) 2 Rb, -OC 2
-
6 alkylNRaRa,
-OC
2
-
6 alkylORa, -SRa, -S(=0)Rb, -S(=0) 2 Rb, -S(=0) 2 NRaRa, -S(=O) 2 N(Ra)C(=0)Rb, -S(=0) 2 N(Ra)C(=O)ORb, -S(=O) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=0)Rb, -N(Ra)C(=0)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O) 2 Rb, -N(Ra)S(=0) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa and -NRaC 2
-
6 alkylORa, and the ring is additionally 30 substituted by 0, 1, 2, 3, 4 or 5 substituents independently selected from Br, Cl, F and I;
R
3 is H, phenyl, benzyl or -Ci- 6 alkyl, the phenyl, benzyl and -CI.
6 alkyl being substituted by 0, 1, 2 or 3 substituents independently selected from Re, R9, -C 1 4 haloalkyl, halo, cyano, nitro, -C(=0)Rb, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=0)Rb, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=0) 2 Rb, -OC 2 -6alkylNRaRa, -OC 2
-
6 alkylORa, -SRa, -S(=O)Rb, 4 WO 2006/036664 PCT/US2005/033659 -S(=0) 2 R", -S(=O) 2 NRaRa, -S(=0) 2 N(R")C(=O)Rb, -S(=0) 2 N(Ra)C(=O)ORb, -S(=0) 2 N(Ra)C(=O)NRaRa, -NaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=0) 2 R b, -N(Ra)S(=O) 2 NRaRa, -NRaC 2 -6alkylNRaRa and -NRaC 2
-
6 alkylORa, and additionally substituted by 0, 1, 2, 3, 4, 5 or 6 atom selected from Br, 5 Cl, F and I; R4 is H, phenyl, benzyl or -C 1
.
6 alkyl, the phenyl, benzyl and Ci-alkyl being substituted by 0, 1, 2 or 3 substituents independently selected from C14alkyl, Ci- 3 haloalkyl, -OCi 4 alkyl,
-NH
2 , -NHCI alkyl, and -N(CI.4alkyl)C1.4alkyl, and additionally substituted by 0, 1, 2, 3, 4, 5 or 6 atom selected from Br, Cl, F and I; 10 R5 is a saturated, partially saturated or unsaturated 8-, 9-, 10- or 11 -membered bicyclic or 12-, 13-, 14- or 15- membered tricyclic hydrocarbon ring containing 0, 1, 2, 3 or 4 atoms selected from N, 0 and S, wherein the carbon and sulfur atoms of the ring are substituted by 0, 1 or 2 oxo groups and the ring is substituted by R6, R7 or R8 independently selected from basic moieties, and additionally substituted by 0, 1, 2 or 3 substituents independently selected from 15 R6, R7 and R 8 which are selected from R9, -Ci-salkyl, -CIAhaloalkyl, cyano, nitro, -C(=0)Rb, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)R, -OC(=O)NRaRa, -OC(=0)N(Ra)S(=0) 2 Rb, -OC 2
-
6 alkylNRaRa, -OC 2 -6alkylORa, -SRa, -S(=O)Rb, -S(=0) 2 Rb, -S(=0)2NRaRa, -S(=O) 2 N(Ra)C(=O)Rb, -S(=0) 2 N(Ra)C(=0)ORb, -S(=0) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=0)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, 20 -N(Ra)S(=O) 2 Rb, -N(Ra)S(=O) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa and -NRaC 2
-
6 alkylORa, and the ring is additionally substituted by 0, 1, 2, 3, 4 or 5 substituents selected from R6, R , R', R9 and R1 0 which are independently selected from Br, Cl, F and I; wherein, R3 and R4 together may additionally be C 2
-
3 alkylene substituted by 0, 1 or 2 substituents independently selected from -CI.salkyl, -C1 4 haloalkyl, halo, oxo, cyano, nitro, 25 -C(=0)Re, -C(=0)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)R7, -OC(=0)NRaRa -OC(=0)N(Ra)S(=0) 2 Rb, -OC 2
-
6 alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)R, -S(=0) 2 R, -S(=0) 2 NRaRa, -S(=O) 2 N(Ra)C(=0)Rb, -S(=O) 2 N(Ra)C(=0)ORb, -S(=0) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=0)ORb, -N(Ra)C(=0)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=0) 2 Rb, -N(Ra)S(=0) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa and -NRaC 2
-
6 alkylORa, and 30 additionally substituted by 0, 1, 2, 3 or 4 substituents independently selected from Br, Cl, F and I; or Rlc and R4 together may additionally be C24alkylene substituted by 0, 1 or 2 substituents selected from -CI- 8 alkyl, -Cl4haloalkyl, halo, oxo, cyano, nitro, -C(=0)Rb, -C(=0)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, -OC(=O)NRaRa, 5 WO 2006/036664 PCT/US2005/033659 -OC(=O)N(Ra)S(=O) 2 Rb, -OC 2
-
6 alkylNRaRa, -OC 2 -6alkylORa, -SRa, -S(=O)R, -S(=0) 2 R',
-S(=O)
2 NRaRa, -S(=O) 2 N(Ra)C(=O)Rb, -S(=O) 2 N(Ra)C(=O)ORb, -S(=0) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)R b, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NaRa, -N(Ra)S(=O) 2 Rb, -N(Ra)S(=0) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa and -NRaC 2
-
6 alkylORa, and 5 additionally substituted by 0, 1, 2, 3 or 4 substituents independently selected from Br, Cl, F and I; or a substituent on R 2 that is vicinal to the -S0 2
-R
2 bond together with R 3 may additionally be Ci- 3 alkylene substituted by 0, 1 or 2 substituents selected from -C 1 -salkyl, Ciahaloalkyl, halo, oxo, cyano, nitro, -C(=O)Rb, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, 10 -ORa, -OC(=O)Rb, -OC(=O)NRaRa, -OC(=0)N(Ra)S(=0) 2 Rb, -OC 2
-
6 alkylNRaRa
-OC
2
-
6 alkylORa, -SR a, -S(=O)R, -S(=0) 2 Rb, -S(=0) 2 NRaRa, -S(=O) 2 N(Ra)C(=O)Rb, -S(=0) 2 N(Ra)C(=O)ORb, -S(=0) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O) 2 Re, -N(Ra)S(=0) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa and -NRaC 2
-
6 alkylORa, and additionally substituted 15 by 0, 1, 2, 3 or 4 substituents independently selected from Br, Cl, F and I; Ra is independently, at each instance, H or Rb; Rb is independently, at each instance, phenyl, benzyl or -C 1 -6alkyl, the phenyl, benzyl and -C I-alkyl being substituted by 0, 1, 2 or 3 substituents selected from halo, -C 1 alkyl, Ci- 3 haloalkyl, -OCi-4alkyl, -NH 2 , -NHC 1 alkyl, -N(Cl alkyl)CiAalkyl; 20 Rd is independently at each instance -Ci- 8 alkyl, -Ciahaloalkyl, halo, cyano, nitro, -C(=O)Rb, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=O) 2 Re, -OC 2
-
6 alkylNRaRa, -OC 2 -6alkylORa, -SRa, -S(=O)Rb, -S(=0) 2 Rb, -S(=0) 2 NRaRa, -S(=O) 2 N(Ra)C(=O)Rb, -S(=0) 2 N(Ra)C(=O)ORb, -S(=O) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, 25 -N(Ra)S(=O) 2 Rb, -N(Ra)S(=0) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa or -NRaC 2
-
6 alkylORa; Re is independently at each instance -Ci -alkyl substituted by 0, 1, 2 or 3 substituents independently selected from Rd and additionally substituted by 0 or 1 substituents selected from Rg; and R9 is independently at each instance a saturated, partially saturated or unsaturated 5-, 6 30 or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11 -membered bicyclic hydrocarbon ring containing 0, 1, 2, 3 or 4 atoms selected from N, 0 and S, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups and the ring is substituted by 0, 1, 2 or 3 substituents independently selected from -CI-salkyl, -CIAhaloalkyl, halo, cyano, nitro, -C(=0)Rb, -C(=O)ORb, -C(=O)NRaRa, -C(=NR)NRaRa, -ORa, -OC(=O)Rb, -OC(=O)NRaRa, 6 WO 2006/036664 PCT/US2005/033659 -OC(=O)N(Ra)S(=0) 2 R, -OC 2 -alky1NRaRa, -OC 2 -6alkylORa, -SRa, -S(=O)Rb, -S(=0) 2 Rb, -S(=0) 2 NRaRa, -S(=0) 2 N(Ra)C(=O)Rb, -S(=O) 2 N(Ra)C(=O)ORb, -S(=0) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)OR, -N(Ra)C(=)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O) 2 Rb, -N(Ra)S(=O) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa and -NRaC 2
-
6 alkylORa, and the 5 ring is additionally substituted by 0, 1, 2, 3, 4 or 5 substituents independently selected from Br, Cl, F and I; or any pharmaceutically-acceptable salt or hydrate thereof. In one embodiment, in conjunction with any one of the below embodiments, R' is selected from H or -C 1
.
8 alkyl substituted by 0, 1, 2, or 3 groups independently selected from 10 R9, cyano, oxo, nitro, -C(=O)R, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Ra, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=O) 2 Rb, -OC 2
-
6 alkylNRaRa, -OC 2
-
6 alkylORa -SRa, -S(=O)Re, -S(=0) 2 Rb, -S(=0) 2 NRaRa, -S(=O) 2 N(Ra)C(=o)R, -S(=0) 2 N(Ra)C(=O)ORa,
-S(=O)
2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Re, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O) 2 Rb, -N(Ra)S(=O) 2 NRaRa, -NRaC 2 -alkylNRaRa and 15 -NRaC 2 -6alkylORa, and additionally substituted by 0, 1, 2, 3, 4, 5 or 6 atoms independently selected from Br, Cl, F and I; Ria and Rib are each independently, H, F, Cl, -OCH 3 , -C 1
-
2 alkyl or -CF3; R" is H, -CI- 8 alkyl, -CI-haloalkyl, halo, cyano, nitro, -C(=O)Re, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=0) 2 Rb, 20 -OC 2
-
6 alkylNRaRa, -OC 2
-
6 alkylORa, -SRa, -S(=O)Rb, -S(=O) 2 R, -S(=O) 2 NRaRa, -S(=0) 2 N(Ra)C(=O)Re, -S(=0) 2 N(Ra)C(=O)OR, -S(=0) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(0)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O) 2 Rb, -N(Ra)S(=O) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa, -NRaC 2
-
6 alkylORa, or -C I- 6 alkyl substituted by 0, 1, 2 or 3 substituents selected from -Ci 4 haloalkyl, halo, cyano, nitro, 25 -C(=O)Rb, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)R, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=O) 2 Re, -OC 2
-
6 alkylNRaRa, -OC 2 -6alkylORa, -SRa, -S(=O)Rb, -S(=O) 2 Rb,
-S(=O)
2 NRaRa, -S(=0) 2 N(Ra)C(=O)R, -S(=o) 2 N(Ra)C(=o)ORb, -S(=O) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=0) 2 Rb, -N(Ra)S(=0) 2 NRaRa, -NRaC2- 6 alkylNRaRa or -NRaC 2
-
6 alkylORa; 30 R2 is a saturated, partially saturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 1 1-membered bicyclic hydrocarbon ring containing 0, 1, 2, 3 or 4 atoms selected from N, 0 and S, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups and the ring is substituted by 0, 1, 2 or 3 substituents independently selected from R', R9, C 1 4haloalkyl, halo, cyano, nitro, -C(=0)Rb, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, 7 WO 2006/036664 PCT/US2005/033659 OR, -OC(=O)R, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=0) 2 Rb, -OC 2 -6alkylNRaRa,
-OC
2
.
6 alkylORa, -SRa, -S(=O)Re, -S(=0) 2 Rb, -S(=0) 2 NRaRa, -S(=O) 2 N(Ra)C(=O)Rb, -S(=0) 2 N(Ra)C(=O)ORe, -S(=0) 2 N(Ra)C(=0)NRaRa, -NRaRa, -N(Ra)C(=O)Rb -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O) 2 Rb, 5 -N(Ra)S(=O) 2 NRaRa, -NRaC2-6alkylNRaRa and -NRaC 2
-
6 alkylORa, and the ring is additionally substituted by 0, 1, 2, 3, 4 or 5 substituents independently selected from Br, Cl, F and I;
R
3 is H, phenyl, benzyl or -C 1
.
6 alkyl, the phenyl, benzyl and -Ci- 6 alkyl being substituted by 0, 1, 2 or 3 substituents independently selected from Re, R9, -Cl4haloalkyl, halo, cyano, nitro, -C(=O)Rb, -C(=O)ORe, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, 10 -OC(=O)NRaRa, -OC(=O)N(Ra)S(=O) 2 Rb, -OC 2
-
6 alkylNRaRa, -OC 2
-
6 alkylORa, -SRa, -S(=O)Rb, -S(=0) 2 Rb, -S(=O) 2 NRaRa, -S(=O) 2 N(Ra)C(=O)Rb, -S(=0) 2 N(Ra)C(=O)ORb, -S(=0) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O) 2 Rb, -N(Ra)S(=0) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa and -NRaC 2 -salkylORa, and additionally substituted by 0, 1, 2, 3, 4, 5 or 6 atom selected from Br, 15 Cl, F and I;
R
4 is H, phenyl, benzyl or -Ci- 6 alkyl, the phenyl, benzyl and Ci- 6 alkyl being substituted by 0, 1, 2 or 3 substituents independently selected from Ci 4 alkyl, Ci- 3 haloalkyl, -OC14alkyl,
-NH
2 , -NHC Ialkyl, and -N(CI.
4 alkyl)C 14 alkyl, and additionally substituted by 0, 1, 2, 3, 4, 5 or 6 atom selected from Br, Cl, F and I; 20 R 5 is a saturated, partially saturated or unsaturated 8-, 9-, 10- or 11 -membered bicyclic or 12-, 13-, 14- or 15- membered tricyclic hydrocarbon ring containing 0, 1, 2, 3 or 4 atoms selected from N, 0 and S, wherein the carbon and sulfur atoms of the ring are substituted by 0, 1 or 2 oxo groups and the ring is substituted by R 6, R7 or R8 independently selected from basic moieties, and additionally substituted by 0, 1, 2 or 3 substituents independently selected from 25 R 6, R 7 and R8 which are selected from R9, -Ci - 8 alkyl, -C 1 4haloalkyl, cyano, nitro, -C(=0)Rb, -C(=O)ORe, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=0) 2 Rb, -OC 2
-
6 alkylNRaRa, -OC 2 -6alkylORa, -SRa, -S(=O)Rb, -S(= 0
)
2 R , -S(=0) 2 NRaRa, -S(=0) 2 N(Ra)C(=0)Rb, -S(=0) 2 N(Ra)C(=0)ORb, -S(=0) 2 N(Ra)C(=O)NRaRa -NRaRa, -N(Ra)C(=0)Rb, -N(Ra)C(=0)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NR aRa, 30 -N(Ra)S(=0) 2 Rb, -N(Ra)S(=O) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa and -NRaC 2
-
6 alkylORa, and the ring is additionally substituted by 0, 1, 2, 3, 4 or 5 substituents selected from R6, R7, R', R9 and R10 which are independently selected from Br, Cl, F and I; wherein, R 3 and R4 together may additionally be C 2
-
3 alkylene substituted by 0, 1 or 2 substituents independently selected from -Ci-salkyl, -C 1 Ahaloalkyl, halo, oxo, cyano, nitro, 8 WO 2006/036664 PCT/US2005/033659 -C(=O)R", -C(=O)OR", -C(=O)NR"R", -C(=NRa)NRaRa, -OR a, -OC(=O)R, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=0) 2 Rb, -OC 2
-
6 alkylNRaRa, -OC 2 -6alkylORa, -SRa, -S(=O)Rb, -S(=0) 2 Rb, -S(=0) 2 NRaRa, -S(=O) 2 N(Ra)C(=O)Rb, -S(=0) 2 N(Ra)C(=O)ORb, -S(=O) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa 5 -N(Ra)S(=O) 2 Rb, -N(Ra)S(=O) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa and -NRaC 2
-
6 alkylORa, and additionally substituted by 0, 1, 2, 3 or 4 substituents independently selected from Br, Cl, F and I; or Rc and R 4 together may additionally be C 2 .4alkylene substituted by 0, 1 or 2 substituents selected from -CIsalkyl, -C, 4 haloalkyl, halo, oxo, cyano, nitro, -C(=O)Rb, 10 -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=O) 2 Re, -OC 2
-
6 alkylNRaRa, -OC 2 -6alkylORa, -SRa, -S(=O)Rb, -S(=0) 2 Rb, -S(=0) 2 NRaRa, -S(=O) 2 N(Ra)C(=O)Rb, -S(=0) 2 N(Ra)C(=O)ORb, -S(=O) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O) 2 Re, -N(Ra)S(=O) 2 NRaRa, -NRaC2- 6 alkylNRaRa and -NRaC 2
-
6 alkylORa, and 15 additionally substituted by 0, 1, 2, 3 or 4 substituents independently selected from Br, Cl, F and I; or a substituent on R 2 that is vicinal to the -S0 2
-R
2 bond together with R 3 may additionally be CI.
3 alkylene substituted by 0, 1 or 2 substituents selected from -CI.
8 alkyl, C 14 haloalkyl, halo, oxo, cyano, nitro, -C(=O)Rb, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, 20 -ORa, -OC(=0)Rb, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=O) 2 Rb, -OC 2
-
6 alkylNRaRa,
-OC
2
.
6 alkylORa, -SRa, -S(=O)Rb, -S(=O) 2 Re, -S(=0) 2 NRaRa, -S(=O) 2 N(Ra)C(=O)Rb, -S(=0) 2 N(Ra)C(=O)ORb, -S(=0) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O) 2 Re, -N(Ra)S(=O) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa and -NRaC 2 -6alkylORa, and additionally substituted 25 by 0, 1, 2, 3 or 4 substituents independently selected from Br, Cl, F and I; Ra is independently, at each instance, H or Rb; Rb is independently, at each instance, phenyl, benzyl or -Ci- 6 alkyl, the phenyl, benzyl and -Ci-salkyl being substituted by 0, 1, 2 or 3 substituents selected from halo, -Ci alkyl, CI- 3 haloalkyl, -OC 14 alkyl, -NH 2 , -NHCIAalkyl, -N(CI-4alkyl)CiAalkyl; 30 Rd is independently at each instance -Ci-salkyl, -Ciahaloalkyl, halo, cyano, nitro, -C(=O)Rb, C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=O) 2 Re, -OC 2
-
6 alkylNRaRa, -OC 2 -6alkylORa, -SRa, -S(=O)Rb, -S(=0) 2 Rb, -S(=0) 2 NRaRa, -S(=O) 2 N(Ra)C(=O)Rb, -S(=O) 2 N(Ra)C(=O)ORb, -S(=0) 2 N(Ra)C(=O)NRaRa, 9 WO 2006/036664 PCT/US2005/033659 -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)OR", -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O) 2 Rb, -N(Ra)S(=0) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa or -NRaC2- 6 alkylORa; Re is independently at each instance -Ci-6alkyl substituted by 0, 1, 2 or 3 substituents independently selected from Rd and additionally substituted by 0 or 1 substituents selected 5 from Rg; and R' is independently at each instance a saturated, partially saturated or unsaturated 5-, 6 or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11 -membered bicyclic hydrocarbon ring containing 0, 1, 2, 3 or 4 atoms selected from N, 0 and S, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups and the ring is substituted by 0, 1, 2 or 3 substituents 10 independently selected from -CI-salkyl, -CIAhaloalkyl, halo, cyano, nitro, -C(=O)Rb, -C(=O)ORb, -C(=0)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=0)Rb, -OC(=O)NRaRa, -OC(=0)N(R)S(=0) 2 Rb, -OC 2
-
6 alkylNRaRa, -OC 2 -6alkylORa, -SRa, -S(=O)Rb, -S(=0) 2 R, -S(=0) 2 NRaRa, -S(=0) 2 N(Ra)C(=0)Rb, -S(=0) 2 N(Ra)C(=O)ORb, -S(=0) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)R, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, 15 -N(Ra)S(=O) 2 Rb, -N(Ra)S(=0) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa and -NRaC 2
-
6 alkylORa, and the ring is additionally substituted by 0, 1, 2, 3, 4 or 5 substituents independently selected from Br, Cl, F and I. In another embodiment, in conjunction with any one of the below embodiments, R' is selected from H or -Ci salkyl substituted by 0, 1, 2, or 3 groups independently selected from 20 R9, cyano, oxo, nitro, -C(=0)Rb, -C(=0)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Ra, -OC(=0)NRaRa, -OC(=O)N(Ra)S(=O) 2 Rb, -OC 2 -6alkylNRaRa, -OC 2
-
6 alkylORa, -SRa, -S(=O)Rb, -S(=0) 2 Rb, -S(=0) 2 NRaRa, -S(=0) 2 N(Ra)C(=O)Rb, -S(=0) 2 N(Ra)C(=O)ORa, -S(=0) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NWRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O) 2 Rb, -N(Ra)S(=0) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa and 25 -NRaC 2 -6alkylORa, and additionally substituted by 0, 1, 2, 3, 4, 5 or 6 atoms selected from Br, Cl, F and I; Ria and Rib are each independently, H, F, Cl, -OCH 3 , -Ci- 2 alkyl or -CF 3 ; R" is H, -CI.salkyl, -CIAhaloalkyl, halo, cyano, nitro, -C(=0)Rb, -C(=0)ORb, -C(=0)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=0) 2 Rb, 30 -OC 2
-
6 alkylNRaRa, -OC 2
-
6 alkylORa, -SRa, -S(=O)Rb, -S(=O) 2 Rb, -S(=O) 2 NRaRa, -S(=0) 2 N(Ra)C(=O)Rb, -S(=0) 2 N(Ra)C(=O)ORb, -S(=0) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=0)Rb, -N(Ra)C(=0)ORb, -N(Ra)C(=0)NRaRa, -N(Ra)C(=NRa)NRaa -N(Ra)S(=0) 2 Rb, -N(Ra)S(=O) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa, -NRaC 2
-
6 alkylORa, or -CI- 6 alkyl substituted by 0, 1, 2 or 3 substituents selected from CiAhaloalkyl, halo, cyano, nitro, 10 WO 2006/036664 PCT/US2005/033659 -C(=O)R', -C(=O)OR, -C(=O)NRaRa, -C(=NRa)NRaa, -ORa, -OC(=O)R, -OC(=O)NaRa, -OC(=O)N(Ra)S(=O) 2 Rb, -OC 2 -6alkylNRaRa, -OC 2 -salkylORa, -SRa, -S(=O)Rb, -S(=0) 2 Rb, -S(=0) 2 NRaRa, -S(=0) 2 N(Ra)C(=O)Rb, -S(=O) 2 N(Ra)C(=O)ORb, -S(=0) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa 5 -N(Ra)S(=O) 2 Rb, -N(Ra)S(=0) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa or -NRaC 2
-
6 alkylORa; R2 is a saturated, partially saturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 1 1-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, 0 and S, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups and the ring is substituted by 0, 1, 2 or 3 substituents selected from Re, R9, -CI 4 haloalkyl, halo, 10 cyano, nitro, -C(=O)Rb, -C(=O)ORb, -C(=0)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=0)Rb, -OC(=0)NRaRa, -OC(=O)N(Ra)S(=O) 2 Rb, -OC 2
-
6 alkylNRaRa, -OC 2
-
6 alkylORa, -SRa, -S(=0)Rb, -S(=0) 2 Rb, -S(=0) 2 NRaRa, -S(=0) 2 N(Ra)C(=0)Rb, -S(=0) 2 N(Ra)C(=O)OR, -S(=0) 2 N(Ra)C(=0)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=0)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O) 2 Rb, -N(Ra)S(=0) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa and 15 -NRaC 2 -6alkylORa, and the ring is additionally substituted by 0, 1, 2, 3, 4 or 5 substituents independently selected from Br, Cl, F and I;
R
3 is H, phenyl, benzyl or -Ci- 6 alkyl, the phenyl, benzyl and -C 1
-
6 alkyl being substituted by 0, 1, 2 or 3 substituents selected from R*, R9, Ci_4haloalkyl, halo, cyano, nitro, -C(=O)Rb, -C(=O)ORb, -C(=0)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, -OC(=O)NRaRa, 20 -OC(=O)N(Ra)S(=O) 2 Rb, -OC 2
-
6 alkylNRaRa, -OC 2 -6alkylORa, -SRa, -S(=O)Rb, -S(=0) 2 Rb, -S(=0) 2 NRaRa, -S(=0) 2 N(Ra)C(=O)Rb, -S(=0) 2 N(Ra)C(=0)OR , -S(=0) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Re, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa -N(Ra)S(=0) 2 Rb, -N(Ra)S(=0) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa and -NRaC 2 -6alkylORa, and additionally substituted by 0, 1, 2, 3, 4, 5 or 6 atom selected from Br, Cl, F and I; 25 R 4 is H, phenyl, benzyl or -CI alkyl, the phenyl, benzyl and -C1.
6 alkyl being substituted by 0, 1, 2 or 3 substituents selected from C1.4alkyl, CI- 3 haloalkyl, -OCi alkyl,
-NH
2 , -NHCI.4alkyl, and -N(Ci.
4 alkyl)C1.
4 alkyl, and additionally substituted by 0, 1, 2, 3, 4, 5 or 6 atom selected from Br, Cl, F and I;
R
5 is a saturated, partially saturated or unsaturated 8-, 9-, 10- or l l-membered bicyclic 30 or 12-, 13-, 14- or 15- membered tricyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, 0 and S, wherein the carbon and sulfur atoms of the ring are substituted by 0, 1 or 2 oxo groups and the ring is substituted by 1, 2 or 3 basic moieties, and additionally substituted by 0, 1, 2 or 3 substituents selected from R9, -Cisalkyl, -CI.
4 haloalkyl, cyano, nitro, -C(=0)Rb, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, -OC(=O)NRaR, 11 WO 2006/036664 PCT/US2005/033659 -OC(=O)N(Ra)S(=0) 2 Rb, -OC 2
-
6 allylNRaRa, -OC 2 -6alkylORa, -SRa, -S(=O)Rb, -S(=O) 2 Rb,
-S(=O)
2 NRaRa, -S(=0) 2 N(Ra)C(=O)Rb, -S(=O) 2 N(Ra)C(=O)ORb, -S(=0) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)OR, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=0) 2 Rb, -N(Ra)S(=O) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa and -NRaC 2
-
6 alkylORa, and the 5 ring is additionally substituted by 0, 1, 2, 3, 4 or 5 substituents independently selected from Br, Cl, F and I; wherein, R 3 and R 4 together may additionally be C2-3alkylene substituted by 0, 1 or 2 substituents selected from -C 1 .salkyl, -CI.
4 haloalkyl, halo, oxo, cyano, nitro, -C(=O)R , -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, -OC(=O)NRaRa, 10 -OC(=O)N(Ra)S(=O) 2 Rb, -OC 2
-
6 alkylNRaRa, -OC 2 -6alkylORa, -SRa, -S(=O)R, -S(=O) 2 Rb, -S(=0) 2 NRaRa, -S(=O) 2 N(Ra)C(=O)R, -S(=O) 2 N(Ra)C(=O)ORb, -S(=O) 2 N(Ra)C(=O)NRaRa -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRa, -N(Ra)C(=NRa)NRRa, -N(Ra)S(=0) 2 Rb, -N(Ra)S(=O) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa and -NRaC 2
-
6 alkylORa, and additionally substituted by 0, 1, 2, 3 or 4 substituents independently selected from Br, Cl, F and 15 I; or RIC and R 4 together may additionally be C 2 4alkylene substituted by 0, 1 or 2 substituents selected from -CI-.alkyl, -C14haloalkyl, halo, oxo, cyano, nitro, -C(=O)R , -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=0) 2 Rb, -OC 2
-
6 alkylNRaRa, -OC 2 -6alkylORa, -SRa, -S(=O)Rb, -S(=0) 2 Rb, 20 -S(=0) 2 NRaRa, -S(=O) 2 N(Ra)C(=O)Rb, -S(=O) 2 N(Ra)C(=O)ORb, -S(=O) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=o)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRa, -N(Ra)S(=O) 2 Rb, -N(Ra)S(=O) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa and -NRaC 2
-
6 alkylORa, and additionally substituted by 0, 1, 2, 3 or 4 substituents independently selected from Br, Cl, F and I; or 25 a substituent on R2 that is vicinal to the -S0 2 -R2 bond together with R 3 may additionally be Ci.
3 alkylene substituted by 0, 1 or 2 substituents selected from CI-salkyl, C-4haloalkyl, halo, oxo, cyano, nitro, -C(=O)Rb, -C(=0)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, -OC(=O)NRaRa, -OC(=0)N(Ra)S(=0) 2 Rb, -OC 2
-
6 alkylNRaRa,
-OC
2
-
6 alkylORa, -SRa, -S(=O)Rb, -S(=O) 2 Rb, -S(=0) 2 NRaRa, -S(=0) 2 N(Ra)C(=0)Rb 30 -S(=0) 2 N(Ra)C(=O)ORb, -S(=0) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O) 2 Rb, -N(Ra)S(=O) 2 NRaRa, -NRaC 2
-
6 alkyNRaRa and -NRaC 2
.
6 alkylORa, and additionally substituted by 0, 1, 2, 3 or 4 substituents independently selected from Br, Cl, F and I; Ra is independently, at each instance, H or Ri; 12 WO 2006/036664 PCT/US2005/033659 1- is independently, at each instance, phenyl, benzyl or -Ci.- 6 alkyl, the phenyl, benzyl and -C 1 6alkyl being substituted by 0, 1, 2 or 3 substituents selected from halo, CI Aalkyl,
C
1 3 haloalkyl, -OCI-alkyl, -NH 2 , -NHCI.4alkyl, -N(Ci-alkyl)Cl.alkyl; Rd is independently at each instance -C1.salkyl, CIAhaloalkyl, halo, cyano, nitro, 5 -C(=O)R, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=0) 2 Rb, -OC 2
-
6 alkylNRaRa, -OC 2 -6alkylORa, -SRa, -S(=O)Rb, -S(=0) 2 Rb, -S(=0) 2 NRaRa, -S(=O) 2 N(Ra)C(=O)Rb, -S(=O) 2 N(Ra)C(=O)ORb, -S(=0) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=0) 2 Rb, -N(Ra)S(=O) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa or -NRaC 2
-
6 alkylORa; 10 Re is independently at each instance -C 1 .6alkyl substituted by 0, 1, 2 or 3 substituents independently selected from Rd and additionally substituted by 0 or 1 substituents selected from Rg; and R9 is independently at each instance a saturated, partially saturated or unsaturated 5-, 6 or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 15 2, 3 or 4 atoms selected from N, 0 and S, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups and the ring is substituted by 0, 1, 2 or 3 substituents selected from CI.
8 alkyl, -C I 4 haloalkyl, halo, cyano, nitro, -C(=0)Rb, -C(=0)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=0)Rb, -OC(=0)NRaRa, -OC(=O)N(Ra)S(=O) 2 Re,
-OC
2
-
6 alkylNRaRa, -OC 2
-
6 alkylORa, -SRa, -S(=0)Rb, -S(=0) 2 Rb, -S(=0) 2 NRaRa, 20 -S(=0) 2 N(Ra)C(=0)Rb, -S(=0) 2 N(Ra)C(=O)ORb, -S(=O) 2 N(Ra)C(=0)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=0)ORb, -N(Ra)C(=0)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O) 2 Rb, -N(Ra)S(=O) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa and -NRaC2- 6 alkylORa, and the ring is additionally substituted by 0, 1, 2, 3, 4 or 5 substituents independently selected from Br, Cl, F and I. 25 In another embodiment, in conjunction with any one of the above and below embodiments, the basic moieties are independently selected from amino, cycloalkylamino
(CI-C
6 )alkyl, cycloalkyl(Ci-C 6 ) alkylamino(Ci-C 6 )alkyl, heterocyclylamino(Ci-C 6 )alkyl, heterocyclyl(Ci-C 6 )alkyl-amino(Ci-C 6 )alkyl, arylamino(Ci-C 6 )alkyl, aryl(Ci-C 6 )alkylamino (Ci-C 6 )alkyl, (C 1
-C
6 )alkylamino(Ci-C 6 )alkoxy, (CI-C 6 )alkylamino(Ci-C 6 )alkoxy(CI-C 6
)
30 alkoxy, amino(Ci -C 6 )alkoxy, amino(C 1
-C
6 )alkyl, (C I-C 6 )alkylamino(C 1
-C
6 )alkyl, (CI -C 4 )alkylamino-(C 2
-C
6 )alkenyl, 4-8-membered nitrogen-containing heterocyclyl(C 2
-C
6 )alkenyl, 5-6 membered heterocyclyloxy, 5-6 membered nitrogen containing heterocyclyl and 5-7 membered nitrogen-containing heterocyclylalkyl; more specifically amino, cycloalkylamino(Ci -C 6 )alkyl, cycloalkyl(Ci -C 6 )alkylamino-(Ci -C 6 )alkyl, 13 WO 2006/036664 PCT/US2005/033659 heterocyclylamino(Ci-C 6 )alkyl, heterocyclyl(Ci-C 6 )alkylamino-(Ci-C 6 )alkyl, arylamino(C-C 6 )alkyl, aryl(C-C 6 )alkylamino(CI-C6)alkyl, (C-C 6 )alkyl amino(Ci-C 6 )alkoxy, (CI -C 6 )alkylamino(C I-C 6 )alkoxy(Ci -C 6 )alkoxy, amino(Ci -C 6 )alkoxy, amino(C 1
-C
6 )alkyl,
(C
1
-C
6 )alkylamino(C 1
-C
6 )alkyl, (CI-C 4 )alkylamino-(C 2
-C
6 )alkenyl, 5-8-membered nitrogen 5 containing heterocyclyl(C 2
-C
6 )alkenyl, heterocyclyl(Ci-C 6 )amino(C 2
-C
6 )alkyl, 5-6 membered heterocyclyloxy, 5-6 membered nitrogen-containing heterocyclyl and 5-7 membered nitrogen containing heterocyclyl(CI-C 6 )alkyl wherein each basic moiety can be substituted by 0, 1, 2 or 3 groups independently selected from halo, -NH 2 , -OH, -CN, -CF 3 , (CI-C 6 )alkylamino, haloalkyl, oxo, (C 1
-C
6 )alkoxy, (Ci-C 6 )alkoxyalkyl, (C 2
-C
6 )alkenyl, (C 2
-C
6 )alkynyl, 10 di(CI-C 6 )alkylamino, =NCN and (CI-C 6 )alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl, each of which is substituted by 0, 1, 2 or 3 groups independently selected from halo, -NH 2 , -OH, -CN, -CF 3 , (C 1
-C
6 )alkylamino, haloalkyl, oxo, (Ci-C 6 )alkoxy, (CI-C 6 )alkoxyalkyl, (C I-C 6 )alkyl, (C 2
-C
6 )alkenyl, (C 2
-C
6 )alkynyl, or di(C1 -C 6 )alkylamino. In another embodiment, in conjunction with any one of the above and below 15 embodiments, the basic moieties are independently selected from amino, mono-C 1 -4 alkylamino-CiA-alkyl, di-C 14 -alkylamino-Cia-alkyl, mono-Ci4-alkylamino-C 2
.
4 -alkenyl, di-Ci4-alkylamino-C 24 -alkenyl, 5-8 membered nitrogen-containing heterocyclyl-C 2 4-alkenyl, optionally substituted 5-6 membered nitrogen-containing heterocyclyl or 5-8 membered nitrogen-containing heterocyclyl-Ci4-alkyl. 20 In another embodiment, in conjunction with any one of the above and below embodiments, the basic moieties are independently selected from amino, aminomethyl, isopropylaminomethyl, t-butylaminomethyl, 2-t-butylaminoethyl, 2-tert-butylamino-1-methyl ethyl, 1-tert-butylaminoethyl, 1-(tert-butylamino-methyl)-vinyl, 1-(piperidin-1-ylmethyl) vinyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl, N 25 isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl, N-t-butyl-N methylaminomethyl, N-iso-butyl-N-methylaminomethyl, N-t-butyl-N-ethylaminomethyl, N isobutyl-N-methylaminomethyl, N-t-butyl-N-isopropylaminomethyl, N,N di(isopropyl)aminomethyl, N,N-dimethylaminomethyl, N,N-diethylaminomethyl, N,N-di(t butyl)-aminomethyl, cyclopropylaminomethyl, cyclopropylaminoethyl, 30 cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl, cyclobutylaminomethyl, cyclobutylaminoethyl, cyclobutylmethylaminomethyl, cyclobutylmethylaminoethyl, 4,5 dihydro-imidazolyl, 1 -piperidinylmethyl, 4-fluoropiperidin- 1 -ylmethyl, 4,4-difluoropiperidin 1 -yhmethyl, 3-hydroxypiperidin- 1 -ylmethyl, 4-hydroxypiperidin- 1 -ylmethyl, 4-(piperidin- 1 yl)piperidinylmethyl, 4-(dimethylamino)piperidin- I -ylmethyl, 2,6-dimethylpiperidin- 1 14 WO 2006/036664 PCT/US2005/033659 ylmethyl, 4-morpholinylnethyl, 1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl, 2,5 dimethylpyrrolidin-1-ylmethyl, piperazin-1-ylmethyl, azocan-1-ylmethyl, azepan-1-ylmethyl, (7-azabicyclo[2.2.1]hept-7-yl)methyl, (1,3,3-trimethyl-6-azaicyclo[3.2.1]oct-6-yl)methyl, 2 piperidinyl and 4-methylpiperazin-1-ylmethyl, in conjunction with any of the above or below 5 embodiments. In another embodiment, in conjunction with any one of the above and below embodiments, R 1 is H. In another embodiment, in conjunction with any one of the above and below embodiments, R1 is Ci-salkyl substituted by 0, 1, 2, or 3 groups independently selected from 10 R9, cyano, oxo, nitro, -C(=O)Rb, -C(=O)ORa, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=O) 2 Rb, -OC 2 .alkylNRaRa, -OC 2 -6alkylORa, -SRa, -S(=O)Rb, -S(=O) 2 Rb, -S(=0) 2 NRaRa, -S(=0) 2 N(Ra)C(=O)Rb, -S(=0) 2 N(Ra)C(=O)ORb,
-S(=O)
2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Re, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O) 2 Re, -N(Ra)S(=0) 2 NRaRa, -NRaC2-6alkylNRaRa and 15 -NRaC 2 -6alkylORa, and additionally substituted by 0, 1, 2, 3, 4, 5 or 6 atoms selected from Br, Cl, F and I. In another embodiment, in conjunction with any one of the above and below embodiments, R 1 is C I-alkyl substituted by 0, 1, 2, or 3 groups independently selected from R9, cyano, nitro, -C(=O)Rb, -C(=0)ORa, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, 20 -OC(=O)NRaRa, -OC(=O)N(Ra)S(=O) 2 Re, -OC 2
.
6 alkylNRaRa, -OC 2
-
6 alkylORa, -SRa, -S(=O)Rb, -S(=0) 2 Rb, -S(=0) 2 NRaRa, -S(=O) 2 N(Ra)C(=O)Rb, -S(=O) 2 N(Ra)C(=O)ORb, -S(=0) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Re, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O) 2 Rb, -N(Ra)S(=O) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa and -NRaC 2 -6alkylORa, and additionally substituted by 0, 1, 2, 3, 4, 5 or 6 atoms selected from Br, 25 Cl, F and I. In another embodiment, in conjunction with any one of the above and below embodiments, R1 is -Ci-salkyl. In another embodiment, in conjunction with any one of the above and below embodiments, R' is -C 3 -salkyl. 30 In another embodiment, in conjunction with any one of the above and below embodiments, R' is -CH 3 . In another embodiment, in conjunction with any one of the above and below embodiments, R' is -CI.
8 alkyl substituted by 1, 2, 3, 4, 5 or 6 atoms selected from Br, Cl, F and I. 15 WO 2006/036664 PCT/US2005/033659 In another embodiment, m conjunction with any one of the above and below embodiments, R' is -CF 3 . In another embodiment, in conjunction with any one of the above and below embodiments, R' is -C 1
.
8 alkyl substituted by 1, 2, or 3 groups independently selected from R9, 5 cyano, oxo, nitro, -C(=o)Rb, -C(=o)ORa, -C(=0)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=O) 2 Rb, -OC 2 6 alkylNRaRa, -OC 2
-
6 alkylORa, -SRa, -S(=O)Rb, -S(=0) 2 Rb, -S(=0) 2 NaRa, -S(=O) 2 N(Ra)C(=O)Rb, -S(=0) 2 N(Ra)C(=O)ORa, -S(=0) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Re, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=0) 2 Rb, -N(Ra)S(=0) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa and 10 -NRaC 2 -6alkylORa, and additionally substituted by 0, 1, 2, 3, 4, 5 or 6 atoms selected from Br, Cl, F and I. In another embodiment, in conjunction with any one of the above and below embodiments, R' is -CI 8 alkyl substituted by 1 oxo group and 0, 1 or 2 groups independently selected from R9, cyano, nitro, -C(=O)Rb, -C(=O)ORa, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa 15 -OC(=O)Rb, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=0) 2 Rb, -OC 2
-
6 alkylNRaRa, -OC 2 -6alkylORa, -SRa, -S(=0)Rb, -S(=0) 2 Rb, -S(=0) 2 NRaRa, -S(=O) 2 N(Ra)C(=O)Rb, -S(=O) 2 N(Ra)C(=O)ORa, -S(=0) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O) 2 Rb, -N(Ra)S(=O) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa and -NRaC 2 -6alkylORa, and additionally substituted by 0, 1, 2, 3, 4, 5 or 6 atoms selected from Br, 20 Cl, F and I. In another embodiment, in conjunction with any one of the above and below embodiments, R 1 is -Ci- 8 alkyl substituted by 1, 2 or 3 groups independently selected from oxo, -C(=O)ORa, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, -OC(=O)NRaRa -OC(=O)N(Ra)S(=0) 2 Rb, -OC 2
.
6 alkylNRaRa, -OC 2
-
6 alkylORa, ,-S(=O)Rb, -S(=0) 2 Rb, 25 -S(=0) 2 NRaRa, -S(=0) 2 N(Ra)C(=O)R , -S(=O) 2 N(Ra)C(=O)ORa, -S(=O) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Re, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NaRa -N(Ra)S(=O) 2 Rb, -N(Ra)S(=O) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa and -NRaC 2
.
6 alkylORa, and additionally substituted by 0, 1, 2, 3, 4, 5 or 6 atoms selected from Br, Cl, F and I. In another embodiment, in conjunction with any one of the above and below 30 embodiments, R' is -C(=O)ORa or -C(=O)NRaRa. In another embodiment, in conjunction with any one of the above and below embodiments, Ria and Rib are each independently, H, F, Cl, -OCH 3 , -CI-2alkyl or -CF 3 . In another embodiment, in conjunction with any one of the above and below embodiments, Ria is H and Rib F, Cl, -OCH 3 , -Ci- 2 alkyl or -CF 3 . 16 WO 2006/036664 PCT/US2005/033659 In another embodiment, m conjunction with any one of the above and below embodiments, Ria is F, Cl, -OCH 3 , -Ci- 2 alkyl or -CF 3 and Rib is H. In another embodiment, in conjunction with any one of the above and below embodiments, Rila and Rib are each independently, H or F. 5 In another embodiment, in conjunction with any one of the above and below embodiments, Ric is -C1.salkyl, -C 14 haloalkyl, halo, cyano, nitro, -C(=O)Rb, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)R, -OC(=0)NRaRa, -OC(=O)N(Ra)S(=0) 2 Rb,
-OC
2
-
6 alkylNRaRa, -OC 2
-
6 alkylORa, -SRa, -S(=O)Rb, -S(=O) 2 Rb, -S(=0) 2 NRaRa, -S(=0) 2 N(Ra)C(=O)Re, -S(=0) 2 N(Ra)C(=O)ORb, -S(=0) 2 N(Ra)C(=O)NRaRa, -NRaRa, 10 -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O) 2 Rb, -N(Ra)S(=O) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa, -NRaC 2
-
6 alkylORa, or -C I- 6 alkyl substituted by 0, 1, 2 or 3 substituents selected from -Ci-haloalkyl, halo, cyano, nitro, -C(=O)Rb, -C(=0)ORe, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, -OC(=O)NRaRa -OC(=O)N(Ra)S(=O) 2 Rb, -OC 2
.
6 alkylNRaRa, -OC 2 -6alkylORa, -SRa, -S(=O)Rb, -S(=O) 2 Rb, 15 -S(=0) 2 NRaRa, -S(=O) 2 N(Ra)C(=O)Rb, -S(=0) 2 N(Ra)C(=O)ORb, -S(=0) 2 N(Ra)C(=O)NRaRa -NRaRa, -N(Ra)C(=O)R, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=0) 2 Rb, -N(Ra)S(=0) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa or -NRaC 2
-
6 alkylORa. In another embodiment, in conjunction with any one of the above and below embodiments, R'C is -C I- 6 alkyl substituted by 0, 1, 2 or 3 substituents selected from 20 CIAhaloalkyl, halo, cyano, nitro, -C(=o)Rb, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=0) 2 Rb, -OC 2
-
6 alkylNRaRa,
-OC
2
.
6 alkylORa, -SRa, -S(=O)R, -S(=0) 2 Rb, -S(=0) 2 NRaRa, -S(=O) 2 N(Ra)C(=O)R, -S(=0) 2 N(Ra)C(=O)ORb, -S(=O) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O) 2 R, 25 -N(Ra)S(=0) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa or -NRaC 2
-
6 alkylORa; In another embodiment, in conjunction with any one of the above and below embodiments, RI'c is H or F. In another embodiment, in conjunction with any one of the above and below embodiments, Ria, Rib, and RIC are H. 30 In another embodiment, in conjunction with any one of the above and below embodiments, R 2 is phenyl or napthyl, both of which are substituted by 0, 1, 2 or 3 substituents selected from R", R', -Ci Ahaloalkyl, halo, cyano, nitro, -C(=O)Rb, -C(=0)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=O) 2 Rb,
-OC
2
-
6 alkylNRaRa, -OC 2
-
6 alkylORa, -SRa, -S(=O)Rb, -S(=0) 2 Rb, -S(=0) 2 NRaRa, 17 WO 2006/036664 PCT/US2005/033659 -S(=0) 2 N(Ra)C(=O)R, -S(=0) 2 N(R")C(=O)ORb, -S(=0) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NaRa, -N(Ra)S(=O) 2 Rb, -N(Ra)S(=O) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa and -NRaC 2
-
6 alkylORa, and additionally substituted by 0, 1, 2, 3, 4 or 5 substituents independently selected from Br, Cl, F 5 and I. In another embodiment, in conjunction with any one of the above and below embodiments, R2 is phenyl or napthyl, both of which are substituted by 1, 2 or 3 substituents selected from Re, R9, -CI 4 haloalkyl, halo, cyano, nitro, -C(=O)Re, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=O) 2 Re, 10 -OC 2
-
6 alkylNRaRa, -OC 2
-
6 alkylORa, -SRa, -S(=O)Rb, -S(=O) 2 R, -S(=O) 2 NRaRa
-S(=O)
2 N(Ra)C(=O)Rb, -S(=0) 2 N(Ra)C(=O)ORb, -S(=O) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=0) 2 Re, -N(Ra)S(=O) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa and -NRaC2- 6 alkylORa, and additionally substituted by 0, 1, 2, 3, 4 or 5 substituents independently selected from Br, Cl, F 15 and I. In another embodiment, in conjunction with any one of the above and below embodiments, R 2 is a saturated, partially saturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 1 1-membered bicyclic ring containing 1, 2, 3 or 4 atoms selected from N, 0 and S, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo 20 groups and the ring is substituted by 0, 1, 2 or 3 substituents selected from R', R9, CI 4 haloalkyl, halo, cyano, nitro, -C(=0)Rb, -C(=O)OR, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)R, -OC(=0)NRaRa, -OC(=O)N(Ra)S(=O) 2 Rb, -OC 2
-
6 alkylNRaRa,
-OC
2
-
6 alkylORa, -SRa, -S(=O)R, -S(=0) 2 Rb, -S(=0) 2 NRaRa, -S(=0) 2 N(Ra)C(=O)Re, -S(=0) 2 N(Ra)C(=O)OR, -S(=0) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)R, 25 -N(Ra)C(=0)ORb, -N(Ra)C(=0)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=0) 2 Rb, -N(Ra)S(=0) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa and -NRaC 2
-
6 alkylORa, and the ring is additionally substituted by 0, 1, 2, 3, 4 or 5 substituents independently selected from Br, Cl, F and I. In another embodiment, in conjunction with any one of the above and below embodiments, R 2 is a saturated, partially saturated or unsaturated 5-, 6- or 7-membered 30 monocyclic or 6-, 7-, 8-, 9-, 10- or 1 1-membered bicyclic hydrocarbon ring containing 1, 2, 3 or 4 atoms selected from N, 0 and S, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups and the ring is substituted by 0, 1, 2 or 3 substituents selected from R*, R9, Ci 4 haloalkyl, halo, cyano, nitro, -C(=O)Rb, -C(=0)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa -ORa, -OC(=O)R, -OC(=0)NRaRa, -OC(=0)N(Ra)S(=O) 2 Rb, -OC 2
.
6 alkylNRaRa, 18 WO 2006/036664 PCT/US2005/033659
-OC
2
-
6 alkylORa, -SRa, -S(=O)R", -S(=0) 2 Rb, -S(=0) 2 NRaRa, -S(=O) 2 N(Ra)C(=O)R,
-S(=O)
2 N(Ra)C(=O)ORb, -S(=O) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)R, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O) 2 Rb, -N(Ra)S(=O) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa and -NRaC 2
-
6 alkylORa, and the ring is additionally 5 substituted by 0, 1, 2, 3, 4 or 5 substituents independently selected from Br, Cl, F and I. In another embodiment, in conjunction with any one of the above and below embodiments, R 2 is an unsaturated 5-, 6- or 7-membered monocyclic 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 and the ring is substituted by 0, 1, 2 or 3 substituents selected from R*, R9, 10 ClAhaloalkyl, halo, cyano, nitro, -C(=O)Rb, -C(=0)ORb, -C(=O)NRaRa, -C(=NRa)NaRa, -ORa, -OC(=0)R, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=0) 2 Rb, -OC 2
.
6 alkylNRaRa,
-OC
2
-
6 alkylORa, -SRa, -S(=O)Rb, -S(=0) 2 Rb, -S(=0) 2 NRaRa, -S(=0) 2 N(Ra)C(=0)Rb, -S(=0) 2 N(Ra)C(=O)ORe, -S(=0) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Re, -N(Ra)C(=O)ORe, -N(Ra)C(=0)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O) 2 Rb, 15 -N(Ra)S(=0) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa and -NRaC 2
-
6 alkylORa, and the ring is additionally substituted by 0, 1, 2, 3, 4 or 5 substituents independently selected from Br, Cl, F and I. In another embodiment, in conjunction with any one of the above and below embodiments, R 2 is an unsaturated 5-, 6- or 7-membered monocyclic hydrocarbon ring containing 1, 2 or 3 atoms selected from N, 0 and S, wherein the carbon atoms of the ring are 20 substituted by 0, 1 or 2 oxo groups and the ring is substituted by 0, 1, 2 or 3 substituents selected from R*, R9, -CiAhaloalkyl, halo, cyano, nitro, -C(=O)Rb, -C(=O)ORe, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=0)R", -OC(=0)NRaRa, -OC(=O)N(Ra)S(=0) 2 Re,
-OC
2
-
6 alkylNRaRa, -OC 2
-
6 alkylORa, -SRa, -S(=0)Rb, -S(=0) 2 Rb, -S(=0) 2 NRaRa -S(=0) 2 N(Ra)C(=O)Rb, -S(=0) 2 N(Ra)C(=0)ORb, -S(=O) 2 N(Ra)C(=O)NRaRa, -NRaRa, 25 -N(Ra)C(=O)Rb, -N(Ra)C(=0)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O) 2 Rb, -N(Ra)S(=0) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa and -NRaC 2
-
6 alkylORa, and the ring is additionally substituted by 0, 1, 2, 3, 4 or 5 substituents independently selected from Br, Cl, F and I. In another embodiment, in conjunction with any one of the above and below 30 embodiments, R 2 is selected from 2-naphthyl, 1-naphthyl, phenyl, 3-chlorophenyl, 4 chlorophenyl, 3,5-dichlorophenyl, 3,4-dichlorophenyl, 2,4,6-trichlorophenyl, 3-fluorophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-biphenyl, 3-chloro-4-methylphenyl, 4-chloro-3 methylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 3 methylphenyl, [2.1.3]-benzoxadiazol-4-yl, thien-2-yl, 3-pyridyl, 8-quinolyl and 5-isoquinolyl. 19 WO 2006/036664 PCT/US2005/033659 in anotner emboanment, m conjunction with any one of the above and below embodiments, R 3 is H. In another embodiment, in conjunction with any one of the above and below embodiments, R 3 is phenyl, benzyl or C 1
.
6 alkyl, the phenyl, benzyl and -CI.
6 alkyl being 5 substituted by 0, 1, 2 or 3 substituents selected from R*, R9, -C14haloalkyl, halo, cyano, nitro, -C(=O)Rb, -C(=O)ORe, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=O) 2 R , -OC 2
-
6 alkylNRaRa, -OC 2 -6alkylORa, -SRa, -S(=O)Rb, -S(=O) 2 R , -S(=0) 2 NRaRa, -S(=O) 2 N(Ra)C(=O)Rb, -S(=0) 2 N(Ra)C(=O)ORb, -S(=O) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaWa 10 -N(Ra)S(=O) 2 Rb, -N(Ra)S(=O) 2 NRaRa, -NRaC 2
.
6 alkylNRRa and -NRaC 2
-
6 alkylORa, and additionally substituted by 0, 1, 2, 3, 4, 5 or 6 atom selected from Br, Cl, F and I. In another embodiment, in conjunction with any one of the above and below embodiments, RW is phenyl substituted by 0, 1, 2 or 3 substituents selected from Re, R9, CI.4haloalkyl, halo, cyano, nitro, -C(=O)Rb, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, 15 -ORa, -OC(=O)Rb, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=0) 2 Rb, -OC 2
-
6 alkylNRaRa,
-OC
2 6 alkylORa, -SRa, -S(=O)Re, -S(=0) 2 Rb, -S(=0) 2 NRaRa, -S(=O) 2 N(Ra)C(=O)Rb, -S(=0) 2 N(Ra)C(=O)OR, -S(=O) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O) 2 Rb, -N(Ra)S(=O) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa and -NRaC 2
-
6 alkylORa, and additionally substituted 20 by 0, 1, 2, 3, 4, 5 or 6 atom selected from Br, Cl, F and I. In another embodiment, in conjunction with any one of the above and below embodiments, R3 is -Ci1. salkyl substituted by 0, 1, 2 or 3 substituents selected from R*, R, Ci 4 haloalkyl, halo, cyano, nitro, -C(=O)Re, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=0)Rb, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=0) 2 Rb, -OC 2
-
6 alkylNRaRa, 25 -OC 2
.
6 alkylORa, -SRa, -S(=0)Rb, -S(=0) 2 Rb, -S(=0) 2 NRaRa, -S(=O) 2 N(Ra)C(=O)Rb,
-S(=O)
2 N(Ra)C(=O)ORb, -S(=O) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)R , -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NaRa, -N(Ra)S(=O) 2 Rb, -N(Ra)S(=O) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa and -NRaC 2
-
6 alkylORa, and additionally substituted by 0, 1, 2, 3, 4, 5 or 6 atom selected from Br, Cl, F and I. 30 In another embodiment, in conjunction with any one of the above and below embodiments, R 4 is H. In another embodiment, in conjunction with any one of the above and below embodiments, R 4 is phenyl, benzyl or -C 1
-
6 alkyl, the phenyl, benzyl and C 1 -6alkyl being substituted by 0, 1, 2 or 3 substituents selected from CI alkyl, Ci- 3 haloalkyl, -OCI.4alkyl, 20 WO 2006/036664 PCT/US2005/033659
-NH
2 , -NHCI 4 alkyl, and -N(C 14 alkyl)Cialkyl, and additionally substituted by 0, 1, 2, 3, 4, 5 or 6 atom selected from Br, Cl, F and I. In another embodiment, in conjunction with any one of the above and below embodiments, R 5 is: C \/8 5 R 6 R7 wherein the C ring is a saturated or partially saturated 6- or 7-membered ring containing 0, 1 or 2 atoms selected from N, 0 and S, wherein the carbon and sulfur atoms of the ring are 10 substituted by 0, 1 or 2 oxo groups and the ring is substituted by 0 or 1 substituents selected from R9, Ci-salkyl, CIAhaloalkyl, cyano, nitro, -C(=O)R, -C(=0)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, -OC(=0)NRaRa, -OC(=O)N(Ra)S(=O) 2 Re,
-OC
2
.
6 alkylNRaRa, -OC 2
-
6 alkylORa, -SRa, -S(=O)Rb, -S(=0) 2 Rb, -S(=0) 2 NaRa
-S(=O)
2 N(Ra)C(=O)Rb, -S(=0) 2 N(Ra)C(=0)ORb, -S(=O) 2 N(Ra)C(=O)NRaRa, -NRaRa, 15 -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=0) 2 Rb, -N(Ra)S(=0) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa and -NRaC 2
-
6 alkylORa, and the ring is additionally substituted by 0, 1, 2 or 3 substituents independently selected from Br, Cl, F and I; and R6; R7 and R8 are independently selected from H, a basic moiety, R9, CI.salkyl, 20 Ci 4 haloalkyl, cyano, nitro, -C(=O)Rb, -C(=O)ORb, -C(=0)NRaRa, -C(=NRa)NRaRa, -ORa -OC(=O)Rb, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=0) 2 R, -OC 2
-
6 alky1NRaRa, -OC 2 -6alkylORa, -SRa, -S(=0)Rb, -S(=0) 2 Rb, -S(=O) 2 NRaRa, -S(=0) 2 N(Ra)C(=O)Rb, -S(=0) 2 N(Ra)C(=O)ORb, -S(=0) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=0)NRaRa -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=0) 2 Rb, -N(Ra)S(=0) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa, 25 -NRaC 2 -6alkylORa, Br, Cl, F and I; provided that 1 or 2 of R 6 , R 7 and R 8 are a basic moiety. In another embodiment, in conjunction with any one of the above and below embodiments, R5 is: 21 WO 2006/036664 PCT/US2005/033659 \/8
R
6 R7 wherein: the part of the ring that is attached to the nitrogen atom in Formula (I) is a saturated or partially saturated 6- or 7-membered hydrocarbon ring containing 0, 1 or 2 atoms selected from 5 N, 0 and S, wherein the carbon and sulfur atoms of the ring are substituted by 0, 1 or 2 oxo groups and the ring is substituted by 0 or I substituents selected from R9, CI - 8 alkyl, C1Ahaloalkyl, cyano, nitro, -C(=O)R , -C(=0)ORb, -C(=0)NaRa, -C(=NRa)NRaRa, -ORa -OC(=O)Re, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=0) 2 Rb, -OC 2
-
6 alkylNRaRa, -OC 2 -6alkylORa, -SRa, -S(=0)R, -S(=0) 2 Rb, -S(=0) 2 NRaa, -S(=0) 2 N(Ra)C(=0)Rb, -S(=O) 2 N(Ra)C(=O)ORb, 10 -S(=0) 2 N(Ra)C(=0)NRaRa, -NRaRa, -N(Ra)C(=0)R, -N(Ra)C(=0)ORb, -N(Ra)C(=O)NaRa -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=0) 2 Rb, -N(Ra)S(=0) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa and -NRaC 2
-
6 alkylORa, and the ring is additionally substituted by 0, 1, 2 or 3 substituents independently selected from Br, Cl, F and I; and R6, R7 and R are independently selected from H, a basic moiety, R9, C 8 alkyl, 15 CIAhaloalkyl, cyano, nitro, -C(=O)Rb, -C(=O)ORb, -C(=0)NRRa, -C(=NRa)NRaRa, -ORa -OC(=0)Rb, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=0) 2 Rb, -OC 2
-
6 alkyNRaRa, -OC 2
-
6 alkylORa, -SRa, -S(=0)Rb, -S(=0) 2 Rb, -S(=0) 2 NWaRa, -S(=O) 2 N(Ra)C(=O)Rb, -S(=0) 2 N(Ra)C(=O)ORb -S(=0) 2 N(Ra)C(=0)NRaRa, -NRaRa, -N(Ra)C(=0)Rb, -N(Ra)C(=O)OR, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O) 2 Rb, -N(Ra)S(=0) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa, 20 -NRaC 2 -6alkylORa, Br, Cl, F and I; provided that 1 or 2 of R 6 , R 7 and R 8 are a basic moiety. In another embodiment, in conjunction with any one of the above and below embodiments, R6 and R8 are H; and wherein R7 is selected from amino, aminomethyl, isopropylaminomethyl, t-butylaminomethyl, 2-t-butylaminoethyl, 2-tert-butylamino-1-methyl ethyl, 1-tert-butylaminoethyl, 1-(tert-butylamino-methyl)-vinyl, 1-(piperidin-1-ylmethyl) 25 vinyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl, N isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl, N-t-butyl-N methylaminomethyl, N-iso-butyl-N-methylaminomethyl, N-t-butyl-N-ethylaminomethyl, N isobutyl-N-methylaminomethyl, N-t-butyl-N-isopropylaminomethyl, N,N di(isopropyl)aminomethyl, NN-dimethylaminomethyl, NN-diethylaminomethyl, NN-di(t 30 butyl)-aminomethyl, cyclopropylaminomethyl, cyclopropylaminoethyl, 22 WO 2006/036664 PCT/US2005/033659 cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl, cyclobutylaminomethyl, cyclobutylaminoethyl, cyclobutylmethylaminomethyl, cyclobutylmethylaminoethyl, 4,5 dihydro-imidazolyl, 1-piperidinylmethyl, 4-fluoropiperidin-1-ylmethyl, 4,4-difluoropiperidin 1 -ylmethyl, 3-hydroxypiperidin- 1 -ylmethyl, 4-hydroxypiperidin- 1 -ylmethyl, 4-(piperidin- 1 5 yl)piperidinylmethyl, 4-(dimethylamino)piperidin- 1 -ylmethyl, 2,6-dimethylpiperidin- 1 ylmethyl, 4-morpholinylmethyl, 1 -pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl, 2,5 dimethylpyrrolidin- 1 -ylmethyl, piperazin- 1 -ylmethyl, azocan- 1 -ylmethyl, azepan- 1 -ylmethyl, (7-azabicyclo[2.2.1]hept-7-yl)methyl, (1,3,3-trimethyl-6-azaicyclo[3.2.1]oct-6-yl)methyl, 2 piperidinyl and 4-methylpiperazin- 1 -ylmethyl. 10 In another embodiment, in conjunction with any one of the above and below embodiments, R 7 and R 8 are H; and R 6 is selected from amino, aminomethyl, isopropylaminomethyl, t-butylaminomethyl, 2-t-butylaminoethyl, 2-tert-butylamino-1-methyl ethyl, 1-tert-butylaminoethyl, 1-(tert-butylamino-methyl)-vinyl, 1-(piperidin-1-ylmethyl) vinyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl, N 15 isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl, N-t-butyl-N methylaminomethyl, N-iso-butyl-N-methylaminomethyl, N-t-butyl-N-ethylaminomethyl, N isobutyl-N-methylaminomethyl, N-t-butyl-N-isopropylaminomethyl, NN di(isopropyl)aminomethyl, NN-dimethylaminomethyl, N,N-diethylaminomethyl, NN-di(t butyl)-aminomethyl, cyclopropylaminomethyl, cyclopropylaminoethyl, 20 cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl, cyclobutylaminomethyl, cyclobutylaminoethyl, cyclobutylmethylaminomethyl, cyclobutylmethylaminoethyl, 4,5 dihydro-imidazolyl, 1 -piperidinylmethyl, 4-fluoropiperidin- 1 -ylmethyl, 4,4-difluoropiperidin 1-ylmethyl, 3-hydroxypiperidin-1-ylmethyl, 4-hydroxypiperidin-1-ylmethyl, 4-(piperidin-1 yl)piperidinylmethyl, 4-(dimethylamino)piperidin-1-ylmethyl, 2,6-dimethylpiperidin-1 25 ylmethyl, 4-morpholinylmethyl, 1 -pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl, 2,5 dimethylpyrrolidin- 1 -ylmethyl, piperazin- 1 -ylmethyl, azocan- 1 -ylmethyl, azepan- 1 -ylmethyl, (7-azabicyclo[2.2. 1 ]hept-7-yl)methyl, (1,3,3-trimethyl-6-azaicyclo[3.2.1 ]oct-6-yl)methyl, 2 piperidinyl and 4-methylpiperazin- 1 -ylmethyl. In another embodiment, in conjunction with any one of the above and below 30 embodiments, R 6 and R 7 are H; and R 8 is selected from amino, aminomethyl, isopropylaminomethyl, t-butylaminomethyl, 2-t-butylaminoethyl, 2-tert-butylamino-1-methyl ethyl, 1-tert-butylaminoethyl, 1-(tert-butylamino-methyl)-vinyl, 1-(piperidin-1-ylmethyl) vinyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl, N isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl, N-t-butyl-N 23 WO 2006/036664 PCT/US2005/033659 methylaminomethyl, N-iso-butyl-N-methylaminomethyl, N-t-butyl-N-ethylaminomethyl, N isobutyl-N-methylaminomethyl, N-t-butyl-N-isopropylaminomethyl, N,N di(isopropyl)aminomethyl, NN-dimethylaminomethyl, N,N-diethylaminomethyl, N,N-di(t butyl)-aminomethyl, cyclopropylaminomethyl, cyclopropylaminoethyl, 5 cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl, cyclobutylaminomethyl, cyclobutylaminoethyl, cyclobutylmethylaminomethyl, cyclobutylmethylaminoethyl, 4,5 dihydro-imidazolyl, 1 -piperidinylmethyl, 4-fluoropiperidin- 1 -ylmethyl, 4,4-difluoropiperidin 1-ylmethyl, 3-hydroxypiperidin-1-ylmethyl, 4-hydroxypiperidin-1-yhnethyl, 4-(piperidin-1 yl)piperidinylmethyl, 4-(dimethylamino)piperidin- 1 -ylmethyl, 2,6-dimethylpiperidin- 1 10 ylmethyl, 4-morpholinylmethyl, 1 -pyrrolidinylmethyl, 2-methylpyrrolidin- 1 -ylmethyl, 2,5 dimethylpyrrolidin-1-ylmethyl, piperazin-1-ylmethyl, azocan-1-ylmethyl, azepan-1-ylmethyl, (7-azabicyclo[2.2.1]hept-7-yl)methyl, (1,3,3-trimethyl-6-azaicyclo[3.2.1]oct-6-yl)methyl, 2 piperidinyl and 4-methylpiperazin- 1 -ylmethyl. In another embodiment, in conjunction with any one of the above and below 15 embodiments, Rs is: NRa S S02 NRa or R8 RB R8 R8 R8 R6 R7 R 6
R
7
R
6
R
7 each of which are substituted by 0 or 1 substituents selected from RE, C 1 .alkyl, CIAhaloalkyl, cyano, nitro, -C(=O)Rb, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, 20 -OC(=O)Rb, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=O) 2 Rb, -OC 2
-
6 alky1NRaRa, -OC 2 -6alkylORa, -SRa, -S(=O)Rb, -S(=0) 2 Rb, -S(=O) 2 NRaRa, -S(=0) 2 N(Ra)C(=O)Rb, -S(=0) 2 N(Ra)C(=O)ORb,
-S(=O)
2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O) 2 Rb, -N(Ra)S(=O) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa and -NRaC 2 -6alkylORa, and additionally substituted by 0, 1, 2 or 3 substituents independently 25 selected from Br, Cl, F and I. In another embodiment, in conjunction with any one of the above and below embodiments, R 5 is: 24 WO 2006/036664 PCT/US2005/033659 0 NH S S02 NH R8 _R8 _R8 R8 R8 or R6 R7 R 6
R
7
R
6 R ' R 6
R
7
R
6 R7 where the part of the above rings that is attached to the nitrogen atom in Formula (I) [i.e., dihydropyranyl, tetrahydropyridinyl, dihydrothiopyranyl, 1,1-dioxodihydrothiopyranyl portion of the ring including the nitrogen ring atom] is substituted by 0 or I substituents 5 selected from R', Ci- 8 alkyl, C 14 haloalkyl, cyano, nitro, -C(=O)Rb, -C(=O)ORb, -C(=O)NRaRa -C(=NRa)NRaRa, -ORa, -OC(=O)b, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=O) 2 Re,
-OC
2
-
6 alkylNRaRa, -OC 2
-
6 alkylORa, -SRa, -S(=O)Rb, -S(=O) 2 Rb, -S(=0) 2 NRaRa,
-S(=O)
2 N(Ra)C(=O)Re, -S(=0) 2 N(Ra)C(=O)ORb, -S(=O) 2 N(Ra)C(=O)NRaRa, -NRaRa -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa 10 -N(Ra)S(=O) 2 Rb, -N(Ra)S(=O) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa and -NRaC 2
-
6 alkylORa, and additionally substituted by 0, 1, 2 or 3 substituents independently selected from Br, Cl, F and I and R6, R7 and R8 are independently selected from H, a basic moiety, R9, C1- 8 alkyl, CiAhaloalkyl, cyano, nitro, -C(=O)Re, -C(=O)OR , -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa -OC(=O)R , -OC(=O)NRaRa, -OC(=O)N(Ra)S(=O) 2 Rb, -OC 2
-
6 alkylNRaRa, -OC 2
-
6 alkylORa, 15 -SRa, -S(=O)Rb, -S(=O) 2 Rb, -S(=0) 2 NRaRa, -S(=O) 2 N(Ra)C(=O)Re, -S(=0) 2 N(Ra)C(=O)OR , -S(=0) 2 N(Ra)C(=O)NRaRa, -NRaa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=0) 2 Rb, -N(Ra)S(=0) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa, -NRaC 2 _,alkylORa, Br, Cl, F and I; provided that 1 or 2 of R 6 , R7 and Re are a basic moiety. In another embodiment, in conjunction with any one of the above and below embodiments, R5 _so2 o - NH - S - so 2 -NH or RRR8 RR 8 R8 \8 R8 20 is: R 6
R
7 R' R 7
R
6 R7 R6 RT R 7 each of which are substituted by 0 or 1 substituents selected from R9, C 1
.
8 alkyl, Cihaloalkyl, cyano, nitro, -C(=O)Rb, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, 25 WO 2006/036664 PCT/US2005/033659 -OC(=O)RD, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=O) 2 Rb, -OC 2
.
6 alkylNRaRa, -OC 2 -6alkylORa, -SRa, -S(=O)Rb, -S(=0) 2 Rb, -S(=0) 2 NRaRa, -S(=O) 2 N(Ra)C(=O)Rb, -S(=0) 2 N(Ra)C(=O)ORb,
-S(=O)
2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=0) 2 R, -N(Ra)S(=O) 2 NRaRa, -NRaC 2 -6alkylNRaRa and 5 -NRaC 2 -6alkylORa, and additionally substituted by 0, 1, 2 or 3 substituents independently selected from Br, Cl, F and I. In another embodiment, in conjunction with any one of the above and below embodiments, R5 is: sO 2
-
0 NH - -r R8 _R8 \R8 \R8 R8 R6 R 7 R6 R 7 R6 R ' R6 R ' R6 R7 -0111. O lim preferably, or R8/ R \ / R 8
R
6 R7 R 6 R7 R6 R7 10 where the part of the above rings that is attached to the nitrogen atom in Formula (I) [i.e., dihydropyranyl, tetrahydropyridinyl, dihydrothiopyranyl, 1,1-dioxodihydrothiopyranyl portion of the ring including the nitrogen ring atom] is substituted by 0 or 1 substituents selected from R9, C 1 _-alkyl, C 1 4 haloalkyl, cyano, nitro, -C(=O)Rb, -C(=O)ORb, -C(=O)NRaRa -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=O) 2 R, 15 -OC 2
-
6 alkylNRaRa, -OC 2
-
6 alkylORa, -SRa, -S(=O)Rb, -S(=0) 2 Rb, -S(=0) 2 NRaRa, -S(=0) 2 N(Ra)C(=O)Rb, -S(=0) 2 N(Ra)C(=O)ORb, -S(=O) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NWRa, -N(Ra)S(=O) 2 Rb, -N(Ra)S(=0) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa and -NRaC 2
-
6 alkylORa, and additionally substituted by 0, 1, 2 or 3 substituents independently selected from Br, Cl, F and I 20 and R 6 , R7 and R 8 are independently selected from H, a basic moiety, R9, CIgalkyl, ClAhaloalkyl, cyano, nitro, -C(=O)Rb, -C(=O)ORb, -C(=O)NRaRa, C(=NRa)NRaRa, -ORa -OC(=O)Rb, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=O) 2 Rb, -OC 2
-
6 alkylNRaRa, -OC 2 -6alkylORa, -SRa, -S(=O)Rb, -S(=0) 2 Rb, -S(=0) 2 NRaRa, -S(=0) 2 N(Ra)C(=O)Rb, -S(=0) 2 N(Ra)C(=O)ORb, -S(=0) 2 N(Ra)C(=O)NRaRa, -NR Ra, -N(Ra)C(=O)Rb, -N(Ra)C(=O)OR, -N(Ra)C(=O)NRaRa 26 WO 2006/036664 PCT/US2005/033659 -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O)Rb, -N(Ra)S(=0) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa, -NRaC 2 -6alkylORa, Br, Cl, F and I; provided that 1 or 2 of R 6 , R 7 and R 8 are a basic moiety. In another embodiment, in conjunction with any one of the above and below embodiments, R 3 and R 4 together may additionally be C 2
-
3 alkylene substituted by 1 or 2 5 substituents selected from C1.salkyl, C14haloalkyl, halo, oxo, cyano, nitro, -C(=O)Re, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=0) 2 Rb, -OC 2
.
6 alkylNRaRa, -OC 2 -salkylORa, -SRa, -S(=O)Rb, -S(=0) 2 Rb, -S(=0) 2 NRaRa, -S(=O) 2 N(Ra)C(=O)Rb, -S(=O) 2 N(Ra)C(=O)ORb, -S(=0) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, 10 -N(Ra)S(=O) 2 Rb, -N(Ra)S(=0) 2 NRaRa, -NRaC2-6alkylNRaRa and -NRaC 2
-
6 alkyORa, and additionally substituted by 0, 1, 2, 3 or 4 substituents independently selected from Br, Cl, F and I. In another embodiment, in conjunction with any one of the above and below embodiments, R 3 and R 4 together may additionally be C 2
-
3 alkylene. 15 In another embodiment, in conjunction with any one of the above and below embodiments, RIC and R 4 together may additionally be C 24 alkylene substituted by 1 or 2 substituents selected from Ci-salkyl, CI.4haloalkyl, halo, oxo, cyano, nitro, -C(=O)Re, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=0) 2 Rb, -OC 2
-
6 alkylNRaRa, -OC 2 -6alkylORa, -SRa, -S(=O)Rb, -S(=0) 2 R, 20 -S(=O) 2 NRaRa, -S(=O) 2 N(Ra)C(=O)Rb, -S(=O) 2 N(Ra)C(=O)ORb, -S(=0) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa -N(Ra)S(=O) 2 Rb, -N(Ra)S(=0) 2 NRaRa, -NRaC 2
-
6 alkylNRaRa and -NRaC 2
-
6 alkylORa, and additionally substituted by 0, 1, 2, 3 or 4 substituents independently selected from Br, Cl, F and I. 25 In another embodiment, in conjunction with any one of the above and below embodiments, RIC and R 4 together may additionally be C24alkylene. In another embodiment, in conjunction with any one of the above and below embodiments, a substituent on R 2 that is vicinal to the -S0 2
-R
2 bond together with R 3 may additionally be Ci- 3 alkylene substituted by 1 or 2 substituents selected from C1-salkyl, 30 Cl4haloalkyl, halo, oxo, cyano, nitro, -C(=O)Rb, -C(=0)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=O) 2 Rb, -OC 2
-
6 alkylNaRa,
-OC
2
-
6 alkylOR, -SRa, -S(=0)Rb, -S(=0) 2 R, -S(=0)2NR, -S(=O) 2 N(Ra)C(=O)R, -S(=0) 2 N(Ra)C(=O)ORb, -S(=0) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O) 2 Rb, 27 WO 2006/036664 PCT/US2005/033659 -N(Ra)S(=O) 2 NR'e,~-NRC~2-6akyflkaRa and -NRaC 2
-
6 alkylORa, and additionally substituted by 0, 1, 2, 3 or 4 substituents independently selected from Br, Cl, F and I. In another embodiment, in conjunction with any one of the above and below embodiments, a substituent on R 2 that is vicinal to the -S0 2
-R
2 bond together with R3 may 5 additionally be C 1 3 alkylene. In another embodiment, in conjunction with any one of the above and below embodiments, a substituent on R2 that is vicinal to the -S0 2
-R
2 bond together with R3 may additionally be -C(=O). In another embodiment, in conjunction with any one of the above and below 10 embodiments: R3 R2-S-1-7 02 is o 0 with the remaining substituents on R2 and the vicinal substituent-R 3 bridge are as defined above. In another embodiment, in conjunction with any one of the above and below embodiments, 0
R
3 R2sR2 15 02 is so with the remaining substituents on R2 are as defined above. In another embodiment, in conjunction with any one of the above and below embodiments, R3 R2_g/ Nl 02 is o \o with the remaining substituents on R2 as defined above. In another embodiment: 20 R' is hydrogen, cyano, -C(O)OCi-salkyl, -C(O)OH, , -C(=O)NRaRa, -C 1 .salkyl substituted by 0, 1, 2, 3 atoms independently selected from halo; preferably R1 is hydrogen or trifluoromethyl, -C(0)0-tert-butyl, -C(O)OH, cyano, or -C(O)NH 2 ; more preferably hydrogen or trifluoromethyl; Ria, Rib, R', and RW are hydrogen; and 25 R'c is hydrogen, halo, or -OH, preferably hydrogen, fluoro or -OH, more preferably hydrogen. 28 WO 2006/036664 PCT/US2005/033659 - Within this embodiment, and more preferred groups of compounds contained therein, a more preferred group of compounds is that wherein:
R
2 is phenyl, naphthenyl, 5- or 6-membered monocyclic saturated or unsaturated hydrocarbon ring containing 1, 2, 3 or 4 atoms selected from N, 0 and S, or 9- or 10 5 membered unsaturated hydrocarbon ring containing 1, 2, 3 or 4 atoms selected from N, 0 and S, preferably phenyl, benzodioxinyl, quinolinyl, isoquinolinyl, napthalenyl, 2,3 dihydrobenzofuranyl, tetrahydrofuranyl, 2,3-dihydroindolyl, 3,4-dihydro-2H benzo[b][1,4]dioxepinyl, or 3,4-dihydro-2H-benzo[b][1,4]oxazine substituted with 0, 1, 2, or three substitutents independently selected from halo, CI.
4 haloalkyl, -C 1.alkyl, nitro, -OH, 10 NH 2 , R 5 , -OCI- 6 alkyl, or -OC I- 6 alkyl substituted with one, two, or three halo; preferably, 0, 1, 2, or three substitutents independently selected from fluoro, chloro, trifluoromethyl, methyl, tert-butyl, trifluoromethoxy, methoxy, nitro, -OH, -NH 2 , phenyl, or oxazolyl; more preferably R2 is 2-trifluoromethylphenyl, 3-bromophenyl, 4-bromo-3-trifluoromethylphenyl, 3-chloro-4 fluorophenyl, 3-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 3-methylphenyl, 4-chloro-2 15 fluorophenyl, 2-chloro-4-fluorophenyl, naphthalene-2-yl, 3-tert-butylphenyl, 4-tert butylphenyl, [1.3]-oxazol-4-ylphenyl, 3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl, 1,2,3,4 tetrahydroquinolin-8-yl, 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl, 3-chloro-2 fluorophenyl, 3-methoxyphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 3,5-dimethylphenyl, 3,4-dimethylphenyl, 2-fluoro-5-methylphenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, 2,5 20 dichlorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6 dichlorophenyl, 2-chloro-6-methylphenyl, 3-fluoro-6-methylphenyl, 5-chloro-2 methoxyphenyl, 4-chloro-3-trifluoromethylphenyl, 2-chloro-5-trifluoromethylphenyl, 5 chloro-2-fluorophenyl, 3-chloro-2-fluorophenyl, 2,6-dichloro-4-trifluoromethylphenyl, 4 ethylphenyl, 4-chloro-3-methylphenyl, 4-chloro-2,5-dimethylphenyl, 3-chloro-4-methylphenyl, 25 3,4-dimethoxyphenyl, 3,5-dichloro-2-hydroxyphenyl, isoquinolin-6-yl, quinolin-8-yl, 2,3 dihydrobenzofuran-5-yl, 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 2-nitrophenyl, 2-aminophenyl, 2-fluoro-5-trifluoromethylphenyl, 6-chloronaphthalen-2-yl, 5-chloronaphthalen-1-yl, 2-nitro-4 trifluoromethylphenyl, or 4-biphenyl, 3-biphenyl. Within the above embodiment and preferred and more preferred groups contained 30 within this embodiment, an even more preferred group of compounds is that wherein R 5 is unsaturated 10-membered bicyclic hydrocarbon ring containing 0, 1, 2, 3 or 4 atoms selected from N, 0 and S, preferably 1(R)-i ,2,3,4-tetrahydronaphthalen-1 -yl or 4(R)-chroman-4-yl, substituted with cycloalkylamino-(Ci-C 6 )alkyl, cycloalkyl(Ci-C 6 )alkylamino(CI-C 6 )alkyl, CI.6 alkylamino-Ci-6-alkyl, 5-8 membered nitrogen-containing saturated heterocyclyl-C 24 -alkenyl, 29 WO 2006/036664 PCT/US2005/033659 >o memoerea mtrogen-contamng partially unsaturated or unsaturated heterocyclyl, 6 or 7 membered saturated heterocyclyl-(Ci-)-alkylamino(Ci- 6 )alkyl, (Ci- 6 )alkylamino(Ci- 6 )alkyl substituted with -OH, (CI-6)alkoxy (C .)alkylamino or -NHCO(C 1
.
6 )alkyl, or 5-7 membered nitrogen-containing saturated heterocyclyl-C14-alkyl wherein the heterocyclyl ring optionally 5 contains an oxygen or nitrogen ring atom and is substituted with 0, 1, or 2 substitutents independently selected from halo, -OH, or -CI- 6 alkyl and additionally with 0 or 1 substitutuent selected from halo or nitro. Preferably, R 5 is 1,2,3,4-tetrahydronaphthalen- I -yl substituted at the 6-position or chroman-4-yl substituted at the 7 position with cyclopropylaminomethyl, cyclopropylmethylaminomethyl, cyclobutylaminomethyl, cyclohexylaminomethyl, 10 cyclopentylaminomethyl, 1-cyclopropylaminoethyl, 1-cyclobutylaminoethyl, 1 cyclopenylaminoethyl, 2-methylpropylaminomethyl, 2,2-dimethylpropylaminomethyl, 1 methylethylaminomethyl, tert-butylaminomethyl, 1,1 -dimethylpropylaminomethyl, pyridine-4 ylaminomethyl, (piperidin-1-ylCH 2
)C=CH
2 , tetrahydrofuran-2-ylmethylaminomethyl, morpholin-4-ylmethyl, piperidin- I -ylmethyl, pyrrolidin- 1 -ylmethyl, 4-hydroxypiperidin- 1 15 ylmethyl, 4-fluoropiperidin-1-ylmethyl, 4-methylpiperidin-1-ylmethyl, 3-hydroxypiperidin-1 ylmethyl, 2,6-dimethylpiperidin- 1 -ylmethyl, homopiperidin- 1 -ylmethyl, 4-methylpiperazin- 1 ylmethyl, 2-(pyrrolidin-1-yl)ethylaminomethyl, 2-(piperidin-1-yl)ethylaminomethyl, 2 (morpholin- 1 -yl)ethylaminomethyl, -CH 2
NH(CH
3
)
2
CH
2 OH, -CH 2
NH(CH
3
)
2
CH
2 0CH 3 , 2 (dimethylamino)ethylaminomethyl, 2-(diethylamino)ethylaminomethyl or 2,5-dihydro-1H 20 imidazol-2-yl. A family of specific compounds of particular interest within Formula (I) consists of compounds and pharmaceutically-acceptable salts thereof as follows: (2R)-3-(((2,3-dichlorophenyl)sulfonyl)(methyl)amino)-2-hydroxy-N-((1R)-6-( 1 piperidinylmethyl)- 1,2,3,4-tetrahydro- I -naphthalenyl)propanamide; 25 (2R)-3-(((2,3-dichlorophenyl)sulfonyl)(methyl)amino)-2-methyl-N-((IR)-6-( 1 piperidinylmethyl)-1,2,3,4-tetrahydro-1 -naphthalenyl)propanamide; (2R)-3-(((2,3-dichlorophenyl)sulfonyl)amino)-2-methyl-N-((1R)-6-(1-piperidinyl methyl)- 1,2,3,4-tetrahydro-1 -naphthalenyl)propanamide; (2R,3R)-4,4,4-trifluoro-2-hydroxy-N-((1R)-6-(1 -piperidinylmethyl)- 1,2,3,4-tetrahydro 30 1 -naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3R)-3-(((2,3-dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((IR)-6-(I -piperidinyl methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R)-3-(((2,3-dichlorophenyl)sulfonyl)amino)-N-((1R)-6-(((1,1-dimethylethyl)amino) methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-4,4,4-trifluorobutanamide; 30 WO 2006/036664 PCT/US2005/033659 k3An)-.-i-kk/,J-aicnioropneny1)sulfonyl)amino)-4,4,4-tnifluoro-N-(( 1R)-6-( 1-piperidinyl methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R)-3-(((2,5-dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((4R)-7-( 1-piperidinyl methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide; 5 (3R)-3-(((2,5-dichlorophenyl)sulfonyl)amino)-N-(( 1R)-6-((( 1,1 -dimethylethyl)amino) methyl)- 1,2,3,4-tetrahydro-I -naphthalenyl)-4,4,4-trifluorobutanamide; (3R)-3-(((2,6-dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-(( IR)-6-(I -piperidinyl methyl)- 1,2,3 ,4-tetrahyclro- 1 -naphthalenyl)butanamide; (3R)-3-(((3 ,4-dichlorophenyl)sulfonyl)amino)-4-fluoro-N-(( 1R)-6-( I -piperidinyl 10 methyl)- 1,2,3,4-tetrahydro-l1-naphthalenyl)butanamide; (3R)-3-(((3,4-dichlorophenyl)sulfonyl)amino)-N-(( 1R)-6-(((, 1, -dimethylethyl)amino) methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-4,4,4-trifluorobutanamide; (3R)-3 -(((4-chloro-2,5-dimtethylphenyl)sulfonyl)amino)-N-((I R)-6-(((, I, -dimethyl ethyl)amino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-4,4,4-trifluorobutanamide; 15 (3R)-3-(((4-chlorophenyl)sulfonyl)amino)-N-(( IR)-6-((( 1,1-dimethylethyl)amino) methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-4,4,4-trifluorobutanamide; (3R)-3-(((5-chloro-2-(methyloxy)phenyl)sulfonyl)amino)-4,4,4-trifluoro-N-(( 1R)-6-( 1 piperidinylmethyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R)-3 -(((5 -chloro-2-fluorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-(( I R)-6-( 1 20 piperidinylmethyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R)-3-((2,3-dihydro- 1,4-benzodioxin-6-ylsulfonyl)amino)-4,4,4-trifluoro-N-(( 1R)-6 (1 -piperidmnylinethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R)-4,4,4-trifluoro-3-(((8-(methyloxy)-5-quinolinyl)sulfonyl)amino)-N-(( 1R)-6-( 1 piperidinylmethyl)- 1,2,3 ,4-tetrahycfro- 1 -naphthalenyl)butanamide; 25 (3R)-4,4,4-trifluoro-3-((2-naphthalenylsulfonyl)amino)-N-(( 1R)-6-( 1 -piperidinyl methyl)-1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R)-4,4,4-trifluoro-N-(( 1R)-6-( 1 -piperidinylmethyl)- 1,2,3 ,4-tetrahydro- 1 naphdialenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3R)-4,4,4-trifluoro-N-(( 1R)-6-( I -piperidinylmethyl)- 1,2,3 ,4-tetrahydro- 1 30 naphthalenyl)-3-((8-quinolinylsulfonyl)amino)butanamide; (3R)-4-hydroxy-3-(((4-methylphenyl)sulfonyl)amino)-N-(( IR)-6-( I -piperidinyl methyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R)-N-(( I R)-6-(((l 1, -dimethylethyl)amino)methyl)- I ,2,3,4-tetrahyclro- I naphthalenyl)-4-fluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 31 WO 2006/036664 PCT/US2005/033659 (3R)-N-((1R)-6-(((1,1-dimethylethyl)amino)methyl)-1 ,2,3,4-tetrahydro- 1 naphthalenyl)-4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3R)-N-((l R)-6-((( 1,1 -dimethylethyl)amino)methyl)- 1,2,3,4-tetrahydro- 1 naphthalenyl)-4,4,4-trifluoro-3-((2-naphthalenylsulfonyl)amino)butanamide; 5 (3R)-N-((1 R)-6-(((1,1 -dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro- 1 naphthalenyl)-4,4,4-trifluoro-3-(((2,4,6-trimethylphenyl)sulfonyl)amino)butanamide; (3R)-N-((1 R)-6-((( 1,1 -dimethylethyl)amino)methyl)- 1,2,3,4-tetrahydro-1 naphthalenyl)-4,4,4-trifluoro-3-(((4-methylphenyl)sulfonyl)amino)butanamide; (3R)-N-((1 R)-6-((cyclopentylamino)methyl)- 1,2,3,4-tetrahydro- I -naphthalenyl)-4 10 fluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3R)-N-((4R)-7-((cyclopentylamino)methyl)-3,4-dihydro-2H-chromen-4-yl)-4,4,4 trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3R,4R)-3-(((3,4-dichlorophenyl)sulfonyl)amino)-4-hydroxy-N-((1R)-6-(1-piperidinyl methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)pentanamide; 15 (3S)-3-(((2,3-dichlorophenyl)sulfonyl)amino)-4,4,4-trfluoro-N-((1R)-6-(1 -piperidinyl methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-(((2,5-dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((1R)-6-(1 -piperidinyl methyl)-1,2,3,4-tetrahydro-1 -naphthalenyl)butanamide; (3S)-3-(((2,6-dichloro-4-(trifluoromethyl)phenyl)sulfonyl)amino)-N-((1R)-6-(1 20 piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-(((2,6-dichloro-4-(trifluoromethyl)phenyl)sulfonyl)amino)-N-((1R)-6-(((1,1 dimethylethyl)amino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-(((2-chloro-5-(trifluoromethyl)phenyl)sulfonyl)amino)-N-((1R)-6-(1 piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; 25 (3S)-3-(((2-chloro-5-(trifluoromethyl)phenyl)sulfonyl)amino)-N-((1R)-6-((cyclopentyl amino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-(((2-fluoro-5-(trifluoromethyl)phenyl)sulfonyl)amino)-N-((1R)-6-(1-piperidinyl methyl)-1,2,3,4-tetrahydro-1 -naphthalenyl)butanamide; (3S)-3-(((2-nitro-4-(trifluoromethyl)phenyl)sulfonyl)amino)-N-((1R)-6-(I-piperidinyl 30 methyl)- 1,2,3,4-tetrahydro-1 -naphthalenyl)butanamide; (3S)-3-(((3,4-bis(methyloxy)phenyl)sulfonyl)amino)-4,4,4-trfluoro-N-((lR)-6-( 1 piperidinylmethyl)- 1,2,3,4-tetrahydro- I -naphthalenyl)butanamide; (3S)-3-(((3,4-dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((1R)-6-(1 -piperidinyl methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; 32 WO 2006/036664 PCT/US2005/033659 (3S)-3-(((3,4-dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((1R)-6-(1 -(1 piperidinylmethyl)ethenyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-(((3,5-dichloro-2-hydroxyphenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((1R)-6-( 1 piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; 5 (3S)-3-(((3-chloro-2-fluorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((1R)-6-(1 piperidinylmethyl)- 1,2,3,4-tetrahydro- I -naphthalenyl)butanamide; (3S)-3-(((3-chloro-4-methylphenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((1R)-6-( 1 piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-(((4-(1,1 -dinethylethyl)phenyl)sulfonyl)amino)-N-((1R)-6-(1 -piperidinyl 10 methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-(((4-(1,3-oxazol-5-yl)phenyl)sulfonyl)amino)-N-((1R)-6-(1 -piperidinylmethyl) 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-(((4-bromo-3-(trifluoromethyl)phenyl)sulfonyl)amino)-N-((1R)-6-( 1 piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; 15 (3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((1R)-6-( 1 piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((1R)-6-((3 hydroxy- 1 -piperidinyl)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((1R)-6-(((2 20 (1 -pyrrolidinyl)ethyl)amino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((4R)-7-( 1 piperidinylmethyl)-3,4-dihydro-2H-chromen-4-yl)butanamide; (3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((4R)-7-((3 hydroxy-1-piperidinyl)methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide; 25 (3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((1R)-6-((( 1,1 -dimethyl ethyl)amino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((1R)-6-((cyclopentyl amino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((1R)-6-(1 -piperidinyl 30 methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((1R)-6-(((2-methylpropyl) amino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((1R)-6-(((1 -methylethyl) amino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; 33 WO 2006/036664 PCT/US2005/033659 (3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((1R)-6-(((cyclopropyl methyl)amino)methyl)- 1,2,3,4-tetrahydro-1 -naphthalenyl)butanamide; (3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((1R)-6-((cyclobutylamino) methyl)-1,2,3,4-tetrahydro-1 -naphthalenyl)butanamide; 5 (3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((1R)-6-(((3S)-3-hydroxy-1 piperidinyl)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((lR)-6-(1 -pyrrolidinyl methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4R)-7-(((1,1-dimethyl 10 ethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide; (3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4R)-7-(cyclopentylamino) methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide; (3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4R)-7-(1-piperidinyl methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide; 15 (3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4R)-7-(((2-methylpropyl) amino)methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide; (3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4R)-7-(((1 -methylethyl) amino)methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide; (3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4R)-7-(((cyclopropyl 20 methyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide; (3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4R)-7-((cyclobutylamino) methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide; (3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4R)-7-(((3S)-3-hydroxy- 1 piperidinyl)methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide; 25 (3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4R)-7-(1-pyrrolidinyl methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide; (3S)-3-(((4-chloro-3-(trifluoromethyl)phenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((1R) 6-(1 -piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-(((5-chloro- 1 -naphthalenyl)sulfonyl)amino)-N-((1R)-6-((cyclopentylamino) 30 methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-(((6-chloro-2-naphthalenyl)sulfonyl)amino)-N-((1R)-6-((((6-chloro-2 naphthalenyl)sulfonyl)(cyclopentyl)amino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl) butanamide; 34 WO 2006/036664 PCT/US2005/033659 (3S)-3-(((6-chloro-2-naphthalenyl)sulfonyl)amino)-N-((1R)-6-((cyclopentylamino) methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-(((6-chloro-2-naphthalenyl)sulfonyl)amino)-N-((1R)-6-(1 -piperidinylmethyl) 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; 5 (3S)-3-((1,1 '-biphenyl-3-ylsulfonyl)amino)-N-((1R)-6-(1 -piperidinylmethyl)- 1,2,3,4 tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-((1,1 '-biphenyl-4-ylsulfonyl)amino)-N-((1R)-6-(((1,1 -dimethylethyl) amino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-((1,1 '-biphenyl-4-ylsulfonyl)amino)-N-((1R)-6-(1 -piperidinylmethyl)- 1,2,3,4 10 tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-((2,3-dihydro-1 -benzofuran-5-ylsulfonyl)amino)-4,4,4-trifluoro-N-((1R)-6-( 1 piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-(methyl((3-(trifluoromethyl)phenyl)sulfonyl)amino)-N-((1R)-6-(1-piperidinyl methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; 15 (3S)-4,4,4-trifluoro-3-((2-naphthalenylsulfonyl)amino)-N-((1R)-6-(1 -piperidinyl methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-4,4,4-trifluoro-3-((2-naphthalenylsulfonyl)amino)-N-((1R)-6-(1 -piperidinyl methyl)- 1,2,3,4-tetrahydro- I -naphthalenyl)butanamide; (3S)-4,4,4-trifluoro-3-((2-naphthalenylsulfonyl)amino)-N-((1R)-6-(1 -(1 -piperidinyl 20 methyl)ethenyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-4,4,4-trifluoro-3-((6-isoquinolinylsulfonyl)amino)-N-((IR)-6-(1 -piperidinyl methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-4,4,4-trifluoro-3-(methyl((3-(trifluoromethyl)phenyl)sulfonyl)amino)-N-((1R)-6 (1 -piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; 25 (3S)-4,4,4-trifluoro-N-((1R)-6-((((2R)-tetrahydro-2-furanylmethyl)amino)methyl) 1,2,3,4-tetrahydro- 1 -naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-4,4,4-trifluoro-N-((1R)-6-((((2S)-tetrahydro-2-furanylmethyl)amino)methyl) 1,2,3,4-tetrahydro- 1 -naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-4,4,4-trifluoro-N-((1R)-6-(((1 -methylethyl)amino)methyl)- 1,2,3,4-tetrahydro- 1 30 naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-4,4,4-trifluoro-N-((1R)-6-(((2-(1 -piperidinyl)ethyl)amino)methyl)- 1,2,3,4 tetrahydro- 1 -naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-4,4,4-trifluoro-N-((lR)-6-(((2-(l-pyrrolidinyl)ethyl)amino)methyl)-1,2,3,4 tetrahydro- 1 -naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 35 WO 2006/036664 PCT/US2005/033659 (35)-4,4,4-trifluoro-N-(( 1R)-6-(((2-(4-morpholinyl)ethyl)amino)methyl)- 1,2,3,4 tetrahydro- 1 -naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-4,4,4-trifluoro-N-(( 1R)-6-(((2-hydroxy- 1, 1 -dimethylethyl)amino)methyl)- 1,2,3,4 tetrahydro- 1 -naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)ammo)butanamide; 5 (3S)-4,4,4-trifluoro-N-(( 1R)-6-(((2-methylpropyl)ammno)methyl)- 1 ,2,3,4-tetrahydro- 1 naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-4,4,4-trifluoro-N-(( 1R)-6-(((3.S)-3-hydroxy- 1 -piperidinyl)methyl)- 1,2,3,4 tetrahydro- 1 -naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-4,4,4-trifluoro-N-(( 1R)-6-((4-fluoro- 1 -piperidmnyl)methyl)- 1 ,2,3,4-tetrahydro- 1 10 naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-4,4,4-trifluoro-N-(( 1R)-6-((4-hydroxy- 1 -piperidinyl)methyl)- 1 ,2,3,4-tetrahydro- 1 naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-4,4,4-trifluoro-N-(( 1R)-6-((4-methyl- 1 -piperazinyl)methyl)- 1,2,3 ,4-tetrahydro- 1 naphthalenyl)-3-(((3 -(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 15 (3S)-4,4,4-trifluoro-N-(( 1R)-6-((4-methyl- 1 -piperidinyl)methyl)- 1,2,3 ,4-tetrahydro- 1 naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-4,4,4-trifluoro-N-(( 1 R)-6-( 1 -(1 -piperidinylmethyl)ethenyl)- 1,2,3 ,4-tetrahydro- 1 naphthalenyl)-3-(((2,4,6-trimethylphenyl)sulfonyl)amino)butanamide; (35) -4,4,4-trifluoro-N-(( 1R)-6-( 1 -piperidinylmethyl)- 1,2,3 ,4-tetrahydro- 1 20 naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-4,4,4-trifluoro-N-(( 1R)-6-( 1 -piperidmnylmethyl)- 1 ,2,3,4-tetrahydro- 1 naphthalenyl)-3-(((2,4,6-trimethylphenyl)sulfonyl)amino)butanamide; (3S)-4,4,4-trifluoro-N-(( 1R)-6- (1 -piperidinylmethyl)- 1,2,3 ,4-tetrahydro- 1 naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 25 (3S)-4,4,4-trifluoro-N-(( 1R)-6-( 1 -pyrrolidinylmethyl)- 1,2,3 ,4-tetrahydro- 1 naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-4,4,4-trifluoro-N-((1R)-6-(4-morpholinylmethyl)- 1,2,3,4-tetrahydro- 1 naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-4,4,4-trifluoro-N-(( 1R)-6-(hydroxymethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-3 30 (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-4,4,4-trifluoro-N-((4R)-7-(((2-methylpropyl)amino)methyl)-3,4-dihydro-2H chromen-4-yl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-4,4,4-trifluoro-N-((4R)-7-(((3R)-3-hydroxy- 1 -piperidinyl)methyl)-3 ,4-dihydro-2H chromen-4-yl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 36 WO 2006/036664 PCT/US2005/033659 (3S)-4,4,4-trifluoro-N-((4R)-7-((4-methyl-l1-piperazinyl)methyl)-3,4-dihydro-2H chromen-4-yl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3.S)-4,4,4-trifluoro-N-((4R)-7-( 1 -piperidinylmethyl)-3 ,4-dihydro-2H-chromen-4-yl)-3 (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 5 (3S)-4,4,4-trifluoro-N-((4R)-7-(4-morpholinylmethyl)-3 ,4-dihydro-2H-cbromen-4-yl) 3-(((3 -(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-4-fluoro-N-(( 1R)-6-( 1 -piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-3 (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-(( 1R)-6-((( 1,1 -dimethylethyl)ammno)methyl)- 1,2,3 ,4-tetrahydro-l1-naphthalenyl) 10 3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)-5-hexynamide; (3S)-N-(( 1R)-6-((( 1,1 -dimethylethyl)amino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl) 4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-(( 1R)-6-(((, 1, -dimethylethyl)amino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naplihalenyl) 3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 15 (3S)-N-(( 1R)-6-(((, 1, -dimethylethyl)amino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl) 4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-(( 1R)-6-((( 1,1 -dimethylethyl)amino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl) 3-(((2-nitro-4-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-(( 1R)-6-(((2-(acetylamino)ethyl)amino)methyl)- 1,2,3 ,4-tetrahydro- 1 20 naphthalenyl)-4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3SJ-N-(( 1 R)-6-(((2-(diethylammno)ethyl)ammno)methyl)- 1 ,2,3,4-tetrahydro- 1 naphthalenyl)-4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-(( 1R)-6-(((2-(dimethylamino)ethyl)ammno)methyl)- 1,2,3,4-tetrahydro- 1 naphthalenyl)-4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 25 (3S)-N-(( 1 R)-6-(((2-(methyloxy)ethyl)amino)methyl)- 1 ,2,3,4-tetrahydro- 1 naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-(( 1R)-6-(((2,2-dimethylpropyl)amino)methyl)- 1 ,2,3,4-tetrahydro- 1 naphthalenyl)-4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-(( 1R)-6-(((2-methylpropyl)amino)methyl)- 1 ,2,3,4-tetrahydro- I -naphthalenyl)-3 30 (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-(( 1R)-6-(((2R,6S)-2,6-dinethyl- 1 -piperidinyl)methyl)- 1 ,2,3,4-tetrahydro- 1 naphthalenyl)-4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-(( 1 R)-6-(((cyclopropylmethyl)amino)methyl)- 1 ,2,3,4-tetrahydro- 1 naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 37 WO 2006/036664 PCT/US2005/033659 (3S)-N-((IR)-6-((1 R)- 1 -((2-(methyloxy)ethyl)amino)ethyl)- 1,2,3,4-tetrahydro- 1 naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((1R)-6-((1 R)- 1 -(cyclobutylamino)ethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-3 (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 5 (3S)-N-((1R)-6-((1 R)- 1 -(cyclopropylamino)ethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl) 3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((1R)-6-((1 S)- 1 -((2-methylpropyl)amino)ethyl)- 1,2,3,4-tetrahydro- 1 naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((1R)-6-((1 S)- 1 -((cyclopropylmethyl)amino)ethyl)- 1,2,3,4-tetrahydro- 1 10 naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((1R)-6-((1 S)- 1 -(cyclopentylamino)ethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-3 (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((1 R)-6-((3-pyridinylamino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-3 -(((3 (trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 15 (3S)-N-((1R)-6-((cyclobutylamino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-4,4,4 trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((1R)-6-((cyclohexylamino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-4,4,4 trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((1R)-6-((cyclopentyl((2-fluoro-5-(trifluoromethyl)phenyl)sulfonyl)amino) 20 methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-3-(((2-fluoro-5-(trifluoromethyl)phenyl) sulfonyl)amino)butanamide; (3S)-N-((1R)-6-((cyclopentylamino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-3-(((3 (trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((1R)-6-((cyclopentylamino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-4,4,4 25 trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((1R)-6-((cyclopentylamino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-3-(((2 fluoro-5-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((1R)-6-((cyclopentylamino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-4,4,4 trifluoro-3-(methyl((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 30 (3S)-N-((1R)-6-(1 -(1 -piperidinylmethyl)ethenyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-3 (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((1R)-6-(1 -azepanylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-4,4,4-trifluoro 3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 38 WO 2006/036664 PCT/US2005/033659 (3SJ-N-(( 1R)-6-( 1 -azepanylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-3-(((4-chloro 2,5-dimethylphenyl)sulfonyl)amino)-4,4,4-trifluorobutanamide; (3S)-N-(( 1 R)-6-( 1 -azepanylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-3-(((3-chloro-4 methylphenyl)sulfonyl)amino)-4,4,4-trifluorobutanamide; 5 (3S)-N-(( 1R)-6-( 1 -azepanylmethyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)-3-(((3 ,4 bis(methyloxy)phenyl)sulfonyl)amino)-4,4,4-trifluorobutanamide; (3S)-N-(( 1R)-6-( 1 -piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-3-(((3 (trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-(( 1R)-6-( 1 -pyrrolidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-3-(((3 10 (trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-(( 1R)-6-acetyl- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-3-(((3-(trifluoromethyl) phenyl)sulfonyl)amino)butanamide; (35)-N-(( 1R)-6-formyl- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-3 -(((3-(trifluoromethyl) phenyl)sulfonyl)amino)butanamide; 15 (3S)-N-((4R)-6-chloro-7-((( 1,1-dimethylethyl)amino)methyl)-3,4-dihydro-2H-cbromen 4-yl)-4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((4R)-7-((( 1,1 -dimethylethyl)ammno)methyl)-3 ,4-dihydro-2H-chromen-4-yl) 4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((4R)-7-((( 1,1 -dimethylethyl)ammno)methyl)-3,4-dihydro-2H-chromen-4-yl)-3 20 (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((4R)-7-((( 1 -methylethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)-3-(((3 (trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((4R)-7-(((2-(methyloxy)ethyl)amino)methyl)-3 ,4-dihydro-2H-chromen-4-yl)-3 (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 25 (3S)-N-((4R)-7-(((2,2-dimethylpropyl)amino)methyl)-3 ,4-dihydro-2H-chromen-4-yl) 4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((4R)-7-(((2-methylpropyl)amino)methyl)-3 ,4-dihydro-2H-chromen-4-yl)-3 (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((4R)-7-(((3R)-3-hydroxy-l1-piperidinyl)methyl)-3 ,4-dihydro-2H-chromen-4 30 yl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanarm'de; (3SJ-N-((4R)-7-(((cyclopropylmethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)-3 (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((4R)-7-((4-methyl- 1 -piperazinyl)methyl)-3,4-dihydro-2H-chromen-4-yl)-3 (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 39 WO 2006/036664 PCT/US2005/033659 (3S)-N-((4R)-7-((cyclohexylamino)methyl)-3,4-dihydro-2H-chromen-4-yl)-4,4,4 trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((4R)-7-((cyclopentylamino)methyl)-3,4-dihydro-2H-chromen-4-yl)-3-(((3 (trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 5 (3S)-N-((4R)-7-((cyclopropylamino)methyl)-3,4-dihydro-2H-chromen-4-yl)-3-(((3 (trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((4R)-7-(1-azepanylmethyl)-3,4-dihydro-2H-chromen-4-yl)-3-(((4-chloro-2,5 dimethylphenyl)sulfonyl)amino)-4,4,4-trifluorobutanamide; (3S)-N-((4R)-7-(1-azepanylmethyl)-3,4-dihydro-2H-chromen-4-yl)-4,4,4-trifluoro-3 10 (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((4R)-7-(1 -piperidinylmethyl)-3,4-dihydro-2H-chromen-4-yl)-3-(((3-(trifluoro methyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((4R)-7-(1 -pyrrolidinylmethyl)-3,4-dihydro-2H-chromen-4-yl)-3-(((3-(trifluoro methyl)phenyl)sulfonyl)amino)butanamide; 15 1,1 -dimethylethyl N-2-((3,4-dichlorophenyl)sulfonyl)-N-4-((1R)-6-(1 -piperidinyl methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-D-alpha-asparaginate; 1,1 -dimethylethyl N-2-((3,4-dichlorophenyl)sulfonyl)-N-4-((1R)-6-(hydroxymethyl) 1,2,3,4-tetrahydro- 1 -naphthalenyl)-D-alpha-asparaginate; 1,1 -dimethylethyl N-2-((3,4-dichlorophenyl)sulfonyl)-N-4-((1R)-6-((( 1,1 -dimethyl 20 ethyl)amino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-D-alpha-asparaginate; 1,1 -dimethylethyl N-2-((3,4-dichlorophenyl)sulfonyl)-N-4-((1R)-6-(1 -pyrrolidinyl methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-D-alpha-asparaginate; 2-((2R)-2-methyl-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1 piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)acetamide; 25 2-(3,4-dichloro-benzenesulfonylamino)-N-(6-pyrrolidin- 1 -ylmethyl- 1,2,3,4-tetrahydro naphthalen-1-yl)-succinamic acid; 3-(2-chloro-5-trifluoromethyl-benzenesulfonylamino)-N-(6- {[(2-chloro-5-trifluoro methyl-benzenesulfonyl)-cyclopentyl-amino]-methyl} -1,2,3,4-tetrahydro-naphthalen- 1 -yl) butyramide; 30 3-(6-bromo- 1,1 -dioxido-3-oxo- 1,2-benzisothiazol-2(3H)-yl)-N-((1R)-6-(1 -piperidinyl methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)propanamide; 3-(6-bromo- 1,1 -dioxido-3-oxo- 1,2-benzisothiazol-2(3H)-yl)-N-((1R)-6-(((1,1 dimethylethyl)amino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)propanamide; 40 WO 2006/036664 PCT/US2005/033659 3R-(3,4-dichloro-benzenesulfonylamino)-4,4,4-trifluoro-N-(6-piperidin- 1 -ylmethyl 1,2,3,4-tetrahydro-naphthalen-1 -yl)-butyramide; 3S-(3,4-dichloro-benzenesulfonylamino)-4,4,4-trifluoro-N-(6-piperidin- 1 -ylmethyl 1,2,3,4-tetrahydro-naphthalen- 1 -yl)-butyramide; 5 N-i -((1R)-6-(((1,1 -dimethylethyl)amino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-N 3-phenyl-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide; N-1 -((1R)-6-((( 1,1 -dimethylethyl)amino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-N 3-(3-(trifluoromethyl)phenyl)-N-3-((3-(trifluoromethyl)pheny)sulfonyl)-beta-alaninamide; N-i -((1R)-6-(((1,1 -dimethylethyl)amino)methyl)- 1,2,3,4-tetrahydro- I -naphthalenyl)-N 10 3-(4-fluorophenyl)-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide; N-1 -((1R)-6-(((1,1 -dimethylethyl)amino)methyl)- 1,2,3,4-tetrahydro- I -naphthalenyl)-N 3-methyl-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide; N-1 -((1R)-6-(((2,2-dimethylpropyl)amino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl) N-3-(4-fluorophenyl)-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide; 15 N-i -((1R)-6-((1 S)- 1 -(cyclopentylamino)ethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-N-3 phenyl-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide; N-1 -((1R)-6-((1S)- 1 -(cyclopentylamino)ethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-N-3 methyl-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide; N-1 -((I R)-6-((4-fluoro- 1 -piperidinyl)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-N-3 20 phenyl-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide; N-i -((1R)-6-((4-fluoro- 1 -piperidinyl)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-N-3 methyl-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide; N-i -((1R)-6-((cyclopentylamino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-N-3-(4 fluorophenyl)-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide; 25 N-i -((1R)-6-((diethylamino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-N-3-(4 fluorophenyl)-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide; N-1 -((1R)-6-(1 -piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-N-3-((3 (trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide; N-i -((I R)-6-(1 -piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-N-3-(4 30 (trifluoromethyl)phenyl)-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide; N-2-((3,4-dichlorophenyl)sulfonyl)-N-4-((1R)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-D aspartamide; N-2-((3,4-dichlorophenyl)sulfonyl)-N-4-((1R)-6-((( 1,1 -dimethylethyl)amino)methyl) 1,2,3,4-tetrahydro- 1 -naphthalenyl)-D-aspartamide; 41 WO 2006/036664 PCT/US2005/033659 N-2-((3,4-dichlorophenyl)sulfonyl)-N-4-(( 1R)-6-(((, 1, -dimethylethyl)amino)methyl) 1 , 2 ,3,4-tetrahydro-1I -naphthalenyl)-D-asparagine; N-2-((3,4-dichlorophenyl)sulfonyl)-N-4-(( 1R)-6-(((2-methylpropyl)amino)methyl) 1 , 2 ,3,4-tetrahydro- 1 -naphthalenyl)-D-aspartamide; 5 N-2-((3 ,4-dichlorophenyl)sulfonyl)-N-4-(( 1R)-6-((4-fluoro-l1-piperidinyl)methyl) 1 , 2 ,3,4-tetrahydro- 1 -naphthalenyl)-D-aspartamide; N-2-((3 ,4-dichlorophenyl)sulfonyl)-N-4-(( 1R)-6-(l1-piperidinylmethyl)- 1,2,3,4 tetrahydro- 1 -naphthalenyl)-D-aspartamide; N-2-((3,4-dichlorophenyl)sulfonyl)-N-4-(( 1R)-6-( 1 -piperidinylmethyl)- 1,2,3,4 10 tetrahydro- 1 -naphthalenyl)-D-asparagine; N-2-((3 ,4-dichlorophenyl)sulfonyl)-N-4-((I R)-6-( 1 -pyrrolidinylmethyl)- 1,2,3,4 tetrahydro- 1 -naphthalenyl)-D-aspartamide; N-2-((3,4-dichlorophenyl)sulfonyl)-N-4-(( 1R)-6-(hydroxymethyl)- 1 ,2,3,4-tetrahydro- 1 naphthalenyl)-D-aspartamide; 15 N-2-((4-methylphenyl)sulfonyl)-N-4-(( IR)- 1,2,3,4-tetrahydro-l1-naphthalenyl)-D aspartamide; N-2-((4-methylphenyl)sulfonyl)-N-4-(( IR)-6-( 1-piperidinylmethyl)- 1,2,3,4-tetrahydro 1 -naphthalenyl)-D-aspartamide; N-2-((4-methylphenyl)sulfonyl)-N-4-(( 1 R)-6-( 1 -piperidinylmethyl)- 1 ,2,3,4-tetrahydro 20 1 -naphthalenyl)-D-asparagine; N-3-((2-aminophenyl)sulfonyl)-N- 1-((4R)-7-( 1-piperidmnylmethyi)-3,4-dihydro-2H chromen-4-yl)-beta-alaninamide; N-3-((2-nitrophenyl)sulfonyl)-N- 1 -((4R)-7-( 1 -piperidinylmethyl)-3,4-dihydro-2H cbromen-4-yl)-beta-alaninamide; 25 N-3-((3,4-dichlorophenyl)sulfonyl)-N- 1 -(( 1R)-6-(((, 1, -dimethylethyl)amino)methyl) 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-N-3-(4-fluorophenyl)-beta-alaninamide; N-3-( 1 -methylethyl)-N- 1 -(( 1R)-6-( 1 -piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 naphthalenyl)-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alannamide; N-3-(2-amino-2-oxoethyl)-N- 1 -(( 1R)-6-(((, 1, -dimethylethyl)amino)methyl)- 1,2,3,4 30 tetrahydro- 1 -naphthalenyl)-N-3-((3 -(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide; N-3-(2-fluoroethyl)-N- 1 -(( 1R)-6-( 1 -piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 naphthalenyl)-N-3-((3-(trifluoromethyl)phenyl)sulfonyl).beta-alaninamide; N-3-(2-naphthalenylsulfonyl)-N-3 -(phenylmethyl) -N-i -((4R)-7-( 1-piperidinylinethyl) 3,4-dihydro-2H-chromen-4-yl)-beta-alaninamide; 42 WO 2006/036664 PCT/US2005/033659 N-3-(2-nap"hihiain1i sfonyl)-N-3-pheny1-N- 1-((4R)-7-(1 -piperidmnylmethyl)-3,4 dihydro-2H-chromen-4-yl)-beta-alaninamide; N-3-(3-amino-3-oxopropyl)-N- 1-(( 1R)-6-((( 1,1-dimethylethyl)amino)methyl)- 1,2,3,4 tetrahydro-l1-naphthalenyl)-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alanmnamide; 5 N-3-(4-fluorophenyl)-N- 1-(( 1R)-6-(((2-methylpropyl)amino)methyl)- 1,2,3,4 tetrahydro-l1-naphthalenyl)-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alanmnamide; N-3-(4-fluorophenyl)-N- 1-(( 1R)-6-((4-fluoro-l1-piperidinyl)methyl)-l1,2,3,4-tetrahydro 1 -naphthalenyl)-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide; N-3-cyclohexyl-N- 1-(( 1R)-6-( 1-piperidinylmethyl)- 1,2,3,4-tetrahydro-l1-naphthalenyl) 10 N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide; N-3-cyclopropyl-N- 1-(( 1R)-6-((( 1,1-diunethylethyl)amino)methyl)- 1,2,3,4-tetrahydro- 1 naphthalenyl)-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alannamile; N-3-cyclopropyl-N- 1-(( 1R)-6-(l1-piperidinylmethyl)- 1,2,3 ,4-tetrahydro- 1 naphthalenyl)-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide; 15 N-3-methyl-N- 1-(( 1R)-6-( 1-piperidmnylmethyl)- 1,2,3 ,4-tetrahydro-l1-naphthalenyl)-N-3 ((3 -(trifluoromethyl)phenyl) sulfonyl)-beta-alaninamide; N-4-(( 1R)-6-((( 1,1-dimethylethyl)amino)methyl)- 1,2,3,4-tetrahydro-l1-naphthalenyl)-N 2-((4-methylphenyl)sulfonyl)-D-aspartamide; N-4-((4R)-6-chloro-7-methyl-3,4-dihydro-2H-chromen-4-yl)-N-2-((3,4 20 dichlorophenyl)-sulfonyl)-D-aspartamide; N-4-((4R)-6-chloro-7-methyl-3 ,4-dihydro-2H-chromen-4-yl)-N-2-((4-methylphenyl) sulfonyl)-D-aspartamide; phenylmethyl N-2-((4-methylphenyl)sulfonyl)-N-4-(( 1 R)-6-( 1 -piperidinylmethyl) 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-D-alpha-asparaginate; 25 (R)-4,4,4-trifluoro-N-((R)-6-(piperidin- 1 -ylmethyl)- 1 ,2,3,4-tetrahydronaphthalen- Il-yl) 3-(2-(trifluoromethyl)phenylsulfonamido)butanamide; (R)-3-(3-bromophenylsulfonamido)-4,4,4-trifluoro-N-((R)-6-(piperidin- 1 -ylmethyl) 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide; (R)-3 -(3-chloro-4-fluorophenylsulfonamido)-4,4,4-trifluoro-N-((R)-6-(piperidin- Il-yl 30 methyl)- 1,2,3 ,4-tetrahydronaphthalen- 1 -yl)butanamide; (R)-4,4,4-trifluoro-N-methyl-N-((R)-7-(piperidin- 1-ylmethyl)chroman-4-yl)-3-(3 (trifluoromethyl)phenylsulfonamido)butanamide; (R)-4,4,4-trifluoro-N-((R)-6-(piperidin- I -yhnethyl)- 1,2,3 ,4-tetrahydronaphthalen- Il-yl) 3-(4-(trifluoromethoxy)phenylsulfonamido)butanamide; 43 WO 2006/036664 PCT/US2005/033659 (R)-4,4,4-tritluoro-3-(3-methylphenylsulfonamido)-N-((R)-6-(piperidin-1-yhnethyl) 1,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide; (R)-3 -(4-chloro-2-fluorophenylsulfonamido)-4,4,4-trifluoro-N-((R)-6-(piperidin- 1-yl methyl)- 1,2,3,4-tetrahydronaphthalen-1 -yl)butanamide; 5 (R)-3 -(2-chloro-4-fluorophenylsulfonamido)-4,4,4-trifluoro-N-((R)-6-(piperidin- 1-yl methyl)- 1,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide; (R)-tert-butyl 2-(naphthalene-3-sulfonamido)-4-oxo-4-((R)-6-(piperidin-1-ylmethyl) 1,2,3,4-tetrahydronaphthalen- 1 -ylamino)butanoate; (R)-4,4,4-trifluoro-N-((R)-6-((4-methylpiperidin- 1 -yl)methyl)- 1,2,3,4-tetrahydro 10 naphthalen- 1-yl)-3-(3 -(trifluoromethyl)phenylsulfonamido)butanamide; (R)-methyl 4-oxo-4-((R)-6-(piperidin- 1 -ylmethyl)- 1,2,3,4-tetrahydronaphthalen- 1-yl amino)-2-(3-(trifluoromethyl)phenylsulfonamido)butanoate; (R)-4-oxo-4-((R)-6-(piperidin- 1 -ylmethyl)- 1,2,3,4-tetrahydronaphthalen- 1 -ylamino)-2 (3-(trifluoromethyl)phenylsulfonamido)butanoic acid; 15 (R)-N1-((R)-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(3 (trifluoromethyl)phenylsulfonamido)succinamide; (R)-3-cyano-N-((R)-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(3 (trifluoromethyl)phenylsulfonamido)propanamide; (R)-2-(naphthalene-3-sulfonamido)-4-oxo-4-((R)-6-(piperidin-1-ylmethyl)-1,2,3,4 20 tetrahydronaphthalen-1-ylamino)butanoic acid; (R)-methyl 2-(naphthalene-3-sulfonamido)-4-oxo-4-((R)-6-(piperidin-1-ylmethyl) 1,2,3,4-tetrahydronaphthalen- 1 -ylamino)butanoate; (R)-3-(3-tert-butylphenylsulfonamido)-4,4,4-trifluoro-N-((R)-6-(piperidin- 1 -ylmethyl) 1,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide; 25 (R)-methyl 2-(3,4-dichlorophenylsulfonamido)-4-oxo-4-((R)-6-(pyrrolidin- 1 -yhnethyl) 1,2,3,4-tetrahydronaphthalen- 1 -ylamino)butanoate; (R)-4,4,4-trifluoro-3-(3-(oxazol-5-yl)phenylsulfonamido)-N-((R)-6-(piperidin- 1-yl methyl)- 1,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide; (R)-3-(3,4-dihydro-2H-benzo[b] [1,4]dioxepine-8-sulfonamido)-4,4,4-trifluoro-N-((R) 30 6-(piperidin- 1 -ylmethyl)- 1,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide; (R)-N-((S)-6-(4,5-dihydro-1H-imidazol-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)-4,4,4 trifluoro-3-(3-(trifluoromethyl)phenylsulfonamido)butanamide; (R)-4,4,4-trifluoro-N-((R)-6-(piperidin- 1 -ylmethyl)- 1,2,3,4-tetrahydronaphthalen- 1-yl) 3-(1,2,3,4-tetrahydroquinoline-8-sulfonamido)butanamide; 44 WO 2006/036664 PCT/US2005/033659 (R)-4,4,4-trifluoro-3-(4-methyl-3,4-dihydro-2H-belzo[b] [ 1,4]oxazine-7-sulfonamnido) N-((R)-6-(piperidin- 1 -ylmethyl)- 1,2,3 ,4-tetrahydronaphthalen- 1 -yl)butanamide; (R)-3-(3-choro-2-fluorophenylsulfonamido)-4,4,4-trifluoro-N-((R)-6-(( 4 methylpiperidin- 1 -yl)methyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide; 5 (R)-4,4,4-trifluoro-N-((R)-5-nitro-6-(piperidifl- 1 -ylmethyl)- 1,2,3 ,4 tetrahydronaphthalen- 1 -yl)-3-(3-(trifluoromethyl)phenylsulfonamido)butalamide; (R)-4,4,4-trifluoro-N-((R)-6-(((S)-2-(pyrrolidin- I -ylmethyl)pyrrolidin- I -yI)methyl) 1 ,2,3,4-tetrahydronaphthalen-l -yl)-3-(3-(trifluoromethyl)phenylsulfonamido)butanamide;
(R)
3-(3-chloro-2-fluoro-N-methylphenylsulfonamido)-4,4,4-trifluoro-N-methy1-N-((R)-7 10 (piperidin-1I-ylmethyl)chroman-4-yI)butanamide; (R)-4,4,4-trifluoro-N-((R)-7-nitro-6-(piperidin- 1 -ylmethyl)- 1 ,2,3,4-tetrahydro naplithalen- 1-yl)-3-(3-(trifluoromethyl)phenylsulfonamido)butananiide; (R)-4,4,4-trifluoro-3-(3-methoxyphenysulfonamido)-N-((R)-6-(piperidfl- 1 -yl-methyl) 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)butananide; 15 (R)-3 -(3 ,5-dimethylphenylsulfonamido)-4,4,4-trifluoro-N-((R)-6-(piperidil- I1 ylmethyl)- 1,2,3,4-tetrahydronaphthalen-1I-yl)butanamide; (R)-3-(3 ,4-dimnethylphenylsulfonamido)-4,4,4-trifluoro-N-((R)-6-(piperidil- 1-yl methyl)-I ,2,3,4-tetrahyclronaphthalen- I -yl)butanamide (2R,3R)-3-(3-chloro-2-fluorophenylsulfonamido)-N-((R)-6-chloro-7-(piperidil- 1 20 ylmethyl)chroman-4-yl)-4,4,4-trifluoro-2-hydroxybutanamide; (R)-4,4,4-trifluoro-3-(2-fluoro-5-methylphenylsulfonamido)-N-((R)-6-(piperidil- 1 ylmethyl)- 1,2,3,4-tetrahydronaphthalen- 1-yl)butanamide; (R)-4,4,4-trifluoro-N-((R)-6-(piperidin- 1 -ylmethyl)- 1,2,3,4-tetrahydronaphthalen- Il-yl) 3-(4-(trifluoromethyl)phenylsulfonamido)butanamide; 25 (2R,3R)-3-(2,5-dichlorophenylsulfonamido)-4,4,4-trifluoro-2-hydroxy-N-((R)-6 (piperidin- 1 -ylmethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide; (21,3R)-3-(2,3 -dichlorophenylsulfonamido)-4,4,4-trifluoro-2-hydroxy-N-((R)-6 (piperidin- 1 -ylmethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide; (2R,3R)-3-(3,4-dichlorophenylsulfonamido)-4,4,4-trifluoro-2-hydroxy-N-((R)-6 30 (piperidin- 1 -ylmethyl)- 1,2,3 ,4-tetrahydronaphthalen- I -yl)butanamide; (R)-3-(2-chloro-6-methylphenylsulfonamido)-4,4,4-trifluoro-N-((R)-6-(piperidil- 1 ylmethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide; (R)-4,4,4-trifluoro-3-(5-fluoro-2-methylphenylsulfonamido)-N-((R)-6-(piperidil- 1 ylmethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide; 45 WO 2006/036664 PCT/US2005/033659 (R)-4,4,4-trifluoro-N-((R)-7-(piperidin- 1 -ylmethyl)chroman-4-yl)-3-(3 (trifluoromethyl)phenylsulfonamido)butanamide; and (R)-3-(4-ethylphenylsulfonamido)-4,4,4-trifluoro-N-((R)-6-(piperidin-1-ylmethyl) 1,2,3,4-tetrahydronaphthalen-1 -yl)butanamide. 5 In a second aspect, this invention is directed to a pharmaceutical composition comprising a compound of Formula (I) or any pharmaceutically-acceptable salt or hydrate thereof and a pharmaceutically acceptable excipient. In a third aspect, this invention is directed to a method of treating a disease in a patient mediated by the B 1 receptor comprising administering to the patient a pharmaceutical 10 composition comprising a therapeutically effective amount of a compound of Formula (I) or any pharmaceutically-acceptable salt or hydrate thereof and a pharmaceutically acceptable excipient. Specifically, the compounds of the present invention are useful in the treatment of a disorder such as acute pain, dental pain, back pain, lower back pain, pain from trauma, surgical pain, pain resulting from amputation or abscess, causalgia, fibromyalgia, 15 demyelinating diseases, trigeminal neuralgia, cancer, chronic alcoholism, stroke, thalamic pain syndrome, diabetes, acquired immune deficiency syndrome ("AIDS"), toxins and chemotherapy, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, lupus, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or 20 unstable bladder disorders, psoriasis, skin complaints with inflammatory components, sunburn, carditis, dermatitis, myositis, neuritis, collagen vascular diseases, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, sympathetically maintained pain, deafferentation syndromes, asthma, vasomotor or allergic rhinitis, epithelial tissue 25 damage or dysfunction, herpes simplex, post-herpetic neuralgia, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritis, vitiligo, general gastrointestinal disorders, colitis, inflammatory bowel disease, gastric ulceration, duodenal ulcers, thalamic pain syndrome, diabetes, toxins and chemotherapy, septic shock, and bronchial disorders preferably 30 osteroarthritis. The invention also provides for the use of the compounds of the present invention for the prevention or for the treatment of a disorder such as acute pain, dental pain, back pain, lower back pain, pain from trauma, surgical pain, pain resulting from amputation or abscess, causalgia, fibromyalgia, demyelinating diseases, trigeminal neuralgia, cancer, chronic 46 WO 2006/036664 PCT/US2005/033659 aiconoism, stroke, thalamic pam syndrome, diabetes, acquired immune deficiency syndrome ("AIDS"), toxins and chemotherapy, general headache, migraine, cluster headache, mixed vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, lupus, osteoarthritis, inflammatory bowel disorders, inflammatory eye 5 disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, sunburn, carditis, dermatitis, myositis, neuritis, collagen vascular diseases, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, sympathetically maintained pain, deafferentation syndromes, asthma, vasomotor or 10 allergic rhinitis, epithelial tissue damage or dysfunction, herpes simplex, post-herpetic neuralgia, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, bums, allergic skin reactions, pruritis, vitiligo, general gastrointestinal disorders, colitis, inflammatory bowel disease, gastric ulceration, duodenal ulcers, thalamic pain syndrome, diabetes, toxins and chemotherapy, septic shock, and bronchial 15 disorders. In a fourth aspect, this invention is directed to the use of one or more of the compounds of the present invention in the manufacture of a medicament. Preferably, the medicament is useful in the treatment of a disorder such as acute pain, dental pain, back pain, lower back pain, pain from trauma, surgical pain, pain resulting from amputation or abscess, causalgia, 20 fibromyalgia, demyelinating diseases, trigeminal neuralgia, cancer, chronic alcoholism, stroke, thalamic pain syndrome, diabetes, acquired immune deficiency syndrome ("AIDS"), toxins and chemotherapy, general headache, migraine, cluster headache, mixed-vascular and non vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, lupus, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory 25 or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, sunburn, carditis, dermatitis, myositis, neuritis, collagen vascular diseases, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, sympathetically maintained pain, deafferentation syndromes, asthma, vasomotor or allergic 30 rhinitis, epithelial tissue damage or dysfunction, herpes simplex, post-herpetic neuralgia, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, bums, allergic skin reactions, pruritis, vitiligo, general gastrointestinal disorders, colitis, inflammatory bowel disease, gastric ulceration, duodenal ulcers, thalamic pain syndrome, diabetes, toxins and chemotherapy, septic shock, and bronchial disorders. 47 WO 2006/036664 PCT/US2005/033659 hven more preterably, the mealcament is useful in the treatment of a disorder such as pain or inflammation. The compounds of this invention may also act as inhibitors of other receptors or kinases, and thus be effective in the treatment of diseases associated with other protein kinases. 5 Besides being useful for human treatment, these compounds are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats. Definitions: 10 Unless otherwise stated, the following terms used in the specification and claims have the meanings given below: The term "Capalkyl" means an alkyl group having a minimum of a and a maximum of p carbon atoms in a branched, cyclical or linear relationship or any combination of the three, wherein a and P represent integers as indicated in the claims unless otherwise indicated. The 15 alkyl groups described in this section may also contain one or two double or triple bonds. When the alkyl group has a double bond it is also referred to herein as alkenyl. When the alkyl group has a triple bond it is also referred to herein as alkynyl. Examples of C1.6alkyl include, but are not limited to, the following: ,or methyl, and the like. 20 The term "alkylamino" denotes amino groups which have been substituted with one alkyl radical and with two alkyl radicals, including terms "N-alkylamino" and "NN dialkylamino". More preferred alkylamino radicals are "lower alkylamino" radicals having one or two alkyl radicals of one to six carbon atoms, attached to a nitrogen atom. Even more preferred are lower alkylamino radicals having one to three carbon atoms. Suitable 25 "alkylamino" may be mono or dialkylamino such as N-methylamino, N-ethylamino, NN dimethylamino, NN-diethylamino and the like. The terms "N-aralkyl-N-alkylamino" and "N-alkyl-N-arylamino" denote amino groups which have been substituted with one aralkyl and one alkyl radical, or one aryl and one alkyl radical, respectively, to an amino group. 30 The term "aminoalkyl" embraces linear or branched alkyl radicals having one to ten carbon atoms any one of which may be substituted with one or more amino radicals. More preferred aminoalkyl radicals are "lower aminoalkyl" radicals having one to six carbon atoms 48 WO 2006/036664 PCT/US2005/033659 and one or more amino radicals. Examples of such radicals include aminomethyl, aminoethyl, aminopropyl, aminobutyl and aminohexyl. Even more preferred are lower aminoalkyl radicals having one to three carbon atoms. The term "alkylaminoalkyl" embraces aminoalkyl radicals having the nitrogen atom 5 independently substituted with an alkyl radical. More preferred alkylaminoalkyl radicals are "lower alkylaminoalkyl" radicals having alkyl radicals of one to six carbon atoms. Even more preferred are lower alkylaminoalkyl radicals having alkyl radicals of one to three carbon atoms. Suitable alkylaminoalkyl radicals may be mono or dialkyl substituted, such as N methylaminomethyl, NN-dimethyl-aminoethyl, N,N-diethylaminomethyl and the like. 10 The term "aminoalkenyl" embraces linear or branched alkyl radicals having two to ten carbon atoms any one of which may be substituted with one or more amino radicals. More preferred aminoalkenyl radicals are "lower aminoalkenyl" radicals having two to six carbon atoms and one or more amino radicals. Examples of such radicals include aminoethenyl, aminopropenyl, aminobutenyl and aminohexenyl. Even more preferred are lower 15 aminoalkenyl radicals having two or three carbon atoms. The term "alkylaminoalkenyl" embraces aminoalkenyl radicals having the nitrogen atom independently substituted with an alkyl radical. More preferred alkylaminoalkenyl radicals are "lower alkylaminoalkenyl" radicals having alkyl radicals of one to six carbon atoms. Even more preferred are lower alkylaminoalkenyl radicals having alkyl radicals of one 20 to three carbon atoms. Suitable alkylaminoalkenyl radicals may be mono or dialkyl substituted, such as N-methylaminovinyl, N,N-dimethyl-aminovinyl, N,N-diethylaminovinyl, and the like. The term "alkoxy" embrace linear or branched oxy-containing radicals (-OR) having alkyl portions of one to ten carbon atoms. More preferred alkoxy radicals are "lower alkoxy" 25 radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy. Even more preferred are lower alkoxy radicals having one to three carbon atoms. The "alkoxy" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkoxy" radicals. Even more preferred are lower haloalkoxy radicals having one to three carbon atoms. Examples of such radicals 30 include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy, and fluoropropoxy. The term "alkoxyalkyl" embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more alkoxyl radicals. More preferred alkoxyalkyl radicals are "lower alkoxyalkyl" radicals respectively having one 49 WO 2006/036664 PCT/US2005/033659 to six carbon atoms. Examples of such radicals include methoxymethyl, methoxyethyl, and the like. Even more preferred are lower alkoxyalkyl radicals respectively having one to three carbon atoms alkyl radicals. The term "aminoalkoxy" embraces alkoxy radicals substituted with an amino radical. 5 More preferred aminoalkoxy radicals are "lower aminoalkoxy" radicals having alkoxy radicals of one to six carbon atoms. Suitable aminoalkoxy radicals may be aminoethoxy, aminoethoxy, aminopropoxy and the like. The term "alkylaminoalkoxy" embraces alkoxy radicals substituted with alkylamino radicals. More preferred alkylaminoalkoxy radicals are "lower alkylaminoalkoxy" radicals 10 having alkoxy radicals of one to six carbon atoms. Even more preferred are lower alkylaminoalkoxy radicals having alkyl radicals of one to three carbon atoms. Suitable alkylaminoalkoxy radicals may be mono or dialkyl substituted, such as N-methylaminoethoxy, N,N-dimethylaminoethoxy, NN-diethylaminoethoxy and the like. The term "alkylaminoalkoxyalkoxy" embraces alkoxy radicals substituted with 15 alkylaminoalkoxy radicals as defined above. More preferred alkylaminoalkoxyalkoxy radicals are "lower alkylaminoalkoxyalkoxy" radicals independently having alkoxy radicals of one to six carbon atoms. Even more preferred are lower alkylaminoalkoxyalkoxy radicals having alkyl radicals of one to three carbon atoms. Suitable alkylaminoalkoxyalkoxy radicals may be mono or dialkyl substituted, such as N-methylaminoethoxymethoxy, NN 20 dimethylaminoethoxymethoxy, N,N-diethylaminomethoxymethoxy, and the like. The term "aryl", alone or in combination, means a carbocyclic aromatic system containing one or two rings wherein such rings may be attached together in a pendent manner or may be fused. The term "aryl" embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. More preferred aryl is phenyl. The "aryl" group 25 may have I to 3 substituents such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, and lower alkylamino unless otherwise indicated. The term "aralkyl" embraces aryl substituted alkyl radicals. Preferable aralkyl radicals are "lower aralkyl" radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms. Even more preferred are lower aralkyl radicals phenyl attached to alkyl portions 30 having one to three carbon atoms. Examples of such radicals include benzyl, diphenylmethyl and phenylethyl. The aryl in said aralkyl may be additionally substituted with halo, alkyl, alkoxy, haloalkyl and haloalkoxy. The term "arylalkenyl" embraces aryl substituted alkenyl radicals. Preferable arylalkenyl radicals are "lower arylalkenyl" radicals having aryl radicals attached to alkenyl 50 WO 2006/036664 PCT/US2005/033659 radicals having two to six carbon atoms. Examples of such radicals include phenylethenyl. The aryl in said arylalkenyl may be additionally substituted with halo, alkyl, alkoxy, haloalkyl and haloalkoxy unless otherwise indicated. The term "N-arylaminoalkyl" denotes aminoalkyl radicals substituted with an aryl 5 radical. More preferred arylaminoalkyl radicals are "lower N-arylaminoalkyl" radicals having alkyl radicals of one to six carbon atoms. Even more preferred are phenylaminoalkyl radicals having one to three carbon atoms. Examples of such radicals include N-phenylaminomethyl and N-phenylaminoethyl. The term "aralkylaminoalkyl" embraces aralkyl radicals as described above, attached to 10 an aminoalkyl radical as defined herein. More preferred are lower arylalkylaminoalkyl radicals independently having alkyl radicals of one to three carbon atoms. The term "basic moiety" or "basic moieties" means a chemical moiety that has a measured or calculated pKa of from about 7 to about 13. The term also can include a chemical moiety that is protonable, to some extent, between a pH range of from about 7 to about 10. 15 Examples of basic moieties include, but are not limited to, amino, cycloalkylamino (Ci-C 6 )alkyl, cycloalky(CI-C 6 )alkylamino(CI-C 6 )alkyl, heterocyclylamino(C 1
-C
6 )alkyl, heterocyclyl(Ci-C 6 )alkylamino(Ci-C 6 )alkyl, arylamino(Ci-C 6 )alkyl, aryl(C 1
-C
6 )alkylamino
(C
1
-C
6 )alkyl, (Ci-C 6 )alkylamino(CI-C 6 )alkoxy, (Ci-C 6 )alkylamino(C 1
-C
6 )alkoxy(CI-C 6
)
alkoxy, amino(C 1
-C
6 )alkoxy, amino(CI-C 6 )alkyl, (Ci-C 6 )alkylamino(Ci-C 6 )alkyl, 20 (C 1
-C
4 )alkylamino-(C 2
-C
6 )alkenyl, 4-8-membered nitrogen-containing heterocyclyl(C 2
-C
6 )alkenyl, 5-6 membered heterocyclyloxy, 5-6 membered nitrogen containing heterocyclyl and 5-7 membered nitrogen-containing heterocyclylalkyl; more specifically amino, cycloalkylamino(Ci-C 6 )alkyl, cycloalkyl(Ci-C 6 )alkylamino-(Ci-C 6 )alkyl, heterocyclylamino(Ci-C 6 )alkyl, heterocyclyl(Ci-C 6 )alkylamino-(Ci-C 6 )alkyl, 25 arylamino(Ci-C 6 )alkyl, aryl(Ci-C 6 )alkylamino(Ci-C 6 )alkyl, (CI-C 6 )alkyl amino(Ci-C 6 )alkoxy,
(CI-C
6 )alkylamino(CI-C 6 )alkoxy(Ci-C 6 )alkoxy, amino(Ci-C 6 )alkoxy, amino(Ci-C 6 )alkyl,
(C
1
-C
6 )alkylamino(Ci-C 6 )alkyl, (CI-C4)alkylamino-(C 2
-C
6 )alkenyl, 5-8-membered nitrogen containing heterocyclyl(C 2
-C
6 )alkenyl, heterocyclyl(C 1
-C
6 )amino(C 2
-C
6 )alkyl, 5-6 membered heterocyclyloxy, 5-6 membered nitrogen-containing heterocyclyl and 5-7 membered nitrogen 30 containing heterocyclyl(C1 -C 6 )alkyl. Each basic moiety can be substituted by 0, 1, 2 or 3 groups independently selected from halo, -NH 2 , -OH, -CN, -CF 3 , (Ci -C 6 )alkylamino, haloalkyl, oxo, (CI-C 6 )alkoxy, (C 1
-C
6 )alkoxyalkyl, (C 2
-C
6 )alkenyl, (C 2
-C
6 )alkynyl, di(Ci-C 6 )alkylamino, =NCN; and (CI-C 6 )alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl, each of which is substituted by 0, 1, 2 or 3 groups independently selected from halo, -NH 2 , 51 WO 2006/036664 PCT/US2005/033659 -OH, -CN, CF 3 , (Ci-C 6 )alkylamino, haloalkyl, oxo, (Cl-C 6 )alkoxy, (CI-C 6 )alkoxyalkyl,
(C
1
-C
6 )alkyl, (C 2
-C
6 )alkenyl, (C 2
-C
6 )alkynyl, or di(CI-C 6 )alkylamino. In one emodiment, the basic moiety is selected from cycloalkylamino(C 1
-C
6 )alkyl, cycloalkyl(C 1
-C
6 )alkyl amino(C 1
-C
6 )alkyl, heterocyclylamino(Ci-C 6 )alkyl, heterocyclyl(CI-C 6 )alkylamino 5 (CI-C 6 )alkyl, arylamino(Ci-C 6 )alkyl, aryl(Ci-C 6 )alkylamino(Ci-C 6 )alkyl, (CI-C 6 )alkyl amino(CI-C 6 )alkoxy, (C 1
-C
6 )alkylamino(CI-C 6 )alkoxy(Ci-C 6 )alkoxy, amino(CI-C 6 )alkoxy, amino(Ci-C 6 )alkyl, (Ci-C 6 )alkylamino(Cj-C 6 )alkyl, (C 1
-C
4 )alkylamino-(C 2
-C
6 )alkenyl, 4-8 membered nitrogen-containing heterocyclyl(C 2
-C
6 )alkenyl, heterocyclyl(Ci -C 6 )amino
(C
2
-C
6 )alkyl, 5-6 membered heterocyclyloxy, 5-6 membered nitrogen-containing heterocyclyl 10 and 5-7 membered nitrogen-containing heterocyclylalkyl. In another emodiment, the basic moiety is selected from cycloalkylamino(Ci -C 6 )alkyl, cycloalkyl(Ci -C 6 )alkylamino (Ci-C 6 )alkyl, heterocyclylamino(Ci-C 6 )alkyl, heterocyclyl(Ci-C 6 )alkylamino(Ci-C 6 )alkyl, arylamino(Ci-C 6 )alkyl, aryl(Ci-C 6 )alkylamino(Ci-C 6 )alkyl, (Ci-C 6 )alkyl amino(Ci-C 6 )alkoxy,
(CI-C
6 )alkylamino(C 1
-C
6 )alkoxy(Ci-C 6 )alkoxy, amino(Ci-C 6 )alkoxy, amino(CI-C 6 )alkyl, 15 (C 1
-C
6 )alkylamino(CI-C 6 )alkyl, (CI-C 4 )alkylamino-(C 2
-C
6 )alkenyl, 4-8-membered nitrogen containing heterocyclyl(C 2
-C
6 )alkenyl, heterocyclyl(Ci -C 6 )amino(C 2
-C
6 )alkyl, 5-6 membered heterocyclyloxy, 5-6 membered nitrogen-containing heterocyclyl and 5-7 membered nitrogen containing heterocyclyl-alkyl any of which are substituted by halo, Ci- 6 alkyl or cycloalkyl, preferably halo, C 1
.
6 alkyl or cycloalkyl. More specifically, the basic moiety is amino, 20 aminomethyl, isopropylaminomethyl, t-butylaminomethyl, 2-t-butylaminoethyl, 2-tert butylamino-1-methyl-ethyl, 1-tert-butylaminoethyl, 1-(tert-butylamino-methyl)-vinyl, 1 (piperidin- 1 -ylmethyl)-vinyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2 dimethyl)propylaminomethyl, N-isopropyl-N-ethylaminomethyl, N-isopropyl-N methylaminomethyl, N-t-butyl-N-methylaminomethyl, N-iso-butyl-N-methylaminomethyl, N-t 25 butyl-N-ethylaminomethyl, N-isobutyl-N-methylaminomethyl, N-t-butyl-N isopropylaminomethyl, N,N-di(isopropyl)aminomethyl, NN-dimethylaminomethyl, NN diethylaminomethyl, N,N-di(t-butyl)-aminomethyl, cyclopropylaminomethyl, cyclopropylaminoethyl, cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl, cyclobutylaminomethyl, cyclobutylaminoethyl, cyclobutylmethylaminomethyl, 30 cyclobutylmethylaminoethyl, 4,5-dihydro-imidazolyl, 1-piperidinylmethyl, 4-fluoropiperidin 1-ylmethyl, 4,4-difluoropiperidin-1-ylmethyl, 3-hydroxypiperidin-1-ylmethyl, 4-hydroxy piperidin- 1 -ylmethyl, 4-(piperidin- 1 -yl)piperidinylmethyl, 4-(dimethylamino)piperidin- 1 ylmethyl, 2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl, 1-pyrrolidinylmethyl, 2 methylpyrrolidin-1-ylmethyl, 2,5-dimethylpyrrolidin-1-ylmethyl, piperazin-1-ylmethyl, 52 WO 2006/036664 PCT/US2005/033659 azocan- 1 -ylmethyl, azepan- 1 -ylmethyl, (7-azabicyclo[2.2. 1 ]hept-7-yl)methyl, (1,3,3-trimethyl 6-azaicyclo[3.2.1 ]oct-6-yl)methyl, 2-piperidinyl or 4-methylpiperazin- 1 -ylmethyl. The term "cycloalkyl" includes saturated carbocyclic groups. Preferred cycloalkyl groups include C 3
-C
6 rings. More preferred compounds include cyclopentyl, cyclopropyl, and 5 cyclohexyl. The term "cycloalkylaminoalkyl" refers to aminoalkyl radicals where the nitrogen atom of the amino group is independently substituted, respectively, with one cycloalkyl radical, or two cycloalkyl radicals and therefore includes "N-cycloalkylaminoalkyl" and "NN dicycloalkylaminoalkyl". More preferred cycloalkylaminoalkyl radicals are "lower 10 cycloalkylaminoalkyl" radicals having alkyl radicals with one to six carbon atoms. Even more preferred are lower cycloalkylaminoalkyl radicals having alkyl radicals with one to three carbon atoms. Examples of such lower alkylaminosulfonyl radicals include N cyclohexylaminomethyl, and N-cyclopentylaminoethyl. The term "cycloalkylalkylaminoalkyl" embraces cycloalkyl radicals as described above, 15 attached to an alkylaminoalkyl radical. More preferred are lower cycloalkyl-alkylaminoalkyl radicals independently having alkyl radicals of one to three carbon atoms. "Halo" or "halogen" means a halogen atoms selected from F, Cl, Br and . "Caphaloalkyl" means an alkyl group as described above, unless otherwise indicated, wherein any number--at least one--of the hydrogen atoms attached to the alkyl chain are 20 replaced by F, Cl, Br or I. "Heterocycle" or "heterocyclyl" means a ring comprising at least one carbon atom and at least one other atom selected from N, 0 and S. The term heterocycle embraces saturated, partially saturated and unsaturated heteroatom-containing ring radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. It does not include rings containing -0-0 25 or -S-S- portions. Preferably, the heterocycle ring contains 3 to 10 ring atoms. Unsaturated heteroatom-containing ring radicals as used herein means a heterocycle containing at least one aromatic ring. Unsaturated heteroatom-containing ring radicals are also referred to herein as heteroaryl. Partially saturated heteroatom-containing ring radicals as used herein means a heterocycle containing one or more double bonds provided that it is not aromatic. 30 Examples of heterocycles that may be found in the claims include, but are not limited to, the following: 53 WO 2006/036664 PCT/US2005/033659 0C 0 S 0 Q_ N0S0 S o 0 0 S N N N N co C N0 CQ0C( 0/0 0_ 0 00 N N rt N co N 0[XU N N c/ CI N CQ CN> NQN 0 0~ N j~ ON 0 ,O R,, N, N/ N,,N, 0N N N N N and NN. The term "heterocyclylaminoalkcyl" embraces heterocyclyl radicals as described above, attached to an aminoalkyl radical as defined herein. 5 The term "heterocyclylalkylaminoalkyl" embraces heterocyclylalkyl radicals as described below, attached to an aminoalkyl radical. More preferred are lower heterocyclylalkylaminoalkyl radicals having, independently, alkyl radicals of one to three carbon atoms. The term "heterocyclylalkyl" embraces heterocyclic-substituted alkyl radicals. More 10 preferred heterocyclylalkyl radicals are "5- or 6-membered heteroarylalkyl" radicals having alkyl portions of one to six carbon atoms and a 5- or 6-membered heteroaryl radical. Even more preferred are lower heteroarylalkyl radicals having alkyl portions of one to three carbon atoms. Examples include such radicals as pyridinylmethyl and thienylmethyl. The term "heterocyclylalkenyl" embraces heterocyclyl-substituted alkenyl radicals. 15 Preferable heterocyclylalkenyl radicals are "lower heterocyclylalkenyl" radicals having heterocyclyl radicals attached to alkenyl radicals having two to six carbon atoms. Examples of such radicals include pyridinylethenyl. When the heterocyclyl ring contains 4 to 8 ring atoms 54 WO 2006/036664 PCT/US2005/033659 having at least a nitrogen ring atom it is referred to herein as 4-8 membered nitrogen containing heterocyclylalkenyl. The term "heterocyclyloxy" embraces optionally substituted heterocyclyl radicals, as defined above, attached to an oxygen atom. Examples of such radicals include piperidyloxy. 5 The term "H" denotes a single hydrogen atom. This radical may be attached, for example, to an oxygen atom to form a hydroxyl radical. The terms "oxo" represent the group =0 (as in carbonyl). The term "hydroxyalkyl" embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl 10 radicals. The terms "carboxy" or "carboxyl" denotes -CO 2 H. The term "carbonyl" denotes -(C=0)-. The term "comprising" is meant to be open ended, including the indicated component but not excluding other elements. 15 The specification and claims contain listing of species using the language "selected from . .. and. . ." and "is ... or. . ." (sometimes referred to as Markush groups). When this language is used in this application, unless otherwise stated it is meant to include the group as a whole, or any single members thereof, or any subgroups thereof. The use of this language is merely for shorthand purposes and is not meant in any way to limit the removal of individual 20 elements or subgroups from the genus. The term "partially saturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11 -membered bicyclic hydrocarbon ring" means a hydrocarbon ring that is not completely aromatic e.g., tetrahydronaphthyl, tetrahydrochromenyl, dihydroindolyl, and the like. The term "unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 25 11 -membered bicyclic hydrocarbon ring" means a hydrocarbon ring that is aromatic. A "pharmaceutically acceptable carrier or excipient" means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use. "A pharmaceutically 30 acceptable carrier/excipient" as used in the specification and claims includes both one and more than one such excipient. The phrase "therapeutically-effective" is intended to qualify the amount of each agent, which will achieve the goal of improvement in disorder severity and the frequency of incidence over treatment of each agent by itself, while avoiding adverse side effects typically associated 55 WO 2006/036664 PCT/US2005/033659 with alternative therapies. For example, effective pain therapeutic agents relieve the pain sensation of the patient. Alternatively, effective therapeutic agents for the treatment of inflammation minimize the damage from the inflammation, and the like. The term "treatment" includes therapeutic treatment as well as prophylactic treatment 5 (either preventing the onset of disorders altogether or delaying the onset of a pre-clinically evident stage of disorders in individuals). The compounds of this invention may also be represented in multiple tautomeric forms, for example, as illustrated below: N4 NH HN/NN 10 The invention expressly includes all tautomeric forms of the compounds described herein. The compounds may also occur in cis- or trans- or E- or Z- double bond isomeric forms. All such isomeric forms of such compounds are expressly included in the present invention. All crystal forms of the compounds described herein are expressly included in the 15 present invention. Substituents on ring moieties (e.g., phenyl, thienyl, etc.) may be attached to specific atoms, whereby they are intended to be fixed to that atom, or they may be drawn unattached to a specific atom, whereby they are intended to be attached at any available atom that is not already substituted by an atom other than H (hydrogen). 20 The compounds of this invention may contain heterocyclic ring systems attached to another ring system. Such heterocyclic ring systems may be attached through a carbon atom or a heteroatom in the ring system. Compounds of the present invention can possess, in general, one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers as well as in the 25 form of racemic or non-racemic mixtures thereof. Unless otherwise indicated, the compounds of the present invention, as depicted or named, may exist as the racemate, a single enantiomer, or any uneven (i.e. non 50/50) mixture of enantiomers. All such isomeric forms are within the scope of the invention. The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, e.g., by formation of diastereoisomeric salts, by 30 treatment with an optically active acid or base. Examples of appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and then 56 WO 2006/036664 PCT/US2005/033659 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, such as, for example, a CHIRAL-AGP column, optimally chosen to maximize the separation of the enantiomers. Still another 5 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 10 can likewise be obtained by using optically active starting materials. These isomers may be in the form of a free acid, a free base, an ester or a salt. Preferred compounds of the invention have an R configuration at the carbon that is attached to the amide bond as shown below: NH 0 15 Compounds of the present invention can possess, in general, tautomeric forms, including any enolate anions. All such forms are included within the scope of this invention. Also included in the family of compounds of Formula (I) are the pharmaceutically acceptable salts thereof. The term "pharmaceutically-acceptable salts" embraces salts 20 commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically-acceptable. Suitable pharmaceutically-acceptable acid addition salts of compounds of Formula (I) may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. 25 Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic carboxylic and sulfonic classes of organic acids, example of which are formic, acetic, adipic, butyric, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, 30 ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, camphoric, camphorsulfonic, digluconic, cyclopentanepropionic, dodecylsulfonic, glucoheptanoic, glycerophosphonic, heptanoic, 57 WO 2006/036664 PCT/US2005/033659 hexanoic, 2-hydroxy-ethanesultome, nicotinic, 2-naphthalenesulfonic, oxalic, palmoic, pectinic, persulfuric, 2-phenylpropionic, picric, pivalic propionic, succinic, tartaric, thiocyanic, mesylic, undecanoic, stearic, algenic, p-hydroxybutyric, salicylic, galactaric and galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of compounds of Formula (I) 5 include metallic salts, such as salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or salts made from organic bases including primary, secondary and tertiary amines, substituted amines including cyclic amines, such as caffeine, arginine, diethylamine, N-ethyl piperidine, histidine, glucamine, isopropylamine, lysine, morpholine, N ethylmorpholine, piperazine, piperidine, triethylamine, trimethylamine. All of these salts may 10 be prepared by conventional means from the corresponding compound of the invention by reacting, for example, the appropriate acid or base with the compound of Formula (I) Also, the basic nitrogen-containing 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 15 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 HCl, H 2 S0 4 and H 3
PO
4 and such organic acids as 20 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. General Synthetic Procedures 25 Compounds of this invention can be made by the methods depicted in the reaction schemes shown below. The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis, Mo.) or are prepared by methods known to 30 those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1994); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers); Organic Reactions, Volumes 1-46 (John Wiley and Sons, 2003), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition) and Larock's 58 WO 2006/036664 PCT/US2005/033659 Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and various modifications to these schemes can be made and will be suggested to one skilled in the art having referred to this disclosure. 5 The starting materials and the intermediates of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and the like. Such materials may be characterized using conventional means, including physical constants and spectral data. Unless specified to the contrary, the reactions described herein take place at 10 atmospheric pressure over a temperature range from about -78 C to about 150 C, more preferably from about 0 C to about 125 0 C and most preferably at about room (or ambient) temperature, e.g., about 20 *C. In the reactions described hereinafter it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in 15 the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice, for examples see T. W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry" John Wiley and Sons, 1999. Compounds of this invention can be made by the methods depicted in the reaction schemes shown below. 20 Compounds of Formula (I) where R', R 2 , Ria, R' b, RIc, R 4 and R are as defined in the Summary of the Invention can be prepared as shown in Scheme A below. Scheme A R3Rlb RiC R3Rlb Ric l ~ RSCI + H ) OH R2 OH + RR R4R 02 11~a S R + NHR 4
R
5 -~-. R 2 ,N .9 NRR5 02 R 1 ROS l 1 2 34 02 R1 R 18 0 (1) 25 Compounds of Formula (I) where R',R 2 , Ria, Rib, Ri*, R 4 and R' are as defined in the Summary of the Invention can be prepared as shown in Scheme A above. Reaction of a sulfonyl chloride of formula 1 where R 2 is as defined in the Summary of the Inventio with a p amino acids of formula 2 provides a compound of formula 3. The reaction is carried out in the presence of a base such as triethylamine, pyridine, and the like and in a suitable organic solvent 30 such as tetrahydrofuran, dimethylformamide and the like, or in the presence of inorganic base such as sodium bicarbonate and sodium carbonate, and the like and in a suitable solvent system such as dioxane/water (1/1, v/v). Alternatively, the reaction can be carried out in neat base. 59 WO 2006/036664 PCT/US2005/033659 Compounds of formula 1 are either commercially available or they can be prepared by methods well known in the art. Compounds of formula 2 are either commercially available or they can be prepared by methods well known in the art. Reaction of acid 3 with an amine of formula 4 where R 4 and R 5 are as defined in the Summary of the invention under standard peptidic 5 coupling reaction conditions provide a compound of Formula (I). The reaction is carried out in the presence of a coupling agent such as are coupled with the substituted amine 2 using standard peptide coupling conditions coupling agent (e.g., benzotriazol-1-yloxy trispyrrolidinophosphonium hexafluorophosphate (PyBOP*.), 1-(3-dimethylamino-propyl)-3 ethylcarbodiimide hydrochloride (EDCI), O-(7-azabenzotrizol- 1 -yl)- 1,1,3,3, tetra 10 methyluronium-hexafluoro- phosphate (HATU), 0-benzotriazol-1-yl-N,N,N,N-tetramethyl uronium hexafluorophosphate (HBTU), 1,3-dicyclohexylcarbodiimide (DCC), or the like) and optionally an appropriate catalyst (e.g., 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7 azabenzotriazole (HOAt), or the like) and non-nucleophilic base (e.g., triethylamine, N methylmorpholine, and the like, or any suitable combination thereof) at ambient temperature. 15 Suitable reaction solvents include, but are not limited to, dimethylformamide, methylene chloride, and the like. Amines of formula 2 are commercially available or may be prepared by methods well known in the art. A detailed description of syntheses of amines is provided in working examples below. 20 Alternatively, the compounds of Formula (I) can be prepared as shown in Scheme B below. Scheme B R3Rib Ric R3RIb R 1 c R3Rlb Ric N
NHR
4 PG
R
1 N OH+NHR4PG -R N NR4PG NR4PG 0202 R Ra 02 R RO 3 5 6 6 (1) 25 Compounds of Formula (I) can also be prepared by reacting compound 3 with a an amine of formula 5 where PG is a precursor group to R 5 group. Conversion of the PG group to R group then provides a compound of Formula (I). For example, a compound of Formula (I) where RW is a saturated, partially saturated or unsaturated 8-, 9-, 10- or 11-membered bicyclic or 12-, 13-, 14- or 15- membered tricyclic ring 30 substituted with cycloalkylamino-(CI-C 6 )alkyl, cycloalkyl(CI-C 6 )alkylamino(CI-C 6 )alkyl, heterocyclylamino(C -C 6 )alkyl, heterocyclyl(C -C 6 )alkylamino(Ci -C 6 )alkyl, arylamino(C -C 6 )alkyl, aryl(C -C 6 )alkylamino-(C -C 6 )alkyl, (C 1
-C
6 )alkylamino(C -C 6 )alkoxy, 60 WO 2006/036664 PCT/US2005/033659
(CI-C
6 )alkylamino(Ci-C 6 )alkoxy(Ci-C 6 )-alkoxy, amino(Ci-C 6 )alkoxy, amino(Ci-C 6 )alkyl,
(CI-C
6 )alkylamino(C 1
-C
6 )alkyl, and 5-7 membered nitrogen-containing heterocyclylalkyl can be prepared by from a corresponding compound of formula 6 where PG is a saturated, partially saturated or unsaturated 8-, 9-, 10- or 1 1-membered bicyclic or 12-, 13-, 14- or 15- membered 5 tricyclic ring substituted with a hydroxyalkyl group by treating the hydroxyalkyl compound with an oxidizing agent such as manganese oxide and treating the resulting aldehyde compound with an amine optionally substituted with cycloalkyl, cycloalkylalkyl, heterocyclyl, alkyl, aryl, aralkyl, or nitrogen containing heterocyclyl group under reductive amination reaction conditions to provide a compound of Formula (I) with the above listed substitutents. .10 Alternatively, the aldehyde can first treated with an unsubstituted amine and then the amine can be alkylation under standard alkylation reaction conditions or treated with an aldehyde under reductive amination reaction conditions. The above compounds can also be prepared from a corresponding compound of formula 6 carrying an alkene group by first converting the alkyne group to an aldehyde under ozonolysis reaction conditions and then 15 proceeding as described above. Additionally, the aldehyde can be first converted to a ketone by treating it with a Grignard reagent and then reacted with amine to provide compounds of Formula (I) where the carbon atom alpha to the amino group is substituted. Compounds of Formula (I) where R 5 is a saturated, partially saturated or unsaturated 8-, 20 9-, 10- or 1-membered bicyclic or 12-, 13-, 14- or 15- membered tricyclic ring substituted with 5-6 membered heterocyclyloxy can be prepared from a corresponding compound of formula 6 where PG is a saturated, partially saturated or unsaturated 8-, 9-, 10- or 11 -membered bicyclic or 12-, 13-, 14- or 15- membered tricyclic ring substituted with a hydroxyl group by reacting it with heterocyclyl halide under alkylating reaction conditions. 25 It will be well recognized by a person skilled in the art that if one or more functional groups, for example carboxy, hydroxy, amino, or mercapto, need to be protected during the synthesis of a compound of Formula (I) because they should not take part in the reaction such groups should be suitably protected prior to or during the synthesis procedure. A person skilled in the art would be able to easily establish, which protecting groups are suitable with the 30 reactions mentioned above and hereinafter. Salts of a compound of Formula (I) with a salt-forming group may be prepared in a manner known per se. Acid addition salts of compounds of Formula (I) may thus be obtained by treatment with an acid or with a suitable anion exchange reagent. A salt with two acid molecules (for example a dihalogenide of a compound of Formula (I)) may also be converted 61 WO 2006/036664 PCT/US2005/033659 into a salt with one acid molecule per compound (for example a monohalogenide); this may be done by heating to a melt, or for example by heating as a solid under a high vacuum at elevated temperature, for example from 130-170 'C, one molecule of the acid being expelled per molecule of a compound of Formula (I). 5 Salts can usually be converted to free compounds, e.g. by treating with suitable basic agents, for example with alkali metal carbonates, alkali metal hydrogen carbonates, or alkali metal hydroxides, typically potassium carbonate or sodium hydroxide. The compounds of Formula (I), including their salts, are also obtainable in the form of hydrates, or their crystals can include for example the solvent used for crystallization (present 10 as solvates). All such forms are within the scope of this invention. As can be appreciated by the skilled artisan, the above synthetic schemes are not intended to comprise a comprehensive list of all means by which the compounds described and claimed in this application may be synthesized. Further methods will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps described above may be 15 performed in an alternate sequence or order to give the desired compounds. Utility The compound of Formula (I) are B 1 receptor antagonists and hence are useful in the treatment of a disorder such as acute pain, dental pain, back pain, lower back pain, pain from 20 trauma, surgical pain, pain resulting from amputation or abscess, causalgia, fibromyalgia, demyelinating diseases, trigeminal neuralgia, cancer, chronic alcoholism, stroke, thalamic pain syndrome, diabetes, acquired immune deficiency syndrome ("AIDS"), toxins and chemotherapy, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, lupus, 25 osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, sunburn, carditis, dermatitis, myositis, neuritis, collagen vascular diseases, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, sympathetically maintained 30 pain, deafferentation syndromes, asthma, vasomotor or allergic rhinitis, epithelial tissue damage or dysfunction, herpes simplex, post-herpetic neuralgia, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritis, vitiligo, general gastrointestinal disorders, colitis, 62 WO 2006/036664 PCT/US2005/033659 inflammatory bowel disease, gastric ulceration, duodenal ulcers, thalamic pain syndrome, diabetes, toxins and chemotherapy, septic shock, and bronchial disorders. Biological Testing 5 The in vitro binding affinity of the compounds of the invention to the human B 1 and B2 bradykinin receptors can be tested using the radioligand binding assay described in Biological Example 1 below. The antagonistic activity of the compounds of the invention for the human B 1 and B2 bradykinin receptors can be tested using the calcium flux assay, Rabbit endothelial cell B 1-specific PGI 2 secretion Assay, and umblical vein Assay described in Biological 10 Examples 2 and 3 below. The antinociceptive activity of the compounds of the invention was determined using the rat and monkey pain models described in Example 4 below. The antiinflammatory activity of the compounds of the invention was determined using the Green Monkey LPS inflammation model described in Example 5 below. 15 Pharmaceutical Compositions and Administration The present invention also embraces pharmaceutical compositions comprising the active compounds of Formula (I) in association with one or more non-toxic, pharmaceutically acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as "carrier" materials) and, if desired, other active ingredients. The compounds of the present invention 20 may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The compounds and compositions of the present invention may, for example, be administered orally, mucosally, topically, rectally, pulmonarily such as by inhalation spray, or parentally including intravascularly, intravenously, intraperitoneally, subcutaneously, intramuscularly 25 intrasternally and infusion techniques, in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles. 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. 30 For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules. For example, these may contain an amount of active ingredient from about 1 to 2000 mg, preferably from about 1 to 500 mg or 5 63 WO 2006/036664 PCT/US2005/033659 to 1000 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 amount of compounds which are administered and the dosage regimen for treating 5 a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex and medical condition of the subject, the type of disease, the severity of the disease, the route and frequency of administration, and the particular compound employed. Thus, the dosage regimen may vary widely, but can be determined routinely using standard methods. A daily dose of about 0.01 to 500 mg/kg, 10 preferably between about 0.1 and about 50 mg/kg, and more preferably about 0.1 and about 20 mg/kg body weight may be appropriate. The daily dose can be administered in one to four doses per day. For therapeutic purposes, the active compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If 15 administered per os, the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled 20 release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. In the case of psoriasis and other skin conditions, it may be preferable to apply a topical preparation of compounds of this invention to the affected area two to four times a day. Formulations suitable for topical administration include liquid or semi-liquid 25 preparations suitable for penetration through the skin (e.g., liniments, lotions, ointments, creams, or pastes) and drops suitable for administration to the eye, ear, or nose. 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 times daily. For topical administration, the active ingredient may comprise from 0.001% to 10% w/w, e.g., from 1% to 2% by weight of 30 the formulation, although 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. When formulated in an ointment, the active ingredients may be employed with either paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the 64 WO 2006/036664 PCT/US2005/033659 cream base may include, for example at least 30% w/w of a polyhydric alcohol such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof. The topical formulation may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. 5 Examples of such dermal penetration enhancers include DMSO and related analogs. The compounds of this invention can also be administered by a transdermal device. Preferably transdermal administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. In either case, the active agent is delivered continuously from the reservoir or microcapsules through a membrane into the 10 active agent permeable adhesive, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient. In the case of microcapsules, the encapsulating agent may also function as the membrane. The oily phase of the emulsions of this invention may be constituted from known 15 ingredients in a known manner. While the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make-up the so-called emulsifying wax, and the wax together with 20 the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate alone or with a wax, or other materials well known in the art. 25 The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low. Thus, the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di 30 isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters may be used. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used. 65 WO 2006/036664 PCT/US2005/033659 Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredients are dissolved or suspended in suitable carrier, especially an aqueous solvent for the active ingredients. The active ingredients are preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% and particularly 5 about 1.5% w/w. Formulations for parenteral administration may be in the form of aqueous or non aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules using one or more of the carriers or diluents mentioned for use in the formulations for oral administration or by using other suitable 10 dispersing or wetting agents and suspending agents. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth gum, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art. The active ingredient may also be administered by injection as a composition with suitable 15 carriers including saline, dextrose, or water, or with cyclodextrin (ie. Captisol), cosolvent solubilization (ie. propylene glycol) or micellar solubilization (i.e., Tween 80). 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 1,3 butanediol. Among the acceptable vehicles and solvents that may be employed are water, 20 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. For pulmonary administration, the pharmaceutical composition may be administered in 25 the form of an aerosol or with an inhaler including dry powder aerosol. Suppositories for rectal administration of the drug can be prepared by 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. 30 The pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers etc. Tablets and pills can additionally be prepared with enteric coatings. Such compositions may also comprise adjuvants, such as wetting, sweetening, flavoring, and perfuming agents. 66 WO 2006/036664 PCT/US2005/033659 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 administered at the same time or sequentially 5 at different times, or the therapeutic agents can be given as a single composition. The phrase "co-therapy" (or "combination-therapy"), in defining use of a compound of the present invention and another pharmaceutical agent, is intended to embrace administration of each agent in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and is intended as well to embrace co-administration of these agents in a 10 substantially simultaneous manner, such as in a single capsule having a fixed ratio of these active agents or in multiple, separate capsules for each agent. The present compounds may also be used in combination therapies with opioids and other anti-pain analgesics, including narcotic analgesics, Mu receptor antagonists, Kappa receptor antagonists, non-narcotic (i.e. non- addictive) analgesics, monoamine uptake 15 inhibitors, adenosine regulating agents, cannabinoid derivatives, Substance P antagonists, neurokinin- 1 receptor antagonists, COX-2 inhibitors such as celecoxib, rofecoxib, valdecoxib, parecoxib, and darecoxib, NSAID's, and sodium channel blockers, among others. More preferred would be combinations with compounds selected from morphine, meperidine, codeine, pentazocine, buprenorphine, butorphanol, dezocine, meptazinol, hydrocodone, 20 oxycodone, methadone, tetrahydrocannibinol, pregabalin, Tramadol [(+) enantiomer], DuP 747, Dynorphine A, Enadoline, RP-60180, HN-1 1608, E-2078, ICI- 204448, acetominophen (paracetamol), propoxyphene, nalbuphine, E-4018, filenadol, mirtentanil, amitriptyline, DuP631, Tramadol [(-) enantiomer], GP-531, acadesine, AKI-1, AKI-2, GP-1683, GP-3269, 4030W92, tramadol racemate, Dynorphine A, E-2078, AXC3742, SNX-1 11, ADL2-1294, ICI 25 204448, CT-3, CP-99,994, and CP-99,994. Alternatively, the present compounds may also be used in co-therapies with other treatments for inflammation, e.g. steroids, NSAIDs, iNOS inhibitors, p38 inhibitors, TNF inhibitors, 5-lipoxygenase inhibitors, LTB 4 receptor antagonists and LTA 4 hydrolase inhibitors. 30 Examples In order that the invention described herein may be more readily understood, the following references (intermediates) and examples (final compound) are set forth. These detailed descriptions fall within the scope, and serve to exemplify the above-described General Synthetic Procedures which form part of the invention. These detailed descriptions are 67 WO 2006/036664 PCT/US2005/033659 presented tor illustrative purposes only and are not intended as a restriction on the scope of the invention. Unless otherwise noted, all materials were obtained from commercial suppliers and used without further purification. All parts are by weight unless otherwise indicated. All compounds showed NMR spectra consistent with their assigned structures. Melting points 5 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. Unless otherwise stated, reactions were run at RT. The following abbreviations are used: 10 AcOH, HOAc - acetic acid
CH
3 CN - acetonitrile
NH
3 - ammonia NH4C1 - ammonium chloride
NH
4 0H - ammonium hydroxide 15 HATU - O-(7-Azabenzotriazol-1 -yl)-NN,N,N tetramethyluronium hexafluorophosphate AIBN - 2,2'-azobisisobutyronitrile (PPh 3
)
2 NiBr 2 - bis(triphenylphosphine)nickel(II) bromide
BH
3 - borane 20 BH 3 SMe 2 - borane-methyl sulfide complex Br 2 - bromine NBS - N-bromosuccinimide CCl4 - carbon tetrachloride CHCl 3 - chloroform 25 DBU - 1,8-diazabicyclo[5.4.0]undec-7-ene DCE - 1,2-dichloroethane
CH
2 Cl 2 - dichloromethane; DCM Et 2 O - diethyl ether Ip 2 NEt, DIEA - diisopropylethylamine 30 Me 2 NH - dimethylamine EDC - (3-dimethylamino-propyl)-ethyl carbodiimide-HCI salt DMAP - 4-(dimethylamino)pyridine DMF - dimethylformamide 68 WO 2006/036664 PCT/US2005/033659 DMSO - dimethyl sulfoxide (also known as methyl sulfoxide) DPPA - diphenylphosphoryl azide EtOH - ethanol 5 EtOAc - ethyl acetate
HCO
2 H - formic acid g - gram h - hour HCl - hydrochloric acid 10 H 2 - hydrogen HOAt - 1-hydroxy-7-azabenzotriazole HOBt - 1-hydroxybenzotriazole IPA - isopropanol iPrOH - isopropanol 15 ISCO - ISCO liquid chromatography system LAH - lithium aluminum hydride LDA - lithium diisopropylamide LiOH - lithium hydroxide MgSO 4 - magnesium sulfate 20 MeOH - methanol NMM - N-methylmorpholine NMP - 1 -methyl-2-pyrrolidone mL - milliliter min - minutes 25 N 2 - nitrogen Pd/C - palladium on carbon Pd(OH) 2 - palladium hydroxide
H
3
PO
4 - phosphoric acid
K
2 C0 3 - potassium carbonate 30 KCN - potassium cyanide KOH - potassium hydroxide RT - room temperature SiO 2 - silica NaOAc - sodium acetate 69 WO 2006/036664 PCT/US2005/033659 INaN 3 - sodium azide NaHC0 3 - sodium bicarbonate NaBH 4 - sodium borohydride NaOH - sodium hydroxide 5 NaBH(OAc) 3 - sodium triacetoxyborohydride
H
2
SO
4 - sulfuric acid SOC1 2 - thionyl chloride THF - tetrahydrofuran TsCl - p-tosyl chloride 10 TsOH - p-toluene sulfonic acid TEA, Et 3 N - triethylamine TFA - trifluoroacetic acid PPh 3 - triphenylphosphine
H
2 0 - water 15 Reference 1 Synthesis of (5(R)-amino-5,6,7,8-tetrahydronaphthalen-2-yl)methanol
NH
2 HO 20 Step A: Synthesis of 5(S)-hydroxy-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid methyl ester To an oven-dried 2 L round-bottomed flask equipped with an argon inlet/outlet and magnetic stirring was added (R)-2-methyl-CBS-oxazaborolidine (7.4 mL of a I M soln in toluene, 7.4 mmol, Aldrich). Toluene (190 mL) was added and the reaction mixture was 25 cooled in an ice-salt bath (bath temp. = -10 *C). BH 3 -SMe 2 was added (17 mL, 180 mmol, Aldrich), followed by a solution of 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid methyl ester (30 g, 150 mmol, Albany Molecular) in THF (200 mL) was added over 5 h using a syringe pump. After the addition was complete, the reaction mixture was stirred for an additional 1 h. The reaction mixture was poured into an addition funnel, and the reaction 30 mixture was added to MeOH (200 mL), cooled in a ice-salt bath, over 30 min at such a rate that the internal temp. was kept below 0 *C. The reaction mixture was concentrated in vacuo. Et 2 O (1 L) was added, and the mixture was washed with IM H 3
PO
4 (3x), satd NaHCO 3 , and 70 WO 2006/036664 PCT/US2005/033659 brine (ca. 400 mL each wash). The organic layer was dried over MgSO 4 , filtered and concentrated in vacuo. The residue was dissolved in Et 2 O again (500 mL), and the mixture was washed with IM H 3
PO
4 (3 x 200 mL), satd NaHCO 3 , and brine. After drying the organic layer over MgSO 4 , the mixture was filtered and concentrated in vacuo, which gave the title 5 compound as a white-yellow solid. MS (+ ion ESI) m/z = 207 (MH+), 189 (MH*-H 2 O). Step B: Synthesis of 5(R)-azido-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid methyl ester To a 500 mL three-neck round-bottomed flask equipped with argon inlet/outlet, thermometer, and magnetic stirring was added 5(S)-hydroxy-5,6,7,8-tetrahydro-naphthalene-2 carboxylic acid methyl ester (29 g, 140 mmol) in toluene (280 mL). The reaction mixture was 10 cooled in a ice-salt bath, and DPPA (36 mL, 170 mmol, Aldrich) was added (internal temp. -4 *C). DBU (25 mL, 170 mmol, Aldrich) was added over 10 min at such a rate that the internal temp. of the reaction was kept below 1 *C. The ice in the bath was allowed to melt, and the reaction continued for 12 h during which time the reaction mixture stopped stirring because a precipitate had formed. Stirring was resumed, and the reaction mixture was stirred 15 at RT for another 11 h. The reaction contents were poured into a 2 L sep funnel, and the lower dark-brown layer was removed. Water (250 mL) was added to the remaining top layer, and the reaction mixture was extracted with Et 2 O (3 x 250 mL). The combined organic layers were washed with IM H 3
PO
4 , water, satd NaHCO 3 , and brine. The organic layer was dried over MgSO 4 , filtered and concentrated in vacuo. Purification by silica gel chromatography (330 g 20 Isco Redisep* column, 1:1 hexane-CH 2 C1 2 ) of the crude material provided the title compound. MS (+ ion ESI) m/z = 232 (MH*). Step C: Synthesis (5(R)-amino-5,6,7,8-tetrahydronaphthalen-2-yl)methanol To an oven-dried, 3-neck, 2 L round-bottomed flask equipped with argon inlet/outlet, addition funnel, thermometer, and overhead stirring was added THF (700 mL) and LAH (470 25 mL of a IM soln in THF, 470 mmol, Aldrich). The reaction mixture was cooled in a ice-salt bath, and 5-azido-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid methyl ester (27 g, 120 mmol) in THF (100 mL) was added over ca. 30 min. The reaction mixture was warmed to RT overnight, then cooled in an ice-salt bath the next morning. Water (18 mL) in THF (20 mL) was added to the reaction mixture over 4 h. Vigorous gas evolution occurred. 5N NaOH (18 30 mL) was added over 30 min followed by water (54 mL). After stirring for an additional 1 h, the reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was reconstituted in MeOH and CH 3 CN, and concentrated in vacuo again to provide the title compound as light-brown solid. MS (+ ion ESI) m/z = 161 (M-NH 3 ). 71 WO 2006/036664 PCT/US2005/033659 Similarly (4-(R)-aminochroman-7-yl)-methanol and (1-(R)-aminoindan-5-yl)methanol were prepared. Reference 2 5 Synthesis of (R)-6-(1-piperidin-1-ylmethylvinyl)-1,2,3,4-tetrahydronaphthalen-1-ylamine
NH
2 Step A: Synthesis of 2-trifluoromethanesulfonic acid 5-oxo-5,6,7,8-tetrahydronaphthalen-2-y ester 10 To a 1 -L round-bottomed flask charged with 6-hydroxy- 1 -tetralone (Aldrich, 21.97 g, 0.136 mol) at 0 *C was added CH 2 Cl 2 (500 mL) and pyridine (Aldrich, 11 mL, 0.136 mol). Triflic anhydride (Aldrich, 23 mL, 0.136 mol) was added through an additional funnel over a period of 12 min. The reaction mixture was gradually warmed to room temperature and stirred at room temperature overnight. The residue was diluted with water and the two phases were 15 separated. The organic phase was washed with IN HCl (100 mL x 2), saturated NaHCO 3 , and brine, dried over Na 2
SO
4 . After filtration and concentration in vacuo, the crude was purified by flash chromatography (5-11% EtOAc-hexane) to provide the title product as yellow oil. MS (ESI): 295 (M+H)*. Step B: Synthesis of 2-trifluoromethanesulfonic acid 5(S)-hydroxy-5,6,7,8-tetrahydro 20 naphthalen-2-yl ester To a dry three-necked flask containing (R)-2-methyl-CBS-oxazaborolidine (Aldrich, 1.94 mL, 1.OM in toluene, 1.93 mmol, 0.05 eq) under N 2 was added a solution of borane methylsulfide (BMS) (Aldrich, 3.30 mL, 34.80 mmol, 0.9 eq) in toluene (200 mL) through an additional funnel. After the addition was complete, the reaction mixture was allowed to cool to 25 0 *C. A solution of 2-trifluoromethanesulfonic acid 5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester (11.37 g, 38.67 mmol, 1.0 eq) in THF (180 mL) was added dropwise through an additional funnel. Following the addition, the reaction mixture was stirred at RT for additional 40 min, quenched with MeOH. The solvent was removed in vacuo and the crude was diluted with H 2 0 (50 mL). The aqueous phase was extracted with ether (3 x 150 mL). The combined 30 organic layer was washed with brine, dried over Na 2
SO
4 , filtered and concentrated. The title 72 WO 2006/036664 PCT/US2005/033659 compound was obtained as an off-white solid by flash chromatography (16-22% EtOAc hexane). Step C: Synthesis of 2-trifluoromethanesulfonic acid 5(R)-azido-5,6,7,8-tetrahydro-naphthalen 2-yl ester 5 To a solution of 2-trifluoromethanesulfonic acid 5(S)-hydroxy-5,6,7,8-tetrahydro naphthalen-2-yl ester (11.2 g, 37.9 mmol, 1.0 eq) in THF (150 mL) at RT was added DPPA (Aldrich, 11.1 mL, 51.6 mmol, 1.36 eq). The resulting mixture was allowed to cool to 0 *C and DBU (Aldrich, 7.7 mL, 51.6 mmol, 1.36 eq) was added slowly through a syringe. The reaction mixture was allowed to warm to RT and stirred over the weekend. The reaction 10 mixture was concentrated in vacuo. The crude product was dissolved in EtOAc (400 mL). The organic layer was washed with NH4Cl (twice), H 2 0, and brine, dried over Na 2
SO
4 . After filtration and concentration in vacuo, the crude was purified by flash chromatography (5% EtOAc-hexane) to provide the title compound. Step D: Synthesis of 2-trifluoromethanesulfonic acid 5(R)-amino-5,6,7,8-tetrahydro 15 naphthalen-2-yl ester A solution of 2-trifluoromethanesulfonic acid 5(R)-azido-5,6,7,8 tetrahydronaphthalen-2-yl ester (10.3 g, 32.1 mmol, 1.0 eq) in THF (70 mL) was added PPh 3 (Aldrich, 8.4 g, 32.1 mmol, 1.0 eq), and H 2 0 (30 mL) at 0 *C. The reaction mixture was allowed to warmed to RT and stirred overnight. 2N HC was added until the mixture was 20 acidic (PH = 1-2). The mixture was extracted with toluene (3 x 100 mL). The aqueous phase was neutralized with 5N NaOH until the pH is 12-13, and the product was extracted with ether (3 x 150 mL). The ether solution was dried over Na 2
SO
4 , filtered and concentrated in vacuo. The crude was purified by flash chromatography (6% MeOH-CH 2 Cl 2 ) to provide the title compound. 25 Step E: Synthesis of 2-trifluoromethanesulfonic acid 5(R)-tert-butoxycarbonyl-amino-5,6,7,8 tetrahydro-naphthalen-2-yl ester A solution of 2-trifluoromethanesulfonic acid 5(R)-amino-5,6,7,8-tetrahydro naphthalen-2-yl ester (2.0 g, 6.8 mmol, 1.0 eq) in CH 2
C
2 (20 mL) was added Et 3 N (1.9 mL, 13.6 mmol, 2.0 eq) and di-tert-butyl carbonate (Aldrich, 1.8 g, 8.1 mmol, 1.2 eq). The reaction 30 mixture was stirred at RT overnight, washed with saturated NaHCO 3 (2 x 20 mL), brine, dried over Na 2
SO
4 . After filtration and concentration in vacuo, the crude was purified by flash chromatography (4-10% EtOAc-hexane) to provide the title compound as a white solid. 73 WO 2006/036664 PCT/US2005/033659 step r: syntmesis o [ to-(I -pipenam- I -ylmethylvinyl)- 1(R)-1,2,3,4-tetrahydro-naphthalen- 1 yl]-carbamic acid tert-butyl ester A solution of 2-trifluoromethanesulfonic acid 5(R)-tert-butoxycarbonylamino-5,6,7,8 tetrahydronaphthalen-2-yl ester (1.89 g, 4.79 mmol, 1.0 eq) in CH 3 CN (25 mL) purged with N 2 5 was added palladium (II) acetate (Strem Chemicals, 65 mg, 0.29 mmol, 0.06 eq), 1,1' bis(diphenylphosphino)ferrocene (Aldrich, 0.70 g, 1.26 mmol, 0.26 eq), K 2 C0 3 (0.99 g, 7.18 mmol, 1.5 eg) and N-allylpiperdine (Lancaster, 3.00 g, 23.96 mmol, 5.0 eq). The reaction mixture sealed with a septum was heated to 80 *C overnight, cooled to RT, diluted with H20, and extracted with ether. The ether solution was dried over Na 2
SO
4 , filtered and concentrated in 10 vacuo. The crude was purified by flash chromatography (14-21% EtOAc-Hexane) to provide the title compound. MS (ESI): 371(M+H) *. Step G: Synthesis of 6-(I-piperidin-1-ylmethylvinyl)-1,2,3,4-tetrahydronaphthalen-1-ylamine To a solution of [6-(1-piperidin-1-ylmethylvinyl)-1(R)-1,2,3,4-tetrahydro-naphthalen 1 -yl]-carbamic acid tert-butyl ester in CH 2 Cl 2 (3 mL) was added TFA (3 mL). The reaction 15 mixture was stirred at RT for 4 h and then concentrated in vacuo. The crude was neutralized with 10% Na 2
CO
3 until the aqueous phase is basic, extracted with CH 2 Cl 2 . The organic solution was washed with brine, dried over Na 2
SO
4 , filtered and concentrated in vacuo to provide the title compound. MS (ESI): 271 (M+H) *. 20 Reference 3 Synthesis of (R)-6-((tert-butylamino)methyl)-1,2,3,4-tetrahydronaphthalen-1-ylamine
NH
2 H Step A: Synthesis of (R)-tert-butyl 6-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1-yl 25 carbamate Triethylamine (27.7 mL, 199 mmol) and di-tert-butyl-dicarbonate (17.4 g, 79.6 mmol) were added consecutively to a solution of (5(R)-amino-5,6,7,8-tetrahydronaphthalen-2-yl) methanol (7.05 g, 39.8 mmol) in a mixed solvent of ethyl acetate (100 mL), methanol (100 mL), and dichloromethane (100 mL) and the reaction mixture was stirred at RT for 2 h. The 30 solvents were removed in vacuo, the residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic portion was separated, washed with brine, the solvents were removed to afford a white solid, used in the following reaction without purification. 74 WO 2006/036664 PCT/US2005/033659 Step B: Synthesis of (R)-tert-butyl 6-formyl-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate A mixture of (R)-tert-butyl 6-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1 ylcarbamate (11.0 g, 39.8 mmol) and MnO 2 (Aldrich, <5 micron, 85%, 20.3 g, 198 mmol) in dichloromethane (500 mL) was stirred at r.t. overnight, filtered through a pad of Celite and the 5 solvents were removed to afford a light yellowish viscous oil which was used in the following reaction without purification. Step C: Synthesis of (R)-tert-butyl 6-((tert-butylamino)methyl)-1,2,3,4-tetrahydronaphthalen-1 ylcarbamate A mixture of (R)-tert-butyl 6-formyl-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate (39.8 10 mmol), tert-butylamine (21.0 mL, 199 mmol), and acetic acid (2.4 mL, 36.0 mmol) in of DMF (50 mL) in a sealed vessel was stirred at 60 "C for 1 h, cooled to r.t. and diluted with MeOH. NaBH 4 (3.0 g, 80 mmol) was added portion wise and the reaction mixture was stirred at RT for 10 min. MeOH was removed under reduced pressure and the DMF solution was partitioned between ethyl acetate and water. The organic portion was separated and the solvents were 15 removed to afford a viscous oil which was used in the following reaction without purification. Step D: Synthesis of (R)-6-((tert-butylamino)methyl)-1,2,3,4-tetrahydronaphthalen- 1 -ylamine A solution of (R)-tert-butyl 6-((tert-butylamino)methyl)-1,2,3,4-tetrahydronaphthalen 1-ylcarbamate (13.3 g, 39.8 mmol) in 300 mL of a saturated hydrogen chloride solution in ethyl acetate was stirred at RT overnight in a sealed flask and the solids were collected by 20 filtration. Similarly, (R)-7-((tert-butylamino)methyl)chroman-4-amine and (R)-5-((tert butylamino)methyl)-2,3-dihydro- 1 H-inden- 1-amine were prepared. Reference 4 25 Synthesis of (R)-6-(piperidin- 1 -ylmethyl)- 1,2,3,4-tetrahydronaphthalen- 1 -ylamine
NH
2 ON Step A: Synthesis of (R)-tert-butyl 6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1 ylcarbamate. 30 (R)-tert-Butyl 6-formyl-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate (12.2 g, 44.33 mmol) and piperidine (22 mL, 221.6 mmol, 5.0 equiv) were dissolved in 1,2-dichloroethane (400 mL). Acetic acid (10 drops) and sodium triacetoxyborohydride (23.4 g, 110.82 mmol, 2.5 equiv) were added and the reaction mixture was heated at 50 *C for 15 h. The reaction mixture 75 WO 2006/036664 PCT/US2005/033659 was cooled to room temperature, diluted with EtOAc (600 mL), washed with saturated sodium bicarbonate solution (2x250 mL), saturated ammonium chloride solution (200 mL), brine (200 mL), dried (MgSO 4 ) and purified on silica gel using 5% methanol in dichloromethane as eluant, affording (R)-tert-butyl-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1 5 ylcarbamate. MS: 345.2 (M+H). Step B: Synthesis of (R)-6-(piperidin- 1 -ylmethyl)- 1,2,3,4-tetrahydronaphthalen- 1-amine A solution of (R)-tert-butyl 6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1 ylcarbamate (15.0 g, 43.57 mmol) in methanol (325 mL) was treated with a 1.OM solution of HCl in diethyl ether (300 mL, 300 mmol, 6.8 equiv), capped and stirred at room temperature 10 for 14 h. The reaction mixture was concentrated in vacuo and partioned in dichloromethane (300 mL) and 1.ON NaOH (300 mL). The aqueous layer was separated and extracted with dichloromethane (2x250 mL). The combined organic layers were washed with brine (200 mL), dried (MgSO 4 ) and concentrated, affording (R)-6-(piperidin-1-ylmethyl)-1,2,3,4 tetrahydronaphthalen-l-amine as a dark yellow oil. MS: 245.2 (M+H). 15 Similarly, (R)-7-(piperidin-1-ylmethyl)chroman-4-amine, (R)-5-(piperidin-1-ylmethyl) 2,3-dihydro-1H-inden-1-amine and (R)-6-((4-methylpiperidin-1-yl)methyl)-1,2,3,4 tetrahydronaphthalen- 1-amine were prepared. Reference 5 20 Synthesis of 7 -(tert-butylaminomethyl)-6-chloro-chroman-(4R)-ylamine
NH
2 C1 *H= Step A: Synthesis of 7 -bromomethyl-6-chlorochroman-4-one A mixture of 6 -chloro-7-methylchroman-4-one (20 g, 102 mmol), NBS (19.9 g, 112 25 mmol), and AIBN (4.17 g, 25.4 mmol) in anhydrous CC14 (300 mL) was heated at reflux for 24 h. The reaction mixture was cooled and the solid was filtered off. The filtrate was concentrated and used in the next step without purification. Step B: Synthesis of 7 -(tert-butylamino-methyl)-6-chloro-chroman-4-one To a stirred mixture of tert-butylamine (7.3 g, 100. Mmol) and Et 3 N (10.1 g, 99.8 30 mmol) in anhydrous CH 2
CI
2 (50 ml) was added a solution of 7-bromomethyl-6-chloro chroman-4-one (25 g, 91 mmol) in CH 2 C1 2 (150 ml) dropwise. Stirring was continued for 16 h after which the mixture was concentrated, taken up in H20, acidified with 10% HCl until ph 1, and extracted with Et 2 O (discarded). The acidic aqueous layer was neutralized with 5N NaOH, 76 WO 2006/036664 PCT/US2005/033659 and extracted with CH 2 Cl 2 (3x). The combined extracts were dried over MgSO 4 , concentrated to give a yellow solid. Step C: Synthesis of 7-(tert-butylamino-methyl)-6-chloro-chroman-(4S)-ol To a stirred solution of (1 S,2S)-(+)-N-(4-toluene-sulfonyl)- 1,2-diphenylethylene 5 diamine (0.29 g, 8.1 mmol) in i-PrOH (15 ml) was added [RuCl 2 (N6-p-cymene)] 2 , and Et 3 N under argon. The reaction mixture was heated at 80 'C for 1 h, cooled, and concentrated to dryness. To this mixture was added a solution of 7-(tert-butylamino-methyl)-6-chloro chroman-4-one (12 g, 45 mol) in anhydrous CH 3 CN (150 ml), followed by 5:2 formic acid/TEA (6 ml). The reaction was stirred at rt for 24 h and then concentrated, taken up in 10 H 2 0, neutralized with 10% Na 2
CO
3 , extracted with CH 2 Cl 2 (3x), dried over MgSO 4 , concentrated to give a brown foam which was stirred in hexane/ether (1:1), and filtered. The filtrate was concentrated to give a light brown foam. Step D: Synthesis of 4(R)-azido-6-chloro-chroman-7-ylmethyl)-tert-butylamine To a stirred, cooled (0 *C) solution of 7-(tert-butylaminomethyl)-6-chlorochroman 15 (4S)-ol (11.55 g, 42.91 mmol) in anhydrous toluene (150 mL) was added DPPA (23.6 g, 85.8 mmol) dropwise in 0.5 h and DBU (13.1 g, 85.9 mmol). The reaction mixture was stirred at rt for 24 h. The reaction mixture was concentrated, taken up in H 2 0, extracted with CH 2 Cl 2 (3x), dried over MgSO 4 , concentrated and purified by ISCO (3% MeOH/CH 2 Cl 2 ) to give a brown oil. MS (APCI) m/z 296 (M+2). 20 Step E: Synthesis of 7-(tert-butylaminomethyl)-6-chlorochroman-(4R)-ylamine A mixture of (4R)-azido-6-chlorochroman-7-ylmethyl)-tert-butylamine (12 g, 41 mmol) and Ph 3 P (16 g, 61 mmol) in anhydrous THF (100 mL) was stirred at RT in 3 h. H20 (100 mL) was added and the reaction mixture was heated at reflux for 24 h. The reaction mixture was cooled, concentrated, taken up in toluene, extracted with 5N HCL. The aqueous 25 layer was neutralized with ION NaOH, extracted with CHC1 3 (3x), dried over MgSO 4 , concentrated to give a brown oil. MS (APCI) m/z 270 (M+2). Similarly, (R)-6-chloro-7-(piperidin-1-ylmethyl)chroman-4-amine was prepared. Reference 6 30 Synthesis of (R)-6-(2-(piperidin-1-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-1-amine
NH
2 N 77 WO 2006/036664 PCT/US2005/033659 3tep A: 3ynnesis o (t)-rer-ouyi o-(iodomethyl)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate To a solution of (R)-tert-butyl 6-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1 ylcarbamate (415.5 mg, 1.5 mmol) in dichloromethane/ether (1:1, 30 mL) at room temperature were added triphenylphosphine (590 mg, 2.25 mmol) and imidazole (153 mg, 2.25 mmol). To 5 this stirred solution was then added iodine (571 mg, 2.25 mmol). After stirring for 20 min, the reaction was quenched with 10% Na 2
S
2
O
3 (15 mL) until it became a clear two-phase solution. The aqueous phase was extracted with ether. The combined organic phase was dried over Na 2
SO
4 , filtered, and evaporated to dryness. Flash chromatography (SiO 2 , hexane/CH 2 Cl 2 = 3:1 to pure CH 2 Cl 2 ) afforded the desired product as a white solid. 10 Step B: Synthesis of (R)-tert-butyl 6-((1,3-dithian-2-yl)methyl)-1,2,3,4-tetrahydronaphthylen 1-ylcarbamate To a solution of 1,3-dithiane (1.01 g, 8.4 mmol) in 10 mL of dry THF at -30 *C was added dropwise 2.5M n-butyllithium in hexane (3.36 mL, 8.4 mmol). After stirring at -20 'C for 1.5 h, a solution of the iodide obtained in Step A (542 mg, 1.4 mmole, azeotroped with benzene) 15 in dry THF (10 mL) was added dropwise at -20 *C. The reaction mixture was stirred at -5 'C to 0 *C for 1 h. The reaction mixture was quenched with sat. NH 4 CI solution, extracted with EtOAc, dried over Na 2
SO
4 , filtered, and evaporated to dryness. Flash chromatography (Si0 2 ,
CH
2 Cl2/hexane = 1:1 to 2:1 to CH 2 Cl 2 /EtOAc = 100:3) afforded the title compound as a white solid. 20 Step C: Synthesis of (R)-tert-butyl 6-(2-oxoethyl)- 1,2,3,4-tetrahydronaphthalen-1 -ylcarbamate (R)-tert-Butyl 6-((1,3-dithian-2-yl)methyl)-1,2,3,4-tetrahydronaphthylen-1-ylcarbamate (6.1 g, 16.1 mmol) and CaCO 3 (3.23 g, 32.3 mmol) were suspended in THF/water (120 mL, 5:1 ratio) and Hg(Cl0 4
)
2 (9.65 g, 24.15 mmol) was added portion wise. After stirring at room temperature for 2 h, the reaction mixture was filtered through a celite pad with the help 25 of EtOAc. The filtrate was evaporated to dryness and the residue was purified by flash chromatography (Si0 2 , DCM to DCM/EtOAc = 3:1 to 2:1) gave the title compound as a colorless sticky oil. Step D: Synthesis of (R)-tert-butyl-6-(2-(piperidin- 1 -yl)ethyl)- 1,2,3,4-tetrahydronaphthalen- 1 ylcarbamate 30 To a solution of (R)-tert-butyl 6-(2-oxoethyl)-1,2,3,4-tetrahydronaphthalen-1 ylcarbamate (2.02 g, 7 mmol) and piperidine (1.79 g, 21 mmol) in dichloroethane (10 mL) was added sodium triacetoxyborohydride (2.97 g, 14 mmol). After stirring overnight at room temperature, the reaction solution was diluted with EtOAc and washed with sat. NaHCO 3 and brine. The organic phase was dried over Na 2
SO
4 and evaporated to dryness in vacuo. The crude 78 WO 2006/036664 PCT/US2005/033659 was purified by flash chromatography (Si0 2 , DCM to EtOAc to EtOAc/MeOH =100:20) to give the title compound as a sticky oil. Step E: Synthesis of (R)-6-(2-(piperidin- 1 -yl) ethyl)- 1,2,3,4-tetrahydronaphthalen- 1-amine To a solution of (R)-tert-butyl-6-(2-(piperidin-1-yl)ethyl)-1,2,3,4-tetrahydronaphthalen 5 1-ylcarbamate (2.0 g, 5.35 mmol) in DCM (25 mL) at room temperature was added TFA (3.66 g, 32 mmol). After stirring at room temperature overnight, the reaction mixture was evaporated to dryness. The residue was treated with 2.5 mL of triethylamine and it was evaporated again in vacuo. The crude product was azeotroped with benzene and was directly used in the next step. 10 Reference 7 Synthesis of 2-(5(R/S)-amino-5,6,7,8-tetrahydroquinazolin-2-yl)ethanol
NH
2 HO N 15 Step A: Synthesis of 3-(tert-butyldiphenylsilyloxy)-propanenitrile To a solution of 3-hydroxypropanenitrile (7.1 g, 0.1 mol) and DMAP (1.22 g, 0.01 mmol) in dry DCM (30 mL) at room temperature was added Et 3 N (30.3 g, 0.3 mol), followed by TBDPSC (27.5 g, 0.1 mol). A lot of white solid were formed. After stirring at room 20 temperature overnight, the reaction mixture was quenched with sat. NH 4 C solution, extracted with DCM, dried over Na 2
SO
4 , and evaporated in vaco. Flash chromatography (Si0 2 , hexane/EtOAc = 100:2 to 100:5 to 100:10) of the crude gave of 3-(tert-butyldiphenyl silyloxy)propanenitrile as a white solid. Step B: Synthesis of 3-(tert-butyldiphenylsilyloxy)-propanamidine 25 To a suspension of NH4C1 (5.35 g, 0.1 mol) in dry benzene (60 mL) at 0 'C was slowly added a solution of trimethylaluminum in toluene (50 mL, 2M). After the addition was complete, the reaction mixture was allowed to warm up to room temperature and was stirred for 2 h until gas evolution had ceased. A solution of 3-(tert-butyldiphenylsilyloxy)propanenitrile (9.27 g, 0.03 mol) in dry benzene (20 mL) was added to the aluminum amide reagent and the 30 resulting mixture was heated up to 80 *C for 20 h. The reaction mixture was slowly cooled to room temperature and then carefully poured into a slurry of 300 mL of DCM and 200 g of silica gel. It was then filtered and washed thoroughly with MeOH/DCM (1:2). After concentration, 79 WO 2006/036664 PCT/US2005/033659 nasn cnromatograpny (1U2, iut-c to EtOAc/MeOH = 100:20 to 100:30 to EtOAc/2M NH 3 in MeOH = 100:30) gave the title compound as a white solid. Step C: Synthesis of 2-(2-(tert-butyldiphenylsilyloxy)ethyl)-7,8-dihydroquinazolin-5(6H)-one A solution of 3-(tert-butyldiphenylsilyloxy)-propanamidine (25 g, 77 mmol) and 2 5 ((dimethylamino)methylene)cyclohexane-1,3-dione (12.8 g, 77 mmol) in dry EtOH (400 mL) was heated at 80 'C for 3 h. After cooling to room temperature, the solvent was evaporated. Flash chromatography (Si0 2 , EtOAc/hexane = 1:1) gave the title compound as a white solid. Step D: Synthesis of 2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5,6,7,8-tetrahydroquinazolin-5-ol A solution of 2-(2-(tert-butyldiphenylsilyloxy)ethyl)-7,8-dihydroquinazolin-5(6H)-one 10 (2.16 g, 5 mmol) in dry MeOH (30 mL) was treated with NaBH 4 (189 mg, 5 mmol). After 5 min, the reaction was quenched with 5 mL of sat. NH 4 Cl solution. The MeOH was evaporated and the residue was extracted with DCM, dried over Na 2
SO
4 and evaporated. Flash chromatography (Si0 2 , DCM to EtOAc) gave the title compound as a white solid. Step E: Synthesis of 5-azido-2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5,6,7,8-tetrahydro 15 quinazoline To a solution of 2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5,6,7,8-tetrahydroquinazolin-5-o (2.0 g, 4.63 mmol) in toluene (25 mL) at -10 C was added DPPA (1.2 mL, 5.56 mmol). To this stirred solution was then added DBU (0.83 mL, 5.56 mmol) dropwise while keeping the temperature below 0 *C. After stirring at room temperature for 16 h, the reaction was evaporated 20 to dryness and directly submitted to flash chromatography (Si0 2 , hexane/DCM = 1:2) to afford the title compound as a white solid. Step F: Synthesis of 2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5,6,7,8-tetrahydroquinazolin-5 amine A suspension of Pd/C (80 mg, 10% w/w) in a solution of 5-azido-2-(2-(tert 25 butyldiphenylsilyloxy)ethyl)-5,6,7,8-tetrahydroquinazoline (800 mg, 1.75 mmol) in EtOAc (30 mL) was stirred under H 2 atomosphere overnight. The reaction mixture was then directly submitted to flash chromatograph (SiO 2 , EtOAc to EtOAc/MeOH = 100:15 to EtOAc/2M NH 3 in MeOH = 2:1) to give the title compound as a white solid. Step G: Synthesis of 2-(5-amino-5,6,7,8-tetrahydroquinazolin-2-yl)ethanol 30 A solution of 2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5,6,7,8-tetrahydroquinazolin-5 amine (570 mg, 1.32 mmol) in THF (10 mL) at 0 *C was treated with a IM TBAF solution in THF (1.56 mL, 1.56 mmol). After stirring at room temperature overnight, the reaction mixture was directly submitted to flash chromatograph (Si0 2 , EtOAc to EtOAc/MeOH = 100:15 to EtOAc/2M NH 3 in MeOH = 1:1) to give crude product as a white solid. 80 WO 2006/036664 PCT/US2005/033659 Reference 8 Synthesis of 1-(2-(tert-butyldimethylsilyloxy)ethyl)-4,5,6,7-tetrahydro-1H-indazol-4-ylamine
NH
2
,
1 I// N 5 Step A: Synthesis of 1-(2-hydroxyethyl)-6,7-dihydro-1H-indazol-4(5H)-one 2-Hydroxyethyl hydrazine (1.36 mL, 20 mmol) was slowly added to an ice-cooled solution of 2-((dimethylamino)methylene)cyclohexane-1,3-dione (3.34 g) in methanol (50 mL). After stirring the reaction mixture at room temperature for 20 min, the solvent was 10 evaporated. Flash chromatography (Si0 2 , EtOAc/MeOH = 100:5 to 100:7 to 100:10) on the crude product gave the title compound as a white solid. Step B: Synthesis of 1-(2-(tert-butyldimethylsilyloxy)ethyl)-6,7-dihydro-1H-indazol-4(5H) one To a solution of 1-(2-hydroxyethyl)-6,7-dihydro-1H-indazol-4(5H)-one (14 g, 77.8 15 mmol) in dry DCM (100 mL) was added Et 3 N (22 mL, 155.6 mmol), followed by TBSCl (14 g, 93.3 mmol) and DMAP (95 mg, 0.78 mmol). After stirring at room temperature overnight, the reaction mixture was quenched with brine and extracted with EtOAc. Flash chromatography (Si0 2 , EtOAc/hexane = 1:1) of the crude product gave the title compound as a white solid. 20 Step C: Synthesis of 1-(2-(tert-butyldimethylsilyloxy)ethyl)-4,5,6,7-tetrahydro- 1 H-indazol-4-ol A solution of 1-(2-(tert-butyldimethylsilyloxy)ethyl)-6,7-dihydro-1H-indazol-4(5H) one (21 g, 71.4 mmol) in dry MeOH (200 mL) was treated with NaBH4 (2.7 g, 71.4 mmol). After 30 min, the reaction mixture was quenched with 15 mL of Sat. NH 4 Cl solution. The MeOH was evaporated and the residue was extracted with EtOAc, dried over Na 2
SO
4 and 25 evaporated. Flash chromatography (Si0 2 , EtOAc/hexane = 1:1 to EtOAc) of the crude product gave the title compound as a white solid. Step D: Synthesis of 4-azido-1-(2-(tert-butyldimethyl silyloxy)ethyl)-4,5,6,7-tetrahydro-1H indazole To a solution of 1-(2-(tert-butyldimethylsilyloxy)ethyl)-4,5,6,7-tetrahydro- 1 H-indazol 30 4-ol (23 g, 77.7 mmol) in 200 mL of toluene at -10 *C was added DPPA (20 mL, 93.2 mmol). DBU (13.9 mL, 93.2 mmol) was added dropwise while keeping the temperature below 0 *C. 81 WO 2006/036664 PCT/US2005/033659 After stirring at room temperature for 18 h, the reaction mixture was evaporated to dryness and directly submitted to flash chromatography (SiO 2 , hexane/EtOAc = 2:1 to EtOAc) to afford the title compound as a colorless liquid, together with 12 g of recovered starting alcohol. Step E: Synthesis of 1-(2-(tert-butyldimethylsilyloxy)ethyl)-4,5,6,7-tetrahydro-1H-indazol-4 5 amine A suspension of 150 mg of Pd/C (10% w/w) in a solution of 4-azido-1-(2-(tert-butyl dimethylsilyloxy)ethyl)-4,5,6,7-tetrahydro-1H-indazole (2.0 g, 6.23 mmol) in EtOAc (100 mL) was stirred under H 2 atomosphere overnight. The reaction mixture was then directly submitted to flash chromatograph (SiO 2 , EtOAc to EtOAc/MeOH = 100:20 to EtOAc/2M NH 3 in MeOH 10 100:20 to 100:30 to 100:40) to give the title compound as a white solid. Reference 9 Synthesis of (S)-3-(3-(trifluoromethyl)phenylsulfonamido)butanoic acid
CF
3 H 6 "S'N - CO2H 02 z 15 A mixture of L-homoalanine hydrogen chloride (1.0 g, 7.16 mmol) and sodium hydroxide (0.63 g, 15.8 mmol) in water (15 mL) was stirred at r.t. for 5 min. The reaction mixture was cooled to 0 *C, diluted with 1,4-dioxane (15 mL), and triethyl amine (1.2 mL, 8.60 mmol) and 3-trifluoromethylbenzenesulphony chloride (95%, 1.2 mL, 7.16 mmol) were 20 added sequentially. The reaction mixture was gradually warmed to r.t., 1,4-dioxane was removed in vacuo and the aqueous portion was acidified to pH 4 with 1.ON HCl. The product was extracted with EtOAc. Removal of the solvents afforded the titled compound as a colorless oil, which was used in the following reaction without purification. Similarly, the following acids were made: 25 (S)-3-(naphthalene-3-sulfonamido)butanoic acid; (S)-3-(4-chloro-2,5-dimethylphenyl-sulfonamido)butanoic acid; (S)-3-(2-chloro-5-(trifluoromethyl)phenylsulfonamido)butanoic acid; (S)-3-(2-fluoro-5-(trifluoromethyl)phenylsulfonamido)butanoic acid; (S)-3-(2,5-dichlorophenylsulfonamido)butanoic acid; 30 (S)-3-(2,3-dichlorophenyl-sulfonamido)butanoic acid; (S)-3-(3,4-dichlorophenylsulfonamido)butanoic acid; (S)-3-(3,5-dichlorophenyl-sulfonamido)butanoic acid; (S)-3-(2,6-dichlorophenylsulfonamido)butanoic acid; 82 WO 2006/036664 PCT/US2005/033659 (S)-3-(5-chloro-2-fluorophenylsulfonamido)butanoic acid; (S)-3-(3-chloro-2-fluorophenylsulfonamido)butanoic acid; (S)-3-(3-methylphenyl-sulfonamido)butanoic acid; (S)-3-(4-tert-butylphenylsulfonamido)butanoic acid; 5 (S)-3-(3-(trifluoromethyl)phenyl-sulfonamido)hex-5-ynoic acid; and (R)-4-methyl-3-(3-(trifluoromethyl)phenylsulfonamido)pentanoic acid. Reference 10 Synthesis of (R)-4-amino-4-oxo-3-(3,4-dichlorophenylsulfonamido)butanoic acid CI H 2 O 10
H
2 N O 0 To (R)-3,4-diamino-4-oxobutanoic acid (Chem-impex, 5g) in dioxane (36 mL) and water (36 mL) was added sodium carbonate (9.2 g) at RT. 3,4-Dichlorobenzenesulfonyl chloride (Aldrich; 7.1 mL) was added and the reaction mixture was stirred overnight. EtOAc (500 mL) 15 was added and the reaction mixture was acidified with 10% HCl and brine. The organic layer was separated and washed with brine three times, dried and evaporated to give the crude product which was used directly in the next step. Similarly the following acids were prepared: (R)-4-amino-4-oxo-3-(3-(trifluoromethyl)phenylsulfonamido)butanoic acid; (R)-4-amino 20 4-oxo-3-(4-methylphenylsulfonamido)butanoic acid; (R)-3-(4-chloro-2,5-dimethylphenylsulfonamido)butanoic acid; (R)-4-(benzyloxy)-3-(3,4 dichlorophenylsulfonamido)-4-oxobutanoic acid; (R)-4-tert-butoxy-3-(3,4-dichlorophenylsulfonamido)-4-oxobutanoic acid; (R)-3-(3,4 dichlorophenylsulfonamido)-4-methoxy-4-oxobutanoic acid; 25 (R)-3-(3,4-dichlorophenylsulfonamido)-4-ethoxy-4-oxobutanoic acid. Reference 11 Synthesis of 4,4,4-trifluoro-3-(3-(trifluoromethyl)phenylsulfonamido)butanoic acid
CF
3 H N < 0OH
CF
3 0 83 WO 2006/036664 PCT/US2005/033659 Step A: Synthesis of ethyl 4,4,4-trifluoro-3-(3-(trifluoromethyl)phenylsulfonamido)butanoate 3-Trifluoromethylbenzenesulphonyl chloride (From Lancaster, 98%, 5.10 mL, 31.3 mmol) was added to a solution of ethyl 3-amino-4,4,4-trifluorobutyrate (From Lancaster, 95%, .5 6.10 g, 31.3 mmol) in anhydrous pyridine (10 mL) at r.t. After 1 h, the reaction mixture was partitioned between diethyl ether and 5% of HCI (aq). The organic portion was separated, washed with water, brine, and concentrated to afforded the title compound as a yellow oil, used in the following reaction without purification. Step B: Synthesis of 4,4,4-trifluoro-3-(3-(trifluoromethyl)phenylsulfonamido)butanoic acid 10 A mixture of ethyl 4,4,4-trifluoro-3-(3-(trifluoromethyl)phenylsulfonamido)butanoate (13.5 g) and lithium hydroxide monohydrate (4.32 g, 103 mmol) in a methanol:THF:water solvent mixture (60 mL, 1:1:1) was stirred at r.t. overnight. After removing about two thirds of the solvents in vacuo, the aqueous residue was diluted with water, washed with diethyl ether, then acidified to pH 4 with 5% of HCl, and extracted with EtOAc. The organic portion 15 was washed with brine, removal of the solvents afforded the title compound as a light pinkish solid. Similarly, (R)-4, 4
,
4 -trifluoro-3-(3-(trifluoromethyl)phenylsulfonamido)butanoic acid was prepared from (R)-ethyl 3-amino-4,4,4-trifluorobutanoate (prepared according to literature procedure: Soloshonok, V.A.; Ono, T.; Soloshonok, I.V. J. Org. Chem. 1997, 62, 7538-39). 20 The following sulfonylated acids were prepared similarly: (R)-4,4,4-trifluoro-3-(3-methylphenylsulfonamido)butanoic acid; (R)-4,4,4-trifluoro-3-(naphthalene-3-sulfonamido)butanoic acid; (R)-3-(4-chloro-2,5-dimethylphenylsulfonamido)-4,4,4-trifluorobutanoic acid;
(R)-
3
-(
2 -chloro-5-(trifluoromethyl)phenylsulfonamido)-4,4,4-trifluorobutanoic acid; 25 (R)-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)-4,4,4-trifluorobutanoic acid; (R)-3-(2,5-dichlorophenylsulfonamido)-4,4,4-trifluorobutanoic acid; (R)-3-(2,6-dichlorophenylsulfonamido)-4,4,4-trifluorobutanoic acid; (R)-3-(2,3-dichlorophenylsulfonamido)-4,4,4-trifluorobutanoic acid; (R)-3-(3,4-dichlorophenylsulfonamido)-4,4,4-trifluorobutanoic acid; 30 (R)-3-( 3 ,5-dichlorophenylsulfonamido)-4,4,4-trifluorobutanoic acid;
(R)-
3 -(5-chloro-2-fluorophenylsulfonamido)-4,4,4-trifluorobutanoic acid;
(R)-
3 -(3-chloro-2-fluorophenylsulfonamido)-4,4,4-trifluorobutanoic acid; (R)-3-(2,3-dihydrobenzo[b][1,4]dioxine-6-sulfonamido)-4,4,4-trifluorobutanoic acid; (R)-3-(4-chlorobenzo[c][1, 2 ,5]oxadiazole-7-sulfonamido)-4,4,4-trifluorobutanoic acid; 35 (R)- 3 -(5-chloro-2-methoxyphenylsulfonamido)-4,4,4-trifluorobutanoic acid; 84 WO 2006/036664 PCT/US2005/033659 a;-t,-t,-t-u muuou-.>-kquuiine-8-sulfonamido)butanoic acid; (R)-3-(3,5-dichloro-2-hydroxyphenylsulfonamido)-4,4,4-trifluorobutanoic acid; (R)-3-(2,3-dihydrobenzofuran-5-sulfonamido)-4,4,4-trifluorobutanoic acid; (R)-3-(3,4-difluorophenylsulfonamido)-4,4,4-trifluorobutanoic acid; 5 (R)-3-(3,5-difluorophenylsulfonamido)-4,4,4-trifluorobutanoic acid; and (R)-3-(2,3-difluorophenylsulfonamido)-4,4,4-trifluorobutanoic acid. Reference 12 Synthesis of ( 2 R,3R)-4, 4
,
4 -trifluoro-2-hydroxy-3-(3-(trifluoromethyl) 10 phenylsulfonamido)butanoic acid
CF
3 H OH H H 02
CF
3 0 Step A: Synthesis of (S,E)- 1 -phenyl-N-(2,2,2-trifluoroethylidene)ethanamine A solution of (S)-1-phenylethanamine (26.9 g, 222 mmol), 2,2,2-trifluoro-I 15 methoxyethanol (40.2 g, 309 mmol) and p-toluenesulfonic acid monohydrate (4.23 g, 0.222 mmol) in toluene (300 mL) was refluxed in Dean-Stark apparatus for 3 h. Et 2 O (250 mL) was added and washed with sat NaHCO 3 aq. (500 mL x 3) and sat NaCl aq. (500 mL x 2), and then dried over Na 2
SO
4 . The solvents were removed under reduced pressure (40 *C, 28 mmHg), and the resulting crude product was used without further purification. 20 Step B: Synthesis of (2R,3R)-2-(benzyloxy)-4-((R)-1-phenylethyl)-3-(trifluoromethyl) cyclobutanone A solution of (SE)-1-phenyl-N-(2,2,2-trifluoroethylidene)ethanamine (9.97 g, 49.6 mmol) and 2-(benzyloxy)acetyl chloride (15.4 mL, 99.2 mmol) in CH 2 Cl 2 (64 mL) was stirred at 0 'C under N 2 . Triethylamine (20.0 mL, 143 mmol) was added dropwise and the resulting 25 mixture was then stirred at 40 *C for 18 h. H 2 0 (150 mL) was added to the reaction mixture and extracted with AcOEt (150 mL x 2). The combined organic phase was washed with sat NaCl aq. (200 mL with IN HCI 10 mL x 3, 200 mL with sat NaHCO 3 aq. 10 mL x 3), and dried over Na 2
SO
4 . The solvent was removed under reduced pressure, and the crude product was chromatographed on silica (CH 2 Cl 2 ) and recrystallized twice from EtOH and isopropanol, 30 respectively, to yield the title compound. MS (M+1): 350.1 85 WO 2006/036664 PCT/US2005/033659 Step C: Synthesis of (2R,3R)-methyl 2-(benzyloxy)-4,4,4-trifluoro-3-((S)-1-phenylethyl amino)butanoate A solution of (2R,3R)-2-(benzyloxy)-4-((R)-1-phenylethyl)-3-(trifluoromethyl) cyclobutanone (9.53 g, 27.3 mmol) and HCl gas (23.3 g, 638 mmol) in methanol (300 mL) 5 was stirred at 50 'C for 2 days. The solvent was removed under reduced pressure and residue was dissolved in CH 2
C
2 (400 mL) and washed with sat NaHCO 3 aq. (400 mL x 2) and sat NaCl aq. (400 mL x 2), and then dried over Na 2
SO
4 . The solvent was removed under reduced pressure, and the crude product was chromatographed on silica (hexane--hexane/CH 2 C1 2 = 1/1) to yield the title compound. MS (M+1): 382.2 10 Step D: Synthesis of (2R,3R)-methyl 3-amino-4,4,4-trifluoro-2-hydroxybutanoate The title compound was synthesized by modification of the reported procedure (Abouabdellah, A.; B6gu6, J. P.; Bonnet-Delpon, D.; Nga, T. T. T. J. Org. Chem. 1997, 62, 8826-8833). A solution of (2R,3R)-methyl 2-(benzyloxy)-4,4,4-trifluoro-3-((S)-1 phenylethylamino)butanoate (9.74 g, 25.5 mmol) and 10% Pd/C (1.93 g) in anhydrous AcOEt 15 (300 mL) was stirred under H 2 atmosphere for 27 h. To the filtrate of the mixture on Celite IN HCl in Et 2 O (100 mL) was added and stirred for 2.5 h. The solvent was removed under reduced pressure and dried in vacuo to yield the title compound as hydrochloride salt. MS (M+1): 188.2 Step E: Synthesis of (2R,3R)-methyl 4,4,4-trifluoro-2-hydroxy-3-(3-(trifluoromethyl) 20 phenylsulfonamido)butanoate To a solution of (2R,3R)-methyl 3-amino-4,4,4-trifluoro-2-hydroxybutanoate (0.436 g, 1.95 mmol) in pyridine (4.0 mL) was added 3-(trifluoromethyl)benzene-1-sulfonyl chloride (0.449 g, 1.84 mmol), and stirred at r.t. for 1.5 h. Et 2 O (100 mL) was added and washed with 2.5N HCl aq. (100 mL x 4) and sat NaHCO 3 aq. (100 mL x 2), and then dried over Na 2
SO
4 . 25 The solvent was removed under reduced pressure and the crude product was chromatographed on silica (CH 2 Cl 2 -> CH 2 Cl 2 /MeOH= 40/1) to yield the title compound. MS (M+1): 396.2 Step F: Synthesis of (2R,3R)-4,4,4-trifluoro-2-hydroxy-3-(3-(trifluoromethyl)phenyl sulfonamido)butanoic acid A solution of (2R,3R)-methyl 4,4,4-trifluoro-2-hydroxy-3-(3-(trifluoromethyl) 30 phenylsulfonamido)butanoate (0.414 g, 1.05 mmol) and lithium hydroxide mono hydrate (0.353 g, 8.41 mmol) in H 2 0/MeOH/THF (4.0 mL/4.Oml/4.Oml) was stirred at r.t. for 3 h. The solvent was evaporated down to 20 mL under reduced pressure, and the resulting solution was acidified to pH 1 with 5N HCl aq. The product was extracted with AcOEt (40 mL x 4) and the combined organic phase was washed with sat NaCl aq. (20 mL x 2) and dried over Na 2
SO
4 . The solvent 86 WO 2006/036664 PCT/US2005/033659 was iremoveu unuer reauceu pressure and dried in vacuo to yield the title compound. MS (M-1): 380.2. Similarly, the following acids are made: (2R,3S)-3-(5-chloro-2-fluorophenylsulfonamido)-4,4,4-trifluoro-2-hydroxybutanoic acid; 5 (2R,3S)-3-(3-chloro-2-fluorophenylsulfonamido)-4,4,4-trifluoro-2-hydroxybutanoic acid; (2R,3S)-3-(2,3-dichlorphenylsulfonamido)-4,4,4-trifluoro-2-hydroxybutanoic acid; (2R,3S)-3-(3,4-dichlorphenylsulfonamido)-4,4,4-trifluoro-2-hydroxybutanoic acid; (2R,3S)-3-(2,5-dichlorphenylsulfonamido)-4,4,4-trifluoro-2-hydroxybutanoic acid; and (2R,3S)-4,4,4-trifluoro-2-hydroxy-3-(naphthalene-2-sulfonamido)butanoic acid. 10 Reference 13 Synthesis of (2R,3S)-4,4,4-trifluoro-2-hydroxy-3-(N-methyl-3 (trifluoromethyl)phenylsulfonamido)butanoic acid
CF
3 i OH N OH 02
CF
3 0 15 Step A: Synthesis of (2R,3S)-methyl 4,4,4-trifluoro-2-hydroxy-3-(N-methyl-3-(trifluoro methyl)phenylsulfonamido)butanoate To (2R,3R)-methyl 4,4,4-trifluoro-2-hydroxy-3-(3-(trifluoromethyl)phenyl sulfonamido)butanoate (1.1 g) prepared in Referece 12, Step E in dry DMF (10 mL) was added potassium carbonate (1.14 g) and iodomethane (0.52 mL). The reaction mixture was stirred at 20 RT for 2 h. EtOAc (200 mL) was added and washed with brine (3x100 mL), dried and evaporated to give the title compound. Step B: Synthesis of (2R,3S)-4,4,4-trifluoro-2-hydroxy-3-(N-methyl-3-(trifluoromethyl) phenylsulfonamido)butanoic acid (2R,3S)-Methyl 4,4,4-trifluoro-2-hydroxy-3-(N-methyl-3-(trifluoromethyl) 25 phenylsulfonamido)butanoate was converted to the title compound according to Reference 12, Step F. Similarly, (2R,3S)-3-(3-chloro-2-fluoro-N-methylphenylsulfonamido)-4,4,4-trifluoro-2 hydroxybutanoic acid was prepared. 87 WO 2006/036664 PCT/US2005/033659 Reference 14 Synthesis of (S)-3-(3-chloro-2-fluoro-N-methylphenylsulfonamido)-4,4,4-trifluorobutanoic acid CI F N OH 5 02 CF 3 0 Step A: Synthesis of (S)-ethyl 3-(3-chloro-2-fluoro-N-methylphenylsulfonamido)-4,4,4 trifluorobutanoate (S)-Ethyl 3
-(
3 -chloro-2-fluorophenylsulfonamido)-4,4,4-trifluorobutanoate, prepared 10 according to Reference 11, Step A, was converted to the title compound according to Refrence 13, Step A. Step B: Synthesis of (S)-3-(3-chloro-2-fluoro-N-methylphenylsulfonamido)-4,4,4 trifluorobutanoic acid (S)-Ethyl 3-(3-chloro- 2 -fluoro-N-methylphenylsulfonamido)-4,4,4-trifluorobutanoate (1.5 15 g) was dissolved in 25 mL of dioxane. 25 mL of 10% hydrochloric acid solution was added and the reaction mixture was heated at 90 *C for 9 h. The solvents were concentrated and extracted with EtOAc to give the title compound. Similarly, (S)- 4
,
4
,
4 -trifluoro-3-(3-(trifluoromethyl)phenylsulfonamido)butanoic acid was prepared. 20 Reference 15 Synthesis of (R)-7-nitro-6-(piperidin- I -ylmethyl)- 1,2,3,4-tetrahydronaphthalen- 1 -ylamine H 2N,,, 0 2 N N 25 Step A: Synthesis of (R)-2,2,2-trifluoro-N-(6-(hydroxymethyl)- 1,2,3,4-tetrahydronaphthalen- 1 yl)acetamide To a solution of (R)-(5-amino-5,6,7,8-tetrahydronaphthalen-2-yl)methanol (5.32 g, 30 mmol) and trfluoroacetic anhydride (4.66 mL, 33 mL) in 20 mL of dry THF at RT was added 88 WO 2006/036664 PCT/US2005/033659 dropwise triethylamine (5.0 mL, 36 mmol). After stirring at RT for 2 h, the reaction was quenched with sat. NaHCO 3 , extracted with EtOAc, washed with brine, dried over Na 2
SO
4 , filtered, and evaporated to dryness. Flash chromatography (SiO 2 , DCM/EtOAc = 1:1 to pure EtOAc) afforded the title compound (7.2 g) as a white solid. 5 Step B: Synthesis of (R)-(5-( 2
,
2
,
2 -trifluoroacetamido)-5,6,7,8-tetrahydronaphthalen-2-yl) methylacetate To a solution of (R)-2,2,2-trifluoro-N-(6-(hydroxymethyl)-1,2,3,4-tetrahydro naphthalen- 1 -yl)acetamide (546 mg, 2 mmol) in 10 mL of dry DCM was added acetic anhydride (0.30 mL, 3 mmol) and triethylamine (0.8 mL, 6 mmol), followed by DMAP (10 10 mg). After stirring for 2 h at RT, the solution was evaporated to dryness and directly submitted to flash chromatography (SiO2, DCM) to give the title compound (610 mg) as a white solid. Step C: Synthesis of (R)-(1-nitro-5-( 2
,
2 ,2-trifluoroacetamido)-5,6,7,8-tetrahydronaphthalen-2 yl)methyl acetate and (R)-( 3 -nitro-5-( 2 ,2,2-trifluoroacetamido)-5,6,7,8-tetrahydronaphthalen-2 yl)methyl acetate 15 To a solution of (R)-(5-(2,2,2-trifluoroacetamido)-5,6,7,8-tetrahydronaphthalen-2-yl) methyl acetate (160 mg, 0.508 mmol) in MeCN (2 mL) was added NO 2
*BF
4 - (66 mg, 0.508 mmol). After stirring at RT for 20 min, the reaction was quenched with 0.5 mL of Sat. NaHCO 3 , and the solvent was evaporated to dryness. Flash chromatography (Si0 2 , DCM/hexane = 5:1 to pure DCM) gave (R)-(l-nitro-5-(2,2,2-trifluoroacetamido)-5,6,7,8 20 tetrahydronaphthalen-2-yl)methyl acetate (40 mg) as a white solid and (R)-(3-nitro-5-(2,2,2 trifluoroacetamido)-5,6,7,8-tetrahydronaphthalen-2-yl)methy acetate (90 mg) as a white solid. Step D: Synthesis of (R)-2,2,2-trifluoro-N-(6-(hydroxymethyl)-7-nitro-1,2,3,4-tetrahydro naphthalen- 1 -yl)acetamide To a solution of (R)-( 3 -nitro-5-(2,2,2-trifluoroacetamido)-5,6,7,8-tetrahydronaphthalen 25 2-yl)methyl acetate (17 mg) in 10 mL of MeOH was added one drop of 96% H 2
SO
4 and the resulting mixture was stirred at 50 0 C for 3 h. After cooling to RT, the reaction was quenched with Sat. NaHCO 3 (0.5 mL). The MeOH was evaporated and the residue was directly loaded on column chromatography (Si02, DCM to DCM/EtOAc = 2:1 to 1:1) to give the title compound (15 mg) as a white solid. 30 Step E: Synthesis of (R)-2,2,2-trifluoro-N-(6-formyl-7-nitro-1,2,3,4-tetrahydronaphthalen-1 yl)acetamide To a solution of (R)-2,2,2-trifluoro-N-(6-(hydroxymethyl)-7-nitro-1,2,3,4 tetrahydronaphthalen- 1 -yl)acetamide (350 mg, 1.1 mmol) in DCM (100 mL) was added portionwise MnO 2 (957 mg, 11 mmol). After stirring at RT for 3 h, the reaction mixture was 89 WO 2006/036664 PCT/US2005/033659 filtered through silica gel with the help of hexane/EtOAc = 1:1 to give the title compound (350 mg) as a white solid. Step F: Synthesis of (R)-2,2,2-trifluoro-N-(7-nitro-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydro naphthalen- 1 -yl)acetamide 5 To a solution of (R)-2,2,2-trifluoro-N-(6-formyl-7-nitro-1,2,3,4-tetrahydronaphthalen 1-yl)acetamide (350 mg, 1.1 mmol) in 1,2-dichloroethane (6 mL) was added piperidine (187 mg, 2.2 mmol) and NaBH(OAc) 3 (350 mg, 1.65 mmol). After stirring at RT overnight, the reaction was quenched with Sat. NaHCO 3 , extracted with EtOAc, dried over Na 2
SO
4 , filtered, and evaporated to dryness. Flash chromatography (Si02, EtOAc/hexane = 1:1) afforded the 10 title compound (270 mg) as a white solid. Step G: Synthesis of (R)-7-nitro-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1 amine A solution of (R)-2,2,2-trifluoro-N-(7-nitro-6-(piperidin-1-ylmethyl)-1,2,3,4 tetrahydronaphthalen-1 -yl)acetamide (230 mg, 0.6 mmol) and NaOH (108 mg, 2.7 mmol) in a 15 mixed solvent (THF/MeOH/H20 = 5mL/5mL/lmL) was heated at 70 C for 3 h. After cooling to RT, the solvent was evaporated to dryness and the residue was directly loaded on column chromatography (Si0 2 , EtOAc to EtOAc/2M NH 3 in MeOH = 100:15 to 100:20) to give the title (200 mg) as a white solid. 20 Reference 16 Synthesis of (R)-5-nitro-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamine H 2N,,,
NO
2 N 25 Step A: Synthesis of (R)-2,2,2-trifluoro-N-(6-(hydroxymethyl)-5-nitro-1,2,3,4-tetrahydro naphthalen- 1 -yl)acetamide To a solution of (R)-(1-nitro-5-(2,2,2-trifluoroacetamido)-5,6,7,8-tetrahydronaphthalen 2-yl)methyl acetate (560 mg) in 10 mL of MeOH was added one drop of 96% H 2
SO
4 and the resulting mixture was stirred at 50 C for 3 h. After cooling to RT, the reaction was quenched 30 with Sat. NaHCO 3 (0.5 mL). The MeOH was evaporated and the residue was directly loaded 90 WO 2006/036664 PCT/US2005/033659 on column cnromatograpny IU 2 , nexane/EtOAc = 2:1) to give the title compound (15 mg) as a white solid. Step B: Synthesis of (R)-2,2,2-trifluoro-N-(6-formyl-5-nitro-1,2,3,4-tetrahydronaphthalen- 1 yl)acetamide 5 To a solution of (R)-2,2,2-trifluoro-N-(6-(hydroxymethyl)-5-nitro-1,2,3,4-tetrahydro naphthalen-1-yl)acetamide (440 mg, 1.38 mmol) in DCM (50 mL) was added portionwise MnO 2 (1.20 g, 13.8 mmol). After stirring at RT for 1 h, the reaction mixture was filtered through silica gel with the help of hexane/EtOAc = 1:1 to give the title compound (250 mg) as a white solid. 10 Step C: Synthesis of (R)-2,2,2-trifluoro-N-(5-nitro-6-(piperidin-1-ylmethyl)-1,2,3,4 tetrahydronaphthalen- 1 -yl)acetamide To a solution of (R)-2,2,2-trifluoro-N-(6-formyl-5-nitro-1,2,3,4-tetrahydronaphthalen l-yl)acetamide (250 mg, 0.79 mmol) in 1,2-dichloroethane (2 mL) and 0.5 mL of HOAc was added piperidine (135 mg, 1.58 mmol) and NaBH(OAc) 3 (251 mg, 1.19 mmol). After stirring 15 at RT overnight, the reaction was quenched with sat. NaHCO 3 , extracted with EtOAc, dried over Na 2
SO
4 , filtered, and evaporated to dryness. Flash chromatography (Si02, EtOAc/hexane = 1:4 to 1:3 to 1:2) afforded the title compound (240 mg) as a white solid. Step D: Synthesis of (R)-5-nitro-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1 amine 20 A solution of (R)-2,2,2-trifluoro-N-(5-nitro-6-(piperidin-1-ylmethyl)-1,2,3,4 tetrahydronaphthalen-1-yl)acetamide (230 mg, 0.6 mmol) and NaOH (48 mg, 1.2 mmol) in a mixed solvent (MeOH/H 2 0 = 1 OmL/1 mL) was heated at 70 0 C for 3 h. After cooling to RT, the solvent was evaporated to dryness and the residue was directly loaded on column chromatography (SiO 2 , EtOAc to EtOAc/2M NH 3 in MeOH = 100:10 to 100:20 to 100:30) to 25 give the title compound (130 mg) as a white solid. Example I Synthesis of (S)-N-((R)-6-((cyclopentylamino)methyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-3 (3-(trifluoromethyl)phenylsulfonamido)butanamide 30 91 WO 2006/036664 PCT/US2005/033659 H H
F
3 C 02N N aN H Step A: Synthesis of (S)-N-((R)-6-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(3 (trifluoromethyl)phenylsulfonamido)butanamide A mixture of (S)-3-(3-(trifluoromethyl)phenylsulfonamido)butanoic acid (2.05 g, 6.59 5 mmol described in Reference 9 ), (R)-(5-amino-5,6,7,8-tetrahydronaphthalen-2-yl)methanol, (1.17 g, 6.59 mmol), TBTU (from Advanced ChemTech, 2.33 g, 7.25 mmol), and Hunig's base(1.73 mL, 9.89 mmol) in DMF (20 mL)was stirred at r.t. for 2 h. The reaction mixture was partitioned between ethyl acetate and aqeous Na 2
CO
3 . The organic portion was separated, washed with water, brine, and the solvents were removed to afford the title compound as an 10 off-white solid which was used in the following reaction without purification. Step B: Synthesis of (S)-N-((R)-6-formyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(3-(trifluoro methyl)phenylsulfonamido)butanamide A mixture of (S)-N-((R)-6-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(3 (trifluoromethyl) phenylsulfonamido)butanamide (3.41 g, 7.25 mmol) and MnO 2 (from 15 Aldrich, <5 micron, activated, -85%, 3.5 g, 34.2 mmol) in 300 mL of methylene chloride was stirred at r.t. overnight. The reaction mixture was filtered through a pad of silica gel, eluted with 0 to 30% of ethyl acetate in methylene chloride, the title compound was obtained as an off-white waxy solid. Step C: Synthesis of (S)-N-((R)-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-3 20 (3-(trifluoromethyl)phenylsulfonamido)butanamide A mixture of (S)-N-((R)-6-fornyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(3 (trifluoromethyl)phenylsulfonamido)butanamide (0.28 g, 0.60 mmol), cyclopentylamine (0.59 mL, 6.0 mmol), and acetic acid (0.036 mL, 0.60 mmol) in 2 mL of DMF in a sealed tube was stirred at 60 0 C for 16 h. The reaction mixture was cooled to r.t., diluted with MeOH and 25 NaBH4 (0.068 g, 1.8 mmol) was added. After for 10 min, the volatiles were removedin vacuo and the residue was partitioned between EtOAc and water. The organic portion was separated, washed with brine and the solvents were removed. Tthe crude product was purified by flash column chromatography (0 - 10% of MeOH-NH40H (aq, 28 - 30 %) (volume ratio 3:1) in methylene chloride in 21 min, 10 - 15% of MeOH-NH40H(aq, 28 - 30 %) (volume ratio 3:1) 92 WO 2006/036664 PCT/US2005/033659 in menyiene cmonae m o mm) to give the titled compound was obtained as a white solid. MS m/z: 538.3 (M+H)*. Calc'd for C 27
H
3 4
F
3
N
3 0 3 S - 537.64. Proceeding as described above, the following compounds were prepared: (3S)-N-((1R)-6-(((1,1-dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl) 5 3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((1R)-6-(I-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-3-(((3 (trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((IR)-6-((cyclopentylamino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-3-(((3 (trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 10 (3S)-N-((1R)-6-(((2-(methyloxy)ethyl)amino)methyl)-1,2,3,4-tetrahydro-1 naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((1R)-6-(((cyclopropylmethyl)amino)methyl)-1,2,3,4-tetrahydro-1 naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((1R)-6-(1-pyrrolidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-3-(((3 15 (trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((1R)-6-(((2-methylpropyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-3 (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((4R)-7-(1 -piperidinylmethyl)-3,4-dihydro-2H-chromen-4-yl)-3-(((3-(trifluoro methyl)phenyl)sulfonyl)amino)butanamide; 20 (3S)-N-((4R)-7-(((1,1 -dimethylethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)-3 (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((4R)-7-((cyclopentylamino)methyl)-3,4-dihydro-2H-chromen-4-yl)-3-(((3 (trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((4R)-7-((cyclopropylamino)methyl)-3,4-dihydro-2H-chromen-4-yl)-3-(((3 25 (trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((4R)-7-(((1 -methylethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)-3-(((3 (trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((4R)-7-((4-methyl-1-piperazinyl)methyl)-3,4-dihydro-2H-chromen-4-yl)-3 (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 30 (3S)-N-((4R)-7-(((3S)-3-hydroxy-1-piperidinyl)methyl)-3,4-dihydro-2H-chromen-4-yl) 3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((4R)-7-(1 -pyrrolidinylmethyl)-3,4-dihydro-2H-chromen-4-yl)-3-(((3 (trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 93 WO 2006/036664 PCT/US2005/033659 .(3S)-N-((4R)-7-(((2-(methyloxy)ethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)-3 (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((4R)-7-(((cyclopropylmethyl)amino)methyl)-3 ,4-dihydro-2H-chromen-4-yl)-3 (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 5 (3S)-N-((4R)-7-(((2-methylpropyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)-3 (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-(( 1R)-6-( 1 -(1 -piperidinylmethyl)ethenyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-3 (((3 -(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-(( 1R)-6-((( 1,1-dimethyl 10 ethyl)amino)methyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-(((4-chloro-2,5-diinethylphenyl)sulfonyl)amino)-N-((4R)-7-((( 1,1 -dimnethyl ethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide; (3.S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-(( 1R)-6-((cyclopentyl amino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; 15 (3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4R)-7-((cyclopentyl amino)methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide; (3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-(( 1R)-6-( 1 -piperidinyl methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4R)-7-( 1 -piperidinyl 20 methyl)-3 ,4-dihydro-2H-chromen-4-yl)butanamide; (3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)ammno)-N-(( 1R)-6-(((2-methylpropyl) amino)methyl)-1 ,2,3,4-tetrahydro-1 -naphthalenyl)butanamide; (3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4R)-7-(((2-methylpropyl) amino)methyl)-3 ,4-dihydro-2H-chromen-4-yl)butanamide; 25 (3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-(( 1R)-6-(((l1-methylethyl) amino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (35)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4R)-7-(((l1-methylethyl) amino)methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide; (3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-(( 1R)-6-(((cyclopropyl 30 methyl)amino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4R)-7-(((cyclopropyl methyl)amino)methyl)-3,4-dihydro-2H-cbromen-4-yl)butanamide; (3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-(( 1R)-6-((cyclobutyl-amino) methyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide; 94 WO 2006/036664 PCT/US2005/033659 (3S)-3-(((4-chloro-2,A-clnmethylpheny)sulfony)amino)-N-((4R)-7-((cyc1obutyl-amilo) methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide; (3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)am'mo)-N-(( 1R)-6-(((3S)-3-hydroxy- 1 piperidmnyl)methyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide; 5 (3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-(( 1R)-6-(((3R)-3-hydroxy- 1 piperidinyl)methyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide; (35)-3-(((4-chloro-2,5-dimethylpheny1)sulfony)amino)-N-((4R)-7-(((3S)-3-hydroxy- 1 piperidinyl)methyl)-3,4-dihydro-2H-cbromen-4-yl)butanamide; (35)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4R)-7-(((3R)-3-hydroxy- 1 10 piperidinyl)methyl)-3 ,4-dihydro-2Hr-chromen-4-yl)butanamide; (3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-(( 1R)-6-( 1-pyrrolidinyl methyl)- I ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-(((4-chloro-2,5-diniethylphenyl)sulfonyl)amino)-N-((4R)-7-( 1 -pyrrolidinyl methyl) -3 ,4-dihydro-2H-chromen-4-yl)butanamide; 15 (3S)-3-(((4-( 1-dimnethylethyl)phenyl)sulfonyl)amino)-N-(( 1R)-6-( 1 -piperidinyl methyl)-1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-(((4-bromo-3-(trifluoromethyl)phenyl)sulfonyl)amino)-N-(( 1R)-6-( 1 piperidinylmethyl)-1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-(((2-fluoro-5-(trifluoromethyl)phenyl)sulfonyl)amino)-N-(( 1R)-6-( 1 -piperidinyl 20 methyl)- 1,2,3 ,4-tetrahydro- I -naphthalenyl)butanamide; (3S)-3-(((2-chloro-5-(trifluoromethyl)phenyl)sulfonyl)amino)-N-(( IR)-6-( 1-piperidinyl methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-(((2-chloro-5-(trifluoromethyl)phenyl)sulfony)amino)-N-(( 1R)-6-( 1 -piperidinyl methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; 25 (3S)-N-(( IR)-6-((3-pyridinylamino)methyl)- 1,2,3,4-tetrahydro- 1-naphthalenyl)-3 -(((3 (trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-3-(((6-chloro-2-naphthalenyl)sulfonyl)ammno)-N-(( 1R)-6-( 1 -piperidinyl-methyl) 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-N-(( 1R)-6-((cyclopentylamino)methyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)-3-(((2 30 fluoro-5-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-3-(((2-chloro-5-(trifluoromethyl)phenyl)sulfonyl)amino)-N-(( 1R)-6-((cyclopentyl amino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-(((6-chloro-2-naphthalenyl)sulfonyl)amino)-N-(( 1R)-6-((cyclopentylamino) methyl)- 1 ,2,3,4-tetrahydro- I -naphthalenyl)butanamide; 95 WO 2006/036664 PCT/US2005/033659 0arm-em-oro-I -napntnaienyl)sulfonyl)amino)-N-((1R)-6-((cyclopentyl amino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-(methyl((3-(trifluoromethyl)phenyl)sulfonyl)amino)-N-((I R)-6-(1 -piperidinyl methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; 5 (3S)-3-(((2-nitro-4-(trifluoromethyl)phenyl)sulfonyl)amino)-N-((1R)-6-(1 -piperidinyl methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-(((2,6-dichloro-4-(trifluoromethyl)phenyl)sulfonyl)amino)-N-((IR)-6-(1 piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-((1,1 -biphenyl-4-ylsulfonyl)amino)-N-((I R)-6-(1 -piperidinylmethyl)- 1,2,3,4 10 tetrahydro- I -naphthalenyl)butanamide; (3S)-N-((1R)-6-(((1,1 -dimethylethyl)amino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl) 3-(((2-nitro-4-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-3-(((2,6-dichloro-4-(trifluoromethyl)phenyl)sulfonyl)amino)-N-((1 R)-6-(((1,1 dimethylethyl)amino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; 15 (3S)-3-((1,1 '-biphenyl-4-ylsulfonyl)amino)-N-((1 R)-6-(((1,1 -dimethylethyl) amino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-((1,1 '-biphenyl-3 -ylsulfonyl)amino)-N-((1R)-6-(1 -piperidinylmethyl)- 1,2,3,4 tetrahydro- I -naphthalenyl)butanamide; and (3S)-3-(((4-(1,3-oxazol-5-yl)phenyl)sulfonyl)amino)-N-((1R)-6-(I -piperidinyl-methyl) 20 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide. The following compounds in Table 1 can be prepared similarly. Table 1 X' X H H
R
1 0 Y R 7 X X' X" R Y R/ 3-CF 3 H H CH 3
CH
2
-CH
2 NHPr-i 3-CF 3 H H CH 3
CH
2
-CH
2
NHC
4
H
7 -c 3-Cl H H CH 3
CH
2
-CH
2
NHC
4
H
7 -c 2-F 5-CF 3 H CH 3
CH
2
-CH
2
NHC
4
H
7 -c 2-Cl 5-CF 3 H CH 3
CH
2
-CH
2
NHC
4
H
7 -c 96 WO 2006/036664 PCT/US2005/033659 X X' X" R' Y R 7 2-Napthyl H H CH 3
CH
2
-CH
2
NHC
4
H
7 -c 2-Cl 3-Cl H CH 3
CH
2
-CH
2
NHC
4
H
7 -c 2-Cl 5-Cl H CH 3
CH
2
-CH
2
NHC
4
H
7 -c 3-Cl 4-Cl H CH 3
CH
2
-CH
2
NHC
4
H
7 -c 2-Cl 6-Cl H CH 3
CH
2
-CH
2
NHC
4
H
7 -c 2-F 5-Cl H CH 3
CH
2
-CH
2
NHC
4
H
7 -c 2-F 3-Cl H CH 3
CH
2
-CH
2
NHC
4
H
7 -c 2-Me 4-Cl 5-Me CH 3
CH
2
-CH
2
NHC
4
H
7 -c 4-Bu-tert H H CH 3
CH
2
-CH
2
NHC
4
H
7 -c 2-Me 4-Cl 5-Me CH 3 0 -CH 2
NHC
4 H7-c 2-Me 4-Cl 5-Me CH 3 direct bond -CH 2
NHC
4
H
7 -c 2Me 4-Cl 5-Me CF 3 direct bond -CH 2
NHC
4
H
7 -c 4-Cl H H CF 3
CH
2
-CH
2
NHC
4
H
7 -c 2-Cl 5-Cl H CF 3
CH
2
-CH
2
NHC
4
H
7 -c 3-Me H H CF 3
CH
2
-CH
2
NHC
4
H
7 -c 3-Cl H H CF 3
CH
2
-CH
2
NHC
4
H
7 -c 2-F 4-Cl H CF 3
CH
2
-CH
2
NHC
4
H
7 -c 2-F 3-Cl H CF 3
CH
2
-CH
2
NHC
4
H
7 -c 2-F 5-Cl H CF 3
CH
2
-CH
2
NHC
4
H
7 -c 2-Cl 3-Cl H CF 3
CH
2
-CH
2
NHC
4
H
7 -c 2-Cl 6-Cl H CF 3
CH
2
-CH
2
NHC
4
H
7 -c 3-Cl 4-Cl H CF 3
CH
2
-CH
2
NHC
4
H
7 -c 2-Napthyl H H CF 3
CH
2
-CH
2
NHC
4
H
7 -c 2-Napthyl H H CF 3 0 -CH 2
NHC
5
H
9 -c Example 2 Synthesis of (R)-4,4,4-trifluoro-N-(6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1 yl)-3-(3-(trifluoromethyl)phenylsulfonamido)butanamide 97 WO 2006/036664 PCT/US2005/033659 H H F3C N,, N,,. 02
CF
3 O Step A: Synthesis of (R)-4,4,4-trifluoro-N-(6-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen 1 -yl)-3-(3-(trifluoromethyl)phenylsulfonamido)butanamide 5 A mixture of 4,4,4-trifluoro-3-(3-(trifluoromethyl)phenylsulfonamido)butanoic acid (described in Reference 11, 2.84 g, 7.78 mmol), (R)-(5-amino-5,6,7,8-tetrahydronaphthalen-2 yl)methanol (1.38 g, 7.78 mmol), TBTU (from Advanced ChemTech, 2.75g, 8.55 mmol), and Hunig's base (2.0 mL, 11.7 mmol) in 20 mL of DMF was stirred at r.t. for 3 h. The reaction mixture was partitioned between ethyl acetate and water. The organic portion was separated, 10 washed with water, and brine. The solvents were removed to give the title compound as an off-white solid which was used in the following reaction without purification. The product was contaminated with benzotriazol- 1 -ol which was easily separated from the product in the following reaction. Step B: Synthesis of (R)-4,4,4-trifluoro-N-(6-formyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(3 15 (trifluoromethyl)phenylsulfonamido)butanamide A mixture of (R)-4,4,4-trifluoro-N-(6-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1 yl)-3-(3-(trifluoromethyl)phenylsulfonamido)butanamide (crude, -7.8 mmol) and MnO 2 (From Aldrich, <5 micron, activated, -85%, 6.0 g, 58.6 mmol) in 500 mL of methylene chloride was stirred at r.t. overnight. The reaction mixture was filtered through a pad of silica gel, eluted 20 with 10 - 15 % of ethyl acetate in methylene chloride and concentrated to give the title compound was obtained as a light yellowish solid. Step C: Synthesis of (R)-4,4,4-trifluoro-N-(6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydro naphthalen-1-yl)-3-(3-(trifluoromethyl) phenylsulfonamido)butanamide A mixture of (R)-4,4,4-trifluoro-N-(6-formyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(3 25 (trifluoromethyl) phenylsulfonamido)butanamide (0.56 g, 1.07 mmol), piperidine(0. 16 mL, 1.61 mmol) and acetic acid (0.10 mL, 1.61 mmol ) in 1 mL of DMF and 2 mL of 1,2 dichloroethane was stirred at r.t. for 2 h. Sodium triacetoxy borohydride (From Aldrich, 95%, 0.48 g, 2.14 mmol) was added and the reaction mixture was then stirred at 60 *C overnight. The reaction mixture was cooled to r.t., diluted with EtOAc/H 2 0, acidified with 10% of HCl 30 to pH 2, and stirred for 30 min. NaHCO 3 (aq) was added to bring pH to 8-9 and the organic 98 WO 2006/036664 PCT/US2005/033659 portion was separated, and washed with brine. The solvents were removed and the crude product was purified by flash column chromatography (0-13% of MeOH-NH 4 0H (aq, 28 - 30 %) (volume ratio 3:1) in methylene chloride in 20 min, 13 - 15% of MeOH-NH40H (aq, 28 ~ 30 %) (volume ratio 3:1) in methylene chloride in 8 min) to give the title compound as a white 5 solid. MS m/z: 592.2 (M+H)*. Calc'd for C 27
H
3 1
F
6
N
3 0 3 S - 591.61. Similarly the following compounds were prepared. (3R/S)-N-((1R)-6-(((1,1-dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro-1 naphthalenyl)-4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3R/S)-N-((4R)-7-(((1,1 -dimethylethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl) 10 4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3R/S)-4,4,4-trifluoro-N-((4R)-7-(1-piperidinylmethyl)-3,4-dihydro-2H-chromen-4-yl) 3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3R/S)-4,4,4-trifluoro-N-((1R)-6-(1 -piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 15 (3R/S)-N-((1R)-6-((cyclopentylamino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-4,4,4 trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3R/S)-N-((4R)-6-chloro-7-(((1,1 -dimethylethyl)amino)methyl)-3,4-dihydro-2H chromen-4-yl)-4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3R/S)-N-((4R)-7-((cyclopentylamino)methyl)-3,4-dihydro-2H-chromen-4-yl)-4,4,4 20 trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3R)-N-((1R)-6-(((1,1 -dimethylethyl)amino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl) 4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((lR)-6-((( 1,1 -dimethylethyl)amino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl) 4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 25 (3R/S)-3-(((3,4-dichlorophenyl)sulfonyl)amino)-N-((1R)-6-(((1,1 dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro- 1 -naphthalenyl)-4,4,4-trifluorobutanamide; (3R/S)-N-((1R)-6-(((1,1 -dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro- 1 naphthalenyl)-4,4,4-trifluoro-3-((2-naphthalenylsulfonyl)amino)butanamide; (3R/S)-N-((1R)-6-((( 1,1 -dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro- 1 30 naphthalenyl)-4,4,4-trifluoro-3-(((2,4,6-trimethylphenyl)sulfonyl)amino)butanamide; (3R/S)-N-((1R)-6-(((1,1 -dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro- 1 naphthalenyl)-4,4,4-trifluoro-3-(((4-methylphenyl)sulfonyl)amino)butanamide; (3R/S)-3-(((4-chlorophenyl)sulfonyl)amino)-N-((1R)-6-(((1,1 -dimethylethyl) amino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-4,4,4-trifluorobutanamide 99 WO 2006/036664 PCT/US2005/033659 k1t/)j)-.,-kkkQ-cnioro-Lp-uimLnylphenyl)sulfony1)amino)-N-(( 1R)-6-((( 1,1 dimethylethyl)amino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-4,4,4-trifluorobutanamide; (3R15)-3-(((3,4-dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-(( 1R)-6-( 1 piperidmnylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; 5 (3R/S)-4,4,4-trifluoro-3-((2-naphthalenylsulfonyl)amino)-N-(( 1R)-6-( 1 pipenidinylmethyl)- 1 ,2,3,4-tetrahyclro- 1 -naphthalenyl)butanamide; (3R/S)-4,4,4-trifluoro-N-(( 1R)-6-( I -piperidinylmethyl)- 1,2,3 ,4-tetrahydro- 1 naphthalenyl)-3-(((2,4,6-trimethylphenyl)sulfonyl)amino)butanamide; (3.S)-4,4,4-trifluoro-N-(( I R)-6-( I -piperidmnylmethyl)- I ,2,3,4-tetrahydro- 1 10 naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)ammo)butanamide; (3R)-4,4,4-trifluoro-N-(( 1R)-6-( 1 -piperidinylinethyl)- 1 ,2,3,4-tetrahydro- 1 naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-4,4,4-trifluoro-N-(( 1R)-6-((( 1 -methylethyl)amino)methyl)-1 ,2,3,4-tetrahydro- 1 naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 15 (3R)-4,4,4-trifluoro-N-(( 1R)-6-((( 1 -methylethyl)amino)methyl)- 1 ,2,3,4-tetrahydro- 1 naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((4R)-7-( 1-azepanylmethyl)-3,4-dihydro-2H-chromen-4-yl)-4,4,4-trifluoro-3 (((3 -(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3R)-N-((4R)-7-( 1 -azepanylmethyl)-3,4-dihydro-2H-chromen-4-yI)-4,4,4-trifluoro-3 20 (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3R/S)-4,4,4-trifluoro-N-((4R)-7-(4-morpholinylmethyl)-3,4-dihydro-2H-chromen-4 yI)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3R/S)-4,4,4-trifluoro-N-(( 1R)-6-(((3S)-3-hydroxy- 1 -piperidinyl)methyl)-1 ,2,3 ,4 tetrahydro- 1 -naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 25 (3R/SJ-N-(( 1R)-6-((cyclohexylamino)methyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)-4,4,4 trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (31?/S)-4,4,4-trifluoro-N-((4R)-7-((4-methyl-l1-piperazmnyl)methyl)-3,4-dihydro-2H chromen-4-yl)-3--(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (31/S)-4,4,4-trifluoro-N-((4R)-7-(((3R)-3-hydroxy- 1 -piperidinyl)methyl)-3,4-dihydro 30 2H-chromen-4-yl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3R/S)-3-(((3-chloro-4-(trifluoromethyl)phenyl)sulfonyl)amino)-4,4,4-trifluoro-N-(6-( I piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R/S)-4,4,4-trifluoro-N-((l R)-6-(((2-methylpropyl)amino)methyl)- 1 ,2,3,4-tetrahydro- 1 naphthalenyl)-3-(((3 -(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 100 WO 2006/036664 PCT/US2005/033659 (3R/,S)-N-((l R)-6-((cyclobutylamino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-4,4,4 trifluoro-3-(((3-(trifluoromethy)phenyl)sufoflyl)amno)butalamlide; (3R/S)-N-(( 1R)-6-( I -azepanylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-4,4,4 trifluoro-3-(((3-(trifluoromethy)pheyl)sufofl)amilo)butaflamide; 5 (3R/S)-N-(( 1R)-6-( 1 -azepanylniethyl)- I ,2,3,4-tetrahydro- I -naphthalenyl)-4,4,4 trifluoro-3-(((3-(trifluoromethy)phelyl)sulfoflyl)amllino)butaflamfide; (3R/S)-N-(( 1R)-6-(((2,2-dimnethylpropyl)amino)mfethyl)- 1 ,2,3,4-tetrahydro- 1 nahhlnl-,,-zfur--(3(rfurmty~hnlsloy~mn~uaaie (3R/S)-4,4,4-trifluoro-3-((2-naphthaenysufoflyl)amiflo)-N-(( 1R)-6-( 1 10 piperidinylmethyl)- 1 ,2,3,4-tetrahydro-1 -naphthalenyl)butanamide; (3R/g)-4,4,4-trifluoro-3-((2-naphthalenylsulfony1)amino)-N-(( 1R)-6-( 1 -piperidinyl methyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R/S)-4,4,4-trifluoro-N-(( 1R)-6-(4-morpholinylmethyl)- 1 ,2,3,4-tetrahydro- I1 naphthaleny)-3-(((3-(trifluoromethy)pheny)sufonl)amiflo)butaflamide; 15 (3R/S)-4,4,4-trifluoro-N-((l R)-6-((4-methyl- 1 -piperazinyl)methyl)- 1 ,2,3,4-tetrahydro- 1 naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sufofl)amiflo)butaflamide; (3R/S)-4,4,4-trifluoro-N-((l R)-6-( 1 -pyrrolidinylmethyl)- I ,2,3,4-tetrahydro- 1 naphthalenyl)-3-(((3 -(trifluoromethyl)phenyl)sulfonyl)amino)butaflamide; (3R/S)-N-((4R)-7-(((2,2-dinmethylpropyl)amino)methy)-3,4-dihydro-2H-chromel- 4 -yl) 20 4,4,4-trifluoro-3-(((3-(trifluoromethyl)phelyl)sulfofl)amilo)butaflamide; (3RS)-N-((4R)-7-((cyclohexylamino)methyl)-3,4-dihydro-2H-chromefl-4-yl)- 4
,
4 4 trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amilo)butaflamide; (3R/S)-4,4,4-trifluoro-N-(( 1J)-6-(((2-(1 -pyrrolidinyl)ethyl)amino)methyl)- 1,2,3,4 tetrahydro- 1 -naphthalenyl)-3-(((3-(trifluoromethy)phelyl)sulfoflyl)amiflo)butaflamide; 25 (3R/S)-4,4,4-trifluoro-N-((l R)-6-(((2-(1 -piperidinyl)ethyl)amino)methyl)- 1,2,3,4 tetrahydro- 1 -naphthatenyl)-3-(((3-(trifluoromethyl)phenyl)sulfofl)amiflo)butaflamide; (3RIS)-4,4,4-trifluoro-N-(( 1R)-6-(((2-(4-morpholmnyl)ethyl)amino)methyl)- 1,2,3,4 tetrahydro- 1 -naphthalenyl)-3 -(((3 -(trifluoromethyl)phelyl)sulfofl)amiflo)butaflamide; (3RIS)-N-((l R)-6-(((2-(acetylamino)ethyl)amino)methyl)- 1 ,2,3,4-tetrahydro- 1 30 nahhlnl-,,-rfur--(3(rfurmty~hnlsloy~mn~uaaie (3R/S)-N-(( 1R)-6-(((2-(dimethylamino)ethyl)amino)methyl)- 1,2,3,4-tetrahydro- 1 nahhlnl-,,-rfur--(3(rfurmty~hnlsloy~mn~uaaie (3R1S)-N-((l R)-6-(((2-(diethylaniino)ethyl)amino)methyl)- 1 ,2,3,4-tetrahydro- I nahhlnl-,,-rfur--(3(rfurmty~hnlsloy~mn~uaaie 101 WO 2006/036664 PCT/US2005/033659 (3R/S)-N-((1R)-6-(((2R,6S)-2,6-dimethyl- 1 -piperidinyl)methyl)- 1,2,3,4-tetrahydro- 1 naphthalenyl)-4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3R/S)-4,4,4-trifluoro-N-((1R)-6-((4-hydroxy- 1 -piperidinyl)methyl)- 1,2,3,4-tetrahydro 1 -naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 5 (3R/S)-4,4,4-trifluoro-N-((1R)-6-((4-hydroxy- 1 -piperidinyl)methyl)- 1,2,3,4-tetrahydro 1 -naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3R/S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((1R)-6-(1 piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R/S)-N-((1R)-6-(1 -azepanylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-3-(((4-chloro 10 2,5-dimethylphenyl)sulfonyl)amino)-4,4,4-trifluorobutanamide; (3R/S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((1R)-6-((3 hydroxy- 1 -piperidinyl)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R/S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((1R)-6 (((2-(1 -pyrrolidinyl)ethyl)amino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; 15 (3R/S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((4R)-7-(1 piperidinylmethyl)-3,4-dihydro-2H-chromen-4-yl)butanamide; (3R/S)-N-((4R)-7-(1 -azepanylmethyl)-3,4-dihydro-2H-chromen-4-yl)-3 -(((4-chloro-2,5 dimethylphenyl)sulfonyl)amino)-4,4,4-trifluorobutanamide; (3R/S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((4R)-7-((3 20 hydroxy-1-piperidinyl)methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide; (3R/S)-4,4,4-trifluoro-3-((6-isoquinolinylsulfonyl)amino)-N-((lR)-6-(1-piperidinyl methyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R/S)-3-(((3-chloro-4-methylphenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((1R)-6-( 1 piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; 25 (3RIS)-N-((1R)-6-(1 -azepanylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-3-(((3-chloro 4-methylphenyl)sulfonyl)amino)-4,4,4-trifluorobutanamide; (3S)-3 -(((3,4-bis(methyloxy)phenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((1R)-6-( 1 piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R/S)-3-(((3,4-bis(methyloxy)phenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((1R)-6-( 1 30 piperidinylmethyl)-1,2,3,4-tetrahydro-1 -naphthalenyl)butanamide; (3R/S)-N-((1R)-6-(1 -azepanylmethyl)- 1,2,3,4-tetrahydro-1 -naphthalenyl)-3-(((3,4 bis(methyloxy)phenyl)sulfonyl)amino)-4,4,4-trifluorobutanamide; (3R)-3-(((3,4-dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((1R)-6-(1 -piperidinyl methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; 102 WO 2006/036664 PCT/US2005/033659 (35)-3-(((3,4-dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((1R)-6-(1-piperidinyl methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R/S)-4,4,4-trifluoro-3-(methyl((3-(trifluoromethyl)phenyl)sulfonyl)amino)-N-((1R)-6 (1 -piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; 5 (3R/S)-4,4,4-trifluoro-N-((1R)-6-(((2-hydroxy-1,1-dimethylethyl)amino)methyl) 1,2,3,4-tetrahydro- 1 -naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3R/S)-4,4,4-trifluoro-N-((1R)-6-((((2S)-tetrahydro-2-furanylmethyl)amino)methyl) 1,2,3,4-tetrahydro-I -naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3R/S)-4,4,4-trifluoro-N-((1R)-6-((((2R)-tetrahydro-2-furanylmethyl)amino)methyl) 10 1,2,3,4-tetrahydro-1-naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3R/S)-4,4,4-trifluoro-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1 naphthalenyl)-3-((8-quinolinylsulfonyl)amino)butanamide; (3R/S)-3-(((2,3-dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((1R)-6-(1 piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; 15 (3R/S)-3-(((2,5-dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((1R)-6-(1 piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R/S)-3-(((5-chloro-2-(methyloxy)phenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((1R)-6 (1 -piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R/S)-3-(((2,6-dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((1R)-6-( 1 20 piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-(((4-chloro-3-(trifluoromethyl)phenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((1R)-6 (1 -piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R/S)-3-(((4-chloro-3-(trifluoromethyl)phenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((1R) 6-(1 -piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; 25 (3R/S)-3-(((5-chloro-2-fluorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((1R)-6-( 1 piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R/S)-3-(((3-chloro-2-fluorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((1 R)-6-( 1 piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R)-3-(((2,3 -dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((1R)-6-( 1 30 piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R)-4,4,4-trifluoro-3-(((8-(methyloxy)-5-quinolinyl)sulfonyl)amino)-N-((1R)-6-( 1 piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-4,4,4-trifluoro-3-(((8-(methyloxy)-5-quinolinyl)sulfonyl)amino)-N-((1R)-6-( 1 piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; 103 WO 2006/036664 PCT/US2005/033659 (3R/S)-3-((2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)amino)-4,4,4-trifluoro-N-((1R)-6 (1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)butanamide; (3R)-3-(((2,5-dichlorophenyl)sulfonyl)amino)-N-((1R)-6-(((1,1 -dimethylethyl) amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-4,4,4-trifluorobutanamide; 5 (3R)-3-(((2,3-dichlorophenyl)sulfonyl)amino)-N-((1R)-6-(((1,1 -dimethylethyl) amino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-4,4,4-trifluorobutanamide; (3R)-3 -(((2,5-dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((1R)-6-(1 -piperidinyl methyl)-1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R/S)-4,4,4-trifluoro-N-((1R)-6-((4-methyl- 1 -piperidinyl)methyl)- 1,2,3,4-tetrahydro- 1 10 naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3R./S)-4,4,4-trifluoro-N-((1R)-6-((4-fluoro- 1 -piperidinyl)methyl)- 1,2,3,4-tetrahydro- 1 naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3R)-3 -(((2,5-dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((4R)-7-(1 -piperidinyl methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide; 15 (3R)-N-(6-chloro-7-(1-piperidinylmethyl)-3,4-dihydro-2H-chromen-4-yl)-4,4,4 trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3R)-4,4,4-trifluoro-N-((7R)-1,2,3,4,7,8,9,10-octahydrobenzo[flisoquinolin-7-yl)-3-(((3 (trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3R)-3-(((2,3-dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((4R)-7-( 1 20 piperidinylmethyl)-3,4-dihydro-2H-chromen-4-yl)butanamide; (3R)-3-(((2,5-difluorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((4R)-7-(1-piperidinyl methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide; (3R)-4,4,4-trifluoro-3 -(((5-methyl-2-(methyloxy)phenyl)sulfonyl)amino)-N-((1R)-6-( 1 piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; 25 (3R)-3 -(((5-chloro-2-(methyloxy)phenyl)sulfonyl)amino)-N-((1R)-6-((( 1,1 -dimethyl ethyl)amino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-4,4,4-trifluorobutanamide; (3R)-3-(((3,5-difluorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((1R)-6-(1-piperidinyl methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R)-3-(((2,5-difluorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((1R)-6-(1-piperidinyl 30 methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R)-4,4,4-trifluoro-3-(((3-methylphenyl)sulfonyl)amino)-N-((lR)-6-(1-piperidinyl methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R)-3-(((3,5-difluorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((4R)-7-(1 -piperidinyl methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide; 104 WO 2006/036664 PCT/US2005/033659 (3R)-N-((1R)-6-((4aR,8aR)-octahydro-2(1H)-isoquinolinylmethyl)-1,2,3,4-tetrahydro-1 naphthalenyl)-4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3R)-4,4,4-trifluoro-N-((1R)-6-((4-(2-hydroxyethyl)-1-piperidinyl)methyl)-1,2,3,4 tetrahydro- 1 -naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 5 (3R)-N-((lR)-6-(((cyclopropylmethyl)(propyl)amino)methyl)- 1,2,3,4-tetrahydro- 1 naphthalenyl)-4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3R)-N-((1R)-6-((3,3 -dimethyl- 1 -piperidinyl)methyl)- 1,2,3,4-tetrahydro- 1 naphthalenyl)-4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3R)-3-(((3-chloro-2-fluorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((1R)-6-( 1 10 piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R)-3-(((5-chloro-2-fluorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((1R)-6-( 1 piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R)-3-(((5-chloro-2-fluorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((4R)-7-( 1 piperidinylmethyl)-3,4-dihydro-2H-chromen-4-yl)butanamide; 15 (3R)-3 -(((3 -chloro-2-fluorophenyl)sulfonyl)amino)-N-((1R)-6-((( 1,1 -dimethylethyl) amino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-4,4,4-trifluorobutanamide; (3R)-3-(((5-chloro-2-fluorophenyl)sulfonyl)amino)-N-((4R)-6-chloro-7-( 1 piperidinylmethyl)-3,4-dihydro-2H-chromen-4-yl)-4,4,4-trifluorobutanamide; (3R)-3-(((3-chloro-2-fluorophenyl)sulfonyl)amino)-N-((4R)-6-chloro-7-(1-piperidinyl 20 methyl)-3,4-dihydro-2H-chromen-4-yl)-4,4,4-trifluorobutanamide; (3R)-3-(((3-chloro-2-fluorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((4R)-7-( 1 piperidinylmethyl)-3,4-dihydro-2H-chromen-4-yl)butanamide; (3R)-3-((2,3-dihydro- 1,4-benzodioxin-6-ylsulfonyl)amino)-4,4,4-trifluoro-N-((1R)-6-( 1 piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; 25 1,1-dimethylethyl-4-(((5R)-5-(((3R)-4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl) sulfonyl)amino)butanoyl)amino)-5,6,7,8-tetrahydro-2-naphthalenyl)methyl)- 1 piperazinecarboxylate; (3R)-4,4,4-trifluoro-N-((1R)-6-(1 -piperazinylmethyl)-1,2,3,4-tetrahydro-1 naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 30 (3R)-4,4,4-trifluoro-N-((1R)-6-(((2R)-2-methyl- 1 -piperidinyl)methyl)- 1,2,3,4 tetrahydro- 1 -naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3R)-4,4,4-trifluoro-N-((1R)-6-(((3S)-3-methyl- 1 -piperidmyl)methyl)- 1,2,3,4 tetrahydro- 1 -naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 105 WO 2006/036664 PCT/US2005/033659 (3R)-4,4,4-trifluoro-N-(( 1R)-6-(((3S)-3-hydroxy-l1-pyrrolidinyl)methyl)- 1,2,3,4 tetrahydro-l1-naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3R)-4,4,4-trifluoro-N-(( 1R)-6-(((3R)-3-hydroxy-l1-pyrrolidinyl)methyl)- 1,2,3,4 tetrahydro-l1-naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 5 (3R)-4,4,4-trifluoro-N-(( 1R)-6-(((3R)-3-(hydroxymethyl)-l1-piperidinyl)methyl)- 1,2,3,4 tetrahydro-l1-naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3R)-4,4,4-trifluoro-N-(( 1R)-6-(((3R)-3-(methyloxy)-l1-piperidinyl)methyl)- 1,2,3,4 tetrahydro- 1 -naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3R)-4,4,4-trifluoro-N-(( 1R)-6-((4-(methylsulfonyl)-l1-piperazmnyl)methyl)- 1,2,3,4 10 tetrahydro- 1 -naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3R)-N-(( 1R)-6-( 1 -azepanylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-4,4,4-trifluoro 3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3R)-N-(( 1R)-6-( 1 -azepanylinethyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)-4,4,4-trifluoro 3-(((3 -(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 15 (3R)-3-(((5-chloro-2-fluorophenyl)sulfonyl)amino)-N-(( 1R)-6-((( 1,1 -dimethylethyl) amino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-4,4,4-tnifluorobutanamide; (3R/S)-4,4,4-trifluoro-N-(( 1R)-6-((3-oxo- 1 -piperidinyl)methyl)- 1 ,2,3,4-tetrahydro- 1 naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3k/S)-3-(((2-chloro-5-(trifluoromethyl)phenyl)sulfonyl)amino)-4,4,4-trifluoro-N-(( 1R) 20 6-(l1 -piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R/S)-3-(((3 ,5-dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-(( I R)-6-( 1 piperidinylmethyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R)-3-(((3-chloro-2-fluorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-methyl-N-(( 1R)-6 (1 -piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; 25 (31)-4,4,4-trifluoro-3-((phenylsulfonyl)amino)-N-(( 1R)-6-( 1 -piperidinylmethyl) 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R)-3-(((2-bromo-5-(trifluoromethyl)phenyl)sulfonyl)amino)-4,4,4-trifluoro-N-(( 1R) 6-( 1 -piperidinylmethyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R)-3 -(((2-bromophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-(( 1R)-6-( 1 -piperidmnyl 30 methyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R)-4,4,4-trifluoro-3-(((2-nitrophenyl)sulfonyl)amino)-N-(( 1R)-6-( 1 -piperidinyl methyl)- 1 ,2,3,4-tetrahydro-1 -naphthalenyl)butanamide; (3R)-4,4,4-trifluoro-N-((4R)-6-fluoro-7-( I -piperidinylmethyl)-3,4-dihydro-2H cbromen-4-yl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 106 WO 2006/036664 PCT/US2005/033659 k i1j--t,','t,-tnnuorv-j-kk -isoquinolinylsulfonyl)amino)-N-(( 1R)-6-( 1-piperidmnyl methyl)- 1 ,2,3,4-tetrahydro- I -naphthalenyl)butanamide; (3R)-4,4,4-trifluoro-N-(( 1R)-6-( 1 -piperidinylmethyl)- I ,2,3,4-tetrahydro- 1 naphthalenyl)-3-(((3 -((trifluoromethyl)oxy)phenyl)sulfonyl)amino)butanamide; 5 (3R)-3-(((5-chloro-2-fluorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-(( IR)-6-((4 methyl- I -piperidinyl)methyl)- 1 , 2 ,3,4-tetrahyciro- 1 -naphthalenyl)butanamide; (3R)-N-(( 1R)-6-((((2R,3S,4S,5S,6S)-3,5-dihydroxy-2-(hydroxymethyl)-6 (methyloxy)tetrahydro-2H-pyran-4-yl)amino)methyl)- I ,2,3,4-tetrahydro- 1 -naphthalenyl) 4 ,4, 4 -trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 10 (3R)-4,4,4-trifluoro-3 -(((2-fluorophenyl)sulfonyl)amino)-N-(( 1 R)-6-( 1 -piperidinyl methyl)- 1 ,2,3,4-tetrahyclro- I -naphthalenyl)butanamide; (3R)-4,4,4-trifluoro-3-(((4-methylphenyl)sulfonyl)amino)-N-(( 1R)-6-( 1-piperidinyl methyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R)-4,4,4-trifluoro-3-(((4-fluorophenyl)sulfonyl)amino)-N-(( 1R)-6-( 1-piperidinyl 15 methyl)- I ,2,3,4-tetrahydro- I -naphthalenyl)butanamide; (3R)-3-(((3 -chloro-2-fluorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((4R)-6-fluoro-7 (1 -piperidinyhmethyl)-3,4-dihydro-2H-chromen-4-yl)butanamide; (3R)-4,4,4-trifluoro-N-((4R)-6-fluoro-7-(1 -piperidinylmethyl)-3,4-dihydro-2H chromen-4-yl)- 3 -(((3-((trifluoromethyl)oxy)phenyl)sulfonyl)amino)butanamide; 20 (3R)-3-(((3-chlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-(( 1R)-6-( 1 -piperidinyl methyl)- 1,2,3,4-tetrahydro-1I-naphthalenyl)butanamide; (3R)-3 -(((4-chlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((I R)-6-( 1 -piperidinyl methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R)-3-(((2-chlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-(( 1R)-6-( I -piperidinyl 25 methyl)- I ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R)-4,4,4-trifhioro-3 -(((3-fluorophenyl)sulfonyl)amino)-N-(( lR)-6-( 1 -piperidinyl methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R)-4,4,4-trifluoro-N-(( IR)-6-((4-methyl- 1 -piperidinyl)methyl)- 1 ,2,3,4-tetrahydro- 1 naphthalenyl)-3-(((3 -(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 30 (3R)-3-(((2-aminophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-(( 1R)-6-( I -piperidinyl methyl)-l ,2,3,4-tetrahyclro-1I-naphthalenyl)butanamide; (3R)-3-(((2-chloro-4-fluorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-(( IR)-6-( 1 piperidinylmethyl)- I ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; 107 WO 2006/036664 PCT/US2005/033659 piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R)-4,4,4-trifluoro-3-(((3-methylphenyl)sulfonyl)amino)-N-(( 1R)-6-( 1-piperidmnyl methyl)- 1 ,2,3,4-tetrahyclro- 1 -naphthalenyl)butanamide; 5 (3R)-4,4,4-trifluoro-N-((l R)-6-( 1 -piperidinylinethyl)- 1 ,2,3,4-tetrahydro- 1 naphthalenyl)-3-(((4-((trifluoromethyl)oxy)phenyl)sulfonyl)amino)butanamide; (3R)-3 -(((3 -chloro-4-fluorophenyl)sulfonyl)ammno)-4,4,4-trifluoro-N-(( 1 R)-6-( 1 piperidmylmethyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R)-3-(((3-bromophenyl)sulfonyl)ammno)-4,4,4-trifluoro-N-(( 1R)-6-( 1 -piperidmnyl 10 methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R)-4,4,4-trifluoro-N-((l R)-6-( 1 -piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 naphthalenyl)-3-(((2-(trifluoromnethyl)phenyl)sulfonyl)amino)butanamide; (3R)-3 -(((4-ethylphenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((I R)-6-( 1 -piperidmnyl methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; 15 (3R)-4,4,4-trifluoro-N-((4R)-7-( 1 -piperidinylmethyl)-3,4-dihydro-2H-chromen-4-yl)-3 (((3 -(trifluoromethyl)phenyl)sul fonyl)amino)butanamide; (3R)-4,4,4-trifluoro-3-(((5-fluoro-2-methylphenyl)sulfonyl)amino)-N-(( 1R)-6-( 1 piperidinylmethyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R)-3-(((2-chloro-6-methylphenyl)sulfonyl)amino)-4,4,4-trifluoro-N-(( 1R)-6-( 1 20 pipenidinylmethyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R)-4,4,4-trifluoro-N-(( 1R)-6-( 1 -piperidinylmethyl)- 1 ,2,3,4-tetrahydro- I1 naphthalenyl)-3-(((4-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3R)-4,4,4-trifluoro-3-(((2-fluoro-5-methylphenyl)sulfonyl)amino)-N-(( LR)-6-( 1 piperidinylmethyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide; 25 (3R)-3-(((3,4-dimethylphenyl)sulfonyl)amino)-4,4,4-trifluoro-N-(( 1R)-6-( 1 piperidinylmethyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R)-3-(((3,5-dimethylphenyl)sulfonyl)ammno)-4,4,4-trifluoro-N-(( 1R)-6-( 1-piperidinyl methyl)- 1,2,3,4-tetrahydro-1I-naphthalenyl)butanamide; (3R)-4,4,4-trifluoro-3-(((3-(methyloxy)phenyl)sulfonyl)amino)-N-(( 1R)-6-( 1 30 piperidinylmethyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R)-4,4,4-trifluoro-N-((l R)-6-( 1-(4-methyl)piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 naphthalenyl)-3-(((2-fluoro-3-chlorophenyl)sulfonyl)amino)butanamide; (3R)-4,4,4-trifluoro-3 -(((4-methyl-3 ,4-dihydro-2H- 1,4-benzoxazin-7-yl)sulfonyl) amino)-N-(( 1R)-6-( 1 -piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-butanamide; 108 WO 2006/036664 PCT/US2005/033659 (5K)-4,4,4-tntluoro-v-(( i)-o-(1 -piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 naphthalenyl)-3-((1,2,3,4-tetrahydro-8-quinolinylsulfonyl)amino)butanamide; (3R)-3-(((3,5-dichloro-4-hydroxyphenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((1R)-6-( 1 piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; 5 (3R)-3-((3,4-dihydro-2H- 1,5-benzodioxepin-7-ylsulfonyl)amino)-4,4,4-trifluoro-N ((1 R)-6-(1 -piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R)-4,4,4-trifluoro-3-(((3-(1,3-oxazol-5-yl)phenyl)sulfonyl)amino)-N-((I R)-6-( 1 piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)butanamide; and (3R)-4,4,4-trifluoro-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1 10 naphthalenyl)-3-(((3-tert-butylphenyl)sulfonyl)amino)butanamide. Unless indicated otherwise, the following compound can be prepared following the procedure described above. Table 2 X H H X" X
R
1 0 Y
R
7 X X' X" R, Y R 3-CF 3 H H CH 3
CH
2
-CH
2 piperidin-1-yl 3-CF 3 H H CH 3
CH
2
-CH
2 (1-Mepiperazin-4-yl) 3-CF 3 H H CH 3
CH
2
-CH
2 (4-Mepiperidin-1-yl) 3-CF 3 H H CH 3
CH
2 -CH2(3-Mepiperidin-1-yl) 3-CF 3 H H CH 3
CH
2 -CH2-azepan-1-yl 3-CF 3 H H CH 3
CH
2
-CH
2 (3-OHpiperidin-1-yl) 3-CF 3 H H CH 3
CH
2
-CH
2 (3-HOCH 2 piperidin-1-yl) 3-Cl H H CH 3
CH
2 -CH2piperidin-1-yl 2-F 5-CF 3 H CH 3
CH
2
-CH
2 piperidin-1-yl 2-Cl 5-CF 3 H CH 3
CH
2
-CH
2 piperidin-1-yl 2-Naphthyl H H CH 3
CH
2
-CH
2 piperidin-1-yl 2-Cl 3-Cl H CH 3
CH
2
-CH
2 piperidin-1-yl 2-Cl 5-Cl H CH 3
CH
2
-CH
2 piperidin-1-yl 3-Cl 4-Cl H CH 3
CH
2
-CH
2 piperidin-1-yl 109 WO 2006/036664 PCT/US2005/033659 X ~~X" R Y 2-Cl 6-Cl H CH 3
CH
2
-CH
2 piperidin-1-yl 2-F 5-Cl H CH 3
CH
2
-CH
2 piperidin-1-yl 2-F 3-Cl H CH 3
CH
2
-CH
2 piperidin-1-yl 2-Me 5-Me 4-Cl CH 3
CH
2
-CH
2 piperidin-1-yl 4-Bu-tert H H CH 3
CH
2
-CH
2 piperidin-1-yl 2-Me 5-Me 4-Cl CH 3 0 -CH 2 piperidin-1-yl 2-Me 5-Me 4-Cl CH 3 - -CH 2 piperidin-1-yl 2-Me 5-Me 4-Cl CF 3 - -CH 2 piperidin-1-yl 4-Cl H H CF 3
CH
2
-CH
2 piperidin-1-yl 2-Cl H H CF 3
CH
2
-CH
2 piperidin-1-yl 2-OCF 3 H H CF 3
CH
2
-CH
2 piperidin-1-yl 3-OMe H H CF 3
CH
2
-CH
2 piperidin-1-yl 3-OCF 3 H H CF 3
CH
2
-CH
2 piperidin-1-yl 2-Cl 3-Cl H CF 3
CH
2
-CH
2 azepan-1-yl 3-CF 3 H H CF 3
CH
2
-CH
2 azepan-1-yl 3-CF 3 H H CF 3
CH
2
-CH
2 piperidin-1-yl 3-CF 3 H H CF 3
CH
2
-CH
2 (4-Mepiperidin-1-yl) 3-CF 3 H H CF 3
CH
2
-CH
2 (3-OHpiperidin-1-yl) 3-CF 3 H H CF 3
CH
2
-CH
2 (3-HOCH 2 piperidin-1-yl) H H H CF 3
CH
2
-CH
2 piperidin-1-yl 2-Cl 5-Cl H CF 3
CH
2
-CH
2 piperidin-1-yl 3-Me H H CF 3
CH
2
-CH
2 piperidin-1-yl 3-Cl H H CF 3
CH
2
-CH
2 piperidin-1-yl 2-F 4-Cl H CF 3
CH
2
-CH
2 piperidin-1-yl 2-F 3-Cl H CF 3
CH
2
-CH
2 piperidin-1-yl 2-F 5-Cl H CF 3
CH
2
-CH
2 piperidin-1-yl 2-Cl 3-Cl H CF 3
CH
2
-CH
2 piperidin-1-yl 2-Cl 6-Cl H CF 3
CH
2
-CH
2 piperidin- 1-yl 3-Cl 4-Cl H CF 3
CH
2
-CH
2 piperidin-1-yl 3-Cl 5-Cl H CF 3
CH
2
-CH
2 piperidin-1-yl 2-Cl 3-CF 3 H CF 3
CH
2
-CH
2 piperidin-1-yl 2-naphthyl H H CF 3
CH
2
-CH
2 piperidin- 1-yl 110 WO 2006/036664 PCT/US2005/033659 X X X" R, Y R' 2-naphthyl H H CF 3 0 -CH 2 piperidin-1-yl 2-Me 5-Me 4-Cl CF 3 0 -CH 2 piperidin-1-yl 2-naphthyl H H Et CH 2
-CH
2 piperidin-1-yl 2-naphthyl H H i-Pr CH 2
-CH
2 piperidin- 1-yl 2-naphthyl H H c-Pr CH 2
-CH
2 piperidin-1-yl 2-naphthyl H H tert-Bu CH 2
-CH
2 piperidin-1-yl 2-naphthyl H H CN CH 2
-CH
2 piperidin-1-yl 2-naphthyl H H C=CH CH 2
-CH
2 piperidin-1-yl 2-naphthyl H H CH 2 C=CH CH 2
-CH
2 piperidin-1-yl 2-naphthyl H H CH 2 F CH 2
-CH
2 piperidin-1-yl 2-naphthyl H H CH 2 CN CH 2
-CH
2 piperidin-1-yl Example 3 Synthesis of (S)-N-((R)-6-(1-(cyclopropylamino)ethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-3 (3-(trifluoromethyl)phenylsulfonamido)butanamide 5 - H F 3 Ca -Q N, NH Step A: Synthesis of [6-(1-hydroxy-ethyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-carbamic acid tert-butyl ester To a solution of (6-formyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-carbamic acid tert-butyl 10 ester (2.80 g, 10.2 mmol, 1.0 eq) in THF (100 mL) at -78 C was added a solution of MeMgBr [Aldrich, 1.4M in toluene/THF (3:1), 29 mL, 40.7 mmol, 4.0 eq] slowly. The reaction mixture was stirred at -78 *C for 20 min, warmed up to room temperature and stirred at room temperature for 2 h. The reaction was quenched with saturated NaHCO 3 (120 mL), and the crude product was extracted with EtOAc (100 mL x 3). The extract phase was washed with 15 saturated NaCl, dried over Na 2
SO
4 , filtered and concentrated. The title compound was obtained as a white solid. MS (ESI, pos. ion) m/z: 292 (M+1). 111 WO 2006/036664 PCT/US2005/033659 Step B: Synthesis of (6-acetyl-1,2,3,4-tetrahydro-naphthalen-1 -yl)-carbamic acid tert-butyl ester A mixture of [6-(1-hydroxy-ethyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-carbamic acid tert-butyl ester (2.63 g, 9.04 mmol, 1.0 eq) and MnO 2 (Aldrich, 10.2 g, 117.5 mmol, 13 eq) in 5 CH 2 Cl2 (100 mL) was stirred at room temperature overnight. The reaction mixture was allowed to pass through a pad of Celite and the pad was washed with CH 2 Cl 2 (100 mL x 2). The concentration of the filtrate afforded the title compound as a white sticky semi-solid (1.89 g). MS (ESI, pos. ion) m/z: 290 (M+1). Step C: Synthesis of (S)-N-((R)-6-acetyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(3 10 (trifluoromethyl)phenylsulfonamido)butanamide A mixture of (6-acetyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-carbamic acid tert-butyl ester (650 mg, 2.25 mmol, 1.0 eq) in HClI/EtOAc (4.7M, 20 mL) was stirred at room temperature for 3 h, 20 min. The solvent was removed with a rotary evaporator, and the resulting 1-(5-amino-5,6,7,8-tetrahydro-naphthalen-2-yl)-ethanone hydrogen chloride was 15 dried in vacuo. To the flask was added (S)-3-(3-(trifluoromethyl)phenylsulfonamido)butanoic acid (840 mg, 2.7 mmol, 1.2 eq), EDCI (Aldrich, 776 mg, 4.05 mmol, 1.8 eq), HOBt (Aldrich, 61 mg, 0.45 mmol, 0.2 eq) and diisobutylethylamine (Aldrich, 582 mg, 4.50 mmol, 2.0 eq) in
CH
2 Cl 2 (20 mL) and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with H 2 0 (100 mL). The crude product was extracted with CH 2 Cl 2 20 (100 mL x 3). The extract phase was washed with saturated NaCl, dried over Na 2
SO
4 , filtered and concentrated. Flash column chromatography (silica gel, 0-7 % MeOH-CH 2 Cl 2 ) afforded the title compound as a white solid. MS (ESI, pos. ion) m/z: 483 (M+1). (S)-N-((R)-6-Acetyl 1,2,3,4-tetrahydronaphthalen-1-yl)-3-(3-(trifluoromethyl)phenylsulfonamido)butanamide was converted to (S)-N-((R)-6-(1 -(cyclopropylamino)ethyl)- 1,2,3,4-tetrahydronaphthalen- 1 -yl)-3 25 (3-(trifluoromethyl)phenylsulfonamido)butanamide by reacting it with cyclopropylamine as described Example 2, Step C above. Similarly the following compounds were made. (3S)-N-((1R/S)-6-((1S)-i-(cyclopentylamino)ethyl)-1,2,3,4-tetrahydro-1-naphthalenyl) 3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 30 (3S)-N-((1R/S)-6-((1S)-i-((2-methylpropyl)amino)ethyl)-1,2,3,4-tetrahydro-1 naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((1R/S)-6-((1R)-1-(cyclobutylamino)ethyl)-1,2,3,4-tetrahydro-1-naphthalenyl) 3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 112 WO 2006/036664 PCT/US2005/033659 (3S)-N-((lR/S)-6-((1 S)- 1 -((cyclopropylmethyl)amino)ethyl)- 1,2,3,4-tetrahydro- 1 naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; and (3S)-N-((IR)-6-((1R/S)-I-((2-(methyloxy)ethyl)amino)ethyl)-1,2,3,4-tetrahydro-1 naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide. 5 Example 4 Synthesis of (S)-N-((R)-6-(3-(piperidin-1-yl)prop-1-en-2-yl)-1,2,3,4-tetrahydronaphthalen-1 yl)-3-(3-(trifluoromethyl)phenylsulfonamido)butanamide F N 10 To a 20 mL flask equipped with stirring was added (S)-3-(3-(trifluoromethyl)phenyl sulfonamido)butanoic acid (68 mg, 0.22 mmol), 6-(1-piperidin-1-ylmethyl-vinyl)-1,2,3,4 tetrahydro-naphthalen-1-ylamine (54 mg, 0.20 mmol), EDC (Aldrich, 58 mg, 0.30 mmol), HOBt (Aldrich, 27 mg, 0.2 mmol), and CH 2 C1 2 (2 mL). The reaction mixture was stirred at 15 room temperature overnight and diluted with CH 2 Cl 2 (50 mL). The organic phase was washed with saturated NaHCO 3 and brine, dried over Na 2
SO
4 , filtered and concentrated in vacuo. The crude was purified by preparative TLC in 10% MeOH-CH 2
CI
2 to afford the title compound. MS (ESI): 564 (M+H) +. Similarly (R)-4,4,4-trifluoro-N-((R)-6-(3-(piperidin- 1 -yl)prop- 1 -en-2-yl)- 1,2,3,4 20 tetrahydronaphthalen-1-yl)-3-(3-(trifluoromethyl)phenylsulfonamido)butanamide was prepared. Example 5 Synthesis of (R)-3-(3,4-dichlorophenylsulfonamido)-N1-((R)-6-(piperidin-1-ylmethyl)-1,2,3,4 25 tetrahydronaphthalen- 1 -yl)succinamide 113 WO 2006/036664 PCT/US2005/033659 C1H H 02
H
2 N O O (R)-4-Amino-3-(3,4-dichlorophenylsulfonamido)-4-oxobutanoic acid (250 mg, 0.733 mmol) was dissolved in anhydrous DMF (7 mL). (R)-6-(piperidin-1-ylmethyl)-1,2,3,4 5 tetrahydronaphthalen-1-amine (259 mg, 0.953 mmol) and HOBt (Aldrich, 129 mg, 0.953 mmol) were added followed by EDCI (Aldrich, 183 mg, 0.953 mmol). The reaction mixture was stirred at RT for 2 h. EtOAc/water (2:1, 50 mL) was added and the solution was washed with saturated sodium bicarbonate/brine (1:1, 2x30 mL), then with brine (30 mL). It was concentrated and dried in vacuo to give 0.481 g of crude product. It was purified by flash 10 column chromatography (10% MeOH/CH 2 Cl 2 , ISCO CombiFlash) to give (R)-3-(3,4 dichlorophenylsulfonamido)-N -(R)-6-(piperidin- 1 -ylmethyl)- 1,2,3,4-tetrahydronaphthalen- 1 yl)succinamide. MS 567 (M+H). Similarly, (R)-benzyl 2-(3,4-dichlorophenylsulfonamido)-4-oxo-4-((R)-6-(piperidin- 1 ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)butanoate; and (R)-benzyl 2-(4 15 -methylphenylsulfonamido)-4-oxo-4-((R)-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydro naphthalen- 1 -ylamino)butanoate were prepared. Example 6 Synthesis of (R)-tert-butyl 2-(3,4-dichlorophenylsulfonamido)-4-oxo-4-((R)-6-(piperidin- 1 20 ylmethyl)- 1,2,3,4-tetrahydronaphthalen- 1 -ylamino)butanoate c1 C'a H H CI S'N N,,. N, 0 The title compound was prepared according to Example 5 from (R)-4-tert-butoxy-3 (3,4-dichlorophenylsulfonamido)-4-oxobutanoic acid. MS: 624.4 (M+H). 114 WO 2006/036664 PCT/US2005/033659 Example 7 Synthesis of (R)-2-(3,4-dichlorophenylsulfonamido)-4-oxo-4-((R)-6-(piperidin-1-ylmethyl) 1,2,3,4-tetrahydronaphthalen-1-ylamino)butanoic acid CI -SN -- YN, 5 To (R)-tert-butyl 2-(3,4-dichlorophenylsulfonamido)-4-oxo-4-((R)-6-(piperidin-1 ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)butanoate prepared in Example 6 (0.15 g) in DCM (2 mL) was added TFA (2 mL). The reaction mixture was stirred overnight at RT. The solvents were evaporated and dried to give the titled compound. MS: 568.2 (M+H). 10 Example 8 Synthesis of (R)-4-hydroxy-3-(4-methylphenylsulfonamido)-N-((R)-6-(piperidin-1-ylmethyl) 1,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide H H 2N N HO' 15 N To (R)-benzyl 2-(4-methylphenylsulfonamido)-4-oxo-4-((R)-6-(piperidin-1-ylmethyl) 1,2,3,4-tetrahydronaphthalen-1-ylamino)butanoate (described in Example 5; 80 mg) in 5 mL of DCM was added DIBAL (Aldrich, 1.5M in tolune, 0.8 mL). The reaction mixture was stirred at RT overnight. EtOAc (1 mL) was added and stirred for 10 min. Sodium sulfate (about 1 g) 20 was added and followed by 15 drops of saturated ammonium chloride. The reaction mixture was filtered after stirring for 10 min. The filtrate was evaporated. The crude product was further purified by preparative TLC (10% 2N NH 3 /MeOH/DCM) to give the title compound. MS: 500.2 (M+H). Example 9 25 Synthesis of (3R,4R)-3-(3,4-dichlorophenylsulfonamido)-4-hydroxy-N-((R)-6-(piperidin-1-yl methyl)- 1,2,3,4-tetrahydronaphthalen- 1 -yl)pentanamide 115 WO 2006/036664 PCT/US2005/033659 CI Cli H~K~ H cl ~ sN N,,, HO-,O' QN Step A:Synthesis of 3,4-dichloro-N-((2R,3R)-2-methyl-5-oxo-tetrahydrofiran-3-yl)benzene sulfonamide To a mixture of L-p-homothreonine hydrochloride (1.04 g) and sodium carbonate (1.8 5 g) in dioxane (10 mL) and water (10 mL) at RT was added 3,4-dichlorobenzenesulfonyl chloride (2.0 g) and the reaction mixture was stirred overnight. EtOAc (100 mL) and brine (70 mL) were added. The reaction mixture was acidified and stirred for 20 min. The organic layer was separated, washed with brine (3x 70 mL), dried and evaporated to give the crude product. Column chromatograph purification (silica gel; 10-30% ethyl acetate/hexanes) gave 10 the title compound. MS: 322 (M+H). Step B: Synthesis of (3R,4R)-3-(3,4-dichlorophenylsulfonamido)-4-hydroxy-N-((R)-6 (hydroxymethyl)- 1,2,3,4-tetrahydronaphthalen- 1 -yl)pentanamide To a mixture of (R)-(5-amino-5,6,7,8-tetrahydronaphthalen-2-yl)methanol (0.17 g) in DCM (10 mL) at 0 "C was added trimethylaluminm (1 mL of 2.OM in toluene, Aldrich). The 15 reaction mixture was stirred for 30 min. The above lactone (0.36 g) was added. The reaction mixture was stirred for 4 h. HC1 solution (2 mL, 0.05N) was added. The organic layer was separated and dried. The organic layer was separated and dried to give the title compound. Step C: Synthesis of (3R,4R)-3-(3,4-dichlorophenylsulfonamido)-N-((R)-6-formyl-1,2,3,4 tetrahydronaphthalen- 1 -yl)-4-hydroxypentanamide 20 (3R,4R)-3-(3,4-Dichlorophenylsulfonamido)-4-hydroxy-N-((R)-6-(hydroxymethyl) 1,2,3,4-tetrahydronaphthalen- 1 -yl)pentanamide (0.12 g) in DCM (300-400 mL) was stirred with MnO 2 at RT for 2 h. The reaction mixture was filtered through a pad of celite. The filtrate was evaporated to give the title compound. MS: 497.2 (M+H). Step D: Synthesis of (3R,4R)-3-(3,4-dichlorophenylsulfonamido)-4-hydroxy-N-((R)-6 25 (piperidin-1 -ylmethyl)- 1,2,3,4-tetrahydronaphthalen-1 -yl)pentanamide A mixture of (3R,4R)-3-(3,4-dichlorophenylsulfonamido)-N-((R)-6-formyl-1,2,3,4 tetrahydronaphthalen-1-yl)-4-hydroxypentanamide (0.14 g), piperidine (0.2 g), and NaBH(OAc) 3 (0.36 g) in DCE (10 mL) was stirred at RT overnight. DCM (50 mL) and brine (15 mL) were added. The organic layer was separated, dried, and evaporated. The crude 116 WO 2006/036664 PCT/US2005/033659 product was purified by column chromatography (silica gel, 0-1.5% MeOH/DCM) to give the title compound. MS: 568.2 (M+H). Example 10 5 Synthesis of (R)-3-(N-(4-fluorophenyl)-3-(trifluoromethyl)phenylsulfonamido)-N-(6-((4 fluoropiperidin- 1 -yl)methyl)- 1,2,3,4-tetrahydronaphthalen- 1 -yl)propanamide F H
F
3 C N N NF Step A: Synthesis of methyl 3-(4-fluorophenylamino)propanoate 10 To a 30-mL microwave vial containing methyl 3-bromopropanoate (6.2 mL, 57 mmol, Aldrich) was added 4-fluorophenylaniline (5.5 mL, 57 mmol, Aldrich). The reaction was stirred at 100 'C for 4 min in microwave. Purification with column chromatography over silica gel with hexane:EtOAc (5:1) gave the title compound. MS (ESI, pos. ion.) m/z: 198 (M+1). Step B: Synthesis of methyl 3-(N-(4-fluorophenyl)-3-(trifluoromethyl) 15 phenylsulfonamido)propanoate To a 50-mL round-bottomed flask containing methyl 3-(4-fluorophenylamino) propanoate (1.4 g, 7.3 mmol, Step A) in THF (15 mL), was added 3-trifluoromethylbenzene sulfonylchloride (2.7 g, 11 mmol, Aldrich) and sat. K 2 C0 3 (10 mL). The reaction was stirred at RT for 4 h. The compound was extracted with EtOAc (2x20 mL). The combined organic 20 phase was washed with 5% brine (2x15 mL), dried over Na 2
SO
4 . Purification with column chromatography over silica gel with hexane:EtOAc (5:1) gave the title compound. MS (ESI, pos. ion.) m/z: 406 (M+1). Step C: Synthesis of 3-(N-(4-fluorophenyl)-3-(trifluoromethyl)phenylsulfonamido)propanoic acid 25 To a 100-mL round-bottomed flask containing methyl 3-(N-(4-fluorophenyl)-3 (trifluoromethyl)phenylsulfonamido) propanoate (2.0 g, 4.8 mmol, Step B) in THF (10 mL), was added LiOH.H 2 0 (2.0 g, 48 mmol, Aldrich) and water (10 mL). The reaction was stirred at RT for 5 h. After acidified to pH 5 with 2N HCl, the compound was extracted with EtOAc 117 WO 2006/036664 PCT/US2005/033659 (2x20 mL). The organic phase was washed with 5% brine (2x 15 mL), dried over Na 2
SO
4 , filtered, and concentrated to yield the title compound. MS (ESI, pos. ion.) m/z: 390 (M-1). Step D: Synthesis of (R)-3-(N-(4-fluorophenyl)-3-(trifluoromethyl)phenylsulfonamido)-N-(6 (hydroxymethyl)- 1,2,3,4-tetrahydronaphthalen- 1 -yl)propanamide 5 To a 50-mL reaction tube containing 3-(N-(4-fluorophenyl)-3-(trifluoromethyl) phenylsulfonamido)propanoic acid (1.6 g, 4.1 mmol, Step C) in CH 2
C
2 (10 mL), was slowly added oxalyl chloride (10 mL, 21 mmol, 2.OM, Aldrich). After the reaction was stirred at RT for 0.5 h, the solvent was removed in vacuo. To the residue was added (R)-(5-amino-5,6,7,8 tetrahydronaphthalen-2-yl)methanol (0.72 g) in THF (8 mL) and sat. K 2 C0 3 (5 mL). The 10 reaction was stirred at RT for 2.5 h. The compound was extracted with EtOAc (2 x10 mL). The organic phase was washed with 5% brine (2x5 mL), dried over Na 2
SO
4 , filtered, and concentrated. Purification with column chromatography over silica gel with hexane:EtOAc (1:1) gave the title compound as a white solid. MS (ESI, pos. ion.) m/z: 551 (M+1). Step E: Synthesis of (S)-N-(4-fluorophenyl)-N-(4-(6-formyl-1,2,3,4-tetrahydronaphthalen-1 15 yl)-3-oxobutyl)-3-(trifluoromethyl)benzenesulfonamide To a 50-mL reaction tube containing (R)-3-(N-(4-fluorophenyl)-3-(trifluoromethyl) phenylsulfonamido)-N-(6-(hydroxymethyl)- 1,2,3,4-tetrahydronaphthalen- 1 -yl)propanamide (0.6 g, 1.1 mmol, Step D) in CH 2 C1 2 (15 mL), was added MnO 2 (1.4 g, 16 mmol, Aldrich). The reaction was stirred at RT for 4 h, and filtration through Celite gave the title compound as 20 a yellow solid. MS (ESI, pos. ion.) m/z: 549 (M+1). Step F: Synthesis of (R)-3-(N-(4-fluorophenyl)-3-(trifluoromethyl)phenylsulfonamido)-N-(6 ((4-fluoropiperidin- 1 -yl)methyl)- 1,2,3,4-tetrahydronaphthalen- 1 -yl)propanamide To a 50-mL reaction tube containing (S)-N-(4-fluorophenyl)-N-(4-(6-formyl-1,2,3,4 tetrahydronaphthalen- 1 -yl)-3-oxobutyl)-3-(trifluoromethyl)benzenesulfonamide (80 mg, 0.15 25 mmol, Step E) in DMF (3 mL), was added 4-fluoropiperidine hydrobromide (0.27 g, 1.5 mmol, Oakwood Products), Et 3 N (0.20 mL, 1.5 mmol, Aldrich), NaBH(OAc) 3 (0.16 g, 0.7 mmol, Aldrich), and 2 drops of AcOH (J.T. Baker). The reaction was stirred at RT for 12 h. The reaction was quenched with K 2 C0 3 (8 mL, 5%), and the compound was extracted with EtOAc (2x10 mL). The organic phase was washed with 5% brine (2x5 mL), dried over Na 2
SO
4 , 30 filtered, and concentrated. Purification with column chromatography over silica gel with hexane:EtOAc:MeOH (2M, NH 3 ) (10:10:1) gave the title compound as a white solid. MS (ESI, pos. ion.) m/z: 636 (M+1). Similarly, (R)-3-(N-phenylnaphthalene-2-sulfonamido)-N-(6-(piperidin-1-ylmethyl)-1,2,3,4 tetrahydronaphthalen-1-yl)propanamide; (R)-3-(N-phenylnaphthalene-2-sulfonamido)-N-(7 118 WO 2006/036664 PCT/US2005/033659 (piperidin- 1 -ylmethyl)chroman-4-yl)propanamide; and (R)-N-(6-((cyclopentylamino)methyl) 1,2,3,4-tetrahydronaphthalen- 1 -yl)-3-(N-phenyl-3-(trifluoromethyl)phenylsulfonamido) propanamide were made. 5 Example 11 Synthesis of (R)-N-(6-((4-fluoropiperidin-1-yl)methyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-3 (N-methyl-3-(trifluoromethyl)phenylsulfonamido)propanamide NN | H
F
3 C N F 10 Step A: Synthesis of N-methyl-3-(trifluoromethyl)benzenesulfonamide To a 50-mL round-bottomed flask containing 3-trifluoromethylbenzene sulfonyl chloride (2.5 mL, 6.7 mmol, Aldrich) in THF (15 mL), was slowly added a methyl amine solution (575 jiL, 6.7 mmol, 40wt.%, Aldrich). The reaction was stirred at RT for 1 h. The reaction mixture was acidified to pH 5 with 2N HCI and the compound was extracted with 15 EtOAc (2x10 mL). The combined organic phase was washed with 5% brine (2x8 mL), dried over Na 2
SO
4 . Purification with column chromatography over silica gel with hexane:EtOAc (5:1) gave the title compound. MS (ESI, pos. ion.) m/z: 362 (M+Na). Step B: Synthesis of methyl 3-(N-methyl-3-(trifluoromethyl)phenylsulfonamido)propanoate To a 100-mL round-bottomed flask containing N-methyl-3-(trifluoromethyl) 20 benzenesulfonamide (1.5 g, 6.3 mmol, Step A) in DMF (10 mL), was added methyl 3-bromo propanoate (28 mL, 257 mmol, Aldrich) and K 2 C0 3 (2.3 g, 17 mmol, Aldrich). The reaction mixture was refluxed at 140 'C for 13 h. The reaction was quenched with water (15 mL) and the compound was extracted with EtOAc (2x20 mL). The organic phase was washed with 5% brine (2x10 mL), dried over Na 2
SO
4 , filtered, and concentrated. Purification with column 25 chromatography over silica gel with hexane:EtOAc (5:1) gave the title compound. MS (ESI, pos. ion.) m/z: 326 (M+1). Step C: Synthesis of 3-(N-methyl-3-(trifluoromethyl)phenylsulfonamido)propanoic acid To a 50-mL round-bottomed flask containing methyl 3-(N-methyl-3-(trifluoromethyl) phenylsulfonamido)propanoate (1.3 g, 4.0 mmol, Step B) in THF (8 mL), was added 30 LiOH.H 2 0 (1.3 mg, 8.0 mmol, Aldrich) and water (8 mL). The reaction was stirred at RT for 5 119 WO 2006/036664 PCT/US2005/033659 h. After acidified to pH 5 with 2N HCl, the compound was extracted with EtOAc (2x10 mL). The organic phase was washed with 5% brine (2x8 mL), dried over Na 2
SO
4 , filtered, and concentrated to yield the title compound. MS (ESI, pos. ion.) m/z: 312 (M+1). Step D: Synthesis of (R)-N-(6-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(N 5 methyl-3-(trifluoromethyl)phenylsulfonamido)propanamide To a 50-mL reaction tube containing 3-(N-methyl-3-(trifluoromethyl)phenyl sulfonamido)propanoic acid (0.25 g, 0.80 mmol, Step C) in DMF (3 mL), was added (R)-(5 amino-5,6,7,8-tetrahydronaphthalen-2-yl)methanol (0.14 g, 0.80 mmol), TBTU (0.36 g, 1.1 mmol, Advanced ChemTech), and iPr 2 EtN (0.56 mL, 3.2 mmol, Aldrich). The reaction was 10 stirred at RT for 5 h. The reaction was quenched with 5% brine (5 mL) and the compound was extracted with EtOAc (2x10 mL). The organic phase was washed with 5% brine (2x5 mL), dried over Na 2 SO4, filtered, and concentrated. Purification with column chromatography over silica gel with hexane:EtOAc:MeOH (2M, NH 3 ) (5:5:1) gave the title compound as a white powder. MS (ESI, pos. ion.) m/z: 471 (M+1). 15 Step E: Synthesis of (R)-N-(6-formyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(N-methyl-3 (trifluoromethyl)phenylsulfonamido)propanamide To a 50-mL reaction tube containing (R)-N-(6-(hydroxymethyl)-1,2,3,4 tetrahydronaphthalen-1-yl)-3-(N-methyl-3-(trifluoromethyl)phenylsulfonamido)propanamide (0.12 g, 0.25 mmol, Step D) in CH 2
CI
2 (4 mL), was added MnO 2 (0.17 g, 2.0 mmol, Aldrich). 20 The reaction was stirred at RT for 2 h, and filtration through Celite gave the title compound as a yellow solid. MS (ESI, pos. ion.) m/z: 469 (M+1). Step F: Synthesis of (R)-N-(6-((4-fluoropiperidin-1-yl)methyl)-1,2,3,4-tetrahydronaphthalen 1-yl)-3-(N-methyl-3-(trifluoromethyl)phenylsulfonamido)propanamide. To a 50-mL reaction tube containing (R)-N-(6-formyl-1,2,3,4-tetrahydronaphthalen-1 25 yl)-3-(N-methyl-3-(trifluoromethyl)phenylsulfonamido)propanamide (0.11 g, 0.23 mmol, Step E) in DMF (3 mL), was added 4-fluoropiperidine hydrochloride (66 mg, 0.47 mmol, Matrix), Et 3 N (66 EL, 0.73 mmol, Aldrich), NaBH(OAc) 3 (0.15 g, 0.70 mmol, Aldrich), and 2 drops of AcOH (J.T. Baker). The reaction was stirred at RT for 12 h. The reaction was quenched with
K
2 C0 3 (8 mL 5%), and the compound was extracted with EtOAc (2x 10 mL). The organic 30 phase was washed with 5% brine (2x5 mL), dried over Na 2
SO
4 , filtered, and concentrated. Purification with column chromatography over silica gel with hexane:EtOAc:MeOH (2M,
NH
3 ) (10:10:1) gave the title compound as clear oil. MS (ESI, pos. ion.) m/z: 556 (M+1). Example 12 120 WO 2006/036664 PCT/US2005/033659 Synthesis of (R)- 3 -(N-cyclopropyl- 3 -(trifluoromethyl)phenylsulfonamido)-N-(6-(piperidin-1 ylmethyl)- 1,2,3,4-tetrahydronaphthalen- 1 -yl)propanamide H 00 0 N 5 Step A: Synthesis of N-cyclopropyl-3-(trifluoromethyl) benzenesulfonamide To a 50-mL round-bottomed flask containing 3-trifluoromethylbenzenesulfonyl chloride (4.0 mL, 25 mmol, Aldrich) in THF (15 mL), was slowly added cyclopropylamine (0.74 g, 13 mmol, Aldrich). The reaction was stirred at RT for 1 h. The reaction mixture was quenched with water (10 mL), and the compound was extracted with EtOAc (2x15 mL). The 10 combined organic phase was washed with 5% brine (2x8 mL), dried over Na 2
SO
4 . Purification with column chromatography over silica gel with hexane:EtOAc (5:1) gave the title compound as a clear oil. MS (ESI, pos. ion.) m/z: 264 (M-1). Step B: Synthesis of tert-butyl 3 -(N-cyclopropyl-3-(trifluoromethyl)phenyl sulfonamido)propanoate. 15 To a 100-mL round-bottomed flask containing N-cyclopropyl-3-(trifluoromethyl) benzenesulfonamide (1.7 g, 6.2 mmol, step A) in DMF (10 mL), was added tert-butyl acrylate (6.9 mL, 47 mmol, Aldrich) and K 2 C0 3 (4.3 g, 31 mmol, Aldrich). The reaction mixture was refluxed at 100 'C for 2 h. The reaction was quenched with water (15 mL) and the compound was extracted with EtOAc (2x20 mL). The organic phase was washed with 5% brine (2x10 20 mL), dried over Na 2
SO
4 , filtered, and concentrated. Purification with column chromatography over silica gel with hexane:EtOAc (5:1) gave the title compound. MS (ESI, pos. ion.) m/z: 394 (M+ 1). Step C: Synthesis of 3 -(N-cyclopropyl- 3 -(trifluoromethyl)phenylsulfonamido)propanoic acid. To a 50-mL round-bottomed flask containing tert-butyl 3-(N-cyclopropyl-3 25 (trifluoromethyl) phenylsulfonamido) propanoate (1.7 g, 4.2 mmol, step B), was added trifluoroacetic acid (5.0 mL, 65 mmol, Aldrich). The reaction was stirred at RT for 1.5 h. Evaporation in vacuo provided the title compound as a white solid. MS (ESI, pos. ion.) m/z: 338 (M+1). 121 WO 2006/036664 PCT/US2005/033659 Step D: Synthesis of (R)-3-(N-cyclopropyl-3-(trifluoromethyl)phenylsulfonamido)-N-(6 (piperidin- 1 -ylmethyl)- 1,2,3,4-tetrahydronaphthalen- 1 -yl)propanamide. To a 50-mL reaction tube containing 3-(N-cyclopropyl-3-(trifluoromethyl)phenyl sulfonamido)propanoic acid (0.13 g, 0.39 mmol, step C) in DMF (5 mL), was added (R)-6 5 (piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-amine (0.14 g), TBTU (0.30 g, 0.78 mmol, Advanced ChemTech), and iPr 2 EtN (0.27 mL, 1.6 mmol, Aldrich). The reaction was stirred at RT for 5 h. The reaction was quenched with 5% brine (10 mL) and the compound was extracted with EtOAc (2x15 mL). The organic phase was washed with 5% brine (2x8 mL), dried over Na 2
SO
4 , filtered, and concentrated. Purification with column chromatography 10 over silica gel with hexane:EtOAc:MeOH (2M, NH 3 ) (5:5:1) gave the title compound as a white solid. MS (ESI, pos. ion.) m/z: 564 (M+1). Similarly, (R)-3-(N-cyclohexyl-3-(trifluoromethyl)phenylsulfonamido)-N-(6-(piperidin-1 ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)propanamide; (R)-3-(N-isopropyl-3 (trifluoromethyl)phenylsulfonamido)-N-(6-(piperidin-1-ylmethyl)-1,2,3,4 15 tetrahydronaphthalen-1-yl)propanamide, (R)-N-(6-((tert-butylamino)methyl)-1,2,3,4 tetrahydronaphthalen-1-yl)-3-(N-cyclopropyl-3-(trifluoromethyl)phenylsulfonamido) propanamide were synthesized. Example 13 20 Synthesis of (R)-3-(3-bromosaccharinyl-N-(6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydro naphthalen- 1 -yl)propanamide 0 ,N H Br O OSN,, N Step A: Synthesis of methyl 3-(3-bromo-saccharinyl)propanoate 25 To a 100-mL round-bottomed flask containing 3-bromosaccharin (1.0 g, 3.8 mmol, Synthelee) in DMF (5 mL), was slowly added NaH (0.15 g, 3.8 mmol, 60% in mineral oil, Aldrich) at room temp. Methyl 3-bromo-propanoate (2.1 mL, 19 mmol, Aldrich) was added and the reaction mixture was refluxed at 130 *C for 6 h. The reaction was quenched with water (15 mL) and the compound was extracted with EtOAc (2x20 mL). The organic phase was 30 washed with 5% brine (2x 10 mL), dried over Na 2
SO
4 , filtered, and concentrated. Purification 122 WO 2006/036664 PCT/US2005/033659 with column chromatography over silica gel with hexane:EtOAc:MeOH (5:5:1) gave the title compound. Step B: Synthesis of 3-(3-bromosaccharinyl)propanoic acid To a 50-mL round-bottomed flask containing methyl 3-(3-bromo-saccharinyl) 5 propanoate (0.61 g, 1.8 mmol, step A) in THF (6 mL), was added LiOH.H 2 0 (0.37 g, 8.8 mmol, Aldrich) and water (6 mL). The reaction was stirred at RT for 6 h. The reaction mixture was acidified to pH 5, and the compound was extracted with EtOAc (15 mL). The organic phase was washed with water, dried over Na 2
SO
4 , filtered, and concentrated to yield the title compound. 10 Step C: Synthesis of (R)-3-(3-bromo-saccharinyl-N-(6-(piperidin-1-ylmethyl)-1,2,3,4 tetrahydronaphthalen- 1 -yl)propanamide To a 50-mL reaction tube containing 3-(3-bromo-saccharinyl) propanoic acid (0.11 g, 0.33 mmol, step B) in DMF (5 mL), was added (R)-6-(piperidin-1-ylmethyl)-1,2,3,4 tetrahydronaphthalen-1-amine (80 mg, 0.33 mmol), TBTU (0.25 g, 0.66 mmol, Advanced 15 ChemTech), and iPr 2 EtN (0.23 mL, 1.3 mmol, Aldrich). The reaction was stirred at RT for 5 h. The reaction was quenched with 5% brine (10 mL) and the compound was extracted with EtOAc (2x 15 mL). The organic phase was washed with 5% brine (2x8 mL), dried over Na 2
SO
4 , filtered, and concentrated. Purification with column chromatography over silica gel with hexane:EtOAc:MeOH (2M, NH 3 ) (5:5:1) gave the title compound as a yellow solid. MS 20 (ESI, pos. ion.) m/z: 561 (M+1). Example 14 Synthesis of 4,4,4-trifluoro-3-(N-methyl-3-(trifluoromethyl)phenylsulfonamido)-N-((R)-6 (piperidin- I -ylmethyl)- 1,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide F3C S\N,,-yN, 0 0 CF 3 0 25~ NC 25 Step A: Synthesis of ethyl 4,4,4-trifluoro-3-(3-(trifluoromethyl)phenylsulfonamido)butanoate To a 50-mL round-bottomed flask containing ethyl 3-amino-4,4,4-trifluorobutanoate (0.40 g, 2.2 mmol, Lancaster) in THF (5 mL), was added 3-trifluoromethylbenzene sulfonylchloride (0.36 mL, 3.4 mmol, Aldrich) and sat. K 2 C0 3 (4 mL). The reaction was 30 stirred at RT for 1 h. The reaction mixture was acidified to pH 5 with 2N HCl and the 123 WO 2006/036664 PCT/US2005/033659 compouna was extracted wnn rtuAc (2x10 mL). The combined organic phase was washed with 5% brine (2x8 mL), dried over Na 2
SO
4 . Purification with column chromatography over silica gel with hexane:EtOAc (3:1) gave the title compound. MS (ESI, pos. ion.) m/z: 394 (M+1). 5 Step B: Synthesis of 4,4,4-trifluoro-3-(3-(trifluoromethyl)phenylsulfonamido)butanoic acid To a 50-mL round-bottomed flask containing ethyl 4,4,4-trifluoro-3-(3-(trifluoro methyl) phenylsulfonamido)butanoate (0.37 g, 0.95 mmol, step A) in THF (2 mL), was added LiOH.H 2 0 (0.12 g, 2.9 mmol, Aldrich) and water (2 mL). The reaction was stirred at RT for 6 h. After acidified to pH 5 with 2N HCl, the compound was extracted with EtOAc (2x5 mL). 10 The organic phase was washed with 5% brine (2x4 mL), dried over Na 2
SO
4 , filtered, and concentrated to yield the title compound. MS (ESI, pos. ion.) m/z: 364 (M-1). Step C: Synthesis of 4,4,4-trifluoro-N-((R)-6-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1 yl)-3-(3-(trifluoromethyl)phenylsulfonamido)butanamide To a 50-mL reaction tube containing 4,4,4-trifluoro-3-(3-(trifluoromethyl)phenyl 15 sulfonamido)butanoic acid (1.6 g, 4.1 mmol, step B) in DMF (10 mL), was added (R)-(5 amino-5,6,7,8-tetrahydronaphthalen-2-yl)methanol (0.72 g, 4.1 mmol), TBTU (0.25 g, 0.66 mmol, Advanced ChemTech), and iPr 2 EtN (0.23 mL, 1.3 mmol, Aldrich). The reaction was stirred at RT for 5 h. The reaction was quenched with 5% brine (10 mL) and the compound was extracted with EtOAc (2x15 mL). The organic phase was washed with 5% brine (2x8 20 mL), dried over Na 2
SO
4 , filtered, and concentrated. Purification with column chromatography over silica gel with hexane:EtOAc:MeOH (2M, NH 3 ) (10:10:1) gave the title compound. MS (ESI, pos. ion.) m/z: 525 (M+1). Step D: Synthesis of 4,4,4-trifluoro-N-((R)-6-formyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(3 (trifluoromethyl)phenylsulfonamido)butanamide 25 To a 50-mL reaction tube containing 4,4,4-trifluoro-N-((R)-6-(hydroxymethyl)-1,2,3,4 tetrahydronaphthalen-1-yl)-3-(3-(trifluoromethyl)phenylsulfonamido)butanamide 1.5 g, 2.9 mmol, step C) in CH 2 Cl 2 (25 mL), was added MnO 2 (1.4 g, 16 mmol, Aldrich). The reaction was stirred at RT for 10 h, and filtration through Celite gave the title compound as a clear oil. MS (ESI, pos. ion.) m/z: 523 (M+1). 30 Step E: Synthesis of 4,4,4-trifluoro-N-((R)-6-formyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(N methyl-3-(trifluoromethyl)phenylsulfonamido)butanamide To a 1 00-mL round-bottomed flask containing 4,4,4-trifluoro-N-((R)-6-formyl- 1,2,3,4 tetrahydronaphthalen-1-yl)-3-(3-(trifluoromethyl)phenylsulfonamido)butanamide (0.35 g, 0.67 mmol, step D) in DMF (5 mL), was added Mel (0.13 mL, 2.0 mmol, Aldrich) and K 2 C0 3 (0.17 124 WO 2006/036664 PCT/US2005/033659 g, z.u mmol, Alancn). i Tne reaction mixture was stirred at RT for 1 h. The reaction was quenched with water (8 mL) and the compound was extracted with EtOAc (2x10 mL). The organic phase was washed with 5% brine (2x 10 mL), dried over Na 2
SO
4 , filtered, and concentrated to yield the title compound. MS (ESI, pos. ion.) m/z: 535 (M-1). 5 Step F: Synthesis of 4,4,4-trifluoro-3-(N-methyl-3-(trifluoromethyl)phenylsulfonamido)-N ((R)-6-(piperidin-1 -ylmethyl)- 1,2,3,4-tetrahydronaphthalen-1 -yl)butanamide To a 50-mL reaction tube containing 4,4,4-trifluoro-N-((R)-6-formyl-1,2,3,4 tetrahydronaphthalen-1-yl)-3-(N-methyl-3-(trifluoromethyl)phenylsulfonamido)butanamide (0.30 g, 0.56 mmol, step E) in DMF (3 mL), was added piperidine (0.17 mL, 1.7 mmol, 10 Aldrich), NaBH(OAc) 3 (0.37 g, 1.7 mmol, Aldrich), and 2 drops of AcOH (J.T. Baker). The reaction was stirred at RT for 12 h. The reaction was quenched with K 2 C0 3 (8 mL, 5%), and the compound was extracted with EtOAc (2x10 mL). The organic phase was washed with 5% brine (2x5 mL), dried over Na 2
SO
4 , filtered, and concentrated. Purification with column chromatography over silica gel with hexane:EtOAc:MeOH (2M, NH 3 ) (5:5:1) gave the title 15 compound as a white solid. MS (ESI, pos. ion.) m/z: 606 (M+1). Similarly, (S)-3-(5-chloro-2-fluoro-N-methylphenylsulfonamido)-4,4,4-trifluoro-N-((R)-6 (piperidin- 1 -ylmethyl)- 1,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide; (S)-3-(3-chloro-2-fluoro-N-methylphenylsulfonamido)-4,4,4-trifluoro-N-((R)-6 20 (piperidin- 1 -ylmethyl)- 1,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide; (S)-3-(2,5-dichloro-N-methylphenylsulfonamido)-4,4,4-trifluoro-N-((R)-6-(piperidin-1 ylmethyl)- 1,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide; (S)-3-(3,4-dichloro-N-methylphenylsulfonamido)-4,4,4-trifluoro-N-((R)-6-(piperidin- I ylmethyl)- 1,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide; 25 (S)-3-(2,3-dichloro-N-methylphenylsulfonamido)-4,4,4-trifluoro-N-((R)-6-(piperidin-1 ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)butanamide; (S)-3-(2,5-dichloro-N-methylphenylsulfonamido)-4,4,4-trifluoro-N-((R)-7-(piperidin-1 ylmethyl)chroman-4-yl)butanamide; (S)-3-chloro-2-fluoro-N-methylphenylsulfonamido)-4,4,4-trifluoro-N-((R)-7-(piperidin 30 1 -ylmethyl)chroman-4-yl)butanamide; 3-(2,3-dichloro-N-methylphenylsulfonamido)-2-methyl-N-((R)-6-(piperidin- 1 ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)propanamide; and 3-(2,3 -dichloro-N-methylphenylsulfonamido)-2-hydroxy-N-((R)-6-(piperidin- 1 ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)propanamide were made. 125 WO 2006/036664 PCT/US2005/033659 Example 15 Synthesis of 3-(2,6-dichlorophenylsulfonamido)-4,4,4-trifluoro-N-((R)-6-(piperidin-1 ylmethyl)- 1,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide 5 Cl H H CI CF3 O No Step A: Synthesis of ethyl 3-(tert-butoxycarbonyl)-4,4,4-trifluorobutanoate To a 50-mL round-bottomed flask containing ethyl 3-amino-4,4,4-trifluorobutanoate (1.4 g, 81 mmol, Lancaster) in THF (40 mL), was added tBOC 2 0 (27 g, 120 mmol, Aldrich) 10 and sat. K 2 C0 3 (35 mL). The reaction was stirred at RT for 8 h. The compound was extracted with EtOAc (2x30 mL) and he combined organic phase was washed with 5% brine (2x20 mL), dried over Na 2 S0 4 . Purification with column chromatography over silica gel with hexane:EtOAc (5:1) gave the title compound. MS (ESI, pos. ion.) m/z: 286 (M+1). Step B: Synthesis of 3-(tert-butoxycarbonyl)-4,4,4-trifluorobutanoic acid 15 To a 50-mL round-bottomed flask containing ethyl 3-(tert-butoxycarbonyl)-4,4,4 trifluorobutanoate (12 g, 42 mmol, step A) in THF (15 mL), was added LiOH.H 2 0 (3.5 g, 84 mmol, Aldrich) and water (10 mL). The reaction was stirred at RT for 6 h. After acidified to pH 5 with 2N HCl, the compound was extracted with EtOAc (2x50 mL). The organic phase was washed with 5% brine (2x20 mL), dried over Na 2
SO
4 , filtered, and concentrated to yield 20 the title compound. MS (ESI, pos. ion.) m/z: 258 (M+1). Step C: Synthesis of tert-butyl 1,1,1 -trifluoro-4-oxo-4-((R)-6-(piperidin-1-ylmethyl)-1,2,3,4 tetrahydronaphthalen- 1 -ylamino)butan-2-ylcarbamate To a 1 00-mL reaction tube containing 3-(tert-butoxycarbonyl)-4,4,4-trifluorobutanoic acid (0.46 g, 1.8 mmol, step B) in DMF (8 mL), was added (R)-6-(piperidin-1-ylmethyl) 25 1,2,3,4-tetrahydronaphthalen-1-amine (0.65 g, 2.7 mmol), TBTU (1.4 g, 3.6 mmol, Advanced ChemTech), and iPr 2 EtN (1.3 mL, 7.2 mmol, Aldrich). The reaction was stirred at RT for 5 h. The reaction was quenched with 5% brine (15 mL) and the compound was extracted with EtOAc (2x25 mL). The organic phase was washed with 5% brine (2x10 mL), dried over Na 2
SO
4 , filtered, and concentrated. Purification with column chromatography over silica gel 126 WO 2006/036664 PCT/US2005/033659 h xwM 1, NH 3 ) (5:5:1) gave the title compound as a light yellow solid. MS (ESI, pos. ion.) m/z: 484 (M+l). Step D: Synthesis of 3-amino-4,4,4-trifluoro-N-((R)-6-(piperidin-1-ylmethyl)-1,2,3,4 tetrahydronaphthalen- I -yl)butanamide bis-hydrochloride 5 To a 50-mL reaction tube containing tert-butyl 1,1,1-trifluoro-4-oxo-4-((R)-6 (piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-ylamino)butan-2-ylcarbamate (0.54 g, 1.1 mmol, step C), was added HCI (3.0 mL, 12 mmol, 4.ON in 1,4-dioxane, Aldrich). The reaction was stirred at RT for 2 h, and evaporation in vacuo gave the title compound. MS (ESI, pos. ion.) m/z: 384 (M+1). 10 Step E: Synthesis of 3-(2,6-dichlorophenylsulfonamido)-4,4,4-trifluoro-N-((R)-6-(piperidin-1 ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)butanamide To a 50-mL round-bottomed flask containing 3-amino-4,4,4-trifluoro-N-((R)-6 (piperidin- 1 -ylmethyl)- 1,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide bis-hydrochloride 0.12 g, 0.26 mmol, step D), was added 2,6-dichlorobenzene sulfonylchloride (0.19 g, 0.78 mmol, 15 Aldrich) and pyridine (3 mL, Aldrich). After the reaction was stirred at 50 *C for 1.5 h, the solvent was evaporated in vacuo. The residue was taken in EtOAc (20 mL) and was washed with 5% brine (2x8 mL), dried over Na 2
SO
4 . Purification with column chromatography over silica gel with hexane:EtOAc:MeOH (2M, NH 3 ) (5:5:1) gave the title compound as a white solid. MS (ESI, pos. ion.) m/z: 592 (M+1). 20 Similarly, 3-(2,3-dihydrobenzo[b][1,4]dioxine-6-sulfonamido)-4,4,4-trifluoro-N-((R)-6-(piperidin 1 -ylmethyl)- 1,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide; 4,4,4-trifluoro-3-(3-methylphenylsulfonamido)-N-((R)-6-(piperidin- 1 -ylmethyl) 1,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide; and 25 3-(benzo[c] [1,2,5]oxadiazole-4-sulfonamido)-4,4,4-trifluoro-N-((R)-6-(piperidin- 1 ylmethyl)- 1,2,3,4-tetrahydronaphthalen-1 -yl)butanamide were made. Example 16 Synthesis of 3-(3-chloro-2-fluorophenylsulfonamido)-4,4,4-trifluoro-N-methyl-N-((R)-6 30 (piperidin- I -ylmethyl)- 1,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide 127 WO 2006/036664 PCT/US2005/033659 - ~ N,, 0 0 FF Step A: Synthesis of (R)-(5-(methylamino)-5,6,7,8-tetrahydronaphthalen-2-yl)methanol To a solution of acetic formic anhydride (prepared by stirring 12 mL of acetic anhydride and 4.3 mL of formic acid at 600 C for 2 h then cooling to room temperature) was 5 added 3.0 g of (R)-(5-amino-5,6,7,8-tetrahydronaphthalen-2-yl-methanol. The reaction mixture was stirred at room temp for 3 h. The reaction was monitored by TLC (10% MeOH in EtOAc) of aliquots quenched in sat. NaHCO 3 and extracted with EtOAc. After the reaction was complete the reaction mixture was slowly quenched with sat. NaHCO 3 until the solution was slightly basic and then extracted with EtOAc (2 x 100 mL), washed with brine (1 x 100 10 mL), and dried with sodium sulfate. After concentration the crude material was dissolved in dry THF (20 mL) and slowly added to lithium aluminum hydride (2.4 g) in THF (75 mL). The reaction mixture was heated to 40* C for 3 h and quenched with sodium potassium tartrate solution. After filteration, the filtrated was diluted with 100 mL of EtOAc, dried with sodium sulfate, and concentrated. Purification by chromatography over silica gel with 0 to 5% MeOH 15 (2M, NH 3 ) in DCM gave the title compound. MS (ESI, pos. ion) m/z: 192 (M+1). Step B: Synthesis of 3-(3-chloro-2-fluorophenylsulfonamido)-4,4,4-trifluoro-N-((R)-6-( hydroxymethyl)- 1,2,3,4-tetrahydronaphthalen- 1 -yl)-N-methylbutanamide In dry DCM (10 mL), 3 -( 3 -chloro-2-fluorophenylsulfonamido)-4,4,4-trifluorobutanoic acid (0.5 mmol) and PyClU (1-(choro-1-pyrrolidinylmethylene)pyrrolidinium 20 hexafluorophosphate) (0.5 mmol) were combined. (R)-(5-(Methylamino)-5,6,7,8 tetrahydronaphthalen-2-yl)methanol (0.6 mmol) and DIEA (1.5 mmol) were added and the mixture was stirred at room temperature under nitrogen for 1 h. The reaction mixture was quenched with 20 mL of saturated sodium bicarbonate, then extracted with EtOAc (2 x 30 mL), washed with brine (1 x 20 mL), dried with sodium sulfate, and concentrated. Purification 25 by chromatography over silica gel with 20 to 60% EtOAc in hexane gave the title compound. MS (ESI, pos. ion) m/z: 523 (M+1). 128 WO 2006/036664 PCT/US2005/033659 Sfe C: Synthesis of 3-(3~ohloro-2-fluorophenylsulfonamido)-4,4,4,-trifluoro-N-((R)-6-formyl 1,2,3,4-tetrahydronaphthalen- 1 -yl)-N-methylbutanamide Manganese dioxide (2.5 mmol) was added to a solution of 3-(3-chloro-2 fluorophenylsulfonamido)-4,4,4-trifluoro-N-((R)-6-(hydroxymethyl)-1,2,3,4 5 tetrahydronaphthalen-1-yl)-N-methylbutanamide (0.25 mmol) in 15 mL of DCM. The reaction mixture was stirred at room temp for 4 h, then filtered through celite. The residue was washed repeatedly with EtOAc and MeOH, then the filtrate was concentrated to give the title compound. MS (ESI, pos. ion) m/z: 521 (M+1). Step D: Synthesis of 3-(3-chloro-2-fluorophenylsulfonamido)-4,4,4-trifluoro-N-methyl-N 10 ((R)-6-(piperidin- 1 -ylmethyl)- 1,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide In 1,2-dichloroethane (10 mL), 3-(3-chloro-2-fluorophenylsulfonamido)-4,4,4-trifluoro N-((R)-6-formyl-1,2,3,4-tetrahydronaphthalen-1-yl)-N-methylbutanamide (0.2 mmol) was dissolved. Piperidine (0.6 mmol) and sodium triacetoxyborohydride (0.4 mmol) were added. The reaction mixturewas stirred at room temperature under nitrogen overnight, then quenched 15 with saturated sodium bicarbonate. The product was extracted with ethyl acetate (2 x 20 mL), and washed with brine (1 x 20 mL), dried with sodium sulfate, and concentrated. Purification by chromatography over silica gel with 0 to 5% MeOH (2M, NH 3 ) in DCM gave the title compound. MS (ESI, pos. ion) m/z: 590 (M+1). Similarly, 20 (S)-3-(3-chlorophenylsulfonamido)-4,4,4-trifluoro-N-methyl-N-((R)-6-(piperidin-1 ylmethyl)- 1,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide; (S)-4,4,4-trifluoro-N-methyl-N-((R)-6-(piperidin- 1 -ylmethyl)- 1,2,3,4 tetrahydronaphthalen- 1 -yl)-3-(3-(trifluoromethyl)phenylsulfonamido)butanamide; (2R,3S)-4,4,4-trifluoro-2-hydroxy-N-methyl-N-((R)-6-(piperidin-1-ylmethyl)-1,2,3,4 25 tetrahydronaphthalen- 1 -yl)-3-(3-(trifluoromethyl)phenylsulfonamido)butanamide; (S)-3-(5-chloro-2-fluorophenylsulfonamido)-4,4,4-trifluoro-N-methyl-N-((R)-6 (piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)butanamide; and (S)-3-(2,3-dichlorophenylsulfonamido)-4,4,4-trifluoro-N-methyl-N-((R)-6-(piperidin-1 ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)butanamide were made. 30 Example 17 Synthesis of 1-(3-chloro-2-fluorophenylsulfonyl)-4-((R)-6-(piperidin-1-ylmethyl)-1,2,3,4 tetrahydronaphthalen-1-yl)-7(R)-(trifluoromethyl)-1,4-diazepan-5-one 129 WO 2006/036664 PCT/US2005/033659 F O2S'N N"'
F
3 C\<>O N- < Step A: Synthesis of (R)-ethyl 3-(3-chloro-2-fluoro-N-(2-oxoethyl)phenylsulfonamido)-4,4,4 trifluorobutanoate: 5 A solution of (R)-ethyl 3-(N-allyl-3-chloro-2-fluorophenylsulfonamido)-4,4,4 trifluorobutanoate, prepared according to Reference 14, Step A (776 mg, 1.86 mmol) in tert butanol (15 mL), THF (3 mL) and water (1.5 mL) was treated with osmium tetroxide (567 mg of a 2.5 mol% w/w in tert-butanol, 0.05 mmol, 0.03 equiv) and 4-methylmorpholine N-oxide (435 mg, 3.72 mmol, 2.0 equiv). The reaction mixture was stirred at room temperature for 17 10 h. A solution of a pH 7.2 phosphate buffer (20 mL) was added, followed by sodium periodate (1.99 g, 9.3 mmol, 5.0 equiv). The white suspension was stirred for 2 h, diluted with saturated ammonium chloride solution (25 mL) and extracted with EtOAc (3x40 mL). The combined organic layers were washed with brine (30 mL), dried (MgSO 4 ) and purified on silica gel using 25% ethyl acetate in hexane as eluant, affording (R)-ethyl 3-(3-chloro-2-fluoro-N-(2 15 oxoethyl)phenylsulfonamido)-4,4,4-trifluorobutanoate. MS: 420.2 (M+H)*. Step B: Synthesis of (R)-ethyl 3-(3-chloro-2-fluoro-N-(2-((R)-6-(piperidin-1-ylmethyl)-1,2,3,4 tetrahydronaphthalen-1 -ylamino)ethyl)phenylsulfonamido)-4,4,4-trifluorobutanoate A solution of (R)-ethyl 3-(3-chloro-2-fluoro-N-(2-oxoethyl)phenylsulfonamido)-4,4,4 trifluorobutanoate (689 mg, 1.64 mmol) in 1,2-dichloroethane (20 mL) was treated with (R)-6 20 (piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-l-amine (595 mg, 2.43 mmol, 1.48 equiv), sodium triacetoxyborohydride (700 mg, 3.28 mmol, 2.0 equiv) and catalytic glacial acetic acid (5 drops). After being stirred at room temperature for 16 h, the reaction was diluted with saturated sodium bicarbonate solution (30 mL) and extracted with dichloromethane (3x25 mL). The combined organic layers were dried (MgSO 4 ) and purified on silica gel using 5% 25 methanol in dichloromethane as eluant, affording (R)-ethyl 3-(3-chloro-2-fluoro-N-(2-((R)-6 (piperidin- 1 -ylmethyl)- 1,2,3,4-tetrahydronaphthalen- 1 -ylamino)ethyl)phenylsulfonamido) 4,4,4-trifluorobutanoate. MS: 648.2 (M+H)*. Step C: Synthesis of (R)-3-(3-chloro-2-fluoro-N-(2-((R)-6-(piperidin-1-ylmethyl)-1,2,3,4 tetrahydronaphthalen-1-ylamino)ethyl)phenylsulfonamido)-4,4,4-trifluorobutanoic acid. 130 WO 2006/036664 PCT/US2005/033659 A solution of (R)-ethyl 3-(3-chloro-2-fluoro-N-(2-((R)-6-(piperidin- 1 -ylmethyl) 1,2,3,4-tetrahydronaphthalen- 1 -ylamino)ethyl)phenylsulfonamido)-4,4,4-trifluorobutanoate (653 mg, 1.01 mmol) in 10% aqueous hydrochloric acid (20 mL) and dioxane (20 mL) was heated to reflux for 24 h. The reaction was cooled to room remperature and concentrated in 5 vacuo to afford (R)-3-(3-chloro-2-fluoro-N-(2-((R)-6-(piperidin-1-ylmethyl)-1,2,3,4 tetrahydronaphthalen- 1 -ylamino)ethyl)phenylsulfonamido)-4,4,4-trifluorobutanoic acid as a HCl salt. MS: 620.2 (M+H)+. Step D: Synthesis of (R)-1-(3-chloro-2-fluorophenylsulfonyl)-4-((R)-6-(piperidin-1-ylmethyl) 1,2,3,4-tetrahydronaphthalen-1-yl)-7-(trifluoromethyl)-1,4-diazepan-5-one 10 (R)-3-(3-Chloro-2-fluoro-N-(2-((R)-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydro naphthalen-1-ylamino)ethyl)phenylsulfonamido)-4,4,4-trifluorobutanoic acid dihydrochloride salt (210 mg, 0.30 mmol) in N,N-dimethylformamide (30 mL) was treated triethylamine (0.1 mL, 0.60 mmol, 2.0 equiv). After stirring at room temperature for 10 min, coupling agents HOBT (62 mg, 0.45 mmol, 1.5 equiv) and EDCI (88 mg, 0.45 mmol, 1.5 equiv) were added. 15 The reaction was stirred at room temperature for further 23 h, diluted with saturated sodium bicarbonate solution (40 mL) and extracted with EtOAc (2x40 mL). The combined organic layers were washed with water (40 mL), brine (40 mL), dried (MgSO 4 ) and purified on silica gel using 5% methanol in dichloromethane as eluant, affording (R)-1-(3-chloro-2 fluorophenylsulfonyl)-4-((R)-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-7 20 (trifluoromethyl)-1,4-diazepan-5-one. MS: 602.1 (M+H)+. Example 18 Synthesis of (2R,3R)-4,4,4-trifluoro-2-methyl-N-((R)-6-(piperidin-1-ylmethyl)-1,2,3,4-tetra hydronaphthalen-1-yl)-3-(3-(trifluoromethyl)phenylsulfonamido)butanamide 25 H H
F
3 C SN N, 02
CF
3 O NQ Step A: Synthesis of (2R,3R)-ethyl 4,4,4-trifluoro-2-methyl-3-(3-(trifluoromethyl)phenyl sulfonamido)butanoate A solution of (R)-ethyl 4,4,4-trifluoro-3-(3-(trifluoromethyl)phenylsulfon 30 amido)butanoate (760 mg, 1.93 mmol) and lithium chloride (410 mg, 9.65 mmol, 5.0 equiv) in 131 WO 2006/036664 PCT/US2005/033659 THF (15 mL) waIs--oolefio -78 *C and treated with lithium bis(trimethylsilyl)amide (4.85 mL of a 1.OM solution in THIF, 4.85 mmol, 2.5 equiv). Methyl iodide (0.24 mL, 3.86 mmol, 2.0 equiv) was added after 30 min, and the bath was allowed to warm to -35 *C over 4 h. The reaction was quenched with 9:1 THF:water (5 mL), warmed to room temperature, diluted with 5 ethyl acetate (30 mL), washed with saturated ammonium chloride solution (25 mL) and brine (30 mL), dried (MgSO 4 ) and purified on silica gel using 20% ethyl acetate in hexane as eluant, affording (2R,3R)-ethyl 4,4,4-trifluoro-2-methyl-3-(3-(trifluoromethyl)phenysulfonamido) butanoate. MS: 408.2 (M+H)*. Step B: Synthesis of (2R,3R)-4,4,4-trifluoro-2-methyl-3-(3-(trifluoromethyl)phenyl 10 sulfonamido)butanoic acid A solution of (2R,3R)-ethyl 4,4,4-trifluoro-2-methyl-3-(3-(trifluoromethyl)phenyl sulfonamido)butanoate (654 mg, 1.60 mmol) in THF (8 mL) and water (2 mL) was treated with lithium hydroxide monohydrate (340 mg, 8.03 mmol, 5.0 equiv). After being stirred at room temperature for 4 days, the reaction was quenched with Dowex-50 acid ion-exchange 15 resin (till the pH was acidic). The resin was filtered and the filtrate was concentrated and azeotroped with toluene (3xl0 mL) to remove excess water, affording (2R,3R)-4,4,4-trifluoro 2-methyl-3-(3-(trifluoromethyl)phenylsulfonamido)butanoic acid. MS: 380.2 (M+H)+. Step C: (2R,3R)-4,4,4-trifluoro-2-methyl-N-((R)-6-(piperidin-1-ylmethyl)-1,2,3,4 tetrahydronaphthalen-1-yl)-3-(3-(trifluoromethyl)phenylsulfonamido)butanamide. 20 A solution of (2R,3R)-4,4,4-trifluoro-2-methyl-3-(3-(trifluoromethyl)phenyl sulfonamido)butanoic acid (275 mg, 0.72 mmol) in N,N-dimethylformamide (5 mL) was treated with (R)-6-(piperidin- 1 -ylmethyl)- 1,2,3,4-tetrahydronaphthalen- 1-amine (180 mg, 0.72 mmol, 1.0 equiv), the coupling agent TBTU (346 mg, 1.08 mmol, 1.5 equiv) and NN diisopropylethylamine (0.31 mL, 1.80 mmol, 2.0 equiv). The reaction was stirred at room 25 temperature for 15 h, diluted with ethyl acetate (15 mL), washed with saturated sodium bicarbonate solution (15 mL), water (15 mL), brine (15 mL) and dried (MgSO 4 ). The crude mixture was purified on silica gel using 5% methanol in dichloromethane as eluant, affording (2R,3R)-4,4,4-trifluoro-2-methyl-N-((R)-6-(piperidin-1-ylmethyl)-1,2,3,4 tetrahydronaphthalen-1-yl)-3-(3-(trifluoromethyl)phenylsulfonamido)butanamide. MS: 606.3 30 (M+H)*. Example 19 Synthesis of N-((R)-2,2,2-trifluoro- 1 -((R)-2-oxo- 1 -((R)-6-(piperidin- 1 -ylmethyl)- 1,2,3,4 tetrahydronaphthalen- 1 -yl)pyrrolidin-3-yl)ethyl)-3-(trifluoromethyl)benzene-sulfonamide 35 132 WO 2006/036664 PCT/US2005/033659 I H
F
3 C S
CF
3 O N Step A: Synthesis of (R)-ethyl 2-((R)-2,2,2-trifluoro- 1 -(3-(trifluoromethyl)phenyl sulfonamido)ethyl)pent-4-enoate A solution of (R)-ethyl 4
,
4 ,4-trifluoro-3-(3-(trifluoromethyl)phenylsulfonamido) 5 butanoate (3.26 g, 8.29 mmol) and lithium chloride (1.75 mg, 41.47 nimol, 5.0 equiv) in THF (40 mL) was cooled to -78 *C and treated with lithium bis(trimethylsilyl)amide (21.0 mL of a 1.0 M solution in THF, 21.0 mmol, 2.5 equiv). Allyl bromide (1.4 mL, 16.58 mmol, 2.0 equiv) was added after 30 min, and the bath was allowed to warm to 0 'C over 7 h. The reaction was quenched with saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate 10 (75 mL). The organic layer was washed with brine (50 mL), dried (MgSO 4 ) and purified on silica gel using 15% ethyl acetate in hexane as eluant, affording (R)-ethyl 2-((R)-2,2,2 trifluoro-1-(3-(trifluoromethyl)phenylsulfonamido)ethyl)pent-4-enoate. MS: 432.2 (M-H)-. Step B: Synthesis of (2R,3R)-ethyl 4,4, 4 -trifluoro-2-(2-oxoethyl)-3-(3-(trifluoromethyl)phenyl sulfonamido)-butanoate 15 A solution of (R)-ethyl 2-((R)-2,2,2-trifluoro-1-(3-(trifluoromethyl)phenyl sulfonamido)ethyl)pent-4-enoate (1.37 g, 3.16 mmol) in tert-butanol (30 mL): THF (6 mL): water (3 mL) was treated with osmium tetroxide (965 mg of a 2.5 mol % w/w in tert-butanol, 0.09 mmol, 0.03 equiv) and 4-methylmorpholine N-oxide (740 mg, 6.32 mmol, 2.0 equiv). The reaction was stirred at room temperature for 15 h. A solution of a pH 7.2 phosphate buffer 20 (40 mL) was added, followed by sodium periodate (3.4 g, 15.8 mmol, 5.0 equiv). The white suspension was stirred for 2 h, diluted with saturated ammonium chloride solution (50 mL) and extracted with EtOAc (3x75 mL). The combined organic layers were washed with brine (75 mL), dried (MgSO 4 ) and purified on silica gel using 25% ethyl acetate in hexane as eluant, affording (2R,3R)-ethyl 4 ,4,4-trifluoro-2-(2-oxoethyl)-3-(3-(trifluoromethyl)phenyl 25 sulfonamido)butanoate. MS: 434.2 (M-H)~. Step C: Synthesis of N-((R)-2,2,2-trifluoro-1-((R)-2-oxo-1-((R)-6-(piperidin-1-ylmethyl) 1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidin-3-yl)ethyl)-3-(trifluoromethyl)benzene sulfonamide 133 WO 2006/036664 PCT/US2005/033659 A solution of (2R,3R)-ethyl 4,4,4-trifluoro-2-(2-oxoethyl)-3-(3-(trifluoromethyl) phenylsulfon-amido)butanoate (333 mg, 0.76 mmol) in 1,2-dichloroethane (8 mL) was treated with (R)-6-(piperidin- 1 -ylmethyl)- 1,2,3,4-tetrahydronaphthalen- 1-amine (206 mg, 0.84 mmol, 1.11 equiv), sodium triacetoxyborohydride (324 mg, 1.53 mmol, 2.0 equiv) and catalytic 5 glacial acetic acid (5 drops). The reaction was heated at 60 *C for 15 h, diluted with saturated sodium bicarbonate solution (10 mL) and extracted with dichloromethane (3 x 15 mL). The combined organic layers were washed with brine (20 mL) and dried (MgSO 4 ). The crude mixture was purified on silica gel using 5% methanol in dichloromethane as eluant, affording N-((R)-2,2,2-trifluoro-1-((R)-2-oxo-1-((R)-6-(piperidin-1-ylmethyl)-1,2,3,4 10 tetrahydronaphthalen-1-yl)pyrrolidin-3-yl)ethyl)-3-(trifluoromethyl)benzene-sulfonamide. MS: 618.3 (M+H)+. Example 20 Synthesis of (R)-4,4,4-trifluoro-3-(1,1-dioxo-7-methylbenzo[e][1,4,3]oxathiazin-2(3H)-yl)-N 15 ((R)-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)butanamide ~N N<< o oCF 3 O No Step A: Synthesis of (R)-4,4,4-trifluoro-3-(2-methoxy-5-methylphenylsulfonamido)butanoic acid. To a 150-mL round-bottomed flask containing 2-methoxy-5-methylbenzene- 1 -sulfonyl 20 chloride (0.44 g, 2.0 mmol, Trans World Chemicals) was added (R)-ethyl 3-amino-4,4,4 trifluorobutanoate (0.37 g, 2.0 mmol) and pyridine (3 mL). The reaction mixture was stirred at RT for 2 h. Evaporation of the solvents in vacuo gave an oily material, which was taken in THF (3 mL). LiOH.H 2 0 (0.17 g, 4.0 mmol, Aldrich) and water (2 mL) was added and the reaction mixture was stirred at RT for 8 h. The reaction mixture was acidified to pH-5 by 25 adding 2N HCl and the product was extracted with EtOAc, and the organic phase was separated and washed withn 5% brine, dried over Na 2
SO
4 . Filtration and evaporation in vacuo gave title compound (0.47 g, 69%). MS (ESI, pos. ion.) m/z: 342 (M+1). Step B: Synthesis of (R)-4,4,4-trifluoro-N-((R)-6-(hydroxymethyl)-1,2,3,4-tetrahydro naphthalen-1-yl)-3-(2-methoxy-5-methylphenylsulfonamido)butanamide. 134 WO 2006/036664 PCT/US2005/033659 To a 50-mL round-bottomed tlask containing (R)-4,4,4-trifluoro-3-(2-methoxy-5 methylphenylsulfonamido)butanoic acid [0.60 g, 1.8 mmol, Step (a)] in DMF (5 mL), was added (R)-(5-amino-5,6,7,8-tetrahydronaphthalen-2-yl)methanol (0.31 mg, 1.8 mmol), TBTU (1.3 g, 3.5 mmol, Advanced ChemTech), and iPr 2 EtN (1.2 mL, 7.0 mmol, Aldrich). The 5 reaction mixture was stirred at RT for 10 h and then the reaction mixture was quenched with 5% brine (5 mL) then acidified to pH-5 by adding I N HCl. The product was extracted with EtOAc (2x10 mL). The organic phase was washed with 5% brine (2x5 mL), dried over Na 2
SO
4 , filtered, and concentrated. The residue was taken in a solvent mixture of EtOAc:CH 2
C
2 :MeOH (5:5:2) and the product was precipitated. Filtration gave the title 10 compound (0.73 g, 83%) as a pale yellow solid. MS (ESI, pos. ion.) m/z: 501 (M+1). Step C: Synthesis of (R)-N-((R)-6-(bromomethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-4,4, 4 trifluoro-3-(2-hydroxy-5-methylphenylsulfonamido)butanamide To a 100-mL round-bottomed flask containing a suspension of (R)-4,4,4-trifluoro-N ((R)-6-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-methoxy-5 15 methylphenylsulfonamido)butanamide [0.73 g, 1.5 mmol, Step (b)] in CH 2
CI
2 (20 mL), was added BBr 3 (15 mL, 15 mmol, Aldrich) through a syringe at 0 *C under N 2 . The reaction mixture was then stirred at RT for 12 h. The reaction mixture was cooled to 0 'C with an ice bath, and the reaction was quenched slowly with ice water. The product was extracted with
CH
2 Cl 2 (2x8 mL). The organic phase was washed with 5% brine (2x 10 mL) and the product 20 was precipitated. Filtration gave the title compound (0.68 g, 85%) as a white solid. MS (ESI, neg. ion.) m/z: 548 (M-1). Step D: Synthesis of (R)-4,4,4-trifluoro-3-(1,1-dioxo-7-methylbenzo[e][1,4,3]oxathiazin 2(3H)-yl)-N-((R)-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)butanamide To a 100-mL round-bottomed flask containing a solution of (R)-N-((R)-6 25 (bromomethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-4,4,4-trifluoro-3-(2-hydroxy-5 methylphenylsulfonamido)butanamide [0.16 g, 0.47 mmol, Step (c)] and paraformaldehyde (0.18 g, 6.4 mmol, Aldrich) in 1,4-dioxane (10 mL), was bubbled HC1 gas through a tubing for 5 min. The reaction mixture was then stirred at RT for 4 h. The solvent was removed in vacuo and the residue was taken in THF (15 mL) and piperidine (0.25 mL, 2.6 mmol, Aldrich) was 30 added. The reaction mixture was stirred at RT for I h and then diluted with EtOAc (15 mL). The organic phase was washed with 5% brine (2x8 mL), dried over Na 2
SO
4 , filtered, and concentrated. Column chromatography over silica gel with hexane:EtOAc:MeOH (2M, NH 3 ) (10:10:1) gave the title compound (0.12 g, 32%). MS (ESI, pos. ion.) m/z: 566 (M+1). 35 135 WO 2006/036664 PCT/US2005/033659 Example 21 Synthesis of (R)-4,4,4-trifluoro-3-(1,1-dioxo-8-methyl-3,4-dihydrobenzo[b][1,4,5] oxathiazepin-2-yl)- N-((R)-6-(piperidin- 1 -ylmethyl)- 1,2,3,4 tetrahydronaphthalen- 1 -yl)butanamide OC H N N,,. O OCF 3 O 5 N Step A:Synthesis of (R)-4,4,4-trifluoro-3-(2-methoxy-5-methylphenylsulfonamido)butanoic acid. To a 150-mL round-bottomed flask containing 2-methoxy-5-methylbenzene-1-sulfonyl 10 chloride (0.44 g, 2.0 nimol, Trans World Chemicals) was added (R)-ethyl 3-amino-4,4,4 trifluorobutanoate (0.37 G, 2.0 mmol) and pyridine (3 mL). The reaction mixture was stirred at RT for 2 h. Evaporation of the solvents in vacuo gave an oily material, which was taken in THF (3 mL). Then LiOH.H 2 0 (0.17 g, 4.0 mmol, Aldrich) and water (2 mL) was added. The reaction mixture was stirred at RT for 8 h. The reaction mixture was acidified to pH-5 by 15 adding 2 N HCl and the product was extracted with EtOAc, and the organic phase was separated and washed withn 5% brine, dried over Na 2
SO
4 . Filtration and evaporation in vacuo gave title compound (0.47 g, 69%). MS (ESI, pos. ion.) m/z: 342 (M+1). Step B: Synthesis of (R)-4,4,4-trifluoro-N-((R)-6-(hydroxymethyl)-1,2,3,4 tetrahydronaphthalen-1-yl)-3-(2-methoxy-5-methylphenylsulfonamido)butanamide 20 To a 50-mL round-bottomed flask containing (R)-4,4,4-trifluoro-3-(2-methoxy-5 methylphenylsulfonamido)butanoic acid [0.60 g, 1.8 mmol, Step (a)] in DMF (5 mL), was added (R)-(5-amino-5,6,7,8-tetrahydronaphthalen-2-yl)methanol (0.31 mg, 1.8 mmol), TBTU (1.3 g, 3.5 mmol, Advanced ChemTech), and iPr 2 EtN (1.2 mL, 7.0 mmol, Aldrich). The reaction was stirred at RT for 10 h and then quenched with 5% brine (5 mL) and acidified to 25 pH-5 by adding 1 N HCL. The product was extracted with EtOAc (2x10 mL). The organic phase was washed with 5% brine (2x5 mL), dried over Na 2
SO
4 , filtered, and concentrated. The residue was taken in a solvent mixture of EtOAc:CH 2 C1 2 :MeOH (5:5:2) and the product was precipitated. Filtration gave the title compound (0.73 g, 83%) as a pale yellow solid. MS (ESI, pos. ion.) m/z: 501 (M+1). 136 WO 2006/036664 PCT/US2005/033659 Step C: Synthesis ot (R)-N-((R)-6-(bromomethyl)- 1,2,3,4-tetrahydronaphthalen- 1-yl)-4,4,4 trifluoro-3-(2-hydroxy-5-methylphenylsulfonamido)butanamide To a 100-mL round-bottomed flask containing a suspension of (R)-4,4,4-trifluoro-N ((R)-6-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-methoxy-5-methylphenyl 5 sulfonamido)butanamide [0.73 g, 1.5 mmol, Step (b)] in CH 2 Cl 2 (20 mL), was added BBr 3 (15 mL, 15 mmol, Aldrich) through a syringe at 0 *C under N 2 . The reaction mixture was then stirred at RT for 12 h. The reaction mixture was cooled to 0 IC with an ice bath, and the reaction was quenched slowly with ice water. The product was extracted with CH 2 Cl 2 (2x8 mL). The organic phase was washed with 5% brine (2x10 mL) and the product was 10 precipitated. Filtration gave the title compound (0.68 g, 85%) as a white solid. MS (ESI, neg. ion.) m/z: 548 (M-1). Step D: Synthesis of (R)-4,4,4-trifluoro-3-(1,1-dioxo-8-methyl-3,4-dihydrobenzo[b][1,4,5] oxathiazepin-2-yl)- N-((R)-6-(piperidin- 1 -ylmethyl)- 1,2,3,4-tetrahydronaphthalen- 1 yl)butanamide 15 To a 100-mL round-bottomed flask containing a solution of (R)-N-((R)-6 (bromomethyl)- 1,2,3,4-tetrahydronaphthalen- 1 -yl)-4,4,4-trifluoro-3-(2-hydroxy-5 methylphenylsulfonamido)butanamide [0.35 g, 0.64 mmol, step (c)] in DMF (8 mL), was added 1,2-dibromoethane (0.23 mL, 2.7 mmol, Aldrich) and Cs 2
CO
3 (0.83 g, 2.5 mmol, Aldrich). The reaction mixture was then stirred at 55 'C for 3 h. The reaction mixture was 20 diluted with EtOAc (15 mL). The organic phase was washed with 5% brine (2x8 mL), dried over Na 2
SO
4 , filtered, and concentrated. The residue was taken in THF (6 mL) and piperidine (0.25 mL, 2.6 mmol, Aldrich) was added. The reaction mixture was stirred at 55 'C for 3 h then diluted with EtOAc (15 mL). The organic phase was washed with 5% brine (2x8 mL), dried over Na 2
SO
4 , filtered, and concentrated. Column chromatography over silica gel with 25 EtOAc gave the title compound (0.16 g, 43%). MS (ESI, pos. ion.) m/z: 580 (M+1). Example 22 Synthesis of (R)-4,4,4-trifluoro-N-((R)-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen 1-yl)-3-(1,2,3,4-tetrahydroquinoline-8-sulfonamido)butanamide 30 137 WO 2006/036664 PCT/US2005/033659 H H IN N,,. NHe O CF3 O N Step A: Synthesis of (R)-ethyl 4,4,4-trifluoro-3-(quinoline-8-sulfonamido)butanoate To a 150-mL round-bottomed flask containing quinoline-8-sulfonyl chloride (1.5 g, 6.6 mmol, Aldrich), was added (R)-ethyl 3-amino-4,4,4-trifluorobutanoate (1.0 G, 5.5 mmol) and 5 pyridine (3 mL). The reaction mixture was stirred at RT for 2 h. Evaporation of the solvents in vacuo gave an oily material, which was taken in EtOAc (15 mL), and the organic phase was separated and washed with 5% brine, dried over Na 2
SO
4 . Filtration and evaporation in vacuo gave title compound (1.7 g, 82%). MS (ESI, pos. ion.) m/z: 377 (M+1). Step B: Synthesis of (R)-ethyl 4,4,4-trifluoro-3-(1,2,3,4-tetrahydroquinoline-8 10 sulfonamido)butanoate To a 150-mL round-bottomed flask containing (R)-ethyl 4,4,4-trifluoro-3-(quinoline-8 sulfonamido)butanoate [3.3 g, 8.9 mmol, from the above (a)] in EtOAc:EtOH (1:1, 20 mL), was added 10% Pd/C (0.94 G, 0.89 mmol, Aldrich) and AcOH (3 mL) under N 2 . The reaction mixture was purged with H2 and then stirred at RT for 18 h under H2 (H2 balloon) atmosphere. 15 After filtration through Celite, the filtrate was concentrated in vacuo to yield the title compound (3.3 g, 98%). MS (ESI, pos. ion.) m/z: 381 (M+1). Step C: Synthesis of (R)-4,4,4-trifluoro-3-(1,2,3,4-tetrahydroquinoline-8-sulfonamido) butanoic acid. To a 50-mL round-bottomed flask containing (R)-ethyl 4,4,4-trifluoro-3-(1,2,3,4 20 tetrahydroquinoline-8-sulfonamido)butanoate [3.3 g, 8.7 mmol, step (b)] in THF (8 nL), was added LiOH.H 2 0 (1.4 g, 34 mmol, Aldrich) and water (8 mL). The reaction was stirred at 50 *C for 3 h. After acidification to pH 5 with 2 N HCl, the product was extracted with EtOAc (2x50 mL). The organic phase was washed with 5% brine (2x20 mL), dried over Na 2
SO
4 , filtered, and concentrated to yield the title compound (2.8 g, 91%). MS (ESI, pos. ion.) m/z: 25 535 (M+1). Step D: Synthesis of (R)-4,4,4-trifluoro-N-((R)-6-(piperidin-1-ylmethyl)-1,2,3,4 tetrahydronaphthalen-1-yl)-3-(1,2,3,4-tetrahydroquinoline-8-sulfonamido)butanamide. To a 100-mL reaction tube containing R)-4,4,4-trifluoro-3-(1,2,3,4-tetrahydroquinoline 8-sulfonamido)butanoic acid [0.16 g, 0.45 mmol, step (c)] in DMF (5 mL), was added (R)-6 30 (piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-l-amine (0.65 g, 2.7 mmol), TBTU (0.34 138 WO 2006/036664 PCT/US2005/033659 g, 0.90 mmol, Advanced ChemTech), and iPr 2 EtN (0.31 mL, 1.8 mmol, Aldrich). The reaction was stirred at RT for 5 h and then quenched with 5% brine (15 mL). The product was extracted with EtOAc (2x25 mL). The organic phase was washed with 5% brine (2x 10 mL), dried over Na 2
SO
4 , filtered, and concentrated. Purification with column chromatography over 5 silica gel with hexane:EtOAc:MeOH (2M, NH 3 ) (10:10:1) gave the title compound (0.18 g, 69%) as a light yellow solid. MS (ESI, pos. ion.) m/z: 579 (M+1). Example 23 Synthesis of (R)-3-cyano-N-((R)-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-yl) 10 3-(3-(trifluoromethyl)phenylsulfonamido)propanamide NN H H
F
3 C S O CN O No Step A: Synthesis of (R)-4-amino-4-oxo-3-(3-(trifluoromethyl)phenylsulfonamido)butanoic acid 15 To a 150-mL round-bottomed flask containing 3-trifluoromethylbenzenesulfonyl chloride (3.7 g, 15 mmol, Aldrich) in THF (15 mL), was added H-(D)-ASP-NH 2 (2.0 g, 15 mmol, Chemlmpex) and 5% K 2 C0 3 (15 mL). The reaction mixture was stirred at RT for 5 h. The reaction mixture was acidified to pH-5 by adding 2 N HCI, and the product was extracted with EtOAc (25 mL). The organic phase was separated and washed with 5% brine, dried over 20 Na 2
SO
4 . Filtration and evaporation in vacuo gave title compound (3.8 g, 74%). MS (ESI, pos. ion.) m/z: 341 (M+1). Step B: Synthesis of (R)-3-cyano-N-((R)-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydro naphthalen-1-yl)-3-(3-(trifluoromethyl)phenylsulfonamido)propanamide. To a 100-mL round-bottomed flask containing (R)-4-amino-4-oxo-3-(3 25 (trifluoromethyl)phenylsulfonamido)butanoic acid [3.8 g, 11 mmol, step (a)] in DMF (8 mL), was added (R)-6-(piperidin- 1 -ylmethyl)- 1,2,3,4-tetrahydronaphthalen- 1 -amine dihydrochloride (3.9 g, 12 mmol), TBTU (3.6 g, 11 mmol, Advanced ChemTech), and iPr 2 EtN (4.3 g, 34 mmol, Aldrich). The reaction mixture was stirred at RT for 5 h and then quenched with 5% brine (15 mL). The product was extracted with EtOAc (2x25 mL). The organic phase was 30 washed with 5% brine (2x 10 mL), dried over Na 2
SO
4 , filtered, and concentrated. Purification 139 WO 2006/036664 PCT/US2005/033659 with column chromatography over silica gel with hexane:EtOAc:MeOH (2M, NH 3 ) (10:10:1) gave the title compound (3.3 g, 54%). MS (ESI, pos. ion.) m/z: 549 (M+1). Example 24 5 Synthesis of (R)-N-((S)-6-(4,5-dihydro-1H-imidazol-2-yl)-1,2,3,4-tetrahydro-naphthalen-2-yl) 4,4,4-trifluoro-3-(3-(trifluoromethyl)phenylsulfonamido)butanamide IH H
F
3 Cii N N 0
OCF
3 0 HN Step A: Synthesis of (S)-N-(6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)-2,2,2-trifluoro 10 acetamide To a solution of (S)-6-bromo-1,2,3,4-tetrahydronaphthalen-2-amine hydrochloride (2.62 g, 10 mmol) in DCM (30 mL) was added trifluoroacetic anhydride (1.554 mL, 11 mmol) followed by triethylamine (4.13 mL, 30 mL). After stirring at RT overnight, the reaction solution was washed with water, dried over Na 2
SO
4 and filtered through silica gel pad with 15 DCM to give the title compound (3.24 g, 100%) as a white solid. Step B: Synthesis of (S)-N-(6-cyano-1,2,3,4-tetrahydronaphthalen-2-yl)-2,2,2 trifluoroacetamide A mixture of (S)-N-(6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)-2,2,2 trifluoroacetamide (0.969 g, 3 mmol), NiBr2 (655 mg, 3 mmol) and NaCN (294 mg, 6 mmol) 20 in 3 mL of NMP was heated at 200 C in microwave for 30 min. After cooling to RT, the reaction mixture was filtered with the help of excess of DCM. The filtrate was evaporated and was submitted to flash chromatography (Si02, DCM to DCM/EtOAc = 4:1) to afford the title compound (0.39 g) as a white solid and 0.45 g of recovered starting material. Step C: Synthesis of (S)-6-amino-5,6,7,8-tetrahydronaphthalene-2-carbonitrile 25 To a solution of (S)-N-(6-cyano-1,2,3,4-tetrahydronaphthalen-2-yl)-2,2,2 trifluoroacetamide (700 mg, 2.61 mmol) in a mixture of solvents THF/MeOH/H20 = 8 mL/20 mL/4 mL was added NaOH (209 mg, 5.22 mmol). After stirring at RT for 12 h, the solvent was evaporated and the residue was submitted to flash chromatograph (Si0 2 , EtOAc to EtOAc/2 M NH 3 in MeOH = 100:10 to 100:20 to 100:30) to give the title compound (320 mg) 30 as a white solid. 140 WO 2006/036664 PCT/US2005/033659 Step D: Synthesis of (R)-N-((S)-6-cyano-1,2,3,4-tetrahydronaphthalen-2-yl)-4,4,4-trifluoro-3 (3-(trifluoromethyl)phenylsulfonamido)butanamide A solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (70 mg, 0.364 mmol), 1-hydroxybenzotriazole (49 mg, 0.364 mmol), (R)-4,4,4-trifluoro-3-(3 5 (trifluoromethyl)phenylsulfonamido)butanoic acid (132.5 mg, 0.363 mmol) and (S)-6-amino 5,6,7,8-tetrahydronaphthalene-2-carbonitrile (75 mg, 0.436 mmol) in 1.0 mL of DMF was stirred overnight. The reaction was quenched with Sat. NaHCO 3 , extracted with EtOAc/hexane = 3:1, washed with brine, dried over Na 2
SO
4 , and evaporated. Column chromatography (SiO2, EtOAc/hexane = 1:2 to 2:3 to 1:1) gave the title compound (120 mg) 10 as a white solid. Step E: Synthesis of (R)-N-((S)-6-(4,5-dihydro- 1 H-imidazol-2-yl)-1,2,3,4-tetrahydro naphthalen-2-yl)-4,4,4-trifluoro-3-(3-(trifluoromethyl)phenylsulfonamido)butanamide (R)-N-((S)-6-cyano-1,2,3,4-tetrahydronaphthalen-2-yl)-4,4,4-trifluoro-3-(3 (trifluoromethyl)phenylsulfonamido)butanamide (90 mg) was azeotroped with benzene and 15 was dissolved in 10 mL of anhydrous EtOH. To this solution dry HCl was bubbled through for 90 min at 0 0 C. The solvent was evaporated to dryness under high vaccum to give a yellow solid. This yellow solid was dissolved in 10 mL of dry EtOH. Ethylene diamine (0.4 mL) was added and the resulting solution was stirred at RT overnight. The solvent was evaporated to dryness under high vacuum. Flash chromatography (Si0 2 , EtOAc/2M NH 3 in MeOH = 100:15 20 to 100:30) afforded the title compound (100 mg) as a white solid. Example 25 Synthesis of (R)-(N)-((R)-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-4,4,4 trifluoro-3-[1,1-dioxo-8-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepin-1-yl] 25 butanamide
F
3 C
F
3 C N,,, 0 NQ Step A: Synthesis of (R)-ethyl 3-(2-bromo-5-(trifluoromethyl)phenylsulfonamido)-4,4,4 trifluorobutanoate 141 WO 2006/036664 PCT/US2005/033659 i L a sounon o kK,-emfy )-amino-4,4,4-trifluorobutanoate (3.25 g, 13 mol) in pyridine (2 mL) was added 2-bromo-5-(trifluoromethyl)benzene- 1 -sulfonyl chloride (3.72 mL) dropwise. The resulting solution was then stirred at room temperature for 16 h, and then poured into ethyl acetate (50 ml)-ice water mixture. The layers are separated, the aqueous 5 layer is extracted with ethyl acetate (3 x 50 mL) and the combined organic layers are washed with water (3x50 ml) and dried over sodium sulfate. The crude product was purified by silica gel chromatograph to give (R)-ethyl 3-( 2 -bromo-5-(trifluoromethyl)phenylsulfonamido)-4,4,4 trifluorobutanoate (5.7 g) as oil product. LC-MS: m/z 473.9 (M+H)+. Step B: Synthesis of (R)-ethyl 4,4,4-trifluoro-3-(2-(3-hydroxyprop-1-ynyl)-5-(trifluoromethyl) 10 phenylsulfonamido)butanoate To a solution of (R)-ethyl 3-(2-bromo-5- (trifluoromethyl) phenylsulfonamido)-4,4,4 trifluorobutanoate (100 mg,) in toluene (2 mL) was added copper (I) iodide (20 mg), tetrakis (triphenylphosphine) palladium(0) (20 mg), and propargyl alcohol (0.1 mL). The reaction mixture was heated in microwave at 80 'C for 90 min. The reaction mixture was cooled to 15 room temperature and then filtered through celite. The crude product was purified by silica gel chromatograph to give (R)-ethyl 4,4,4-trifluoro-3-(2-(3-hydroxyprop-1-ynyl)-5 (trifluoromethyl)phenylsulfonamido)butanoate (50 mg) as oil product. LC-MS: m/z 465.0
(M+H
2 O)+ Step C: Synthesis of (R)-ethyl 4, 4 ,4-trifluoro-3-(2-(3-hydroxypropyl)-5-(trifluoromethyl) 20 phenylsulfonamido)butanoate To a solution of (R)-ethyl 4,4,4-trifluoro-3-(2-(3-hydroxyprop-1-ynyl)-5 (trifluoromethyl)phenylsulfonamido)butanoate (200 mg) in Ethanol (20 mL) was added palladium (10 wt. % on carbon, 50 mg). The reaction solution was stirred under hydrogen balloon for 2 days. It was filtered through celite and concentrated under vacuum to give (R) 25 ethyl 4 ,4, 4 -trifluoro-3-(2-(3-hydroxypropyl)-5-(trifluoromethyl)phenylsulfonamido)butanoate (80 mg,) as oil product. LC-MS: m/z 469.1 (M+H)+. Step D: Synthesis of (R)-ethyl-4,4,4-trifluoro-3-[1,1-dioxo-8-(trifluoromethyl)-2,3,4,5 tetrahydrobenzo[f][1,2]thiazepin-1-yl]butanoate To a solution of (R)-ethyl 4,4,4-trifluoro-3-(2-(3-hydroxypropyl)-5-(trifluoromethyl) 30 phenylsulfonamido)butanoate (100 mg, 0.2 mol) in THF (50 mL) was added diisopropyl azodicarboxylate (60 mg, 0.3 mol) and triphenyl phosphine (75 mg, 0.3 mole) at room temperature. The reaction mixture was stirred at room temperature for 24 hours. Ethyl acetate was added to the reaction mixture and filtered through Celite. The crude product was purified 142 WO 2006/036664 PCT/US2005/033659 Dy silica gel preparation [LU pate to give (R)-ethyl-4,4,4-trifluoro-3-[ 1,1 -dioxo-8 (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepin-1-yl]butanoate (80 mg) as an oil. LC-MS: m/z 434 (M+H)+; 451 (M+18)+. Step E: Synthesis of (R)-4,4,4-trifluoro-3-[1,1-dioxo-8-(trifluoromethyl)-2,3,4,5 5 tetrahydrobenzo[f][1,2]thiazepin-1-yl]butanoic acid To a solution (R)-ethyl-4,4,4-trifluoro-3-[1,1-dioxo-8-(trifluoromethyl)-2,3,4,5 tetrahydrobenzo[f][1,2]thiazepin-1-yl]butanoate (80 mg, 185 pmol) in dioxane (2 mL), and water (2 mL) was added hydrochloride solution (1 mL, 10%). The reaction mixture was heated in 80 *C oil bath for 1 h. The reaction mixture was cooled to room temperature, diluted 10 with ethylacetate (10 ml), and then extracted with Na 2
CO
3 solution (10%, 10 mlx2). The basic aqueous layer was acidified with hydrochloride (10%) to pH = 4. It was extracted with methylene chloride (15 mLx3), dried with Na 2
SO
4 and concentrated on vacuum to give the title compound as an oil (12 mg, yield: 10%). LC-MS: m/z 403.9 (M-H)+ Step F: Synthesis of (R)-(N)-((R)-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-yl) 15 4,4,4-trifluoro-3-[1,1-dioxo-8-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[fj[1,2]thiazepin-1 yl]butanamide To a solution of (R)-4,4,4-trifluoro-3-[1,1-dioxo-8-(trifluoromethyl)-2,3,4,5 tetrahydrobenzo[fj[1,2]thiazepin-1-yl]butanoic acid (12 mg) in DMF (2mL) was added TBTU (80 mg), (R)-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1 -amine (15 mg) and 20 DIEA (0.2 mL) at room temperature. The reaction mixture was stirred at room temperature for 45 min. The reaction mixture was diluted with EtAc (15 mL) and extracted with Na 2
CO
3 solution (10%, 10 mLx2). The organic layer was dried with Na 2
SO
4 and concentrated on vacuum. The residue was purified by prep-TLC using 5% MeOH (NH3)-CH 2 Cl 2 to give the title compound (12 mg, yield 63%). LC-MS: m/z 632.2 (M+H)+ 25 Example 26 Synthesis of (R)-4,4,4-trifluoro-N-methyl-N-((R)-7-(piperidin- 1 -ylmethyl)chroman-4-yl) 3-(3-(trifluoromethyl)phenylsulfonamido)butanamide 143 WO 2006/036664 PCT/US2005/033659 FF F F F NC Step A: Synthesis of (R)-tert-butyl 7-(hydroxymethyl)chroman-4-ylcarbamate To (R)-(4-aminochroman-7-yl)methanol (10 g) was added ethyl acetate (30 mL), DCM (30 mL), methanol (30 mL), and TEA(30 mL). Di-t-butyldicarbonate (18 g, 280 mmol) was 5 slowly added and the mix was stirred under nitrogen overnight. The reaction mixture was then concentrated, dissolved in ethyl acetate (300 mL), and washed with saturated sodium carbonate (50 mL) twice. The ethyl acetate layer was then dried with sodium sulfate and concentrated to give the title compound (14 g). Step B: Synthesis of (R)-4-aminochroman-7-carbaldehyde. 10 In DCM (200 mL), (R)-tert-butyl 7-(hydroxymethyl)chroman-4-ylcarbamate (5 g) and manganese oxide (7.5 g) were combined and the reaction mixture was stirred under nitrogen overnight. The solution was then filtered through celite and the pad was washed with methanol. The filtrate was then concentrated to give the title compound (4.65 g) which was used in the next step without further purification. 15 Step C: Synthesis of (R)-tert-butyl 7-(piperidin-1-ylmethyl)chroman-4-ylcarbamate In 1,2-dichloroethane (100 mL), ((R)-4-aminochroman-7-carbaldehyde (4.65 g) and piperidine (2.8 g) were combined. Sodium triacetoxy borohydride (6.9 g) was added and the reaction mixture was stirred under nitrogen overnight. The reaction mixture was then dissolved in ethyl acetate, washed with saturated sodium bicarbonate, brine, dried with sodium 20 sulfate and concentrated. The crude product was then purified on silica using 0 to 20% MeOH (2 M ammonia) in DCM to give the title compound (4.6 g). Step D: Synthesis of (R)-7-(piperidin-1-ylmethyl)chroman-4-amine In dry toluene (200 mL), (R)-tert-butyl 7-(piperidin-1-ylmethyl)chroman-4-ylcarbamate (4.6 g) and lithium aluminum hydride (1.5 g , 41 mmol) were combined and gently refluxed for 25 24 h. The reaction mixture was quenched with 5 g of sodium sulfate decahydrate and allowed to stir for 2 h. The reaction mixture was then filtered over celite and the pad was washed with ethyl acetate several times. The filtrate was then concentrated and the crude was purified on silica using 0 to 20% MeOH (2 M ammonia) in ethyl acetate to give the title compound (1.7 g). MS (ESI, pos. ion) m/z 261.7 144 WO 2006/036664 PCT/US2005/033659 Step E: Synthesis of (R)-4,4,4-trifluoro-N-methyl-N-((R)-7-(piperidin-1-ylmethyl)chroman-4 yl)-3-(3-(trifluoromethyl)phenylsulfonamido)butanamide In dry DMF (2 mL), (R)-4,4,4-trifluoro-3-(3-(trifluoromethyl)phenyl-sulfonamido) butanoic acid (0.50 mmol) and PyClU (0.60 mmol) are combined.. (R)-7-(piperidin-1 5 ylmethyl)chroman-4-amine (0.57 mmol), and DIEA (1.71 mmol) were added and the reaction mixture was stirred at room temperature under nitrogen for 1 h. The reaction mixture was quenched with 20 mL saturated sodium bicarbonate, then extracted with EtOAc (2 x 30 ml), washed with brine (1 x 20 ml), dried with sodium sulfate, and concentrated. Purification by chromatography over silica gel with 20 to 60% EtOAc in hexane gave the title compound. MS 10 (ESI, pos. ion) m/z 608.2 Example 27 Synthesis of (R)-3-(3-chloro-2-fluoro-N-methylphenylsulfonamido)-4,4,4-trifluoro-N methyl-N-((R)-7-(piperidin-1-ylmethyl)chroman-4-yl)butanamide 15 F o~, N N,, 0 0 F F NQ Step A: Synthesis of (R)-tert-butyl 7-(hydroxymethyl)chroman-4-ylcarbamate To (R)-(4-aminochroman-7-yl)methanol (10 g) was added ethyl acetate (30 mL), DCM 20 (30 mL), methanol (30 mL), and TEA(30 mL). Di-t-butyldicarbonate (18 g, 280 mmol) was slowly added and the mix was stirred under nitrogen overnight. The reaction mixture was then concentrated, dissolved in 300 mL of ethyl acetate, and washed with 50 mL of saturated sodium carbonate twice. The ethyl acetate layer was then dried with sodium sulfate and concentrated to give the title compound (14 g). 25 Step B: Synthesis of (R)-4-aminochroman-7-carbaldehyde In DCM (200 mL), (R)-tert-butyl 7-(hydroxymethyl)chroman-4-ylcarbamate (5 g) and manganese oxide (7.5 g) were combined and the mix was stirred under nitrogen overnight. The solution was then filtered through celite and the pad was washed with methanol. The filtrate was then concentrated to give the title compound (4.65 g). 145 WO 2006/036664 PCT/US2005/033659 Step C: Synthesis of (R)-tert-butyl 7-(piperidin-1-ylmethyl)chroman-4-ylcarbamate In 1,2-dichloroethane (100 mL), ((R)-4-aminochroman-7-carbaldehyde (4.65) and piperidine (2.8 g) were combined. Sodium triacetoxy borohydride (6.9 g) was added and the reaction mixture was stirred under nitrogen overnight. The reaction mixture was then dissolved 5 in 100 mL of ethyl acetate, washed with saturated sodium bicarbonate, brine, dried with sodium sulfate and concentrated. The crude was then purified on silica using 0 to 20% MeOH (2 M ammonia) in DCM to give the title compound (4.6 g). Step D: Synthesis of (R)-7-(piperidin- 1 -ylmethyl)chroman-4-amine In dry toluene (200 mL), (R)-tert-butyl 7-(piperidin-1-ylmethyl)chroman-4-ylcarbamate 10 (4.6 g) and lithium aluminum hydride (1.5 g, 41 mmol) were combined and gently refluxed for 24 h. The reaction mixture was quenched with sodium sulfate decahydrate (5 g) and allowed to stir for 2 h. The reaction mixture was then filtered over celite and the pad was washed with ethyl acetate several times. The filtrate was then concentrated and the crude was purified on silica using 0 to 20% MeOH (2 M ammonia) in ethyl acetate to give the title compound (1.7 g). 15 MS (ESI, pos. ion) m/z 261.7 Step E: Synthesis of (R)-3-(3-chloro-2-fluoro-N-methylphenylsulfonamido)-4,4,4-trifluoro-N methyl-N-((R)-7-(piperidin-1-ylmethyl)chroman-4-yl)butanamide In dry DMF (2 mL), (R)-3-(3-chloro-2-fluoro-N-methylphenylsulfonamido)-4,4,4 trifluorobutanoic acid (0.5 mmol) and PyClU (0.6 mmol) were combined. (R)-7-(Piperidin-1 20 ylmethyl)chroman-4-amine (0.57 mmol), and DIEA (1.71 mmol) were added and the reaction mixture was stirred at room temperature under nitrogen for 1 h. The reaction mixture was quenched with saturated sodium bicarbonate, then extracted with EtOAc (2 x 30 ml), washed with brine (1 x 20 ml), dried with sodium sulfate, and concentrated. Purification by chromatography over silica gel with 20 to 60% EtOAc in hexane gave the title compound. MS 25 (ESI, pos. ion) m/z 606.1 Biological Testing Although the pharmacological properties of the compounds of Formula (I) vary with structural change, in general, activity possessed by compounds of Formula (I) may be 30 demonstrated in vivo. The pharmacological properties of the compounds of this invention may be confirmed by a number of pharmacological in vitro assays. The exemplified pharmacological assays, which follow, have been carried out with the compounds according to the invention and their salts. Compounds of the present invention showed binding IC 50 's of B 1 at doses less than 20 pM. 146 WO 2006/036664 PCT/US2005/033659 Human Bradykinin B 1 Receptor and human B2 Receptor In Vitro Binding Assays Example 1 Radioligand Binding Assay for human B 1 and human B2 bradykinin receptor 5 Step 1 Preparation of membranes expressing human B I bradykinin receptor: Membranes were prepared from CHO-dAQN cells stably transfected with human bradykinin B 1 receptor cDNA. For large-scale production of membranes, cells were grown in I OOL suspension culture to 1.0E8 cells/mL then harvested using the Viafuge at continuous centrifugation of 1 000g. For pilot studies, cells were grown in 2 L spinner culture and 10 harvested by centrifugation (1900 g, 10 min, 4 *C). The cell pellet was washed with PBS, centrifuged (1900 g, 10 min, 4 C), then the cells resuspended in lysis buffer (25 mM HEPES, pH 7.4, 5 mM EDTA, 5 mM EGTA, 3 mM MgCl 2 , 10% (w/v) sucrose, Complete Protease Inhibitor tablets (EDTA-free)) to a density of 14% w/v for passage through a microfluidizer (Microfluidics 110S, 3 passes, 6,000 psi). The resulting cell lysate was centrifuged (19 0 0g, 10 15 min, 4 *C), and the crude particulate fraction isolated by centrifugation (1 42 ,000g, I h, 4 'C) of the low-speed supernatant. The resulting pellet was resuspended in 1/3 the original lysis buffer volume, homogenized, and recentrifuged as above. The membrane pellet was resuspended by homogenization in storage buffer (25 mM HEPES, pH 7.4, 3 mM MgCl 2 , 10% (w/v) sucrose and Complete Protease Inhibitor tablets (EDTA-free)). Single-use aliquots were made and 20 flash-frozen in liquid N 2 prior to storage at -80 *C. Membranes containing human bradykinin B2 receptor were purchased from Receptor Biology (now Perkin Elmer Life Sciences). They were derived from a CHO-KI line stably expressing the human B2 receptor developed by Receptor Biology and subsequently purchased by Amgen. For some studies, membranes were prepared in-house from this same cell line 25 using the method described for human B 1 receptor membranes, except cells were grown in roller bottles and harvested using Cellmate. Step 2 Human B I receptor binding assay was performed in 96-well polypropylene plates (Costar 3365) by adding 50 p1l [ 3 H) des-arg 10 kallidin (NET1064; Perkin Elmer Life Sciences) to 10 pL test compound diluted in 90 ptL assay buffer (24 mM TES, pH 6.8, 1 mM 1,10 o 30 phenanthroline, 0.3% BSA, 0.5 mM Pefabloc SC, 2 pg/mL aprotinin, 5 Ig/mL leupeptin, and 0.7 ptg/mL pepstatin A). Membranes (50 ptL) were added last. [ 3 H] des-arg 0 kallidin was diluted from stock into assay buffer to yield a final concentration of -0.3nM in the assay but was adjusted as needed to ensure a concentration at or below the Kd determined for each batch of receptor membranes. Nonspecific binding was defined with 2 pM des-Arg' 0 Leu 9 kallidin. 147 WO 2006/036664 PCT/US2005/033659 Membranes were diluted in assay buffer to yield a final concentration of 0.068 nM hB 1 receptor in the assay. Compounds were solubilized in either DMSO or ddH 2 0, plated into polypropylene plates (Costar 3365), then serially diluted in either DMSO or dilution buffer (20 mM Hepes, pH 7.6, 0.1% BSA) to yield a final concentration of either 5% DMSO or no 5 DMSO in the assay. The assay mixture was incubated with shaking for 1 h at RT and then filtered through GF/C plates presoaked in 0.5% polyethyleneimine (Unifilter; Perkin Elmer Life Sciences) using a Filtermate 96-well harvester (Perkin Elmer Life Sciences). Filter plates were rapidly washed 6 times with 200 tL ice-cold buffer (50mM Tris, pH 7.4), dried in a vacuum oven at 55 *C for 15-20 min, backed, and 40 pL per well of Microscint 20 was added. 10 The plates were sealed and activity read on Topcount (Perkin Elmer Life Sciences) using a count time of 3 min per channel. For human B2 bradykinin receptor, the same procedure was followed with the following exceptions: [ 3 H] bradykinin (NET706; Perkin Elmer Life Sciences) was used at a final concentration of -0.2 nM and non-specific binding was defined with 2 1 iM bradykinin. 15 Human B2 receptor concentration was 0.068 nM final in the assay. Data analysis Data was analyzed in XLFit with the four-parameter logistic y = A + ((B A)/(1+((C/x)AD))) and fit with the Levenburg-Marquardt algorithm. Raw cpm were converted to percent of control values prior to analysis (POC = ((compound cpm - nonspecfic cpm) / (no 20 compound cpm - nonspecific cpm)*100)). Ki values were determined from the IC 50 using the Cheng-Prusoff equation and Kd values determined by direct saturation binding of the radioligands. Example 2 In vitro B 1-Inhibition Activity 25 In vitro Assay of human B 1 Receptor Function using Calcium Flux Activation of the Gq linked B 1 receptor results in an increase in intracellular calcium. The calcium sensitive photoprotein aequorin can, therefore, be used as an indicator of B 1 receptor activation. Aequorin is a 21 -kDa photoprotein that forms a bioluminescent complex when linked to the chromophore cofactor coelenterazine. Following the binding of calcium to 30 this complex, an oxidation reaction of coelenterazine results in the production of apoaequorin, coelenteramide, CO 2 , and light that can be detected by conventional luminometry. A stable CHO D-/hB 1 /Aequorin cell line was established and the cells were maintained in suspension in spinner bottles containing a 1:1 ratio of DMEM and HAM F12 (Gibco 11765 047), high glucose (Gibco 11965-084), 10% Heat Inactivated Dialyzed serum (Gibco 26300 148 WO 2006/036664 PCT/US2005/033659 U61), IA Non-Essential Amino Acids (Gibco 11140-050), IX Glutamine-Pen-Strep (Gibco 10378-016), and Hygromycin, 300 pg/mL (Roche 843555). 15-24 h prior to the luminometer assay, 25,000 cells/well (2.5E6 cells/10 mL/plate) were plated in 96-well black-sided clear bottom assay plates (Costar #3904). 5 Media was removed from the wells and replaced with 60 gL of serum free HAM's F 12 with 30 mM HEPES (pH 7.5) and 15gM coelenterazine (Coelenterazine h Luciferin #90608 from Assay Designs). The plates were incubated for 1.5-2 h. Ten point IC 50 compound plates containing 1:3 or 1:5 dilutions of antagonist compounds and an agonist activator plate (20nM des-ArgO-Kallidin final concentration, ECso) were prepared using Ham's F12 with 30mM 10 HEPES, pH 7.5. Following coelenterazine incubation, an automated flash-luminometer platform was used to dispense the B 1 antagonist compounds (dissolved in DMSO and diluted with buffer to the desired concentration (final DMSO concentration <1% DMSO)) to the cell plate, a CCD camera situated underneath the cell plate took 12 images of the cell plate at 5 second intervals to determine if there was any agonist activity with the compounds. The hB 1 15 agonist, des-Argio-Kallidin, was added to the cell plate and another 12 images were recorded to determine the ICso of the antagonist(s). In vitro Assay of hB2 Receptor Function using Calcium Flux The intracellular calcium flux induced by hB2 receptor activation was analyzed using an hB2 recombinant cell line (CHO-KI) purchased from PerkinElmer (Catalog Number: 20 RBHB2COOOEA) on a fluorometric imaging plate reader (FLIPR). The cells were cultured in T225 flask containing Ham's F12 Nutrient Mixture (Invitrogen Corp., Cat # 11765-047), 10% Fetal Clone II Bovine Serum (HyClone, Cat # SH3006603), 1 mM Sodium pyruvate (100 mM stock, Invitrogen Corp., Cat# 12454-013), and 0.4 mg/mL Geneticin (G418; 50 mg/mL active geneticin, Invitrogen, Cat# 10131-207). Culture medium was changed every other day. 24 h 25 prior to the FLIPR assay, the hB2/CHO cells were washed once with PBS (Invitrogen) and 10 mL of Versene (1:5000, Invitrogen, Cat# 15040-066) was added to each flask. After 5 min incubation at 37 'C, Versene was removed and cells were detached from the flask and resuspended in culture medium. Cells were counted and 25,000 cells/well were plated in 96 well black-sided clear bottom assay plates (Costar #3904). Cells were incubated in a 37 'C 30 CO 2 incubator overnight. The media was aspirated from the cells and replaced with 65 RL of dye-loading buffer. The loading buffer was prepared by diluting a stock solution of 0.5mM Fluo-4 AM (Molecular Probes, dissolved in DMSO containing 10% [w/v] pluronic acid) to a concentration of IpM in Clear Dulbecco's Modified Eagle Medium (DMEM) containing 0.1% BSA, 20 mM HEPES, 149 WO 2006/036664 PCT/US2005/033659 and 2.5 mM probenecid. The cells were dye-loaded for 1 h at RT. The excess dye was removed by washing the cells 2x with assay buffer. The assay buffer consists of Hank's Balanced Salt Solution (HBSS) containing 20 mM HEPES, 0.1% BSA, and 2.5 mM probenecid. After the wash cycles, a volume of 100 pL was left in each well, and the plate was 5 ready to be assayed in the FLIPR System. Single point (10 pM final concentration) POC antagonist compound plates or ten point IC 50 compound plates containing 1:3 or 1:5 dilutions of antagonist compounds (dissolved in DMSO and diluted with buffer to the desired concentration (final DMSO concentration <1% DMSO)) and an agonist activator plate (0.3 nM bradykinin final concentration, ECso) were prepared using assay buffer. The cell plate and the 10 compound plates were loaded onto the FLIPR and during the assay, fluorescence readings are taken simultaneously from all 96 wells of the cell plate. Ten 1-second readings were taken to establish a stable baseline for each well, then 25 pL from the B1 antagonist plate was rapidly (50 pL/sec.) added. The fluorescence signal was measured in 1-second (1 min) followed by 6 second (2 min) intervals for a total of 3 min to determine if there is any agonist activity with 15 the compounds. The B2 agonist, bradykinin, was added to the cell plate and another 3 min were recorded to determine the percent inhibition at 10 pM (POC plates) or the IC 50 of the antagonist. Example 3 Cell and Tissue based In Vitro Assays of hB 1 Receptor Binding 20 These studies established the antagonist activity of several compounds at the bradykinin B 1 receptors in in vitro cell-based and isolated organ assays. 1. Rabbit endothelial cell B 1-specific PGI 2 secretion Assay 2. BI and B2 umblical vein Assay In vitro B 1 -Inhibition Activity: 25 The effectiveness of the compounds as inhibitors of B 1 activity (i.e., B 1 "neutralization") can be evaluated by measuring the ability of each compound to block B 1 stimulated CGRP and substance P release and calcium signaling in Dorsal Root Ganglion (DRG) neuronal cultures. Dorsal Root Ganglion Neuronal Cultures: 30 Dorsal root ganglia are dissected one by one under aseptic conditions from all spinal segments of embryonic 19-day old (E19) rats that are surgically removed from the uterus of timed-pregnant, terminally anesthetized Sprague-Dawley rats (Charles River, Wilmington, MA). DRG are collected in ice-cold L-15 media (GibcoBRL, Grand Island, NY) containing 5% heat inactivated horse serum (GibcoBRL), and any loose connective tissue and blood 150 WO 2006/036664 PCT/US2005/033659 vessels are removed. The DRG are rinsed twice in Ca 2 '- and Mg 2 +-free Dulbecco's phosphate buffered saline (DPBS), pH 7.4 (GibcoBRL). The DRG are dissociated into single cell suspension using a papain dissociation system (Worthington Biochemical Corp., Freehold, NJ). Briefly, DRG are incubated in a digestion solution containing 20 U/mL of papain in Earle's 5 . Balanced Salt Solution (EBSS) at 37 *C for fifty minutes. Cells are dissociated by trituration through fire-polished Pasteur pipettes in a dissociation medium consisting of MEM/Ham's F12, 1:1, 1 mg/mL ovomucoid inhibitor and 1 mg/mL ovalbumin, and 0.005% deoxyribonuclease I (DNase). The dissociated cells are pelleted at 200 x g for 5 min and re suspended in EBSS containing I mg/mL ovomucoid inhibitor, 1 mg/mL ovalbumin and 10 0.005% DNase. Cell suspension is 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, then filtered through a 88- M nylon mesh (Fisher Scientific, Pittsburgh, PA) to remove any clumps. Cell number is determined with a hemocytometer, and cells are seeded into poly ornithine 100 pg/mL (Sigma, St. Louis, MO) and mouse laminin 1 pg/mL (GibcoBRL)-coated 15 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), streptomycin (100 Rg/mL), and 10% heat inactivated horse serum (GibcoBRL). The cultures are kept at 37 *C, 5% CO 2 and 100% humidity. For controlling the growth of non-neuronal cells, 5-fluoro 2'-deoxyuridine (75 jM) and uridine (180pgM) are included in the medium. 20 Two hours after plating, cells are treated with recombinant human p-b 1 or recombinant rat P-bl at a concentration of 10 mg/ml (0.38 nm). Positive controls comprising serial-diluted anti-b 1 antibody (r&d systems, minneapolis, mn) are applied to each culture plate. Compounds are added at ten concentrations using 3.16-fold serial dilutions. All samples are diluted in complete medium before being added to the cultures. Incubation time is generally 25 around 40 h prior to measurement of vrl expression. Measurement of VRI Expression in DRG Neurons: Cultures are fixed with 4% paraformaldehyde in Hanks' balanced salt solution for 15 min, blocked with Superblock (Pierce, Rockford, IL), and permeabilized with 0.25% Nonidet P-40 (Sigma) in Tris.HCl (Sigma)-buffered saline (TBS) for 1 h at RT. Cultures are rinsed 30 once with TBS containing 0.1% Tween 20 (Sigma) and incubated with rabbit anti-VR1 IgG (prepared at Amgen) for 1.5 h at RT, followed by incubation of Eu-labeled anti-rabbit second antibody (Wallac Oy, Turku, Finland) for 1 h at RT. Washes with TBS (3 x five min with slow shaking) are applied after each antibody incubation. Enhance solution (150 mL/well, Wallac Oy) is added to the cultures. The fluorescence signal is measured in a time-resolved 151 WO 2006/036664 PCT/US2005/033659 nuorometer w auac uy). v K i expression in samples treated with the compounds is determined by comparing to a standard curve of B I titration from 0-1000 ng/mL. Percent inhibition (compared to maximum possible inhibition) of B I effect on VR1 expression in DRG neurons is determined by comparing to controls that are not B 1-treated. 5 Example 4 In vivo antinociceptive activity in rat and monkey pain models Rat Neuropathic Pain Model Male Sprague-Dawley rats (200 g) are anesthetized with isoflurane inhalant anesthesia 10 and the left lumbar spinal nerves at the level of L5 and L6 are tightly ligated (4-0 silk suture) distal to the dorsal root ganglion and prior to entrance into the sciatic nerve, as first described by Kim and Chung (Kim, S.H.; Chung, J.M. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 50:355-363, (1992)). The incisions are closed and the rats are allowed to recover. This procedure results in mechanical 15 (tactile) allodynia in the left hind paw as assessed by recording the pressure at which the affected paw (ipsilateral to the site of nerve injury) was withdrawn from graded stimuli (von Frey filaments ranging from 4.0 to 148.1 mN) applied perpendicularly to the plantar surface of the paw (between the footpads) through wire-mesh observation cages. A paw withdrawal threshold (PWT) was determined by sequentially increasing and decreasing the stimulus 20 strength and analyzing withdrawal data using a Dixon non-parametric test, as described by Chaplan et al. (Chaplan, S.R.; Bach, F.W.; Pogrel, J.W.; Chung, J.M.; Yaksh, T.L. Quantitative assessment of tactile allodynia in the rat paw. J. Neurosci. Meth., 53:55-63 (1994)). Normal rats and sham surgery rats (nerves isolated but not ligated) withstand at least 148.1 mN (equivalent to 15 g) of pressure without responding. Spinal nerve ligated rats 25 respond to as little as 4.0 mN (equivalent to 0.41 g) of pressure on the affected paw. Rats are included in the study only if they did not exhibit motor dysfunction (e.g., paw dragging or dropping) and their PWT was below 39.2 mN (equivalent to 4.0 g). At least seven days after surgery rats are treated with compounds (usually a screening dose of 60 mg/kg) or control diluent (PBS) once by s.c. injection and PWT was determined each day thereafter for 7 days. 30 Rat CFA Inflammatory Pain Model Male Sprague-Dawley rats (200 g) are lightly anesthetized with isoflurane inhalant anesthesia and the left hindpaw is injected with complete Freund's adjuvant (CFA), 0.15 mL. This procedure results in mechanical (tactile) allodynia in the left hind paw as assessed by recording the pressure at which the affected paw is withdrawn from graded stimuli (von Frey 152 WO 2006/036664 PCT/US2005/033659 tilaments ranging trom 4.0 to 148.1 mN) applied perpendicularly to the plantar surface of the paw (between the footpads) through wire-mesh observation cages. PWT is determined by sequentially increasing and decreasing the stimulus strength and analyzing withdrawal data using a Dixon non-parametric test, as described by Chaplan et al. (1994). Rats are included in 5 the study only if they do not exhibit motor dysfunction (e.g., paw dragging or dropping) or broken skin and their PWT is below 39.2 mN (equivalent to 4.0 g). At least seven days after CFA injection rats are treated with compounds (usually a screening dose of 60 mg/kg) or control solution (PBS) once by s.c. injection and PWT is determined each day thereafter for 7 days. Average paw withdrawal threshold (PWT) is converted to percent of maximum possible 10 effect (%MPE) using the following formula: %MPE = 100 * (PWT of treated rats - PWT of control rats)/(15-PWT of control rats). Thus, the cutoff value of 15 g (148.1 mN) is equivalent to 100% of the MPE and the control response is equivalent to 0% MPE. At the screening dose of 60 mg/kg, compounds in vehicle are expected to produce an antinociceptive effect with a PD relationship. 15 Example 5 Green Monkey LPS Inflammation Model The effectiveness of the compounds as inhibitors of B1 activity are evaluated in Male green monkeys (Cercopithaecus aethiops St Kitts) challenged locally with B 1 agonists 20 essentially as described by deBlois and Horlick (British Journal of Pharmacology, 132:327-335 (2002), which is hereby incorporated by reference in its entirety). In order to determine whether compounds of the present invention inhibit B 1 induced oedema the studies described below are conducted on male green monkeys (Cercopithaecus aethiops St Kitts) at the Caribbean Primates Ltd. experimental farm (St Kitts, West Indies). 25 Procedures are reviewed and accepted by the Animal Care Committees of the CR-CHUM (Montreal, Canada) and of Caribbean Primates Ltd. (St Kitts, West Indies). Animals weighing 6.0 ± 0.5 kg (n=67) were anaesthetized (50 mg ketamine kg') and pretreated with a single intravenous injection of LPS (90 ptg kg') or saline (1 mL) via the saphenous vein. Inflammation studies 30 Kinin-induced oedema is evaluated by the ventral skin fold assay (Sciberras et al., 1987). Briefly, anaesthetized monkeys were injected with captopril (1 mg kg' 30 min before assay). A single subcutaneous injection of dKD, BK or the vehicle (2 mM amastatin in 100 PL Ringer's lactate) is given in the ventral area and the increase in thickness of skin folds is monitored for 30-45 min using a calibrated caliper. The results are expressed as the difference 153 WO 2006/036664 PCT/US2005/033659 between the skin told thickness before and after the subcutaneous injection. Captopril and amastatin are used to reduce degradation of kinins at the carboxyl- and amino-terminus, respectively. Antagonist schild analysis: 5 The dose-response relationship for dKD (1-100 nmol)-induced oedema is determined at 24 h post-LPS in the absence or presence of different concentrations of antagonist. BK (30 nmol) is used as a positive control. Antagonist time course The time course of inhibition by antagonist is determined at 4, 24 and 48 h, 72 and/or 10 96 h after single bolus administration. BK (30 nmol) is used as a positive control. Drugs Ketamine hydrochloride, LPS, amastatin and captopril are from Sigma (MO, U.S.A.). All peptides are from Phoenix Pharmaceuticals (CA, U.S.A.). Statistics 15 Values are presented as mean standard error of the mean (s.e. mean). In edema studies, the pre-injection thickness of the skin folds was subtracted from the values after subcutaneous challenge. Curve fitting and EC 50 calculations were obtained using the Delta Graph 4.0 software for Apple Computers. Data were compared by two-way analysis of variance followed by unpaired, one tail Student's t-test with Bonferroni correction. P <0.05 was 20 considered statistically significant. 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. 25 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. No unacceptable toxological effects are expected when compounds of the present 30 invention are administered in accordance with the present invention. All mentioned references, patents, applications and publications, are hereby incorporated by reference in their entirety, as if here written. 35 154

Claims (14)

1. A compound of of Formula (I): R 3 Rlb Ric R 4 R2 YN-R5 R_g-N N'R 02R1 Ra O 5 (I) wherein: R 1 is selected from H, cyano, -C(O)OC 1 .salkyl, -C(O)OH, -C(=O)NRaRa, or -C1.ISalkyl substituted by 0, 1, 2, or 3 groups independently selected from R9, cyano, oxo, nitro, -C(=O)Rb, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Ra, -OC(=0)NRaRa 10 -OC(=O)N(Ra)S(=O) 2 R , -OC 2 - 6 alkylNRaRa, -OC 2 - 6 alkylORa, -SRa, -S(=O)Rb, -S(=0) 2 R, -S(=0) 2 NRaRa, -S(=O) 2 N(Ra)C(=O)Rb, -S(=O) 2 N(Ra)C(=O)ORa, -S(=0) 2 N(Ra)C(=O)NRaRa -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O) 2 Rb, -N(Ra)S(=0) 2 NRaRa, -NRaC 2 - 6 alkylNRaRa and -NRaC 2 - 6 alkylORa, and additionally substituted by 0, 1, 2, 3, 4, 5 or 6 atoms independently selected from Br, Cl, F and 15 I; Ria and Rib are each independently, H, F, Cl, -OCH 3 , -C 1 - 2 alkyl or -CF 3 ; RIC is H, -CIsalkyl, -C14haloalkyl, halo, cyano, nitro, -C(=O)Rb, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=O) 2 Rb, -OC 2 - 6 alkylNRaRa, -OC 2 - 6 alkylORa, -SRa -S(=O)Rb, -S(=0) 2 Rb, -S(=O) 2 NRaRa, 20 -S(=0) 2 N(Ra)C(=O)Rb, -S(=O) 2 N(Ra)C(=O)ORb, -S(=0) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa -N(Ra)S(=O) 2 Rb, -N(Ra)S(=O) 2 NRaRa, -NRaC 2 - 6 alkylNRaRa, -NRaC 2 - 6 alkylORa, or -CI- 6 alkyl substituted by 0, 1, 2 or 3 substituents selected from -C14haloalkyl, halo, cyano, nitro, -C(=O)Rb, -C(=O)ORb, -C(=0)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, -OC(=O)NRaRa, 25 -OC(=O)N(Ra)S(=O) 2 Rb, -OC 2 . 6 alkylNRaRa, -OC 2 -6alkylORa, -SRa, -S(=O)Rb, -S(=0) 2 Rb, -S(=0) 2 NRaRa, -S(=O) 2 N(Ra)C(=O)R, -S(=O) 2 N(Ra)C(=O)ORb, -S(=O) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O) 2 Rb, -N(Ra)S(=O) 2 NRaRa, -NRaC 2 - 6 alkylNRaRa or -NRaC 2 - 6 alkylORa; R 2 is a saturated, partially saturated or unsaturated 5-, 6- or 7-membered monocyclic or 30 6-, 7-, 8-, 9-, 10- or 1 1-membered bicyclic hydrocarbon ring containing 0, 1, 2, 3 or 4 atoms selected from N, 0 and S, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups and the ring is substituted by 0, 1, 2 or 3 substituents independently selected from R", R9, C1 4 haloalkyl, halo, cyano, nitro, -C(=O)Rb, -C(=O)OR , -C(=O)NRaRa, -C(=NRa)NRaRa, 155 WO 2006/036664 PCT/US2005/033659 -ORa, -OC(=O)Rb, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=0) 2 R', -OC 2 - 6 alkylNRaRa, -OC 2 - 6 alkylORa, -SRa, -S(=O)Rb, -S(=O) 2 Rb, -S(=O) 2 NRaRa, -S(=O) 2 N(Ra)C(=O)Rb, -S(=0) 2 N(Ra)C(=O)ORb, -S(=0) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O) 2 Rb, 5 -N(Ra)S(=O) 2 NRaRa, -NRaC 2 - 6 alkylNRaRa and -NRaC 2 - 6 alkylORa, and the ring is additionally substituted by 0, 1, 2, 3, 4 or 5 substituents independently selected from Br, Cl, F and I; R 3 is H, phenyl, benzyl or -CI- 6 alkyl, the phenyl, benzyl and -CI. 6 alkyl being substituted by 0, 1, 2 or 3 substituents independently selected from R", R9, -Ci Ihaloalkyl, halo, cyano, nitro, -C(=O)Rb, -C(=O)OR', -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, 10 -OC(=O)NRaRa, -OC(=O)N(Ra)S(=0) 2 Rb, -OC 2 - 6 alkylNRaRa, -OC 2 - 6 alkylORa, -SRa, -S(=O)Rb, -S(=0) 2 Rb, -S(=O) 2 NRaRa, -S(=O) 2 N(Ra)C(=O)Rb, -S(=O) 2 N(Ra)C(=O)ORb, -S(=0) 2 N(R)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O) 2 Rb, -N(Ra)S(=0) 2 NRaRa, -NRaC 2 - 6 alkylNRaRa and -NRaC 2 . 6 alkylORa, and additionally substituted by 0, 1, 2, 3, 4, 5 or 6 atom selected from Br, 15 Cl, F and I; R4 is H, phenyl, benzyl or -C 1 6 alkyl, the phenyl, benzyl and C - 6 alkyl being substituted by 0, 1, 2 or 3 substituents independently selected from CIAalkyl, Ci 3 haloalkyl, -OCI alkyl, -NH 2 , -NHC Ialkyl, and -N(C 1 Aalkyl)Cigalkyl, and additionally substituted by 0, 1, 2, 3, 4, 5 or 6 atom selected from Br, Cl, F and I; 20 R 5 is a saturated, partially saturated or unsaturated 8-, 9-, 10- or 11 -membered bicyclic or 12-, 13-, 14- or 15- membered tricyclic hydrocarbon ring containing 0, 1, 2, 3 or 4 atoms selected from N, 0 and S, wherein the carbon and sulfur atoms of the ring are substituted by 0, 1 or 2 oxo groups and the ring is substituted by R 6 , R7 or R 8 independently selected from basic moieties, and additionally substituted by 0, 1, 2 or 3 substituents independently selected from 25 R , R7 and R 8 which are selected from R9, -Ci-salkyl, -ClAhaloalkyl, cyano, nitro, -C(=O)R, -C(=0)OR, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=0)R, -OC(=O)NRaRa, -OC(=0)N(Ra)S(=0) 2 Rb, -OC 2 - 6 alkylNRaRa, -OC 2 - 6 alkylORa, -SRa, -S(=O)Rb, -S(=0) 2 Rb, -S(=0) 2 NRaRa, -S(=0) 2 N(Ra)C(=0)Rb, -S(=0) 2 N(Ra)C(=O)ORb, -S(=0) 2 N(Ra)C(=O)NRaRa -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=0)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, 30 -N(Ra)S(=0) 2 Rb, -N(Ra)S(=O) 2 NRaRa, -NRaC 2 - 6 alkylNRaRa and -NRaC 2 - 6 alkylORa, and the ring is additionally substituted by 0, 1, 2, 3, 4 or 5 substituents selected from R6, R 7 , R', R' and R1 0 which are independently selected from Br, Cl, F and I; wherein, R3 and R4 together may additionally be C 2 - 3 alkylene substituted by 0, 1 or 2 substituents independently selected from -Cl.salkyl, -C.4haloalkyl, halo, oxo, cyano, nitro, 156 WO 2006/036664 PCT/US2005/033659 -C(=O)Re, -C(=0)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, -OC(=O)NRaR, -OC(=O)N(Ra)S(=0) 2 Re, -OC 2 - 6 akylNRaRa, -OC 2 -6alkylORa, -SRa, -S(=O)Re, -S(=0) 2 R, -S(=0) 2 NRaRa, -S(=O) 2 N(Ra)C(=O)Re, -S(=0) 2 N(Ra)C(=O)ORb, -S(=0) 2 N(Ra)C(=O)NRa 8 , -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORe, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, 5 -N(Ra)S(=O) 2 R, -N(Ra)S(=O) 2 NRaRa, -NRaC 2 -6alkylNRaRa and -NRaC 2 - 6 alkylORa, and additionally substituted by 0, 1, 2, 3 or 4 substituents independently selected from Br, Cl, F and I; or Ri and R 4 together may additionally be C 2 -4alkylene substituted by 0, 1 or 2 substituents selected from -C 1 .salkyl, -C 1 4 haloalkyl, halo, oxo, cyano, nitro, -C(=O)Rb, 10 -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=O) 2 Rb, -OC 2 6 alkylNRaRa, -OC 2 -6alkylORa, -SRa, -S(=O)R, -S(=O) 2 Rb, -S(=0) 2 NRaRa, -S(=0) 2 N(Ra)C(=O)Rb, -S(=0) 2 N(Ra)C(=O)ORb, -S(=0) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaR, -N(Ra)S(=0) 2 Rb, -N(Ra)S(=O) 2 NRaRa, -NRaC 2 - 6 alkylNRaRa and -NRaC 2 - 6 alkylORa, and 15 additionally substituted by 0, 1, 2, 3 or 4 substituents independently selected from Br, Cl, F and I; or a substituent on R2 that is vicinal to the -SO2-R2 bond together with R3 may additionally be CI- 3 alkylene substituted by 0, 1 or 2 substituents selected from -Ci -alkyl, CI 4 haloalkyl, halo, oxo, cyano, nitro, -C(=O)Re, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaR, 20 -ORa, -OC(=O)Re, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=O) 2 Re, -OC 2 - 6 alkylNRaRa, -OC 2 - 6 alkylORa, -SRa, -S(=O)Rb, -S(= 0 ) 2 Rb, -S(=0) 2 NRaRa, -S(=0) 2 N(Ra)C(=O)R, -S(=0) 2 N(Ra)C(=0)ORb, -S(=0) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)R, -N(Ra)C(=O)ORe, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=0) 2 R, -N(Ra)S(=O) 2 NPaRa, -NRaC 2 . 6 alkylNRaRa and -NRaC 2 - 6 alkylORa, and additionally substituted 25 by 0, 1, 2, 3 or 4 substituents independently selected from Br, Cl, F and I; Ra is independently, at each instance, H or Rb; R is independently, at each instance, phenyl, benzyl or -CI- 6 alkyl, the phenyl, benzyl and -C 1 alkyl being substituted by 0, 1, 2 or 3 substituents selected from halo, -C 14 alkyl, CI 3 haloalkyl, -OC 1 Ialkyl, -NH 2 , -NHC 1 4 alkyl, -N(C 1 ialkyl)Ci Ialkyl; 30 Rd is independently at each instance -Ci-salkyl, -C haloalkyl, halo, cyano, nitro, -C(=O)Re, -C(=O)ORe, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=0) 2 R, -OC 2 - 6 alkylNRaRa, -OC 2 4alkylORa, -SRa, -S(=0)Re, -S(=O) 2 Rb, -S(=0) 2 NRaRa, -S(=O) 2 N(Ra)C(=O)Rb, -S(=0) 2 N(Ra)C(=O)ORb, -S(=0) 2 N(Ra)C(=O)NRaRa, 157 WO 2006/036664 PCT/US2005/033659 -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa -N(Ra)S(=O) 2 Rb, -N(Ra)S(=0) 2 NRaRa, -NRaC 2 - 6 alkylNRaRa or -NRaC 2 - 6 alkylORa; Re is independently at each instance -C I-alkyl substituted by 0, 1, 2 or 3 substituents independently selected from Rd and additionally substituted by 0 or 1 substituents selected 5 from Rg; and R' is independently at each instance a saturated, partially saturated or unsaturated 5-, 6 or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11 -membered bicyclic hydrocarbon ring containing 0, 1, 2, 3 or 4 atoms selected from N, 0 and S, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups and the ring is substituted by 0, 1, 2 or 3 substituents 10 independently selected from -Ci-salkyl, -CI-4haloalkyl, halo, cyano, nitro, -C(=0)R , -C(=0)ORb, -C(=O)NRaRa, -C(=NRa)NRaR a, - , -OC(=0)Rb, -OC(=0)NRaRa, -OC(=O)N(Ra)S(=0) 2 Rb, -OC 2 . 6 alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=0)Rb, -S(=O) 2 Rb, -S(=0) 2 NRaRa, -S(=O) 2 N(Ra)C(=O)Rb, -S(=0) 2 N(Ra)C(=O)ORb, -S(=0) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, 15 -N(Ra)S(=O) 2 Rb, -N(Ra)S(=0) 2 NRaRa, -NRaC 2 - 6 alkylNRaRa and -NR aC 2 - 6 alkylORa, and the ring is additionally substituted by 0, 1, 2, 3, 4 or 5 substituents independently selected from Br, Cl, F and I; or any pharmaceutically-acceptable salt or hydrate thereof.
2. The compound of Claim 1 wherein: 20 R' is selected from H or -Ci-salkyl substituted by 0, 1, 2, or 3 groups independently selected from R9, cyano, oxo, nitro, -C(=O)Rb, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=0)Ra, -OC(=0)NRaRa, -OC(=O)N(Ra)S(=0) 2 Rb, -OC2. 6 akylNRaRa, -OC 2 - 6 alkylORa, -SRa, -S(=0)Rb, -S(=O) 2 Rb, -S(=O) 2 NRaRa, -S(=O) 2 N(Ra)C(=O)Rb, -S(=0) 2 N(Ra)C(=O)ORa, -S(=O) 2 N(Ra)C(=0)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, 25 -N(Ra)C(=0)ORb, -N(Ra)C(=0)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=0) 2 Rb, -N(Ra)S(=0) 2 NRaRa, -NRaC 2 - 6 alkylNRaRa and -NRaC 2 - 6 alkylORa, and additionally substituted by 0, 1, 2, 3, 4, 5 or 6 atoms selected from Br, Cl, F and I; Ria and RIb are each independently, H, F, Cl, -OCH 3 , -Ci 2 alkyl or -CF 3 ; R1c is H, -Ci-salkyl, -C1.4haloalkyl, halo, cyano, nitro, -C(=O)R, -C(=O)OR, 30 -C(=0)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=0)Rb, -OC(=0)NRaRa, -OC(=O)N(Ra)S(=0) 2 Rb, -OC 2 - 6 alkylNRaRa, -OC 2 - 6 alkylORa, -SRa, -S(=0)Rb, -S(=0) 2 Rb, -S(=0) 2 NRaRa, -S(=0) 2 N(Ra)C(=O)Rb, -S(=0) 2 N(Ra)C(=O)ORb, -S(=0) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O) 2 Rb, -N(Ra)S(=0) 2 NRaRa, -NRaC 2 - 6 alkylNRaRa, -NRaC 2 - 6 alkylORa, or -C I-6alkyl 158 WO 2006/036664 PCT/US2005/033659 substituted by 0, 1, 2 or 3 substituents selected from Ci Ahaloalkyl, halo, cyano, nitro, -C(=O)Re, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRa, -ORa, -OC(=O)R, -OC(=O)NRaRa -OC(=O)N(Ra)S(=0) 2 Rb, -OC 2 - 6 alkylNRaRa, -OC 2 -6alkylORa, -SRa, -S(=O)R, -S(=0) 2 R, -S(=0) 2 NRaRa, -S(=0) 2 N(Ra)C(=O)Rb, -S(=0) 2 N(Ra)C(=O)ORb, -S(=0) 2 N(Ra)C(=O)NRaRa, 5 -NRaRa, -N(Ra)C(=O)R, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O) 2 Rb, -N(Ra)S(=0) 2 NRaRa, -NRaC 2 - 6 alkylNRaRa or -NRaC 2 - 6 alkylORa; R2 is a saturated, partially saturated or unsaturated 5-, 6- or 7-membered monocyclic or
6-, 7-, 8-, 9-, 10- or 1 1-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, 0 and S, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups and 10 the ring is substituted by 0, 1, 2 or 3 substituents selected from R*, R9, -C I haloalkyl, halo, cyano, nitro, -C(=O)R, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)R, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=0) 2 Rb, -OC 2 - 6 alkylNRaRa, -OC 2 - 6 alkylORa, -SRa, -S(=O)Rb, -S(=0) 2 Rb, -S(=0) 2 NRaRa, -S(=0) 2 N(Ra)C(=0)Rb, -S(=O) 2 N(Ra)C(=O)ORb, -S(=O) 2 N(Ra)C(=O)NRRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=0)OR , -N(Ra)C(=O)NRaRa 15 -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=0) 2 Rb, -N(Ra)S(=0) 2 NRaRa, -NRaC2-6alkylNRaRa and -NRaC 2 -6alkylORa, and the ring is additionally substituted by 0, 1, 2, 3, 4 or 5 substituents independently selected from Br, Cl, F and I; R3 is H, phenyl, benzyl or -C I- 6 alkyl, the phenyl, benzyl and -CI 6 alkyl being substituted by 0, 1, 2 or 3 substituents selected from Re, R9, Ciahaloalkyl, halo, cyano, nitro, 20 -C(=O)Rb, -C(=0)OR, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Re, -OC(=0)NWRa, -OC(=O)N(Ra)S(=0) 2 Rb, -OC 2 - 6 alkylNRaRa, -OC 2 -6alkylORa, -SRa, -S(=O)R, -S(=0) 2 Rb, -S(=0) 2 NRaRa, -S(=0) 2 N(Ra)C(=O)Rb, -S(=0) 2 N(Ra)C(=O)ORb, -S(=0) 2 N(Ra)C(=O)NRRa, -NRaRa, -N(Ra)C(=0)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=0) 2 Rb, -N(Ra)S(=O) 2 NRaRa, -NRaC 2 - 6 alkylNRaRa and -NRaC 2 - 6 alkylORa, and 25 additionally substituted by 0, 1, 2, 3, 4, 5 or 6 atom selected from Br, Cl, F and I; R4 is H, phenyl, benzyl or -C 1 6 alkyl, the phenyl, benzyl and -CI- 6 alkyl being substituted by 0, 1, 2 or 3 substituents selected from Ci alkyl, Ci- 3 haloalkyl, -OCi 4 alkyl, -NH 2 , -NHCI 4 alkyl, and -N(Ci 4 alkyl)Ci-4alkyl, and additionally substituted by 0, 1, 2, 3, 4, 5 or 6 atom selected from Br, Cl, F and I; 30 R 5 is a saturated, partially saturated or unsaturated 8-, 9-, 10- or 11 -membered bicyclic or 12-, 13-, 14- or 15- membered tricyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, 0 and S, wherein the carbon and sulfur atoms of the ring are substituted by 0, 1 or 2 oxo groups and the ring is substituted by 1, 2 or 3 basic moieties, and additionally substituted by 0, 1, 2 or 3 substituents selected from R9, -C 1 . 8 alkyl, -C1 4 haloalkyl, cyano, nitro, -C(=0)R, 159 WO 2006/036664 PCT/US2005/033659 -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)R', -OC(=O)NRaRa, -OC(=O)N(Ra)S(=0) 2 Rb, -OC 2 - 6 alkyNRaRa, -OC 2 -6alkylORa, -SRa, -S(=O)Rb, -S(=O) 2 Rb, -S(=O) 2 NRaRa, -S(=O) 2 N(Ra)C(=O)Re, -S(=O) 2 N(Ra)C(=O)ORb, -S(=O) 2 N(Ra)C(=O)NRRa -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, 5 -N(Ra)S(=O) 2 R, -N(Ra)S(=O) 2 NRaRa, -NRaC 2 - 6 alkylNRaRa and -NRaC 2 . 6 alkylORa, and the ring is additionally substituted by 0, 1, 2, 3, 4 or 5 substituents independently selected from Br, Cl, F and I; wherein, R 3 and R4 together may additionally be C 2 - 3 alkylene substituted by 0, 1 or 2 substituents selected from -C 1 . 8 alkyl, -Cl4haloalkyl, halo, oxo, cyano, nitro, -C(=O)Rb, 10 -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)R, -OC(=O)NRaRa -OC(=O)N(Ra)S(=0) 2 R, -OC 2 - 6 alkylNRaRa, -OC 2 -6alkylORa, -SRa, -S(=O)Rb, -S(=O) 2 Rb, -S(=0) 2 NRaRa, -S(=0) 2 N(Ra)C(=O)Rb, -S(=0) 2 N(Ra)C(=O)ORb, -S(=O) 2 N(Ra)C(=O)NRaRa -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O) 2 Rb, -N(Ra)S(=0) 2 NRaRa, -NRaC 2 - 6 alkylNRaRa and -NRaC 2 - 6 alkylORa, and 15 additionally substituted by 0, 1, 2, 3 or 4 substituents independently selected from Br, Cl, F and I; or R and R 4 together may additionally be C 2 -4alkylene substituted by 0, 1 or 2 substituents selected from -C 1 salkyl, -C 4haloalkyl, halo, oxo, cyano, nitro, -C(=O)Rb, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, -OC(=O)NRaRa, 20 -OC(=O)N(Ra)S(=0) 2 Rb, -OC 2 - 6 alkylNRaRa, -OC 2 -6alkylORa, -SRa, -S(=O)Rb, -S(=O) 2 Rb, -S(=0) 2 NRaRa, -S(=0) 2 N(Ra)C(=O)Re, -S(=0) 2 N(Ra)C(=O)ORb, -S(=0) 2 N(Ra)C(=O)NRaRa -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORe, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O) 2 Rb, -N(Ra)S(=O) 2 NRaRa, -NRaC 2 - 6 alkylNRaRa and -NRaC 2 - 6 alkylORa, and additionally substituted by 0, 1, 2, 3 or 4 substituents independently selected from Br, Cl, F and 25 I; or a substituent on R 2 that is vicinal to the -S0 2 -R 2 bond together with R 3 may additionally be C 13 alkylene substituted by 0, 1 or 2 substituents selected from C 1 8 alkyl, C 1 4haloalkyl, halo, oxo, cyano, nitro, -C(=o)Rb, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=0)Rb, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=0) 2 Rb, -OC 2 - 6 alkylNRaRa, 30 -OC 2 - 6 alkylORa, -SRa, -S(=O)Re, -S(=O) 2 Rb, -S(=O) 2 NRaRa, -S(=0) 2 N(Ra)C(=O)Rb, -S(=O) 2 N(Ra)C(=O)ORe, -S(=0) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O) 2 R, -N(Ra)S(=O) 2 NRaRa, -NRaC 2 - 6 alkylNRaRa and -NRaC 2 - 6 alkylORa, and additionally substituted by 0, 1, 2, 3 or 4 substituents independently selected from Br, Cl, F and I; 160 WO 2006/036664 PCT/US2005/033659 Ra is independently, at each instance, H or R"; Rb is independently, at each instance, phenyl, benzyl or -CI. 6 alkyl, the phenyl, benzyl and -Ci-alkyl being substituted by 0, 1, 2 or 3 substituents selected from halo, CI 4 alkyl, Ci 3 haloalkyl, -OCI 4 alkyl, -NH 2 , -NHC 1 Aalkyl, -N(C I 4 alkyl)Ci Aalkyl; 5 Rd is independently at each instance -Ci-salkyl, CIAhaloalkyl, halo, cyano, nitro, -C(=O)Rb, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=0) 2 Rb, -OC 2 - 6 alkylNRaRa, -OC 2 -salkylORa, -SRa, -S(=O)Rb, -S(=0) 2 Rb, -S(=O) 2 NRaRa, -S(=O) 2 N(Ra)C(=O)Rb, -S(=O) 2 N(Ra)C(=O)OR , -S(=O) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, 10 -N(Ra)S(=O) 2 Rb, -N(Ra)S(=O) 2 NRaRa, -NRaC 2 - 6 alkylNRaRa or -NRaC 2 - 6 alkylORa; Re is independently at each instance -C I-alkyl substituted by 0, 1, 2 or 3 substituents independently selected from Rd and additionally substituted by 0 or 1 substituents selected from Rg; and R9 is independently at each instance a saturated, partially saturated or unsaturated 5-, 6 15 or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 1-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, 0 and S, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups and the ring is substituted by 0, 1, 2 or 3 substituents selected from Ci- 8 alkyl, -Ciahaloalkyl, halo, cyano, nitro, -C(=0)Rb, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, -OC(=0)NRaRa, -OC(=O)N(Ra)S(=0) 2 Rb, 20 -OC 2 - 6 alkylNRaRa, -OC 2 - 6 alkylORa, -SRa, -S(=O)Rb, -S(=0) 2 R, -S(=0) 2 NRaRa -S(=0) 2 N(Ra)C(=O)Rb, -S(=0) 2 N(Ra)C(=O)ORb, -S(=0) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=0)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=0) 2 Rb, -N(Ra)S(=O) 2 NRaRa, -NRaC 2 - 6 alkylNRaRa and -NRaC 2 - 6 alkylORa, and the ring is additionally substituted by 0, 1, 2, 3, 4 or 5 substituents independently selected from Br, 25 Cl, F and I. 3. The compound of Claim 1 or 2 wherein the basic moieties are independently selected from from amino, cycloalkylamino-(Ci-C 6 )alkyl, cycloalkyl(CI-C 6 )alkylamino(CI-C 6 )alkyl, heterocyclylamino(Ci-C 6 )alkyl, heterocyclyl(Ci-C 6 )alkylamino(Ci-C 6 )alkyl, arylamino(Ci-C 6 )alkyl, aryl(Ci-C 6 )alkylamino-(Ci-C 6 )alkyl, (Ci-C 6 )alkylamino(CI-C 6 )alkoxy, 30 (CI-C 6 )alkylamino(Ci-C 6 )alkoxy(CI-C 6 )-alkoxy, amino(CI-C 6 )alkoxy, amino(Ci-C 6 )alkyl, (Ci-C 6 )alkylamino(CI-C 6 )alkyl, (CI-C 4 )alkylamino-(C 2 -C 6 )alkenyl, 4-8-membered nitrogen containing heterocyclyl(C 2 -C 6 )alkenyl, 5-6 membered heterocyclyloxy, 5-6 membered nitrogen-containing heterocyclyl and 5-7 membered nitrogen-containing heterocyclylalkyl wherein each basic moiety can be substituted by 0, 1, 2 or 3 groups independently selected 161 WO 2006/036664 PCT/US2005/033659 from halo, -NH 2 , -OH, -CN, -CF 3 , (CI-C 6 )alkylamino, haloalkyl, oxo, (Ci-C 6 )alkoxy, (C 1 -C 6 )alkoxyalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, di(C I-C 6 )alkylamino, =NCN; and (Ci -C 6 )alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl, each of which is substituted by 0, 1, 2 or 3 groups independently selected from halo, -NH 2 , -OH, -CN, -CF 3 , (CI-C 6 )alkylamino, 5 haloalkyl, oxo, (CI-C 6 )alkoxy, (C 1 -C 6 )alkoxyalkyl, (CI-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, or di(Ci-C 6 )alkylamino. 4. The compound of Claim 3 wherein the basic moieties are independently selected from amino, aminomethyl, isopropylaminomethyl, t-butylaminomethyl, 2-t-butylaminoethyl, 2-tert butylamino-1-methyl-ethyl, 1-tert-butylaminoethyl, 1-(tert-butylamino-methyl)-vinyl, 1 10 (piperidin-1-ylmethyl)-vinyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2 dimethyl)propylaminomethyl, N-isopropyl-N-ethylaminomethyl, N-isopropyl-N methylaminomethyl, N-t-butyl-N-methylaminomethyl, N-iso-butyl-N-methylaminomethyl, N t-butyl-N-ethylaminomethyl, N-isobutyl-N-methylaminomethyl, N-t-butyl-N isopropylaminomethyl, N,N-di(isopropyl)aminomethyl, N,N-dimethylaminomethyl, N,N 15 diethylaminomethyl, N,N-di(t-butyl)-aminomethyl, cyclopropylaminomethyl, cyclopropylaminoethyl, cyclopropylnethylaminomethyl, cyclopropylmethylaminoethyl, cyclobutylaminomethyl, cyclobutylaminoethyl, cyclobutylmethylaminomethyl, cyclobutylmethylaminoethyl, 4,5-dihydro-imidazolyl, 1-piperidinylmethyl, 4-fluoropiperidin 1-ylmethyl, 4,4-difluoropiperidin-1-ylmethyl, 3-hydroxypiperidin-1-ylmethyl, 4 20 hydroxypiperidin- 1 -ylmethyl, 4-(dimethylamino)piperidin- 1 -ylmethyl, 2,6-dimethylpiperidin 1 -ylmethyl, 4-morpholinylmethyl, 1 -pyrrolidinylmethyl, 2-methylpyrrolidin- 1 -ylmethyl, 2,5 dimethylpyrrolidin- 1 -ylmethyl, piperazin- 1 -ylmethyl, azocan- 1 -ylmethyl, azepan- 1 -ylmethyl, (7-azabicyclo[2.2.1]hept-7-yl)methyl, (1,3,3-trimethyl-6-azaicyclo[3.2.1]oct-6-yl)methyl, 2 piperidinyl or 4-methylpiperazin- 1 -ylmethyl. 25 5. The compound of any of the Claims 1-4 wherein R' is -C1.salkyl substituted by 1, 2, 3, 4, 5 or 6 atoms selected from F, Cl, Br or I. 6. The compound of any of the Claims 1-4 wherein R' is trifluoromethyl and Ria, Rib, Rc and R 3 are hydrogen.
7. The compound of any of the Claims 3-6 wherein: 30 R 4 is hydrogen and R 2 is phenyl or napthyl, both of which are substituted by 1, 2 or 3 substituents selected from Re, R9, -C 1 .4haloalkyl, halo, cyano, nitro, -C(=O)Rb, -C(=O)OR , -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=0) 2 Rb, -OC 2 . 6 alkylNRaRa, -OC 2 - 6 alkylORa, -SRa, -S(=O)Rb, -S(=0) 2 Rb, -S(=0) 2 NRaRa, -S(=0) 2 N(Ra)C(=O)Rb, -S(=O) 2 N(Ra)C(=O)ORb, -S(=O) 2 N(Ra)C(=O)NRaRa, -NRaRa, 162 WO 2006/036664 PCT/US2005/033659 -N(Ra)C(=O)R", -N(Ra)C(=O)OR", -N(R")C(=O)NR"R", -N(R")C(=NR")NR"R", -N(Ra)S(=0) 2 Rb, -N(Ra)S(=O) 2 NRaRa, -NRaC 2 -6alkylNRaRa and -NRaC 2 - 6 alkylORa, and additionally substituted by 0, 1, 2, 3, 4 or 5 substituents independently selected from Br, Cl, F and I. 5 8. The compound of any of the Claims 3-6 wherein: R4 is hydrogen and R2 is an unsaturated 5-, 6- or 7-membered monocyclic 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 and the ring is substituted by 0, 1, 2 or 3 substituents selected from R", R9, -CI haloalkyl, halo, cyano, nitro, -C(=O)R, -C(=O)OR, -C(=O)NRaRa, 10 -C(=NRa)NRaRa, -ORa, -OC(=O)R, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=0) 2 Rb, -OC 2 - 6 alkylNRaRa, -OC 2 - 6 alkylORa, -SRa, -S(=O)Rb, -S(= 0 ) 2 Rb, -S(=O) 2 NRaRa, -S(=0) 2 N(Ra)C(=O)Rb, -S(=O) 2 N(Ra)C(=0)ORb, -S(=0) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=0)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=0)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O) 2 Rb, -N(Ra)S(=0) 2 NRaRa, -NRaC 2 - 6 alkylNRaRa and -NRaC 2 - 6 alkylORa, and the 15 ring is additionally substituted by 0, 1, 2, 3, 4 or 5 substituents independently selected from Br, Cl, F and I.
9. The compound of any of the Claims 3-6 wherein: R4 is hydrogen and R2 is 2-trifluoromethylphenyl, 3-bromophenyl, 4-bromo-3 trifluoromethylphenyl, 3-chloro-4-fluorophenyl, 3-trifluoromethylphenyl, 4 20 trifluoromethoxyphenyl, 3-methylphenyl, 4-chloro-2-fluorophenyl, 2-chloro-4-fluorophenyl, naphthalene-2-yl, 3-tert-butylphenyl, 4-tert-butylphenyl, [1.3]-oxazol-4-ylphenyl, 3,4-dihydro 2H-benzo[b][1,4]dioxepin-7-yl, 1,2,3,4-tetrahydroquinolin-8-yl, 4-methyl-3,4-dihydro-2H benzo[b][1,4]oxazin-7-yl, 3-chloro-2-fluorophenyl, 3-methoxyphenyl, 4-methylphenyl, 2,4 dimethylphenyl, 3,5-dimethylphenyl, 3,4-dimethylphenyl, 2-fluoro-5-methylphenyl, 4 25 trifluoromethylphenyl, 4-chlorophenyl, 2,5-dichlorophenyl, 2,3-dichlorophenyl, 3,4 dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 2-chloro-6-methylphenyl, 3-fluoro-6 methylphenyl, 5-chloro-2-methoxyphenyl, 4-chloro-3-trifluoromethylphenyl, 2-chloro-5 trifluoromethylphenyl, 5-chloro-2-fluorophenyl, 3-chloro-2-fluorophenyl, 2,6-dichloro-4 trifluoromethylphenyl, 4-ethylphenyl, 4-chloro-3-methylphenyl, 4-chloro-2,5-dimethylphenyl, 30 3-chloro-4-methylphenyl, 3,4-dimethoxyphenyl, 3,5-dichloro-2-hydroxyphenyl, isoquinolin-6 yl, quinolin-8-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 2 nitrophenyl, 2-aminophenyl, 2-fluoro-5-trifluoromethylphenyl, 6-chloronaphthalen-2-yl, 5 chloronaphthalen-1-yl, 2-nitro-4-trifluoromethylphenyl, or 4-biphenyl, 3-biphenyl. 163 WO 2006/036664 PCT/US2005/033659
10. The compound of any of the Claims 3-5 wherein R' is trifluoromethyl, R'", R"', R" and a substituent on R2 that is vicinal to the -S0 2 -R 2 bond together with R 3 may additionally be C 1 3 alkylene substituted by 0, 1 or 2 substituents selected from C 1 .salkyl, Ci 4 haloalkyl, halo, oxo, cyano, nitro, -C(=O)Rb, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, 5 -OC(=O)NRaRa, -OC(=O)N(Ra)S(=0) 2 Rb, -OC 2 - 6 alkylNRaRa, -OC 2 - 6 alkylORa, -SRa, -S(=O)R, -S(=0) 2 Rb, -S(=O) 2 NRaRa, -S(=O) 2 N(Ra)C(=O)Rb, -S(=O) 2 N(Ra)C(=O)ORb, -S(=0) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O) 2 Rb, -N(Ra)S(=O) 2 NRaRa, -NRaC 2 - 6 alkylNRaRa and -NRaC 2 -6alkylORa, and additionally substituted by 0, 1, 2, 3 or 4 substituents independently 10 selected from Br, Cl, F and I.
11. The compound of Claim 10 wherein: R 2 _ N i s 02 is 0 0 substituted by 0, 1 or 2 substituents selected from C 1 . 8 alkyl, CIAhaloalkyl, halo, oxo, cyano, nitro, -C(=O)Rb, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb 15 -OC(=O)NRaRa, -OC(=O)N(Ra)S(=O) 2 Rb, -OC 2 - 6 alkyNRaRa, -OC 2 - 6 alkylORa, -SRa, -S(=O)Rb, -S(=O) 2 Rb, -S(=O) 2 NRaRa, -S(=0) 2 N(Ra)C(=O)Rb, -S(=O) 2 N(Ra)C(=O)OR, -S(=0) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=0) 2 Rb, -N(Ra)S(=0) 2 NRaRa, -NRaC 2 - 6 alkylNRaRa and -NRaC 2 -6alkylORa, and additionally substituted by 0, 1, 2, 3 or 4 substituents independently 20 selected from Br, Cl, F and I.
12. The compound of Claim 10 wherein: 10 II.\I / R2_OS is 02 is 0 substituted by 0, 1 or 2 substituents selected from Ci-salkyl, CIAhaloalkyl, halo, oxo, 25 cyano, nitro, -C(=O)Rb, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=O) 2 Rb, -OC 2 - 6 alkylNRaRa, -OC 2 - 6 alkylORa, -SRa, -S(=O)Rb -S(=0) 2 Rb, -S(=O) 2 NRaRa, -S(=0) 2 N(Ra)C(=O)Rb, -S(=O) 2 N(Ra)C(=O)ORb, -S(=0) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=0)NRaRa -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=0) 2 Rb, -N(Ra)S(=0) 2 NRaRa, -NRaC 2 - 6 alkylNRRa and 164 WO 2006/036664 PCT/US2005/033659 -NR"C 2 -6alkylORa, and additionally substituted by 0, 1, 2, 3 or 4 substituents independently selected from Br, Cl, F and I.
13. The compound of any of the Claims 3-12 wherein R 5 is: S02 -- O - NH - S -S S2 NH \ /R 8 _. R 8 \ /R 8 \ / R 8 \ /R 8 R6 R 7 R R R 7 R6 R 7 R6 R 7 5 where the part of the above rings that is attached to the nitrogen atom in Formula (I) is substituted by 0 or 1 substituents selected from R9, CI.alkyl, CI4haloalkyl, cyano, nitro, -C(=O)Rb, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=O) 2 Rb, -OC 2 - 6 alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=0)Rb, -S(=O) 2 R, -S(=O) 2 NRaRa, -S(=0) 2 N(Ra)C(=0)Rb, -S(=0) 2 N(Ra)C(=O)ORb, -S(=O) 2 N(Ra)C(=O)NRaRa, 10 -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O) 2 Rb, -N(Ra)S(=0) 2 NRaRa, -NRaC 2 - 6 alkylNRaRa and -NRaC 2 - 6 alkylORa, and additionally substituted by 0, 1, 2 or 3 substituents independently selected from Br, Cl, F and I 67 8 and R , R7 and R are independently selected from H, a basic moiety, R9, C - 8 alkyl, Ci 4 haloalkyl, cyano, nitro, -C(=O)Rb, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa 15 -OC(=O)Rb, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=0) 2 Rb, -OC 2 - 6 alkylNRaRa, -OC 2 - 6 alkylORa, -SRa, -S(=O)Rb, -S(=O) 2 Rb, -S(=0) 2 NRaRa, -S(=O) 2 N(Ra)C(=O)Rb, -S(=0) 2 N(Ra)C(=O)ORb, -S(=O) 2 N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=0) 2 Rb, -N(Ra)S(=0) 2 NRaRa, -NRaC 2 - 6 alkylNRaRa -NRaC 2 - 6 alkylORa, Br, Cl, F and I; provided that 1 or 2 of R 6 , R 7 and R 8 are a basic moiety. 20 14. The compound of Claim 3-12 wherein R 5 is: R7 where R 7 is a basic moiety.
15. The compound of any of the Claims 3-12 wherein R 5 is: 165 WO 2006/036664 PCT/US2005/033659 R 7 where R 7 is a basic moiety.
16. A compound selected from the group consisting of: 5 ( 2 R)-3-((( 2 , 3 -dichlorophenyl)sulfonyl)(methyl)amino)-2-hydroxy-N-((1R)-6-(1 piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)propanamide; (2R)-3-(((2,3 -dichlorophenyl)sulfonyl)(methyl)amino)-2-methyl-N-((1R)-6-( 1 piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)propanamide; ( 2 R)- 3 -((( 2 ,3-dichlorophenyl)sulfonyl)amino)-2-methyl-N-((1R)-6-(1-piperidinyl 10 methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)propanamide; ( 2 R,3R)-4,4,4-trifluoro-2-hydroxy-N-((IR)-6-(1 -piperidinylmethyl)- 1,2,3,4-tetrahydro 1-naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; ( 3 R)- 3 -((( 2 , 3 -dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((1R)-6-(1 -piperidinyl methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; 15 ( 3 R)- 3 -(((2,3-dichlorophenyl)sulfonyl)amino)-N-((IR)-6-((( 1,1 -dimethylethyl)amino) methyl)- 1,2,3,4-tetrahydro- I -naphthalenyl)-4,4,4-trifluorobutanamide; ( 3 R)- 3 -((( 2 ,5-dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((IR)-6-(1 -piperidinyl methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; ( 3 R)- 3 -((( 2 ,5-dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((4R)-7-(1 -piperidinyl 20 methyl)- 3 , 4 -dihydro-2H-chromen-4-yl)butanamide; ( 3 R)-3-(((2,5-dichlorophenyl)sulfonyl)amino)-N-((1R)-6-((( 1,1 -dimethylethyl)amino) methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-4,4,4-trifluorobutanamide; ( 3 R)- 3 -((( 2 , 6 -dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((IR)-6-(I -piperidinyl methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; 25 ( 3 R)- 3 -((( 3 ,4-dichlorophenyl)sulfonyl)amino)-4-fluoro-N-((1R)-6-(1 -piperidinyl methyl)- 1,2,3,4-tetrahydro- I -naphthalenyl)butanamide; ( 3 R)- 3 -((( 3 ,4-dichlorophenyl)sulfonyl)amino)-N-((1R)-6-((( 1,1 -dimethylethyl)amino) methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-4,4,4-trifluorobutanamide; ( 3 R)- 3 -((( 4 -chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((1R)-6-((( 1,1 -dimethyl 30 ethyl)amino)methyl)- 1,2,3,4-tetrahydro- I -naphthalenyl)-4,4,4-trifluorobutanamide; 166 WO 2006/036664 PCT/US2005/033659 (3R)-3-(((4-cblorophenyl)sulfonyl)amino)-N-((1R)-6-(((, 1, -dimethylethyl)amino) methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-4,4,4-trifluorobutanamide; (3R)-3-(((5-chloro-2-(methyloxy)phenyl)sulfonyl)amino)-4,4,4-tifluoro-N-(( 1R)-6-( 1 piperidmnylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; 5 (3R)-3-(((5-chloro-2-fluorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-(( I R)-6-( 1 piperidinylmethyl)- I ,2,3,4-tetrahydro- I -naphthalenyl)butanamide; (3R)-3-((2,3-dihydro- 1 ,4-benzodioxin-6-ylsulfonyl)amino)-4,4,4-trifluoro-N-(( 1R)-6 (1 -piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R)-4,4,4-trifluoro-3-(((8-(methyloxy)-5-quinolinyl)sulfonyl)amino)-N-(( 1R)-6-( 1 10 piperidinylmethyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R)-4,4,4-trifluoro-3-((2-naphthalenylsulfonyl)amino)-N-(( 1R)-6-( 1 -piperidinyl methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R)-4,4,4-trifluoro-N-(( 1R)-6-( 1 -piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 15 (3R)-4,4,4-trifluoro-N-((l R)-6-( 1 -piperidinylmethyl)- 1 ,2,3,4-tetrahyclro- I naphthalenyl)-3-((8-quinolinylsulfonyl)amino)butanamide; (3R)-4-hydroxy-3-(((4-methylphenyl)sulfonyl)amino)-N-(( 1R)-6-( 1-piperidinyl methyl)- 1,2,3 ,4-tetrahydro-1 -naphthalenyl)butanamide; (3R)-N-(( 1 R)-6-(((, 1, -dimethylethyl)amino)methyl)- 1 ,2,3,4-tetrahydro- 1 20 naphthalenyl)-4-fluoro-3-(((3 -(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3R)-N-(( 1 R)-6-((( 1,1 -dimethylethyl)amino)methyl)- 1,2,3 ,4-tetrahydro- 1 naphthalenyl)-4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3R)-N-(( 1 R)-6-((( 1,1 -dimethylethyl)amino)methyl)- 1,2,3 ,4-tetrahydro- 1 naphthalenyl)-4,4,4-trifluoro-3-((2-naphthalenylsulfonyl)amino)butanamide; 25 (3R)-N-(( I R)-6-(((, 1, -dimethylethyl)amino)methyl)-1 ,2,3,4-tetrahydro- 1 naphthalenyl)-4,4,4-trifluoro-3-(((2,4,6-trimethylphenyl)sulfonyl)amino)butanamide; (3R)-N-(( 1 R)-6-(((, 1, -dimethylethyl)amino)methyl)- 1,2,3 ,4-tetrahydro- 1 naphthalenyl)-4,4,4-trifluoro-3-(((4-methylphenyl)sulfonyl)amino)butanamide; (3R)-N-(( 1 R)-6-((cyclopentylamino)methyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)-4 30 fluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3R)-N-((4R)-7-((cyclopentylamino)methyl)-3,4-dihydro-2H-chromen-4-yI)-4,4,4 trifluoro-3-(((3-(ttifluoromethyl)phenyl)sulfonyl)amino)butanamide; . (3R,4R)-3-(((3,4-dichlorophenyl)sulfonyl)amino)-4-hydroxy-N-(( IR)-6-( 1-piperidinyl methyl)- 1,2,3 ,4-tetrahydro- I -naphthalenyl)pentanamide; 167 WO 2006/036664 PCT/US2005/033659 ( 3 S)- 3 -((( 2 , 3 -dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((IR)-6-(1-piperidinyl methyl)- 1,2,3, 4 -tetrahydro- 1 -naphthalenyl)butanamide; ( 3 S)- 3 -((( 2 ,5-dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((1R)-6-(1 -piperidinyl methyl)- 1, 2 , 3 ,4-tetrahydro-1 -naphthalenyl)butanamide; 5 ( 3 S)-3-(((2,6-dichloro-4-(trifluoromethyl)phenyl)sulfonyl)amino)-N-((1R)-6-( 1 piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; ( 3 S)- 3 -((( 2 , 6 -dichloro-4-(trifluoromethyl)phenyl)sulfonyl)amino)-N-((1R)-6-((( 1,1 dimethylethyl)amino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; ( 3 S)- 3 -(((2-chloro-5-(trifluoromethyl)phenyl)sulfonyl)amino)-N-((1R)-6-( 1 10 piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; ( 3 S)- 3 -(((2-chloro-5-(trifluoromethyl)phenyl)sulfonyl)amino)-N-((IR)-6-((cyclopentyl amino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; ( 3 S)- 3 -((( 2 -fluoro-5-(trifluoromethyl)phenyl)sulfonyl)amino)-N-((lR)-6-(1 -piperidinyl methyl)- 1, 2 ,3,4-tetrahydro- 1 -naphthalenyl)butanamide; 15 ( 3 S)- 3 -(((2-nitro-4-(trifluoromethyl)phenyl)sulfonyl)amino)-N-((1R)-6-(1 -piperidinyl methyl)- 1, 2 ,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-(((3, 4 -bis(methyloxy)phenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((1R)-6-( 1 piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; ( 3 S)- 3 -((( 3 ,4-dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((1R)-6-( 1 -piperidinyl 20 methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; ( 3 S)- 3 -((( 3 ,4-dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((1R)-6-(1 -(1 piperidinylmethyl)ethenyl)- 1, 2 ,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-(((3,5-dichloro-2-hydroxyphenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((R)-6-( 1 piperidinylmethyl)- 1, 2 ,3,4-tetrahydro- 1 -naphthalenyl)butanamide; 25 ( 3 S)- 3 -((( 3 -chloro-2-fluorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((1R)-6-( 1 piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3 -(((3 -chloro-4-methylphenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((1R)-6-( 1 piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-(((4-(1,1 -dimethylethyl)phenyl)sulfonyl)amino)-N-((1R)-6-(1 -piperidinyl 30 methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-(((4-(1, 3 -oxazol-5-yl)phenyl)sulfonyl)amino)-N-((lR)-6-(1 -piperidinylmethyl) 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-(((4-bromo-3-(trifluoromethyl)phenyl)sulfonyl)amino)-N-((IR)-6-(1 piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; 168 WO 2006/036664 PCT/US2005/033659 kjJJ)-J-tk-(u)ro-LJ-uJn uLnYlpnenY1)SU1Iony1)aMMO)-4,44-r1IluorojV-(( IK)-6-( 1 piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; ( 3 SJ- 3 -(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)4,4,4trifluoro-N(( 1R)-6-((3 hydroxy- 1 -piperidinyl)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; 5 (3SJ-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-4,4,4trifluoroN(( 1R)-6-(((2 (1 -pyrrolidinyl)ethyl)amino)methyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide; ( 3 S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-4,4,4-trifluoroN((4R-7{( 1 piperidinylmethyl)-3,4-dihydro-2H-chromen-4..yl)butanamide; ( 3 )-3-(((4-chloro-2,5-dimethylpheny)sufony)amino)-4,4,4-fluoroN((4R)-7((3 10 hydroxy-l1-piperidinyl)methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide; (3ST-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-(( 1R)-6-((( 1,1 dimethylethyl)amino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; ( 3 S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-(( 1R)-6 ((cyclopentylamino)methyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide; 15 ( 3 S7-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N(( 1R)-6-( 1 -piperidinyl methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; ( 3 S)- 3 -((( 4 -chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-(( 1R)-6-(((2-methylpropyl) amino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-(( 1R)-6-((( I -methylethyl) 20 amino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; ( 3 S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N(( 1R)-6-(((cyclopropyl methyl)amino)methyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide; ( 35 )- 3 -((( 4 -chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-(( 1R)-6-((cyclobutylamino) methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; 25 ( 3 S)-3 -(((4-chloro-2,5 -dimethylphenyl)sulfonyl)amino)-N-((I R)-6-(((3 S)-3 -hydroxy- 1 piperidinyl)methyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide; ( 3 S)- 3 -((( 4 -chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((I R)-6-( 1 -pyrrolidinyl methyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3 -(((4-chloro-2,5 -dimethylphenyl)sulfonyl)amino)-N((4R)7(((, 1, 30 dimethylethyl)amino)methyl)-3 ,4-dihydro-2H-chromen-4-yl)butanamide; ( 3 SJ- 3 -((( 4 -chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4R)-7-(cyclopentylamino). methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide; (35)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4R)7( 1 -piperidinyl methyl)-3 ,4-dihydro-2H-chromen-4-yl)butanamide; 169 WO 2006/036664 PCT/US2005/033659 (3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4R)-7-(((2-methylpropyl) amino)methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide; (3S)-3 -((( 4 -chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4R)-7-(((1 -methylethyl) amino)methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide; 5 (3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4R)-7-(((cyclopropyl methyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide; (3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4R)-7-((cyclobutylamino) methyl)- 3 , 4 -dihydro-2H-chromen-4-yl)butanamide; ( 3 S)- 3 -(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4R)-7-((( 3 S)-3 -hydroxy- 1 10 piperidinyl)methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide; (3S)- 3 -((( 4 -chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4R)-7-(1-pyrrolidinyl methyl)- 3 , 4 -dihydro-2H-chromen-4-yl)butanamide; (3S)-3-(((4-chloro-3-(trifluoromethyl)phenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((lR) 6-(1 -piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; 15 (3S)-3-(((5-chloro- 1-naphthalenyl)sulfonyl)amino)-N-((1R)-6-((cyclopentylamino) methyl)- 1, 2 ,3,4-tetrahydro- 1 -naphthalenyl)butanamide; ( 3 S)- 3 -((( 6 -chloro-2-naphthalenyl)sulfonyl)amino)-N-((1R)-6-((((6-chloro-2 naphthalenyl)sulfonyl)(cyclopentyl)amino)methyl)- 1, 2 , 3 ,4-tetrahydro- 1 -naphthalenyl) butanamide; 20 ( 3 S)- 3 -(((6-chloro-2-naphthalenyl)sulfonyl)amino)-N-((IR)- 6 -((cyclopentylamino) methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; ( 3 S)- 3 -(((6-chloro-2-naphthalenyl)sulfonyl)amino)-N-((1R)-6-(1 -piperidinylmethyl) 1, 2 ,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-((1,1 '-biphenyl-3-ylsulfonyl)amino)-N-((1R)-6-(1 -piperidinylmethyl)- 1,2,3,4 25 tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-((1, 1'-biphenyl-4-ylsulfonyl)amino)-N-((1R)-6-(((1, I -dimethylethyl) amino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-((1,1'-biphenyl-4-ylsulfonyl)amino)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4 tetrahydro- 1 -naphthalenyl)butanamide; 30 (3S)-3-((2,3-dihydro- I-benzofuran-5-ylsulfonyl)amino)-4,4,4-trifluoro-N-((1R)-6-( 1 piperidinylmethyl)- 1, 2 , 3 ,4-tetrahydro- 1 -naphthalenyl)butanamide; ( 3 S)- 3 -(methyl((3-(trifluoromethyl)phenyl)sulfonyl)amino)-N-((1R)-6-(1 -piperidinyl methyl)- 1,2,3,4-tetrahydro- I -naphthalenyl)butanamide; 170 WO 2006/036664 PCT/US2005/033659 ( 3 S)- 4 , 4 , 4 -trifluoro-3-((2-naphthalenylsulfonyl)amino)-N-((1R)-6-(1 -piperidinyl methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; ( 3 S)- 4 , 4 , 4 -trifluoro-3-((2-naphthalenylsulfonyl)amino)-N-((1R)-6-(1 -piperidinyl methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; 5 ( 3 S)- 4 , 4 , 4 -trifluoro-3-((2-naphthalenylsulfonyl)amino)-N-((1R)-6-(1 -(1 -piperidinyl methyl)ethenyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-4,4,4-trifluoro-3-((6-isoquinolinylsulfonyl)aming)-N-((1R)-6-(1 -piperidinyl methyl)- 1, 2 ,3,4-tetrahydro- 1 -naphthalenyl)butanamide; ( 3 S)- 4 ,4, 4 -trifluoro-3-(methyl((3-(trifluoromethyl)phenyl)sulfonyl)amino)-N-((1R)-6 10 (1 -piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; ( 3 S)-4,4,4-trifluoro-N-((lR)- 6 -(((( 2 R)-tetrahydro-2-furanylmethyl)amino)methyl) 1,2,3,4-tetrahydro- I-naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; ( 3 S)-4,4,4-trifluoro-N-((1R)- 6 -(((( 2 S)-tetrahydro-2-furanylmethyl)amino)methyl) 1, 2 ,3,4-tetrahydro- 1-naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 15 (3S)-4,4,4-trifluoro-N-((1R)-6-(((1 -methylethyl)amino)methyl)- 1, 2 ,3,4-tetrahydro- 1 naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; ( 3 S)-4,4,4-trifluoro-N-((l R)-6-(((2-(1 -piperidinyl)ethyl)amino)methyl)- 1,2,3,4 tetrahydro- 1-naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; ( 3 S)-4,4,4-trifluoro-N-((l R)-6-(((2-(1 -pyrrolidinyl)ethyl)amino)methyl)- 1,2,3,4 20 tetrahydro- 1-naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-4,4,4-trifluoro-N-((lR)-6-(((2-(4-morpholinyl)ethyl)amino)methyl)-1,2,3,4 tetrahydro- 1-naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-4,4,4-trifluoro-N-((1R)-6-(((2-hydroxy- 1,1 -dimethylethyl)amino)methyl)- 1,2,3,4 tetrahydro- 1-naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 25 ( 3 S)-4,4,4-trifluoro-N-((1R)- 6 -((( 2 -methylpropyl)amino)methyl)- 1,2,3,4-tetrahydro- 1 naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-4,4,4-trifluoro-N-((l R)-6-(((3S)-3-hydroxy- 1 -piperidinyl)methyl)- 1,2,3,4 tetrahydro- 1-naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; ( 3 S)-4,4,4-trifluoro-N-((l R)-6-((4-fluoro- 1 -piperidinyl)methyl)- 1,2,3,4-tetrahydro- 1 30 naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-4,4,4-trifluoro-N-((1 R)-6-((4-hydroxy- 1 -piperidinyl)methyl)- 1, 2 ,3,4-tetrahydro- 1 naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; ( 3 S)-4,4,4-trifluoro-N-((l R)-6-((4-methyl- 1 -piperazinyl)methyl)- 1,2,3,4-tetrahydro- 1 naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 171 WO 2006/036664 PCT/US2005/033659 (3S)-4,4,4-trifluoro-N-(( 1 R)-6-((4-methyl- 1 -piperidinyl)methyl)- 1 ,2,3,4-tetrahydro- 1 naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-4,4,4-trifluoro-N-(( 1R)-6-( 1 -(1 -piperidinylmethyl)ethenyl)- 1,2,3 ,4-tetrahydro- 1 naphthalenyl)-3-(((2,4,6-trimethylphenyl)sulfonyl)amino)butanamide; 5 (3S)-4,4,4-trifluoro-N-(( 1R)-6-( 1 -piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 naphthalenyl)-3-(((3 -(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-4,4,4-trifluoro-N-(( 1R)-6-( 1 -piperidinylmethyl)- 1,2,3 ,4-tetrahydro- 1 naphthalenyl)-3-(((2,4,6-trimethylphenyl)sulfonyl)amino)butanamide; (3S)-4,4,4-trifluoro-N-((1R)-6-(1 -piperidmnylmethyl)- 1,2,3,4-tetrahydro-1I 10 naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-4,4,4-trifluoro-N-(( 1R)-6-( 1 -pyrrolidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-4,4,4-trifluoro-N-(( 1 R)-6-(4-morpholinylmethyl)- 1 ,2,3,4-tetrahydro- 1 naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 15 (3S)-4,4,4-trifluoro-N-(( 1R)-6-(hydroxymethyl)- 1,2,3 ,4-tetrahydro- I -naphthalenyl)-3 (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-4,4,4-trifluoro-N-((4R)-7-(((2-methylpropyl)amino)methyl)-3,4-dihydro-2H chromen-4-yl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-4,4,4-trifluoro-N-((4R)-7-(((3R)-3-hydroxy- 1 -piperidinyl)methyl)-3 ,4-dihydro-2H 20 chromen-4-yl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-4,4,4-trifluoro-N-((4R)-7-((4-methyl- 1 -piperazinyl)methyl)-3,4-dihydro-2H chromen-4-yl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-4,4,4-trifluoro-N-((4R)-7-( 1 -piperidinylmethyl)-3 ,4-dihydro-2H-chromen-4-yl)-3 (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 25 (3S)-4,4,4-trifluoro-N-((4R)-7-(4-morpholinylmethyl)-3,4-dihydro-21-chromen-4-yl) 3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (35)-4-fluoro-N-(( 1R)-6-( 1 -piperidinylmethyl)- 1 ,2,3,4-tetrahydro- I -naphthalenyl)-3 (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (35)-N-(( 1R)-6-((( 1,1 -dimethylethyl)amino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl) 30 3-(((3 -(trifluoromethyl)phenyl)sulfonyl)amino)-5-hexynamide; (38)-N-(( 1R)-6-((( 1 -dimethylethyl)amino)methyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl) 4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-(( 1R)-6-((( 1,1 -dimethylethyl)amino)methyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl) 3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 172 WO 2006/036664 PCT/US2005/033659 (3S)-N-((1R)-6-((( 1,1 -dimethylethyl)amino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl) 4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((1R)-6-(((1,1 -dimethylethyl)amino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl) 3-(((2-nitro-4-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 5 (3S)-N-((1R)-6-(((2-(acetylamino)ethyl)amino)methyl)- 1,2,3,4-tetrahydro- 1 naphthalenyl)-4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((1 R)-6-(((2-(diethylamino)ethyl)amino)methyl)- 1,2,3,4-tetrahydro- 1 naphthalenyl)-4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((1R)-6-(((2-(dimethylamino)ethyl)amino)methyl)-1,2,3,4-tetrahydro-1 10 naphthalenyl)-4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((1R)-6-(((2-(methyloxy)ethyl)amino)methyl)- 1,2,3,4-tetrahydro- 1 naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((lR)-6-(((2,2-dimethylpropyl)amino)methyl)- 1,2,3,4-tetrahydro- 1-. naphthalenyl)-4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 15 (3S)-N-((1 R)-6-(((2-methylpropyl)amino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-3 (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((1 R)-6-(((2R,6S)-2,6-dimethyl- 1 -piperidinyl)methyl)- 1,2,3,4-tetrahydro- 1 naphthalenyl)-4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((1 R)-6-(((cyclopropylmethyl)amino)methyl)- 1,2,3,4-tetrahydro- 1 20 naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((1 R)-6-((1 R)- 1 -((2-(methyloxy)ethyl)amino)ethyl)- 1,2,3,4-tetrahydro- 1 naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((1R)-6-((1 R)- 1 -(cyclobutylamino)ethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-3 (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 25 (3S)-N-((1R)-6-((1 R)- 1 -(cyclopropylamino)ethyl)- 1,2,3,4-tetrahydro- I -naphthalenyl) 3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((1R)-6-((1 S)- 1 -((2-methylpropyl)amino)ethyl)- 1,2,3,4-tetrahydro- 1 naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((1 R)-6-((l S)- 1 -((cyclopropylmethyl)amino)ethyl)- 1,2,3,4-tetrahydro- 1 30 naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((lR)-6-((1 S)- 1 -(cyclopentylamino)ethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-3 (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((l R)-6-((3-pyridinylamino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-3 -(((3 (trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 173 WO 2006/036664 PCT/US2005/033659 -Yo -kin)-u-kLyL~AuuuLyluitno)memnyi)- i,4,4,-tetralydiro-lI-naphthalenyl)-4,4,4 trifluoro- 3 -(((3-(tiinuoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-(( lR)-6-((cyclohexylamino)methyl).1 ,2,3,4-tetrahydro-l1-naphthalenyl)-4,4,4 trifluoro- 3 -(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 5 (3S)-N-(( lR)- 6 -((cyclopentyl((2-fluoro5-trifluoromethy)pheny)sufony)amin) methyl)- 1,2,3 ,4-tetrahydro-l1-naphthalenyl)-3-(((2-fluoro-5-(trifluoromethy)pheny). sulfonyl)amino)butanamide; (3S)-N-(( 1R)-6-((cyclopentylamino)methyl). 1,2,3 ,4-tetrahydro-l1-naphthalenyl)-3 -(((3 (trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 10 (3S)-N-(( lR)- 6 -((cyclopentylamino)methyl) 1 ,2,3,4-tetrahydro-l1-naphthalenyl)-4,4,4 trifluoro- 3 -(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-(( lR)-6-((cyclopentylamino)methyly 1 ,2,3,4-tetrahydro-l1-naphthalenyl)-3-(((2 floo5(rfurmty~hnlsloy~mn~uaaie (3S)-N-(( 1R)- 6 -((cyclopentylamino)methyl> 1 ,2,3,4-tetrahydro-l1-naphthalenyl)-4,4,4 15 trfur--mty(3(rfurmty~hnlsloy~mn~uaaie (35)-N-(( 1R)-6-( 1-(1 -piperidinylinethyl)ethenyl)- 1,2,3,4-tetrahydro-l1-naphthalenyl)-3 ((( 3 -(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-(( 1R)-6-( 1-azepanylmethyl)- 1,2,3,4-tetrahydro-l1-naphthalenyl)-4,4,4-trifluoro 3 -((( 3 -(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 20 (3S)-N-(( 1R)-6-( 1-azepanylmethyl)- 1,2,3,4-tetrahydro-l1-naphthalenyl)-3-(((4-chloro 2 ,5-dimethylphenyl)sulfonyl)amino)4,4,4trifluorobutanamide; (3S)-N-(( 1R)-6-( 1-azepanylmethyl)- 1,2,3,4-tetrahydro-l1-naphthalenyl)-3-(((3-chloro-4 methylphenyl)sulfonyl)amino)-4,4,4-trifluorobutanamide; (3S)-N-(( 1R)-6-( 1-azepanylmethyl)- 1,2,3,4-tetrahydro-l1-naphthalenyl)-3-(((3,4 25 bis(methyloxy)phenyl)sulfonyl)amino)-4,4,4.trifluorobutanamide; (3S)-N-(( 1R)-6-(1I-piperidinylmethyl)- 1,2,3,4-tetrahydro-l1-naphthalenyl)-3 -(((3 (trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-(( 1R)-6-( I-pyrrolidinylmethyl)- 1,2,3,4-tetrahydro-l1-naphthalenyl)-3-(((3 (trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 30 (3S)-N-(( 1R)-6-acetyl- 1,2,3,4-tetrahydro-l1-naphthalenyl)-3-(((3-(trifluoromethyl). phenyl)sulfonyl)amino)butanamide; (3S)-N-(( 1R)-6-formyl- 1,2,3,4-tetrahydro-l1-naphthalenyl)-3-(((3-(trifluoromethyl) phenyl)sulfonyl)amino)butanamide; 174 WO 2006/036664 PCT/US2005/033659 (3S)-N-((4R)-6-chloro-7-((( 1,1-dimethylethyl)ammno)methyl)-3 ,4-dihydro-2H-chromen 4-yl)-4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((4R)-7-((( 1,1 -dimethylethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl) 4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 5 (3S)-N-((4R)-7-((( 1,1 -dimethylethyl)amino)methyl)-3 ,4-dihydro-2H-chromen-4-yl)-3 (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((4R)-7-((( 1-methylethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)-3-(((3 (trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((4R)-7-(((2-(methyloxy)ethyl)amino)methyl)-3,4-dihydro-2H-cbromen-4-yl)-3 10 (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((4R)-7-(((2,2-dimethylpropyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl) 4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((4R)-7-(((2-methylpropyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)-3 (((3-(trifluoromethyl)phenyl)sulfonyl)aniino)butanamide; 15 (3S)-N-((4R)-7-(((3R)-3-hydroxy-l1-piperidinyl)methyl)-3,4-dihydro-2H-chromen-4 yl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((4R)-7-(((cyclopropylmethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)-3 (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((4R)-7-((4-methyl- 1 -piperazinyl)methyl)-3 ,4-dihydro-2H-chromen-4-yl)-3 20 (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((4R)-7-((cyclohexylamino)methyl)-3,4-dihydro-2H-chromen-4-yl)-4,4,4 trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((4R)-7-((cyclopentylamino)methyl)-3,4-dihydro-2H-chromen-4-yl)-3-(((3 (trifluoromethyl)phenyl)sulfonyl)amino)butanamide; 25 (3S)-N-((4R)-7-((cyclopropylamino)methyl)-3,4-dihydro-2H-chromen-4-yl)-3-(((3 (trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((4R)-7-( 1 -azepanylmethyl)-3 ,4-dihydro-2H-chromen-4-yl)-3-(((4-chloro-2,5 dimethylphenyl)sulfonyl)amino)-4,4,4-trifluorobutanamide; (3S)-N-((4R)-7-( 1 -azepanylmethyl)-3,4-dihydro-2H-chromen-4-yl)-4,4,4-trifluoro-3 30 (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (35)-N-((4R)-7-( 1 -piperidinylmethyl)-3,4-dihydro-2H-chromen-4-yl)-3-(((3-(trifluoro methyl)phenyl)sulfonyl)amino)butanamide; (3.S)-N-((4R)-7-( 1 -pyrrolidinylmethyl)-3,4-dihydro-2H-chromen-4-yl)-3- (((3-(trifluoro methyl)phenyl)sulfonyl)amino)butanamide; 175 WO 2006/036664 PCT/US2005/033659 1,1 -ulmemyemy y-z-'v-L- ,+-aicmoropnenyl)sullony)-v-4-(( K)-6-(I -pipendinyl methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-D-alpha-asparaginate; 1,1 -dimethylethyl N-2-((3,4-dichlorophenyl)sulfonyl)-N-4-((1R)-6-(hydroxymethyl) 1,2,3,4-tetrahydro- 1 -naphthalenyl)-D-alpha-asparaginate; 5 1,1 -dimethylethyl N-2-((3,4-dichlorophenyl)sulfonyl)-N-4-((1R)-6-((( 1,1 -dimethyl ethyl)amino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-D-alpha-asparaginate; 1,1 -dimethylethyl N-2-((3,4-dichlorophenyl)sulfonyl)-N-4-((1R)-6-(1 -pyrrolidinyl methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-D-alpha-asparaginate; 2-((2R)-2-methyl-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1 10 piperidinylmethyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)acetamide; 2 -(3,4-dichloro-benzenesulfonylamino)-N-(6-pyrrolidin-1 -ylmethyl- 1,2,3,4-tetrahydro naphthalen-1-yl)-succinamic acid; 3 -( 2 -chloro-5-trifluoromethyl-benzenesulfonylamino)-N-(6- {[(2-chloro-5-trifluoro methyl-benzenesulfonyl)-cyclopentyl-amino]-methyl} -1,2,3,4-tetrahydro-naphthalen-1 -yl) 15 butyramide; 3-(6-bromo- 1,1 -dioxido-3-oxo- 1,2-benzisothiazol-2(3H)-yl)-N-((1R)-6-(1 -piperidinyl methyl)- 1,2,3,4-tetrahydro-1 -naphthalenyl)propanamide; 3-(6-bromo-1,1 -dioxido-3-oxo- 1,2-benzisothiazol-2(3H)-yl)-N-((1R)-6-(((1,1 dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro- 1 -naphthalenyl)propanamide; 20 3 R-(3, 4 -dichloro-benzenesulfonylamino)-4,4,4-trifluoro-N-(6-piperidin-1 -ylmethyl 1,2,3,4-tetrahydro-naphthalen- 1 -yl)-butyramide; 3S-(3, 4 -dichloro-benzenesulfonylamino)-4,4,4-trifluoro-N-(6-piperidin-1 -ylmethyl 1,2,3,4-tetrahydro-naphthalen- 1 -yl)-butyramide; N-1 -((1R)-6-((( 1,1 -dimethylethyl)amino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-N 25 3 -phenyl-N- 3 -((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide; N-1 -((lR)-6-((( 1,1 -dimethylethyl)amino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-N 3-(3-(trifluoromethyl)phenyl)-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide; N-1 -((lR)-6-((( 1,1 -dimethylethyl)amino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-N 3-( 4 -fluorophenyl)-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide; 30 N-i -((lR)-6-((( 1,1 -dimethylethyl)amino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl)-N 3 -methyl-N- 3 -((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide; N-1 -((I R)- 6 -(((2,2-dimethylpropyl)amino)methyl)- 1,2,3,4-tetrahydro- 1 -naphthalenyl) N- 3 -( 4 -fluorophenyl)-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide; 176 WO 2006/036664 PCT/US2005/033659 N- I -(( iR)-6-(( 1S)- I -(cyclopentylamino)ethyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)-N-3 phenyl-N-3-((3 -(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide; N- I -(( 1R)-6-(( 1S)-i1 -(cyclopentylamino)ethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthaienyl)-N-3 methyl-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide; 5 N- I -(( 1R)-6-((4-fluoro- 1 -piperidinyl)methyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)-N-3 phenyl-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide; N- I -(( iR)-6-((4-fluoro- 1 -piperidinyl)methyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)-N-3 methyl-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide; N-i -(( iR)-6-((cyclopentylamino)methyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)-N-3-(4 10 fluorophenyl)-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide; N- I -(( 1R)-6-((diethylammno)methyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)-N-3-(4 fluorophenyl)-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide; N- I -(( iR)-6-( 1 -piperidinyimethyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)-N-3-((3 (trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide; 15 N-i1 -(( 1R)-6-( 1 -piperidmnylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyi)-N-3-(4 (trifluoromethyl)phenyl)-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide; N-2-((3 ,4-dichlorophenyl)sulfonyl)-N-4-(( iR)- 1 ,2,3,4-tetrahydro- I -naphthalenyl)-D aspartamide; N-2-((3 ,4-dichlorophenyl)sulfonyl)-N-4-(( LR)-6-(((, 1, -dimethylethyl)amino)methyl) 20 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)-D-aspartamide; N-2-((3,4-dichlorophenyl)sulfonyl)-N-4-(( iR)-6-((( 1 -dimethylethyl)amino)methyl) 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-D-asparagine; N-2-((3 ,4-dichlorophenyl)sulfonyl)-N-4-(( IR)-6-(((2-methylpropyl)amino)methyl) 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-D-aspartamide; 25 N-2-((3 ,4-dichlorophenyl)sulfonyl)-N-4-(( iR)-6-((4-fluoro-l1-piperidinyl)methyl) 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)-D-aspartamide; N-2-((3,4-dichlorophenyl)sulfonyl)-N-4-(( iR)-6-( 1 -piperidinylmethyl)- 1,2,3,4 tetrahydro- 1 -naphthalenyl)-D-aspartamide; N-2-((3 ,4-dichlorophenyl)sulfonyl)-N-4-(( 1R)-6-(l1-piperidinylmethyl)- 1,2,3,4 30 tetrahydro- 1 -naphthalenyl)-D-asparagine; N-2-((3,4-dichlorophenyl)sulfonyl)-N-4-(( iR)-6-( 1 -pyrrolidinylmethyl)- 1,2,3,4 tetrahydro- 1 -naphthalenyl)-D-aspartamide; N-2-((3 ,4-dichlorophenyl)sulfonyl)-N-4-(( iR)-6-(hydroxymethyl)- 1,2,3 ,4-tetrahydro- I1 naphthalenyl)-D-aspartamide; 177 WO 2006/036664 PCT/US2005/033659 N-2-((4-methylphenyl)sulfonyl)-N-4-(( LR)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-D aspartamide; N-2-((4-methylphenyl)sulfonyl)N4(( 1R)-6-( 1 -piperidinylmethyl)- 1 ,2,3,4-tetrahydro 1 -naphthalenyl)-D-aspartamide; 5 N-2-((4-methylphenyl)sulfonyl)-N-4-(( 1 R)-6-( 1 -piperidinylmethyl)- 1,2,3 ,4-tetrahydro I -naphthalenyl)-D-asparagine; N- 3 -((2-aminophenyl)sulfonyl)-N- 1-((4R)-7-( 1-piperidinylmethyl)-3 ,4-dihydro-2H chromen-4-yl)-beta-alaninamide; N-3-((2-nitrophenyl)sulfonyl)-N- 1-((4R)-7-( 1-piperidinylnethyl)-3,4-dihydro-2. 10 chromen-4-yl)-beta-alaninamide; N-3-((3,4-dichlorophenyl)sulfonyl)yN 1 -(( 1R)-6-(((, 1, -dimethylethyl)amino)methyl) 1 ,2,3,4-tetrahydro- 1 -nptaey)N3(-loohnl-eaaaiaie N-3-( 1 -methylethyl)-N- 1 -(( 1R)-6-( 1 -piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 naphthalenyl)-N- 3 -((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide; 15 N-3-(2-amino-2-oxoethyl)-N- 1 -(( 1R)-6-(((, 1, -dimnethylethyl)amino)methyl)- 1,2,3,4 tetrahydro- 1 -naphthalenyl)-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaminamide; N-3-(2-fluoroethyl)-N- 1 -(( 1R)-6-( 1 -piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 naphthalenyl)-N-3-((3-(trifluoromethyl)phenyl)sulfonyl).beta-alaninamide; N-3-(2-naphthalenylsulfonyl)-N-3-(phenylmethyl)-N I -((4R)-7-( 1 -piperidinylinethyl) 20 3 , 4 -dihydro-2H-chromen-4-yl)-beta-alaninamide; N-3-(2-naphthalenylsulfonyl)-N-3-phenyl.N- 1 -((4R)-7-( 1 -piperidmnylmethyl)-3,4 dihydro-2H-chromen-4-yl)-beta-alaninamide; N-3-(3-amino-3-oxopropyl)-N- 1 -(( 1R)-6-(((, 1, -dimethylethyl)amino)methyl)- 1,2,3,4 tetrahydro- 1 -naphthalenyl)-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta.alaminamide; 25 N-3-(4-fluorophenyl)-N- 1 -(( lR)- 6 -((( 2 -methylpropyl)amino)methyl)- 1,2,3,4 tetrahydro- Il-naphthalenyl)-N- 3 -((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaminamide; N-3-(4-fluorophenyl)-N- 1 -(( 1R)-6-((4-fluoro- 1 -piperidinyl)methyl)- 1,2,3 ,4-tetrahydro 1 -naphthalenyl)-N-3-((3 -(trifluoromethyl)phenyl)sulfonyl)-beta.alaninamide; N-3-cyclohexyl-N- 1 -(( 1R)-6-( 1 -piperidinylmethyl)- 1,2,3 ,4-tetrahydro- I -naphthalenyl) 30 N- 3 -(( 3 -(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide; N-3-cyclopropyl-N- 1 -(( 1R)-6-((( 1,1 -dimethylethyl)amino)methyl)- 1,2,3 ,4-tetrahydro- I1 naphthalenyl)-N- 3 -((3-(trifluoromethy)pheny)sulfonyl)>beta.alannamide; N-3-cyclopropyl-N- 1 -(( 1R)-6-( 1 -piperidinylmethyl)- 1 ,2,3,4-tetrahydro- I1 naphthalenyl)-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)>beta-alannamide; 178 WO 2006/036664 PCT/US2005/033659 N-3-methyl-N- 1-(( 1R)-6-( 1-piperidinylmethyl)- 1,2,3 ,4-tetrahydro-l1-naphthalenyl)-N-3 ((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide; N-4-(( 1R)-6-((( 1,1-dimethylethyl)amino)methyl)- 1,2,3,4-tetrahydro-l1-naphthalenyl)-N 2-((4-methylphenyl)sulfonyl)-D-aspartamide; 5 N-4-((4R)-6-chloro-7-methyl-3 ,4-dihydro-2H-chromen-4-yl)-N-2-((3,4 dichlorophenyl)-sulfonyl)-D-aspartamide; N-4-((4R)-6-chloro-7-methyl-3 ,4-dihydro-2H-chromen-4-yl)-N-2-((4-methylphenyl) sulfonyl)-D-aspartamide; phenylmethyl N-2-((4-methylphenyl)sulfonyl)-N-4-(( 1 R)-6-( 1 -piperidinylmethyl) 10 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-D-alpha-asparaginate; (R)-4,4,4-trifluoro-N-((R)-6-(piperidin- 1 -ylmethyl)- 1 ,2,3,4-tetrahydronaphthalen- Il-yl) 3-(2-(trifluoromethyl)phenylsulfonamido)butanamide; (R)-3 -(3 -bromophenylsulfonamido)-4,4,4-trifluoro-N-((R)-6-(piperidin- 1 -ylmethyl) 1,2,3 ,4-tetrahydronaphthalen- 1 -yl)butanamide; 15 (R)-3-(3-chloro-4-fluorophenylsulfonamido)-4,4,4-trifluoro-N-((R)-6-(piperidin- 1 ylmethyl)- 1,2,3 ,4-tetrahydronaphthalen- 1 -yl)butanamide; (R)-4,4,4-trifluoro-N-methyl-N-((R)-7-(piperidin- 1 -ylmethyl)chroman-4-yl)-3-(3 (trifluoromethyl)phenylsulfonamido)butanamide; (R)-4,4,4-trifluoro-N-((R)-6-(piperidin- 1 -ylmethyl)- 1,2,3 ,4-tetrahydronaphthalen- Il-yl) 20 3-(4-(trifluoromethoxy)phenylsulfonamido)butanamide; (R)-4,4,4-trifluoro-3-(3-methylphenylsulfonamido)-N-((R)-6-(piperidin- 1 -ylmethyl) 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide (R)-3-(4-chloro-2-fluorophenylsulfonamido)-4,4,4-trifluoro-N-((R)-6-(piperidm- Il-yl methyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide; 25 (R)-3-(2-chloro-4-fluorophenylsulfonamido)-4,4,4-trifluoro-N-((R)-6-(piperidin- Il-yl methyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide; (R)-tert-butyl 2-(naphthalene-3-sulfonamido)-4-oxo-4-((R)-6-(piperidin- 1-ylmethyl) 1,2,3 ,4-tetrahydronaphthalen- 1 -ylamino)butanoate; (R)-4,4,4-trifluoro-N-((R)-6-((4-methylpiperidin- 1 -yl)methyl)- 1,2,3,4 30 tetrahydronaphthalen- 1 -yl)-3-(3-(trifluoromethyl)phenylsulfonamido)butanamide; (R)-methyl 4-oxo-4-((R)-6-(piperidin- 1 -ylmethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 ylamino)-2-(3-(trifluoromethyl)phenylsulfonamido)butanoate; (R)-4-oxo-4-((R)-6-(piperidin- 1 -ylmethyl)- 1 ,2,3,4-tetrahydronaphthalen- I -ylamino)-2 (3-(trifluoromethyl)phenylsulfonamido)butanoic acid; 179 WO 2006/036664 PCT/US2005/033659 (R)-N1 -((R)-6-(piperidin- I -ylmethyl)- 1 ,2,3,4-tetrahydronaphthalen-I -yl)-3-(3 (trifluoromethyl)phenylsulfonamido)succinamide; (R)-3-cyano-N-((R)-6-(piperidin- 1 -ylmethyl)- 1,2,3 ,4-tetrahydronaphthalen- Il-yl)-3-(3 (trifluoromethyl)phenylsulfonamido)propanamide; 5 (R)-2-(naphthalene-3-sulfonamido)-4-oxo-4-((R)-6-(piperidin- 1 -ylmethyl)- 1,2,3,4 tetrahydronaphthalen- 1-ylamino)butanoic acid; (R)-methyl 2-(naphthalene-3-sulfonamido)-4-oxo-4-((R)-6-(piperidin- 1 -ylmethyl) 1 ,2,3,4-tetrahydronaphthalen- 1 -ylamino)butanoate; (R)-3 -(3 -tert-butylphenylsulfonamido)-4,4,4-trifluoro-N-((R)-6-(piperidin- 1 -ylmethyl) 10 1,2,3 ,4-tetrahydronaphthalen- 1 -yl)butanamide; (R)-methyl 2-(3,4-dichlorophenylsulfonamido)-4-oxo-4-((R)-6-(pyrrolidin- 1-ylmethyl) 1 ,2,3,4-tetrahydronaphthalen- 1 -ylamino)butanoate; (R)-4,4,4-trifluoro-3-(3-(oxazol-5-yl)phenylsulfonamido)-N-((R)-6-(piperidin- 1 ylmethyl)- 1,2,3 ,4-tetrahydronaphthalen- 1 -yl)butanamide; 15 (R)-3 -(3 ,4-dihydro-2H-benzo[b] [ 1,4] dioxepine-8-sulfonamido)-4,4,4-trifluoro-N-((R) 6-(piperidin- 1 -ylmethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide; (R)-N-((S)-6-(4,5-dihydro- 1 H-imidazol-2-yl)- 1,2,3 ,4-tetrahydronaphthalen-2-yl)-4,4,4 trifluoro-3-(3-(trifluoromethyl)phenylsulfonamido)butanamide; (R)-4,4,4-trifluoro-N-((R)-6-(piperidin- 1 -ylmethyl)- 1 ,2,3,4-tetrahydronaphthalen- Il-yl) 20 3-( 1,2,3,4-tetrahydroquinoline-8-sulfonamido)butanamide; (R)-4,4,4-trifluoro-3-(4-methyl-3,4-dihydro-2H-benzo[b] [ 1,4]oxazine-7-sulfonamido) N-((R)-6-(piperidin- 1 -ylmethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide; (R)-3-(3-chloro-2-fluorophenylsulfonamido)-4,4,4-trifluoro-N-((R)-6-((4 methylpiperidin- 1 -yl)methyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide; 25 (R)-4,4,4-trifluoro-N-((R)-5 -nitro-6-(piperidin- 1 -ylmethyl)- 1,2,3,4 tetrahydronaphthalen- 1 -yl)-3 -(3 -(trifluoromethyl)phenylsulfonamido)butanamide; (R)-4,4,4-trifluoro-N-((R)-6-(((S)-2-(pyrrolidin- 1 -ylmethyl)pyrrolidin- 1 -yl)methyl) 1,2,3 ,4-tetrahydronaphthalen- 1 -yl)-3-(3-(trifluoromethyl)phenylsulfonamido)butanamide; (R)-3-(3-chloro-2-fluoro-N-methylphenylsulfonamido)-4,4,4-trifluoro-N-methyl-N 30 ((R)-7-(piperidin- 1 -ylmethyl)chroman-4-yl)butanamide; (R)-4,4,4-trifluoro-N-((R)-7-nitro-6-Qpiperidin- 1 -ylmethyl)- 1,2,3,4 tetrahydronaphthalen- 1 -yl)-3-(3-(trifluoromethyl)phenylsulfonamido)butanamide; (R)-4,4,4-trifluoro-3-(3-methoxyphenylsulfonamido)-N-((R)-6-(piperidin- 1 -ylmethyl) 1,2,3 ,4-tetrahydronaphthalen- 1 -yl)butanamide; 180 WO 2006/036664 PCT/US2005/033659 (R)-3-(3,5-dimethylphenylsulfonamido)-4,4,4-trifluoro-N-((R)-6-(piperidin- 1 ylmethyl)- 1,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide; (R)-3-(3,4-dimethylphenylsulfonamido)-4,4,4-trifluoro-N-((R)-6-(piperidin-1 ylmethyl)- 1,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide 5 (2R,3R)-3-(3-chloro-2-fluorophenylsulfonamido)-N-((R)-6-chloro-7-(piperidin- 1 ylmethyl)chroman-4-yl)-4,4,4-trifluoro-2-hydroxybutanamide; (R)-4,4,4-trifluoro-3-(2-fluoro-5-methylphenylsulfonamido)-N-((R)-6-(piperidin- 1 ylmethyl)- 1,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide; (R)-4,4,4-trifluoro-N-((R)-6-(piperidin- 1 -ylmethyl)- 1,2,3,4-tetrahydronaphthalen- 1-yl) 10 3-(4-(trifluoromethyl)phenylsulfonamido)butanamide; (2R,3R)-3-(2,5-dichlorophenylsulfonamido)-4,4,4-trifluoro-2-hydroxy-N-((R)-6 (piperidin- 1 -ylmethyl)- 1,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide; (2R,3R)-3-(2,3-dichlorophenylsulfonamido)-4,4,4-trifluoro-2-hydroxy-N-((R)-6 (piperidin- 1 -ylmethyl)- 1,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide; 15 (2R,3R)-3-(3,4-dichlorophenylsulfonamido)-4,4,4-trifluoro-2-hydroxy-N-((R)-6 (piperidin- 1 -ylmethyl)- 1,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide; (R)-3-(2-chloro-6-methylphenylsulfonamido)-4,4,4-trifluoro-N-((R)-6-(piperidin-1 ylmethyl)- 1,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide; (R)-4,4,4-trifluoro-3-(5-fluoro-2-methylphenylsulfonamido)-N-((R)-6-(piperidin- 1 20 ylmethyl)- 1,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide; (R)-4,4,4-trifluoro-N-((R)-7-(piperidin- 1 -ylmethyl)chroman-4-yl)-3-(3 (trifluoromethyl)phenylsulfonamido)butanamide; and (R)-3-(4-ethylphenylsulfonamido)-4,4,4-trifluoro-N-((R)-6-(piperidin-1-ylmethyl) 1,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide; 25 or a pharmaceutically acceptable salt thereof.
17. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of any of the Claims 1-16.
18. The use of a compound of any of the Claims 1-16 in the manufacture of a medicament for the treatment of a disease condition mediated by bradykinin in a mammalian subject. 30 19. The use of Claim 15 wherein the disease is inflammation, rheumatoid arthritis, cystitis, post-traumatic and post ischemic cerebral edema, liver cirrhosis, Alzheimer's disease, cardiovascular disease, pain, common cold, allergies, asthma, pancreatitis, bums, virus infection, head injury, multiple trauma, rhinitis, hepatorenal failure, diabetes, metastasis, 181 WO 2006/036664 PCT/US2005/033659 pancreatitis, neovascularization, corneal haze, glaucoma, ocular pain, ocular hypertension or angio edema.
20. The use of Claim 18 wherein the disease is osteroarthritis. 182
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