WO2006036664A1 - Substituted sulfonamidopropionamides and methods of use - Google Patents

Substituted sulfonamidopropionamides and methods of use Download PDF

Info

Publication number
WO2006036664A1
WO2006036664A1 PCT/US2005/033659 US2005033659W WO2006036664A1 WO 2006036664 A1 WO2006036664 A1 WO 2006036664A1 US 2005033659 W US2005033659 W US 2005033659W WO 2006036664 A1 WO2006036664 A1 WO 2006036664A1
Authority
WO
WIPO (PCT)
Prior art keywords
amino
sulfonyl
butanamide
tetrahydro
naphthalenyl
Prior art date
Application number
PCT/US2005/033659
Other languages
French (fr)
Inventor
Jr Ben C. Askew
Toshihiro Aya
Kaustav Biswas
Guolin Cai
Jian J. Chen
Christopher H. Fotsch
Nianhe Han
Jason Brooks Human
Aiwen Li
Qingyian Liu
Tanya Peterkin
Wenyuan Qian
Babak Riahi
Chester Chenguang Yuan
Jiawang Zhu
Original Assignee
Amgen Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Amgen Inc. filed Critical Amgen Inc.
Priority to AU2005289881A priority Critical patent/AU2005289881A1/en
Priority to EP05797852A priority patent/EP1799637A1/en
Priority to CA002580461A priority patent/CA2580461A1/en
Publication of WO2006036664A1 publication Critical patent/WO2006036664A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • 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
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • 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
    • C07C311/22—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—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
    • 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
    • C07D211/38—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—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
    • 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
    • C07D233/24—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/08—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D291/00—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms
    • C07D291/08—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • 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

Definitions

  • 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.
  • NSAIDs non-steroidal anti- inflammatory drugs
  • 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.
  • Pain is a perception based on signals received from the environment and transmitted 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.
  • 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.
  • tissue damage causes 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 and nerve damage can induce hyperalgesia.
  • hyperalgesia a phenomenon in which relatively innocuous stimuli are perceived as intensely painful because the person's pain thresholds have been lowered. Both inflammation and nerve damage can induce hyperalgesia.
  • 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.
  • BK and kallidin the active peptides, BK 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 mediate the pathophysiological actions of kinins in man.
  • 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)).
  • des-Arg-BK and des-Arg-kallidin appear to be particularly important mediators of inflammation and inflammatory pain as well as being involved in the maintenance thereof.
  • Bl and B2 The membrane receptors that mediate the pleiotropic actions of kinins are of two distinct classes, designated Bl and B2. Both classes of receptors have been cloned and 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 receptor. Essentially all normal physiological responses and many pathophysio-logical responses to bradykinin are mediated by B2 receptors.
  • Bl receptors have a higher affinity for des-Arg-BK compared with
  • BK whereas des-Arg-BK is inactive at B2 receptors.
  • Bl receptors are not 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.,
  • LPS inflammatory cytokines
  • B 1 receptors inflammatory cytokines
  • the pain-inducing properties of kinins coupled with the inducible expression of B 1 receptors make the Bl 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.
  • this invention is directed to a class of compounds useful in treating inflammation and pain and having the structure of Formula (I):
  • R la and R lb are each independently, H, F, Cl, -OCH 3 , -Ci -2 alkyl or -CF 3 ;
  • R 4 is H, phenyl, benzyl or -Ci- ⁇ alkyl, the phenyl, benzyl and being substituted by 0, 1, 2 or 3 substituents independently selected from Ci ⁇ alkyl, Ci_ 3 haloalkyl, -OQ ⁇ alkyl, -NH 2 , -NHC M alkyl, and -N(C 1-4 alkyl)C M 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 11-membered bicyclic or 12-, 13-, 14- or 15- membered tricyclic hydrocarbon ring containing 0, 1, 2, 3 or 4 atoms selected from N, O 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 , R 7 or R 8 independently selected from basic moie
  • R b is independently, at each instance, phenyl, benzyl or -Ci- ⁇ alkyl, the phenyl, benzyl and -C ⁇ aHcyl, - C 1-3 haloalkyl, -OC ⁇ alkyl, -NH 2 , -NHC M alkyl, -N(C M alkyl)C M alkyl; R d is independently at each instance -Ci -8 alkyl, halo, cyano, nitro,
  • R e is independently at each instance -Ci- ⁇ alkyl substituted by 0, 1, 2 or 3 substituents independently selected from R d and additionally substituted by 0 or 1 substituents selected from R g ;
  • R la and R lb are each independently, H, F, Cl, -OCH 3 , -Ci -2 alkyl or -CF 3 ;
  • R 4 is H, phenyl, benzyl or -Ci- ⁇ alkyl, the phenyl, benzyl and being substituted by 0, 1, 2 or 3 substituents independently selected from Q ⁇ alkyl, -OC M alkyl, -NH 2 , 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 11-membered bicyclic or 12-, 13-, 14- or 15- membered tricyclic hydrocarbon ring containing 0, 1, 2, 3 or 4 atoms selected from N, O 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 , R 7 or R 8 independently selected from basic moieties, and additionally substituted by 0, 1 , 2 or 3 substituents independently selected from R 6 , R 7 and R 8 which are selected from R g
  • R b 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, -Q ⁇ alkyl, - Ciohaloalkyl, -OC M alkyl, -NH 2 , -NHC ⁇ alkyl, -N(C M alkyl)C M alkyl; R d is independently at each instance -C]. 8 alkyl, -C ⁇ haloalkyl, halo, cyano, nitro,
  • R e is independently at each instance -Ci_ ⁇ alkyl substituted by 0, 1, 2 or 3 substituents independently selected from R d and additionally substituted by 0 or 1 substituents selected from R 8 ;
  • R la and R lb are each independently, H, F, Cl, -OCH 3 , -Ci -2 alkyl or -CF 3 ;
  • the basic moieties are independently selected from amino, cycloalkylamino- (Ci-C6)alkyl, cycloalkyl(Ci-C 6 ) alkylamino(Ci-C6)alkyl, heterocyclylamino(Ci-C 6 )alkyl, heterocyc IyI(C i -C 6 )alkyl-amino(C i -C 6 )alkyl, arylamino(C i -Ce)alkyl, aryl(C i -C 6 )alkylamino- (Ci -C 6 )alkyl, (Ci -C 6 )alkylamino(Ci -C 6 )alkoxy, (Q -C 6 )alkylamino(C, -C 6 )alkoxy(Ci -C 6 )- alkoxy, amino(Ci-C 6 )
  • the basic moieties are independently selected from amino, mono-C M - alkylamino-C 1 . 4 -alkyl, di-C 1 ⁇ -alkylamino-C 1 ⁇ -alkyl, mono-C 1 ⁇ - alkylamino-C 2-4 -alkenyl, di-Ci. 4 -alkylamino-C 2-4 -aUcenyl, 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-C M -alkyl.
  • the basic moieties are independently selected from amino, aminomethyl, isopropylaminomethyl, ⁇ -butylaminomethyl, 2-f-butylaminoethyl, 2-tert-butylamino-l -methyl- ethyl, 1-tert-butylaminoethyl, l-(tert-butylamino-methyl)-vinyl, l-(piperidin-l-ylmethyl)- vinyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl, N- isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl, N- ⁇ -butyl-N- methylaminomethyl, N-wo-butyl-N-methylaminomethyl, N- ⁇ -butyl-N
  • R 1 is H
  • R 1 is -Ci -8 alkyl.
  • R 1 is -C 3- SaIlCyI. In another embodiment, in conjunction with any one of the above and below embodiments, R 1 is -CH 3 .
  • R 1 is substituted by 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 -CF 3 .
  • R la and R lb are each independently, H, F, Cl, -OCH 3 , -C ]-2 alkyl or -CF 3 .
  • R la is H and R lb F, Cl, -OCH 3 , -Ci -2 alkyl or -CF 3 .
  • R la is F, Cl, -OCH 3 , -Ci -2 alkyl or -CF 3 and R lb is H.
  • R la and R lb are each independently, H or F.
  • R lc is H or F.
  • R la , R lb , and R lc are H.
  • 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.
  • R 3 is H.
  • R 4 is phenyl, benzyl or -C ⁇ aUcyl, the phenyl, benzyl and C ⁇ alkyl being substituted by 0, 1, 2 or 3 substituents selected from C i ⁇ alkyl, -OC l-4 alkyl, -NH 2 , -NHC M alkyl, and -N(Ci. 4 alkyl)C M alkyl, and additionally substituted by 0, 1, 2, 3, 4, 5 or 6 atom selected from Br, Cl, F and I.
  • R 5 is:
  • R and R are H; and wherein R 7 is selected from amino, aminomethyl, isopropylaminomethyl, /-butylaminomethyl, 2-f-butylaminoethyl, 2-tert-butylamino-l -methyl- ethyl, 1-tert-butylaminoethyl, l-(tert-butylamino-methyl)-vinyl, l-(pi ⁇ eridin-l-ylmethyl)- vinyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl, N- isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl, N- ⁇ -butyl-N- methylaminomethyl, N- ⁇ o-butyl-N-methylaminomethyl, N- ⁇ o-butyl-N-methylaminomethyl,
  • R 7 and R 8 are H; and R 6 is selected from amino, aminomethyl, isopropylaminomethyl, f-butylaminomethyl, 2-7-butylaminoethyl, 2-tert-butylamino-l -methyl- ethyl, 1-tert-butylaminoethyl, l-(tert-butylamino-methyl)-vinyl, l-(piperidin-l-ylmethyl)- vinyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl, N- isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl, N-f-butyl-N- methylaminomethyl, N-w ⁇ -butyl-N-methylaminomethyl, N-£-
  • R 6 and R 7 are H; and R 8 is selected from amino, aminomethyl, isopropylaminomethyl, t-butylaminomethyl, 2-f-butylaminoethyl, 2-tert-butylamino-l -methyl- ethyl, 1-tert-butylaminoethyl, l-(tert-butylamino-methyl)-vinyl, l-(piperidin-l-ylmethyl)- vinyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl, N- isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl, N-r-butyl-N- methylaminomethyl, N-zs ⁇ -butyl-N-methylaminomethyl, N-t
  • R is:
  • R 5 is:
  • R 3 and R 4 together may additionally be C 2-3 alkylene.
  • a substituent on R 2 that is vicinal to the -SO 2 -R 2 bond together with R 3 may additionally be
  • R la , R lb , R 3 , and R 4 are hydrogen; and R lc is hydrogen, halo, or -OH, preferably hydrogen, fluoro or -OH, more preferably hydrogen.
  • R lc is hydrogen, halo, or -OH, preferably hydrogen, fluoro or -OH, more preferably hydrogen.
  • 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, O and S, or 9- or 10- membered unsaturated hydrocarbon ring containing 1, 2, 3 or 4 atoms selected from N, O and S, preferably phenyl, benzodioxinyl, quinolinyl, isoquinolinyl, napthalenyl, 2,3- dihydrobenzofuranyl, tetrahydrofuranyl, 2,3-dihydroindolyl, 3,4-dihydro-2H- benzo[b][l,4]dioxepinyl, or 3,4-dihydro-2H-benzo[b][l,4]oxazine substituted with 0, 1, 2, or three substitutents independently selected from halo, C M haloalkyl, nitro, -OH, - NH 2 , R
  • R 5 is unsaturated 10-membered bicyclic hydrocarbon ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, preferably 1 (R)-1, 2,3, 4-tetrahydronaphthalen-l-yl or 4(Z?)-chroman-4-yl, substituted with cycloalkylamino-(Ci-C 6 )alkyl, cycloalkyl(Ci-C 6 )alkylamino(C]-C 6 )alkyl, Ci -6 - alkylamino-Ci.
  • heterocyclyl ring optionally 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.
  • a family of specific compounds of particular interest within Formula (I) consists of compounds and pharmaceutically-acceptable salts thereof as follows:
  • this invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I) or any pharmaceutically-acceptable salt or hydrate thereof and a pharmaceutically acceptable excipient.
  • this invention is directed to a method of treating a disease in a patient mediated by the Bl receptor comprising administering to the patient a pharmaceutical 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.
  • 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, 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 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
  • 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 aicononsm, stroke, thalamic pain syn ⁇ rome, 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 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
  • this invention is directed to the use of one or more of the compounds of the present invention in the manufacture of a medicament.
  • 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, 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 or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, sunburn, carditis, dermatitis, myositis, neuritis, collagen vascular diseases, chronic inflammatory conditions,
  • a disorder such as
  • 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. 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.
  • C a _palkyl means an alkyl group having a minimum of ⁇ and a maximum of ⁇ carbon atoms in a branched, cyclical or linear relationship or any combination of the three, wherein ⁇ and ⁇ represent integers as indicated in the claims unless otherwise indicated.
  • the alkyl groups described in this section may also contain one or two double or triple bonds.
  • alkenyl When the alkyl group has a double bond it is also referred to herein as alkenyl.
  • alkynyl When the alkyl group has a triple bond it is also referred to herein as alkynyl. Examples include, but are not limited to, the following:
  • 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 “alkylamino” may be mono or dialkylamino such as N-methylamino, N-ethylamino, N,N- dimethylamino, N,N-diethylamino and the like.
  • 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.
  • 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 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.
  • alkylaminoalkyl embraces aminoalkyl radicals having the nitrogen atom 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, N,N-dimethyl-aminoethyl, N,N-diethylaminomethyl and the like.
  • 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 aminoalkenyl radicals having two or three carbon atoms.
  • 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 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.
  • 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" 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 include fiuoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy, and fluoropropoxy.
  • 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 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.
  • aminoalkoxy embraces alkoxy radicals substituted with an amino radical. 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.
  • alkylaminoalkoxy embraces alkoxy radicals substituted with alkylamino radicals. More preferred alkylaminoalkoxy radicals are "lower alkylaminoalkoxy” radicals 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, N,N-diethylaminoethoxy and the like.
  • alkylaminoalkoxyalkoxy embraces alkoxy radicals substituted with 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, N,N- dimethylaminoethoxymethoxy, N ⁇ V-diethylaminomethoxymethoxy, and the like.
  • 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.
  • aryl embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. More preferred aryl is phenyl.
  • the "aryl” group may have 1 to 3 substituents such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, and lower alkylamino unless otherwise indicated.
  • 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 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.
  • arylalkenyl embraces aryl substituted alkenyl radicals.
  • Preferable arylalkenyl radicals are "lower arylalkenyl” radicals having aryl radicals attached to alkenyl 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.
  • N-arylaminoalkyl denotes aminoalkyl radicals substituted with an aryl 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.
  • aralkylaminoalkyl embraces aralkyl radicals as described above, attached to an aminoalkyl radical as defined herein. More preferred are lower arylalkylaminoalkyl radicals independently having alkyl radicals of one to three carbon atoms.
  • basic moiety or “basic moieties” means a chemical moiety that has a measured or calculated pK a 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.
  • Examples of basic moieties include, but are not limited to, amino, cycloalkylamino-
  • the basic moiety is selected from cycloalkylamino(Ci-C 6 )alkyl, cycloalkyl(Ci-C 6 )alkyl- amino(Ci -Ce)alkyl, heterocyclylamino(Ci -C 6 )alkyl, heterocyclyl(C i -C6)alkylamino- (d-C 6 )alkyl, arylamino(Ci-C 6 )alkyl, aryl(Ci-C 6 )alkylamino(Ci-C 6 )alkyl, (C r C 6 )alkyl amino(C i -C 6 )alkoxy, (C i -C 6 )alkylamino(C i -C 6 )alkoxy(C i -C6)alkoxy, amino(C i -Ce)alkoxy, amino(Ci-C 6 )alkyl, (Ci
  • the basic moiety is selected from cycloalkylamino(Ci-C 6 )alkyl, cycloalkyl(Ci-C 6 )alkylamino- (C i -C 6 )alkyl, heterocyclylamino(C i -C 6 )alkyl, heterocyclyl(C i -C 6 )alkylamino(C i -C 6 )alkyl, arylamino(Ci-C 6 )alkyl, aryl(Ci-C 6 )alkylamino(Ci-C 6 )alkyl, (Ci-Ce)alkyl amino(Ci-C 6 )alkoxy, (C i -C 6 )alkylamino(C i -Ce)alkoxy(C i -C 6 )alkoxy, amino(C i -C 6 )alkoxy, amino(C i -Ce)alkoxy, amino(
  • the basic moiety is amino, aminomethyl, isopropylaminomethyl, ⁇ -butylaminomethyl, 2- ⁇ -butylaminoethyl, 2-tert- butylamino-1 -methyl-ethyl, 1-tert-butylaminoethyl, l-(tert-butylamino-methyl)-vinyl, 1- (piperidin-l-yhnethyl)-vinyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2- dimethyl)propylaminomethyl, N-isopropyl-N-ethylaminomethyl, N-isopropyl-N- methylaminomethyl, N-/-butyl-N-methylaminomethyl, N-jso-butyl-N-methylaminomethyl, N-t- butyl-N-ethylaminomethyl, N-isobutyl-N
  • cycloalkyl includes saturated carbocyclic groups.
  • Preferred cycloalkyl groups include C 3 -C 6 rings. More preferred compounds include cyclopentyl, cyclopropyl, and cyclohexyl.
  • 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 1 WW- dicycloalkylaminoalkyl". More preferred cycloalkylaminoalkyl radicals are "lower 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.
  • cycloalkylalkylaminoalkyl embraces cycloalkyl radicals as described above, 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 I.
  • C ⁇ _ ⁇ haloalkyl 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 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 ⁇ , O 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 -O-O- or -S-S- portions.
  • 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. Examples of heterocycles that may be found in the claims include, but are not limited to, the following:
  • heterocyclylaminoalkyl embraces heterocyclyl radicals as described above, attached to an aminoalkyl radical as defined herein.
  • 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.
  • heterocyclylalkyl embraces heterocyclic-substituted alkyl radicals. More 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.
  • heterocyclylalkenyl embraces heterocyclyl-substituted alkenyl radicals.
  • 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.
  • the heterocyclyl ring contains 4 to 8 ring atoms having at least a nitrogen ring atom it is referred to herein as 4-8 membered nitrogen containing heterocyclylalkenyl.
  • heterocyclyloxy embraces optionally substituted heterocyclyl radicals, as defined above, attached to an oxygen atom. Examples of such radicals include piperidyloxy.
  • H denotes a single hydrogen atom. This radical may be attached, for example, to an oxygen atom to form a hydroxyl radical.
  • 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 radicals.
  • 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.
  • unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 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 acceptable carrier/excipient” as used in the specification and claims includes both one and more than one such excipient.
  • 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 with alternative therapies.
  • effective pain therapeutic agents relieve the pain sensation of the patient.
  • effective therapeutic agents for the treatment of inflammation minimize the damage from the inflammation, and the like.
  • treatment includes therapeutic treatment as well as prophylactic treatment (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:
  • 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 present invention.
  • Substituents on ring moieties 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).
  • 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 form of racemic or non-racemic mixtures thereof.
  • 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 treatment with an optically active acid or base.
  • Examples of appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and then separation of the mixture of diastereoisomers by crystallization followed by liberation of the optically active bases from these salts.
  • a different process for separation of optical isomers involves the use of a chiral chromatography column, such as, for example, a CHIRAL-AGP column, optimally chosen to maximize the separation of the enantiomers.
  • Still another available method involves synthesis of covalent diastereoisomeric molecules by reacting compounds of the invention with an optically pure acid in an activated form or an optically pure isocyanate.
  • the synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the enantiomerically pure compound.
  • the optically active compounds of the invention can likewise be 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:
  • compositions of Formula (I) are also included in the family of compounds of Formula (I) and the pharmaceutically- acceptable salts thereof.
  • pharmaceutically-acceptable salts embraces salts 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.
  • 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, ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, camphoric, camphorsulfonic, digluconic, cyclopent
  • Suitable pharmaceutically-acceptable base addition salts of compounds of Formula (I) 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 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)
  • 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 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.
  • 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 de
  • organic acids such as oxalic acid, maleic acid, succinic acid and citric acid.
  • Other examples include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases.
  • 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 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 Comprehensive Organic Transformations (VCH Publishers Inc., 1989).
  • the reactions described herein take place at atmospheric pressure over a temperature range from about -78 0 C to about 150 0 C, more preferably from about 0 0 C to about 125 0 C and most preferably at about room (or ambient) temperature, e.g., about 20 0 C.
  • 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 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 ® .), l-(3-dimethylamino-propyl)-3- ethylcarbodiimide hydrochloride (EDCI), CKT-azabenzotrizol-l-yl)-!,! ⁇ , tetra- methyluroriium-hexafluoro- phosphate (HATU), O-berizotriazol-l-yl-N,N,N,N-tetramethyl- uronium hexafluorophosphate (HBTU), l ⁇ -dicyclohexylcarbodiimide (DCC), or the like) and optionally an appropriate catalyst (e.g., 1-hydroxybenzotriazole (HOBt
  • 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.
  • 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 5 group then provides a compound of Formula (I).
  • 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 proceeding as described above.
  • 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-, 9-, 10- or 11-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.
  • 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)
  • 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 as solvates). All such forms are within the scope of this invention.
  • the compound of Formula (I) are Bl 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 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, 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
  • the in vitro binding affinity of the compounds of the invention to the human Bl 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 Bl and B2 bradykinin receptors can be tested using the calcium flux assay, Rabbit endothelial cell Bl -specific PGI 2 secretion Assay, and umblical vein Assay described in Biological 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.
  • 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.
  • carrier non-toxic, pharmaceutically- acceptable carriers and/or diluents and/or adjuvants
  • the compounds of the present invention 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.
  • 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 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.
  • 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 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 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, 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.
  • the active compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration.
  • 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- release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose.
  • Topical preparation of compounds of this invention 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 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.
  • the active ingredient may comprise from 0.001% to 10% w/w, e.g., from 1% to 2% by weight of 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.
  • the active ingredients 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 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. Examples of such dermal penetration enhancers include DMSO and related analogs.
  • transdermal administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety.
  • the active agent is delivered continuously from the reservoir or microcapsules through a membrane into the 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.
  • the encapsulating agent may also function as the membrane.
  • the oily phase of the emulsions of this invention may be constituted from known 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.
  • Emulsif ⁇ ers 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.
  • 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.
  • 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- 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.
  • 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.
  • 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 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 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 carriers including saline, dextrose, or water, or with cyclodextrin (ie. Captisol), cosolvent solubilization (ie. propylene glycol) or micellar solubilization (i.e., Tween 80).
  • suitable 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.
  • a non-toxic parenterally acceptable diluent or solvent for example as a solution in 1,3- butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed, including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the pharmaceutical composition may be administered in 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.
  • 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.
  • 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.
  • 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.
  • the therapeutic agents can be formulated as separate compositions that are administered at the same time or sequentially at different times, or the therapeutic agents can be given as a single composition.
  • co-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 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 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.
  • opioids and other anti-pain analgesics including narcotic analgesics, Mu receptor antagonists, Kappa receptor antagonists, non-narcotic (i.e. non- addictive) analgesics, monoamine uptake inhibitors, adenosine regulating agents, cannabinoid derivatives, Substance P antagonists, neurokinin
  • 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.
  • steroids e.g., NSAIDs, iNOS inhibitors, p38 inhibitors, TNF inhibitors, 5-lipoxygenase inhibitors, LTB 4 receptor antagonists and LTA 4 hydrolase inhibitors.
  • Step A Synthesis of 5(iS)-hydroxy-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid methyl ester
  • 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 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 0 C. The reaction mixture was concentrated in vacuo.
  • Step B Synthesis of 5(R)-azido-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid methyl ester
  • Step A Synthesis of 2-trifluoromethanesulfonic acid 5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl ester To a 1 -L round-bottomed flask charged with 6-hydroxy- 1 -tetralone (Aldrich, 21.97 g,
  • Step C Synthesis of 2-trifluoromethanesulfonic acid 5(i?)-azido-5,6,7,8-tetrahydro-naphthalen- 2-yl ester
  • 2-trifluoromethanesulfonic acid 5(5)-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).
  • Step E Synthesis of 2-trifluoromethanesulfonic acid 5(/?)-tert-butoxycarbonyl-amino-5,6,7,8- tetrahydro-naphthalen-2-yl ester
  • Step G Synthesis of 6-( 1 -piperidin- 1 -ylmethylvinyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -ylamine
  • TFA 3 mL
  • the reaction 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.
  • Step A Synthesis of (i?)-tert-butyl 6-(hydroxymethyi)-l,2,3,4-tetrahydronaphthalen-l-yl- 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(/?)-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 solvents were removed in vacuo, the residue was partitioned between ethyl acetate and saturated sodium bicarbonate.
  • Step C Synthesis of (R)-tert-butyl 6-((tert-butylamino)methyl)-l,2,3,4-tetrahydronaphthalen-l- ylcarbamate
  • Step D Synthesis of (/?)-6-((tert-butylamino)methyl)- 1,2,3 ,4-tetrahydronaphthalen- 1 -ylamine
  • Step A Synthesis of (R)-tert-buty ⁇ 6-(piperidin-l -ylmethyl)- 1,2,3 ,4-tetrahydronaphthalen- 1- ylcarbamate.
  • Step B Synthesis of (R)- ⁇ -(piperidin- 1 -ylmethyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -amine
  • Step B Synthesis of 7-(tert-butylamino-methyl)-6-chloro-chroman-4-one
  • Step D Synthesis of 4(/?)-azido-6-chloro-chroman-7-ylmethyl)-tert-butylamine
  • Step C Synthesis of (R)-tert-butyl 6-(2-oxoethyl)- 1 ,2,3,4-tetrahydronaphthalen-l -ylcarbamate
  • Step D Synthesis of (/?)-tert-butyl-6-(2-(piperidin- 1 -yl)ethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 - ylcarbamate
  • (R)-tert-butyl 6-(2-oxoethyl)-l,2,3,4-tetrahydronaphthalen-l- ylcarbamate (2.02 g, 7 mmol)
  • piperidine (1.79 g, 21 mmol) in dichloroethane (10 mL) was added sodium triacetoxyborohydride (2.97 g, 14 mmol).
  • Step E Synthesis of ( ⁇ )-6-(2-(piperidin- 1 -yl)ethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -amine
  • Step B Synthesis of 3-(tert-butyldiphenylsilyloxy)-propanamidine To a suspension OfNH 4 Cl (5.35 g, 0.1 mol) in dry benzene (60 mL) at 0 0 C was slowly added a solution of trimethylaluminum in toluene (50 mL, 2M).
  • 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 resulting mixture was heated up to 80 0 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).
  • Step C Synthesis of 2-(2-(tert-butyldiphenylsilyloxy)ethyl)-7,8-dihydroquinazolin-5(6H)-one
  • 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 (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.
  • Step F Synthesis of 2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5,6,7,8-tetrahydroquinazolin-5- amine
  • Step G Synthesis of 2-(5-amino-5,6,7,8-tetrahydroquinazolin-2-yl)ethanol
  • 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 0 C was treated with a IM TBAF solution in THF (1.56 mL, 1.56 mmol).
  • Step A Synthesis of 1 -(2-hydroxyethyl)-6,7-dihydro- 1 H-indazol-4(5H)-one
  • Step B Synthesis of l-(2-(tert-butyldimethylsilyloxy)ethyl)-6,7-dihydro-lH-indazol-4(5H)- one
  • Step C Synthesis of l-(2-(tert-butyldimethylsilyloxy)ethyl)-4,5,6,7-tetrahydro-lH-indazol-4-ol
  • Step D Synthesis of 4-azido-l-(2-(tert-butyldimethyl silyloxy)ethyl)-4,5,6,7-tetrahydro-lH- indazole
  • Step E Synthesis of l-(2-(tert-butyldimethylsilyloxy)ethyl)-4,5,6,7-tetrahydro-lH-indazol-4- amine
  • Step A Synthesis of ethyl 4,4,4-trifluoro-3-(3-(trifluoroniethyl)phenylsulfonamido)butanoate
  • Step B Synthesis of 4,4,4-trifluoro-3-(3-(trifluoromethyl)phenylsulfonamido)butanoic acid A mixture of ethyl 4,4,4-trifluoro-3-(3-(trifluoromethyl)phenylsulfonamido)butanoate
  • (/?)-4,4,4-trifluoro-3-(3-(trifluoromethyl)phenylsulfonamido)butanoic acid was prepared from (i?)-ethyl 3-amino-4,4,4-trifluorobutanoate (prepared according to literature procedure: Soloshonok, V.A.; Ono, T.; Soloshonok, LV. J. Org. Chem. 1997, 62, 7538-39).
  • the following sulfonylated acids were prepared similarly:
  • Step A Synthesis of (5',E)-l-phenyl-N-(2,2,2-trifluoroethylidene)ethanamine
  • Step B Synthesis of (2/?,3/?)-2-(benzyloxy)-4-((/?)-l-phenylethyl)-3-(trifluoromethyl)- cyclobutanone
  • Step A Synthesis of (2R,3S)-methyl 4,4,4-trifluoro-2-hydroxy-3-(N-methyl-3-(trifluoro- methyl)phenylsulfonarnido)butanoate
  • Step B Synthesis of (2R,3S)-4,4,4-trifluoro-2-hydroxy-3-(N-methyl-3-(trifluoromethyl)- phenylsulfonamido)butanoic acid
  • Step A Synthesis of (5)-ethyl 3-(3-chloro-2-fluoro-N-methylphenylsulfonamido)-4,4,4- trifluorobutanoate
  • Step B Synthesis of (5)-3-(3-chloro-2-fluoro-N-methylphenylsulfonamido)-4,4,4- trifluorobutanoic acid
  • Step A Synthesis of ( ⁇ )-2,2,2-trifluoro-N-(6-(hydroxymethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 - yl)acetamide
  • Step B Synthesis of (/?)-(5-(2,2,2-trifluoroacetamido)-5,6,7,8-tetrahydronaphthalen-2-yl)- methylacetate
  • Step C Synthesis of (i?)-(l-nitro-5-(2,2,2-trifluoroacetamido)-5,6,7,8-tetrahydronaphthalen-2- yl)methyl acetate and (i?)-(3-nitro-5-(2,2,2-trifluoroacetamido)-5,6,7,8-tetrahydronaphthalen-2- yl)methyl acetate
  • (/?)-(5-(2,2,2-trifluoroacetamido)-5 ,6,7,8-tetrahydronaphthalen-2-yl)- methyl acetate 160 mg, 0.508 mmol
  • MeCN 2 mL
  • Step F Synthesis of ( ⁇ -trifluoro-N-CT-nitro- ⁇ -Cpiperidin-l-yhnethyO-l ⁇ -tetrahydro- naphthalen- 1 -yl)acetamide
  • (i?)-2,2,2-trifluoro-N-(6-formyl-7-nitro-l ,2,3,4-tetrahydronaphthalen- l-yl)acetamide 350 mg, 1.1 mmol
  • 1,2-dichloroethane (6 mL)
  • piperidine 187 mg, 2.2 mmol
  • NaBH(OAc) 3 350 mg, 1.65 mmol
  • Step G Synthesis of (/?)-7-nitro-6-(piperidin-l-ylmethyl)-l,2,3,4-tetrahydronaphthalen-l- amine
  • Step A Synthesis of (/?)-2,2,2-trifluoro-N-(6-(hydroxymethyl)-5-nitro-l,2,3,4-tetrahydro- naphthalen- 1 -yl)acetamide
  • Step B Synthesis of (i?)-2,2,2-trifluoro-N-(6-formyl-5-nitro-l,2,3,4-tetrahydronaphthalen-l- yl)acetamide
  • (R)-2,2,2-trifluoro-N-(6-(hydroxymethyl)-5-nitro-l ,2,3,4-tetrahydro- naphthalen-l-yl)acetamide 440 mg, 1.38 mmol
  • DCM 50 mL
  • Step C Synthesis of ( ⁇ )-2,2,2-trifluoro-N-(5-nitro-6-(piperidin-l-ybnethyl)-l,2,3,4- tetrahydronaphthalen- 1 -yl)acetamide
  • Step D Synthesis of (/?)-5-nitro-6-(piperidin- 1 -ylmethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 - amine
  • a solution of (/?)-2,2,2-trifluoro-N-(5-nitro-6-(piperidin-l-ymiethyl)-l,2,3,4- tetrahydronaphthalen-l-yl)acetamide 230 mg, 0.6 mmol
  • NaOH 48 mg, 1.2 mmol
  • Step A Synthesis of (5)-N-((R)-6-(hydroxymethyl)-l ,2,3,4-tetrahydronaphthalen-l-yl)-3-(3- (trifluoromethyl)phenylsulfonamido)butanamide
  • Step B Synthesis of (5)-N-((/?)-6-formyl-l,2,3,4-tetrahydronaphthalen-l-yl)-3-(3-(trifluoro- methyl)phenylsulfonamido)butanamide
  • Step C Synthesis of (S)-N-((/?)-6-(piperidin- 1 -ylmethyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)-3- (3 -(trifluoromethyl)phenylsulfonamido)butanamide
  • Step A Synthesis of (/?)-4,4,4-trifluoro-N-(6-(hydroxymethyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)-3 -(3 -(trifluoromethyl)phenylsulfonamido)butanamide A mixture of 4,4,4-trifluoro-3-(3-(trifluoromethyl)phenylsulfonamido)butanoic acid
  • Step B Synthesis of (i?)-4,4,4-trifluoro-N-(6-formyl-l ,2,3,4-tetrahydronaphthalen-l -yl)-3-(3- (trifluoromethyl)phenylsulfonamido)butanamide
  • Step C Synthesis of ( ⁇ )-4,4,4-trifluoro-N-(6-(piperidin-l-ylmethyl)-l,2,3,4-tetrahydro- naphthalen- 1 -yl)-3-(3-(trifluoromethyl) phenylsulfonamido)butanamide
  • Step A Synthesis of [6-(l-hydroxy-ethyl)-l,2,3,4-tetrahydro-naphthalen-l-yl]-carbamic acid tert-butyl ester
  • Step A Synthesis of 3,4-dichloro-N-((2R,3R)-2-methyl-5-oxo-tetrahydrofuran-3-yl)benzene- sulfonamide
  • Step B Synthesis of (3/?,4i?)-3-(3,4-dichlorophenylsulfonamido)-4-hydroxy-N-((i?)-6- (hydroxymethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)pentanamide
  • Step C Synthesis of (3R,4R)-3-(3,4-dichlorophenylsulfonamido)-N-((i?)-6-formyl-l,2,3,4- tetrahydronaphthalen- 1 -yl)-4-hydroxypentanamide (3i?,4 ⁇ )-3-(3,4-Dichlorophenylsulfonamido)-4-hydroxy-N-((i?)-6-(hydroxymethyl)- l,2,3,4-tetrahydronaphthalen-l-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.
  • Step A Synthesis of methyl 3-(4-fluorophenylamino)propanoate To a 30-mL microwave vial containing methyl 3-bromopropanoate (6.2 mL, 57 mmol,
  • Step C Synthesis of 3-(N-(4-fluorophenyl)-3-(trifluoromethyl)phenylsulfonamido)propanoic acid To a 100-mL round-bottomed flask containing methyl 3-(N-(4-fluorophenyl)-3-
  • Step D Synthesis of (/?)-3-(N-(4-fluorophenyl)-3-(trifluoromethyl)phenylsulfonamido)-N-(6- (hydroxymethyl)-l,2,3,4-tetrahydronaphthalen-l-yl)propanamide
  • oxalyl chloride 10 mL, 21 mmol, 2.0M, Aldrich.
  • Step E Synthesis of (S)-N-(4-fluorophenyl)-N-(4-(6-formyl- 1 ,2,3 ,4-tetrahydronaphthalen- 1 - yl)-3-oxobutyl)-3-(trifluoromethyl)benzenesulfonamide
  • Step F Synthesis of (i?)-3-(N-(4-fluorophenyl)-3-(trifluoromethyl)phenylsulfonamido)-N-(6- ((4-fiuoropiperidin- 1 -yl)methyl)- 1,2,3 ,4-tetrahydronaphthalen- 1 -yl)propanamide
  • Step B Synthesis of methyl 3-(N-methyl-3-(trifluoromethyl)phenylsulfonamido)propanoate
  • N-methyl-3-(trifluoromethyl) benzenesulfonamide 1.5 g, 6.3 mmol, Step A
  • DMF 10 mL
  • methyl 3-bromo- propanoate 28 mL, 257 mmol, Aldrich
  • K 2 CO 3 2.3 g, 17 mmol, Aldrich
  • Step D Synthesis of (i?)-N-(6-(hydroxymethyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)-3-(2V- methyl-3-(trifluoromethyl)phenylsulfonamido)propanamide
  • Step E Synthesis of (R)-N-(6-formyl-l,2,3,4-tetrahydronaphthalen-l-yl)-3-(N-methyl-3- (trifluoromethyl)phenylsulfonamido)propanamide
  • Step F Synthesis of (/?)-N-(6-((4-fluoropiperidin-l-yl)methyl)-l,2,3,4-tetrahydronaphthalen- l-yl)-3-(N-methyl-3-(trifluoromethyl)phenylsulfonamido)propanamide.
  • Step A Synthesis of N-cyclopro ⁇ yl-3-(trifluoromethyl) benzenesulfonamide
  • Step B Synthesis of f ⁇ r/-butyl 3-(N-cyclopropyl-3-(trifluoromethyl)phenyl- sulfonamido)propanoate.
  • N-cyclopropyl-3-(trifluoromethyl) benzenesulfonamide 1.7 g, 6.2 mmol, step A
  • DMF 10 mL
  • Step C Synthesis of 3-(N-cyclopropyl-3-(trifluoromethyl)phenylsulfonamido) ⁇ ropanoic acid.
  • Step D Synthesis of (/?)-3-(N-cyclopropyl-3-(trifluoromethyl)phenylsulfonamido)-N-(6- (piperidin- 1 -ylmethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)propanamide.
  • Step A Synthesis of methyl 3-(3-bromo-saccharinyl)propanoate To a 100-mL round-bottomed flask containing 3-bromosaccharin (1.0 g, 3.8 mmol,
  • Step C Synthesis of (/?)-3-(3-bromo-saccharinyl-N-(6-(piperidin-l-ylmethyl)-l,2,3,4- tetrahydronaphthalen- 1 -yl)propanamide
  • Step A Synthesis of ethyl 4,4,4-trifluoro-3-(3-(trifluoromethyl)phenylsulfonamido)butanoate

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)

Abstract

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.

Description

SUBSTITUTED SULFONAMIDOPROPIONAMIDES AND METHODS OF USE
BACKGROUND OF THE INVENTION
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.
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 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 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 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, 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 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, 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 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 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 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 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 Bl and B2. Both classes of receptors have been cloned and 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 receptor. Essentially all normal physiological responses and many pathophysio-logical responses to bradykinin are mediated by B2 receptors.
Bl 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, Bl receptors are not 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 Bl receptors are up-regulated from a null level following administration of bacterial lipopolysaccharide
(LPS) or inflammatory cytokines in rabbits, rats, and pigs. The pain-inducing properties of kinins coupled with the inducible expression of B 1 receptors make the Bl 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, 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. 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 inflammation and pain and having the structure of Formula (I):
Figure imgf000004_0001
(I) wherein: R1 is selected from H, cyano, -C(O)OCi-8alkyl, -C(O)OH, -C(=O)NRaRa, or -Ci-8alkyl substituted by 0, 1, 2, or 3 groups independently selected from Rg, cyano, oxo, nitro, -C(=O)Rb, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Ra, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=O)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORa, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2.6alkyl0Ra, and additionally substituted by 0, 1, 2, 3, 4, 5 or 6 atoms independently selected from Br, Cl, F and
I;
Rla and Rlb are each independently, H, F, Cl, -OCH3, -Ci-2alkyl or -CF3; Rlc is H, -Ci-galkyl, -CiΛialoalkyl, 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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa,
-S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa, -NRaC2-6alkylORa, or -Ci-6alkyl substituted by 0, 1, 2 or 3 substituents selected from -Ci-4haloalkyl, 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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa or -NRaC2-6alkylORa; R2 is 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, O 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 Re, Rg, CMhaloalkyl, 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)2Rb, -OC2-6alkylNRaRa,
-OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkyl0Ra, 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^aUcyl, the phenyl, benzyl and -Ci-galkyl being substituted by 0, 1, 2 or 3 substituents independently selected from Re, Rg,
Figure imgf000005_0001
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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2RD, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkylORa, and 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 -Ci-βalkyl, the phenyl, benzyl and
Figure imgf000006_0001
being substituted by 0, 1, 2 or 3 substituents independently selected from Ci^alkyl, Ci_3haloalkyl, -OQ^alkyl, -NH2, -NHCMalkyl, and -N(C1-4alkyl)CMalkyl, and additionally substituted by 0, 1, 2, 3, 4, 5 or 6 atom selected from Br, Cl, F and I; 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, O 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 R6, R7 and R8 which are selected from Rg, -Ci.8alkyl, -CMhaloalkyl, 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)2Rb, -OC2-6alkylNRaRa, -OC^alkylOR3, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkyl0Ra, and the ring is additionally substituted by 0, 1, 2, 3, 4 or 5 substituents selected from R6, R7, R8, R9 and R10 which are independently selected from Br, Cl, F and I; wherein, R3 and R4 together may additionally be C2-3alkylene substituted by 0, 1 or 2 substituents independently selected from -C1-8alkyl, -Ci^thaloalkyl, halo, oxo, 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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkylORa, and 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 C2^alkylene substituted by 0, 1 or 2 substituents selected from -Ci-8alkyl,
Figure imgf000006_0002
halo, oxo, 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)2Rb, -OC2-6alkylNRaRa, -OC^alkylOR3, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkylORa, and 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-3alkylene substituted by 0, 1 or 2 substituents selected from -Ci.8alkyl, - CMhaloalkyl, halo, oxo, 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)2Rb, -OC2.6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkylORa, 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 R ;
Rb is independently, at each instance, phenyl, benzyl or -Ci-βalkyl, the phenyl, benzyl and
Figure imgf000007_0001
-C^aHcyl, - C1-3haloalkyl, -OC^alkyl, -NH2, -NHCMalkyl, -N(CMalkyl)CMalkyl; Rd is independently at each instance -Ci-8alkyl,
Figure imgf000007_0002
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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2.6alkylNRaRa or -NRaC2-6alkyl0Ra;
Re is independently at each instance -Ci-βalkyl substituted by 0, 1, 2 or 3 substituents independently selected from Rd and additionally substituted by 0 or 1 substituents selected from Rg; and
R8 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, O 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_8alkyl, -Ci^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(=O)2Rb, -OC2^alkylNRaRa, -OC2-salkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2.6alkyl0Ra, 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.
In one embodiment, in conjunction with any one of the below embodiments, R1 is selected from H or -C^aUcyl substituted by 0, 1, 2, or 3 groups independently selected from Rg, cyano, oxo, nitro, -C(=O)Rb, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa,
-OC(=O)Ra, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=O)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=0)2N(Ra)C(O)Rb, -S(=O)2N(Ra)C(=O)ORa, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2.6alkylNRaRa and -NRaC2-6alkylORa, and additionally substituted by 0, 1 , 2, 3, 4, 5 or 6 atoms independently selected from Br, Cl, F and I;
Rla and Rlb are each independently, H, F, Cl, -OCH3, -Ci-2alkyl or -CF3; Rlc is H, -Ci.8alkyl, -C^aloalkyl, 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)2Rb, -OC2-6alkylNRaRa, -OC2.6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa,
-S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa, -NRaC2-6alkyl0Ra, or -Ci.6alkyl substituted by 0, 1, 2 or 3 substituents selected from
Figure imgf000008_0001
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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa or -NRaC2-6alkylORa; R2 is 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, O 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 Re, R8, CMhaloalkyl, halo, cyano, nitro, -C(=O)Rb, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)RD, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=O)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkylORa, 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^aHcyl, the phenyl, benzyl and -C^aHcyl being substituted by 0, 1, 2 or 3 substituents independently selected from Re, R8, -CMhaloalkyl, 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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkyl0Ra, and 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 -Ci-βalkyl, the phenyl, benzyl and
Figure imgf000009_0001
being substituted by 0, 1, 2 or 3 substituents independently selected from Q
Figure imgf000009_0002
^alkyl, -OCMalkyl, -NH2,
Figure imgf000009_0003
and additionally substituted by 0, 1, 2, 3, 4, 5 or 6 atom selected from Br, Cl, F and I; 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, O 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 R6, R7 and R8 which are selected from Rg, -Ci-8alkyl, -CMhaloalkyl, 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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkyl0Ra, and the ring is additionally substituted by 0, 1, 2, 3, 4 or 5 substituents selected from R6, R7, R8, R9 and R10 which are independently selected from Br, Cl, F and I; wherein, R3 and R4 together may additionally be C2-3alkylene substituted by 0, 1 or 2 substituents independently selected from -Ci-8alkyl, -Ci^haloalkyl, halo, oxo, cyano, nitro, -C(O)R", -C(=O)ORU, -C(=O)NR"Rα, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=O)2Rb, -OC2-6alkylNRaRa, -OC^alkylOR3, -SRa, -S(=0)Rb, -S(=O)2Rb, -S(=0)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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(=0)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2.6alkyl0Ra, and additionally substituted by O, 1, 2, 3 or 4 substituents independently selected from Br, Cl, F and I; or
Rlc and R4 together may additionally be C2-4alkylene substituted by O, 1 or 2 substituents selected from -C1-8alkyl, -Ci^haloalkyl, halo, oxo, cyano, nitro, -C(=O)Rb, -C(=O)ORb, -C(=0)NRaRa, -C(=NRa)NRaRa, -0Ra, -OC(=O)Rb, -OC(=O)NRaRa,
-OC(=O)N(Ra)S(=O)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(-O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=0)Rb, -N(Ra)C(=0)0Rb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkyl0Ra, and additionally substituted by O, 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-3alkylene substituted by O, 1 or 2 substituents selected from -Q-salkyl, - CMhaloalkyl, halo, oxo, 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(=O)2Rb, -OC2-6alkylNRaRa,
-OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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(=O)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkylORa, 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 Rb;
Rb is independently, at each instance, phenyl, benzyl or -Ci.6alkyl, the phenyl, benzyl and -Ci-βalkyl being substituted by 0, 1, 2 or 3 substituents selected from halo, -Q^alkyl, - Ciohaloalkyl, -OCMalkyl, -NH2, -NHC^alkyl, -N(CMalkyl)CMalkyl; Rd is independently at each instance -C].8alkyl, -C^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(=O)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)RD, -N(Ra)C(=O)ORD, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa or -NRaC2-6alkyl0Ra;
Re is independently at each instance -Ci_όalkyl substituted by 0, 1, 2 or 3 substituents independently selected from Rd and additionally substituted by 0 or 1 substituents selected from R8; and
Rg 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, O 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,
Figure imgf000011_0001
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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(-O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkyl0Ra, 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, R1 is selected from H or -Ci-8alkyl substituted by 0, 1, 2, or 3 groups independently selected from Rg, cyano, oxo, nitro, -C(=O)Rb, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa,
-OC(=O)Ra, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=O)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORa, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2^alkylORa, and additionally substituted by 0, 1, 2, 3, 4, 5 or 6 atoms selected from Br, Cl, F and I;
Rla and Rlb are each independently, H, F, Cl, -OCH3, -Ci-2alkyl or -CF3; Rlc is H, -C1-8alkyl,
Figure imgf000011_0002
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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa,
-S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa, -NRaC2-6alkyl0Ra, or -Ci-6alkyl substituted by 0, 1, 2 or 3 substituents selected from Ci^haloalkyl, halo, cyano, nitro, -C(=O)R°, -C(=O)ORD, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=O)2Rb, -OC2-6alkylNRaRa, -OC2^alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa or -NRaC2.6alkyl0Ra;
R2 is 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, 2, 3 or 4 atoms selected from N, O 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, Rg,
Figure imgf000012_0001
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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-galkylORa, 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
Figure imgf000012_0002
being substituted by 0, 1, 2 or 3 substituents selected from Re, Rg,
Figure imgf000012_0003
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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkylORa, and 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 -Ci-βalkyl, the phenyl, benzyl and -Ci-δalkyl being substituted by 0, 1, 2 or 3 substituents selected from C^aUcyl, Ci-3haloalkyl, -OCi-4alkyl, -NH2, -NHCMalkyl, and -N(CMaUcyl)CMalkyl, and additionally substituted by 0, 1, 2, 3, 4, 5 or 6 atom selected from Br, Cl, F and I;
R5 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, O 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 Rg, -Ci-8alkyl,
Figure imgf000012_0004
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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaR8, -NRaC2-6alkylNRaRa and -NRaC2-6alkyl0Ra, and the ring is additionally substituted by 0, 1, 2, 3, 4 or 5 substituents independently selected from Br, Cl, F and I; wherein, R3 and R4 together may additionally be C2.3alkylene substituted by 0, 1 or 2 substituents selected from -Ci-8alkyl, -Ci^haloalkyl, halo, oxo, cyano, nitro, -C(=O)Rb, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, -OC(=O)NRaR\ -OC(=O)N(Ra)S(=O)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkyl0Ra, and 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 C^alkylene substituted by 0, 1 or 2 substituents selected from -Ci-salkyl, -Q^aloalkyl, halo, oxo, 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)2Rb, -OC2-6alkylNRaRa, -OC2^alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkyl0Ra, and 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
Figure imgf000013_0001
substituted by 0, 1 or 2 substituents selected from Ci-salkyl, CMhaloalkyl, halo, oxo, 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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkylORa, 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 Rb; K" is independently, at each instance, phenyl, benzyl or -Ci-6alkyl, the phenyl, benzyl and
Figure imgf000014_0001
Q^alkyl, Ci.jhaloalkyl, -OCMalkyl, -NH2, -NHCMalkyl, -N(CMalkyl)CMalkyl;
Rd is independently at each instance -Ci-8alkyl,
Figure imgf000014_0002
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(=O)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa or -NRaC2-6alkyl0Ra; 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
R8 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, 2, 3 or 4 atoms selected from N, O 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-8alkyl, -CMhaloalkyl, 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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkyl0Ra, 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, the basic moieties are independently selected from amino, cycloalkylamino- (Ci-C6)alkyl, cycloalkyl(Ci-C6) alkylamino(Ci-C6)alkyl, heterocyclylamino(Ci-C6)alkyl, heterocyc IyI(C i -C6)alkyl-amino(C i -C6)alkyl, arylamino(C i -Ce)alkyl, aryl(C i -C6)alkylamino- (Ci -C6)alkyl, (Ci -C6)alkylamino(Ci -C6)alkoxy, (Q -C6)alkylamino(C, -C6)alkoxy(Ci -C6)- alkoxy, amino(Ci-C6)alkoxy, amino(Ci-C6)alkyl, (Ci-C6)alkylamino(Ci-C6)alkyl, (Ci-C4)alkylamino-(C2-C6)alkenyl, 4-8-membered nitrogen-containing heterocyclyl(C2-C6)alkenyl, 5-6 membered heterocyclyloxy, 5-6 membered nitrogen- containing heterocyclyl and 5-7 membered nitrogen-containing heterocyclylalkyl; more specifically amino, cycloalkylamino(Ci-C6)alkyl, cycloalkyl(Ci-C6)alkylamino-(Ci-C6)alkyl, heterocyclylamino(Ci-C6)alkyl, heterocyclyl(Ci-C6)alkylamino-(Ci-C6)alkyl, arylamino(Ci-C6)alkyl, aryl(Ci-C6)alkylamino(C]-C6)alkyl, (d-C6)alkyl amino(Ci-C6)alkoxy, (Ci -C6)alkylamino(C1 -C6)alkoxy(Ci -C6)alkoxy, amino(C) -C6)alkoxy, amino(C] -C6)alkyl, (Ci-C6)alkylamino(Ci-C6)alkyl, (Ci-C4)alkylamino-(C2-C6)alkenyl, 5-8-membered nitrogen- containing heterocyclyl(C2-C6)alkenyl, heterocyclyl(Ci-C6)amino(C2-C6)alkyl, 5-6 membered heterocyclyloxy, 5-6 membered nitrogen-containing heterocyclyl and 5-7 membered nitrogen- containing heterocyclyl(Ci-C6)alkyl wherein each basic moiety can be substituted by 0, 1, 2 or 3 groups independently selected from halo, -NH2, -OH, -CN, -CF3, (Ci-C6)alkylamino, haloalkyl, oxo, (CrC6)alkoxy, (CrC6)alkoxyalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, di(Ci-C6)alkylamino, =NCN and (Ci-C6)alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl, each of which is substituted by 0, 1, 2 or 3 groups independently selected from halo, -NH2, -OH, -CN, -CF3, (Ci-C6)alkylamino, haloalkyl, oxo, (C)-C6)alkoxy, (Ci-C6)alkoxyalkyl, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, or di(Ci-C6)alkylamino.
In another embodiment, in conjunction with any one of the above and below embodiments, the basic moieties are independently selected from amino, mono-CM- alkylamino-C 1.4-alkyl, di-C 1 ^-alkylamino-C 1 ^-alkyl, mono-C 1 ^- alkylamino-C2-4-alkenyl, di-Ci.4-alkylamino-C2-4-aUcenyl, 5-8 membered nitrogen-containing heterocyclyl-C2-4-alkenyl, optionally substituted 5-6 membered nitrogen-containing heterocyclyl or 5-8 membered nitrogen-containing heterocyclyl-CM-alkyl. In another embodiment, in conjunction with any one of the above and below embodiments, the basic moieties are independently selected from amino, aminomethyl, isopropylaminomethyl, ^-butylaminomethyl, 2-f-butylaminoethyl, 2-tert-butylamino-l -methyl- ethyl, 1-tert-butylaminoethyl, l-(tert-butylamino-methyl)-vinyl, l-(piperidin-l-ylmethyl)- vinyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl, N- isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl, N-^-butyl-N- methylaminomethyl, N-wo-butyl-N-methylaminomethyl, N-^-butyl-N-ethylaminomethyl, N- isobutyl-N-methylaminomethyl, N-ϊ-butyl-N-isopropylaminomethyl, N,N- di(isopropyl)aminomethyl, N,N-dimethylaminomethyl, N,N-diethylaminomethyl, N,N-di(/- butyl)-aminomethyl, cyclopropylaminomethyl, cyclopropylaminoethyl, cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl, cyclobutylaminomethyl, cyclobutylaminoethyl, cyclobutylmethylaminomethyl, cyclobutylmethylaminoethyl, 4,5- dihydro-imidazolyl, 1-piperidinylmethyl, 4-fluoropiperidin-l-ylmethyl, 4,4-difluoropiperidin- 1-yhnethyl, 3-hydroxypiperidin-l-ylmethyl, 4-hydroxypiperidin-l-ylmethyl, 4-(piperidin-l- yl)piperidinyknethyl, 4-(dimethylamino)piperidin- 1 -yhnethyl, 2,6-dimethylpiperidin- 1 - ylmethyl, 4-morpholinylmethyl, 1-pyrrolidinylmethyl, 2-methylpyrrolidin-l-ylmethyl, 2,5- dimethylpyrrolidin-1-ylmethyl, piperazin-1 -ylmethyl, azocan-1 -ylmethyl, azepan-1 -ylmethyl, (7-azabicyclo[2.2.1]hept-7-yl)methyl, (l^^-trimethyl-ό-azaicyclofS^.lloct-ό-yOmethyl, 2- piperidinyl and 4-methylpiperazin-l-ylmethyl, in conjunction with any of the above or below embodiments.
In another embodiment, in conjunction with any one of the above and below embodiments, R1 is H.
In another embodiment, in conjunction with any one of the above and below embodiments, R1 is Ci-8alkyl substituted by 0, 1, 2, or 3 groups independently selected from Rg, 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)2Rb, -OC2-6alkylNRaRa, -OC^alkylOR", -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkylORa, 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, R1 is Ci^alkyl substituted by 0, 1, 2, or 3 groups independently selected from R8, cyano, 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)2Rb, -OC2.6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2^ahcylORa, 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, R1 is -Ci-8alkyl.
In another embodiment, in conjunction with any one of the above and below embodiments, R1 is -C3-SaIlCyI. In another embodiment, in conjunction with any one of the above and below embodiments, R1 is -CH3.
In another embodiment, in conjunction with any one of the above and below embodiments, R1 is
Figure imgf000016_0001
substituted by 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, R1 is -CF3.
In another embodiment, in conjunction with any one of the above and below embodiments, R1 is
Figure imgf000017_0001
substituted by 1, 2, or 3 groups independently selected from R8, 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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORa, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkylORa, 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, R1 is
Figure imgf000017_0002
substituted by 1 oxo group and 0, 1 or 2 groups independently selected from Rs, cyano, 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)2Rb, -OC2-6alkylNRaRa, -OC2^alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORa, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkyl0Ra, 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, R1 is -Ci-galkyl 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(=O)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORa, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkylORa, 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, R1 is -C(=O)ORa or -C(=O)NRaRa.
In another embodiment, in conjunction with any one of the above and below embodiments, Rla and Rlb are each independently, H, F, Cl, -OCH3, -C]-2alkyl or -CF3.
In another embodiment, in conjunction with any one of the above and below embodiments, Rla is H and Rlb F, Cl, -OCH3, -Ci-2alkyl or -CF3. in another embodiment, in conjunction with any one of the above and below embodiments, Rla is F, Cl, -OCH3, -Ci-2alkyl or -CF3 and Rlb is H.
In another embodiment, in conjunction with any one of the above and below embodiments, Rla and Rlb are each independently, H or F. In another embodiment, in conjunction with any one of the above and below embodiments, Rlc is -Ci-8alkyl, -CMhaloalkyl, 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)2Rb, -OC2-6alkylNRaRa, -OC2.6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2.6alkylNRaRa, -NRaC2-6alkylORa, or -Ci-6alkyl substituted by 0, 1, 2 or 3 substituents selected from
Figure imgf000018_0001
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)2Rb, -OC2-6alkylNRaRa, -OC2^alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa or -NRaC2-6alkyl0Ra.
In another embodiment, in conjunction with any one of the above and below embodiments, Rlc is -Ci^alkyl substituted by 0, 1, 2 or 3 substituents selected from CMhaloalkyl, 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)2Rb, -OC2.6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa or -NRaC2-6alkylORa;
In another embodiment, in conjunction with any one of the above and below embodiments, Rlc is H or F.
In another embodiment, in conjunction with any one of the above and below embodiments, Rla, Rlb, and Rlc are H. 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 0, 1, 2 or 3 substituents selected from Re, RB, -CMhaloalkyl, 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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)RD, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkyl0Ra, and 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, R2 is phenyl or napthyl, both of which are substituted by 1, 2 or 3 substituents selected from Re, Rg, -CMhaloalkyl, 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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa,
-S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkyl0Ra, and 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, R2 is a saturated, partially saturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 1, 2, 3 or 4 atoms selected from N, O 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, Rg, -
Figure imgf000019_0001
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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb,
-N(Ra)S(=O)2NRaRa, -NRaC2.6alkylNRaRa and -NRaC2-6alkylORa, 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, R2 is 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 1, 2, 3 or 4 atoms selected from N, O 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, R8, - CMhaloalkyl, 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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)RD, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2.6alkylORa, 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, R2 is an unsaturated 5-, 6- or 7-membered monocyclic ring containing 1, 2 or 3 atoms selected from N, O and S, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups and the ring is substituted by 0, 1, 2 or 3 substituents selected from Re, Rg, - C1-4haloalkyl, 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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkyl0Ra, 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, R2 is an unsaturated 5-, 6- or 7-membered monocyclic hydrocarbon ring containing 1, 2 or 3 atoms selected from N, O and S, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups and the ring is substituted by 0, 1, 2 or 3 substituents selected from Re, Rg, -CMhaloalkyl, 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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkyl0Ra, 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, R2 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. in anotner embodiment, in conjunction with any one of the above and below embodiments, R3 is H.
In another embodiment, in conjunction with any one of the above and below embodiments, R3 is phenyl, benzyl or Ci^alkyl, the phenyl, benzyl and -C^alkyl being substituted by 0, 1, 2 or 3 substituents selected from Re, R8,
Figure imgf000021_0001
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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkyl0Ra, 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, R3 is phenyl substituted by 0, 1, 2 or 3 substituents selected from Re, Rg, - CMhaloalkyl, 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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(Ra)C(=O)NRaR\ -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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2.6alkylNRaRa and -NRaC2-6alkyl0Ra, 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, R3 is
Figure imgf000021_0002
substituted by 0, 1, 2 or 3 substituents selected from Re, Rg, CMhaloalkyl, 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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkylORa, 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, R4 is H.
In another embodiment, in conjunction with any one of the above and below embodiments, R4 is phenyl, benzyl or -C^aUcyl, the phenyl, benzyl and C^alkyl being substituted by 0, 1, 2 or 3 substituents selected from C
Figure imgf000021_0003
i^alkyl, -OCl-4alkyl, -NH2, -NHCMalkyl, and -N(Ci.4alkyl)CMalkyl, 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, R5 is:
Figure imgf000022_0001
wherein the C ring is a saturated or partially saturated 6- or 7-membered ring containing 0, 1 or 2 atoms selected from N, O 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 1 substituents selected from Rg, C1-8alkyl, CMhaloalkyl, 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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkylORa, 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, Rg, Ci-8alkyl,
Figure imgf000022_0002
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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa, -NRaC2-6alkylORa, Br, Cl, F and I; provided that 1 or 2 of R6, R7 and R8 are a basic moiety.
In another embodiment, in conjunction with any one of the above and below embodiments, R5 is:
Figure imgf000023_0001
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 N, O 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 1 substituents selected from Rg, Ci-salkyl, CMhaloalkyl, 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)2Rb, -OC2-6alkylNRaRa, -OC^alkylOR3, -SR\ -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkylORa, 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, R8, Q-salkyl, CMhaloalkyl, 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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa, -NRaC2-6alkyl0Ra, Br, Cl, F and I; provided that 1 or 2 of R6, R7 and R8 are a basic moiety.
In another embodiment, in conjunction with any one of the above and below embodiments, R and R are H; and wherein R7 is selected from amino, aminomethyl, isopropylaminomethyl, /-butylaminomethyl, 2-f-butylaminoethyl, 2-tert-butylamino-l -methyl- ethyl, 1-tert-butylaminoethyl, l-(tert-butylamino-methyl)-vinyl, l-(piρeridin-l-ylmethyl)- vinyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl, N- isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl, N-ϊ-butyl-N- methylaminomethyl, N-ώo-butyl-N-methylaminomethyl, N-Mxityl-N-ethylaminomethyl, N- isobutyl-N-methylaminomethyl, N-/-butyl-N-isopropylaminomethyl, NJV- di(isopropyl)aminomethyl, NJV-dimethylaminomethyl, NJV-diethylaminomethyl, NJV-di(t- butyl)-aminomethyl, cyclopropylaminomethyl, cyclopropylaminoethyl, cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl, cyclobutylaminomethyl, cyclobutylaminoethyl, cyclobutylmethylaminomethyl, cyclobutylmethylaminoethyl, 4,5- dihydro-imidazolyl, 1-piperidinylmethyl, 4-fluoropiperidin-l-ylmethyl, 4,4-difluoropiperidin- 1-ylmethyl, 3-hydroxypiperidin-l-ylmethyl, 4-hydroxypiperidin-l-ylmethyl, 4-(piperidin-l- yl)piperidinylmethyl, 4-(dimethylamino)piperidin- 1 -ylmethyl, 2,6-dimethylpiperidin- 1 - ylmethyl, 4-morpholinylmethyl, l-pyrrolidinylmethyl, 2-methylpyrrolidin-l -ylmethyl, 2,5- dimethylpyrrolidin-1 -ylmethyl, piperazin-1 -ylmethyl, azocan-1-yhnethyl, azepan-1 -ylmethyl, (7-azabicyclo[2.2.1]hept-7-yl)methyl, (l,3,3-trimethyl-6-azaicyclo[3.2.1]oct-6-yl)methyl, 2- piperidinyl and 4-methylpiperazin-l -ylmethyl. In another embodiment, in conjunction with any one of the above and below embodiments, R7 and R8 are H; and R6 is selected from amino, aminomethyl, isopropylaminomethyl, f-butylaminomethyl, 2-7-butylaminoethyl, 2-tert-butylamino-l -methyl- ethyl, 1-tert-butylaminoethyl, l-(tert-butylamino-methyl)-vinyl, l-(piperidin-l-ylmethyl)- vinyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl, N- isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl, N-f-butyl-N- methylaminomethyl, N-wø-butyl-N-methylaminomethyl, N-£-butyl-N-ethylaminomethyl, N- isobutyl-N-methylaminomethyl, N-^-butyl-N-isopropylaminomethyl, NJf- di(isopropyl)aminomethyl, N,N-dimethylaminomethyl, N^V-diethylaminomethyl, NJV-di(t- butyl)-aminomethyl, cyclopropylaminomethyl, cyclopropylaminoethyl, cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl, cyclobutylaminomethyl, cyclobutylaminoethyl, cyclobutylmethylaminomethyl, cyclobutylmethylaminoethyl, 4,5- dihydro-imidazolyl, 1-piperidinylmethyl, 4-fluoropiperidin-l -ylmethyl, 4,4-difluoropiperidin- 1 -ylmethyl, 3-hydroxypiperidin-l-ylmethyl, 4-hydroxypiperidin-l-ylmethyl, 4-(piperidin-l- yl)piperidinylmethyl, 4-(dimethylamino)piperidin- 1 -ylmethyl, 2,6-dimethylpiperidin- 1 - ylmethyl, 4-morpholinylmethyl, 1 -pyrrolidinyhnethyl, 2-methylpyrrolidin-l -ylmethyl, 2,5- dimethylpyrrolidin-1 -ylmethyl, piperazin-1 -ylmethyl, azocan-1-yhnethyl, azepan-1 -ylmethyl, (7-azabicyclo[2.2. l]hept-7-yl)methyl, (l,3,3-trimethyl-6-azaicyclo[3.2. l]oct-6-yl)methyl, 2- piperidinyl and 4-methylpiperazin-l -ylmethyl.
In another embodiment, in conjunction with any one of the above and below embodiments, R6 and R7 are H; and R8 is selected from amino, aminomethyl, isopropylaminomethyl, t-butylaminomethyl, 2-f-butylaminoethyl, 2-tert-butylamino-l -methyl- ethyl, 1-tert-butylaminoethyl, l-(tert-butylamino-methyl)-vinyl, l-(piperidin-l-ylmethyl)- vinyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl, N- isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl, N-r-butyl-N- methylaminomethyl, N-zsø-butyl-N-methylaminomethyl, N-t-butyl-N-ethylaminomethyl, N- isobutyl-N-methylaminomethyl, N-^-butyl-N-isopropylaminomethyl, N5N- di(isopropyl)aminomethyl, N,N-dimethylaminomethyl, N,N-diethylaminomethyl, NN-di(/- butyl)-aminomethyl, cyclopropylaminomethyl, cyclopropylaminoethyl, cyclopropylmethylaniinomethyl, cyclopropylmethylaminoethyl, cyclobutylaminomethyl, cyclobutylaminoethyl, cyclobutylmethylaminomethyl, cyclobutylmethylaminoethyl, 4,5- dihydro-imidazolyl, 1 -piperidinylmethyl, 4-fluoropiperidin-l-ylmethyl, 4,4-difluoropiperidin- 1-ylmethyl, 3-hydroxypiperidin-l-ylmethyl, 4-hydroxypiperidin-l-ylniethyl, 4-(piperidin-l- yl)piperidinylmethyl, 4-(dimethylamino)piperidin- 1 -ylmethyl, 2,6-dimethylpiperidin- 1 - ylmethyl, 4-moφholinylmethyl, 1-pyrrolidinylmethyl, 2-methylpyrrolidin-l -ylmethyl, 2,5- dimethylpyrrolidin-1 -ylmethyl, piperazin-1 -ylmethyl, azocan-1-yhnethyl, azepan-1 -ylmethyl, (7-azabicyclo[2.2.1]hept-7-yl)methyl, (l^^-trimethyl-ό-azaicyclotS^.lJoct-ό-y^methyl, 2- piperidinyl and 4-methylpiperazin-l-yhnethyl.
In another embodiment, in conjunction with any one of the above and below embodiments, R is:
Figure imgf000025_0001
each of which are substituted by 0 or 1 substituents selected from Rg, Ci-salkyl, C^haloalkyl, cyano, nitro, -C(=O)Rb, -C(=O)ORb, -C(=O)ΝRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Rb, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=O)2Rb, -OC2-6alkylNRaRa, -OC2^alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkyl0Ra, 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, R is:
Figure imgf000026_0001
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 R8, C^alkyl, CMhaloalkyl, 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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkyl0Ra, 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, R8, C^galkyl, CMhaloalkyl, 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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa, -NRaC2-6alkylORa, Br, Cl, F and I; provided that 1 or 2 of R6, R7 and R8 are a basic moiety. In another embodiment, in conjunction with any one of the above and below embodiments, R5
Figure imgf000026_0002
each of which are substituted by 0 or 1 substituents selected from Rg, Ci-salkyl,
Figure imgf000026_0003
cyano, nitro, -C(=O)Rb, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)RD, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=O)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkylORa, 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:
Figure imgf000027_0001
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 Rg, C,-8alkyl, CMhaloalkyl, 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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa,
-S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkylORa, 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, Rg, Ci-8alkyl,
CMhaloalkyl, 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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)' 2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2.6alkylNRaRa, -NRaC2-6alkyl0Ra, Br, Cl, F and I; provided that 1 or 2 of R6, R7 and R8 are a basic moiety.
In another embodiment, in conjunction with any one of the above and below embodiments, R3 and R4 together may additionally be C2-3alkylene substituted by 1 or 2 substituents selected from Ci-8alkyl,
Figure imgf000028_0001
halo, oxo, 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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2.6alkyl0Ra, 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, R3 and R4 together may additionally be C2-3alkylene. In another embodiment, in conjunction with any one of the above and below embodiments, Rlc and R4 together may additionally be C2-4alkylene substituted by 1 or 2 substituents selected from Ci-8alkyl, Ci^haloalkyl, halo, oxo, 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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkyl0Ra, 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, Rlc and R4 together may additionally be C2^alkylene.
In another embodiment, in conjunction with any one of the above and below embodiments, a substituent on R2 that is vicinal to the -SO2-R2 bond together with R3 may additionally be
Figure imgf000028_0002
C^alkyl, CMhaloalkyl, halo, oxo, 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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaR"7-NRaC2-6aϊkylNRaRa and -NRaC2-6alkyl0Ra, 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 R2 that is vicinal to the -SO2-R2 bond together with R3 may additionally be
Figure imgf000029_0001
In another embodiment, in conjunction with any one of the above and below embodiments, a substituent on R2 that is vicinal to the -SO2-R2 bond together with R3 may additionally be -C(=O).
In another embodiment, in conjunction with any one of the above and below embodiments :
Figure imgf000029_0002
remaining substituents on R and the vicinal- substituent-R3 bridge are as defined above.
In another embodiment, in conjunction with any one of the above and below embodiments,
the remaining substituents on R2 are as defined above.
In another embodiment, in conjunction with any one of the above and below embodiments,
°2
Figure imgf000029_0004
remaining substituents on R2 as defined above.
In another embodiment: R1 is hydrogen, cyano, -C(O)OCi-8alkyl, -C(O)OH, , -C(=O)NRaRa, -Ci-8alkyl substituted by 0, 1, 2, 3 atoms independently selected from halo; preferably R1 is hydrogen or trifluoromethyl, -C(O)O-tert-butyl, -C(O)OH, cyano, or -C(O)NH2; more preferably hydrogen or trifluoromethyl;
Rla, Rlb, R3, and R4 are hydrogen; and Rlc is hydrogen, halo, or -OH, preferably hydrogen, fluoro or -OH, more preferably hydrogen. Within this embodiment, and more preferred groups of compounds contained therein, a more preferred group of compounds is that wherein:
R2 is phenyl, naphthenyl, 5- or 6-membered monocyclic saturated or unsaturated hydrocarbon ring containing 1, 2, 3 or 4 atoms selected from N, O and S, or 9- or 10- membered unsaturated hydrocarbon ring containing 1, 2, 3 or 4 atoms selected from N, O and S, preferably phenyl, benzodioxinyl, quinolinyl, isoquinolinyl, napthalenyl, 2,3- dihydrobenzofuranyl, tetrahydrofuranyl, 2,3-dihydroindolyl, 3,4-dihydro-2H- benzo[b][l,4]dioxepinyl, or 3,4-dihydro-2H-benzo[b][l,4]oxazine substituted with 0, 1, 2, or three substitutents independently selected from halo, CMhaloalkyl,
Figure imgf000030_0001
nitro, -OH, - NH2, Rg , -OCi-δalkyl, or -OCi-6alkyl 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, -NH2, 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- 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][l,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- 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, 3,4-dimethoxyphenyl, 3,5-dichloro-2-hydroxyphenyl, isoquinolin-6-yl, quinolin-8-yl, 2,3- dihydrobenzofuran-5-yl, 2,3-dihydrobenzo[b][l,4]dioxin-6-yl, 2-nitrophenyl, 2-aminophenyl, 2-fluoro-5-trifluoromethylphenyl, 6-chloronaphthalen-2-yl, 5-chloronaphthalen-l-yl, 2-nitro-4- trifluoromethylphenyl, or 4-biphenyl, 3-biphenyl.
Within the above embodiment and preferred and more preferred groups contained within this embodiment, an even more preferred group of compounds is that wherein R5 is unsaturated 10-membered bicyclic hydrocarbon ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, preferably 1 (R)-1, 2,3, 4-tetrahydronaphthalen-l-yl or 4(Z?)-chroman-4-yl, substituted with cycloalkylamino-(Ci-C6)alkyl, cycloalkyl(Ci-C6)alkylamino(C]-C6)alkyl, Ci-6- alkylamino-Ci.6-alkyl, 5-8 membered nitrogen-containing saturated heterocyclyl-C2^-alkenyl, >o memoereα nitrogen-containing partially unsaturated or unsaturated heterocyclyl, 6 or 7 membered saturated heterocyclyl-(C1-6)-alkylamino(Ci-6)alkyl, (Ci.6)alkylamino(Ci-6)alkyl substituted with -OH,
Figure imgf000031_0001
or 5-7 membered nitrogen-containing saturated heterocyclyl-Ci-4-alkyl wherein the heterocyclyl ring optionally contains an oxygen or nitrogen ring atom and is substituted with 0, 1, or 2 substitutents independently selected from halo, -OH, or -Ci,6alkyl and additionally with 0 or 1 substitutuent selected from halo or nitro. Preferably, R5 is 1,2,3,4-tetrahydronaphthalen-l-yl substituted at the 6-position or chroman-4-yl substituted at the 7 position with cyclopropylaminomethyl, cyclopropylmethylaminomethyl, cyclobutylaminomethyl, cyclohexylaminomethyl, cyclopentylaminomethyl, 1-cyclopropylaminoethyl, 1-cyclobutylaminoethyl, 1- cyclopenylaminoethyl, 2-methylpropylaminomethyl, 2,2-dimethylpropylaminomethyl, 1- methylethylaminomethyl, tert-butylaminomethyl, 1,1-dimethylpropylaminomethyl, pyridine-4- ylaminomethyl, (piperidin-1 -ylCH2)C=CH2, tetrahydrofuran-2-ylmethylaminomethyl, morpholin-4-ylmethyl, piperidin-1 -yhnethyl, pyrrolidin-1-ylmethyl, 4-hydroxypiperidin-l- ylmethyl, 4-fluoropiperidin- 1 -yhnethyl, 4-methylpiperidin- 1 -ylmethyl, 3 -hydroxypiperidin- 1 - ylmethyl, 2,6-dimethylpiperidin-l -yhnethyl, homopiperidin-1 -ylmethyl, 4-methylpiperazin-l- ylmethyl, 2-(pyrrolidin-l-yl)ethylaminomethyl, 2-(piperidin-l-yl)ethylaminomethyl, 2- (morpholin-l-yl)ethylaminomethyl, -CH2NH(CH3)2CH2OH, -CH2NH(CH3)2CH2OCH3, 2- (dimethylamino)ethylaminomethyl, 2-(diethylamino)ethylaminomethyl or 2,5-dihydro-lH- imidazol-2-yl.
A family of specific compounds of particular interest within Formula (I) consists of compounds and pharmaceutically-acceptable salts thereof as follows:
(2i?)-3-(((2,3-dichlorophenyl)sulfonyl)(methyl)amino)-2-hydroxy-N-(( lR)-6-( 1 - piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)propanamide; (2Λ)-3-(((2,3-dichlorophenyl)sulfonyl)(methyl)amino)-2-methyl-N-((li?)-6-(l- piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)propanamide;
(2/?)-3-(((2,3-dichlorophenyl)sulfonyl)amino)-2-methyl-N-((li?)-6-(l-piperidinyl- methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)propanamide;
(27?,3i?)-4,4,4-trifluoro-2-hydroxy-N-((li?)-6-(l-piperidinylmethyl)-l,2,3,4-tetrahydro- l-naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3i?)-3-(((2,3-dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((l/?)-6-(l-piperidinyl- methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3Λ)-3-(((2,3-dichlorophenyl)sulfonyl)amino)-N-((li?)-6-(((l,l-dimethylethyl)amino)- methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-4,4,4-trifluorobutanamide; VθΛ;-j-^^z,j-αicnioropnenyi)sulfonyl)amino)-4,4,4-trifluoro-N-((li?)-6-(l-piperidinyl- methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3i?)-3-(((2,5-dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((4i?)-7-(l-piperidinyl- methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide; (3/?)-3-(((2,5-dichlorophenyl)sulfonyl)amino)-N-((lΛ)-6-(((l,l-dimethylethyl)amino)- methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-4,4,4-trifluorobutanamide;
(3Λ)-3-(((2,6-dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((lΛ)-6-(l-ρiperidinyl- methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butananiide;
(3i?)-3-(((3,4-dichlorophenyl)sulfonyl)amino)-4-fluoro-N-((17?)-6-(l-piperidinyl- methyl)- l,2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(3JR)-3-(((3,4-dichlorophenyl)sulfonyl)amino)-N-((lJ(?)-6-(((l , 1 -dimethylethyl)amino)- methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-4,4,4-trifluorobutanamide;
(3Λ)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((l/?)-6-(((l,l-dimethyl- ethyl)amino)methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-4,4,4-trifluorobutanamide; (3/?)-3-(((4-chlorophenyl)sulfonyl)amino)-N-((l/?)-6-(((l,l-dimethylethyl)amino)- methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-4,4,4-trifluorobutanamide;
(3/?)-3-(((5-chloro-2-(methyloxy)phenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((li?)-6-(l- piperidinylmethyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3i?)-3-(((5-chloro-2-fluorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((lR)-6-(l- piperidinylmethyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3i?)-3-((2,3-dihydro-l,4-benzodioxin-6-ylsulfonyl)amino)-4,4,4-trifluoro-N-((li?)-6- ( 1 -piperidinyhnethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3i?)-4,4,4-trifluoro-3-(((8-(methyloxy)-5-quinolinyl)sulfonyl)amino)-N-((lR)-6-(l- piperidinylmethyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide; (3R)-4,4,4-trifluoro-3-((2-naphthalenylsulfonyl)amino)-N-((li?)-6-(l-piperidinyl- methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(3/?)-4,4,4-trifluoro-N-(( lR)-6-( 1 -piperidinyhnethyl)- 1 ,2,3 ,4-tetrahydro- 1- naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3i?)-4,4,4-trifluoro-N-(( \R)-6-( 1 -piperidinylmethyl)- 1 ,2,3 ,4-tetrahydro- 1 - naphthalenyl)-3-((8-quinolinylsulfonyl)amino)butanamide;
(3/?)-4-hydroxy-3-(((4-methylphenyl)sulfonyl)amino)-N-(( 1 R)-6-( 1 -piperidinyl¬ methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3R)-N-(( 1 R)-6-((( 1 , 1 -dimethylethyl)amino)methyl)- 1 ,2,3,4-tetrahydro- 1 - naρhthalenyl)-4-fluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3Λ)-_V-(( 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;
(3i?)-N-(( 1 R)-6-((( 1 , 1 -dimethylethyl)amino)methyl)- 1,2,3 ,4-tetτahydro- 1 - naphthalenyl)-4,4,4-trifluoro-3-((2-naphthalenylsulfonyl)amino)butanamide; (3/?)-N-((lR)-6-(((l,l-dimethylethyl)amino)methyl)-l,2,3,4-tetrahydro-l- naphthalenyl)-4,4,4-trifluoro-3-(((2,4,6-triπiethylphenyl)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;
(3i?)-N-(( 1 R)-6-((cyclopentylamino)methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)-4- fluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3i?)-N-((4R)-7-((cyclopentylamino)methyl)-3,4-dihydro-2H-chromen-4-yl)-4,4,4- trifluoro-S-CCCS-^fluoromethyOphenyOsulfony^aminoJbutanamide;
(3i?,4i?)-3-(((3,4-dichlorophenyl)sulfonyl)amino)-4-hydroxy-N-((li?)-6-(l-piperidinyl- methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)pentanamide; (35)-3-(((2,3-dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((li?)-6-(l-piperidinyl- methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(35)-3-(((2,5-dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((li?)-6-(l-piperidinyl- methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(31S}-3-(((2,6-dichloro-4-(trifluoromethyl)phenyl)sulfonyl)amino)-N-((lΛ)-6-(l- piperidinylmethyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(35)-3-(((2,6-dichloro-4-(trifluoromethyl)phenyl)sulfonyl)amino)-N-((li?)-6-(((l,l- dimethylethyl)amino)methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(35)-3-(((2-chloro-5-(trifluoromethyl)phenyl)sulfonyl)amino)-N-((17?)-6-(l- piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (35)-3-(((2-chloro-5-(trifluoromethyl)phenyl)sulfonyl)amino)-N-((li?)-6-((cyclopentyl- amino)methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(35)-3-(((2-fluoro-5-(trifluoromethyl)phenyl)sulfonyl)amino)-N-((li?)-6-(l-piperidinyl- methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(31S)-3-(((2-nitro-4-(trifluoromethyl)phenyl)sulfonyl)amino)-N-((lΛ)-6-(l-piperidinyl- methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(35}-3-(((3,4-bis(methyloxy)phenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((l/?)-6-(l- piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(35)-3-(((3,4-dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((l/?)-6-(l-piperidinyl- methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3 -(((3 ,4-dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-(( 1 R)-6-( 1 -( 1 - piperidinylmethyl)ethenyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(3S)-3-(((3,5-dichloro-2-hydroxyphenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((l^)-6-(l- piperidinylmethyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide; (35}-3-(((3-chloro-2-fluorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((lR)-6-(l- piperidinylmethyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(35)-3-(((3-chloro-4-methylphenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((lR)-6-(l- piperidinylmethyl)- 1 ,2,3 ,4-tetrahydro 1 -naphthalenyl)butanamide;
(3S)-3-(((4-( 1 , 1 -dimethylethyl)phenyl)sulfonyl)amino)-N-(( \R)-6-( 1 -piperidinyl- methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(35)-3-(((4-(l,3-oxazol-5-yl)phenyl)sulfonyl)amino)-N-((lΛ)-6-(l-piperidinylmethyl)- l,2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(31S)-3-(((4-bromo-3-(trifluoromethyl)phenyl)sulfonyl)amino)-N-((lR)-6-(l- piperidinylmethyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide; (35)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((lΛ)-6-(l- piperidinylmethyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(35)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((lΛ)-6-((3- hydroxy- 1 -piperidinyl)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(35)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((li?)-6-(((2- (1 -pyrrolidinyl)ethyl)amino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(35)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((4i?)-7-(l- piperidinylmethyl)-3,4-dihydro-2H-chromen-4-yl)butanamide;
(3-S}-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((4i?)-7-((3- hydroxy-l-piperidinyl)methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide; (35)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-(( 1 R)-6-((( 1 , 1 -dimethyl- ethyl)amino)methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(35)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((li?)-6-((cyclopentyl- amino)methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3-S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((li?)-6-(l-piperidinyl- methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(35}-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((lR)-6-(((2-methylpropyl)- amino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(35)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((li?)-6-(((l-methylethyl)- amino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((lΛ)-6-(((cyclopropyl- methyl)amino)methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(35)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((li?)-6-((cyclobutylamino)- methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((li?)-6-(((3S)-3-hydroxy-l- piperidinyl)methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3-S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((li?)-6-(l-pyrrolidinyl- methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(35)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4/?)-7-(((l,l-dimethyl- ethyl)amino)methyl)-3 ,4-dihydro-2H-chromen-4-yl)butanamide;
(35)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4iZ)-7-(cyclopentylamino)- methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide;
(3iS)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4i?)-7-(l-piperidinyl- methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide; (35)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((47?)-7-(((2-methylpropyl)- amino)methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide;
(35)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4/?)-7-(((l-methylethyl)- amino)methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide;
(35)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4/?)-7-(((cyclopropyl- methyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide;
(35)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4i?)-7-((cyclobutylamino)- methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide;
(35)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4i?)-7-(((3S)-3-hydroxy-l- piperidinyl)methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide; (35 )-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4/?)-7-(l-pyrrolidinyl- methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide;
(35)-3-(((4-chloro-3-(trifluoromethyl)phenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((li?)- 6-( 1 -piperidinylmethyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(35)-3-(((5-chloro-l-naphthalenyl)sulfonyl)amino)-N-((77?)-6-((cyclopentylamino)- methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3,S)-3-(((6-chloro-2-naphthalenyl)sulfonyl)amino)-N-((l/?)-6-((((6-chloro-2- naphthalenyl)sulfonyl)(cyclopentyl)amino)methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)- butanamide; (36>3-(((6-chloro-2-naphthalenyl)sulfonyl)amino)-N-((lΛ)-6-((cyclopentylamino)- methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(35)-3-(((6-chloro-2-naphthalenyl)sulfonyl)amino)-N-((li?)-6-(l-piperidinylmethyl)- l,2,3,4-tetrahydro-l-naphthalenyl)butanamide; (35)-3-((l,l'-biphenyl-3-ylsulfonyl)amino)-N-((l/?)-6-(l-piperidinylmethyl)-l,2,3,4- tetrahydro- 1 -naphthalenyl)butanamide;
(35)-3-((l,l'-biphenyl-4-ylsulfonyl)amino)-N-((lΛ)-6-(((l,l-dimethylethyl)- amino)methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(35)-3-((l,l'-biphenyl-4-ylsulfonyl)amino)-N-((lΛ)-6-(l-piperidinylmethyl)-l,2,3,4- tetrahydro- 1 -naphthalenyl)butanamide;
(3S)-3-((2,3-dihydro-l-benzofuran-5-ylsulfonyl)amino)-4,4,4-trifluoro-N-((li?)-6-(l- piperidinylmethyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(35)-3-(methyl((3-(trifluoromethyl)phenyl)sulfonyl)amino)-N-((li?)-6-(l-piperidinyl- methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide; (35)-4,4,4-trifluoro-3-((2-naphthalenylsulfonyl)amino)-N-((l/?)-6-(l-piperidinyl- methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(35)-4,4,4-trifluoro-3-((2-naphthalenylsulfonyl)amino)-N-((lΛ)-6-(l-piperidinyl- methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(35)-4,4,4-trifluoro-3-((2-naphthalenylsulfonyl)amino)-N-((li?)-6-(l-(l-piperidinyl- methyl)ethenyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(3-S)-4,4,4-trifluoro-3-((6-isoquinolinylsulfonyl)amino)-N-(( \R)-6-( 1 -piperidinyl- methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(35}-4,4,4-trifluoro-3-(methyl((3-(trifluoromethyl)phenyl)sulfonyl)amino)-N-((li?)-6- ( 1 -piperidinylmethyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide; (35)-4,4,4-trifluoro-N-((li?)-6-((((2/?)-tetrahydro-2-furanylmethyl)amino)methyl)- l,2,3,4-tetrahydro-l-naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-4,4,4-trifluoro-N-((li?)-6-((((25)-tetrahydro-2-ruranylmethyl)amino)methyl)- l,2,3,4-tetrahydro-l-naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3-S)-4,4,4-trifluoro-N-((lR)-6-(((l-methylethyl)amino)methyl)-l,2,3,4-tetrahydro-l- naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35}-4,4,4-trifluoro-N-((li?)-6-(((2-(l-piperidinyl)ethyl)amino)methyl)-l,2,3,4- tetrahydro-l-naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-4,4,4-trifluoro-N-(( 1 R)-6-(((2-( 1 -pyrrolidinyl)ethyl)amino)methyl)- 1 ,2,3 ,4- tetrahydro-l-naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (35)-4,4,4-trifluoro-N-((li?)-6-(((2-(4-moφholinyl)ethyl)amino)methyl)-l,2,3,4- tetrahydro-l-naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3.S)-4,4,4-trifluoro-N-(( lΛ)-6-(((2-hydroxy- 1 , 1 -dimethylethyl)amino)methyl)-l ,2,3,4- tetrahydro-l-naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (35)-4,4,4-trifluoro-N-((l/?)-6-(((2-methylpropyl)amino)methyl)-l,2,3,4-tetrahydro-l- naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-4,4,4-trifluoro-N-((li?)-6-(((35)-3-hydroxy-l-piperidinyl)methyl)-l,2,3,4- tetrahydro-l-naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3iS)-4,4,4-trifluoro-N-(( li?)-6-((4-fluoro- 1 -piperidinyl)methyl)- 1,2,3 ,4-tetrahydro- 1 - naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3S)-4,4,4-trifluoro-N-(( l/?)-6-((4-hydroxy- 1 -piperidinyl)methyl)-l ,2,3,4-tetrahydro- 1 - naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3.S)-4,4,4-trifluoro-N-(( li?)-6-((4-methyl- 1 -piperazinyl)methyl)- 1 ,2,3 ,4-tetrahydro- 1 - naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (35)-4,4,4-trifluoro-N-(( l/?)-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;
(S^^^^-trifluoro-N-CCl^-ό-Cl-piperidinylmethyO-l^^^-tetrahydro-l- naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-4,4,4-trifluoro-N-((li?)-6-(l-piperidinyhnethyl)-l,2,3,4-tetrahydro-l- naphthalenyl)-3-(((2,4,6-trimethylphenyl)sulfonyl)amino)butanamide;
(35)-4,4,4-trifluoro-N-(( 1 R)-6-( 1 -piperidinylmethyl)- 1 ,2 ,3 ,4-tetrahydro- 1 - naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3,S)-4,4,4-trifluoro-N-(( lR)-6-( 1 -pyrrolidinylmethyl)- 1 ,2,3 ,4-tetrahydro- 1 - naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3S)-4,4,4-trifluoro-N-((li?)-6-(4-morpholinylmethyl)-l,2,3,4-tetrahydro-l- naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3-S)-4,4,4-trifluoro-N-((17?)-6-(hydroxymethyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-3- (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3S)-4,4,4-trifluoro-N-((4Λ)-7-(((2-methylpropyl)amino)methyl)-3,4-dihydro-2H- chromen-4-yl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-4,4,4-trifluoro-N-((4/?)-7-(((3R)-3-hydroxy-l-piperidinyl)methyl)-3,4-dihydro-2H- chromen-4-yl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-4,4,4-trifluoro-N-((4i?)-7-((4-methyl-l-piperazinyl)methyl)-3,4-dihydro-2H- chromen-4-yl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-4,4,4-trifluoro-N-((4i?)-7-(l-piperidinylmethyl)-3,4-dihydro-2H-chromen-4-yl)-3- (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3.S)-4,4,4-trifluoro-N-((4/?)-7-(4-moφholinylniethyl)-3,4-dihydro-2H-chromen-4-yl)-
3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-4-fluoro-N-((l/?)-6-(l-piperidinylmethyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-3- (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3S)-N-(( li?)-6-((( 1 , 1 -dimethylethyl)amino)methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)- 3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)-5-hexynamide;
(35)-N-(( l/?)-6-((( 1 , 1 -dimethylethyl)amino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)- 4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-N-(( l/?)-6-((( 1 , 1 -dimethylethyl)amino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)- 3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-(( li?)-6-((( 1 , 1 -dimethylethyl)amino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-
4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-N-((l/?)-6-(((l,l-dimethylethyl)amino)methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)- 3-(((2-nitro-4-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-N-(( lR)-6-(((2-(acerylamino)ethyl)amino)methyl)- 1 ,2,3 ,4-tetrahydro- 1 - naphthalenyl)-4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-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;
(35)-N-((lΛ)-6-(((2-(dimethylamino)ethyl)amino)methyl)-l,2,3,4-tetrahydro-l- naphthalenyl)-4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (35)-N-(( 1 /?)-6-(((2-(methyloxy)ethyl)amino)methyl)- 1 ,2,3,4-tetrahydro- 1 - naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-N-((l/?)-6-(((2,2-dimethylpropyl)amino)methyl)-l,2,3,4-tetrahydro-l- naphthalenyl)-4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3S)-N-((lR)-6-(((2-methylpropyl)amino)methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-3- (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-N-((l/?)-6-(((2R,6S)-2,6-dimethyl-l-piperidinyl)methyl)-l,2,3,4-tetrahydro-l- naphthalenyl)-4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3S)-N-(( 1 /?)-6-(((cyclopropylmethyl)amino)methyl)- 1 ,2,3,4-tetrahydro- 1 - 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;
(35)-N-((lΛ)-6-((lR)-l-(cyclobutylamino)ethyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-3- (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((lR)-6-(( 1 R)- 1 -(cyclopropylamino)ethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-
3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3S)-N-((lR)-6-((l S)-I -((2-methylpropyl)amino)ethyl)-l ,2,3,4-tetrahydro-l - naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-N-(( li?)-6-(( 1 S)- 1 -((cyclopropylmethyl)amino)ethyl)- 1 ,2,3,4-tetrahydro- 1 - naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3S)-N-((lΛ)-6-((lS)-l-(cyclopentylamino)ethyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-3- (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35}-N-((lΛ)-6-((3-pyridinylamino)methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-3-(((3- (trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (35)-N-((li?)-6-((cyclobutylamino)methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-4,4,4- trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-N-((li?)-6-((cyclohexylamino)methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-4,4,4- trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanaπiide;
(3iS)-N-((l/?)-6-((cyclopentyl((2-fluoro-5-(trifluoromethyl)phenyl)sulfonyl)amino)- methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-3-(((2-fluoro-5-(trifluoromethyl)phenyl)- sulfonyl)amino)butanamide;
(3S)-N-((lR)-6-((cyclopentylamino)methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-3-(((3- (trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-N-((li?)-6-((cyclopentylamino)methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-4,4,4- trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-N-((lΛ)-6-((cyclopentylamino)methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-3-(((2- fluoro-5-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35}-N-(( lΛ)-6-((cyclopentylamino)methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)-4,4,4- trifluoro-3-(methyl((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (35)-N-((l/?)-6-(l-(l-piperidinytaiethyl)ethenyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-3-
(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-N-(( lR)-6-( 1 -azepanylmethyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)-4,4,4-trifluoro- 3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (35)-N-((lΛ)-6-(l-azepanylmethyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-3-(((4-chloro- 2,5-dimethylphenyl)sulfonyl)amino)-4,4,4-trifluorobutanamide;
(3S)-N-(X 1 R)-6-( 1 -azepanylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-3-(((3-chloro-4- methylphenyl)sulfonyl)amino)-4,4,4-trifluorobutanamide; (35)-N-(( 1 R)-6-( 1 -azepanylmethyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)-3-(((3 ,4- bis(methyloxy)phenyl)sulfonyl)amino)-4,4,4-trifluorobutanamide;
(35)-N-((l/?)-6-(l-piperidinylniethyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-3-(((3- (trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3S)-N-((\R)-6-( 1 -pyrrolidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-3-(((3- (trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3S)-N-((li?)-6-acetyl-l,2,3,4-tetrahydro-l-naphthalenyl)-3-(((3-(trifluoromethyl)- phenyl)sulfonyl)amino)butanamide;
(3S)-N-((li?)-6-formyl-l,2,3,4-tetrahydro-l-naphthalenyl)-3-(((3-(triπuoromethyl)- phenyl)sulfonyl)amino)butanamide; (35)-N-((4i?)-6-chloro-7-(((l,l-dimethylethyl)amino)methyl)-3,4-dihydro-2H-chromen-
4-yl)-4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-N-((4i?)-7-((( 1 , 1 -dimethylethyl)amino)methyl)-3 ,4-dihydro-2H-chromen-4-yl)- 4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3S)-N-((4i?)-7-((( 1 , 1 -dimethylethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)-3- (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35}-N-((4/?)-7-(((l-methylethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)-3-(((3- (trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3S)-N-((4i?)-7-(((2-(methyloxy)ethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)-3- (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (35)-N-((4i?)-7-(((2,2-dimethylpropyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)-
4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-N-((4Λ)-7-(((2-methylpropyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)-3- (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-N-((4Λ)-7-(((3R)-3-hydroxy-l-piperidinyl)methyl)-3,4-dihydro-2H-chromen-4- yl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-N-((4i?)-7-(((cyclopropylmethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)-3- (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35}-N-((4R)-7-((4-methyl-l-piperazinyl)methyl)-3,4-dihydro-2H-chromen-4-yl)-3- (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (35)-N-((4R)-7-((cyclohexylamino)methyl)-3,4-dihydro-2H-chromen-4-yl)-4,4,4- trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-N-((4Λ)-7-((cyclopentylamino)methyl)-3,4-dihydro-2H-chromen-4-yl)-3-(((3- (trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (35)-N-((4/?)-7-((cyclopropylamino)methyl)-3,4-dihydro-2H-chromen-4-yl)-3-(((3-
(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-N-((4Λ)-7-(l-azepanylmethyl)-3,4-diliydro-2H-chromen-4-yl)-3-(((4-chloro-2,5- dimethylphenyl)sulfonyl)amino)-4,4,4-trifluorobutanamide;
(35}-N-((4i?)-7-(l-azepanylmethyl)-3,4-dihydro-2H-chromen-4-yl)-4,4,4-trifluoro-3- (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-N-((4R)-7-(l-piperidinylmethyl)-3,4-dihydro-2H-chromen-4-yl)-3-(((3-(trifluoro- methyl)phenyl)sulfonyl)amino)butanamide;
(3-S)-N-((4R)-7-(l-pyrrolidinylmethyl)-3,4-dihydro-2H-chromen-4-yl)-3-(((3-(trifluoro- methyl)phenyl)sulfonyl)amino)butanamide; 1,1 -dimethylethyl N-2-((3,4-dichlorophenyl)sulfonyl)-N-4-(( \R)-6-( 1 -piperidinyl- methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-D-alpha-asparaginate; l,l-dimethylethyl N-2-((3,4-dichlorophenyl)sulfonyl)-N-4-((lR)-6-(hydroxymethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-D-alpha-asparaginate;
1 , 1 -dimethylethyl N-2-((3 ,4-dichlorophenyl)sulfonyl)-N-4-(( lR)-6-((( 1 , 1 -dimethyl- ethyl)amino)methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-D-alpha-asparaginate;
1 , 1 -dimethylethyl N-2-((3,4-dichlorophenyl)sulfonyl)-N-4-(( lR)-6-( 1 -pyrrolidinyl- methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-D-alpha-asparaginate;
2-((2i?)-2-methyl-l-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((lR)-6-(l- piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)acetamide; 2-(3,4-dichloro-benzenesulfonylamino)-N-(6-pyπOlidin-l-ylmethyl-l,2,3,4-tetrahydro- naphthalen-l-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; , 3-(6-bromo- 1 , 1 -dioxido-3-oxo-l ,2-benzisothiazol-2(3H)-yl)-N-(( \R)-6-( 1 -piperidinyl- methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)propanamide;
3-(6-bromo- 1 , 1 -dioxido-3-oxo- 1 ,2-benzisothiazol-2(3H)-yl)-N-(( l/?)-6-((( 1,1- dimethylethyl)amino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)propanamide; 37?-(3 ,4-dichloro-benzenesulfonylamino)-4,4,4-trifluoro-N-(6-piperidin- 1 -ylmethyl- l,2,3,4-tetrahydro-naphthalen-l-yl)-butyramide;
35-(3 ,4-dichloro-benzenesulfonylamino)-4,4,4-trifluoro-N-(6-piperidin- 1 -ylmethyl- 1 ,2,3 ,4-tetrahydro-naphthalen- 1 -yl)-butyramide; N- 1 -(( lR)-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 -(( 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 -(( li?)-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;
N- 1 -(( li?)-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 -(( l/?)-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; N-I -(( \R)-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 -(( \R)-6-(( IS)- 1 -(cyclopentylamino)ethyl)-l ,2,3,4-tetrahydro- 1 -naphthalenyl)-N-3- methyl-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide;
N- 1 -(( 17?)-6-((4-fluoro-l -piperidinyl)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-N-3- phenyl-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide;
N-l-((lR)-6-((4-fluoro-l-piperidinyl)methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-N-3- methyl-N-3 -((3 -(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide;
N-l-((lΛ)-6-((cyclopentylamino)methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-N-3-(4- fluorophenyl)-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide; N-l-((17?)-6-((diethylamino)methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-N-3-(4- fluorophenyl)-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide;
N-l-((l/?)-6-(l-piperidinylmethyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-N-3-((3- (trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide;
N- 1 -((\R)-6-( 1 -piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-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- 1 -naphthalenyl)-D- aspartamide;
N-2-((3,4-dichlorophenyl)sulfonyl)-N-4-(( l/?)-6-((( 1 , 1 -dimethylethyl)amino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-D-aspartamide; N-2-((3,4-dichlorophenyl)sulfonyl)-N-4-((l/?)-6-(((l,l-dimethylethyl)amino)methyl)- l,2,3,4-tetrahydro-l-naphthalenyl)-D-asparagine;
N-2-((3,4-dichlorophenyl)sulfonyl)-N-4-((lΛ)-6-(((2-methylpropyl)amino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-D-aspartamide; N-2-((3,4-dichlorophenyl)sulfonyl)-N-4-((l/?)-6-((4-fluoro-l-piperidinyl)methyl)-
1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-D-aspartamide;
N-2-((3 ,4-dichlorophenyl)sulfonyl)-N-4-(( \R)-6-( 1 -piperidinylmethyl)- 1 ,2,3 ,4- tetrahydro- 1 -naphthalenyl)-D-aspartamide;
N-2-((3,4-dichlorophenyl)sulfonyl)-N-4-((lΛ)-6-(l-piperidinylmethyl)-l,2,3,4- tetrahydro- 1 -naphthalenyl)-D-asparagine;
N-2-((3 ,4-dichlorophenyl)sulfonyl)-N-4-(( lR)-6-( 1 -pyrrolidinylmethyl)- 1 ,2,3 ,4- tetrahydro- 1 -naphthalenyl)-D-aspartamide;
N-2-((3,4-dichlorophenyl)sulfonyl)-N-4-((li?)-6-(hydroxymethyl)-l,2,3,4-tetrahydro-l- naphthalenyl)-D-aspartamide; N-2-((4-methylphenyl)sulfonyl)-N-4-(( 1 R)- 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- 1 -naphthalenyl)-D-aspartamide;
N-2-((4-methylphenyl)sulfonyl)-N-4-(( 1 R)-6-( 1 -piperidinylmethyl)- 1,2,3 ,4-tetrahydro- l-naphthalenyl)-D-asparagine;
N-3-((2-aminophenyl)sulfonyl)-N-l-((4/?)-7-(l-piperidinylmethyl)-3,4-dihydro-2H- chromen-4-yl)-beta-alaninamide;
N-3-((2-nitrophenyl)sulfonyl)-N- 1 -((47?)-7-( 1 -piperidinylmethyl)-3,4-dihydro-2H- chromen-4-yl)-beta-alaninamide; N-3-((3,4-dichlorophenyl)sulfonyl)-N- 1 -(( l/?)-6-((( 1 , 1 -dimethylethyl)amino)methyl)-
1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-N-3-(4-fluorophenyl)-beta-alaninamide;
N-3-( 1 -methylethyl)-N- 1 -(( lR)-6-( 1 -piperidinyhnethyl)- 1 ,2,3,4-tetrahydro- 1 - naphthalenyl)-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide;
N-3-(2-amino-2-oxoethyl)-N-l -((lΛ)-6-(((l , 1 -dimethylethyl)amino)methyl)-l ,2,3,4- tetrahydro-l-naphthalenyl)-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide;
N-3-(2-fluoroethyl)-N-l -((lR)-6-( 1 -piperidinyhnethyl)- 1 ,2,3,4-tetrahydro- 1 - naphthalenyl)-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide;
N-3 -(2-naphthalenylsulfonyl)-N-3 -(phenylmethyl)-N- 1 -((4R)-7-( 1 -piperidinylmethyl)- 3,4-dihydro-2H-chromen-4-yl)-beta-alaninamide; N-3-(2-naphtharenylsulfonyl)-N-3-phenyl-N-l-((4i?)-7-(l-piperidinylmethyl)-3,4- dihydro-2H-chromen-4-yl)-beta-alaninamide;
N-3-(3-amino-3-oxopropyl)-N-l -(( li?)-6-((( 1 , 1 -dimethylethyl)amino)methyl)-l ,2,3,4- tetrahydro-l-naphthaleny^-N-S-CCS-^rifluoromethy^pheny^sulfony^-beta-alaninamide; N-3-(4-fluorophenyl)-N-l-((lΛ)-6-(((2-methylpropyl)amino)methyl)-l,2,3,4- tetxahydro-l-naphthalenyl)-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide;
N-3-(4-fluorophenyl)-N-l-((l/?)-6-((4-fluoro-l-piperidinyl)methyl)-l,2,3,4-tetrahydro- l-naphthalenyl)-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide;
N-3-cyclohexyl-N- 1 -(( lR)-6-( 1 -piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)- N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide;
N-3-cyclopropyl-N-l-((li?)-6-(((l,l-dimethylethyl)amino)methyl)-l,2,3,4-tetrahydro-l- naphthaleny^-N-S-CCS-Ctrifluoromethy^pheny^sulfony^-beta-alaninamide;
N-3 -cyclopropyl-N- 1 -(( 1 i?)-6-( 1 -piperidinylmethyl)- 1 ,2,3 ,4-tetrahydro- 1 - naphthalenyl)-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide; N-S-methyl-N-l-CCl^-δ-Cl-piperidinylmethyO-l^^^-tetrahydro-l-naphthalenyO-N-S-
((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide;
N-4-(( li?)-6-((( 1 , 1 -dimethylethyl)amino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-N- 2-((4-methylphenyl)sulfonyl)-D-aspartamide;
7V-4-((4/?)-6-chloro-7-methyl-3,4-dihydro-2H-chromen-4-yl)-N-2-((3,4- dichlorophenyl)-sulfonyl)-D-aspartamide;
N-4-((4Λ)-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; (i?)-4,4,4-trifluoro-N-((7?)-6-(piperidin- 1 -ylmethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)-
3-(2-(trifluoromethyl)phenylsulfonamido)butanamide;
(/?)-3-(3-bromophenylsulfonamido)-4,4,4-trifluoro-N-((/?)-6-(piperidin-l-ylmethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide;
(/?)-3-(3-chloro-4-fluorophenylsulfonamido)-4,4,4-trifluoro-N-((/?)-6-(piperidin-l-yl- methyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)butanamide;
(Λ)-4,4,4-trifluoro-N-methyl-N-((i?)-7-(piperidin-l-yhnethyl)chroman-4-yl)-3-(3- (trifluoromethyl)phenylsulfonamido)butanamide;
(/?)-4,4,4-trifluoro-N-((i?)-6-(piperidin- 1 -ylmethyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)- 3-(4-(trifluoromethoxy)phenylsulfonamido)butanamide; (Λ)-4,4,4-trilluoro-3-(3-methylphenylsulfonamido)-N-((/?)-6-(piperidin-l-ylmethyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)butanamide;
(i?)-3 -(4-chloro-2-fluorophenylsulfonamido)-4,4,4-trifluoro-N-((i?)-6-(piperidin- 1 -yl- methyl)-l,2,3,4-tetrahydronaphthalen-l-yl)butanamide; (i?)-3-(2-chloro-4-fluorophenylsulfonamido)-4,4,4-trifluoro-N-((i?)-6-(piperidin-l-yl- methyl)-l,2,3,4-tetrahydronaphthalen-l-yl)butanamide;
(R)-tert-butyl 2-(naphthalene-3-sulfonamido)-4-oxo-4-((/?)-6-(piperidin-l-ylmethyl)- l,2,3,4-tetrahydronaphthalen-l-ylamino)butanoate;
(7?)-4,4,4-trifluoro-N-((Λ)-6-((4-methylpiperidin- 1 -yl)methyl)- 1 ,2,3,4-tetrahydro- naphthalen- 1 -yl)-3 -(3 -(trifluoromethyl)phenylsulfonamido)butanamide;
(R)-methyl 4-oxo-4-((7?)-6-(piperidin- 1 -ylmethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl- amino)-2-(3-(trifluoromethyl)phenylsulfonamido)butanoate;
(/?)-4-oxo-4-((/?)-6-(piperidin- 1 -ylmethyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -ylamino)-2- (3 -(trifluoromethyl)phenylsulfonamido)butanoic acid; (7?)-Ν 1 -((Λ)-ό-(piperidin- 1 -ylmethyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)-3-(3-
(trifluoromethyl)phenylsulfonamido)succinamide;
(Λ)-3-cyano-N-((R)-6-(piperidin-l-yhnethyl)-l,2,3,4-tetrahydronaphthalen-l-yl)-3-(3- (trifluoromethyl)phenylsulfonamido)propanamide;
(i?)-2-(naphthalene-3-sulfonamido)-4-oxo-4-((/?)-6-(piperidin-l-ylmethyl)-l, 2,3,4- tetrahydronaphthalen-l-ylamino)butanoic acid;
(iZ)-methyl 2-(naphthalene-3-sulfonamido)-4-oxo-4-((i?)-6-(piperidin- 1 -ylmethyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -ylamino)butanoate;
(i?)-3-(3-tert-butylphenylsulfonamido)-4,4,4-trifluoro-N-((i?)-6-(piperidin-l-ylmethyl)- l,2,3,4-tetrahydronaphthalen-l-yl)butanamide; (Λ)-methyl 2-(3,4-dichlorophenylsulfonamido)-4-oxo-4-((/?)-6-(pyrrolidin- 1 -yhnethyl)- l,2,3,4-tetrahydronaphthalen-l-ylamino)butanoate;
(i?)-4,4,4-trifluoro-3-(3-(oxazol-5-yl)phenylsulfonamido)-N-((/?)-6-(piperidin-l -yl¬ methyl)-! ,2,3,4-tetrahydronaphthalen-l -yl)butanamide;
(7?)-3-(3,4-dihydro-2H-benzo[b][l,4]dioxepine-8-sulfonamido)-4,4,4-trifluoro-N-((R)- 6-(piperidin- 1 -ylmethyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)butanamide;
(R)-N-((5}-6-(4,5-dihydro-lH-imidazol-2-yl)-l,2,3,4-tetrahydronaphthalen-2-yl)-4,4,4- trifluoro-3-(3-(trifluoromethyl)phenylsulfonamido)butanamide;
(i?)-4,4,4-trifluoro-N-((i?)-6-(piperidin- 1 -ylmethyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)- 3-(l,2,3,4-tetrahydroquinoline-8-sulfonamido)butanamide; (/?)-4,4,4-trifluoro-3-(4-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-7-sulfonamido)- N-((i?)-6-(piperidin- 1 -ylmethyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)butanamide;
(/?)-3-(3-chloro-2-fluorophenylsulfonamido)-4,4,4-trifluoro-N-((i?)-6-((4- methylpiperidin- 1 -yl)methyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide; (i?)-4,4,4-trifluoro-N-((i?)-5-nitro-6-(piperidin-l-ylmethyl)-l,2,3,4- tetrahydronaphthalen-l-yl)-3-(3-(trifluoromethyl)phenylsulfonaniido)butanamide;
(i?)-4,4,4-trifluoro-N-((R)-6-(((S)-2-(pyn:olidin- 1 -ylmethyl)pyrrolidin- 1 -yl)methyl)- 1 ,2,3,4-tetrahydronaphthalen-l -yl)-3-(3-(trifluoromethyl)phenylsulfonamido)butanamide; (i?)- 3-(3-chloro-2-fluoro-N-methylphenylsulfonamido)-4,4,4-trifluoro-N-methyl-N-((/?)-7- (piperidin- 1 -ylmethyl)chroman-4-yl)butanamide;
(Λ)-4,4,4-trifluoro-N-((Λ)-7-nitro-6-(piperidin-l-ylmethyl)-l,2,3,4-tetrahydro- naphthalen-l-yl)-3-(3-(trifluoromethyl)phenylsulfonamido)butanamide;
(i?)-4,4,4-trifluoro-3-(3-methoxyphenylsulfonamido)-N-((/?)-6-(piperidin-l-yl-methyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide; (/?)-3-(3,5-dimethylphenylsulfonamido)-4,4,4-trifluoro-N-((i?)-6-(piperidin-l- ylmethyl)-l,2,3,4-tetrahydronaphthalen-l-yl)butanamide;
(i?)-3-(3,4-dimethylphenylsulfonamido)-4,4,4-trifluoro-N-((i?)-6-(piperidin-l-yl- methyl)-l,2,3,4-tetrahydronaphthalen-l-yl)butanamide
(2R, 3 R)-3 -(3 -chloro-2-fluorophenylsulfonamido)-N-((/?)-6-chloro-7-(piperidin- 1 - ylmethyl)chroman-4-yl)-4,4,4-trifluoro-2-hydroxybutanamide;
(7?)-4,4,4-trifluoro-3-(2-fluoro-5-methylphenylsulfonamido)-N-((/?)-6-(piperidin-l- ylmethyl)-l,2,3,4-tetrahydronaphthalen-l-yl)butanamide;
(i?)-4,4,4-trifluoro-N-((R)-6-(piperidin-l-ylmethyl)-l,2,3,4-tetrahydronaphthalen-l-yl)- 3-(4-(trifluoromethyl)phenylsulfonamido)butanamide; (2i?,3i?)-3-(2,5-dichlorophenylsulfonamido)-4,4,4-trifluoro-2-hydroxy-N-((i?)-6-
(piperidin- 1 -ylmethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide;
(2Λ,3/?)-3-(2,3-dichlorophenylsulfonamido)-4,4,4-trifluoro-2-hydroxy-N-((/?)-6- (piperidin- 1 -ylmethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide;
(2/?,3i?)-3-(3,4-dichlorophenylsulfonamido)-4,4,4-trifluoro-2-hydroxy-N-((R)-6- (piperidin- 1 -ylmethyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)butanamide;
(/?)-3-(2-chloro-6-methylphenylsulfonamido)-4,4,4-trifluoro-N-((/?)-6-(piperidin-l- ylmethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide;
(i?)-4,4,4-trifluoro-3-(5-fluoro-2-methylphenylsulfonamido)-N-((/?)-6-(piperidin-l- ylmethyl)-l,2,3,4-tetrahydronaphthalen-l-yl)butanamide; (/?)-4,4,4-trifluoro-N-((#)-7-(piperidin- 1 -ylmethyl)chroman-4-yl)-3-(3- (trifluoromethyl)phenylsulfonamido)butanamide; and
(R)-3 -(4-ethylphenylsulfonamido)-4,4,4-trifluoro-N-((Λ)-6-(piperidin- 1 -yhnethyl)- l,2,3,4-tetrahydronaphthalen-l-yl)butanamide. 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 Bl receptor comprising administering to the patient a pharmaceutical 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, 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 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 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 osteoarthritis.
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 aicononsm, stroke, thalamic pain synαrome, 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 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 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.
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, 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 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 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, inflammatory bowel disease, gastric ulceration, duodenal ulcers, thalamic pain syndrome, diabetes, toxins and chemotherapy, septic shock, and bronchial disorders. uven more preterabiy, tne meαicament 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. 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: Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:
The term "Ca_palkyl" means an alkyl group having a minimum of α and a maximum of β carbon atoms in a branched, cyclical or linear relationship or any combination of the three, wherein α and β represent integers as indicated in the claims unless otherwise indicated. The 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
Figure imgf000049_0001
include, but are not limited to, the following:
Figure imgf000049_0002
. ".- , methyl, and the like. 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 "alkylamino" may be mono or dialkylamino such as N-methylamino, N-ethylamino, N,N- dimethylamino, N,N-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. 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 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 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, N,N-dimethyl-aminoethyl, N,N-diethylaminomethyl and the like. 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 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 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" 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 include fiuoromethoxy, 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 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. 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 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, N,N-diethylaminoethoxy and the like.
The term "alkylaminoalkoxyalkoxy" embraces alkoxy radicals substituted with 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, N,N- dimethylaminoethoxymethoxy, N^V-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 may have 1 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 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 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 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 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. Examples of basic moieties include, but are not limited to, amino, cycloalkylamino-
(C i -Ce)alkyl, cycloalkyl(C i -C6)alkylamino(C i -C6)alkyl, heterocyclylamino(C i -Ce)alkyl, heterocyclyl(C i -C6)alkylamino(C i -Ce)alkyl, arylamino(C i -C6)alkyl, aryl(C i -C6)alkylamino- (C i -C6)alkyl, (C i -C6)alkylamino(C , -C6)alkoxy, (C i -C6)alkylamino(C i -C6)alkoxy(C J-C6)- alkoxy, amino(Ci-C6)alkoxy, amino(Ci-C6)alkyl, (Ci-C6)alkylamino(Ci-C6)alkyl, (C]-C4)alkylamino-(C2-C6)alkenyl, 4-8-membered nitrogen-containing heterocyclyl(C2-C6)alkenyl, 5-6 membered heterocyclyloxy, 5-6 membered nitrogen- containing heterocyclyl and 5-7 membered nitrogen-containing heterocyclylalkyl; more specifically amino, cycloalkylamino(Ci-C6)alkyl, cycloalkyl(Ci-C6)alkylamino-(Ci-C6)alkyl, heterocyclylamino(C i -C6)alkyl, heterocyclyl(C i -C6)alkylamino-(C i -Ce)alkyl, arylamino(Ci-C6)alkyl, aryl(Ci-C6)alkylamino(Ci-C6)alkyl, (Ci-C6)alkyl amino(Ci-C5)alkoxy, (C i -C6)alkylamino(C i -Ce)alkoxy(C i -Ce)alkoxy, amino(C i -Cόjalkoxy, amino(C i -C6)alkyl, (Ci-C6)alkylamino(Ci-C6)alkyl, (Ci-C4)alkylamino-(C2-C6)alkenyl, 5-8-membered nitrogen- containing heterocyclyl(C2-C6)alkenyl, heterocyclyl(Ci-C6)amino(C2-C6)alkyl, 5-6 membered heterocyclyloxy, 5-6 membered nitrogen-containing heterocyclyl and 5-7 membered nitrogen- containing heterocyclyl(Ci-C6)alkyl. Each basic moiety can be substituted by 0, 1, 2 or 3 groups independently selected from halo, -NH2, -OH, -CN, -CF3, (C]-C6)alkylamino, haloalkyl, oxo, (CrC6)alkoxy, (Ci-C6)alkoxyalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, di(Ci-C6)alkylamino, =NCN; and (Ci-C6)alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl, each of which is substituted by 0, 1, 2 or 3 groups independently selected from halo, -NH2, -OH, -CN, -CF3, (C,-C6)alkylamino, haloalkyl, oxo, (Ci-C6)alkoxy, (Ci-C6)alkoxyalkyl, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, or di(Ci-C6)alkylamino. In one emodiment, the basic moiety is selected from cycloalkylamino(Ci-C6)alkyl, cycloalkyl(Ci-C6)alkyl- amino(Ci -Ce)alkyl, heterocyclylamino(Ci -C6)alkyl, heterocyclyl(C i -C6)alkylamino- (d-C6)alkyl, arylamino(Ci-C6)alkyl, aryl(Ci-C6)alkylamino(Ci-C6)alkyl, (CrC6)alkyl amino(C i -C6)alkoxy, (C i -C6)alkylamino(C i -C6)alkoxy(C i -C6)alkoxy, amino(C i -Ce)alkoxy, amino(Ci-C6)alkyl, (Ci-C6)alkylamino(Ci-G6)alkyl, (Ci-C4)alkylamino-(C2-C6)alkenyl, 4-8- membered nitrogen-containing heterocyclyl(C2-C6)alkenyl, heterocyclyl(Ci-C6)amino- (C2-C6)alkyl, 5-6 membered heterocyclyloxy, 5-6 membered nitrogen-containing heterocyclyl and 5-7 membered nitrogen-containing heterocyclylalkyl. In another emodiment, the basic moiety is selected from cycloalkylamino(Ci-C6)alkyl, cycloalkyl(Ci-C6)alkylamino- (C i -C6)alkyl, heterocyclylamino(C i -C6)alkyl, heterocyclyl(C i -C6)alkylamino(C i -C6)alkyl, arylamino(Ci-C6)alkyl, aryl(Ci-C6)alkylamino(Ci-C6)alkyl, (Ci-Ce)alkyl amino(Ci-C6)alkoxy, (C i -C6)alkylamino(C i -Ce)alkoxy(C i -C6)alkoxy, amino(C i -C6)alkoxy, amino(C i -Ce)alkyl, (Ci-C6)alkylamino(Ci-C6)alkyl, (C]-C4)alkylamino-(C2-C6)alkenyl, 4-8-membered nitrogen- containing heterocyclyl(C2-C6)alkenyl, heterocyclyl(Ci-C6)amino(C2-C6)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, Q^alkyl or cycloalkyl, preferably halo, Ci^alkyl or cycloalkyl. More specifically, the basic moiety is amino, aminomethyl, isopropylaminomethyl, ^-butylaminomethyl, 2-^-butylaminoethyl, 2-tert- butylamino-1 -methyl-ethyl, 1-tert-butylaminoethyl, l-(tert-butylamino-methyl)-vinyl, 1- (piperidin-l-yhnethyl)-vinyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2- dimethyl)propylaminomethyl, N-isopropyl-N-ethylaminomethyl, N-isopropyl-N- methylaminomethyl, N-/-butyl-N-methylaminomethyl, N-jso-butyl-N-methylaminomethyl, N-t- butyl-N-ethylaminomethyl, N-isobutyl-N-methylaminomethyl, N-/-butyl-N- isopropylaminomethyl, N,N-di(isopropyl)aminomethyl, N,N-dimethylaminomethyl, NJV- diethylaminomethyl, NfN-di(<-butyl)-aminomethyl, cyclopropylaminomethyl, cyclopropylaminoethyl, cyclopropyhnethylaminomethyl, cyclopropylmethylaminoethyl, cyclobutylaminomethyl, cyclobutylaminoethyl, cyclobutylmethylaminomethyl, cyclobutylmethylaminoethyl, 4,5-dihydro-imidazolyl, 1-piperidinylmethyl, 4-fluoropiperidin- 1-yhnethyl, 4,4-difluoropiperidin-l-ylmethyl, 3-hydroxypiperidin-l-ylmethyl, 4-hydroxy- piperidin- 1 -ylmethyl, 4-(piperidin- 1 -yl)piperidinyhnethyl, 4-(dimethylamino)piperidin- 1 - ylmethyl, 2,6-dimethylpiperidin-l -ylmethyl, 4-moφholinylmethyl, 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-l-ylmethyl.
The term "cycloalkyl" includes saturated carbocyclic groups. Preferred cycloalkyl groups include C3-C6 rings. More preferred compounds include cyclopentyl, cyclopropyl, and 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 1WW- dicycloalkylaminoalkyl". More preferred cycloalkylaminoalkyl radicals are "lower 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, 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 I.
"Cα_βhaloalkyl" 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 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 Ν, O 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 -O-O- 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. Examples of heterocycles that may be found in the claims include, but are not limited to, the following:
Figure imgf000055_0001
The term "heterocyclylaminoalkyl" embraces heterocyclyl radicals as described above, attached to an aminoalkyl radical as defined herein.
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 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. 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 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. 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 radicals.
The terms "carboxy" or "carboxyl" denotes -CO2H.
The term "carbonyl" denotes -(C=O)-.
The term "comprising" is meant to be open ended, including the indicated component but not excluding other elements. 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 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 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 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 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 (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:
Figure imgf000057_0001
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 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). 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 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 treatment with an optically active acid or base. Examples of appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and then separation of the mixture of diastereoisomers by crystallization followed by liberation of the optically active bases from these salts. A different process for separation of optical isomers involves the use of a chiral chromatography column, such as, for example, a CHIRAL-AGP column, optimally chosen to maximize the separation of the enantiomers. Still another available method involves synthesis of covalent diastereoisomeric molecules by reacting compounds of the invention with an optically pure acid in an activated form or an optically pure isocyanate. The synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the enantiomerically pure compound. The optically active compounds of the invention can likewise be 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:
Figure imgf000058_0001
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 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. 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, ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, camphoric, camphorsulfonic, digluconic, cyclopentanepropionic, dodecylsulfonic, glucoheptanoic, glycerophosphonic, heptanoic, hexanoic, 2-hydroxy-ethanesultonic, nicotinic, 2-naphthalenesulfonic, oxalic, palmoic, pectinic, persulfuric, 2-phenylpropionic, picric, pivalic propionic, succinic, tartaric, thiocyanic, mesylic, undecanoic, stearic, algenic, β-hydroxybutyric, salicylic, galactaric and galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of compounds of Formula (I) 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 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 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, H2SO4 and H3PO4 and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid. Other examples include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases.
General Synthetic Procedures 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 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 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. 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 atmospheric pressure over a temperature range from about -78 0C to about 150 0C, more preferably from about 0 0C to about 125 0C and most preferably at about room (or ambient) temperature, e.g., about 20 0C.
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 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. Compounds of Formula (I) where R1, R2, Rla, Rlb, Rlc, R4 and R5 are as defined in the
Summary of the Invention can be prepared as shown in Scheme A below.
Scheme A
Figure imgf000060_0001
Compounds of Formula (I) where R1, R2, Rla, Rlb, Rlc, R4 and R5 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 R2 is as defined in the Summary of the Inventio with a β- 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 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. 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 R4 and R5 are as defined in the Summary of the invention under standard peptidic 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®.), l-(3-dimethylamino-propyl)-3- ethylcarbodiimide hydrochloride (EDCI), CKT-azabenzotrizol-l-yl)-!,!^^, tetra- methyluroriium-hexafluoro- phosphate (HATU), O-berizotriazol-l-yl-N,N,N,N-tetramethyl- uronium hexafluorophosphate (HBTU), l^-dicyclohexylcarbodiimide (DCC), or the like) and optionally an appropriate catalyst (e.g., 1-hydroxybenzotriazole (HOBt), l-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. 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.
Alternatively, the compounds of Formula (I) can be prepared as shown in Scheme B below.
Scheme B
RV
Figure imgf000061_0001
(I) 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 R5 group. Conversion of the PG group to R5 group then provides a compound of Formula (I).
For example, a compound of Formula (I) where R5 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 cycloalkylamino-(Ci-C6)alkyl, cycloalkyl(Ci-C6)alkylamino(Ci-C6)alkyl, heterocyclylamino(C i -Ce)alkyl, heterocyclyl(C i -C6)alkylamino(C i -Cό)alkyl, arylamino(C i -C6)alkyl, aryl(C i -C6)alkylamino-(C i -Ce)alkyl, (C i -C6)alkylamino(C i -C6)alkoxy, (C i -C6)alkylamino(Ci -C6)alkoxy(C i -C6)-alkoxy, amino(C i -Ce)alkoxy, amino(C j -C6)alkyl, (Ci-C6)alkylamino(Ci-C6)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 11-membered bicyclic or 12-, 13-, 14- or 15- membered 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. 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 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 R5 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 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. 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 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 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 0C, one molecule of the acid being expelled per molecule of a compound of Formula (I). 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 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 performed in an alternate sequence or order to give the desired compounds.
Utility
The compound of Formula (I) are Bl 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 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, 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 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, inflammatory bowel disease, gastric ulceration, duodenal ulcers, thalamic pain syndrome, diabetes, toxins and chemotherapy, septic shock, and bronchial disorders.
Biological Testing The in vitro binding affinity of the compounds of the invention to the human Bl 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 Bl and B2 bradykinin receptors can be tested using the calcium flux assay, Rabbit endothelial cell Bl -specific PGI2 secretion Assay, and umblical vein Assay described in Biological 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.
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 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 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. 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 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 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, 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 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- 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 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 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 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. 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 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 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 the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. Emulsifϊers 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. 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- 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. 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 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 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 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, 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 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. 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. 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 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 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 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, oxycodone, methadone, tetrahydrocannibinol, pregabalin, Tramadol [(+) enantiomer], DuP 747, Dynorphine A, Enadoline, RP-60180, HN-11608, E-2078, ICI- 204448, acetominophen (paracetamol), propoxyphene, nalbuphine, E-4018, filenadol, mirtentanil, amitriptyline, DuP631, Tramadol [(-) enantiomer], GP-531, acadesine, AKI-I, AKI-2, GP- 1683, GP-3269, 4030W92, tramadol racemate, Dynorphine A, E-2078, AXC3742, SNX-111, ADL2-1294, ICI- 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, LTB4 receptor antagonists and LTA4 hydrolase inhibitors.
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 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 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:
AcOH, HOAc acetic acid
CH3CN acetonitrile
NH3 ammonia
NH4Cl ammonium chloride
NH4OH ammonium hydroxide
HATU O-(7- Azabenzotriazol- 1 -y\)-NflJVJV- tetramethyluronium hexafluorophosphate
AIBN 2,2'-azobisisobutyronitrile
(PPh3)2NiBr2 bis(triphenylphosphine)nickel(II) bromide
BH3 borane
BH3 SMe2 borane-methyl sulfide complex
Br2 bromine
NBS N-bromosuccinimide
CCl4 carbon tetrachloride
CHCl3 chloroform
DBU 1 ,8-diazabicyclo[5.4.0]undec-7-ene
DCE 1 ,2-dichloroethane
CH2Cl2 dichloromethane; DCM
Et2O diethyl ether
Ip2NEt, DIEA diisopropylethylamine
Me2NH dimethylamine
EDC (3-dimethylamino-propyl)-ethyl carbodiimide-HCl salt
DMAP 4-(dimethylamino)pyridine
DMF dimethylformamide DMSO dimethyl sulfoxide
(also known as methyl sulfoxide)
DPPA diphenylphosphoryl azide EtOH ethanol EtOAc ethyl acetate
HCO2H formic acid g gram h hour HCl hydrochloric acid H2 hydrogen
HOAt 1 -hydroxy-7-azabenzotriazole HOBt 1 -hydroxybenzotriazole IPA isopropanol iPrOH isopropanol ISCO ISCO liquid chromatography system
LAH lithium aluminum hydride LDA lithium diisopropylamide LiOH lithium hydroxide MgSO4 magnesium sulfate MeOH methanol
NMM N-methylmorpholine NMP 1 -methyl-2-pyrrolidone mL milliliter min minutes N2 nitrogen
Pd/C palladium on carbon Pd(OH)2 palladium hydroxide H3PO4 phosphoric acid K2CO3 potassium carbonate KCN potassium cyanide
KOH potassium hydroxide RT room temperature SiO2 silica NaOAc sodium acetate INaJN3 sodium azide
NaHCO3 sodium bicarbonate
NaBH4 sodium borohydride
NaOH sodium hydroxide
NaBH(OAc)3 sodium triacetoxyborohydride
H2SO4 sulfuric acid
SOCl2 thionyl chloride
THF tetrahydrofuran
TsCl /»-tosyl chloride
TsOH /j-toluene sulfonic acid
TEA, Et3N triethylamine
TFA trifluoroacetic acid
PPh3 triphenylphosphine
H2O water
Reference 1
Synthesis of (5(/?)-amino-5,6,7,8-tetrahydronaphthalen-2-yl)methanol
Figure imgf000071_0001
Step A: Synthesis of 5(iS)-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 (i?)-2-methyl-CBS-oxazaborolidine (7.4 mL of a IM soln in toluene, 7.4 mmol, Aldrich). Toluene (190 mL) was added and the reaction mixture was cooled in an ice-salt bath (bath temp. = -10 0C). BH3-SMe2 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 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 0C. The reaction mixture was concentrated in vacuo. Et2O (1 L) was added, and the mixture was washed with IM H3PO4 (3χ), satd NaHCO3, and brine (ca. 400 mL each wash). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was dissolved in Et2O again (500 mL), and the mixture was washed with IM H3PO4 (3 x 200 mL), satd NaHCO3, and brine. After drying the organic layer over MgSO4, the mixture was filtered and concentrated in vacuo, which gave the title compound as a white-yellow solid. MS (+ ion ESI) m/z = 207 (MH+), 189 (MH+-H2O).
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(5)-hydroxy-5,6,7,8-tetrahydro-naphthalene-2- carboxylic acid methyl ester (29 g, 140 mmol) in toluene (280 mL). The reaction mixture was cooled in a ice-salt bath, and DPPA (36 mL, 170 mmol, Aldrich) was added (internal temp. = -4 0C). 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 0C. 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 at RT for another H 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 Et2O (3 x 250 mL). The combined organic layers were washed with IM H3PO4, water, satd NaHCO3, and brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (330 g Isco Redisep column, 1 : 1 hexane-CH2Cl2) of the crude material provided the title compound. MS (+ ion ESI) m/z = 232 (MH+). Step C: Synthesis (5(/?)-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 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 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 CH3CN, and concentrated in vacuo again to provide the title compound as light-brown solid. MS (+ ion ESI) m/z = 161 (M-NH3). Similarly (4-(i?)-aminochroman-7-yl)-methanol and (l-(/f)-aminoindan-5-yl)methanol were prepared.
Reference 2 Synthesis of (R)-6-( 1 -piperidin- 1 -ylmethylvinyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -ylamine
Figure imgf000073_0001
Step A: Synthesis of 2-trifluoromethanesulfonic acid 5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl ester To a 1 -L round-bottomed flask charged with 6-hydroxy- 1 -tetralone (Aldrich, 21.97 g,
0.136 mol) at 0 0C was added CH2Cl2 (500 niL) 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 separated. The organic phase was washed with IN HCl (100 mL x 2), saturated NaHCO3, and brine, dried over Na2SO4. 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- naphthalen-2-yl ester
To a dry three-necked flask containing (i?)-2-methyl-CBS-oxazaborolidine (Aldrich, 1.94 mL, 1.0M in toluene, 1.93 mmol, 0.05 eq) under N2 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 0 0C. 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 H2O (50 mL). The aqueous phase was extracted with ether (3 x 150 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The title compound was obtained as an off-white solid by flash chromatography (16-22% EtOAc- hexane).
Step C: Synthesis of 2-trifluoromethanesulfonic acid 5(i?)-azido-5,6,7,8-tetrahydro-naphthalen- 2-yl ester To a solution of 2-trifluoromethanesulfonic acid 5(5)-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 0C 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 mixture was concentrated in vacuo. The crude product was dissolved in EtOAc (400 mL). The organic layer was washed with NH4Cl (twice), H2O, and brine, dried over Na2SO4. 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(i?)-amino-5,6,7,8-tetrahydro- naphthalen-2-yl ester
A solution of 2-trifluoromethanesulfonic acid 5(i?)-azido-5,6,7,8- tetrahydronaphthalen-2-yl ester (10.3 g, 32.1 mmol, 1.0 eq) in THF (70 mL) was added PPh3 (Aldrich, 8.4 g, 32.1 mmol, 1.0 eq), and H2O (30 mL) at 0 0C. The reaction mixture was allowed to warmed to RT and stirred overnight. 2N HCl was added until the mixture was 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 Na2SO4, filtered and concentrated in vacuo. The crude was purified by flash chromatography (6% MeOH-CH2Cl2) to provide the title compound. Step E: Synthesis of 2-trifluoromethanesulfonic acid 5(/?)-tert-butoxycarbonyl-amino-5,6,7,8- tetrahydro-naphthalen-2-yl ester
A solution of 2-trifluoromethanesulfonic acid 5(i?)-amino-5,6,7,8-tetrahydro- naphthalen-2-yl ester (2.0 g, 6.8 mmol, 1.0 eq) in CH2Cl2 (20 mL) was added Et3N (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 mixture was stirred at RT overnight, washed with saturated NaHCO3 (2 x 20 mL), brine, dried over Na2SO4. 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. atep f. synthesis ot [b-(i-pipeπαin-l-ylmethylvinyl)-l(Λ)-l,2,3,4-tetrahydro-naphthalen-l- yl]-carbamic acid tert-butyl ester
A solution of 2-trifluoromethanesulfonic acid 5(/?)-tert-butoxycarbonylamino-5,6,7,8- tetrahydronaphthalen-2-yl ester (1.89 g, 4.79 mmol, 1.0 eq) in CH3CN (25 mL) purged with N2 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), K2CO3 (0.99 g, 7.18 mmol, 1.5 eq) and N-allylpiperidine (Lancaster, 3.00 g, 23.96 mmol, 5.0 eq). The reaction mixture sealed with a septum was heated to 80 0C overnight, cooled to RT, diluted with H2O, and extracted with ether. The ether solution was dried over Na2SO4, filtered and concentrated in 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-( 1 -piperidin- 1 -ylmethylvinyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -ylamine To a solution of [6-(l-piperidin-l-ylmethylvinyl)-l(i?)-l,2,3,4-tetrahydro-naphthalen- l-yl]-carbamic acid tert-butyl ester in CH2Cl2 (3 mL) was added TFA (3 mL). The reaction mixture was stirred at RT for 4 h and then concentrated in vacuo. The crude was neutralized with 10% Na2CO3 until the aqueous phase is basic, extracted with CH2Cl2. The organic solution was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to provide the title compound. MS (ESI): 271 (M+H)+.
Reference 3
Synthesis of (i?)-6-((tert-butylamino)methyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -ylamine
Figure imgf000075_0001
Step A: Synthesis of (i?)-tert-butyl 6-(hydroxymethyi)-l,2,3,4-tetrahydronaphthalen-l-yl- 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(/?)-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 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. Step B: Synthesis of (R)-tert-butyl 6-formyl-l,2,3,4-tetrahydronaphthalen-l-ylcarbamate
A mixture of (R)-tert-butyl 6-(hydroxymethyl)-l,2,3,4-tetrahydronaphthalen-l- ylcarbamate (11.0 g, 39.8 ramol) and MnO2 (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 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)-l,2,3,4-tetrahydronaphthalen-l- ylcarbamate
A mixture of (7?)-tert-butyl 6-formyl-l,2,3,4-tetrahydronaphthalen-l-ylcarbamate (39.8 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 0C for 1 h, cooled to r.t. and diluted with MeOH. NaBH4 (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 removed to afford a viscous oil which was used in the following reaction without purification. Step D: Synthesis of (/?)-6-((tert-butylamino)methyl)- 1,2,3 ,4-tetrahydronaphthalen- 1 -ylamine A solution of (/?)-tert-butyl 6-((tert-butylamino)methyl)-l,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 filtration.
Similarly, (/?)-7-((tert-butylamino)methyl)chroman-4-amine and (i?)-5-((tert- butylamino)methyl)-2,3-dihydro-lH-inden-l -amine were prepared.
Reference 4 Synthesis of (/?)-6-(piperidin- 1 -ylmethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -ylamine
Figure imgf000076_0001
Step A: Synthesis of (R)-tert-buty\ 6-(piperidin-l -ylmethyl)- 1,2,3 ,4-tetrahydronaphthalen- 1- ylcarbamate. (R)-tert-Buty\ 6-formyl-l,2,3,4-tetrahydronaphthalen-l-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 0C for 15 h. The reaction mixture 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 (MgSO4) and purified on silica gel using 5% methanol in dichloromethane as eluant, affording (7?)-ter/-butyl-6-(piperidin- 1 -ylmethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 - ylcarbamate. MS: 345.2 (M+H).
Step B: Synthesis of (R)-β-(piperidin- 1 -ylmethyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -amine
A solution of (R)-tert-butyl 6-(piperidin-l-ylmethyl)-l,2,3,4-tetrahydronaphthalen-l- ylcarbamate (15.0 g, 43.57 mmol) in methanol (325 mL) was treated with a 1.0M solution of HCl in diethyl ether (300 mL, 300 mmol, 6.8 equiv), capped and stirred at room temperature for 14 h. The reaction mixture was concentrated in vacuo and partioned in dichloromethane (300 mL) and 1.0N 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 (MgSO4) and concentrated, affording (i?)-6-(piperidin-l-ylmethyl)-l,2,3,4- tetrahydronaphthalen-1 -amine as a dark yellow oil. MS: 245.2 (M+H). Similarly, (/?)-7-(piperidin-l-yhnethyl)chroman-4-amine, (i?)-5-(piperidin-l-ylmethyl)-
2,3-dihydro- 1 H-inden- 1 -amine and (7?)-6-((4-methylpiperidin- 1 -yl)methyl)- 1 ,2,3,4- tetrahydronaphthalen- 1 -amine were prepared.
Reference 5 Synthesis of 7-(tert-butylaminomethyl)-6-chloro-chroman-(4R)-ylamine
Figure imgf000077_0001
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 mmol), and AIBN (4.17 g, 25.4 mmol) in anhydrous CCl4 (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 Et3N (10.1 g, 99.8 mmol) in anhydrous CH2Cl2 (50 ml) was added a solution of 7-bromomethyl-6-chloro- chroman-4-one (25 g, 91 mmol) in CH2Cl2 (150 ml) dropwise. Stirring was continued for 16 h after which the mixture was concentrated, taken up in H2O, acidified with 10% HCl until ph 1, and extracted with Et2O (discarded). The acidic aqueous layer was neutralized with 5N NaOH, and extracted with CH2Cl2 (3x). The combined extracts were dried over MgSO4, concentrated to give a yellow solid.
Step C: Synthesis of 7-(tert-butylamino-methyl)-6-chloro-chroman-(45)-ol
To a stirred solution of (lS,2S)-(+)-N-(4-toluene-sulfonyl)-l,2-diphenylethylene- diamine (0.29 g, 8.1 mmol) in i-PrOH (15 ml) was added [RuCl2(Ν6-p-cymene)]2, and Et3N under argon. The reaction mixture was heated at 80 0C 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 CH3CN (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 H2O, neutralized with 10% Na2CO3, extracted with CH2Cl2 (3x), dried over MgSO4, 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(/?)-azido-6-chloro-chroman-7-ylmethyl)-tert-butylamine
To a stirred, cooled (0 0C) solution of 7-(tert-butylaminomethyl)-6-chlorochroman- (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 H2O, extracted with CH2Cl2 (3x), dried over MgSO4, concentrated and purified by ISCO (3% MeOH/CH2Cl2) to give a brown oil. MS (APCI) m/z 296 (M+2). Step E: Synthesis of 7-(tert-butylaminomethyl)-6-chlorochroman-(4i?)-ylamine
A mixture of (4R)-azido-6-chlorochroman-7-ylmethyl)-tert-butylamine (12 g, 41 mmol) and Ph3P (16 g, 61 mmol) in anhydrous THF (100 mL) was stirred at RT in 3 h. H2O (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 layer was neutralized with ION NaOH, extracted with CHCl3 (3x), dried over MgSO4, concentrated to give a brown oil. MS (APCI) m/z 270 (M+2).
Similarly, (/?)-6-chloro-7-(piperidin-l-ylmethyl)chroman-4-amine was prepared.
Reference 6 Synthesis of (/?)-6-(2-(piperidin- 1 -yl)ethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -amine
Figure imgf000078_0001
aiep /\: ayninesis oi (K)-ten-ouτyι o-(iodomethyl)-l,2,3,4-tetrahydronaphthalen-l-ylcarbamate
To a solution of (/?)-tert-butyl 6-(hydroxymethyl)-l,2,3,4-tetrahydronaρhthalen-l- 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 this stirred solution was then added iodine (571 mg, 2.25 mmol). After stirring for 20 min, the reaction was quenched with 10% Na2S2O3 (15 mL) until it became a clear two-phase solution. The aqueous phase was extracted with ether. The combined organic phase was dried over Na2SO4, filtered, and evaporated to dryness. Flash chromatography (SiO2, hexane/CH2Cl2 = 3: 1 to pure CH2Cl2) afforded the desired product as a white solid. Step B: Synthesis of (R)-tert-butyl 6-((l,3-dithian-2-yl)methyl)-l,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 0C was added dropwise 2.5M n-butyllithium in hexane (3.36 mL, 8.4 mmol). After stirring at -20 0C for 1.5 h, a solution of the iodide obtained in Step A (542 mg, 1.4 mmole, azeotroped with benzene) in dry THF (10 mL) was added dropwise at -20 0C. The reaction mixture was stirred at -5 0C to 0 0C for 1 h. The reaction mixture was quenched with sat. NH4Cl solution, extracted with EtOAc, dried over Na2SO4, filtered, and evaporated to dryness. Flash chromatography (SiO2, CH2Cl2/hexane = 1:1 to 2:1 to CH2Cl2/Et0Ac = 100:3) afforded the title compound as a white solid. Step C: Synthesis of (R)-tert-butyl 6-(2-oxoethyl)- 1 ,2,3,4-tetrahydronaphthalen-l -ylcarbamate (R)-tert-Buty\ 6-(( 1 ,3-dithian-2-yl)methyl)- 1 ,2,3 ,4-tetrahydronaphthylen- 1 -ylcarbamate (6.1 g, 16.1 mmol) and CaCO3 (3.23 g, 32.3 mmol) were suspended in THF/water (120 mL, 5:1 ratio) and Hg(ClO4)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 of EtOAc. The filtrate was evaporated to dryness and the residue was purified by flash chromatography (SiO2, DCM to DCM/EtOAc = 3:1 to 2:1) gave the title compound as a colorless sticky oil.
Step D: Synthesis of (/?)-tert-butyl-6-(2-(piperidin- 1 -yl)ethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 - ylcarbamate To a solution of (R)-tert-butyl 6-(2-oxoethyl)-l,2,3,4-tetrahydronaphthalen-l- 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. NaHCO3 and brine. The organic phase was dried over Na2SO4 and evaporated to dryness in vacuo. The crude was purified by flash chromatography (SiO2, DCM to EtOAc to EtOAc/MeOH =100:20) to give the title compound as a sticky oil.
Step E: Synthesis of (Λ)-6-(2-(piperidin- 1 -yl)ethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -amine
To a solution of (/?)-tert-butyl-6-(2-(piperidin-l-yl)ethyl)- 1,2,3, 4-tetrahydronaphthalen- 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.
Reference 7 Synthesis of 2-(5(R/S)-amino-5,6,7,8-tetrahydroquinazolin-2-yl)ethanol
Figure imgf000080_0001
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 Et3N (30.3 g, 0.3 mol), followed by TBDPSCl (27.5 g, 0.1 mol). A lot of white solid were formed. After stirring at room temperature overnight, the reaction mixture was quenched with sat. NH4Cl solution, extracted with DCM, dried over Na2SO4, and evaporated in vaco. Flash chromatography (SiO2, 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 To a suspension OfNH4Cl (5.35 g, 0.1 mol) in dry benzene (60 mL) at 0 0C 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 resulting mixture was heated up to 80 0C 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, nasn cnromatograpny (MU2, ZVUJ\C to EtOAc/MeOH = 100:20 to 100:30 to EtOAc/2M NH3 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- ((dimethylamino)methylene)cyclohexane-l,3-dione (12.8 g, 77 mmol) in dry EtOH (400 mL) was heated at 80 0C for 3 h. After cooling to room temperature, the solvent was evaporated. Flash chromatography (SiO2, 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 (2.16 g, 5 mmol) in dry MeOH (30 mL) was treated with NaBH4 (189 mg, 5 mmol). After 5 min, the reaction was quenched with 5 mL of sat. NH4Cl solution. The MeOH was evaporated and the residue was extracted with DCM, dried over Na2SO4 and evaporated. Flash chromatography (SiO2, 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- quinazoline
To a solution of 2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5,6,7,8-tetrahydroquinazolin-5-ol (2.0 g, 4.63 mmol) in toluene (25 mL) at -10 0C 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 0C. After stirring at room temperature for 16 h, the reaction was evaporated to dryness and directly submitted to flash chromatography (SiO2, 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- butyldiphenylsilyloxy)ethyl)-5,6,7,8-tetrahydroquinazoline (800 mg, 1.75 mmol) in EtOAc (30 mL) was stirred under H2 atomosphere overnight. The reaction mixture was then directly submitted to flash chromatograph (SiO2, EtOAc to EtOAc/MeOH = 100:15 to EtOAc/2M NH3 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 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 0C 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 (SiO2, EtOAc to EtOAc/MeOH = 100: 15 to EtOAc/2M NH3 in MeOH = 1 : 1) to give crude product as a white solid. Reference 8 Synthesis of 1 -(2-(tert-butyldimethylsilyloxy)ethyl)-4,5,6,7-tetrahydro- 1 H-indazol-4-ylamine
Figure imgf000082_0001
Step A: Synthesis of 1 -(2-hydroxyethyl)-6,7-dihydro- 1 H-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-l,3-dione (3.34 g) in methanol (50 mL). After stirring the reaction mixture at room temperature for 20 min, the solvent was evaporated. Flash chromatography (SiO2, 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 l-(2-(tert-butyldimethylsilyloxy)ethyl)-6,7-dihydro-lH-indazol-4(5H)- one
To a solution of l-(2-hydroxyethyl)-6,7-dihydro-lH-indazol-4(5H)-one (14 g, 77.8 mmol) in dry DCM (100 mL) was added Et3N (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 (SiO2, EtOAc/hexane = 1:1) of the crude product gave the title compound as a white solid. Step C: Synthesis of l-(2-(tert-butyldimethylsilyloxy)ethyl)-4,5,6,7-tetrahydro-lH-indazol-4-ol A solution of l-(2-(tert-butyldimethylsilyloxy)ethyl)-6,7-dihydro-lH-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. NH4Cl solution. The
MeOH was evaporated and the residue was extracted with EtOAc, dried over Na2SO4 and evaporated. Flash chromatography (SiO2, EtOAc/hexane = 1 : 1 to EtOAc) of the crude product gave the title compound as a white solid.
Step D: Synthesis of 4-azido-l-(2-(tert-butyldimethyl silyloxy)ethyl)-4,5,6,7-tetrahydro-lH- indazole
To a solution of l-(2-(tert-butyldimethylsilyloxy)ethyl)-4,5,6,7-tetrahydro-lH-indazol- 4-ol (23 g, 77.7 mmol) in 200 mL of toluene at -10 0C was added DPPA (20 mL, 93.2 mmol).
DBU (13.9 mL, 93.2 mmol) was added dropwise while keeping the temperature below 0 0C. After stirring at room temperature for 18 h, the reaction mixture was evaporated to dryness and directly submitted to flash chromatography (SiO2, 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 l-(2-(tert-butyldimethylsilyloxy)ethyl)-4,5,6,7-tetrahydro-lH-indazol-4- amine
A suspension of 150 mg of Pd/C (10% w/w) in a solution of 4-azido-l-(2-(tert-butyl- dimethylsilyloxy)ethyl)-4,5,6,7-tetrahydro-lH-indazole (2.0 g, 6.23 mmol) in EtOAc (100 mL) was stirred under H2 atomosphere overnight. The reaction mixture was then directly submitted to flash chromatograph (SiO2, EtOAc to EtOAc/MeOH = 100:20 to EtOAc/2M NH3 in MeOH = 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
Figure imgf000083_0001
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 00C, diluted with 1,4-dioxane (15 mL), and triethyl amine (1.2 mL, 8.60 mmol) and 3-trifluoromethylbenzenesulphonyl chloride (95%, 1.2 mL, 7.16 mmol) were 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 1.0N 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: (£)-3-(naphthalene-3-sulfonamido)butanoic acid;
(-S)-3-(4-chloro-2,5-dimethylphenyl-sulfonamido)butanoic acid;
(5)-3-(2-chloro-5-(trifluoromethyl)phenylsulfonamido)butanoic acid;
(5)-3-(2-fluoro-5-(trifluoromethyl)phenylsulfonamido)butanoic acid;
(5)-3-(2,5-dichlorophenylsulfonamido)butanoic acid; (5)-3-(2,3-dichlorophenyl-sulfonamido)butanoic acid;
(5)-3-(3,4-dichlorophenylsulfonarnido)butanoic acid;
(5)-3-(3,5-dichlorophenyl-sulfonamido)butanoic acid;
(S)-3-(2,6-dichlorophenylsulfonamido)butanoic acid; (5)-3-(5-chloro-2-fluorophenylsulfonamido)butanoic acid; (5)-3-(3-chloro-2-fluorophenylsulfonamido)butanoic acid; (<S)-3 -(3 -methylphenyl-sulfonamido)butanoic acid; (5)-3-(4-tert-butylphenylsulfonamido)butanoic acid; (S)-3-(3-(trifluoromethyl)phenyl-sulfonamido)hex-5-ynoic acid; and (i?)-4-methyl-3-(3-(trifluoromethyl)phenylsulfonamido)pentanoic acid.
Reference 10
Synthesis of (Z?)-4-amino-4-oxo-3-(3,4-dichlorophenylsulfonamido)butanoic acid
Figure imgf000084_0001
To (/?)-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) 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:
(/?)-4-amino-4-oxo-3-(3-(trifluoromethyl)phenylsulfonamido)butanoic acid; (/?)-4-amino- 4-oxo-3-(4-methylphenylsulfonamido)butanoic acid;
(/?)-3-(4-chloro-2,5-dimethylphenylsulfonamido)butanoic acid; (i?)-4-(benzyloxy)-3-(3,4- dichlorophenylsulfonamido)-4-oxobutanoic acid;
(i?)-4-tert-butoxy-3-(3,4-dichlorophenylsulfonamido)-4-oxobutanoic acid; (i?)-3-(3,4- dichlorophenylsulfonamido)-4-methoxy-4-oxobutanoic acid; (/?)-3-(3,4-dichlorophenylsulfonamido)-4-ethoxy-4-oxobutanoic acid.
Reference 11
Synthesis of 4,4,4-trifluoro-3-(3-(trifluoromethyl)phenylsulfonamido)butanoic acid
Figure imgf000084_0002
Step A: Synthesis of ethyl 4,4,4-trifluoro-3-(3-(trifluoroniethyl)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%, 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 HCl (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 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 was washed with brine, removal of the solvents afforded the title compound as a light pinkish solid.
Similarly, (/?)-4,4,4-trifluoro-3-(3-(trifluoromethyl)phenylsulfonamido)butanoic acid was prepared from (i?)-ethyl 3-amino-4,4,4-trifluorobutanoate (prepared according to literature procedure: Soloshonok, V.A.; Ono, T.; Soloshonok, LV. J. Org. Chem. 1997, 62, 7538-39). The following sulfonylated acids were prepared similarly:
(/?)-4,4,4-trifluoro-3-(3-methylρhenylsulfonamido)butanoic acid; (R)-4,4,4-trifluoro-3-(naphthalene-3-sulfonamido)butanoic acid; (/?)-3-(4-chloro-2,5-dimethylphenylsulfonamido)-4,4,4-trifluorobutanoic acid; (/?)-3-(2-chloro-5-(trifluoromethyl)phenylsulfonamido)-4,4,4-trifluorobutanoic acid; (i?)-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)-4,4,4-trifluorobutanoic acid;
(/?)-3-(2,5-dichlorophenylsulfonamido)-4,4,4-trifluorobutanoic acid; (i?)-3-(2,6-dichlorophenylsulfonamido)-4,4,4-trifluorobutanoic acid; (/?)-3-(2,3-dichlorophenylsulfonamido)-4,4,4-trifluorobutanoic acid; (R)-3 -(3 ,4-dichlorophenylsulfonamido)-4,4,4-trifluorobutanoic acid; (i?)-3-(3,5-dichlorophenylsulfonamido)-4,4,4-trifluorobutanoic acid;
(i?)-3-(5-chloro-2-fluorophenylsulfonamido)-4,4,4-trifluorobutanoic acid; (/?)-3-(3-chloro-2-fluorophenylsulfonamido)-4,4,4-trifluorobutanoic acid; (/?)-3-(2,3-dihydrobenzo[b][ 1 ,4]dioxine-6-sulfonamido)-4,4,4-trifluorobutanoic acid; (/?)-3-(4-chlorobenzo[c][ 1 ,2,5]oxadiazole-7-sulfonamido)-4,4,4-trifluorobutanoic acid; (i?)-3-(5-chloro-2-methoxyphenylsulfonamido)-4,4,4-trifluorobutanoic acid; vjv^-t^jt-uuiuυiυ-j-^wuwiώe-δ-sulfonamido^utanoic acid; (/?)-3-(3,5-dichloro-2-hydroxyphenylsulfonamido)-4,4,4-trifluorobutanoic acid; (i?)-3-(2,3-dihydrobenzofiiran-5-sulfonamido)-4,4,4-trifluorobutanoic acid; (i?)-3-(3,4-difluorophenylsulfonamido)-4,4,4-trifluorobutanoic acid; (i?)-3-(3,5-difluorophenylsulfonamido)-4,4,4-trifluorobutanoic acid; and
(/?)-3-(2,3-difluorophenylsulfonamido)-4,4,4-trifluorobutanoic acid.
Reference 12
Synthesis of (2Λ,3/?)-4,4,4-trifluoro-2-hydroxy-3-(3-(trifluoromethyl)- phenylsulfonamido)butanoic acid
Figure imgf000086_0001
Step A: Synthesis of (5',E)-l-phenyl-N-(2,2,2-trifluoroethylidene)ethanamine
A solution of (S)-I -phenylethanamine (26.9 g, 222 mmol), 2,2,2-trifluoro-l- methoxyethanol (40.2 g, 309 mmol) and /?-toluenesulfonic acid monohydrate (4.23 g, 0.222 mmol) in toluene (300 mL) was refluxed in Dean-Stark apparatus for 3 h. Et2O (250 mL) was added and washed with sat NaHCO3 aq. (500 mL x 3) and sat NaCl aq. (500 mL x 2), and then dried over Na2SO4. The solvents were removed under reduced pressure (40 0C, 28 mmHg), and the resulting crude product was used without further purification. Step B: Synthesis of (2/?,3/?)-2-(benzyloxy)-4-((/?)-l-phenylethyl)-3-(trifluoromethyl)- cyclobutanone
A solution of (SJZ)-I -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 CH2Cl2 (64 mL) was stirred at 0 0C under N2. Triethylamine (20.0 mL, 143 mmol) was added dropwise and the resulting mixture was then stirred at 40 0C for 18 h. H2O (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 INHCl 10 mL x 3, 200 mL with sat NaHCO3 aq. 10 mL x 3), and dried over Na2SO4. The solvent was removed under reduced pressure, and the crude product was chromatographed on silica (CH2Cl2) and recrystallized twice from EtOH and isopropanol, respectively, to yield the title compound. MS (M+l): 350.1 Step C: Synthesis of (2R,3i?)-methyl 2-(benzyloxy)-4,4,4-trifluoro-3-((S)-l-phenylethyl- amino)butanoate
A solution of (2Λ,3/?)-2-(benzyloxy)-4-((7?)-l-phenylethyl)-3-(trifluoromethyl)- cyclobutanone (9.53 g, 27.3 mmol) and HCl gas (23.3 g, 638 mmol) in methanol (300 mL) was stirred at 50 0C for 2 days. The solvent was removed under reduced pressure and residue was dissolved in CH2Cl2 (400 mL) and washed with sat NaHCO3 aq. (400 mL x 2) and sat NaCl aq. (400 mL x 2), and then dried over Na2SO4. The solvent was removed under reduced pressure, and the crude product was chromatographed on silica (hexane->hexane/CH2Cl2 = 1/1) to yield the title compound. MS (M+l): 382.2 Step D: Synthesis of (2i?,37?)-methyl 3-amino-4,4,4-trifluoro-2-hydroxybutanoate
The title compound was synthesized by modification of the reported procedure (Abouabdellah, A.; Begue, J. P.; Bonnet-Delpon, D.; Nga, T. T. T. J. Org. Chem. 1997, 62, 8826-8833). A solution of (2R,3R)-mβihyl 2-(benzyloxy)-4,4,4-trifluoro-3-((5)- 1 - phenylethylamino)butanoate (9.74 g, 25.5 mmol) and 10% Pd/C (1.93 g) in anhydrous AcOEt (300 mL) was stirred under H2 atmosphere for 27 h. To the filtrate of the mixture on Celite IN HCl in Et2O (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+l): 188.2 Step E: Synthesis of (27?,3i?)-methyl 4,4,4-trifluoro-2-hydroxy-3-(3-(trifluoromethyl)- phenylsulfonamido)butanoate
To a solution of (2i?,3/?)-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-l-sulfonyl chloride (0.449 g, 1.84 mmol), and stirred at r.t. for 1.5 h. Et2O (100 mL) was added and washed with 2.5N HCl aq. (100 mL x 4) and sat NaHCO3 aq. (100 mL x 2), and then dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was chromatographed on silica (CH2Cl2-* CH2Cl2/MeOH= 40/1) to yield the title compound. MS (M+l): 396.2 Step F: Synthesis of (2/?,3J/?)-4,4,4-trifluoro-2-hydroxy-3-(3-(trifluoromethyl)phenyl- sulfonamido)butanoic acid
A solution of (2/?,3i?)-methyl 4,4,4-trifluoro-2-hydroxy-3-(3-(trifluoromethyl)- phenylsulfonamido)butanoate (0.414 g, 1.05 mmol) and lithium hydroxide mono hydrate (0.353 g, 8.41 mmol) in H2O/MeOH/THF (4.0 mL/4.0ml/4.0ml) 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 Na2SO4. The solvent was icmυveα unuer reαuceu pressure and dried in vacuo to yield the title compound. MS (M-I): 380.2.
Similarly, the following acids are made:
(2R,3S)-3-(5-chloro-2-fluorophenylsulfonamido)-4,4,4-trifluoro-2-hydroxybutanoic acid; (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-dichloφhenylsulfonamido)-4,4,4-trifluoro-2-hydroxybutanoic acid; (2R,3S)-3-(2,5-dichlorphenylsulfonamido)-4,4,4-trifluoro-2-hydroxybutanoic acid; and (2R,3 S)-4,4,4-trifluoro-2-hydroxy-3 -(naphthalene-2-sulfonamido)butanoic acid.
Reference 13
Synthesis of (2R,3S)-4,4,4-trifluoro-2-hydroxy-3-(N-methyl-3- (trifluoromethyl)phenylsulfonamido)butanoic acid
Figure imgf000088_0001
Step A: Synthesis of (2R,3S)-methyl 4,4,4-trifluoro-2-hydroxy-3-(N-methyl-3-(trifluoro- methyl)phenylsulfonarnido)butanoate
To (2i?,3/?)-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 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)- 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. Reference 14 Synthesis of (5')-3-(3-chloro-2-fluoro-N-methylphenylsulfonaniido)-4,4,4-trifluorobutanoic acid
Figure imgf000089_0001
Step A: Synthesis of (5)-ethyl 3-(3-chloro-2-fluoro-N-methylphenylsulfonamido)-4,4,4- trifluorobutanoate
(-?)-Ethyl 3-(3-chloro-2-fluorophenylsulfonamido)-4,4,4-trifluorobutanoate, prepared according to Reference 11, Step A, was converted to the title compound according to Refrence 13, Step A.
Step B: Synthesis of (5)-3-(3-chloro-2-fluoro-N-methylphenylsulfonamido)-4,4,4- trifluorobutanoic acid
(5)-Ethyl 3-(3-chloro-2-fluoro-N-methylphenylsulfonamido)-4,4,4-trifluorobutanoate (1.5 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 0C 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.
Reference 15 Synthesis of ( i?)-7-nitro-6-(piperidin- 1 -ylmethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -ylamine
Figure imgf000089_0002
Step A: Synthesis of (Λ)-2,2,2-trifluoro-N-(6-(hydroxymethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 - yl)acetamide
To a solution of (i?)-(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 dropwise triethylamine (5.0 mL, 36 mmol). After stirring at RT for 2 h, the reaction was quenched with sat. NaHCO3, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, and evaporated to dryness. Flash chromatography (SiO2, DCM/EtOAc = 1 : 1 to pure EtOAc) afforded the title compound (7.2 g) as a white solid. Step B: Synthesis of (/?)-(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)-l,2,3,4-tetrahydro- naphthalen-l-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 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 (i?)-(l-nitro-5-(2,2,2-trifluoroacetamido)-5,6,7,8-tetrahydronaphthalen-2- yl)methyl acetate and (i?)-(3-nitro-5-(2,2,2-trifluoroacetamido)-5,6,7,8-tetrahydronaphthalen-2- yl)methyl acetate To a solution of (/?)-(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 NO2 +BF4 " (66 mg, 0.508 mmol). After stirring at RT for 20 min, the reaction was quenched with 0.5 mL of Sat. NaHCO3, and the solvent was evaporated to dryness. Flash chromatography (SiO2, DCM/hexane = 5:1 to pure DCM) gave (Λ)-(l-nitro-5-(2,2,2-trifluoroacetamido)-5,6,7,8- tetrahydronaphthalen-2-yl)methyl acetate (40 mg) as a white solid and (Λ)-(3-nitro-5-(2,2,2- trifluoroacetamido)-5,6,7,8-tetrahydronaphthalen-2-yl)methyl acetate (90 mg) as a white solid. Step D: Synthesis of (i?)-2,2,2-trifluoro-N-(6-(hydroxymethyl)-7-nitro-l,2,3,4-tetrahydro- naphthalen- 1 -yl)acetamide
To a solution of (i?)-(3-nitro-5-(2,2,2-trifluoroacetamido)-5,6,7,8-tetrahydronaphthalen- 2-yl)methyl acetate ( 17 mg) in 10 mL of MeOH was added one drop of 96% H2SO4 and the resulting mixture was stirred at 50 0C for 3 h. After cooling to RT, the reaction was quenched with Sat. NaHCO3 (0.5 mL). The MeOH was evaporated and the residue was directly loaded on column chromatography (SiO2, DCM to DCM/EtOAc = 2:1 to 1 :1) to give the title compound (15 mg) as a white solid. Step E: Synthesis of (i?)-2,2,2-trifluoro-N-(6-formyl-7-nitro-l,2,3,4-tetrahydronaρhthalen-l- yl)acetamide
To a solution of (/?)-2,2,2-trifluoro-N-(6-(hydroxymethyl)-7-nitro- 1,2,3,4- tetrahydronaphthalen-l-yl)acetamide (350 mg, 1.1 mmol) in DCM (100 mL) was added portionwise MnO2 (957 mg, 11 mmol). After stirring at RT for 3 h, the reaction mixture was 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 (^^^^-trifluoro-N-CT-nitro-ό-Cpiperidin-l-yhnethyO-l^^^-tetrahydro- naphthalen- 1 -yl)acetamide To a solution of (i?)-2,2,2-trifluoro-N-(6-formyl-7-nitro-l ,2,3,4-tetrahydronaphthalen- l-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. NaHCO3, extracted with EtOAc, dried over Na2SO4, filtered, and evaporated to dryness. Flash chromatography (SiO2, EtOAc/hexane = 1: 1) afforded the title compound (270 mg) as a white solid.
Step G: Synthesis of (/?)-7-nitro-6-(piperidin-l-ylmethyl)-l,2,3,4-tetrahydronaphthalen-l- amine
A solution of (/?)-2,2,2-trifluoro-N-(7-nitro-6-(piperidin- 1 -ylmethyl)- 1 ,2,3,4- tetrahydronaphthalen-l-yl)acetamide (230 mg, 0.6 mmol) and ΝaOH (108 mg, 2.7 mmol) in a mixed solvent (THF/MeOH/H2O = 5mL/5mL/lmL) was heated at 70 0C for 3 h. After cooling to RT, the solvent was evaporated to dryness and the residue was directly loaded on column chromatography (SiO2, EtOAc to EtOAc/2M NH3 in MeOH = 100: 15 to 100:20) to give the title (200 mg) as a white solid.
Reference 16
Synthesis of (i?)-5-nitro-6-(piperidin- 1 -ylmethyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -ylamine
Figure imgf000091_0001
Step A: Synthesis of (/?)-2,2,2-trifluoro-N-(6-(hydroxymethyl)-5-nitro-l,2,3,4-tetrahydro- naphthalen- 1 -yl)acetamide
To a solution of (/?)-(l-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% H2SO4 and the resulting mixture was stirred at 50 0C for 3 h. After cooling to RT, the reaction was quenched with Sat. NaHCO3 (0.5 mL). The MeOH was evaporated and the residue was directly loaded on column cnromarograpny i,aiu2, nexane/EtOAc = 2:1) to give the title compound (15 mg) as a white solid.
Step B: Synthesis of (i?)-2,2,2-trifluoro-N-(6-formyl-5-nitro-l,2,3,4-tetrahydronaphthalen-l- yl)acetamide To a solution of (R)-2,2,2-trifluoro-N-(6-(hydroxymethyl)-5-nitro-l ,2,3,4-tetrahydro- naphthalen-l-yl)acetamide (440 mg, 1.38 mmol) in DCM (50 mL) was added portionwise MnO2 (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. Step C: Synthesis of (Λ)-2,2,2-trifluoro-N-(5-nitro-6-(piperidin-l-ybnethyl)-l,2,3,4- tetrahydronaphthalen- 1 -yl)acetamide
To a solution of (i?)-2,2,2-trifluoro-N-(6-formyl-5-nitro-l,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 at RT overnight, the reaction was quenched with sat. NaHCO3, extracted with EtOAc, dried over Na2SO4, filtered, and evaporated to dryness. Flash chromatography (SiO2, EtOAc/hexane = 1 :4 to 1 :3 to 1 :2) afforded the title compound (240 mg) as a white solid. Step D: Synthesis of (/?)-5-nitro-6-(piperidin- 1 -ylmethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 - amine A solution of (/?)-2,2,2-trifluoro-N-(5-nitro-6-(piperidin-l-ymiethyl)-l,2,3,4- tetrahydronaphthalen-l-yl)acetamide (230 mg, 0.6 mmol) and NaOH (48 mg, 1.2 mmol) in a mixed solvent (MeOH/H2O = lOmL/lmL) was heated at 70 0C for 3 h. After cooling to RT, the solvent was evaporated to dryness and the residue was directly loaded on column chromatography (SiO2, EtOAc to EtOAc/2M NH3 in MeOH = 100: 10 to 100:20 to 100:30) to give the title compound (130 mg) as a white solid.
Example 1 Synthesis of (S)-N-((/?)-6-((cyclopentylamino)methyl)-l ,2,3,4-tetrahydronaphthalen-l -yl)-3-
(3-(trifluoromethyl)phenylsulfonamido)butanamide
Figure imgf000093_0001
Step A: Synthesis of (5)-N-((R)-6-(hydroxymethyl)-l ,2,3,4-tetrahydronaphthalen-l-yl)-3-(3- (trifluoromethyl)phenylsulfonamido)butanamide
A mixture of (5)-3-(3-(trifluoromethyl)phenylsulfonamido)butanoic acid (2.05 g, 6.59 mmol described in Reference 9 ), (i?)-(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(l .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 Na2CO3. The organic portion was separated, washed with water, brine, and the solvents were removed to afford the title compound as an off-white solid which was used in the following reaction without purification.
Step B: Synthesis of (5)-N-((/?)-6-formyl-l,2,3,4-tetrahydronaphthalen-l-yl)-3-(3-(trifluoro- methyl)phenylsulfonamido)butanamide
A mixture of (5)-N-((Λ)-6-(hydroxymethyl)-l,2,3,4-tetrahydronaphthalen-l-yl)-3-(3- (trifluoromethyl) phenylsulfonamido)butanamide (3.41 g , 7.25 mmol) and MnO2 (from 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-((/?)-6-(piperidin- 1 -ylmethyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)-3- (3 -(trifluoromethyl)phenylsulfonamido)butanamide
A mixture of (5)-N-((7?)-6-formyl-l ,2,3,4-tetrahydronaphthalen-l -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 0C for 16 h. The reaction mixture was cooled to r.t., diluted with MeOH and 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-NH4OH (aq, 28 ~ 30 %) (volume ratio 3: 1) in methylene chloride in 21 min, 10 - 15% of MeOH-N^OHfaq, 28 ~ 30 %) (volume ratio 3:1) in meinyiene cnioπαe in o minj io give the titled compound was obtained as a white solid. MS m/z: 538.3 (M+H)+. Calc'd for C27H34F3N3O3S - 537.64.
Proceeding as described above, the following compounds were prepared: (3S)-N-(( 1 R)-6-((( 1 , 1 -dimethylethyl)amino)methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)- 3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(S^-N-CCl^-ό-Cl-piperidinyhnethy^-l^^^-tetrahydro-l-naphthalenyO-S-^- (trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3,S)-N-((l/?)-6-((cyclopentylamino)methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-3-(((3- (trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (35)-N-((lΛ)-6-(((2-(methyloxy)ethyl)amino)methyl)-l,2,3,4-tetrahydro-l- naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-N-((l/?)-6-(((cyclopropylmethyl)amino)methyl)-l,2,3,4-tetrahydro-l- naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-N-(( \R)-6-( 1 -pyrrolidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-3-(((3- (trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-N-((l/?)-6-(((2-methylpropyl)amino)methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-3- (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-N-((4R)-7-(l-piperidinylmethyl)-3,4-dihydro-2H-chromen-4-yl)-3-(((3-(trifluoro- methyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((4.K)-7-((( 1 , 1 -dimethylethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)-3-
(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-N-((4i?)-7-((cyclopentylamino)methyl)-3,4-dihydro-2H-chromen-4-yl)-3-(((3- (trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-N-((4i?)-7-((cyclopropylamino)methyl)-3,4-dihydro-2H-chromen-4-yl)-3-(((3- (trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-N-((4JR)-7-(((l-methylethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)-3-(((3- (trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-N-((4/?)-7-((4-methyl-l-piperazinyl)methyl)-3,4-dihydro-2H-chromen-4-yl)-3- (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3-5)-N-((4Λ)-7-(((3S)-3-hydroxy-l-piperidinyl)methyl)-3,4-dihydro-2H-chromen-4-yl)-
3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-N-((4R)-7-(l-pyrrolidinylmethyl)-3,4-dihydro-2H-chromen-4-yl)-3-(((3- (trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3-S)-N-((4i?)-7-(((2-(methyloxy)ethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)-3- (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-N-((4Λ)-7-(((cyclopropylmethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)-3- (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (35)-N-((4i?)-7-(((2-methylpropyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)-3-
(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35}-N-(( lR)-6-( 1 -( 1 -piperidinylmethyl)ethenyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-3- (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((li?)-6-(((l,l-dimethyl- ethyl)amino)methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(35)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4R)-7-(((l,l-dimethyl- ethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide;
(3-S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((lΛ)-6-((cyclopentyl- amino)methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide; (35)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4i?)-7-((cyclopentyl- amino)methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide;
(3,S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((lΛ)-6-(l-piperidinyl- methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(35)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4/?)-7-(l-piperidinyl- methyl)-3 ,4-dihydro-2H-chromen-4-yl)butanamide;
(35)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((li?)-6-(((2-methylpropyl)- amino)methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(35}-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4/?)-7-(((2-methylpropyl)- amino)methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide; (35)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((li?)-6-(((l-methylethyl)- amino)methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(35)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4Λ)-7-(((l-methylethyl)- amino)methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide;
(3iS)-3 -(((4-chloro-2 , 5 -dimethylphenyl)sulfonyl)amino)-N-(( 1 /?)-6-(((cyclopropyl- methyl)amino)methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(35)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4/?)-7-(((cyclopropyl- methyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide;
(35)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((l/?)-6-((cyclobutyl-amino)- methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide; (3ύ>3-(((4-chloro-2,i»-dimethylphenyl)sulfonyl)amino)-N-((4i?)-7-((cyclobutyl-amino)- methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide;
(31S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-(( li?)-6-(((3.S}-3-hydroxy- 1 - piperidinyl)methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide; (35)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((lJR)-6-(((3JR)-3-hydroxy-l- piperidinyl)methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(35)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4i?)-7-(((3S)-3-hydroxy-l- piperidinyl)methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide;
(35)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4Λ)-7-(((3/?)-3-hydroxy-l- ρiperidinyl)methyl)-3 ,4-dihydro-2H-chromen-4-yl)butanamide;
(35)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((lΛ)-6-(l-pyrrolidinyl- methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3-S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((47?)-7-(l-pyrrolidinyl- methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide; (35)-3-(((4-(l,l-dimethylethyl)phenyl)sulfonyl)amino)-N-((li?)-6-(l-piρeridinyl- methyl)-l ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(35)-3-(((4-bromo-3-(trifluoromethyl)phenyl)sulfonyl)amino)-N-((li?)-6-(l- piperidinylmethyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(35)-3-(((2-fluoro-5-(trifluoromethyl)phenyl)sulfonyl)amino)-N-((li?)-6-(l-piperidinyl- methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3S)-3-(((2-chloro-5-(trifluoromethyl)phenyl)sulfonyl)amino)-N-((l/?)-6-(l-piperidinyl- methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(35)-3-(((2-chloro-5-(trifluoromethyl)phenyl)sulfonyl)amino)-N-((li?)-6-(l-piperidinyl- methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (35)-N-(( 1 R)-6-((3-pyridinylamino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-3 -(((3-
(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-3-(((6-chloro-2-naphthalenyl)sulfonyl)amino)-N-((li?)-6-(l-piperidinyl-methyl)- 1 ,2,3,4-tetrahydro-l -naphthalenyl)butanamide;
(35)-N-((lΛ)-6-((cyclopentylamino)methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-3-(((2- fluoro-5-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-3-(((2-chloro-5-(trifluoromethyl)phenyl)sulfonyl)amino)-N-((li?)-6-((cyclopentyl- amino)methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(3S)-3-(((6-chloro-2-naphthalenyl)sulfonyl)amino)-N-((lΛ)-6-((cyclopentylamino)- methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; VJo;-j-^^-cnioro-i-napnuiaienyl)sulfonyl)amino)-N-((li?)-6-((cyclopentyl- amino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(35)-3-(methyl((3-(trifluoromethyl)phenyl)sulfonyl)amino)-N-((l/?)-6-(l-piperidinyl- methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide; (35)-3-(((2-nitro-4-(trifluoromethyl)phenyl)sulfonyl)amino)-N-((li?)-6-(l-piperidinyl- methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(35)-3-(((2,6-dichloro-4-(trifluoromethyl)phenyl)sulfonyl)amino)-N-(( 1 R)-6-( 1 - piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(35)-3-(( 1 , 1 '-biphenyl-4-ylsulfonyl)amino)-N-(( lR)-6-( 1 -piperidinylmethyl)- 1 ,2,3,4- tetrahydro-l-naphthalenyl)butanamide;
(3S)-JV-(( li?)-6-((( 1 , 1 -dimethylethyl)amino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)- 3-(((2-nitro-4-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-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; (35)-3-((l , 1 '-biphenyl-4-ylsulfonyl)amino)-N-((li?)-6-(((l ,1 -dimethylethyl)- amino)methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(35)-3-((l,l'-biphenyl-3-ylsulfonyl)amino)-N-((li?)-6-(l-piperidinylmethyl)-l,2,3,4- tetrahydro- 1 -naphthalenyl)butanamide; and
(35)-3-(((4-(l,3-oxazol-5-yl)ρhenyl)sulfonyl)amino)-N-((l/?)-6-(l-piperidinyl-methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide.
The following compounds in Table 1 can be prepared similarly.
Table 1
Figure imgf000097_0001
Figure imgf000097_0002
Figure imgf000098_0001
Example 2
Synthesis of (i?)-4,4,4-trifluoro-N-(6-(piperidin-l-ylmethyl)-l ,2,3,4-tetrahydronaphthalen-l - yl)-3-(3-(trifluoromethyl)phenylsulfonamido)butanamide
Figure imgf000099_0001
Step A: Synthesis of (/?)-4,4,4-trifluoro-N-(6-(hydroxymethyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)-3 -(3 -(trifluoromethyl)phenylsulfonamido)butanamide A mixture of 4,4,4-trifluoro-3-(3-(trifluoromethyl)phenylsulfonamido)butanoic acid
(described in Reference 11, 2.84 g, 7.78 mmol), (i?)-(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, 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 (i?)-4,4,4-trifluoro-N-(6-formyl-l ,2,3,4-tetrahydronaphthalen-l -yl)-3-(3- (trifluoromethyl)phenylsulfonamido)butanamide
A mixture of (i?)-4,4,4-trifluoro-N-(6-(hydroxymethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 - yl)-3-(3-(trifluoromethyl)phenylsulfonamido)butanamide (crude, ~7.8 mmol) and MnO2 (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 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 (Λ)-4,4,4-trifluoro-N-(6-(piperidin-l-ylmethyl)-l,2,3,4-tetrahydro- naphthalen- 1 -yl)-3-(3-(trifluoromethyl) phenylsulfonamido)butanamide
A mixture of (/?)-4,4,4-trifluoro-N-(6-formyl-l,2,3,4-tetrahydronaphthalen-l-yl)-3-(3- (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 0C overnight. The reaction mixture was cooled to r.t., diluted with EtOAc/H2O, acidified with 10% of HCl to pH 2, and stirred for 30 min. NaHCO3 (aq) was added to bring pH to 8~9 and the organic 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-NH4OH (aq, 28 ~ 30 %) (volume ratio 3:1) in methylene chloride in 20 min, 13 - 15% Of MeOH-NH4OH (aq, 28 ~ 30 %) (volume ratio 3: 1) in methylene chloride in 8 min) to give the title compound as a white solid. MS m/z: 592.2 (M+H)+. Calc'd for C27H3IF6N3O3S - 591.61.
Similarly the following compounds were prepared.
(3JR/S)-N-((l/?)-6-(((l,l-dimethylethyl)amino)methyl)-l,2,3,4-tetrahydro-l- naphthalenyl)-4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3R/S)-N-((4R)-l-((( 1 , 1 -dimethylethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)- 4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3i?/S)-4,4,4-trifluoro-N-((4/?)-7-( 1 -piperidinylmethyl)-3 ,4-dihydro-2H-chromen-4-yl)- 3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3i?XS)-4,4,4-trifluoro-N-(( lR)-6-( 1 -piperidinylmethyl)- 1 ,2,3 ,4-tetrahydro- 1 - naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3Λ/5)-N-((li?)-6-((cyclopentylamino)methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-4,4,4- trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3Λ/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;
(3/2/S)-N-((4R)-7-((cyclopentylamino)methyl)-3,4-dihydro-2H-chromen-4-yl)-4,4,4- trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3R)-N-((\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;
(35)-N-(( li?)-6-((( 1 , 1 -dimethylethyl)amino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)- 4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3Λ/5)-3-(((3,4-dichlorophenyl)sulfonyl)amino)-N-((lJR)-6-(((l,l- dimethylethyl)amino)methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)-4,4,4-trifluorobutanamide;
(3R/S)-N-((lR)-6-(((l , 1 -dimethylethyl)amino)methyl)-l ,2,3 ,4-tetrahydro- 1 - naphthalenyl)-4,4,4-trifluoro-3-((2-naphthalenylsulfonyl)amino)butanamide;
(3i?/S)-N-((li?)-6-(((l,l-dimethylethyl)amino)methyl)-l,2,3,4-tetrahydro-l- naphthalenyl)-4,4,4-trifluoro-3-(((2,4,6-trimethylphenyl)sulfonyl)amino)butanamide;
(3JR/S)-N-((li?)-6-(((l,l-dimethylethyl)amino)methyl)-l,2,3,4-tetrahydro-l- naphthalenyl)-4,4,4-trifluoro-3-(((4-methylphenyl)sulfonyl)amino)butanamide;
(3Λ/5)-3-(((4-chlorophenyl)sulfonyl)amino)-N-((lΛ)-6-(((l,l-dimethylethyl)- amino)methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-4,4,4-trifluorobutanamide ^Λ/o;-j-^^-cnioro--i,-)-uimeιnylphenyl)sulfonyl)amino)-N-((li?)-6-(((l,l- dimethylethyl)amino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-4,4,4-trifluorobutanamide;
(3Λ/S)-3-(((3,4-dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((li?)-6-(l- piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3/2/S)-4,4,4-trifluoro-3-((2-naphthalenylsulfonyl)amino)-N-((li?)-6-(l- piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3R/S)-4,4A-tήfkιoro-N-(( \R)-6-( 1 -piperidinylmethyl)- 1 ,2,3 ,4-tetrahydro- 1 - naphthalenyl)-3-(((2,4,6-trimethylphenyl)sulfonyl)amino)butanamide;
(3S)-4,4,4-trifluoro-N-(( 1 R)-6-( 1 -piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 - naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(S^^^^-trifluoro-N-CCl^-ό-Cl-piperidinyhnethyO-l^^^-tetrahydro-l- naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-4,4,4-trifluoro-N-((li?)-6-(((l-methylethyl)amino)methyl)-l,2,3,4-tetrahydro-l- naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3/?)-4,4,4-trifluoro-N-((li?)-6-(((l-methylethyl)amino)methyl)-l,2,3,4-tetrahydro-l- naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyi)amino)butanamide;
(35)-N-((4R)-7-(l-azepanylmethyl)-3,4-dihydro-2H-chromen-4-yl)-4,4,4-trifluoro-3- (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3/?)-N-((4i?)-7-(l-azepanylmethyl)-3,4-dihydro-2H-chromen-4-yl)-4,4,4-trifluoro-3- (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3/?/S)-4,4,4-trifluoro-N-((4i?)-7-(4-morpholinyhnethyl)-3,4-dihydro-2H-chromen-4- yl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3i?/S)-4,4,4-trifluoro-N-((li?)-6-(((35)-3-hyclroxy-l-piperidinyl)methyl)-l,2,3,4- tetrahydro-l-naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3Λ/S)-N-(( lΛ)-6-((cyclohexylamino)methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)-4,4,4- trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3Λ/5)-4,4,4-trifluoro-N-((4Λ)-7-((4-methyl-l-piperazinyl)methyl)-3,4-dihydro-2H- chromen-4-yl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3i?/5)-4,4,4-trifluoro-N-((4/?)-7-(((3Λ)-3-hydroxy-l-piperidinyl)methyl)-3,4-dihydro- 2H-chromen-4-yl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3i?/S)-3-(((3-chloro-4-(trifluoromethyl)phenyl)sulfonyl)amino)-4,4,4-trifluoro-N-(6-(l- piperidinylmethyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(3R/5)-4,4,4-trifluoro-N-((l/?)-6-(((2-methylpropyl)amino)methyl)-l,2,3,4-tetrahydro-l- naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3i?/S)-N-((li?)-6-((cyclobutylamino)methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-4,4,4- trifluoro-3 -(((3 -(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3Λ/S)-N-((li?)-6-(l-azepanylmethyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-4,4,4- trifluoro-3 -(((3 -(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3R/S)-N-(( lR)-6-( 1 -azepanylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-4,4,4- trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3Λ/S)-N-((lJR)-6-(((2,2-dimethylpropyl)amino)methyl)-l,2,3,4-tetrahydro-l- naphthalenyl)-4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3i?/S)-4,4,4-trifluoro-3-((2-naphthalenylsulfonyl)amino)-N-((lJR)-6-(l- piperidinylmethyl)- 1 ,2,3,4-tetrahydro-l -naphthalenyl)butanamide;
(3Λ/-S)-4,4,4-trifluoro-3-((2-naphthalenylsulfonyl)amino)-N-((lΛ)-6-(l-piperidinyl- methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3Λ/S)-4,4,4-trifluoro-N-((li?)-6-(4-morpholinylmethyl)-l,2,3,4-tetrahydro-l- naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3R/S)-4,4,4-trifluoro-N-(( 1 i?)-6-((4-methyl- 1 -piperazinyl)methyl)- 1,2,3 ,4-tetrahydro- 1 - naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3R/S)-4,4,4-trifluoro-N-(( 1 /?)-6-( 1 -pyrrolidinylmethyl)- 1 ,2,3 ,4-tetrahydro- 1 - naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3R/5}-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;
(3/2/.S)-N-((4/?)-7-((cyclohexylamino)methyl)-3,4-dihydro-2H-chromen-4-yl)-4,4,4- trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3Λ/5)-4,4,4-trifluoro-N-((li?)-6-(((2-(l-pyrrolidinyl)ethyl)amino)methyl)-l,2,3,4- tetrahydro-l-naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3/?/S)-4,4,4-trifluoro-N-((l/?)-6-(((2-(l-piperidinyl)ethyl)amino)methyl)-l52,3,4- tetrahydro-l-naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3R/S)-4,4,4-trifluoro-N-((l/?)-6-(((2-(4-moφholinyl)ethyl)amino)methyl)-l,2,3,4- tetrahydro- 1 -naphthalenyl)-3 -(((3 -(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3R/S)-N-((li?)-6-(((2-(acetylamino)ethyl)amino)methyl)-l,2,3,4-tetrahydro-l- naphthalenyl)-4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3Λ/5)-N-((lΛ)-6-(((2-(dimethylamino)ethyl)amino)methyl)-l,2,3,4-tetrahydro-l- naphthalenyl)-4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3JR/S)-N-((li?)-6-(((2-(diethylamino)ethyl)amino)methyl)-l,2,3,4-tetrahydro-l- naphthalenyl)-4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3Λ/S)-iV-(( li?)-6-(((2R,65)-2,6-dimethyl- 1 -piperidinyl)methyl)- 1 ,2,3 ,4-tetrahydro- 1 - naphthalenyl)-4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3i?/S)-4,4,4-trifluoro-N-(( 17?)-6-((4-hydroxy- 1 -piperidinyl)methyl)- 1 ,2,3 ,4-tetrahydro- l-naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3Λ/-S)-4,4,4-trifluoro-N-(( lR)-6-((4-hydroxy- 1 -piperidinyl)methyl)- 1 ,2,3,4-tetrahydro- l-naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3i?/S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((lJR)-6-(l- piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3R/S)-N-(( lR)-6-( 1 -azepanylmethyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)-3-(((4-chloro- 2,5-dimethylphenyl)sulfonyl)amino)-4,4,4-trifluorobutanamide;
(3Λ/S}-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((17?)-6-((3- hydroxy- 1 -piperidinyl)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3i?/5)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((lR)-6- (((2-(I -pyrrolidinyl)ethyl)amino)methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide; (3Λ/5)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((4i?)-7-(l- piperidinylmethyl)-3,4-dihydro-2H-chromen-4-yl)butanamide;
(3Λ/S)-N-((4i?)-7-(l-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- hydroxy-l-piperidinyl)methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide;
(3/?/S)-4,4,4-trifluoro-3-((6-isoquinolinylsulfonyl)amino)-N-(( \R)-6-( 1 -piperidinyl¬ methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3i?/S)-3-(((3-chloro-4-methylphenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((li?)-6-(l- piperidinylmethyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide; (3/?ΛS)-N-((li?)-6-(l-azepanylmethyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-3-(((3-chloro-
4-methylphenyl)sulfonyl)amino)-4,4,4-trifluorobutanamide;
(35)-3-(((3,4-bis(methyloxy)phenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((lΛ)-6-(l- piperidinylmethyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3/?/S)-3-(((3,4-bis(methyloxy)phenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((li?)-6-(l- piperidinylmethyl)- 1 ,2,3,4-tetrahydro-l -naphthalenyl)butanamide;
(3i?/5)-N-((li?)-6-(l-azepanyhnethyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-3-(((3,4- bis(methyloxy)phenyl)sulfonyl)amino)-4,4,4-trifluorobutanamide;
(3/?)-3-(((3,4-dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((li?)-6-(l-piperidinyl- methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide; (iώ>3-(((3,4-dichlorophenyl)sulfonyl)aπiino)-4,4,4-trifluoro-N-((l/?)-6-(l-piperidinyl- methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(3/?/5)-4,4,4-trifluoro-3-(methyl((3-(trifluoromethyl)ρhenyl)sulfonyl)amino)-N-((17?)-6- ( 1 -piperidinylmethyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide; (3/?/5)-4,4,4-trifluoro-N-(( li?)-6-(((2-hydroxy- 1 , 1 -dimethylethyl)amino)methyl)-
1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3/?/5}-4,4,4-trifluoro-N-((l/?)-6-((((25)-tetrahydro-2-furanylmetliyl)amino)methyl)- l,2,3,4-tetrahydro-l-naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3i?/5)-4,4,4-trifluoro-N-((li?)-6-((((2Λ)-tetrahydro-2-nαranylmethyl)amino)methyl)- l,2,3,4-tetrahydro-l-naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3R/S)-4,4,4-trifluoro-N-(( 1 R)-6-( 1 -piperidinylmethyl)- 1 ,2,3 ,4-tetrahydro- 1 - naphthalenyl)-3-((8-quinolinylsulfonyl)amino)butanamide;
(3Λ/5)-3-(((2,3-dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((lR)-6-(l- piperidinylmethyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide; (3i?/S)-3-(((2,5-dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((li?)-6-(l- piperidinylmethyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3i?/S)-3-(((5-chloro-2-(methyloxy)phenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((17?)-6- ( 1 -piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3i?/S)-3-(((2,6-dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((li?)-6-(l- piperidinylmethyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(35}-3-(((4-chloro-3-(trifluoromethyl)phenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((li?)-6- ( 1 -piperidinylmethyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3Λ/S)-3-(((4-chloro-3-(trifluoromethyl)phenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((l/?)- 6-( 1 -piperidinyhnethyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide; (3Λ/-S)-3-(((5-chloro-2-fluorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((li?)-6-(l- piperidinylmethyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3R/S}-3-(((3-chloro-2-fluorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((lΛ)-6-(l- piperidinylmethyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(3i?)-3-(((2,3-dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((l/?)-6-(l- piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3R)-4,4,4-trifluoro-3-(((8-(methyloxy)-5-quinolinyl)sulfonyl)amino)-N-((lR)-6-(l- piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(35)-4,4,4-trifluoro-3-(((8-(methyloxy)-5-quinolinyl)sulfonyl)amino)-N-(( lR)-6-( 1 - piperidinylmethyl)-!, 2,3,4-tetrahydro-l-naphthalenyl)butanamide; (3Λ/ώ>3-((2,3-dihydro-l,4-benzodioxin-6-ylsulfonyl)amino)-4,4,4-trifluoro-N-((lR)-6- ( 1 -piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3R)-3-(((2,5-dichlorophenyl)sulfonyl)amino)-N-((li?)-6-(((l,l-dimethylethyl)- amino)methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-4,4,4-trifluorobutanamide; (3Λ)-3-(((2,3-dichlorophenyl)sulfonyl)amino)-N-((l/?)-6-(((l,l-dimethylethyl)- amino)methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-4,4,4-trifluorobutanamide;
(3R)-3-(((2,5-dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((li?)-6-(l-piperidinyl- methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(3/?/S)-4,4,4-trifluoro-N-(( lJR)-6-((4-methyl- 1 -piperidinyl)methyl)- 1 ,2,3 ,4-tetrahydro- 1 - naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3/?./-S}-4,4,4-trifluoro-N-(( li?)-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-((4Λ)-7-( 1 -piperidinyl- methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide; (3tf)-N-(6-chloro-7-( 1 -piperidinylmethyl)-3 ,4-dihydro-2H-chromen-4-yl)-4,4,4- trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3Λ)-4,4,4-trifluoro-N-((7R)-l,2,3,4,7,8,9,10-octahydrobenzo[f]isoquinolin-7-yl)-3-(((3- (trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3i?)-3-(((2,3-dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((4i?)-7-(l- piperidinylmethyl)-3,4-dihydro-2H-chromen-4-yl)butanamide;
(3/?)-3-(((2,5-difluorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((4/?)-7-(l-piperidinyl- methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide;
(3R)-4,4,4-trifluoro-3-(((5-methyl-2-(methyloxy)phenyl)sulfonyl)amino)-N-((lR)-6-(l- piperidinylmethyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide; (3i?)-3-(((5-chloro-2-(methyloxy)phenyl)sulfonyl)amino)-N-((l/?)-6-(((l,l-dimethyl- ethyl)amino)methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-4,4,4-trifluorobutanamide;
(3i?)-3-(((3,5-difluorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((17?)-6-(l-piperidinyl- methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3i?)-3-(((2,5-difluorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((li?)-6-(l-piperidinyl- methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3/?)-4,4,4-trifluoro-3-(((3-methylphenyl)sulfonyl)amino)-N-((lΛ)-6-(l-piperidinyl- methyl)-l,2,3,4-tetrahydro-l-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; (3R)-N-(( lΛ)-6-((4a/?,8aR)-octahydro-2( 1 H)-isoquinolinylmethyl)- 1 ,2,3 ,4-tetrahydro- 1 - naphthalenyl)-4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3/?)-4,4,4-trifluoro-N-((li?)-6-((4-(2-hydroxyethyl)-l-piperidinyl)methyl)-l,2,3,4- tetrahydro-l-naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3R)-N-(( li?)-6-(((cyclopropylmethyl)(propyl)amino)methyl)- 1 ,2,3 ,4-tetrahydro- 1 - naphthalenyl)-4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3i?)-N-((lΛ)-6-((3,3-dimethyl-l-piperidinyl)methyl)-l,2,3,4-tetrahydro-l- naphthalenyl)-4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3i?)-3-(((3-chloro-2-fluorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((li?)-6-(l- piperidinylmethyl)-l ,2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(3i?)-3-(((5-chloro-2-fluorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((l/?)-6-(l- piperidinylmethyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3i?)-3-(((5-chloro-2-fluorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((4/?)-7-(l- piperidinyhnethyl)-3,4-dihydro-2H-chromen-4-yl)butanamide; (3/Q-3 -(((3 -chloro-2-fluorophenyl)sulfonyl)amino)-N-(( lR)-6-((( 1 , 1 -dimethylethyl)- amino)methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-4,4,4-trifluorobutanamide;
(3Λ)-3-(((5-chloro-2-fluorophenyl)sulfonyl)amino)-N-((4i?)-6-chloro-7-(l- piperidinylmethyl)-3,4-dihydro-2H-chromen-4-yl)-4,4,4-trifluorobutanamide;
(3i?)-3 -(((3 -chloro-2-fluorophenyl)sulfonyl)amino)-N-((4i?)-6-chloro-7-( 1 -piperidinyl- methyl)-3,4-dihydro-2H-chromen-4-yl)-4,4,4-trifluorobutanamide;
(3/?)-3-(((3-chloro-2-fluorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((4i?)-7-(l- piperidinylmethyl)-3,4-dihydro-2H-chromen-4-yl)butanamide;
(3R)-3-((2,3-dihydro-l,4-benzodioxin-6-ylsulfonyl)amino)-4,4,4-trifluoro-N-((lΛ)-6-(l- piperidinylmethyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide; 1,1 -dimethylethyl-4-(((5i?)-5-(((3i?)-4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)- sulfonyl)amino)butanoyl)amino)-5,6,7,8-tetrahydro-2-naphthalenyl)methyl)-l- piperazinecarboxylate;
(3/?)-4,4,4-trifluoro-N-((li?)-6-(l-piperazinylmethyl)-l,2,3,4-tetrahydro-l- naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (S^^^^-trifluoro-N-CCl^-ό-C^^^-methyl-l-piperidiny^methyl)-!^^^- tetrahydro-l-naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3/?)-4,4,4-trifluoro-N-((li?)-6-(((3S)-3-methyl-l-piperidinyl)methyl)-l,2,3,4- tetrahydro-l-naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3Λ)-4,4,4-trifluoro-N-(( lΛ)-6-(((3S)-3-hydroxy- 1 -pyrrolidinyl)methyl)- 1 ,2,3 ,4- tetrahydro-l-naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3i?)-4,4,4-trifluoro-N-((li?)-6-(((3JR)-3-hydroxy-l-pyrrolidinyl)methyl)-l,2,3,4- tetrahydro-l-naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3i?)-4,4,4-trifluoro-N-((li?)-6-(((3i?)-3-(hydroxymethyl)-l-piperidinyl)methyl)-l,2,3,4- tetrahydro-l-naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3i?)-4,4,4-trifluoro-N-(( li?)-6-(((3i?)-3-(methyloxy)- 1 -piperidinyl)methyl)- 1 ,2,3 ,4- tetrahydro-l-naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3i?)-4,4,4-trifluoro-N-((l/?)-6-((4-(methylsulfonyl)-l-piperazinyl)methyl)-l,2,3,4- tetrahydro- 1 -naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3R)-N-(( 1 R)-6-( 1 -azepanylmethyl)- 1,2,3 ,4-tetτahydro- 1 -naphthalenyl)-4,4,4-trifluoro- 3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3R)-N-(( 1 R)-6-( 1 -azepanylmethyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)-4,4,4-trifluoro- 3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3/?)-3-(((5-chloro-2-fluorophenyl)sulfonyl)amino)-N-((lR)-6-(((l,l-dimethylethyl)- amino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-4,4,4-trifluorobutanamide;
(3Λ/S)-4,4,4-trifluoro-N-((li?)-6-((3-oxo- 1 -piperidinyl)methyl)- 1 ,2,3,4-tetrahydro- 1 - naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3/?/S)-3-(((2-chloro-5-(trifluoromethyl)phenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((li?)- 6-( 1 -piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3Λ/5)-3-(((3 ,5-dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-(( 1 R)-6-( 1 - piperidinylmethyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3i?)-3-(((3-chloro-2-fluorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-methyl-N-((li?)-6- (l-piperidinylmethyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide; (3/?)-4,4,4-trifluoro-3-((phenylsulfonyl)amino)-N-(( \R)-6-( 1 -piperidinylmethyl)-
1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3Λ)-3-(((2-bromo-5-(trifluoromethyl)phenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((li?)- 6-( 1 -piperidinylmethyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3i?)-3 -(((2-bromophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-(( \R)-6-( 1 -piperidinyl- methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3/?)-4,4,4-trifluoro-3-(((2-nitrophenyl)sulfonyl)amino)-N-((17?)-6-(l -piperidinyl¬ methyl)-!, 2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(3i?)-4,4,4-trifluoro-N-((4R)-6-iluoro-7-(l-piperidinyhnethyl)-3,4-dihydro-2H- chromen-4-yl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
Figure imgf000108_0001
/-isoquinolinylsulfonyl)amino)-N-((l/?)-6-(l-piperidinyl- methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3i?)-4,4,4-trifluoro-N-(( li?)-6-( 1 -piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 - naphthalenyl)-3-(((3-((trifluoromethyl)oxy)phenyl)sulfonyl)amino)butanamide; (3i?)-3-(((5-chloro-2-fluorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((lΛ)-6-((4- methyl- 1 -piρeridinyl)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3R)-N-((lR)-6-((((2R,3S,4S,5S,6S)-3,5-dihydroxy-2-(hydroxymethyiy6- (methyloxy)tetrahydro-2H-pyran-4-yl)amino)methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)- 4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3i?)-4,4,4-trifluoro-3 -(((2-fluorophenyl)sulfonyl)amino)-Ν-(( 1 R)-6-( 1 -piperidinyl¬ methyl)-!, 2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(3/?)-4,4,4-trifluoro-3-(((4-methylphenyl)sulfonyl)amino)-N-((lR)-6-(l-piperidinyl- methyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3i?)-4,4,4-trifluoro-3-(((4-fluorophenyl)sulfonyl)amino)-N-((lR)-6-(l-piperidinyl- methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3/?)-3-(((3-chloro-2-fluorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((4R)-6-fluoro-7- (l-piperidinyhnethyl)-3,4-dihydro-2H-chromen-4-yl)butanamide;
(3i?)-4,4,4-trifluoro-N-((4R)-6-fluoro-7-(l-piperidinyhnethyl)-3,4-dihydro-2H- chromen-4-yl)-3-(((3-((trifluoromethyl)oxy)phenyl)sulfonyl)amino)butanamide; (3/?)-3-(((3-chlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((li?)-6-(l-piperidinyl- methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(3/?)-3-(((4-chlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((lΛ)-6-(l-piperidinyl- methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3/?)-3-(((2-chlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((li?)-6-(l-piperidinyl- methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3/?)-4,4,4-trifluoro-3 -(((3 -fluorophenyl)sulfonyl)amino)-N-(( 1 R)-6-( 1 -piperidinyl¬ methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3/?)-4,4,4-trifluoro-N-(( li?)-6-((4-methyl- 1 -piperidinyl)methyl> 1 ,2,3,4-tetrahydro- 1 - naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sυlfonyl)amino)butanamide; (3i?)-3-(((2-aminophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((l/?)-6-(l -piperidinyl¬ methyl)-!, 2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(3/?)-3-(((2-chloro-4-fluorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((lΛ)-6-(l- piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; ^Λ;-j-^^-cnioro-z-πuoropnenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((lR)-6-(l- piperidinylmethyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(3i?)-4,4,4-trifluoro-3-(((3-methylphenyl)sulfonyl)amino)-N-((li?)-6-(l-piperidinyl- methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide; (3R)-4,4,4-trifluoro-N-(( \R)-6-(l -piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 - naphthalenyl)-3-(((4-((trifluoromethyl)oxy)phenyl)sulfonyl)amino)butanamide;
(3R)-3 -(((3-chloro-4-fluorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-(( 1 R)-6-( 1 - piperidinylmethyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3/?)-3-(((3-bromophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((li?)-6-(l-piperidinyl- methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3/?)-4,4,4-trifluoro-N-((lΛ)-6-(l-piperidinyhnethyl)-l,2,3,4-tetrahydro-l- naphthalenyl)-3-(((2-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3/?)-3-(((4-ethylphenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((l/?)-6-(l-piperidinyl- methyl)-l,2,3,4-tetrahydτo-l-naphthalenyl)butanamide; (3R)-4,4,4-trifluoro-N-((4i?)-7-(l -piperidinyhnethyl)-3,4-dihydro-2H-chromen-4-yl)-3-
(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3/?)-4,4,4-trifluoro-3-(((5-fluoro-2-methylphenyl)sulfonyl)amino)-N-((lΛ)-6-(l- piperidinylmethyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3i?)-3-(((2-chloro-6-methylphenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((lR)-6-(l- piperidinylmethyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3/?)-4,4,4-trifluoro-N-(( \R)-6-( 1 -piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 - naphthalenyl)-3-(((4-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3Λ)-4,4,4-trifluoro-3-(((2-fluoro-5-methylphenyl)sulfonyl)amino)-N-((li?)-6-(l- piperidinylmethyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide; (3i?)-3-(((3,4-dimethylphenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((li?)-6-(l- piperidinylmethyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3i?)-3-(((3,5-dimethylphenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((li?)-6-(l-piperidinyl- methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(3i?)-4,4,4-trifluoro-3-(((3-(methyloxy)phenyl)sulfonyl)amino)-N-((l/?)-6-(l- piperidinylmethyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(3R)-4,4,4-trifluoro-N-(( \R)-6-(l -(4-methyl)piperidinyhnethyl)- 1 ,2,3,4-tetrahydro- 1 - naphthalenyl)-3-(((2-fluoro-3-chlorophenyl)sulfonyl)amino)butanamide;
(3Λ)-4,4,4-trifluoro-3-(((4-methyl-3,4-dihydro-2H-l,4-benzoxazin-7-yl)sulfonyl)- amino)-N-(( lR)-6-( 1 -piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-butanamide; (, jκ;-4,4,4-tπtluoro-Λ'-(( IK)-O-(I -piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 - naphthalenyl)-3-((l,2,3,4-tetrahydro-8-quinolinylsulfonyl)amino)butanamide;
(3/?)-3-(((3,5-dichloro-4-hydroxyphenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((li?)-6-(l- piperidinylmethyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3/?)-3-((3,4-dihydro-2H-l,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-(l,3-oxazol-5-yl)phenyl)sulfonyl)amino)-N-((l/?)-6-(l- piperidinylmethyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide; and
(3R)-4,4,4-trifluoro-N-(( \R)-6-( 1 -piperidinyhnethyl)- 1 ,2,3,4-tetrahydro- 1 - naphthalenyl)-3-(((3-tert-butylphenyl)sulfonyl)amino)butanamide.
Unless indicated otherwise, the following compound can be prepared following the procedure described above.
Table 2
Figure imgf000110_0001
Figure imgf000110_0002
Figure imgf000111_0001
Figure imgf000112_0002
Example 3
Synthesis of (S)-N-((R)-6-(\ -(cyclopropylamino)ethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)-3- (3-(trifluoromethyl)phenylsulfonamido)butanamide
Figure imgf000112_0001
Step A: Synthesis of [6-(l-hydroxy-ethyl)-l,2,3,4-tetrahydro-naphthalen-l-yl]-carbamic acid tert-butyl ester
To a solution of (6-formyl-l,2,3,4-tetrahydro-naphthalen-l-yl)-carbamic acid tert-butyl ester (2.80 g, 10.2 mmol, 1.0 eq) in THF (100 mL) at -78 0C 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 0C for 20 min, warmed up to room temperature and stirred at room temperature for 2 h. The reaction was quenched with saturated NaHCO3 (120 mL), and the crude product was extracted with EtOAc (100 mL x 3). The extract phase was washed with saturated NaCl, dried over Na2SO4, filtered and concentrated. The title compound was obtained as a white solid. MS (ESI, pos. ion) m/z: 292 (M+l).
Ill Step B: Synthesis of (6-acetyl-l,2,3,4-tetrahydro-naphthalen-l-yl)-carbamic acid tert-butyl ester
A mixture of [6-(l-hydroxy-ethyl)-l,2,3,4-tetrahydro-naphthalen-l-yl]-carbamic acid tert-butyl ester (2.63 g, 9.04 mmol, 1.0 eq) and MnO2 (Aldrich, 10.2 g, 117.5 mmol, 13 eq) in CH2Cl2 (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 CH2Cl2 (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+l). Step C: Synthesis of (,S)-N-((/?)-6-acetyl-l,2,3,4-tetrahydronaphthalen-l-yl)-3-(3- (trifluoromethyl)phenylsulfonamido)butanamide
A mixture of (6-acetyl-l,2,3,4-tetrahydro-naphthalen-l-yl)-carbamic acid tert-butyl ester (650 mg, 2.25 mmol, 1.0 eq) in HCl/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 l-(5-amino-5,6,7,8-tetrahydro-naphthalen-2-yl)-ethanone hydrogen chloride was 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 CH2Cl2 (20 mL) and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with H2O (100 mL). The crude product was extracted with CH2Cl2 (100 mL x 3). The extract phase was washed with saturated NaCl, dried over Na2SO4, filtered and concentrated. Flash column chromatography (silica gel, 0-7 % MeOH-CH2Cl2) afforded the title compound as a white solid. MS (ESI, pos. ion) m/z: 483 (M+l). (5)-N-((R)-6-Acetyl- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)-3-(3-(trifluoromethyl)phenylsulfonamido)butanamide was converted to (5)-N-((i?)-6-(l-(cyclopropylamino)ethyl)-l,2,3,4-tetrahydronaphthalen-l-yl)-3- (3-(trifluoromethyl)phenylsulfonamido)butanamide by reacting it with cyclopropylamine as described Example 2, Step C above.
Similarly the following compounds were made.
(3S)-Ν-((l/?/5)-6-((lS)-l-(cyclopentylamino)ethyl)-l,2,3,4-tetrahydro-l-naphthalenyl)- 3 -(((3 -(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3 S)-N-(( \R/S)-6-(( 1 S)- 1 -((2-methylpropyl)amino)ethyl)- 1 ,2,3,4-tetrahydro- 1 - naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3 S)-N-(( \R/S)-6-(( 1 R)- 1 -(cyclobutylamino)ethyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)- 3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-(( \R/S)-6-(( 1 S)- 1 -((cyclopropylmethyl)amino)ethyl)- 1 ,2,3,4-tetrahydro- 1 - naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; and
(3 S)-N-(( 1 R)-6-(( \R/S)- 1 -((2-(methyloxy)ethyl)amino)ethyl)- 1 ,2,3,4-tetrahydro- 1 - naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide.
Example 4
Synthesis of (^ len-l-
Figure imgf000114_0001
To a 20 mL flask equipped with stirring was added (5}-3-(3-(trifluoromethyl)phenyl- sulfonamido)butanoic acid (68 mg, 0.22 mmol), 6-(l-piperidin-l-ylmethyl-vinyl)-l,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 CH2Cl2 (2 mL). The reaction mixture was stirred at room temperature overnight and diluted with CH2Cl2 (50 mL). The organic phase was washed with saturated NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified by preparative TLC in 10% MeOH-CH2Cl2 to afford the title compound. MS (ESI): 564 (M+H)+.
Similarly (Λ)-4,4,4-trifluoro-N-((Λ)-6-(3-(piperidin- 1 -yl)prop- 1 -en-2-yl)- 1 ,2,3 ,4- tetrahydronaphthalen-l-yl)-3-(3-(trifluoromethyl)phenylsulfonamido)butanamide was prepared.
Example 5
Synthesis of (/?)-3-(3,4-dichlorophenylsulfonamido)-Ν 1 -((7?)-6-(piperidin- 1 -ylmethyl)- 1 ,2,3 ,4- tetrahydronaphthalen- 1 -yl)succinamide
Figure imgf000115_0001
(/?)-4-Amino-3-(3,4-dichlorophenylsulfonamido)-4-oxobutanoic acid (250 mg, 0.733 mmol) was dissolved in anhydrous DMF (7 mL). (/?)-6-(piperidin-l-ylmethyl)-l,2,3,4- 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. EtO Ac/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 column chromatography ( 10% MeOH/CH2Cl2, ISCO CombiFlash) to give (R)-3-(3 ,A- dichlorophenylsulfonamido^N1 -(/?)-6-(piperidin- 1 -ylmethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 - yl)succinamide. MS 567 (M+H).
Similarly, (/?)-benzyl 2-(3,4-dichlorophenylsulfonamido)-4-oxo-4-((i?)-6-(piperidin- 1 - ylmethyl)-l,2,3,4-tetrahydronaphthalen-l-ylamino)butanoate; and (i?)-benzyl 2-(4- ' methylphenylsulfonamido)-4-oxo-4-((i?)-6-(piperidin- 1 -ylmethyl)- 1 ,2,3 ,4-tetrahydro- naphthalen-l-ylamino)butanoate were prepared.
Example 6
Synthesis of (R)-tert-butyl 2-(3 ,4-dichlorophenylsulfonamido)-4-oxo-4-((7?)-6-(piperidin- 1 - ylmethyl)-!, 2,3,4-tetrahydronaphthalen-l-ylamino)butanoate
Figure imgf000115_0002
The title compound was prepared according to Example 5 from (i?)-4-tert-butoxy-3- (3,4-dichlorophenylsulfonamido)-4-oxobutanoic acid. MS: 624.4 (M+H). Example 7
Synthesis of (/?)-2-(3,4-dichlorophenylsulfonamido)-4-oxo-4-((i?)-6-(piperidin-l -ylmethyl)- l,2,3,4-tetrahydronaphthalen-l-ylamino)butanoic acid
Figure imgf000116_0001
To (i?)-tert-butyl 2-(3 ,4-dichlorophenylsulfonamido)-4-oxo-4-((Λ)-6-(piperidin- 1 - ylmethyl)-l,2,3,4-tetrahydronaphthalen-l-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).
Example 8
Synthesis of (i?)-4-hydroxy-3-(4-methylphenylsulfonamido)-N-((^)-6-(piperidin- 1 -ylmethyl)-
1 ,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide
Figure imgf000116_0002
To (i?)-benzyl 2-(4-methylphenylsulfonamido)-4-oxo-4-((i?)-6-(piperidin- 1 -ylmethyl)- l,2,3,4-tetrahydronaphthalen-l-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) 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% 2Ν NH3/Me0H/DCM) to give the title compound. MS: 500.2 (M+H).
Example 9 Synthesis of (3R,4R)-3-(3,4-dichlorophenylsulfonamido)-4-hydroxy-N-((i?)-6-(piperidin- 1 -yl- methyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)pentanamide
Figure imgf000117_0001
Step A: Synthesis of 3,4-dichloro-N-((2R,3R)-2-methyl-5-oxo-tetrahydrofuran-3-yl)benzene- sulfonamide
To a mixture of L-β-homothreonine hydrochloride (1.04 g) and sodium carbonate (1.8 g) in dioxane (10 mL) and water (10 niL) 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 the title compound. MS: 322 (M+H).
Step B: Synthesis of (3/?,4i?)-3-(3,4-dichlorophenylsulfonamido)-4-hydroxy-N-((i?)-6- (hydroxymethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)pentanamide
To a mixture of (/?)-(5-amino-5,6,7,8-tetrahydronaphthalen-2-yl)methanol (0.17 g) in DCM (10 mL) at 0 0C was added trimethylaluminm (1 mL of 2.0M in toluene, Aldrich). The reaction mixture was stirred for 30 min. The above lactone (0.36 g) was added. The reaction mixture was stirred for 4 h. HCl solution (2 mL, 0.05Ν) 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-((i?)-6-formyl-l,2,3,4- tetrahydronaphthalen- 1 -yl)-4-hydroxypentanamide (3i?,4Λ)-3-(3,4-Dichlorophenylsulfonamido)-4-hydroxy-N-((i?)-6-(hydroxymethyl)- l,2,3,4-tetrahydronaphthalen-l-yl)pentanamide (0.12 g) in DCM (300-400 mL) was stirred with MnO2 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 (3Λ,4R)-3-(3,4-dichlorophenylsulfonamido)-4-hydroxy-N-((/?)-6- (piperidin- 1 -ylmethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)pentanamide
A mixture of (3i?,4Λ)-3-(3,4-dichlorophenylsulfonamido)-N-((J?)-6-formyl- 1,2,3,4- tetrahydronaphthalen-l-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 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 Synthesis of (/?)-3-(N-(4-fluorophenyl)-3-(trifluoromethyl)phenylsulfonamido)-N-(6-((4- fluoropiperidin- 1 -yl)methyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)propanamide
Figure imgf000118_0001
Step A: Synthesis of methyl 3-(4-fluorophenylamino)propanoate 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 0C 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+l). Step B: Synthesis of methyl 3-(N-(4-fluorophenyl)-3-(trifluoromethyl)- 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. K2CO3 (10 mL). The reaction was stirred at RT for 4 h. The compound was extracted with EtOAc (2x20 mL). The combined organic phase was washed with 5% brine (2x15 mL), dried over Na2SO4. Purification with column chromatography over silica gel with hexane:EtOAc (5: 1) gave the title compound. MS (ESI, pos. ion.) m/z: 406 (M+l).
Step C: Synthesis of 3-(N-(4-fluorophenyl)-3-(trifluoromethyl)phenylsulfonamido)propanoic acid To a 100-mL round-bottomed flask containing methyl 3-(N-(4-fluorophenyl)-3-
(trifiuoromethyl)phenylsulfonamido) propanoate (2.0 g, 4.8 mmol, Step B) in THF (10 mL), was added LiOH-H2O (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 2Ν HCl, the compound was extracted with EtOAc (2x20 mL). The organic phase was washed with 5% brine (2x 15 mL), dried over Na2SO4, filtered, and concentrated to yield the title compound. MS (ESI, pos. ion.) m/z: 390 (M-I). Step D: Synthesis of (/?)-3-(N-(4-fluorophenyl)-3-(trifluoromethyl)phenylsulfonamido)-N-(6- (hydroxymethyl)-l,2,3,4-tetrahydronaphthalen-l-yl)propanamide To a 50-mL reaction tube containing 3-(N-(4-fluorophenyl)-3-(trifiuoromethyl)- phenylsulfonamido)propanoic acid (1.6 g, 4.1 mmol, Step C) in CH2Cl2 (10 mL), was slowly added oxalyl chloride (10 mL, 21 mmol, 2.0M, Aldrich). After the reaction was stirred at RT for 0.5 h, the solvent was removed in vacuo. To the residue was added (i?)-(5-amino-5,6,7,8- tetrahydronaphthalen-2-yl)methanol (0.72 g) in THF (8 mL) and sat. K2CO3 (5 mL). The reaction was stirred at RT for 2.5 h. The compound was extracted with EtOAc (2^10 mL). The organic phase was washed with 5% brine (2x5 mL), dried over Na2SO4, 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+l). Step E: Synthesis of (S)-N-(4-fluorophenyl)-N-(4-(6-formyl- 1 ,2,3 ,4-tetrahydronaphthalen- 1 - yl)-3-oxobutyl)-3-(trifluoromethyl)benzenesulfonamide
To a 50-mL reaction tube containing (/?)-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 CH2Cl2 (15 mL), was added MnO2 (1.4 g, 16 mmol, Aldrich). The reaction was stirred at RT for 4 h, and filtration through Celite gave the title compound as a yellow solid. MS (ESI, pos. ion.) m/z: 549 (M+l).
Step F: Synthesis of (i?)-3-(N-(4-fluorophenyl)-3-(trifluoromethyl)phenylsulfonamido)-N-(6- ((4-fiuoropiperidin- 1 -yl)methyl)- 1,2,3 ,4-tetrahydronaphthalen- 1 -yl)propanamide
To a 50-mL reaction tube containing (5)-N-(4-fluorophenyl)-N-(4-(6-formyl- 1,2,3,4- tetrahydronaphthalen-l-yl)-3-oxobutyl)-3-(trifluoromethyl)benzenesulfonamide (80 mg, 0.15 mmol, Step E) in DMF (3 mL), was added 4-fluoropiperidine hydrobromide (0.27 g, 1.5 mmol, Oakwood Products), Et3N (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 K2CO3 (8 mL, 5%), and the compound was extracted with EtOAc (2x 10 mL). The organic phase was washed with 5% brine (2x5 mL), dried over Na2SO4, filtered, and concentrated. Purification with column chromatography over silica gel with hexane:EtOAc:MeOH (2M, NH3) (10: 10: 1) gave the title compound as a white solid. MS (ESI, pos. ion.) m/z: 636 (M+l).
Similarly, (R)-3 -(N-phenymaphthalene-2-sulfonamido)-N-(6-(piperidin- 1 -ylmethyl)- 1 ,2,3 ,4- tetrahydronaphthalen- 1 -yl)propanamide; (Λ)-3-(N-phenylnaphthalene-2-sulfonamido)-N-(7- (piperidin- 1 -ylmethyl)chroman-4-yl)propanamide; and (i?)-N-(6-((cyclopentylamino)methyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)-3-(N-phenyl-3-(trifluoromethyl)phenylsulfonamido)- propanamide were made.
Example 11
Synthesis of (i?)-N-(6-((4-fluoropiperidin-l -yl)methyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)-3- (N-methyl-3-(trifluoromethyl)phenylsulfonamido)propanamide
Figure imgf000120_0001
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 μL, 6.7 mmol, 40wt.%, Aldrich). The reaction was stirred at RT for 1 h. The reaction mixture was acidified to pH 5 with 2Ν HCl and the compound was extracted with EtOAc (2x 10 mL). The combined organic phase was washed with 5% brine (2><8 mL), dried over Na2SO4. 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) 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 K2CO3 (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 (2x 10 mL), dried over Na2SO4, 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: 326 (M+l). 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-(trifiuoromethyl)- phenylsulfonamido)propanoate (1.3 g, 4.0 mmol, Step B) in THF (8 mL), was added LiOH.H2O (1.3 mg, 8.0 mmol, Aldrich) and water (8 mL). The reaction was stirred at RT for 5 h. After acidified to pH 5 with 2N HCl, the compound was extracted with EtOAc (2* 10 mL). The organic phase was washed with 5% brine (2><8 mL), dried over Na2SO4, filtered, and concentrated to yield the title compound. MS (ESI, pos. ion.) m/z: 312 (M+ 1). Step D: Synthesis of (i?)-N-(6-(hydroxymethyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)-3-(2V- 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 (i?)-(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 /Pr2EtN (0.56 mL, 3.2 mmol, Aldrich). The reaction was 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 Na2SO4, filtered, and concentrated. Purification with column chromatography over silica gel with hexane:EtOAc:MeOH (2M, NH3) (5:5:1) gave the title compound as a white powder. MS (ESI, pos. ion.) m/z: 471 (M+l). Step E: Synthesis of (R)-N-(6-formyl-l,2,3,4-tetrahydronaphthalen-l-yl)-3-(N-methyl-3- (trifluoromethyl)phenylsulfonamido)propanamide
To a 50-mL reaction tube containing (/?)-N-(6-(hydroxymethyl)-l, 2,3,4- tetrahydronaphthalen-l-yl)-3-(N-methyl-3-(trifluoromethyl)phenylsulfonamido)propanamide (0.12 g, 0.25 mmol, Step D) in CH2Cl2 (4 mL), was added MnO2 (0.17 g, 2.0 mmol, Aldrich). 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+l).
Step F: Synthesis of (/?)-N-(6-((4-fluoropiperidin-l-yl)methyl)-l,2,3,4-tetrahydronaphthalen- l-yl)-3-(N-methyl-3-(trifluoromethyl)phenylsulfonamido)propanamide.
To a 50-mL reaction tube containing (i?)-N-(6-formyl-l,2,3,4-tetrahydronaphthalen-l- 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), Et3N (66 DL, 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 K2CO3 (8 mL 5%), and the compound was extracted with EtOAc (2x 10 mL). The organic phase was washed with 5% brine (2*5 mL), dried over Na2SO4, filtered, and concentrated. Purification with column chromatography over silica gel with hexane:EtOAc:MeOH (2M, NH3) (10: 10: 1) gave the title compound as clear oil. MS (ESI, pos. ion.) m/z: 556 (M+l).
Example 12 Synthesis of (/?)-3-(N-cycloproρyl-3-(trifluoromethyl)phenylsulfonamido)-N-(6-(piperidin- 1 - ylmethyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)propanamide
Figure imgf000122_0001
Step A: Synthesis of N-cycloproρyl-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 (2x 15 mL). The combined organic phase was washed with 5% brine (2χ8 mL), dried over Na2SO4.
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-I).
Step B: Synthesis of før/-butyl 3-(N-cyclopropyl-3-(trifluoromethyl)phenyl- sulfonamido)propanoate. 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-haty\ acrylate
(6.9 mL, 47 mmol, Aldrich) and K2CO3 (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 (2x 10 mL), dried over Na2SO4, 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+l).
Step C: Synthesis of 3-(N-cyclopropyl-3-(trifluoromethyl)phenylsulfonamido)ρropanoic acid.
To a 50-mL round-bottomed flask containing
Figure imgf000122_0002
3-(N-cyclopropyl-3- (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+l). Step D; Synthesis of (/?)-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-(trifiuoromethyi)phenyl- sulfonamido)propanoic acid (0.13 g, 0.39 mmol, step C) in DMF (5 mL), was added (R)-6- (piperidin-l-ylmethyl)-l,2,3,4-tetrahydronaphthalen-l-amine (0.14 g), TBTU (0.30 g, 0.78 mmol, Advanced ChemTech), and /Pr2EtN (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 Na2SO4, filtered, and concentrated. Purification with column chromatography over silica gel with hexane: EtOAc: MeOH (2M, NH3) (5:5: 1) gave the title compound as a white solid. MS (ESI, pos. ion.) m/z: 564 (M+l).
Similarly, (i?)-3-(N-cyclohexyl-3-(trifluoromethyl)phenylsulfonamido)-N-(6-(piperidin- 1 - ylmethyl)-l,2,3,4-tetrahydronaphthalen-l-yl)propanamide; (/?)-3-(N-isopropyl-3- (trifluoromethyl)phenylsulfonamido)-N-(6-(piperidin- 1 -ylmethyl)- 1 ,2,3 ,4- tetrahydronaphthalen-l-yl)propanamide, (/?)-N-(6-((tert-butylamino)methyl)- 1,2,3,4- tetrahydronaphthalen-l-yl)-3-(N-cyclopropyl-3-(trifluoromethyl)phenylsulfonamido)- propanamide were synthesized.
Example 13 Synthesis of (i?)-3-(3-bromosaccharinyl-N-(6-(piperidin-l-ylmethyl)-l,2,3,4-tetrahydro- naphthalen- 1 -yl)propanamide
Figure imgf000123_0001
Step A: Synthesis of methyl 3-(3-bromo-saccharinyl)propanoate 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 washed with 5% brine (2x 10 mL), dried over Na2SO4, filtered, and concentrated. Purification with column chromatography over silica gel with hexane:EtOAc:MeOH (5:5:1) gave the title compound.
Step B: Synthesis of 3-(3-bromosaccharinyl)ρropanoic acid
To a 50-mL round-bottomed flask containing methyl 3-(3-bromo-saccharinyl) propanoate (0.61 g, 1.8 mmol, step A) in THF (6 mL), was added LiOH.H2O (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 Na2SO4, filtered, and concentrated to yield the title compound. Step C: Synthesis of (/?)-3-(3-bromo-saccharinyl-N-(6-(piperidin-l-ylmethyl)-l,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 (i?)-6-(piperidin-l-ylmethyl)- 1,2,3,4- tetrahydronaphthalen-1 -amine (80 mg, 0.33 mmol), TBTU (0.25 g, 0.66 mmol, Advanced ChemTech), and /Pr2EtN (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 Na2SO4, filtered, and concentrated. Purification with column chromatography over silica gel with hexane:EtOAc:MeOH (2M, NH3) (5:5:1) gave the title compound as a yellow solid. MS (ESI, pos. ion.) m/z: 561 (M+ 1).
Example 14
Synthesis of 4,4,4-trifluoro-3-(N-methyl-3-(trifluoromethyl)phenylsulfonamido)-N-((i?)-6- (piperidin- 1 -ylmethyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)butanamide
Figure imgf000124_0001
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. K2CO3 (4 mL). The reaction was stirred at RT for 1 h. The reaction mixture was acidified to pH 5 with 2Ν HCl and the compounα was extracted witn ntu/vc (2χ 10 mL). The combined organic phase was washed with 5% brine (2x8 mL), dried over Na2SO4. Purification with column chromatography over silica gel with hexane.EtOAc (3:1) gave the title compound. MS (ESI, pos. ion.) m/z: 394 (M+l). 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-H2O (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). The organic phase was washed with 5% brine (2χ4 mL), dried over Na2SO4, filtered, and concentrated to yield the title compound. MS (ESI, pos. ion.) m/z: 364 (M-I). Step C: Synthesis of 4,4,4-trifluoro-N-((/?)-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- 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 /Pr2EtN (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 (2χ8 mL), dried over Na2SO4, filtered, and concentrated. Purification with column chromatography over silica gel with hexane:EtOAc:MeOH (2M, NH3) (10: 10:1) gave the title compound. MS (ESI, pos. ion.) m/z: 525 (M+l).
Step D: Synthesis of 4,4,4-trifluoro-N-((JR)-6-formyl-l,2,3,4-tetrahydronaphthalen-l-yl)-3-(3- (trifluoromethyl)phenylsulfonamido)butanamide To a 50-mL reaction tube containing 4,4,4-trifluoro-N-((i?)-6-(hydroxymethyl)-l,2,3,4- tetrahydronaphthalen-l-yl)-3-(3-(trifluoromethyl)phenylsulfonamido)butanamide 1.5 g, 2.9 mmol, step C) in CH2Cl2 (25 mL), was added MnO2 (1.4 g, 16 mmol, Aldrich). The reaction was stirred at RT for 1O h, and filtration through Celite gave the title compound as a clear oil. MS (ESI, pos. ion.) m/z: 523 (M+l). Step E: Synthesis of 4,4,4-trifluoro-N-((Λ)-6-formyl-l,2,3,4-tetrahydronaphthalen-l-yl)-3-(N- methyl-3-(trifluoromethyl)phenylsulfonamido)butanamide
To a 100-mL round-bottomed flask containing 4,4,4-trifluoro-N-((R)-6-formyl- 1,2,3,4- tetrahydronaphthalen-l-yl)-3-(3-(trifluoromethyl)phenylsulfonamido)butanamide (0.35 g, 0.67 mmol, step D) in DMF (5 mL), was added MeI (0.13 mL, 2.0 mmol, Aldrich) and K2CO3 (0.17 g, z.υ mmoi, Aiαncnj. lne reaction mixture was stirred at RT for 1 h. The reaction was quenched with water (8 mL) and the compound was extracted with EtOAc (2χ 10 mL). The organic phase was washed with 5% brine (2χ 10 mL), dried over Na2SO4, filtered, and concentrated to yield the title compound. MS (ESI, pos. ion.) m/z: 535 (M-I). Step F: Synthesis of 4,4,4-trifluoro-3-(N-methyl-3-(trifluoromethyl)phenylsulfonamido)-N- ((i?)-6-(piperidin-l-ylmethyl)-l,2,3,4-tetrahydronaphthalen-l-yl)butanamide
To a 50-mL reaction tube containing 4,4,4-trifluoro-N-((/?)-6-formyl-l, 2,3,4- tetrahydronaphthalen-l-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, 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 K2CO3 (8 mL, 5%), and the compound was extracted with EtOAc (2x10 mL). The organic phase was washed with 5% brine (2χ5 mL), dried over Na2SO4, filtered, and concentrated. Purification with column chromatography over silica gel with hexane:EtOAc:MeOH (2M, NH3) (5:5: 1) gave the title compound as a white solid. MS (ESI, pos. ion.) m/z: 606 (M+ 1). Similarly,
(5}-3-(5-chloro-2-fluoro-N-methylphenylsulfonamido)-4,4,4-trifluoro-N-((/?)-6- (piperidin- 1 -ylmethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide;
(5)-3-(3-chloro-2-fluoro-N-methylphenylsulfonamido)-4,4,4-trifluoro-N-((/?)-6- (piperidin- 1 -ylmethyl)- 1,2,3 ,4-tetrahydronaphthalen- 1 -yl)butanamide;
(5)-3-(2,5-dichloro-N-methylphenylsulfonamido)-4,4,4-trifluoro-N-((i?)-6-(piperidin-l- ylmethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide;
(5}-3-(3,4-dichloro-N-methylphenylsulfonamido)-4,4,4-trifluoro-N-((/?)-6-(piperidin-l- ylmethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide; (-S}-3-(2,3-dichloro-N-methylphenylsulfonamido)-4,4,4-trifluoro-N-((i?)-6-(piperidin-l- ylmethyl)-l,2,3,4-tetrahydronaphthalen-l-yl)butanamide;
(5)-3-(2,5-dichloro-N-methylphenylsulfonamido)-4,4,4-trifluoro-N-((i?)-7-(piperidin-l- ylmethyl)chroman-4-yl)butanamide;
(5)-3-chloro-2-fluoro-N-methylphenylsulfonamido)-4,4,4-trifluoro-N-((Λ)-7-(piperidin- 1 -yhnethyl)chroman-4-yl)butanamide;
3-(2,3-dichloro-N-methylphenylsulfonamido)-2-methyl-N-((/?)-6-(piperidin-l- ylmethyl)-l,2,3,4-tetrahydronaphthalen-l-yl)propanamide; and
3-(2,3-dichloro-N-methylphenylsulfonamido)-2-hydroxy-N-((i?)-6-(piperidin-l- ylmethyl)-l,2,3,4-tetrahydronaphthalen-l-yl)propanamide were made. Example 15
Synthesis of 3-(2,6-dichlorophenylsulfonamido)-4,4,4-trifluoro-N-((i?)-6-(piperidin-l - ylmethyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)butanamide
Figure imgf000127_0001
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 /BOC2O (27 g, 120 mmol, Aldrich) and sat. K2CO3 (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 Na2SO4. Purification with column chromatography over silica gel with hexane:EtOAc (5:1) gave the title compound. MS (ESI, pos. ion.) m/z: 286 (M+l). Step B: Synthesis of 3-(tert-butoxycarbonyl)-4,4,4-trifluorobutanoic acid 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.H2O (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 Na2SO4, filtered, and concentrated to yield the title compound. MS (ESI, pos. ion.) m/z: 258 (M+l).
Step C: Synthesis of tert-butyl 1, 1,1 -trifluoro-4-oxo-4-((i?)-6-(piperidin-l -ylmethyl)- 1,2,3 ,4- tetrahydronaphthalen- 1 -ylamino)butan-2-ylcarbamate
To a 100-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 (i?)-6-(piperidin-l-ylmethyl)- 1,2,3,4-tetrahydronaphthalen-l-amine (0.65 g, 2.7 mmol), TBTU (1.4 g, 3.6 mmol, Advanced ChemTech), and /Pr2EtN (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 Na2SO4, filtered, and concentrated. Purification with column chromatography over silica gel " wlm%exan'eTEϊOΑc:Met)ΗT2Η, NH3) (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-((i?)-6-(piperidin-l-ylmethyl)-l,2,3,4- tetrahydronaphthalen- 1 -yl)butanamide bis-hydrochloride To a 50-mL reaction tube containing tert-butyl l,l,l-trifluoro-4-oxo-4-((i?)-6-
(piperidin-l-yhnethyl)-l,2,3,4-tetrahydronaphthalen-l-ylamino)butan-2-ylcarbamate (0.54 g,
1.1 mmol, step C), was added HCl (3.0 mL, 12 mmol, 4.0Ν 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+l). Step E: Synthesis of 3-(2,6-dichlorophenylsulfonamido)-4,4,4-trifluoro-N-((i?)-6-(piperidin-l- ylmethyl)-l,2,3,4-tetrahydronaphthalen-l-yl)butanamide
To a 50-mL round-bottomed flask containing 3-amino-4,4,4-trifluoro-N-((/?)-6-
(piperidin-l-yhnethyl)-l,2,3,4-tetrahydronaphthalen-l-yl)butanamide bis-hydrochloride 0.12 g,
0.26 mmol, step D), was added 2,6-dichlorobenzene sulfonylchloride (0.19 g, 0.78 mmol, Aldrich) and pyridine (3 mL, Aldrich). After the reaction was stirred at 50 0C 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 Na2SO4. Purification with column chromatography over silica gel with hexane:EtOAc:MeOH (2M, NH3) (5:5: 1) gave the title compound as a white solid. MS (ESI, pos. ion.) m/z: 592 (M+l). Similarly,
3-(2,3-dihydrobenzo[b][l,4]dioxine-6-sulfonamido)-4,4,4-trifluoro-N-((/?)-6-(piperidin-
1 -ylmethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide;
4,4,4-trifluoro-3-(3-methylphenylsulfonamido)-N-((if)-6-(piperidin-l-ylmethyl)-
1 ,2,3,4-tetrahydronaphthalen-l -yl)butanamide; and 3-(benzo[c][l,2,5]oxadiazole-4-sulfonamido)-4,4,4-trifluoro-N-((/?)-6-(piperidin-l- ylmethyl)-l,2,3,4-tetrahydronaphthalen-l-yl)butanamide were made.
Example 16
Synthesis of 3-(3-chloro-2-fluorophenylsulfonamido)-4,4,4-trifluoro-N-methyl-N-((Λ)-6- (piperidin- 1 -ylmethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide
Figure imgf000129_0001
Step A: Synthesis of (i?)-(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 60° C for 2 h then cooling to room temperature) was added 3.0 g of (i?)-(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. NaHCO3 and extracted with EtOAc. After the reaction was complete the reaction mixture was slowly quenched with sat. NaHCO3 until the solution was slightly basic and then extracted with EtOAc (2 x 100 mL), washed with brine (1 x 100 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 fϊlteration, 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 (2M, NH3) 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-((i?)-6-( hydroxymethyl)-l,2,3,4-tetrahydronaphthalen-l-yl)-N-methylbutanamide
In dry DCM (10 mL), 3-(3-chloro-2-fluorophenylsulfonamido)-4,4,4-trifluorobutanoic acid (0.5 mmol) and PyClU (l-(choro-l-pyrrolidinylmethylene)pyrrolidinium hexafluorophosphate) (0.5 mmol) were combined. (i?)-(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 by chromatography over silica gel with 20 to 60% EtOAc in hexane gave the title compound. MS (ESI, pos. ion) m/z: 523 (M+l). " Step C: Synthesis of 3-(3-chloro-2-fluorophenylsulfonamido)-4,4,4,-trifluoro-N-((/?)-6-formyl- l,2,3,4-tetrahydronaphthalen-l-yl)-N-methylbutanamide
Manganese dioxide (2.5 mmol) was added to a solution of 3-(3-chloro-2- fluorophenylsulfonamido)-4,4,4-trifluoro-N-((i?)-6-(hydroxymethyl)- 1 ,2,3 ,4- tetrahydronaphthalen-l-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+l).
Step D: Synthesis of 3-(3-chloro-2-fluorophenylsulfonamido)-4,4,4-trifluoro-N-methyl-N- ((i?)-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-((i?)-6-formyl-l,2,3,4-tetrahydronaphthalen-l-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 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, NH3) in DCM gave the title compound. MS (ESI, pos. ion) m/z: 590 (M+l). Similarly, (5)-3-(3-chlorophenylsulfonamido)-4,4,4-trifluoro-N-methyl-N-((R)-6-(piperidin-l- ylmethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide;
(5)-4,4,4-trifluoro-N-methyl-N-((Λ)-6-(piperidin- 1 -ylmethyl)- 1 ,2,3 ,4- tetrahydronaphthalen-l-yl)-3-(3-(trifluoromethyl)phenylsulfonamido)butanamide;
(2R,3S)-4,4,4-trifluoro-2-hydroxy-N-methyl-N-((/?)-6-(piperidin-l-yhnethyl)-l,2,3,4- tetrahydronaphthalen- 1 -yl)-3-(3-(trifluoromethyl)phenylsulfonamido)butanamide;
(5)-3-(5-chloro-2-fluorophenylsulfonamido)-4,4,4-trifluoro-N-methyl-N-((/?)-6- (piperidin- 1 -ylmethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide; and
(5)-3-(2,3-dichlorophenylsulfonamido)-4,4,4-trifluoro-N-methyl-N-((/?)-6-(piperidin-l- ylmethyl)-l,2,3,4-tetrahydronaphthalen-l-yl)butanamide were made.
Example 17
Synthesis of l-(3-chloro-2-fluorophenylsulfonyl)-4-((/?)-6-(piperidin-l-ylmethyl)-l,2,3,4- tetrahydronaphthalen- 1 -yl)-7(7?)-(trifluoromethyl)- 1 ,4-diazepan-5-one
Figure imgf000131_0001
Step A: Synthesis of (fl)-ethyl 3-(3-chloro-2-fluoro-N-(2-oxoethyl)phenylsulfonamido)-4,4,4- trifluorobutanoate: A solution of (i?)-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-butamA, 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 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 (MgSO4) and purified on silica gel using 25% ethyl acetate in hexane as eluant, affording (R)-ethyl 3-(3-chloro-2-fluoro-N-(2- oxoethyl)phenylsulfonamido)-4,4,4-trifluorobutanoate. MS: 420.2 (M+H)+.
Step B: Synthesis of (Λ)-ethyl 3-(3-chloro-2-fluoro-N-(2-((Λ)-6-(piperidin-l-ylmethyl)-l,2,3,4- tetrahydronaphthalen-l-ylamino)ethyl)phenylsulfonamido)-4,4,4-trifluorobutanoate
A solution of (β)-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- (piperidin-l-yhnethyl)-l,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 (MgSO4) and purified on silica gel using 5% methanol in dichloromethane as eluant, affording (R)-ethyl 3-(3-chloro-2-fluoro-N-(2-((Λ)-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 (i?)-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. A solution of (R)-ethyl 3-(3-chloro-2-fluoro-N-(2-((i?)-6-(piperidin-l-ylmethyl)- l,2,3,4-tetrahydronaphthalen-l-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 vacuo to afford (i?)-3-(3-chloro-2-fluoro-N-(2-((i?)-6-(piperidin-l-ylmethyl)-l,2,3,4- tetrahydronaphthalen-l-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-((i?)-6-(piperidin- 1 -ylmethyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)-7-(trifluoromethyl)- 1 ,4-diazepan-5-one (Λ)-3-(3-Chloro-2-fluoro-N-(2-((i?)-6-(piperidin-l-ylmethyl)-l,2,3,4-tetrahydro- naphthalen- 1 -ylamino)ethyl)phenylsulfonamido)-4,4,4-trifluorobutanoic acid dihydrochloride salt (210 mg, 0.30 mmol) in NN-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. 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 (MgSO4) and purified on silica gel using 5% methanol in dichloromethane as eluant, affording (i?)-l-(3-chloro-2- fluorophenylsulfonyi)-4-((7?)-6-(piperidin- 1 -ylmethyl)-l ,2,3,4-tetrahydronaphthalen- 1 -yl)-7- (trifluoromethyl)-l,4-diazepan-5-one. MS: 602.1 (M+H)+.
Example 18
Synthesis of (2Λ,3R)-4,4,4-trifluoro-2-methyl-N-((Λ)-6-(piperidin- 1 -ylmethyl)- 1 ,2,3 ,4-tetra¬ hydronaphthalen- 1 -yl)-3 -(3 -(trifluoromethyl)phenylsulfonamido)butanamide
Figure imgf000132_0001
Step A: Synthesis of (2R,3i?)-ethyl 4,4,4-trifluoro-2-methyl-3-(3-(trifluoromethyl)phenyl- sulfonamido)butanoate
A solution of (/?)-ethyl 4,4,4-trifluoro-3-(3-(trifluoromethyl)phenylsulfon- amido)butanoate (760 mg, 1.93 mmol) and lithium chloride (410 mg, 9.65 mmol, 5.0 equiv) in " THF (15 mL) wa's' cooled to -78 0C and treated with lithium bis(trimethylsilyl)amide (4.85 mL of a 1.0M solution in THF, 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 0C over 4 h. The reaction was quenched with 9: 1 THF:water (5 mL), warmed to room temperature, diluted with ethyl acetate (30 mL), washed with saturated ammonium chloride solution (25 mL) and brine (30 mL), dried (MgSO4) and purified on silica gel using 20% ethyl acetate in hexane as eluant, affording (2/?,37?)-ethyl 4,4,4-trifluoro-2-methyl-3-(3-(trifluoromethyl)phenylsulfonamido)- butanoate. MS: 408.2 (M+H)+. Step B: Synthesis of (2i?,3/?)-4,4,4-trifluoro-2-methyl-3-(3-(trifluoromethyl)phenyl- sulfonamido)butanoic acid
A solution of (2/?,3i?)-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 resin (till the pH was acidic). The resin was filtered and the filtrate was concentrated and azeotroped with toluene (3x10 mL) to remove excess water, affording (2i?,3i?)-4,4,4-trifluoro- 2-methyl-3-(3-(trifluoromethyl)phenylsulfonamido)butanoic acid. MS: 380.2 (M+H)+. Step C: (2/?,3i?)-4,4,4-trifluoro-2-methyl-N-((/?)-6-(piperidin-l-ylmethyl)-l,2,3,4- tetrahydronaphthalen-l-yl)-3-(3-(trifluoromethyl)phenylsulfonamido)butanamide. A solution of (2i?,3R)-4,4,4-trifluoro-2-methyl-3-(3-(trifluoromethyl)phenyl- sulfonamido)butanoic acid (275 mg, 0.72 mmol) inN,N-dimethylformamide (5 mL) was treated with (K)-6-(piperidin-l-ylmethyl)-l, 2,3, 4-tetrahydronaphthalen-l -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 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 (MgSO4). 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-((i?)-6-(piperidin-l-ylmethyl)-l,2,3,4- tetrahydronaphthalen-l-yl)-3-(3-(trifluoromethyl)phenylsulfonamido)butanamide. MS: 606.3 (M+H)+.
Example 19
Synthesis of N^^^^^-trifluoro-l-^^-oxo-l-^-ό-φiperidin-l-ylmethyl)-!^^^- tetrahydronaphthalen-l-yl)pyrrolidin-3-yl)ethyl)-3-(trifluoromethyl)benzene-sulfonamide
Figure imgf000134_0001
Step A: Synthesis of (7?)-ethyl 2<(/?)-2,2,2-trifluoro-l-(3-(trifluoromethyl)phenyl- sulfonamido)ethyl)pent-4-enoate
A solution of (7?)-ethyl 4,4,4-trifluoro-3-(3-(trifluoromethyl)phenylsulfonamido)- butanoate (3.26 g, 8.29 mmol) and lithium chloride (1.75 mg, 41.47 mmol, 5.0 equiv) in THF (40 mL) was cooled to -78 0C 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 0C over 7 h. The reaction was quenched with saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (75 mL). The organic layer was washed with brine (50 mL), dried (MgSO4) and purified on silica gel using 15% ethyl acetate in hexane as eluant, affording (i?)-ethyl 2-((/?)-2,2,2- trifluoro-l-(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 A solution of (Λ)-ethyl 2-((/?)-2,2,2-trifluoro-l -(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 ter/-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 (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 (MgSO4) and purified on silica gel using 25% ethyl acetate in hexane as eluant, affording (2Λ,3Λ)-ethyl 4,4,4-trifluoro-2-(2-oxoethyl)-3-(3-(trifluoromethyl)phenyl- sulfonamido)butanoate. MS: 434.2 (M-H)".
Step C: Synthesis of N-(CR)-2,2,2-trifluoro- 1 -((R)-2-oxo- 1 -((i?)-6-(piperidin- 1 -ylmethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)pyrrolidin-3-yl)ethyl)-3-(trifluoromethyl)benzene- sulfonamide A solution of (2i?,3/?)-ethyl 4,4,4-trifluoro-2-(2-oxoethyl)-3-(3-(trifluoromethyl)- phenylsulfon-amido)butanoate (333 mg, 0.76 πunol) in 1,2-dichloroethane (8 mL) was treated with (R)-6-(piperidin-l-ylmethyl)-l,2,3,4-tetrahydronaphthalen-l-amine (206 mg, 0.84 mmol, 1.11 equiv), sodium triacetoxyborohydride (324 mg, 1.53 mmol, 2.0 equiv) and catalytic glacial acetic acid (5 drops). The reaction was heated at 60 0C for 15 h, diluted with saturated sodium bicarbonate solution (10 mL) and extracted with dichloromethane (3x15 mL). The combined organic layers were washed with brine (20 mL) and dried (MgSO4). The crude mixture was purified on silica gel using 5% methanol in dichloromethane as eluant, affording N-((/?)-2,2,2-trifluoro-l-((/?)-2-oxo-l-((/?)-6-(piperidin-l-ylmethyl)-l,2,3,4- tetrahydronaphthalen-l-yl)pyrrolidin-3-yl)ethyl)-3-(trifluoromethyl)benzene-sulfonamide. MS: 618.3 (M+H)+.
Example 20
Synthesis of (i?)-4,4,4-trifluoro-3-(l,l-dioxo-7-methylbenzo[e][l,4,3]oxathiazin-2(3H)-yl)-Ν- ((Λ)-6-(piperidin-l -ylmethyl)-l ,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide
Figure imgf000135_0001
Step A: Synthesis of (/?)-4,4,4-trifluoro-3-(2-methoxy-5-methylρhenylsulfonamido)butanoic acid.
To a 150-mL round-bottomed flask containing 2-methoxy-5-methylbenzene-l-sulfonyl chloride (0.44 g, 2.0 mmol, Trans World Chemicals) was added (i?)-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.H2O (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 adding 2N HCl and the product was extracted with EtOAc, and the organic phase was separated and washed withn 5% brine, dried over Na2SO4. Filtration and evaporation in vacuo gave title compound (0.47 g, 69%). MS (ESI, pos. ion.) m/z: 342 (M+l).
Step B: Synthesis of (i?)-4,4,4-trifluoro-N-((R)-6-(hydroxymethyl)-l ,2,3,4-tetrahydro- naphthalen-l-yl)-3-(2-methoxy-5-methylphenylsulfonamido)butanamide. To a 5ϋ-mL round-bottomed tlask containing (/?)-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 /Pr2EtN (1.2 mL, 7.0 mmol, Aldrich). The reaction mixture was stirred at RT for 1O h and then the reaction mixture was quenched with 5% brine (5 mL) then acidified to 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 Na2SO4, filtered, and concentrated. The residue was taken in a solvent mixture of EtOAc:CH2Cl2: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).
Step C: Synthesis of (i?)-N-((K)-6-(bromomethyl)- 1,2,3, 4-tetrahydronaphthalen- l-yl)-4,4,4- trifluoro-3-(2-hydroxy-5-methylphenylsulfonamido)butanamide
To a 100-mL round-bottomed flask containing a suspension of (/?)-4,4,4-trifluoro-N- ((/?)-6-(hydroxymethyl)-l,2,3,4-tetrahydronaphthalen-l-yl)-3-(2-methoxy-5- methylphenylsulfonamido)butanamide [0.73 g, 1.5 mmol, Step (b)] in CH2Cl2 (20 mL), was added BBr3 (15 mL, 15 mmol, Aldrich) through a syringe at 00C under N2. The reaction mixture was then stirred at RT for 12 h. The reaction mixture was cooled to 0 0C with an ice bath, and the reaction was quenched slowly with ice water. The product was extracted with CH2Cl2 (2x8 mL). The organic phase was washed with 5% brine (2x 10 mL) and the product was precipitated. Filtration gave the title compound (0.68 g, 85%) as a white solid. MS (ESI, neg. ion.) m/z: 548 (M-I).
Step D: Synthesis of (/?)-4,4,4-trifluoro-3-(l,l-dioxo-7-methylbenzo[e][l,4,3]oxathiazin- 2(3H)-yl)-N-((i?)-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- (bromomethyl)-l,2,3,4-tetrahydronaphthalen-l-yl)-4,4,4-trifiuoro-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 HCl 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 added. The reaction mixture was stirred at RT for 1 h and then diluted with EtOAc (15 mL). The organic phase was washed with 5% brine (2x8 mL), dried over Na2SO4, filtered, and concentrated. Column chromatography over silica gel with hexane:EtOAc:MeOH (2M, NH3) (10:10: 1) gave the title compound (0.12 g, 32%). MS (ESI, pos. ion.) m/z: 566 (M+l). Example 21
Synthesis of (/?)-4,4,4-trifluoro-3-(l,l-dioxo-8-methyl-3,4-dihydrobenzo[b][l,4,5]- oxathiazepin-2-yl)- N-((/?)-6-(piperidin-l-ylmethyl)-l,2,3,4- tetrahydronaphthalen- 1 -yl)butanamide
Figure imgf000137_0001
Step A: Synthesis of (i?)-4,4,4-trifluoro-3-(2-methoxy-5-methylphenylsulfonaraido)butanoic acid.
To a 150-mL round-bottomed flask containing 2-methoxy-5-methylbenzene-l-sulfonyl chloride (0.44 g, 2.0 mmol, Trans World Chemicals) was added (i?)-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.H2O (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 adding 2 N HCl and the product was extracted with EtOAc, and the organic phase was separated and washed withn 5% brine, dried over Na2SO4. Filtration and evaporation in vacuo gave title compound (0.47 g, 69%). MS (ESI, pos. ion.) m/z: 342 (M+l). Step B: Synthesis of (7?)-4,4,4-trifluoro-N-((/?)-6-(hydroxymethyl)- 1,2,3,4- tetrahydronaphthalen-l-yl)-3-(2-methoxy-5-methylphenylsulfonamido)butanamide To a 50-mL round-bottomed flask containing (/?)-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 (/?)-(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 /Pr2EtN (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 pH-5 by adding 1 N HCl. The product was extracted with EtOAc (2^10 mL). The organic phase was washed with 5% brine (2x5 mL), dried over Na2SO4, filtered, and concentrated. The residue was taken in a solvent mixture Of EtOACiCH2Cl2)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+l). Step C: Synthesis ot (Λ)-N-((R)-6-(bromomethyl)-l,2,3,4-tetrahydronaphthalen-l-yl)-4,4,4- trifluoro-3-(2-hydroxy-5-methylphenylsulfonamido)butanamide
To a 100-mL round-bottomed flask containing a suspension of (/?)-4,4,4-trifluoro-N- ((i?)-6-(hydroxymethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)-3-(2-methoxy-5-methylphenyl- sulfonamido)butanamide [0.73 g, 1.5 mmol, Step (b)] in CH2Cl2 (20 mL), was added BBr3 (15 mL, 15 mmol, Aldrich) through a syringe at 0 0C under N2. The reaction mixture was then stirred at RT for 12 h. The reaction mixture was cooled to 00C with an ice bath, and the reaction was quenched slowly with ice water. The product was extracted with CH2Cl2 (2χ8 mL). The organic phase was washed with 5% brine (2x10 mL) and the product was precipitated. Filtration gave the title compound (0.68 g, 85%) as a white solid. MS (ESI, neg. ion.) m/z: 548 (M-I).
Step D: Synthesis of (R)-4,4,4-trifluoro-3-(l,l-dioxo-8-methyl-3,4-dihydrobenzo[b][l,4,5]- oxathiazepin-2-yl)- N-((i?)-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-((i?)-6-
(bromomethyl)-l,2,3,4-tetrahydronaphmalen-l-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 Cs2CO3 (0.83 g, 2.5 mmol, Aldrich). The reaction mixture was then stirred at 55 0C for 3 h. The reaction mixture was diluted with EtOAc (15 mL). The organic phase was washed with 5% brine (2x8 mL), dried over Na2SO4, 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 0C for 3 h then diluted with EtOAc (15 mL). The organic phase was washed with 5% brine (2x8 mL), dried over Na2SO4, filtered, and concentrated. Column chromatography over silica gel with EtOAc gave the title compound (0.16 g, 43%). MS (ESI, pos. ion.) m/z: 580 (M+l).
Example 22 Synthesis of (it)-4,4,4-trifluoro-N-((i?)-6-(piperidin-l -ylmethyl)-l ,2,3,4-tetrahydronaphthalen- l-yl)-3-(l,2,3,4-tetrahydroquinoline-8-sulfonamido)butanamide
Figure imgf000139_0001
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 (/?)-ethyl 3-amino-4,4,4-trifluorobutanoate (1.0 G, 5.5 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 EtOAc (15 mL), and the organic phase was separated and washed with 5% brine, dried over Na2SO4. 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 (φ-ethyl 4,4,4-trifluoro-3-(l,2,3,4-tetrahydroquinoline-8- sulfonamido)butanoate
To a 150-mL round-bottomed flask containing (ft)-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 N2. The reaction mixture was purged with H2 and then stirred at RT for 18 h under H2 (H2 balloon) atmosphere. 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+l).
Step C: Synthesis of (/?)-4,4,4-trifluoro-3-(l,2,3,4-tetrahydroquinoline-8-sulfonamido)- butanoic acid.
To a 50-mL round-bottomed flask containing (i?)-ethyl 4,4,4-trifluoro-3-(l,2,3,4- tetrahydroquinoline-8-sulfonamido)butanoate [3.3 g, 8.7 mmol, step (b)] in THF (8 mL), was added LiOH.H2O (1.4 g, 34 mmol, Aldrich) and water (8 mL). The reaction was stirred at 50 0C 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 Na2SO4, filtered, and concentrated to yield the title compound (2.8 g, 91%). MS (ESI, pos. ion.) m/z: 535 (M+l).
Step D: Synthesis of (Λ)-4,4,4-trifluoro-N-((i?)-6-(piperidin- 1 -ylmethyl)- 1 ,2,3 ,4- tetrahydronaphthalen-l-yl)-3-(l,2,3,4-tetrahydroquinoline-8-sulfonamido)butanamide.
To a 100-mL reaction tube containing /?)-4,4,4-trifluoro-3-(l,2,3,4-tetrahydroquinoline- 8-sulfonamido)butanoic acid [0.16 g, 0.45 mmol, step (c)] in DMF (5 mL), was added (R)-6- (piperidin-1 -ylmethyl)- 1,2,3,4-tetrahydronaphthalen-l -amine (0.65 g, 2.7 mmol), TBTU (0.34 g, 0.90 mmol, Advanced ChemTech), and /Pr2EtN (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 Na2SO4, filtered, and concentrated. Purification with column chromatography over silica gel with hexane:EtOAc:MeOH (2M, NH3) (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 (/?)-3-cyano-N-((i?)-6-(piperidin- 1 -ylmethyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)- 3-(3-(trifluoromethyl)phenylsulfonamido)propanarnide
Figure imgf000140_0001
Step A: Synthesis of (/?)-4-amino-4-oxo-3-(3-(trifluoromethyl)phenylsulfonamido)butanoic acid 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-NH2 (2.0 g, 15 mmol, Chemlmpex) and 5% K2CO3 (15 mL). The reaction mixture was stirred at RT for 5 h. The reaction mixture was acidified to pH-5 by adding 2 N HCl, and the product was extracted with EtOAc (25 mL). The organic phase was separated and washed with 5% brine, dried over Na2SO4. Filtration and evaporation in vacuo gave title compound (3.8 g, 74%). MS (ESI, pos. ion.) m/z: 341 (M+l).
Step B: Synthesis of (^-S-cyano-N-^-ό-φiperidin-l-ylmethyO-l^^^-tetrahydro- naphthalen-l-yl)-3-(3-(trifluoromethyl)phenylsulfonamido)propanamide.
To a 100-mL round-bottomed flask containing (/?)-4-amino-4-oxo-3-(3- (trifluoromethyl)phenylsulfonamido)butanoic acid [3.8 g, 11 mmol, step (a)] in DMF (8 mL), was added (i?)-6-(piperidin-l-yhnethyl)-l,2,3,4-tetrahydronaphthalen-l-amine dihydrochloride (3.9 g, 12 mmol), TBTU (3.6 g, 11 mmol, Advanced ChemTech), and JPr2EtN (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 washed with 5% brine (2x 10 mL), dried over Na2SO4, filtered, and concentrated. Purification with column chromatography over silica gel with hexane:EtOAc:MeOH (2M, NH3) (10:10: 1) gave the title compound (3.3 g, 54%). MS (ESI, pos. ion.) m/z: 549 (M+l).
Example 24 Synthesis of (/?)-N-((1S)-6-(4,5-dihydro-lH-imidazol-2-yl)-l,2,3,4-tetrahydro-naphthalen-2-yl)- 4,4,4-trifluoro-3-(3-(trifluoromethyl)phenylsulfonamido)butanamide
Figure imgf000141_0001
Step A: Synthesis of (S)-N-(6-bromo-l,2,3,4-tetrahydronaphthalen-2-yl)-2,2,2-trifluoro- acetamide
To a solution of (5)-6-bromo-l,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 Na2SO4 and filtered through silica gel pad with DCM to give the title compound (3.24 g, 100%) as a white solid.
Step B: Synthesis of (£)-N-(6-cyano-l ,2,3,4-tetrahydronaphthalen-2-yl)-2,2,2- trifluoroacetamide
A mixture of (5)-N-(6-bromo-l,2,3,4-tetrahydronaphthalen-2-yl)-2,2,2- trifluoroacetamide (0.969 g, 3 mmol), ΝiBr2 (655 mg, 3 mmol) and NaCN (294 mg, 6 mmol) in 3 mL of NMP was heated at 200 0C 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 (SiO2, 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 (iS)-6-amino-5,6,7,8-tetrahydronaphthalene-2-carbonitrile To a solution of (5)-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/H2O = 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 (SiO2, EtOAc to EtOAc/2 M NH3 in MeOH = 100: 10 to 100:20 to 100:30) to give the title compound (320 mg) as a white solid. Step D: Synthesis of (i?)-N-((5)-6-cyano- 1 ,2,3,4-tetrahydronaphthalen-2-yl)-4,4,4-trifluoro-3- (3-(trifluoromethyl)phenylsulfonamido)butanamide
A solution of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (70 mg, 0.364 mmol), 1-hydroxybenzotriazole (49 mg, 0.364 mmol), (i?)-4,4,4-trifluoro-3-(3- (trifluoromethyl)phenylsulfonamido)butanoic acid (132.5 mg, 0.363 mmol) and (5)-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. NaHCO3, extracted with EtOAc/hexane = 3: 1, washed with brine, dried over Na2SO4, and evaporated. Column chromatography (SiO2, EtOAc/hexane = 1 :2 to 2:3 to 1: 1) gave the title compound (120 mg) as a white solid.
Step E: Synthesis of (Λ)-N-((5)-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-((5)-6-cyano-l,2,3,4-tetrahydronaphthalen-2-yl)-4,4,4-trifluoro-3-(3- (trifluoromethyl)phenylsulfonamido)butanamide (90 mg) was azeotroped with benzene and was dissolved in 10 mL of anhydrous EtOH. To this solution dry HCl was bubbled through for 90 min at 0 0C. 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 (SiO2, EtOAc/2M NH3 in MeOH = 100:15 to 100:30) afforded the title compound (100 mg) as a white solid.
Example 25 Synthesis of
Figure imgf000142_0001
trifluoro-3-[ 1 , 1 -dioxo-8-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[fJ[ 1 ,2]thiazepin- 1 -yl]- butanamide
Figure imgf000142_0002
Step A: Synthesis of (Λ)-ethyl 3-(2-bromo-5-(trifluoromethyl)phenylsulfonamido)-4,4,4- trifluorobutanoate iu a sυiuuon oi iΛ;-eιnyi j-amino-4,4,4-trifluorobutanoate (3.25 g, 13 mol) in pyridine (2 mL) was added 2-bromo-5-(trifluoromethyl)benzene-l-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 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 (/?)-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-l-ynyl)-5-(trifluoromethyl)- phenylsulfonamido)butanoate
To a solution of (Λ)-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(O) (20 mg), and propargyl alcohol (0.1 mL). The reaction mixture was heated in microwave at 80 0C for 90 min. The reaction mixture was cooled to room temperature and then filtered through celite. The crude product was purified by silica gel chromatograph to give (Λ)-ethyl 4,4,4-trifluoro-3-(2-(3-hydroxyprop-l-ynyl)-5- (trifluoromethyl)phenylsulfonamido)butanoate (50 mg) as oil product. LC-MS: m/z 465.0
(M+H20)+.
Step C: Synthesis of (R)-ethy\ 4,4,4-trifluoro-3-(2-(3-hydroxyproρyl)-5-(trifluoromethyl)- phenylsulfonamido)butanoate
To a solution of (-ft)-ethyl 4,4,4-trifluoro-3-(2-(3-hydroxyprop-l-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)- 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 (Λ)-ethyl-4,4,4-trifluoro-3-[ 1 , 1 -dioxo-8-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[fj[ 1 ,2]thiazepin- 1 -yl]butanoate
To a solution of (Λ)-ethyl 4,4,4-trifluoro-3-(2-(3-hydroxypropyl)-5-(trifluoromethyl)- 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 Dy silica gel preparation llΛJ piate ΪO give (/?)-ethyl-4,4,4-trifluoro-3-[l,l-dioxo-8- (trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][l,2]thiazepin-l-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-[l,l-dioxo-8-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[f][l,2]thiazeρin-l-yl]butanoic acid
To a solution (Λ)-ethyl-4,4,4-trifluoro-3-[l,l-dioxo-8-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[fj[l,2]thiazepin-l-yl]butanoate (80 mg, 185 μmol) in dioxane (2 mL), and water (2 mL) was added hydrochloride solution (1 mL, 10%). The reaction mixture was heated in 80 0C oil bath for Ih. The reaction mixture was cooled to room temperature, diluted with ethylacetate (10 ml), and then extracted with Na2CO3 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 Na2 SO4 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 (Λ)-(N)-((R)-6-(piperidin-l-yhnethyl)- 1,2,3 ,4-tetrahydronaphthalen-l-yl)- 4,4,4-trifluoro-3-[ 1 , 1 -dioxo-8-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][ 1 ,2]thiazepin- 1 - yl]butanamide
To a solution of (i?)-4,4,4-trifluoro-3-[l,l-dioxo-8-(trifluoromethyl)-2,3,4,5- tetrahydrobenzo[fj[l,2]thiazepin-l-yl]butanoic acid (12 mg) in DMF (2mL) was added TBTU (80 mg), (Λ)-6-(piperidin-l-ylmethyl)-l, 2,3, 4-tetrahydronaphthalen-l -amine (15 mg) and 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 Na2CO3 solution (10%, 10 mLx2). The organic layer was dried with Na2Sθ4 and concentrated on vacuum. The residue was purified by prep-TLC using 5% MeOH (NH3)-CH2C12 to give the title compound (12 mg, yield 63%). LC-MS: m/z 632.2 (M+H)+
Example 26 Synthesis of (i?)-4,4,4-trifluoro-N-methyl-N-((/?)-7-(piperidin- 1 -ylmethyl)chroman-4-yl)-
3-(3-(trifluoromethyl)phenylsulfonamido)butanarnide
Figure imgf000145_0001
Step A: Synthesis of (R)-tert-butyl 7-(hydroxymethyl)chroman-4-ylcarbamate
To (i?)-(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 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 (7?)-4-aminochroman-7-carbaldehyde. In DCM (200 mL), (K)-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. Step C: Synthesis of (i?)-tert-butyl 7-(piperidin-l-ylmethyl)chroman-4-ylcarbamate
In 1,2-dichloroethane (100 mL), ((/?)-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 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 (i?)-7-(piperidin-l-ylmethyl)chroman-4-amine
In dry toluene (200 mL), (/?)-tert-butyl 7-(piperidin-l-ylmethyl)chroman-4-ylcarbamate (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 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 Step E: Synthesis of (i?)-4,4,4-trifluoro-N-methyl-N-((Λ)-7-(piperidin-l-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. (i?)-7-(piperidin-l- 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 (ESI, pos. ion) m/z 608.2
Example 27 Synthesis of (/?)-3-(3-chloro-2-fluoro-N-methylphenylsulfonamido)-4,4,4-trifluoro-N- methyl-N-((i?)-7-(piperidin- 1 -yhnethyl)chroman-4-yl)butanamide
Figure imgf000146_0001
Step A: Synthesis of (Λ)-tert-butyl 7-(hydroxymethyl)chroman-4-ylcarbamate
To (i?)-(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 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). Step B: Synthesis of (R)-4-aminochroman-7-carbaldehyde
In DCM (200 mL), (-ft)-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). Step C: Synthesis of (7?)-tert-butyl 7-(piperidin-l-ylmethyl)chroman-4-ylcarbamate
In 1,2-dichloroethane (100 mL), ((/?)-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 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 (i?)-7-(piperidin-l-ylmethyl)chroman-4-amine
In dry toluene (200 mL), (/?)-tert-butyl 7-(piperidin-l-ylmethyl)chroman-4-ylcarbamate (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). MS (ESI, pos. ion) m/z 261.7
Step E: Synthesis of (/?)-3-(3-chloro-2-fluoro-N-methylphenylsulfonamido)-4,4,4-trifluoro-N- methyl-N-((i?)-7-(piperidin- 1 -ylmethyl)chroman-4-yl)butanamide
In dry DMF (2 mL), (Λ)-3-(3-chloro-2-fluoro-N-methylphenylsulfonamido)-4,4,4- trifluorobutanoic acid (0.5 mmol) and PyClU (0.6 mmol) were combined. (i?)-7-(Piperidin-l- 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 (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 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 ICso's of Bl at doses less than 20 μM. Human Bradykinin Bl Receptor and human B2 Receptor In Vitro Binding Assays
Example 1
Radioligand Binding Assay for human Bl and human B2 bradykinin receptor Step 1 Preparation of membranes expressing human Bl bradykinin receptor:
Membranes were prepared from CHO-d'AQN cells stably transfected with human bradykinin Bl receptor cDNA. For large-scale production of membranes, cells were grown in IOOL suspension culture to 1.0E8 cells/mL then harvested using the Viafuge at continuous centrifugation of 100Qg. For pilot studies, cells were grown in 2 L spinner culture and harvested by centrifugation (1900 g, 10 min, 4 °C). The cell pellet was washed with PBS, centrifuged (1900 g, 10 min, 4 0C), then the cells resuspended in lysis buffer (25 mM HEPES, pH 7.4, 5 mM EDTA, 5 mM EGTA, 3 mM MgCl2, 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 (190Og, 10 min, 4 0C), and the crude particulate fraction isolated by centrifugation (142,00Og, 1 h, 4 0C) 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 MgCl2, 10% (w/v) sucrose and Complete Protease Inhibitor tablets (EDTA-free)). Single-use aliquots were made and flash-frozen in liquid N2 prior to storage at -80 0C.
Membranes containing human bradykinin B2 receptor were purchased from Receptor Biology (now Perkin Elmer Life Sciences). They were derived from a CHO-Kl 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 using the method described for human Bl receptor membranes, except cells were grown in roller bottles and harvested using Cellmate.
Step 2 Human Bl receptor binding assay was performed in 96-well polypropylene plates (Costar 3365) by adding 50 μl [3H] des-arg10 kallidin (NET1064; Perkin Elmer Life Sciences) to 10 μL test compound diluted in 90 μL assay buffer (24 mM TES, pH 6.8, 1 mM I5IO o- phenanthroline, 0.3% BSA, 0.5 mM Pefabloc SC, 2 μg/mL aprotinin, 5 μg/mL leupeptin, and 0.7 μg/mL pepstatin A). Membranes (50 μL) were added last. [3H] des-arg10 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 μM des-Arg10Leu9 kallidin. Membranes were diluted in assay buffer to yield a final concentration of 0.068 nM hBl receptor in the assay. Compounds were solubilized in either DMSO or ddH20, 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 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 μL ice-cold buffer (5OmM Tris, pH 7.4), dried in a vacuum oven at 55 0C for 15-20 min, backed, and 40 μL per well of Microscint 20 was added. 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: [3H] bradykinin (NET706; Perkin Elmer Life Sciences) was used at a final concentration of ~0.2 nM and non-specific binding was defined with 2 μM bradykinin. Human B2 receptor concentration was 0.068 nM final in the assay. Data analysis
Data was analyzed inΛZFit with the four-parameter logistic y = A + ((B- A)/(l+((C/x)ΛD))) 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- compound cpm - nonspecific cpm)* 100)). K1 values were determined from the IC50 using the Cheng-Prusoff equation and Kd values determined by direct saturation binding of the radioligands.
Example 2
In vitro Bl -Inhibition Activity In vitro Assay of human Bl Receptor Function using Calcium Flux
Activation of the Gq linked Bl receptor results in an increase in intracellular calcium. The calcium sensitive photoprotein aequorin can, therefore, be used as an indicator of Bl 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 this complex, an oxidation reaction of coelenterazine results in the production of apoaequorin, coelenteramide, CO2, and light that can be detected by conventional luminometry.
A stable CHO D-/hBl /Aequorin cell line was established and the cells were maintained in suspension in spinner bottles containing a 1 : 1 ratio of DMEM and HAM F 12 (Gibco 11765- 047), high glucose (Gibco 11965-084), 10% Heat Inactivated Dialyzed serum (Gibco 26300- υt>l), lλ Mon-bssential Amino Acids (Gibco 11140-050), IX Glutamine-Pen-Strep (Gibco 10378-016), and Hygromycin, 300 μg/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). Media was removed from the wells and replaced with 60 μL of serum free HAM's Fl 2 with 30 mM HEPES (pH 7.5) and 15μM coelenterazine (Coelenterazine h Luciferin #90608 from Assay Designs). The plates were incubated for 1.5-2 h. Ten point IC50 compound plates containing 1:3 or 1:5 dilutions of antagonist compounds and an agonist activator plate (2OnM des-ArglO-Kallidin final concentration, EC8o) were prepared using Ham's Fl 2 with 3OmM 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 hBl agonist, des-Argio-Kallidin, was added to the cell plate and another 12 images were recorded to determine the IC50 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-Kl) purchased from PerkinElmer (Catalog Number: RBHB2C000EA) on a fluorometric imaging plate reader (FLIPR). The cells were cultured in T225 flask containing Ham's Fl 2 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 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 0C, 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 0C CO2 incubator overnight.
The media was aspirated from the cells and replaced with 65 μL 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 lμM in Clear Dulbecco's Modified Eagle Medium (DMEM) containing 0.1% BSA, 20 mM HEPES, 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 μL was left in each well, and the plate was ready to be assayed in the FLIPR System. Single point (10 μM final concentration) POC antagonist compound plates or ten point IC50 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, EC8o) were prepared using assay buffer. The cell plate and the 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 μL from the Bl antagonist plate was rapidly (50 μL/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 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 μM (POC plates) or the IC50 of the antagonist.
Example 3 Cell and Tissue based In Vitro Assays of hBl Receptor Binding These studies established the antagonist activity of several compounds at the bradykinin Bl receptors in in vitro cell-based and isolated organ assays.
1. Rabbit endothelial cell B 1 -specific PGI2 secretion Assay
2. Bl and B2 umblical vein Assay In vitro Bl -Inhibition Activity: 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: Dorsal root ganglia are dissected one by one under aseptic conditions from all spinal segments of embryonic 19-day old (E 19) 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 vessels are removed. The DRG are πnsed twice in Ca2+- and Mg2+-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 • Balanced Salt Solution (EBSS) at 37 0C 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 1 mg/mL ovomucoid inhibitor, 1 mg/mL ovalbumin and 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-μM 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 μg/mL (Sigma, St. Louis, MO) and mouse laminin 1 μg/mL (GibcoBRL)-coated 96-well plates at 10 x 103 cells/well in complete medium. The complete medium consists of minimal essential medium (MEM) and Ham's F12, 1: 1, penicillin (100 U/mL), streptomycin (100 μg/mL), and 10% heat inactivated horse serum (GibcoBRL). The cultures are kept at 37 0C, 5% CO2 and 100% humidity. For controlling the growth of non-neuronal cells, 5-fluoro- 2'-deoxyuridine (75μM) and undine (180μM) are included in the medium. Two hours after plating, cells are treated with recombinant human β-bl or recombinant rat β-bl at a concentration of 10 mg/ml (0.38 nm). Positive controls comprising serial-diluted anti-bl 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 around 40 h prior to measurement of vr 1 expression. Measurement of VRl 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 once with TBS containing 0.1% Tween 20 (Sigma) and incubated with rabbit anti-VRl 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 πuorometer
Figure imgf000153_0001
VΛI expression in samples treated with the compounds is determined by comparing to a standard curve of Bl titration from 0-1000 ng/mL. Percent inhibition (compared to maximum possible inhibition) of Bl effect on VRl expression in DRG neurons is determined by comparing to controls that are not B 1 -treated.
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 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 (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 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 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. 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 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 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 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.
Example 5 Green Monkey LPS Inflammation Model
The effectiveness of the compounds as inhibitors of Bl activity are evaluated in Male green monkeys (Cercopithaecus aethiops StKitts) challenged locally with Bl agonists 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 Bl 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). 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 mgketamine kg'1) and pretreated with a single intravenous injection of LPS (90 μg kg'1) or saline (1 mL) via the saphenous vein. Inflammation studies 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"1 30 min before assay). A single subcutaneous injection of dKD, BK or the vehicle (2 mM amastatin in 100 μL 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 between the skinfold 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: 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 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 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 EC50 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 Mest with Bonferroni correction. P <0.05 was 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. 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 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.

Claims

WHAT IS CLAIMED IS: 1. A compound of of Formula (I):
Figure imgf000156_0001
(I) wherein:
R1 is selected from H, cyano, -C(O)OC i-8alkyl, -C(O)OH, -C(=O)NRaRa, or -Ci-8alkyl substituted by 0, 1, 2, or 3 groups independently selected from Rg, cyano, oxo, nitro, -C(=O)Rb, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Ra, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=O)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORa, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2.6alkyl0Ra, and additionally substituted by 0, 1, 2, 3, 4, 5 or 6 atoms independently selected from Br, Cl, F and I;
Rla and Rlb are each independently, H, F, Cl, -OCH3, -Ci.2alkyl or -CF3; Rlc is H, -Ci-8alkyl,
Figure imgf000156_0002
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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa, -NRaC2-6alkylORa, or -C,.6alkyl substituted by 0, 1, 2 or 3 substituents selected from
Figure imgf000156_0003
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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(Ra)C(=O)NRaRa, -NRaR\ -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa or -NRaC2-6alkylORa;
R2 is 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, O 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 Re, Rg, CMhaloalkyl, 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)2R°, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkylORa, 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 -Ci-βalkyl, the phenyl, benzyl and -Ci-βalkyl being substituted by 0, 1, 2 or 3 substituents independently selected from Re, Rg,
Figure imgf000157_0001
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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and ' -NRaC2-6alkylORa, and 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 -
Figure imgf000157_0002
C^aHcyl, the phenyl, benzyl and being substituted by 0, 1, 2 or 3 substituents independently selected from C
Figure imgf000157_0003
i^alkyl, Ci-3haloalkyl, -NH2, -NHCMalkyl, and -NCCMalkyOd^alkyl, and additionally substituted by 0, 1, 2, 3, 4, 5 or 6 atom selected from Br, Cl, F and I; 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, O 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 R6, R7 and R8 which are selected from Rg, -Ci-8alkyl, -CMhaloalkyl, 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)2R\ -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkylORa, and the ring is additionally substituted by 0, 1, 2, 3, 4 or 5 substituents selected from R6, R7, R8, R9 and R10 which are independently selected from Br, Cl, F and I; wherein, R3 and R4 together may additionally be C2-3alkylene substituted by 0, 1 or 2 substituents independently selected from -Chalky!,
Figure imgf000157_0004
halo, oxo, 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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaR8, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkyl0Ra, and 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 C2-4alkylene substituted by 0, 1 or 2 substituents selected from -Ci-8alkyl, -C^haloalkyl, halo, oxo, 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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkyl0Ra, and 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^alkylene substituted by 0, 1 or 2 substituents selected from -Ci-8alkyl, - CMhaloalkyl, halo, oxo, 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)2Rb, -OC2-6alkylNRaRa,
-OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2^alkylNRaRa and -NRaC2-6alkyl0Ra, 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 Rb;
Rb is independently, at each instance, phenyl, benzyl or
Figure imgf000158_0001
the phenyl, benzyl and being substituted by 0, 1, 2 or 3 substituents selected from halo,
Figure imgf000158_0002
- CI-3haloalkyl, -OCMalkyl, -NH2, -NHC^alkyl, -N(CMalkyl)CMalkyl; Rd is independently at each instance -Ci-8alkyl, -Ci-4haloalkyl, 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)2Rb, -OC2-6alkylNRaRa, -OC«alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa or -NRaC2-6alkyl0Ra;
Re is independently at each instance substituted by 0, 1, 2 or 3 substituents independently selected from Rd and additionally substituted by 0 or 1 substituents selected from R8; and
R8 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, O 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,
Figure imgf000159_0001
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)2Rb, -OC2-6alkylNRaRa, -OC2^alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkyl0Ra, 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: R1 is selected from H or -Ci-8alkyl substituted by 0, 1, 2, or 3 groups independently selected from R8, cyano, oxo, nitro, -C(=O)Rb, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -ORa, -OC(=O)Ra, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=O)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORa, -S(=O)2N(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)2Rb,
-N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkyl0Ra, and additionally substituted by 0, 1, 2, 3, 4, 5 or 6 atoms selected from Br, Cl, F and I;
Rla and Rlb are each independently, H, F, Cl, -OCH3, -C]-2alkyl or -CF3; Rlc is H, -Ci-8alkyl, -Ci^aloalkyl, halo, cyano, nitro, -C(=O)Rb, -C(=O)ORb, -C(=O)NRaRa, -C(=NRa)NRaRa, -OR8, -OC(=O)Rb, -OC(=O)NRaRa, -OC(=O)N(Ra)S(=O)2Rb, -OC2.6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2.6alkylNRaRa, -NRaC2-6alkylORa, or -C1-6alkyl substituted by 0, 1, 2 or 3 substituents selected from
Figure imgf000160_0001
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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa or -NRaC2-6alkylORa;
R2 is 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, 2, 3 or 4 atoms selected from N, O 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, Rs,
Figure imgf000160_0002
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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkyl0Ra, 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
Figure imgf000160_0003
being substituted by 0, 1, 2 or 3 substituents selected from Re, Rg,
Figure imgf000160_0004
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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkyl0Ra, and 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 -Ci.6alkyl, the phenyl, benzyl and -Ci-6alkyl being substituted by 0, 1, 2 or 3 substituents selected from
Figure imgf000160_0005
-NH2, -NHCMalkyl, and -NCC^alkyOCMalkyl, and additionally substituted by 0, 1, 2, 3, 4, 5 or 6 atom selected from Br, Cl, F and I; R5 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, O 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 Re, -Ci.8alkyl,
Figure imgf000160_0006
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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=0)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkylORa, and the ring is additionally substituted by 0, 1, 2, 3, 4 or 5 substituents independently selected from Br, Cl, F and I; wherein, R3 and R4 together may additionally be C2-3alkylene substituted by 0, 1 or 2 substituents selected from -Ci-salkyl,
Figure imgf000161_0001
halo, oxo, 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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkyl0Ra, and 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 C2-4alkylene substituted by 0, 1 or 2 substituents selected from -Ci.galkyl, -CMhaloalkyl, halo, oxo, 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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkyl0Ra, and 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-R bond together with R may additionally be C^alkylene substituted by 0, 1 or 2 substituents selected from Ci^alkyl, CMhaloalkyl, halo, oxo, 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)2Rb, -OC2-6alkylNRaRa, -OC2.6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(K))2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2.6alkyl0Ra, 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 RD;
Rb is independently, at each instance, phenyl, benzyl or -Cj-βalkyl, the phenyl, benzyl and
Figure imgf000162_0001
C^alkyl, Ci-3haloalkyl, -OCMalkyl, -NH2, -NHCMalkyl, -N(CMalkyl)CMalkyl; Rd is independently at each instance -Ci-8alkyl,
Figure imgf000162_0002
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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2.6alkylNRaRa or -NRaC2-6alkyl0Ra;
Re is independently at each instance -Ci-salkyl substituted by 0, 1, 2 or 3 substituents independently selected from Rd and additionally substituted by 0 or 1 substituents selected from Rg; and
Rs is independently at each instance 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, O 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-8alkyl, -C^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(=O)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa,
-S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkylORa, and the ring is additionally substituted by 0, 1, 2, 3, 4 or 5 substituents independently selected from Br, Cl, F and I.
3. The compound of Claim 1 or 2 wherein the basic moieties are independently selected from from amino, cycloalkylamino-(Ci-C6)alkyl, cycloalkyl(Ci-C6)alkylamino(Ci-C6)alkyl, heterocyclylamino(Ci-C6)alkyl, heterocyclyl(Ci-C6)alkylamino(Ci-C6)alkyl, arylamino(C i -C6)alkyl, aryl(C i -C6)alkylamino-(C i -C6)alkyl, (C i -C6)alkylamino(C i -C6)alkoxy, (Ci-C6)alkylamino(C|-C6)alkoxy(Ci-C6)-alkoxy, amino(Ci-C6)alkoxy, amino(Ci-C6)alkyl, (Ci-C6)alkylamino(Ci-C6)alkyl, (Ci-C4)alkylamino-(C2-C6)alkenyl, 4-8-membered nitrogen- containing heterocyclyl(C2-C6)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 from halo, -NH2, -OH, -CN, -CF3, (CrC6)alkylamino, haloalkyl, oxo, (d-C6)alkoxy, (CrC6)alkoxyalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, di(C1-C6)alkylamino, =NCN; and (Ci-C6)alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl, each of which is substituted by 0, 1, 2 or 3 groups independently selected from halo, -NH2, -OH, -CN, -CF3, (CpCόJalkylamino, haloalkyl, oxo, (CrC6)alkoxy, (Ci-C6)alkoxyalkyl, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, or di(Ci-C6)alkylamino.
4. The compound of Claim 3 wherein the basic moieties are independently selected from amino, aminomethyl, isopropylaminomethyl, f-butylaminomethyl, 2-^-butylaminoethyl, 2-tert- butylamino-1 -methyl-ethyl, 1-tert-butylaminoethyl, l-(tert-butylamino-methyl)-vinyl, 1- (piperidin-l-yhnethyl)-vinyl, N-isobutyl-aminomethyl, N-isobutyl-aminoethyl, (2,2- dimethyl)propylaminomethyl, N-isopropyl-N-ethylaminomethyl, N-isopropyl-N- methylaminomethyl, N-/-butyl-N-methylaminomethyl, N-MO-butyl-N-methylaminomethyl, N- /-butyl-N-ethylaminomethyl, N-isobutyl-N-methylaminomethyl, N-f-butyl-N- isopropylaminomethyl, N,N-di(isopropyl)aminomethyl, N,N-dimethylaminomethyl, N,N- diethylaminomethyl, N,N-di(Y-butyl)-aminomethyl, cyclopropylaminomethyl, cyclopropylaminoethyl, cyclopropyhnethylaminomethyl, cyclopropylmethylaminoethyl, cyclobutylaminomethyl, cyclobutylaminoethyl, cyclobutylmethylaminomethyl, cyclobutylmethylaminoethyl, 4,5-dihydro-imidazolyl, 1-piperidinylmethyl, 4-fluoropiperidin- 1-ylmethyl, 4,4-difluoropiperidin-l-yhnethyl, 3-hydroxypiperidin-l-ylmethyl, 4- hydroxypiperidin-1-ylmethyl, 4-(dimethylamino)piperidin-l-ylmethyl, 2,6-dimethylpiperidin- 1-ylmethyl, 4-morpholinylmethyl, 1-pyrrolidinylmethyl, 2-methylpyrrolidin-l-ylmethyl, 2,5- dimethylpyrrolidin-1-ylmethyl, piperazin-1-ylmethyl, azocan-1-ylmethyl, azepan-1-ylmethyl, (7-azabicyclo[2.2.1]hept-7-yl)methyl, (l^^-trimethyl-o-azaicyclofS^.lJoct-o-yOmethyl, 2- piperidinyl or 4-methylpiperazin-l-ylmethyl. 5. The compound of any of the Claims 1-4 wherein R1 is -Ci-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 R1 is trifluoromethyl and Rla, Rlb, Rlc and R3 are hydrogen.
7. The compound of any of the Claims 3-6 wherein: R4 is hydrogen and R2 is phenyl or napthyl, both of which are substituted by 1, 2 or 3 substituents selected from Re, R8, -CMhaloalkyl, 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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)R°, -N(Ra)C(=O)ORD, -N(Rd)C(=O)NR"Rα, -N(Rd)C(=NRd)NR''RΛ, -N(Ra)S(=O)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2.6alkyl0Ra, and additionally substituted by 0, 1, 2, 3, 4 or 5 substituents independently selected from Br, Cl, F and I.
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, O 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, Rg, -CMhaloalkyl, 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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkyl0Ra, and the 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- trifluoromethoxyphenyl, 3-methylphenyl, 4-chloro-2-fluorophenyl, 2-chloro-4-fluorophenyl, naphthalene-2-yl, 3-ter/-butylphenyl, 4-ter£-butylphenyl, [1.3]-oxazol-4-ylphenyl, 3,4-dihydro- 2H-benzo[b][l,4]dioxepin-7-yl, l,2,3,4-tetrahydroquinolin-8-yl, 4-methyl-3,4-dihydro-2H- benzo[b][l,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-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, 3,4-dimethoxyphenyl, 3,5-dichloro-2-hydroxyphenyl, isoquinolin-6- yl, quinolin-8-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzo[b][l,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.
10. The compound of any of the Claims 3-5 wherein R' is trifluoromethyl, R"1, R1", R1" and a substituent on R2 that is vicinal to the -SO2-R2 bond together with R3 may additionally be Q- 3alkylene substituted by 0, 1 or 2 substituents selected from Ci-salkyl,
Figure imgf000165_0001
halo, oxo, 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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkylORa, and additionally substituted by 0, 1, 2, 3 or 4 substituents independently selected from Br, Cl, F and I.
11. The compound of Claim 10 wherein:
Figure imgf000165_0002
substituted by 0, 1 or 2 substituents selected from Cj.8alkyl, C^haloalkyl, halo, oxo, 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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkyl0Ra, and additionally substituted by 0, 1, 2, 3 or 4 substituents independently selected from Br, Cl, F and I.
12. The compound of Claim 10 wherein:
Figure imgf000165_0003
substituted by 0, 1 or 2 substituents selected from Ci-galkyl,
Figure imgf000165_0004
halo, oxo, 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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NR"C2-6alkylORa, 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 R5 is:
Figure imgf000166_0001
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 Rg, Cj-salkyl,
Figure imgf000166_0002
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)2Rb, -OC2-6alkylNRaRa, -OC2-6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(Ra)C(=O)NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(R3)C(=O)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkyl0Ra, and additionally substituted by 0, 1, 2 or 3 substituents independently selected from Br, Cl, F and I and R , R and R are independently selected from H, a basic moiety, Rg, Ci.8alkyl, C1-4haloalkyl, 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)2Rb, -OC2-6alkylNRaRa, -OC2.6alkylORa, -SRa, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRaRa, -S(=O)2N(Ra)C(=O)Rb, -S(=O)2N(Ra)C(=O)ORb, -S(=O)2N(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)2Rb, -N(Ra)S(=O)2NRaRa, -NRaC2-6alkylNRaRa, -NRaC2-6alkylORa, Br, Cl, F and I; provided that 1 or 2 of R6, R7 and R8 are a basic moiety.
14. The compound of Claim 3-12 wherein R5 is:
Figure imgf000166_0003
where R7 is a basic moiety.
15. The compound of any of the Claims 3-12 wherein R5 is:
Figure imgf000167_0001
where R is a basic moiety.
16. A compound selected from the group consisting of: (2i?)-3-(((2,3-dichlorophenyl)sulfonyl)(methyl)amino)-2-hydroxy-N-(( lR)-6-( 1 - piperidinylmethyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)propanamide;
(2/?)-3-(((2,3-dichlorophenyl)sulfonyl)(methyl)amino)-2-methyl-N-((lJR)-6-(l- piperidinylmethyl)-l,2,3,4-tetrahydro-l-naphthalenyl)propanamide;
(2/?)-3-(((2,3-dichlorophenyl)sulfonyl)amino)-2-methyl-N-((lΛ)-6-(l-piperidinyl- methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)propanamide;
(2/?,3/?)-4,4,4-trifluoro-2-hydroxy-N-(( lR)-6-( 1 -piperidinylmethyl)- 1 ,2,3 ,4-tetrahydro- l-naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3i?)-3-(((2,3-dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((l/?)-6-(l -piperidinyl¬ methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide; (3Λ)-3-(((2,3-dichlorophenyl)sulfonyl)amino)-N-(( lΛ)-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-((li?)-6-(l-piperidinyl- methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(3/?)-3-(((2,5-dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((4/?)-7-(l-piperidinyl- methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide;
(3Λ)-3-(((2,5-dichlorophenyl)sulfonyl)amino)-N-((lΛ)-6-(((l , 1 -dimethylethyl)amino)- methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)-4,4,4-trifluorobutanamide;
(3R)-3-(((2,6-dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((l^)-6-(l-piperidinyl- methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3i?)-3-(((3,4-dichlorophenyl)sulfonyl)amino)-4-fluoro-N-((li?)-6-(l-piperidinyl- methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3R)-3-(((3,4-dichlorophenyl)sulfonyl)amino)-N-((l/?)-6-(((l , 1 -dimethylethyl)amino)- methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-4,4,4-trifluorobutanamide;
(3/?)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((li?)-6-(((l,l-dimethyl- ethyl)amino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-4,4,4-trifluorobutanamide; (3i?)-3-(((4-chlorophenyl)sulfonyl)amino)-N-((l/?)-6-(((l,l-dimethylethyl)amino)- methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-4,4,4-trifluorobutanamide;
(3/?)-3-(((5-chloro-2-(methyloxy)phenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((l/?)-6-(l- piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3i?)-3-(((5-chloro-2-fluorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((li?)-6-(l- piperidinylmethyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(3/?)-3-((2,3-dihydro- 1 ,4-benzodioxin-6-ylsulfonyl)amino)-4,4,4-trifluoro-N-(( \R)-6- ( 1 -piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3R)-4,4,4-trifluoro-3-(((8-(methyloxy)-5-quinolinyl)sulfonyl)amino)-N-((li?)-6-(l- piperidinylmethyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3i?)-4,4,4-trifluoro-3-((2-naphthalenylsulfonyl)amino)-N-((17?)-6-(l-piperidinyl- methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(S^^^^-trifluoro-N-CCl^-β-Cl-piperidinylmethyO-l^^^-tetrahydro-l- naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (S^-^^-trifluoro-N-CCl^-ό-Cl-piperidinylmethyO-l^^^-tetrahydro-l- naphthalenyl)-3-((8-quinolinylsulfonyl)amino)butanamide;
(3jf?)-4-hydroxy-3-(((4-methylphenyl)sulfonyl)amino)-N-((li?)-6-(l-piperidinyl- methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(3/?)-N-(( 1 R)-6-((( 1 , 1 -dimethylethyl)amino)methyl)- 1 ,2,3,4-tetrahydro- 1 - 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;
(3/?)-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; (3.K)-N-(C 1 R)-6-((( 1 , 1 -dimethylethyl)amino)methyl)-l ,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- 1 -naphthalenyl)-4- fluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3/?)-N-((4R)-7-((cyclopentylamino)methyl)-3,4-dihydro-2H-chromen-4-yl)-4,4,4- trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3R,4/?)-3-(((3,4-dichlorophenyl)sulfonyl)amino)-4-hydroxy-N-((lR)-6-(l-piperidinyl- methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)pentanamide; ( JύJ-J-(((2,3-dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-(( \R)-6-( 1 -piperidinyl- methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(31S}-3-(((2,5-dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((li?)-6-(l-piperidinyl- methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3S)-3-(((2,6-dichloro-4-(trifluoromethyl)phenyl)sulfonyl)amino)-N-((l/?)-6-(l- piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3S)-3-(((2,6-dichloro-4-(trifluoromethyl)phenyl)sulfonyl)amino)-N-(( lR)-6-((( 1,1- dimethylethyl)amino)methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(35)-3-(((2-chloro-5-(trifluoromethyl)phenyl)sulfonyl)amino)-N-((lJR)-6-(l- piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3S)-3-(((2-chloro-5-(trifluoromethyl)phenyl)sulfonyl)amino)-N-((l/?)-6-((cyclopentyl- amino)methyl)-l ,2,3,4-tetrahydro-l -naphthalenyl)butanamide;
(35)-3-(((2-fluoro-5-(trifluoromethyl)phenyl)sulfonyl)amino)-N-(( lR)-6-( 1 -piperidinyl¬ methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (35)-3-(((2-nitro-4-(trifluoromethyl)phenyl)sulfonyl)amino)-N-((li?)-6-(l-piperidinyl- methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)bυtanamide;
(35}-3-(((3,4-bis(methyloxy)phenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((lΛ)-6-(l- piperidinylmethyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(35)-3-(((3,4-dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((lR)-6-(l-piperidinyl- methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(35)-3-(((3,4-dichlorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((lR)-6-(l-(l- piperidinylmethyl)ethenyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(35)-3-(((3,5-dichloro-2-hydroxyphenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((li?)-6-(l- piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (31S)-3-(((3-chloro-2-fluorophenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((lR)-6-(l- piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(35)-3-(((3-chloro-4-methylphenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((lR)-6-(l- piperidinylmethyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(3-S}-3-(((4-(l,l-dimethylethyl)phenyl)sulfonyl)amino)-N-((lΛ)-6-(l-piperidinyl- methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(35)-3-(((4-(l,3-oxazol-5-yl)phenyl)sulfonyl)amino)-N-((l/?)-6-(l-piperidinylmethyl)- 1 ,2,3,4-tetrahydro-l -naphthalenyl)butanamide;
(35)-3-(((4-bromo-3-(trifluoromethyl)phenyl)sulfonyl)amino)-N-(( \R)-6-( 1 - piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
Figure imgf000170_0001
piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((li?)-6-((3- hydroxy- 1 -piperidinyl)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (35)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((lJR)-6-(((2-
( 1 -pyrrolidinyl)ethyl)amino)methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(35)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-4,4,4-triiluoro-N-((4i?)-7-(l- piperidinylmethyl)-3,4-dihydro-2H-chromen-4-yl)butanamide;
(3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((4i?)-7-((3- hydroxy- 1 -piperidinyl)methyl)-3 ,4-dihydro-2H-chromen-4-yl)butanamide;
(35)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((li?)-6-(((l,l- dimethylethyl)amino)methyl)-l ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((lR)-6- ((cyclopentylamino)methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide; (35)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((li?)-6-(l -piperidinyl¬ methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(36}-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((lR)-6-(((2-methylpropyl)- amino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(35)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-(( lΛ)-6-((( 1 -methylethyl)- amino)methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(35)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((li?)-6-(((cyclopropyl- methyl)amino)methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((lR)-6-((cyclobutylamino)- methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (36)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((l/?)-6-(((3S)-3-hydroxy-l- piperidinyl)methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3iS}-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((lR)-6-(l-pyrrolidinyl- methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(35)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4i?)-7-((( 1 , 1 - dimethylethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide;
(35)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4/?)-7-(cyclopentylamino)- methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide;
(3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4R)-7-(l-piperidinyl- methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide; (36)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4i?)-7-(((2-methylpropyl)- amino)methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide;
(3S)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4/?)-7-(((l-methylethyl)- amino)methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide; (35)-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4Λ)-7-(((cyclopropyl- methyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide;
(35}-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((47?)-7-((cyclobutylamino)- methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide;
(35}-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4i?)-7-(((3S)-3-hydroxy-l- piperidinyl)methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide;
QS )-3-(((4-chloro-2,5-dimethylphenyl)sulfonyl)amino)-N-((4i?)-7-( 1 -pyrrolidinyl- methyl)-3,4-dihydro-2H-chromen-4-yl)butanamide;
(3S)-3-(((4-chloro-3-(trifluorometliyl)phenyl)sulfonyl)amino)-4,4,4-trifluoro-N-((l/?)- 6-( 1 -piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide; (3-S}-3-(((5-chloro- 1 -naphthalenyl)sulfonyl)amino)-N-((7/?)-6-((cyclopentylamino)- methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(35)-3-(((6-chloro-2-naphthalenyl)sulfonyl)amino)-N-((li?)-6-((((6-chloro-2- naphthalenyl)sulfonyl)(cyclopentyl)amino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)- butanamide; (35)-3-(((6-chloro-2-naphthalenyl)sulfonyl)amino)-N-((li?)-6-((cyclopentylamino)- methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide;
(31S}-3-(((6-chloro-2-naphthalenyl)sulfonyl)amino)-N-((li?)-6-(l-piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3S)-3-((l,l'-biphenyl-3-ylsulfonyl)amino)-N-((l/?)-6-(l-piperidinylmethyl)-l,2,3,4- tetrahydro- 1 -naphthalenyl)butanamide;
(35)-3-((l , 1 '-biphenyl-4-ylsulfonyl)amino)-N-((l/?)-6-(((l , 1 -dimethylethyl)- amino)methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(35)-3-((l,r-biphenyl-4-ylsulfonyl)amino)-N-((li?)-6-(l-piperidinylmethyl)-l,2,3,4- tetrahydro- 1 -naphthalenyl)butanamide; (3,S)-3-((2,3-dihydro-l-benzofuran-5-ylsulfonyl)amino)-4,4,4-trifluoro-N-((lΛ)-6-(l- piperidinylmethyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(36)-3-(methyl((3-(trifluoromethyl)phenyl)sulfonyl)amino)-N-(( lR)-6-( 1 -piperidinyl¬ methyl)- 1,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide; (35)-4,4,4-trifluoro-3-((2-naphthalenylsulfonyl)aniino)-N-((l/?)-6-(l-piperidinyl- methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(35)-4,4,4-trifluoro-3-((2-naphthalenylsulfonyl)amino)-N-((li?)-6-(l-piperidinyl- methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)butanamide; (36)-4,4,4-trifluoro-3-((2-naphthalenylsulfonyl)amino)-N-((li?)-6-(l-(l-piperidinyl- methyl)ethenyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3S)-4,4,4-trifluoro-3-((6-isoquinolinylsulfonyl)aminp)-N-(( lR)-6-( 1 -piperidinyl- methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)butanamide;
(3-S)-4,4,4-trifluoro-3-(methyl((3-(trifluoromethyl)phenyl)sulfonyl)amino)-N-((li?)-6- (1 -piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)butanamide;
(3S)-4,4,4-trifluoro-N-((l/?)-6-((((2/?)-tetrahydro-2-ruranylmethyl)amino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-4,4,4-trifluoro-N-((li?)-6-((((25)-tetrahydro-2-ruranylmethyl)amino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (35)-4,4,4-trifluoro-N-(( 17?)-6-((( 1 -methylethyl)amino)methyl)- 1 ,2,3,4-tetrahydro-l - naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3-S)-4,4,4-trifluoro-N-((li?)-6-(((2-(l-piperidinyl)ethyl)amino)methyl)-l,2,3,4- tetrahydro-l-naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-4,4,4-trifluoro-N-((17?)-6-(((2-(l-pyrrolidinyl)ethyl)amino)methyl)-l,2,3,4- tetrahydro- 1 -naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3,S}-4,4,4-trifluoro-N-((lR)-6-(((2-(4-moφholinyl)ethyl)amino)methyl)-l,2,3,4- tetrahydro-l-naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-4,4,4-trifluoro-N-((li?)-6-(((2-hydroxy-l , 1 -dimethylethyl)amino)methyl)-l ,2,3,4- tetrahydro-l -naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (35)-4,4,4-trifluoro-N-((l/?)-6-(((2-methylpropyl)amino)methyl)-l,2,3,4-tetrahydro-l- naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butananiide;
(3-S)-4,4,4-trifluoro-N-(( l/?)-6-(((35)-3 -hydroxy- 1 -piperidinyl)methyl)- 1 ,2,3 ,4- tetrahydro-l-naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-4,4,4-trifluoro-N-(( 1 /?)-6-((4-fluoro- 1 -piperidinyl)methyl)- 1 ,2,3,4-tetrahydro- 1 - naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-4,4,4-trifluoro-N-(( l/?)-6-((4-hydroxy-l -piperidinyl)methyl)- 1 ,2,3,4-tetrahydro- 1 - naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-4,4,4-trifluoro-N-(( l/?)-6-((4-methyl- 1 -piperazinyl)methyl)- 1 ,2,3 ,4-tetrahydro- 1 - naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (35)-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-(( \R)-6-( 1 -( 1 -piperidinylmethyl)ethenyl)- 1 ,2,3 ,4-tetrahydro- 1 - naphthalenyl)-3-(((2,4,6-trimethylphenyl)sulfonyl)amino)butanamide; (3S)-4,4,4-trifluoro-N-(( \R)-6-( 1 -piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 - naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(S-^^^^-trifluoro-N-CCl^-β-Cl-piperidinylmethyO-l^^^-tetrahydro-l- naphthalenyl)-3-(((2,4,6-trimethylphenyl)sulfonyl)amino)butanamide;
(35)-4,4,4-trifluoro-N-(( \R)-6-( 1 -piperidinylmethyl)- 1 ,2,3,4-tetrahydro-l - naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3lS)-4)4)4-trifluoro-N-((li?)-6-(l-pyrrolidinylmethyl)-l,2,3,4-tetrahydro-l- 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; (3S)-4,4,4-trifluoro-N-(( l/?)-6-(hydroxymethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-3-
(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-4,4,4-trifluoro-N-((4i?)-7-(((2-methylpropyl)amino)methyl)-3,4-dihydro-2H- chromen-4-yl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3.S}-4,4,4-trifluoro-N-((4i?)-7-(((3R)-3-hydroxy-l-piperidinyl)methyl)-3,4-dihydro-2H- chromen-4-yl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3JS).4;4)4.trifluoro-N-((4i?)-7-((4-methyl-l-piperazinyl)methyl)-3,4-dihydro-2H- chromen-4-yl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-4,4,4-trifluoro-N-((47?)-7-(l-piperidinylmethyl)-3,4-dihydro-2H-chromen-4-yl)-3- (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (36)-4,4,4-trifluoro-N-((4/?)-7-(4-morpholinylmeihyl)-3,4-dihydro-2H-chromen-4-yl)-
3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3S)-4-fluoro-N-((li?)-6-( 1 -piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-3- (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-N-(( li?)-6-((( 1 , 1 -dimethylethyl)amino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)- 3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)-5-hexynamide;
(3S)-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;
(35)-N-(( l/?)-6-((( 1 , 1 -dimethylethyl)amino)methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)- 3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((\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;
(35}-N-(( 1 /?)-6-((( 1 , 1 -dimethylethyl)amino)methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)- 3-(((2-nitro-4-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (35}-N-(( li?)-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;
(35)-N-(( li?)-6-(((2-(dimethylamino)ethyl)amino)methyl)- 1 ,2,3 ,4-tetrahydro- 1 - naphthalenyl)-4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-N-(( lΛ)-6-(((2-(methyloxy)ethyl)amino)methyl)- 1 ,2,3 ,4-tetrahydro- 1 - naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(31S)-N-((17?)-6-(((2,2-dimethylpropyl)amino)methyl)-l,2,3,4-tetrahydro-l-. naphthalenyl)-4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (35)-N-(( 1 Λ)-6-(((2-methylpropyl)amino)methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)-3-
(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-N-(( 1 /?)-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;
(35}-N-((lR)-6-(((cyclopropylmethyl)amino)methyl)-l,2,3,4-tetrahydro-l- naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3-5}-N-((l/?)-6-((lR)-l-((2-(methyloxy)ethyl)amino)ethyl)-l,2,3,4-tetrahydro-l- naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-N-(( li?)-6-((l R)- 1 -(cyclobutylamino)ethyl)- 1 ,2,3,4-tetrahydro-l -naphthalenyl)-3- (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (35)-N-(( li?)-6-(( 1 R)- 1 -(cyclopropylamino)ethyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)-
3 -(((3 -(trifluoromethyl)phenyl) sulfonyl)amino)butanamide;
(35)-N-((li?)-6-((lS)-l-((2-methylpropyl)amino)ethyl)-l,2,3,4-tetrahydro-l- naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3S)-N-(( 1 R)-6-(( 1 S)- 1 -((cyclopropylmethyl)amino)ethyl)- 1 ,2,3,4-tetrahydro- 1 - naphthalenyl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3S)-N-(X \R)-6-(( 1 S)- 1 -(cyclopentylamino)ethyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)-3- (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-N-((lR)-6-((3-pyridinylamino)methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-3-(((3- (trifluoromethyl)phenyl)sulfonyl)amino)butanamide; VJu/-iY-^iΛ;-υ-^υywυuuιyiainino/)meuiyij-i,z,J,if-ietranydro-I-naphthalenyl_)-4,4,4- trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3S)-N-(( li?)-6-((cyclohexylamino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-4,4,4- trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (35)-N-((l/?)-6-((cyclopentyl((2-fluoro-5-(trifluoromethyl)phenyl)sulfonyl)amino)- methyl)-l,2,3,4-tetrahydro-l-naρhthalenyl)-3-(((2-fluoro-5-(trifluoromethyl)phenyl)- sulfonyl)amino)butanamide;
(35)-N-(( 1 R)-6-((cyclopentylamino)methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)-3 -(((3- (trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((l/?)-6-((cyclopentylamino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-4,4,4- trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-N-(( l/?)-6-((cyclopentylamino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-3-(((2- fluoro-5-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3S)-N-(( 1 /?)-6-((cyclopentylamino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-4,4,4- trifluoro-3-(methyl((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3S)-N-(( 1 R)-6-( 1 -( 1 -piperidinylmethyl)ethenyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-3- (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-N-(( 1 R)-6-( 1 -azepanylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-4,4,4-trifluoro- 3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-(( 1 R)-6-{ 1 -azepanylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-3-(((4-chloro-
2,5-dimethylphenyl)sulfonyl)amino)-4,4,4-trifluorobutanamide;
(3S)-N-((lΛ)-6-(l-azepanylmethyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-3-(((3-chloro-4- methylphenyl)sulfonyl)amino)-4,4,4-trifluorobutanamide;
(3S)-N-((lR)-6-( 1 -azepanylmethyl)- 1 ,2,3,4-tetrahydro-l -naphthalenyl)-3-(((3,4- bis(methyloxy)phenyl)sulfonyl)amino)-4,4,4-trifluorobutanamide;
(3S)-N-(( \R)-6-( 1 -piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-3-(((3- (trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(3S)-N-((lΛ)-6-(l-pyrrolidinylmethyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-3-(((3- (trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (3S)-N-((l/?)-6-acetyl-l,2,3,4-tetrahydro-l-naphthalenyl)-3-(((3-(trifluoromethyl)- phenyl)sulfonyl)amino)butanamide;
(3S)-N-((lR)-6-formyl-l,2,3,4-tetrahydro-l-naphthalenyl)-3-(((3-(trifluoromethyl)- phenyl)sulfonyl)amino)butanamide; (3S)-N-((4K)-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;
(35}-N-((4R)-7-(((l,l-dimethylethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)- 4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (35)-N-((4/?)-7-(((l,l-dimethylethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)-3-
(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-N-((4/?)-7-(((l-methylethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)-3-(((3- (trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-N-((4i?)-7-(((2-(methyloxy)ethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)-3- (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-N-((4Λ)-7-(((2,2-dimethylpropyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)- 4,4,4-trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-N-((4R)-7-(((2-methylpropyl)amino)methyl)-3,4-dihydro-2H-chroπien-4-yl)-3- (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (35)-N-((4i?)-7-(((3R)-3-hydτoxy- 1 -piperidinyl)methyl)-3,4-dihydro-2H-chromen-4- yl)-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-N-((4i?)-7-(((cyclopropylmethyl)amino)methyl)-3,4-dihydro-2H-chromen-4-yl)-3- (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-N-((47?)-7-((4-methyl-l-piperazinyl)methyl)-3,4-dihydro-2H-chromen-4-yl)-3- (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-N-((4Λ)-7-((cyclohexylamino)methyl)-3,4-dihydro-2H-chromen-4-yl)-4,4,4- trifluoro-3-(((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-N-((4Λ)-7-((cyclopentylamino)methyl)-3,4-dihydro-2H-chromen-4-yl)-3-(((3- (trifluoromethyl)phenyl)sulfonyl)amino)butanamide; (35)-N-((4R)-7-((cyclopropylamino)methyl)-3,4-dihydro-2H-chromen-4-yl)-3-(((3-
(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-N-((4/?)-7-(l-azepanylmethyl)-3,4-dihydro-2H-chromen-4-yl)-3-(((4-chloro-2,5- dimethylphenyl)sulfonyl)amino)-4,4,4-trifluorobutanamide;
(35)-N-((4i?)-7-(l-azepanylmethyl)-3,4-dihydro-2H-chromen-4-yl)-4,4,4-trifluoro-3- (((3-(trifluoromethyl)phenyl)sulfonyl)amino)butanamide;
(35)-N-((4/?)-7-(l-piperidinylmethyl)-3,4-dihydro-2H-chromen-4-yl)-3-(((3-(trifluoro- methyl)phenyl)sulfonyl)amino)butanamide;
(3S)-N-((4i?)-7-(l-pyrrolidinylmethyl)-3,4-dihydro-2H-chromen-4-yl)-3-(((3-(trifluoro- methyl)phenyl)sulfonyl)amino)butanamide; i , i -uimemyieinyi iv-z-^ j,t-αicnioropnenyl/)suπonylj-yv-4-(( lΛ)-&-( 1 -pipeπdinyl- methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-D-alpha-asparaginate;
1 , 1 -dimethylethyl N-2-((3,4-dichlorophenyl)sulfonyl)-N-4-(( l/?)-6-(hydroxymethyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)-D-alpha-asparaginate; 1,1 -dimethylethyl N-2-((3 ,4-dichlorophenyl)sulfonyl)-N-4-(( lΛ)-6-((( 1 , 1 -dimethyl- ethyl)amino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-D-alpha-asparaginate; l,l-dimethylethyl N-2-((3,4-dichlorophenyl)sulfonyl)-N-4-((lΛ)-6-(l-pyrrolidinyl- methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-D-alpha-asparaginate;
2-((2/?)-2-methyl- 1 -((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-(( \R)-6-( 1 - piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)acetamide;
2-(3,4-dichloro-benzenesulfonylamino)-N-(6-pyrrolidin-l-yhnethyl-l,2,3,4-tetrahydro- naphthalen- 1 -yl)-succinamic acid;
3-(2-chloro-5-trifluoromethyl-benzenesulfonylamino)-N-(6-{[(2-chloro-5-trifluoro- methyl-benzenesulfony^-cyclopentyl-aminoj-methylj-l^^^-tetrahydro-naphthalen-l-yl)- butyramide;
3-(6-bromo-l,l-dioxido-3-oxo-l,2-benzisothiazol-2(3H)-yl)-N-((li?)-6-(l-piperidinyl- methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)propanamide;
3-(6-bromo-l , 1 -dioxido-3-oxo- 1 ,2-benzisothiazol-2(3H)-yl)-N-(( li?)-6-((( 1,1- dimethylethyl)amino)methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)propanamide; 3R-(3,4-dichloro-benzenesulfonylamino)-4,4,4-trifluoro-N-(6-piperidin- 1 -ylmethyl-
1 ,2,3,4-tetrahydro-naphthalen- 1 -yl)-butyramide;
35-(3 ,4-dichloro-benzenesulfonylamino)-4,4,4-trifluoro-N-(6-piperidin- 1 -ylmethyl- 1 ,2,3,4-tetrahydro-naphthalen- 1 -yl)-butyramide;
N- 1 -(( li?)-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 -(( l/?)-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; N-I -(( \R)-6-(((l , 1 -dimethylethyl)amino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-N-
3-methyl-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide;
N-l-((l/?)-6-(((2,2-dimethylpropyl)amino)methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)- N-3-(4-fluorophenyl)-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide; N- 1 -(( lR)-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 -(( \R)-6-(( 1 S)- 1 -(cyclopentylamino)ethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-N-3- methyl-N-3 -((3 -(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide; N- 1 -(( li?)-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- 1 -(( li?)-6-((4-fluoro- 1 -piperidinyl)methyl)- 1 ,2,3,4-tetrahydro-l -naphthalenyl)-N-3- methyl-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide;
N-l-((l/?)-6-((cyclopentylamino)methyl)-l,2,3,4-tetrahydro-l-naphthalenyl)-N-3-(4- fluorophenyO-N-S-^-Ctrifluoromethytyphenytysulfonyty-beta-alaninamide;
N- 1 -(( lΛ)-6-((diethylamino)methyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)-N-3-(4- fluorophenyl)-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide;
N- 1 -(( li?)-6-( 1 -piperidinylmethyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)-N-3-((3- (trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide; N-I -(( li?)-6-( 1 -piperidinylmethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-N-3-(4-
(trifluoromethyOphenyO-N-S-CCS-Ctrifluoromethy^phenyOsulfonyO-beta-alaninamide;
N-2-((3,4-dichlorophenyl)sulfonyl)-N-4-((l/?)-l,2,3,4-tetrahydro-l-naphthalenyl)-D- aspartamide;
N-2-((3 ,4-dichlorophenyl)sulfonyl)-N-4-(( lR)-6-((( 1 , 1 -dimethylethyl)amino)methyl)- 1 ,2,3,4-tetrahydro-l -naphthalenyl)-D-aspartamide;
N-2-((3,4-dichlorophenyl)sulfonyl)-N-4-((lR)-6-(((l,l-dimethylethyl)amino)methyl)- l,2,3,4-tetrahydro-l-naphthalenyl)-D-asparagine;
N-2-((3 ,4-dichlorophenyl)sulfonyl)-N-4-(( 1 /?)-6-(((2-methylpropyl)amino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-D-aspartamide; N-2-((3,4-dichlorophenyl)sulfonyl)-N-4-((li?)-6-((4-fluoro-l-piperidinyl)methyl)- l,2,3,4-tetrahydro-l-naphthalenyl)-D-aspartamide;
N-2-((3,4-dichlorophenyl)sulfonyl)-N-4-((l/?)-6-(l-piperidinylmethyl)-l,2,3,4- tetrahydro- 1 -naphthalenyl)-D-aspartamide;
N-2-((3 ,4-dichlorophenyl)sulfonyl)-N-4-(( \R)-6-( 1 -piperidinylmethyl)- 1 ,2,3 ,4- tetrahydro- 1 -naphthalenyl)-D-asparagine;
N-2-((3,4-dichlorophenyl)sulfonyl)-N-4-((lΛ)-6-(l-pyrrolidinylmethyl)-l,2,3,4- tetrahydro- 1 -naphthalenyl)-D-aspartamide;
N-2-((3,4-dichlorophenyl)sulfonyl)-N-4-((l/?)-6-(hydroxymethyl)-l ,2,3,4-tetrahydro-l- naphthalenyl)-D-aspartamide; N-2-((4-methylphenyl)sulfonyl)-N-4-((l/?)-l,2,3,4-tetrahydro-l-naphthalenyl)-D- aspartamide;
N-2-((4-methylphenyl)sulfonyl)-N-4-((l/?)-6-(l-piperidinylmethyl)-l,2,3,4-tetτahydro- 1 -naphthalenyl)-D-aspartamide; N-2-((4-methylphenyl)sulfonyl)-N-4-(( 1 R)-6-( 1 -piperidinylmethyl)- 1 ,2,3 ,4-tetrahydro-
1 -naphthalenyl)-D-asparagine;
N-3-((2-aminophenyl)sulfonyl)-N- 1 -((4R)-I -( 1 -piperidinylmethyl)-3 ,4-dihydro-2H- chromen-4-yl)-beta-alaninamide;
N-3-((2-nitrophenyl)sulfonyl)-N-l-((4R)-7-(l-piperidinylmethyl)-3,4-dihydro-2H- chromen-4-yl)-beta-alaninamide;
N-3-((3,4-dichlorophenyl)sulfonyl)-N-l -((\R)-6-(((l , 1 -dimethylethyl)amino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-N-3-(4-fluorophenyl)-beta-alaninamide;
N-I-(I -methylethyl)-N-l -((lR)-6-(l -piperidinylmethyl)- 1 ,2,3,4-tetrahydro-l - naphthalenyty-N-S-C^-CtrifluoromethylJphenytysulfonyty-beta-alaninarnide; N-3-(2-amino-2-oxoethyl)-N- 1 -(( lR)-6-((( 1 , 1 -dimethylethyl)amino)methyl)- 1 ,2,3,4- tetrahydro-l -naphthalenyl)-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide;
N-3-(2-fluoroethyl)-N- 1 -(( \R)-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- 1 -((4/?)-7-( 1 -piperidinylmethyl)- 3,4-dihydro-2H-chromen-4-yl)-beta-alaninamide;
N-3-(2-naphthalenylsulfonyl)-N-3-phenyl-N- 1 -((4R)-7-( 1 -piperidinylmethyl)-3,4- dihydro-2H-chromen-4-yl)-beta-alaninamide;
N-3-(3-amino-3-oxopropyl)-N- 1 -((\R)-6-((( 1 , 1 -dimethylethyl)amino)methyl)-l ,2,3,4- tetrahydro-l -naphthalenyl)-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide; N-3-(4-fluorophenyl)-N-l-((l/?)-6-(((2-methylpropyl)amino)methyl)-l,2,3,4- tetrahydro-l-naphthalenyl)-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide;
N-3-(4-fluorophenyl)-N- 1 -(( li?)-6-((4-fluoro- 1 -piperidinyl)methyl)- 1 ,2,3 ,4-tetrahydro- l-naphthalenyl)-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide;
N-3-cyclohexyl-N- 1 -(( \R)-6-( 1 -piperidinylmethyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)- N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide;
N-3-cyclopropyl-N- 1 -(( lR)-6-((( 1 , 1 -dimethylethyl)amino)methyl)- 1 ,2,3 ,4-tetrahydro- 1 - naphthalenyl)-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide;
N-3-cyclopropyl-N-l-((iy?)-6-(l-piperidinylmethyl)-l,2,3,4-tetrahydro-l- naphthalenyl)-N-3-((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide; N-3-methyl-N- 1 -(( lΛ)-6-( 1 -pipendinylmethyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)-N-3- ((3-(trifluoromethyl)phenyl)sulfonyl)-beta-alaninamide;
N-4-(( li?)-6-((( 1 , 1 -dimethylethyl)amino)methyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-N- 2-((4-methylphenyl)sulfonyl)-D-aspartamide; N-4-((47?)-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)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)-D-alpha-asparaginate;
(i?)-4,4,4-trifluoro-N-((R)-6-(piperidin- 1 -ylmethyl)- 1,2,3 ,4-tetrahydronaphthalen- 1 -yl)- 3-(2-(trifluoromethyl)phenylsulfonamido)butanamide;
(/?)-3-(3-bromophenylsulfonamido)-4,4,4-trifluoro-N-((i?)-6-(piperidin-l-ylmethyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)butanamide; (Λ)-3-(3-chloro-4-fluorophenylsulfonamido)-4,4,4-trifluoro-N-((Λ)-6-(piperidin- 1 - ylmethyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)butanamide;
(/?)-4,4,4-trifluoro-N-methyl-N-((R)-7-(piperidin-l-ylmethyl)chroman-4-yl)-3-(3- (trifluoromethyl)phenylsulfonamido)butanamide;
(Λ)-4,4,4-trifluoro-N-((i?)-6-(piperidin- 1 -ylmethyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)- 3 -(4-(trifluoromethoxy)phenylsulfonamido)butanamide;
(i?)-4,4,4-trifluoro-3-(3-methylphenylsulfonamido)-N-((/?)-6-(piperidin-l-ylmethyl)- l,2,3,4-tetrahydronaphthalen-l-yl)butanamide
(/?)-3-(4-chloro-2-fluorophenylsulfonamido)-4,4,4-trifluoro-N-((/Z)-6-(piperidin-l -yl¬ methyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide; (/?)-3-(2-chloro-4-fluorophenylsulfonamido)-4,4,4-trifluoro-N-((/?)-6-(piperidin-l-yl- methyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide;
(/?)-tert-butyl 2-(naphthalene-3-sulfonamido)-4-oxo-4-((/?)-6-(piperidin-l-ylmethyl)- l,2,3,4-tetrahydronaphthalen-l-ylamino)butanoate;
(Λ)-4,4,4-trifluoro-N-((Λ)-6-((4-methylpiperidin- 1 -yl)methyl)- 1 ,2,3,4- tetrahydronaphthalen- 1 -yl)-3-(3-(trifluoromethyl)phenylsulfonamido)butanamide;
(/?)-methyl 4-oxo-4-((i?)-6-(piperidin- 1 -ylmethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 - ylamino)-2-(3-(trifluoromethyl)phenylsulfonamido)butanoate;
(/?)-4-oxo-4-((/?)-6-(piperidin- 1 -ylmethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -ylamino)-2- (3 -(trifluoromethyl)phenylsulfonamido)butanoic acid; (R)-Nl -((7?)-6-(piperidin- 1 -ylmethyl)- 1 ,2,3,4-tetrahydronaphthalen-l -yl)-3-(3- (trifluoromethyl)phenylsulfonamido)succinamide;
(R)-3-cyano-N-((i?)-6-(piperidin-l-ylmethyl)-l,2,3,4-tetrahydronaphthalen-l-yl)-3-(3- (trifluoromethyl)phenylsulfonamido)propanamide; (Λ)-2-(naphthalene-3-sulfonamido)-4-oxo-4-((/?)-6-(piperidin- 1 -ylmethyl)- 1 ,2,3,4- tetrahydronaphthalen- 1 -ylamino)butanoic acid;
(/?)-methyl 2-(naphthalene-3-sulfonamido)-4-oxo-4-((i?)-6-(piperidin- 1 -ylmethyl)- l,2,3,4-tetrahydronaphthalen-l-ylamino)butanoate;
(/?)-3-(3-tert-butylphenylsulfonamido)-4,4,4-trifluoro-N-((R)-6-(piperidin-l-ylmethyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)butanamide;
(7?)-methyl 2-(3,4-dichlorophenylsulfonamido)-4-oxo-4-((i?)-6-(pyrrolidin- 1 -ylmethyl)- 1 ,2,3,4-tetrahydronaphthalen-l -ylamino)butanoate;
(/?)-4,4,4-trifluoro-3-(3-(oxazol-5-yl)phenylsulfonamido)-N-((i?)-6-(piperidin-l- ylmethyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)butanamide; (/?)-3-(3,4-dihydro-2H-benzo[b][l,4]dioxepine-8-sulfonamido)-4,4,4-trifluoro-N-((i?)-
6-(piperidin- 1 -ylmethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide;
(/?)-N-((5)-6-(4,5-dihydro-lH-imidazol-2-yl)-l,2,3,4-tetrahydronaphthalen-2-yl)-4,4,4- trifluoro-3 -(3 -(trifluoromethyl)phenylsulfonamido)butanamide;
(/?)-4,4,4-trifluoro-N-((R)-6-(piperidin- 1 -yhnethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)- 3-(l,2,3,4-tetrahydroquinoline-8-sulfonamido)butanamide;
(Λ)-4,4,4-trifluoro-3-(4-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine-7-sulfonamido)- N-((/?)-6-(piperidin- 1 -yhnethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide;
(i?)-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; (i?)-4,4,4-trifluoro-N-((i?)-5-nitro-6-(piperidin-l-ylmethyl)-l,2,3,4- tetrahydronaphthalen-l-yl)-3-(3-(trifluoromethyl)phenylsulfonamido)butanamide;
(/?)-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;
(7?)-3-(3-chloro-2-fluoro-N-methylphenylsulfonamido)-4,4,4-trifluoro-N-methyl-N- ((/?)-7-(piperidin- 1 -ylmethyl)chroman-4-yl)butanamide;
(i?)-4,4,4-trifluoro-N-((i?)-7-nitro-6-(piperidin- 1 -ylmethyl)- 1 ,2,3 ,4- tetrahydronaphthalen-l-yl)-3-(3-(trifluoromethyl)phenylsulfonamido)butanamide;
(/?)-4,4,4-trifluoro-3-(3-methoxyphenylsulfonamido)-N-((i?)-6-(piperidin-l-ylmethyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)butanamide; (i?)-3-(3,5-dimethylphenylsulfonamido)-4,4,4-trifluoro-N-((i?)-6-(piperidin-l- ylmethyl)-l,2,3,4-tetrahydronaphthalen-l-yl)butanamide;
(i?)-3 -(3 ,4-dimethylphenylsulfonamido)-4,4,4-trifluoro-N-((/?)-6-(piperidin- 1 - ylmethyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)butanamide (2R,3R)-3-(3-chloro-2-fluorophenylsulfonamido)-N-((i?)-6-chloro-7-(piperidin-l- ylmethyl)chroman-4-yl)-4,4,4-trifluoro-2-hydroxybutanamide;
(R)-4,4,4-trifluoro-3-(2-fluoro-5-methylphenylsulfonamido)-N-((/?)-6-(piperidin-l- ylmethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)butanamide;
(i?)-4,4,4-trifluoro-N-((i?)-6-(piperidin- 1 -ylmethyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)- 3 -(4-(trifluoromethyl)phenylsulfonamido)butanamide;
(2i?,3R)-3-(2,5-dichlorophenylsulfonamido)-4,4,4-trifluoro-2-hydroxy-N-((/?)-6- (piperidin- 1 -ylmethyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)butanamide;
(2i?,3i?)-3-(2,3-dichlorophenylsulfonamido)-4,4,4-trifluoro-2-hydroxy-N-((7?)-6- (piperidin- 1 -yhnethyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)butanamide; (2Λ,3Λ)-3-(3,4-dichlorophenylsulfonamido)-4,4,4-trifluoro-2-hydroxy-N-((Λ)-6-
(piperidin- 1 -ylmethyl)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)butanamide;
(/?)-3-(2-chloro-6-methylphenylsulfonamido)-4,4,4-trifluoro-N-((/?)-6-(piperidin-l- ylmethyl)-l,2,3,4-tetrahydronaphthalen-l-yl)butanamide;
(Λ)-4,4,4-trifluoro-3-(5-fluoro-2-methylphenylsulfonamido)-N-((il?)-6-(piperidin-l- ylmethyl)-l,2,3,4-tetrahydronaphthalen-l-yl)butanamide;
(R)-4,4,4-trifluoro-N-((i?)-7-(piperidin-l-ylmethyl)chroman-4-yl)-3-(3- (trifluoromethyl)phenylsulfonamido)butanamide; and
(i?)-3-(4-ethylphenylsulfonamido)-4,4,4-trifluoro-N-((/?)-6-(piperidin-l-ylmethyl)- 1,2,3 ,4-tetrahydronaphthalen- 1 -yl)butanamide; 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.
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, burns, virus infection, head injury, multiple trauma, rhinitis, hepatorenal failure, diabetes, metastasis, pancreatitis, neovascularization, corneal haze, glaucoma, ocular pain, ocular hypertension or angio edema.
20. The use of Claim 18 wherein the disease is osteroarthritis.
PCT/US2005/033659 2004-09-23 2005-09-19 Substituted sulfonamidopropionamides and methods of use WO2006036664A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU2005289881A AU2005289881A1 (en) 2004-09-23 2005-09-19 Substituted sulfonamidopropionamides and methods of use
EP05797852A EP1799637A1 (en) 2004-09-23 2005-09-19 Substituted sulfonamidopropionamides and methods of use
CA002580461A CA2580461A1 (en) 2004-09-23 2005-09-19 Substituted sulfonamidopropionamides and methods of use

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US61292104P 2004-09-23 2004-09-23
US60/612,921 2004-09-23

Publications (1)

Publication Number Publication Date
WO2006036664A1 true WO2006036664A1 (en) 2006-04-06

Family

ID=35695801

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2005/033659 WO2006036664A1 (en) 2004-09-23 2005-09-19 Substituted sulfonamidopropionamides and methods of use

Country Status (4)

Country Link
EP (1) EP1799637A1 (en)
AU (1) AU2005289881A1 (en)
CA (1) CA2580461A1 (en)
WO (1) WO2006036664A1 (en)

Cited By (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007029587A1 (en) * 2005-09-05 2007-03-15 Dainippon Sumitomo Pharma Co., Ltd. β SECRETASE INHIBITOR
WO2008022945A1 (en) 2006-08-19 2008-02-28 Boehringer Ingelheim International Gmbh Aryl sulfonamides with an analgesic action
EP2025675A1 (en) * 2007-08-14 2009-02-18 Boehringer Ingelheim International GmbH Arylsulfonamides with analgetic activity
EP2025668A1 (en) * 2007-08-14 2009-02-18 Boehringer Ingelheim International GmbH Arylsulfonamides with analgetic activity
EP2025673A1 (en) * 2007-08-14 2009-02-18 Boehringer Ingelheim International GmbH Arylsulfonamides with analgetic activity
WO2009021944A1 (en) * 2007-08-14 2009-02-19 Boehringer Ingelheim International Gmbh New compounds
WO2009021945A1 (en) * 2007-08-14 2009-02-19 Boehringer Ingelheim International Gmbh New compounds
WO2009021758A1 (en) * 2007-08-14 2009-02-19 Boehringer Ingelheim International Gmbh Arylsulfonamides having an analgesic effect
EP2099747A1 (en) * 2007-01-09 2009-09-16 Bayer Schering Pharma Aktiengesellschaft Radiolabelling via fluorination of aziridines
WO2010006939A1 (en) * 2008-07-15 2010-01-21 F. Hoffmann-La Roche Ag Aminotetrahydroindazoloacetic acids
US7820815B2 (en) 2004-11-05 2010-10-26 Boehringer Ingelheim International Gmbh Process for the preparation of chiral 8-(-3-aminopiperidin-1-yl) xanthines
US8106060B2 (en) 2005-07-30 2012-01-31 Boehringer Ingelheim International Gmbh 8-(3-amino-piperidin-1-yl)-xanthines, their preparation, and their use as pharmaceuticals
US8119648B2 (en) 2002-08-21 2012-02-21 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US8124629B2 (en) 2008-11-17 2012-02-28 Hoffmann-La Roche Inc. Naphthylacetic acids
US8188090B2 (en) 2008-11-17 2012-05-29 Hoffman-La Roche Inc. Naphthylacetic acids
US8232281B2 (en) 2006-05-04 2012-07-31 Boehringer Ingelheim International Gmbh Uses of DPP-IV inhibitors
US8470884B2 (en) 2011-11-09 2013-06-25 Hoffmann-La Roche Inc. Alkenyl naphthylacetic acids
US8513264B2 (en) 2008-09-10 2013-08-20 Boehringer Ingelheim International Gmbh Combination therapy for the treatment of diabetes and related conditions
US20130274269A1 (en) * 2010-12-22 2013-10-17 D. Western Therapeutics Institute, Inc. Novel substituted isoquinoline derivative
US8642629B2 (en) 2008-11-17 2014-02-04 Hoffmann-La Roche Inc. Naphthylacetic acids
US8697868B2 (en) 2004-02-18 2014-04-15 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions
US8846695B2 (en) 2009-01-07 2014-09-30 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients with inadequate glycemic control despite metformin therapy comprising a DPP-IV inhibitor
US8853156B2 (en) 2008-08-06 2014-10-07 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients inappropriate for metformin therapy
US8865729B2 (en) 2008-12-23 2014-10-21 Boehringer Ingelheim International Gmbh Salt forms of a xanthine compound
US8883800B2 (en) 2011-07-15 2014-11-11 Boehringer Ingelheim International Gmbh Substituted quinazolines, the preparation thereof and the use thereof in pharmaceutical compositions
US9034883B2 (en) 2010-11-15 2015-05-19 Boehringer Ingelheim International Gmbh Vasoprotective and cardioprotective antidiabetic therapy
US9149478B2 (en) 2010-06-24 2015-10-06 Boehringer Ingelheim International Gmbh Diabetes therapy
US9155705B2 (en) 2008-04-03 2015-10-13 Boehringer Ingelheim International Gmbh DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation
US9186392B2 (en) 2010-05-05 2015-11-17 Boehringer Ingelheim International Gmbh Combination therapy
US9266888B2 (en) 2006-05-04 2016-02-23 Boehringer Ingelheim International Gmbh Polymorphs
US9457029B2 (en) 2009-11-27 2016-10-04 Boehringer Ingelheim International Gmbh Treatment of genotyped diabetic patients with DPP-IV inhibitors such as linagliptin
US9486526B2 (en) 2008-08-06 2016-11-08 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients inappropriate for metformin therapy
US9526730B2 (en) 2012-05-14 2016-12-27 Boehringer Ingelheim International Gmbh Use of a DPP-4 inhibitor in podocytes related disorders and/or nephrotic syndrome
US9526728B2 (en) 2014-02-28 2016-12-27 Boehringer Ingelheim International Gmbh Medical use of a DPP-4 inhibitor
US9555001B2 (en) 2012-03-07 2017-01-31 Boehringer Ingelheim International Gmbh Pharmaceutical composition and uses thereof
US9713618B2 (en) 2012-05-24 2017-07-25 Boehringer Ingelheim International Gmbh Method for modifying food intake and regulating food preference with a DPP-4 inhibitor
US10155000B2 (en) 2016-06-10 2018-12-18 Boehringer Ingelheim International Gmbh Medical use of pharmaceutical combination or composition
US11033552B2 (en) 2006-05-04 2021-06-15 Boehringer Ingelheim International Gmbh DPP IV inhibitor formulations
US11911388B2 (en) 2008-10-16 2024-02-27 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral or non-oral antidiabetic drug

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993005014A1 (en) * 1991-09-05 1993-03-18 Pharno-Wedropharm Gmbh Aromatic sulfonamide derivatives, their use as enzyme inhibitors and pharmaceutical compositions containing them
US6022873A (en) * 1996-10-19 2000-02-08 British Biotech Pharmaceuticals Limited Metalloproteinase inhibitors
US20040116353A1 (en) * 2001-03-28 2004-06-17 Bernard Ferrari Derivatives of n-(arylsulfonyl)beta-aminoacids comprising a substituted aminomethyl group, the preparation method thereof and the pharmaceutical compositions containing same
WO2004092116A1 (en) * 2003-04-10 2004-10-28 Amgen, Inc. Bicyclic compounds having bradykinin receptors affinity and pharmaceutical compositions thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993005014A1 (en) * 1991-09-05 1993-03-18 Pharno-Wedropharm Gmbh Aromatic sulfonamide derivatives, their use as enzyme inhibitors and pharmaceutical compositions containing them
US6022873A (en) * 1996-10-19 2000-02-08 British Biotech Pharmaceuticals Limited Metalloproteinase inhibitors
US20040116353A1 (en) * 2001-03-28 2004-06-17 Bernard Ferrari Derivatives of n-(arylsulfonyl)beta-aminoacids comprising a substituted aminomethyl group, the preparation method thereof and the pharmaceutical compositions containing same
WO2004092116A1 (en) * 2003-04-10 2004-10-28 Amgen, Inc. Bicyclic compounds having bradykinin receptors affinity and pharmaceutical compositions thereof

Cited By (88)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8119648B2 (en) 2002-08-21 2012-02-21 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US9556175B2 (en) 2002-08-21 2017-01-31 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and thier use as pharmaceutical compositions
US8178541B2 (en) 2002-08-21 2012-05-15 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US9108964B2 (en) 2002-08-21 2015-08-18 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US10023574B2 (en) 2002-08-21 2018-07-17 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US9321791B2 (en) 2002-08-21 2016-04-26 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US10202383B2 (en) 2002-08-21 2019-02-12 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US8664232B2 (en) 2002-08-21 2014-03-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US8697868B2 (en) 2004-02-18 2014-04-15 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions
US7820815B2 (en) 2004-11-05 2010-10-26 Boehringer Ingelheim International Gmbh Process for the preparation of chiral 8-(-3-aminopiperidin-1-yl) xanthines
US9499546B2 (en) 2004-11-05 2016-11-22 Boehringer Ingelheim International Gmbh Process for the preparation of chiral 8-(3-aminopiperidin-1-yl)-xanthines
US8541450B2 (en) 2004-11-05 2013-09-24 Boehringer Ingelheim International Gmbh Process for the preparation of chiral 8-(3-aminopiperidin-1yl)-xanthines
US9751855B2 (en) 2004-11-05 2017-09-05 Boehringer Ingelheim International Gmbh Process for the preparation of chiral 8-(3-aminopiperidin-1-yl)-xanthines
US8883805B2 (en) 2004-11-05 2014-11-11 Boehringer Ingelheim International Gmbh Process for the preparation of chiral 8-(3-aminopiperidin-1-yl)-xanthines
US8106060B2 (en) 2005-07-30 2012-01-31 Boehringer Ingelheim International Gmbh 8-(3-amino-piperidin-1-yl)-xanthines, their preparation, and their use as pharmaceuticals
US8637530B2 (en) 2005-07-30 2014-01-28 Boehringer Ingelheim International Gmbh 8-(3-amino-piperidin-1-yl)-xanthines, their preparation, and their use as pharmaceuticals
JP5030781B2 (en) * 2005-09-05 2012-09-19 良明 木曽 β-secretase inhibitor
US7816387B2 (en) 2005-09-05 2010-10-19 Dainippon Sumitomo Pharma Co., Ltd. β secretase inhibitor
WO2007029587A1 (en) * 2005-09-05 2007-03-15 Dainippon Sumitomo Pharma Co., Ltd. β SECRETASE INHIBITOR
US9266888B2 (en) 2006-05-04 2016-02-23 Boehringer Ingelheim International Gmbh Polymorphs
US11084819B2 (en) 2006-05-04 2021-08-10 Boehringer Ingelheim International Gmbh Polymorphs
US11033552B2 (en) 2006-05-04 2021-06-15 Boehringer Ingelheim International Gmbh DPP IV inhibitor formulations
US11291668B2 (en) 2006-05-04 2022-04-05 Boehringer Ingelheim International Gmbh Uses of DPP IV inhibitors
US10301313B2 (en) 2006-05-04 2019-05-28 Boehringer Ingelheim International Gmbh Polymorphs
US9173859B2 (en) 2006-05-04 2015-11-03 Boehringer Ingelheim International Gmbh Uses of DPP IV inhibitors
US8232281B2 (en) 2006-05-04 2012-07-31 Boehringer Ingelheim International Gmbh Uses of DPP-IV inhibitors
US8673927B2 (en) 2006-05-04 2014-03-18 Boehringer Ingelheim International Gmbh Uses of DPP-IV inhibitors
US10080754B2 (en) 2006-05-04 2018-09-25 Boehringer Ingelheim International Gmbh Uses of DPP IV inhibitors
US11919903B2 (en) 2006-05-04 2024-03-05 Boehringer Ingelheim International Gmbh Polymorphs
US9493462B2 (en) 2006-05-04 2016-11-15 Boehringer Ingelheim International Gmbh Polymorphs
US9815837B2 (en) 2006-05-04 2017-11-14 Boehringer Ingelheim International Gmbh Polymorphs
EP2284166A1 (en) * 2006-08-19 2011-02-16 Boehringer Ingelheim International GmbH Arylsulfonamides with analgetic activity
US8252785B2 (en) 2006-08-19 2012-08-28 Boehringer Ingelheim International Gmbh Aryl sulfonamides as bradykinin-B1-receptor antagonists
WO2008022945A1 (en) 2006-08-19 2008-02-28 Boehringer Ingelheim International Gmbh Aryl sulfonamides with an analgesic action
US7858618B2 (en) 2006-08-19 2010-12-28 Boehringer Ingelheim International Gmbh Compounds
EP2402329A1 (en) * 2006-08-19 2012-01-04 Boehringer Ingelheim International GmbH Analgetic phenylsulphonamides
JP2012149086A (en) * 2006-08-19 2012-08-09 Boehringer Ingelheim Internatl Gmbh New compound
EP2099747A1 (en) * 2007-01-09 2009-09-16 Bayer Schering Pharma Aktiengesellschaft Radiolabelling via fluorination of aziridines
WO2009021758A1 (en) * 2007-08-14 2009-02-19 Boehringer Ingelheim International Gmbh Arylsulfonamides having an analgesic effect
JP2010535839A (en) * 2007-08-14 2010-11-25 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング New compounds
EP2025675A1 (en) * 2007-08-14 2009-02-18 Boehringer Ingelheim International GmbH Arylsulfonamides with analgetic activity
EP2025668A1 (en) * 2007-08-14 2009-02-18 Boehringer Ingelheim International GmbH Arylsulfonamides with analgetic activity
EP2025673A1 (en) * 2007-08-14 2009-02-18 Boehringer Ingelheim International GmbH Arylsulfonamides with analgetic activity
WO2009021944A1 (en) * 2007-08-14 2009-02-19 Boehringer Ingelheim International Gmbh New compounds
US8394805B2 (en) 2007-08-14 2013-03-12 Boehringer Ingelheim International Gmbh Compounds
WO2009021945A1 (en) * 2007-08-14 2009-02-19 Boehringer Ingelheim International Gmbh New compounds
WO2009021946A1 (en) 2007-08-14 2009-02-19 Boehringer Ingelheim International Gmbh Novel compounds
US8450306B2 (en) 2007-08-14 2013-05-28 Boehringer Ingelheim International Gmbh Bradykinin B1-receptor antagonists
JP2010535840A (en) * 2007-08-14 2010-11-25 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング New compounds
US9155705B2 (en) 2008-04-03 2015-10-13 Boehringer Ingelheim International Gmbh DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation
US10973827B2 (en) 2008-04-03 2021-04-13 Boehringer Ingelheim International Gmbh DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation
US10022379B2 (en) 2008-04-03 2018-07-17 Boehringer Ingelheim International Gmbh DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation
US9415016B2 (en) 2008-04-03 2016-08-16 Boehringer Ingelheim International Gmbh DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation
WO2010006939A1 (en) * 2008-07-15 2010-01-21 F. Hoffmann-La Roche Ag Aminotetrahydroindazoloacetic acids
CN102099342B (en) * 2008-07-15 2013-07-10 霍夫曼-拉罗奇有限公司 Aminotetrahydroindazoloacetic acids
CN102099342A (en) * 2008-07-15 2011-06-15 霍夫曼-拉罗奇有限公司 Aminotetrahydroindazoloacetic acids
US8124641B2 (en) 2008-07-15 2012-02-28 Hoffmann-La Roche Inc. Aminotetrahydroindazoloacetic acids
US8853156B2 (en) 2008-08-06 2014-10-07 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients inappropriate for metformin therapy
US10034877B2 (en) 2008-08-06 2018-07-31 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients inappropriate for metformin therapy
US9486526B2 (en) 2008-08-06 2016-11-08 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients inappropriate for metformin therapy
US8513264B2 (en) 2008-09-10 2013-08-20 Boehringer Ingelheim International Gmbh Combination therapy for the treatment of diabetes and related conditions
US11911388B2 (en) 2008-10-16 2024-02-27 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral or non-oral antidiabetic drug
US8124629B2 (en) 2008-11-17 2012-02-28 Hoffmann-La Roche Inc. Naphthylacetic acids
US8188090B2 (en) 2008-11-17 2012-05-29 Hoffman-La Roche Inc. Naphthylacetic acids
US8642629B2 (en) 2008-11-17 2014-02-04 Hoffmann-La Roche Inc. Naphthylacetic acids
US8865729B2 (en) 2008-12-23 2014-10-21 Boehringer Ingelheim International Gmbh Salt forms of a xanthine compound
US9212183B2 (en) 2008-12-23 2015-12-15 Boehringer Ingelheim International Gmbh Salt forms of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine
US8846695B2 (en) 2009-01-07 2014-09-30 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients with inadequate glycemic control despite metformin therapy comprising a DPP-IV inhibitor
US9457029B2 (en) 2009-11-27 2016-10-04 Boehringer Ingelheim International Gmbh Treatment of genotyped diabetic patients with DPP-IV inhibitors such as linagliptin
US10092571B2 (en) 2009-11-27 2018-10-09 Boehringer Ingelheim International Gmbh Treatment of genotyped diabetic patients with DPP-IV inhibitors such as linagliptin
US10004747B2 (en) 2010-05-05 2018-06-26 Boehringer Ingelheim International Gmbh Combination therapy
US9186392B2 (en) 2010-05-05 2015-11-17 Boehringer Ingelheim International Gmbh Combination therapy
US9603851B2 (en) 2010-05-05 2017-03-28 Boehringer Ingelheim International Gmbh Combination therapy
US9149478B2 (en) 2010-06-24 2015-10-06 Boehringer Ingelheim International Gmbh Diabetes therapy
US9034883B2 (en) 2010-11-15 2015-05-19 Boehringer Ingelheim International Gmbh Vasoprotective and cardioprotective antidiabetic therapy
US11911387B2 (en) 2010-11-15 2024-02-27 Boehringer Ingelheim International Gmbh Vasoprotective and cardioprotective antidiabetic therapy
US20130274269A1 (en) * 2010-12-22 2013-10-17 D. Western Therapeutics Institute, Inc. Novel substituted isoquinoline derivative
US8883792B2 (en) * 2010-12-22 2014-11-11 D. Western Therapeutics Institute, Inc. Substituted isoquinoline derivative
US8883800B2 (en) 2011-07-15 2014-11-11 Boehringer Ingelheim International Gmbh Substituted quinazolines, the preparation thereof and the use thereof in pharmaceutical compositions
US8962636B2 (en) 2011-07-15 2015-02-24 Boehringer Ingelheim International Gmbh Substituted quinazolines, the preparation thereof and the use thereof in pharmaceutical compositions
US9199998B2 (en) 2011-07-15 2015-12-01 Boehringer Ingelheim Internatioal Gmbh Substituted quinazolines, the preparation thereof and the use thereof in pharmaceutical compositions
US8470884B2 (en) 2011-11-09 2013-06-25 Hoffmann-La Roche Inc. Alkenyl naphthylacetic acids
US9555001B2 (en) 2012-03-07 2017-01-31 Boehringer Ingelheim International Gmbh Pharmaceutical composition and uses thereof
US10195203B2 (en) 2012-05-14 2019-02-05 Boehringr Ingelheim International GmbH Use of a DPP-4 inhibitor in podocytes related disorders and/or nephrotic syndrome
US9526730B2 (en) 2012-05-14 2016-12-27 Boehringer Ingelheim International Gmbh Use of a DPP-4 inhibitor in podocytes related disorders and/or nephrotic syndrome
US9713618B2 (en) 2012-05-24 2017-07-25 Boehringer Ingelheim International Gmbh Method for modifying food intake and regulating food preference with a DPP-4 inhibitor
US9526728B2 (en) 2014-02-28 2016-12-27 Boehringer Ingelheim International Gmbh Medical use of a DPP-4 inhibitor
US10155000B2 (en) 2016-06-10 2018-12-18 Boehringer Ingelheim International Gmbh Medical use of pharmaceutical combination or composition

Also Published As

Publication number Publication date
AU2005289881A1 (en) 2006-04-06
EP1799637A1 (en) 2007-06-27
CA2580461A1 (en) 2006-04-06

Similar Documents

Publication Publication Date Title
WO2006036664A1 (en) Substituted sulfonamidopropionamides and methods of use
US20090048224A1 (en) Compounds and methods of use
EP1656355B1 (en) Piperazine derivatives and methods of use
US7199244B2 (en) Cyclic amine derivatives and methods of use
US20080249106A1 (en) Novel B1 bradykinin receptor antagonists
US20060111347A1 (en) Substituted sulfones and methods of use
US7662811B2 (en) 1,2,3,4-tetrahydropyrazin-2-yl acetamides and methods of use
US7612060B2 (en) Triazoles and methods of use
EP1878728A2 (en) Derivatives of piperazine and higher homologues thereof for the treatment of inflammation-related disorders

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KM KP KR KZ LC LK LR LS LT LU LV LY MA MD MG MK MN MW MX MZ NA NG NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU LV MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2580461

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2005289881

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2005797852

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2005289881

Country of ref document: AU

Date of ref document: 20050919

Kind code of ref document: A

WWP Wipo information: published in national office

Ref document number: 2005289881

Country of ref document: AU

WWP Wipo information: published in national office

Ref document number: 2005797852

Country of ref document: EP