US20120270902A1

US20120270902A1 - N-substituted benzene sulfonamides

Info

Publication number: US20120270902A1
Application number: US13/372,126
Authority: US
Inventors: Martin Neitzel; Jennifer Marugg
Original assignee: Elan Pharmaceuticals LLC
Current assignee: Elan Pharmaceuticals LLC
Priority date: 2004-03-11
Filing date: 2012-02-13
Publication date: 2012-10-25
Also published as: EP1723102A2; CA2559047A1; WO2005090296A3; US8193389B2; EP2374792A1; JP2007528405A; EP2360142A1; US20050245573A1; WO2005090296A2

Abstract

The invention provides N-substituted benzenesulfonamides for use in treating or preventing cognitive disorders, such as Alzheimer's Disease.

Compounds of particular interest are defined by Formula (I), wherein R₁, R₂, R₃, R₄, and R_3′, are as described in the specification. The invention also encompasses pharmaceutical compositions comprising compounds of Formula (I) as well as methods of treating cognitive disorders, including Alzheimer's disease using compounds of Formula (I).

Description

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority from U.S. Provisional Application Ser. No. 60/552,555, filed Mar. 11, 2004, which is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention
The invention relates to N-substituted benzene sulfonamides. More specifically, it relates to such compounds that inhibit β-amyloid peptide release and/or its synthesis and, therefore, are useful in the prevention of cognitive disorders in patients susceptible to cognitive disorders and/or in the treatment of patients with cognitive disorders in order to inhibit further deterioration in their condition.
2. State of the Art
Alzheimer's Disease (AD) is a degenerative brain disorder characterized clinically by progressive loss of memory, cognition, reasoning, judgment and emotional stability that gradually leads to profound mental deterioration and ultimately death. AD is a very common cause of progressive mental failure (dementia) in aged humans and is believed to represent the fourth most common medical cause of death in the United States. AD has been observed in races and ethnic groups worldwide and presents a major present and future public health problem. The disease is currently estimated to affect about two to three million individuals in the United States alone. AD is at present incurable. No treatment that effectively prevents AD or reverses its symptoms and course is currently known.
The brains of individuals with AD exhibit characteristic lesions termed senile (or amyloid) plaques, amyloid angiopathy (amyloid deposits in blood vessels) and neurofibrillary tangles. Large numbers of these lesions, particularly amyloid plaques and neurofibrillary tangles, are generally found in several areas of the human brain important for memory and cognitive function in patients with AD. Smaller numbers of these lesions in a more restrictive anatomical distribution are also found in the brains of most aged humans who do not have clinical AD. Amyloid plaques and amyloid angiopathy also characterize the brains of individuals with Trisomy 21 (Down's Syndrome) and Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch Type (HCHWA-D). At present, a definitive diagnosis of AD usually requires observing the aforementioned lesions in the brain tissue of patients who have died with the disease or, rarely, in small biopsied samples of brain tissue taken during an invasive neurosurgical procedure.
The principal chemical constituent of the amyloid plaques and vascular amyloid deposits (amyloid angiopathy) characteristic of AD and the other disorders mentioned above is an approximately 4.2 kilodalton (kD) protein of about 39-43 amino acids designated the β-amyloid peptide (BAP) or sometimes Aβ, AβP or β/A4. β-Amyloid peptide was first purified and a partial amino acid sequence was provided by Glenner et al., Biochem. Biophys. Res. Commun., 120:885-890 (1984) The isolation procedure and the sequence data for the first 28 amino acids are described in U.S. Pat. No. 4,666,829.
Molecular biological and protein chemical analyses have shown that the β-amyloid peptide is a small fragment of a much larger precursor protein termed the amyloid precursor protein (APP), that is normally produced by cells in many tissues of various animals, including humans. Knowledge of the structure of the gene encoding APP has demonstrated that β-amyloid peptide arises as a peptide fragment that is cleaved from APP by protease enzyme(s). Sequential processing of the precursor protein by the enzymes referred to generically as beta- and gamma-secretases, give rise to the β-amyloid peptide fragment. Both enzymes have now been molecularly cloned, and characterized to differing levels.
Several lines of evidence indicate that progressive cerebral deposition of β-amyloid peptide plays a seminal role in the pathogenesis of AD and can precede cognitive symptoms by years or decades. See, for example, Selkoe, Neuron, 6:487-498 (1991). The most important line of evidence is the discovery that missense DNA mutations at amino acid 717 of the 770-amino acid isoform of APP can be found in affected members but not unaffected members of several families with a genetically determined (familial) form of AD (Goate et al., Nature, 349:704-706 (1990); Chartier Harlan et al., Nature, 353:844-846 (1989); and Murrell et al., Science, 254:97-99 (1991.) Another such mutation, known as the Swedish variant, is comprised of a double mutation changing lysine⁵⁹⁵-methionine⁵⁹⁶to asparagine⁵⁹⁵-leucine⁵⁹⁶(with reference to the 695 isoform was found in a Swedish family) was reported in 1992 (Mullan et al., Nature Genet., 1:345-347 (1992). Genetic linkage analyses have demonstrated that these mutations, as well as certain other mutations in the APP gene, are the specific molecular cause of AD in the affected members of such families. In addition, a mutation at amino acid 693 of the 770-amino acid isoform of APP has been identified as the cause of the β-amyloid peptide deposition disease, HCHWA-D, and a change from alanine to glycine at amino acid 692 appears to cause a phenotype that resembles AD is some patients but HCHWA-D in others. The discovery of these and other mutations in APP in genetically based cases of AD prove that alteration of APP metabolism, and subsequent deposition of its β-amyloid peptide fragment, can cause AD.
Despite the progress which has been made in understanding the underlying mechanisms of AD and other β-amyloid peptide related diseases, there remains a need to develop methods and compositions for treatment of the disease(s). Ideally, the treatment methods would advantageously be based on drugs which are capable of inhibiting β-amyloid peptide release and/or its synthesis in vivo.
One approach toward inhibiting amyloid peptide synthesis in vivo is by inhibiting gamma secretase, the enzyme responsible for the carboxy-terminal cleavage resulting in production of β-amyloid peptide fragments of 40 or 42 residues in length. The immediate substrates for gamma secretase are β-cleaved, as well as α-cleaved carboxy-terminal fragments (CTF) of APP. The gamma-secretase cleavage site on β- and α-CTF fragments occurs in the predicted transmembrane domain of APP. Inhibitors of gamma-secretase have been demonstrated to effect amyloid pathology in transgenic mouse models (Dovey, H. F., V. John, J. P. Anderson, L. Z. Chen, P. de Saint Andrieu, L. Y. Fang, S. B. Freedman, B. Folmer, E. Goldbach, E. J. Holsztynska et al. (2001). “Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain.” J Neurochem 76(1): 173-81.)
Gamma secretase is recognized to be a multi-subunit complex comprised of the presenilins (PS1 or PS2), Nicastrin, Aph-1, and Pen 2 (De Strooper, B. (2003). “Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-Secretase complex.” Neuron 38(1): 9-12; Edbauer, D., E. Winkler, J. T. Regula, B. Pesold, H. Steiner and C. Haass (2003). “Reconstitution of gamma-secretase activity.” Nat Cell Biol 5(5): 486-8; Kimberly, W. T., M. J. LaVoie, B. L. Ostaszewski, W. Ye, M. S. Wolfe and D. J. Selkoe (2003). “Gamma-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2.” Proc Natl Acad Sci USA 100(11): 6382-7). Much evidence indicates that PS comprises the catalytic moiety of the complex, while the other identified subunits are necessary for proper maturation and sub-cellular localization of the active enzyme complex (reviewed in De Strooper, B. (2003). “Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-Secretase complex.” Neuron 38(1): 9-12.) Consistent with this hypothesis: PS knock-out mice exhibit significant reductions in β-amyloid production (De Strooper, B., P. Saftig, K. Craessaerts, H. Vanderstichele, G. Guhde, W. Annaert, K. Von Figura and F. Van Leuven (1998). “Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein.” Nature 391(6665): 387-90; Haass, C. and D. J. Selkoe (1998). “Alzheimer's disease. A technical KO of amyloid-beta peptide.” Nature 391(6665): 339-40; Herreman, A., L. Serneels, W. Annaert, D. Collen, L. Schoonjans and B. De Strooper (2000). “Total inactivation of gamma-secretase activity in presenilin-deficient embryonic stem cells.” Nat Cell Biol 2(7): 461-2); point mutations of putative active site aspartate residues in PS trans-membrane domains inhibit β-amyloid production in cells in a dominant negative fashion (Wolfe, M. S., W. Xia, B. L. Ostaszewski, T. S. Diehl, W. T. Kimberly and D. J. Selkoe (1999). “Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity.” Nature 398(6727): 513-7; Kimberly, W. T., W. Xia, T. Rahmati, M. S. Wolfe and D. J. Selkoe (2000). “The transmembrane aspartates in presenilin 1 and 2 are obligatory for gamma-secretase activity and amyloid beta-protein generation.” J Biol Chem 275(5): 3173-8); active site directed substrate-based transition state isosteres designed to inhibit gamma secretase directly conjugate to PS (Esler, W. P., W. T. Kimberly, B. L. Ostaszewski, T. S. Diehl, C. L. Moore, J. Y. Tsai, T. Rahmati, W. Xia, D. J. Selkoe and M. S. Wolfe (2000). “Transition-state analogue inhibitors of gamma-secretase bind directly to presenilin-1.” Nat Cell Biol 2(7): 428-34; Li, Y. M., M. Xu, M. T. Lai, Q. Huang, J. L. Castro, J. DiMuzio-Mower, T. Harrison, C. Lellis, A. Nadin, J. G. Neduvelil et al. (2000). “Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1.” Nature 405(6787): 689-94); finally, allosteric gamma secretase inhibitors have likewise been demonstrated to bind directly to PS (Seiffert, D., J. D. Bradley, C. M. Rominger, D. H. Rominger, F. Yang, J. E. Meredith, Jr., Q. Wang, A. H. Roach, L. A. Thompson, S. M. Spitz et al. (2000). “Presenilin-1 and -2 are molecular targets for gamma-secretase inhibitors.” J Biol Chem 275(44): 34086-91.)
Current evidence indicates that in addition to APP processing leading to β-amyloid synthesis, gamma-secretase also mediates the intra-membrane cleavage of other type I transmembrane proteins (reviewed in Fortini, M. E. (2002). “Gamma-secretase-mediated proteolysis in cell-surface-receptor signaling.” Nat Rev Mol Cell Biol 3(9): 673-84, see also Struhl, G. and A. Adachi (2000). “Requirements for presenilin-dependent cleavage of notch and other transmembrane proteins.” Mol Cell 6(3): 625-36.) Noteworthy among the known substrates of gamma-secretase is mammalian Notch 1. The Notch 1 protein is important for cell fate determination during development, and tissue homeostasis in the adult. Upon ligand engagement via the Notch ecto-domain, Notch undergoes sequential extra-cellular and intra-membrane processing analogous to APP. The intra-membrane processing of Notch mediated by gamma secretase leads to release of the Notch intracellular domain (NICD). The NICD fragment mediates Notch signaling via translocation to the nucleus, where it regulates expression of genes mediating cellular differentiation in many tissues during development, as well as in the adult.
Disruption of Notch signaling via genetic knock-out (KO) results in embryonic lethal phenotype in mice (Swiatek, P. J., C. E. Lindsell, F. F. del Amo, G. Weinmaster and T. Gridley (1994). “Notch1 is essential for postimplantation development in mice.” Genes Dev 8(6): 707-19; Conlon, R. A., A. G. Reaume and J. Rossant (1995). “Notch1 is required for the coordinate segmentation of somites.” Development 121(5): 1533-45.) The Notch KO phenotype is very similar to the phenotype observed PS1 KO mice, and precisely reproduced by PS1/PS2 double KO mice (De Strooper et al. (1998). “Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein.” Nature 391(6665): 387-90; Donoviel, D. B., A. K. Hadjantonakis, M. Ikeda, H. Zheng, P. S. Hyslop and A. Bernstein (1999). “Mice lacking both presenilin genes exhibit early embryonic patterning defects.” Genes Dev 13(21): 2801-10; Herreman, A., L. Serneels, W. Annaert, D. Collen, L. Schoonjans and B. De Strooper (2000). “Total inactivation of gamma-secretase activity in presenilin-deficient embryonic stem cells.” Nat Cell Biol 2(7): 461-2.) This convergence of phenotypes observed in knock-out mice of either the substrate (Notch) or the enzyme (PS) suggests that inhibitors of gamma secretase that also inhibit Notch function may be limited as therapeutic agents owing to the importance of Notch function in adult tissues (Fortini, M. E. (2002). “Gamma-secretase-mediated proteolysis in cell-surface-receptor signaling.” Nat Rev Mol Cell Biol 3(9): 673-84.) As APP knock-out mice develop normally and without an overt phenotype Zheng, H., M. Jiang, M. E. Trumbauer, R. Hopkins, D. J. Sirinathsinghji, K. A. Stevens, M. W. Conner, H. H. Slunt, S. S. Sisodia, H. Y. Chen et al. (1996). “Mice deficient for the amyloid precursor protein gene.” Ann N Y Acad Sci 777: 421-6; Zheng, H., M. Jiang, M. E. Trumbauer, D. J. Sirinathsinghji, R. Hopkins, D. W. Smith, R. P. Heavens, G. R. Dawson, S. Boyce, M. W. Conner et al. (1995). “beta-Amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity.” Cell 81(4): 525-31, the cumulative evidence, therefore, suggests that preferred gamma secretase inhibitors would have selectivity for inhibiting gamma secretase processing of APP over gamma secretase processing of Notch.

SUMMARY OF THE INVENTION

In a broad aspect, the invention provides compounds of Formula I:
and pharmaceutically acceptable salts thereof, wherein

R₁is C₂-C₆alkynyl, C₂-C₆alkenyl, or C₁-C₈alkyl wherein each is optionally substituted with 1, 2, or 3 groups that are independently C₁-C₆alkoxy, OH, halogen, CN, C₁-C₆thioalkoxy, phenyl, naphthyl, C₃-C₈cycloalkyl, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆alkyl), —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl, —C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl, —C(O)phenyl, or C₁-C₆alkoxycarbonyl,
- wherein each of the cyclic groups is optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, C₁-C₄alkyl, C₁-C₄alkoxy, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆alkyl), —SO₂—(C₁-C₆)alkyl, or OH; or
R₁is C₃-C₈cycloalkyl optionally substituted with 1 or 2 groups that are independently C₁-C₄alkyl, C₁-C₄hydroxyalkyl, or OH; or
R₁is heterocycloalkyl or heterocycloalkyl(C₁-C₄)alkyl wherein the heterocycloalkyl group is piperidinyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolyl, or morpholinyl, wherein the heterocycloalkyl groups are optionally substituted with 1 or 2 groups that are independently C₁-C₄alkyl, C₁-C₄alkoxy, phenyl, phenyl(C₁-C₄)alkyl, OH, halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, or C₁-C₄alkoxycarbonyl; or
R₁is heteroaryl(C₁-C₄)alkyl, wherein the heteroaryl group is pyridyl, pyrimidyl, furanyl, or thienyl and the heteroaryl group is optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₂-C₄)alkyl(C₁-C₄)alkyl, C₁-C₄alkyl, C₁-C₄alkoxy or OH;
R₂is C₁-C₈alkyl, C₁-C₆hydroxyalkyl, or C₂-C₈alkenyl, each of which is optionally substituted with 1, 2, or 3 groups that are independently phenyl, 2H-chromenyl, 1,2,3,4-tetrahydronaphthalenyl, indolyl, 3,4-dihydronaphthalenyl, phenyl, naphthyl, C₃-C₈cycloalkyl, benzofuranyl, indolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, pyridyl, pyrimidyl, C₁-C₄alkyl, halogen, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, NO₂, thiadiazolyl, furanyl, triazolyl, or CN,
- wherein the cyclic portions of each of the above are optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₆alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl, —C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl, C₁-C₄alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, NO₂, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein
  - x is 0, 1, or 2;
  - R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇;
  - R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl; or
  - R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl;
R₃is H, halogen, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, or CN,
R₄is H, halogen, C₁-C₆alkyl optionally substituted with —CO₂—(C₁-C₆alkyl), C₁-C₆alkoxy, C₁-C₆haloalkyl, C₁-C₆haloalkoxy, CN, aryloxy, isocyanato, —SO₂—(C₁-C₆alkyl), —NHR′, —NR′R″, C₁-C₆alkanoyl, pyridyl, or phenyl; or
R₃and R₄and the carbons to which they are attached form a heterocycloalkyl ring which is optionally substituted with 1, 2, or 3 groups that are independently C₁-C₄alkyl, C₁-C₄alkoxy, halogen, or C₁-C₄alkanoyl wherein the alkanoyl group is optionally substituted with up to 3 halogen atoms;
R_3′ is H, —SO₂—NR′R″, halogen, or
R₄and R_3′, and the carbons to which they are attached form a phenyl ring; or
R₄and R_3′ and the carbons to which they are attached form a 1-oxa-2,3-diazacyclopentyl ring;
- R′ is H, C₁-C₆alkyl, phenyl(C₁-C₄)alkyl, C₁-C₆alkanoyl, phenyl(C₁-C₆)alkanoyl, pyridyl(C₁-C₄)alkyl, pyrimidyl(C₁-C₄)alkyl, pyridazyl(C₁-C₄)alkyl, pyrazinyl(C₁-C₄)alkyl, thienyl(C₁-C₄)alkyl, oxazolyl(C₁-C₄)alkyl, thiazolyl(C₁-C₄)alkyl, furanyl(C₁-C₄)alkyl, —SO₂-alkyl, —SO₂-phenyl, —SO₂-pyridyl, —SO₂-pyrimidyl, —SO₂-pyridazyl, —SO₂-pyrazinyl, —SO₂-thienyl, —SO₂-oxazolyl, —SO₂-thiazolyl, —SO₂-furanyl, pyridyl(C₁-C₆)alkanoyl, pyrimidyl(C₁-C₆)alkanoyl, pyridazyl(C₁-C₆)alkanoyl, pyrazinyl(C₁-C₆)alkanoyl, thienyl(C₁-C₆)alkanoyl, oxazolyl(C₁-C₆)alkanoyl, thiazolyl(C₁-C₆)alkanoyl, or furanyl(C₁-C₆)alkanoyl, wherein the alkyl portion of the alkyl and alkanoyl groups are optionally substituted with halogen or C₁-C₆alkoxy,
  - wherein the aryl, and heteroaryl groups are optionally substituted with alkyl, alkoxy, halogen, haloalkyl, haloalkoxy,
- R″ is H, or C₁-C₆alkyl, wherein the alkyl group is optionally substituted with halogen.

The compounds of Formula I inhibit β-amyloid peptide release and/or its synthesis and, therefore, are useful in the prevention of Alzheimer's Disease (AD) in patients susceptible to AD and/or in the treatment of patients with AD in order to inhibit further deterioration in their condition. The invention also, encompasses pharmaceutical compositions containing the compounds of Formula I, and methods employing such compounds or compositions in the treatment of cognitive diseases, including Alzheimer's disease.
The invention also provides a method of treating a patient who has, or in preventing a patient from getting, a disease or condition selected from the group consisting of Alzheimer's disease, for helping prevent or delay the onset of Alzheimer's disease, for treating patients with mild cognitive impairment (MCI) and preventing or delaying the onset of Alzheimer's disease in those who would progress from MCI to AD, for treating Down's syndrome, for treating humans who have Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treating cerebral amyloid angiopathy and preventing its potential consequences, i.e. single and recurrent lobar hemorrhages, for treating other degenerative dementias, including dementias of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, age related macular degeneration or diffuse Lewy body type of Alzheimer's disease and who is in need of such treatment which comprises administration of a therapeutically effective amount of a compound of formula (I).
In another aspect, the invention provides methods of preparing the compounds of interest, as well as intermediates useful in preparing the compounds of interest.

DETAILED DESCRIPTION OF THE INVENTION

In embodiment 2, the invention provides compounds of formula I wherein

R₁is C₁-C₈alkyl which is optionally substituted with 1, 2, or 3 groups that are independently C₁-C₆alkoxy, OH, halogen, CN, C₁-C₆thioalkoxy, phenyl, naphthyl, C₃-C₈cycloalkyl, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆alkyl), —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl, —C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl, —C(O)phenyl, or C₁-C₆alkoxycarbonyl,
- wherein each of the cyclic groups is optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, C₁-C₄alkyl, C₁-C₄alkoxy, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆alkyl), —SO₂— (C₁-C₆)alkyl, or OH.

In embodiment 3, the invention provides compounds according to embodiment 2, wherein

R₃is H, halogen, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, CN;
R₄is H, halogen, C₁-C₆alkyl optionally substituted with —CO₂—(C₁-C₆alkyl), C₁-C₆alkoxy, C₁-C₄haloalkyl, C₁-C₆haloalkoxy, CN, aryloxy, isocyanato, —SO₂—(C₁-C₆alkyl), —NHR′, —NR′R″, C₁-C₆alkanoyl, oxazolyl, pyrazolyl, thiazolyl, pyridyl, furanyl or thienyl, phenyl; and
R_3′ is H, or halogen.

Embodiment 3A

Compounds according to embodiment 3, wherein at least one of R₂, R₄, and R_3′ is hydrogen. In another aspect, two of R₃, R₄, and R_3′ are hydrogen. In still another aspect, R₄is halogen, methyl or CF₃. In yet still another aspect, R₃and R_3′ are hydrogen while R₄is halogen (preferably F or Cl, still more preferably Cl), methyl or CF₃. In yet another embodiment R₄is Cl. In another embodiment R₄is methyl. In still another embodiment R₄is CF₃.
In embodiment 4, the invention provides compounds according to embodiment 3, wherein

R₂is C₁-C₈alkyl, or C₂-C₈alkenyl, each of which is optionally substituted with 1, 2, or 3 groups that are independently, phenyl 2H-chromenyl, 1,2,3,4-tetrahydronaphthalenyl, indolyl, 3,4-dihydronaphthalenyl, phenyl, naphthyl, C₃-C₈cycloalkyl, benzofuranyl, indolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, pyridyl, pyrimidyl, C₁-C₄alkyl, halogen, —CO₂—(C₁-C₆alkyl), pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, triazolyl, or CN,
- wherein the cyclic portions of each of the above are optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₆alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl, —C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl, C₁-C₄alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein
  - x is 0, 1, or 2;
  - R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇;
  - R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl; or
  - R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl.

Embodiment 4A

Compounds according to embodiment 4, wherein

R₁is C₁-C₈alkyl which is optionally substituted with 1, 2, or 3 groups that are independently C₁-C₄alkoxy, OH, halogen, CN, C₁-C₄thioalkoxy, naphthyl, C₃-C₈cycloalkyl, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆alkyl), —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl, —C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl, —C(O)phenyl, or C₁-C₆alkoxycarbonyl,
- wherein each of the cyclic groups is optionally substituted with 1, 2, or 3 groups that are independently halogen, C₁-C₄alkyl, C₁-C₄alkoxy, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆alkyl), —SO₂—(C₁-C₆)alkyl, or OH.

Embodiment 4B

Compounds according to Embodiment 4, wherein

R₁is C₁-C₈alkyl which is optionally substituted with 1, 2, or 3 groups that are independently C₁-C₄alkoxy, OH, halogen, CN, C₁-C₄thioalkoxy, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆alkyl), —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl, —C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl, —C(O) phenyl, or C₁-C₄alkoxycarbonyl.

Embodiment 4C

Compounds according to Embodiment 4, wherein

R₁is C₁-C₈alkyl which is optionally substituted with 1, or 2 groups that are independently C₁-C₄alkoxy, OH, halogen, CN, C₁-C₄thioalkoxy, NH₂, NH(C₁-C₄)alkyl, N(C₁-C₄)alkyl(C₁-C₄alkyl), —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, or C₁-C₄alkoxycarbonyl.

Embodiment 4D

Compounds according to Embodiment 4, wherein

R₁is C₁-C₈alkyl which is optionally substituted with 1 or 2 groups that are independently C₁-C₄alkoxy, OH, halogen, CN, C₁-C₄thioalkoxy, NH₂, NH(C₁-C₄)alkyl, or N(C₁-C₄)alkyl(C₁-C₄alkyl).

Embodiment 4E

Compounds according to Embodiment 4, wherein

R₁is C₁-C₈alkyl which is optionally substituted with 1, or 2 groups that are independently C₁-C₄alkoxy, OH, halogen, CN, or C₁-C₄thioalkoxy.

Embodiment 4F

Compounds according to Embodiment 4, wherein

R₁is C₁-C₈alkyl which is optionally substituted with 1, or 2 groups that are independently NH₂, NH(C₁-C₄)alkyl, or N(C₁-C₄)alkyl(C₁-C₄alkyl).

Embodiment 4G

Compounds according to Embodiment 4, wherein

R₁is C₁-C₈alkyl which is optionally substituted with 1, or 2 groups that are independently —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, or C₁-C₄alkoxycarbonyl.

Embodiment 4H

Compounds according to Embodiment 4, wherein

R₁is C₁-C₈alkyl substituted with C₃-C₈cycloalkyl which is optionally substituted with 1, or 2 groups that are independently halogen, C₁-C₄alkyl, C₁-C₄alkoxy, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆alkyl), or OH.

In embodiment 5, the invention provides compounds according to embodiment 4, wherein

R₁is C₁-C₈alkyl which is optionally substituted with OH.

In embodiment 6, the invention provides compounds according to embodiment 5, wherein

R₃is H, halogen, C₁-C₆alkyl, C₁-C₆alkoxy, CF₃, CN;
R₄is H, halogen, C₁-C₆alkoxy, C₁-C₆alkyl, CF₃, OCF₃, CN, phenyloxy, —SO₂—(C₁-C₆alkyl), —NHR′, —NR′R″, C₁-C₄alkanoyl, pyridyl, furanyl or thienyl, phenyl, or C₁-C₆alkyl optionally substituted with —CO₂—(C₁-C₆alkyl);
R_3′ is H, or halogen;
- R′ is H, C₁-C₆alkyl, phenyl(C₁-C₄)alkyl, C₁-C₆alkanoyl, phenyl(C₁-C₄)alkanoyl, pyridyl(C₁-C₄)alkyl, —SO₂-alkyl, —SO₂-phenyl, —SO₂-pyridyl, pyridyl(C₁-C₆)alkanoyl, wherein the alkyl portion of the alkyl and alkanoyl groups are optionally substituted with halogen or C₁-C₄alkoxy,
  - wherein the phenyl and pyridyl groups are optionally substituted with C₁-C₄alkyl, C₁-C₄alkoxy, halogen, CF₃, OCF₃;
- R″ is H or C₁-C₆alkyl, wherein the alkyl group is optionally substituted with halogen.

Embodiment 6A

Compounds according to embodiment 6, wherein

R₁is C₁-C₈hydroxyalkyl. In one aspect, R₁is C₂-C₆hydroxyalkyl. In another aspect, R₁is a C₃-C₆hydroxyalkyl. In still another aspect, R₁is a C₅-C₆hydroxyalkyl. In another aspect, R₁is a C₇-C₈hydroxyalkyl. In yet another aspect, R₁is

Embodiment 6B

Compounds according to embodiment 6, wherein

R₁is C₁-C₈alkyl. In another aspect, R₁is a C₃-C₆alkyl. In still another aspect, R₁is a C₅-C₆alkyl. In another aspect, R₁is C₅-C₈alkyl. In still another aspect, R₁is C₇-C₈alkyl.

Embodiment 6C

Compounds according to either Embodiment 6A or Embodiment 6B, wherein R₂is C₁-C₈alkyl. In another aspect, the R₂is C₂-C₈alkyl. In still another aspect, R₂is C₂-C₆alkyl. In yet another aspect, R₂is C₃-C₄alkyl (preferably, C₃alkyl.) In another aspect, R₂is C₁, C₃, or C₅alkyl. In still another aspect, R₂is n-propyl or isopropyl. In another aspect, R₂is C₃-C₈alkyl. In yet another aspect, R₂is C₅-C₈alkyl. In still another aspect, R₂is C₇-C₈alkyl. In still another aspect, R₂is C₅-C₇alkyl.

Embodiment 6D

Compounds according to Embodiment 6C, wherein R₃is H, halogen, methyl, methoxy, or CF₃;

R₄is H, halogen (preferably Cl or F, more preferably Cl), methoxy, methyl, or CF₃; and
R_3′ is H, or halogen.

Embodiment 6E

Compounds according to Embodiment 6D, wherein R₃and R_8′ are both H; and R₄is halogen (preferably Cl or F, more preferably Cl), methoxy, methyl, or CF₃. In one aspect, R₄is Cl. In another aspect, R₄is methyl. In still another aspect, R₄is CF₃.
In embodiment 7, the invention provides compounds according to embodiment 6, wherein

R₂is C₁-C₈alkyl which is optionally substituted with 1 or 2 phenyl groups, 2H-chromenyl, 1,2,3,4-tetrahydronaphthalenyl, indolyl, 3,4-dihydronaphthalenyl, phenyl, naphthyl, C₃-C₈cycloalkyl, benzofuranyl, indolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, pyridyl, pyrimidyl, triazolyl, or CN,
- wherein the cyclic portions of each of the above are optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₆alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl, —C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl, C₁-C₄alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein
  - x is 0, 1, or 2;
  - R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇;
  - R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl; or
  - R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl.

Embodiment 7A

Compounds according to embodiment 7, wherein

R₂is C₁-C₈alkyl which is optionally substituted with 2H-chromenyl, 1,2,3,4-tetrahydronaphthalenyl, indolyl, 3,4-dihydronaphthalenyl, naphthyl, C₃-C₈cycloalkyl, benzofuranyl, indolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, pyridyl, triazolyl, or pyrimidyl,
- wherein the cyclic portions of each of the above are optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₆alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl, —C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl, C₁-C₄alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein
  - x is 0, 1, or 2;
  - R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇;
  - R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl; or
  - R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl.

Embodiment 7B

Compounds according to embodiment 7, or embodiment 7A, wherein

R₂is C₁-C₄alkyl which is optionally substituted with 1,4-benzodioxanyl, or 1,3-benzodioxolyl,
- wherein the cyclic portions of each of the above are optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₆alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl, —C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl, C₁-C₄alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein
  - x is 0, 1, or 2;
  - R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇;
  - R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl; or
  - R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl. In another aspect, the cyclic portions are unsubstituted.

Embodiment 7C

Compounds according to embodiment 7, or Embodiment 7A, wherein

R₂is C₁-C₄alkyl which is substituted with 2H-chromenyl, 1,2,3,4-tetrahydronaphthalenyl, indolyl, 3,4-dihydronaphthalenyl, naphthyl, or C₃-C₈cycloalkyl,
- wherein the cyclic portions of each of the above are optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₆alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl, —C(O)N(C₈-C₆)alkyl(C₁-C₆)alkyl, C₁-C₄alkoxy optionally substituted with pyridyl, triazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein
  - x is 0, 1, or 2;
  - R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇;
  - R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl; or
  - R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl. In another aspect, R₂₅is C₁-C₆alkyl or OH.

Embodiment 7d

Compounds according to Embodiment 7A, wherein R₂is C₁-C₄alkyl which is substituted with 2H-chromenyl, 1,2,3,4-tetrahydronaphthalenyl, indolyl, 3,4-dihydronaphthalenyl, naphthyl, C₃-C₈cycloalkyl, benzofuranyl, indolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, pyridyl, triazolyl, or pyrimidyl, each of which is unsubstituted.

Embodiment 7e

Compounds according to Embodiment 7A, wherein R₂is C₁-C₂alkyl which is substituted with 2H-chromenyl, 1,2,3,4-tetrahydronaphthalenyl, indolyl, 3,4-dihydronaphthalenyl, naphthyl, C₃-C₈cycloalkyl, benzofuranyl, indolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, pyridyl, or pyrimidyl, each of which is unsubstituted.

Embodiment 7f

Compounds according to Embodiment 7A, wherein R₂is C₁-C₂alkyl which is substituted with 2H-chromenyl, 1,2,3,4-tetrahydronaphthalenyl, indolyl, 3,4-dihydronaphthalenyl, naphthyl, benzofuranyl, indolyl, 1,4-benzodioxanyl, or 1,3-benzodioxolyl, each of which is unsubstituted.
In embodiment 8, the invention provides compounds according to embodiment 7, wherein

R₂is C₁-C₈alkyl which is optionally substituted with phenyl group, benzofuranyl, 1,4-benzodioxanyl, or 1,3-benzodioxolyl,
- wherein the cyclic portions of each of the above are optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₆alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl, —C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl, C₁-C₄alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein
  - x is 0, 1, or 2;
  - R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇;
  - R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl; or
  - R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl.

Embodiment 8A

Compounds according to embodiment 8, wherein

R₂is C₁-C₈alkyl substituted with phenyl, benzofuranyl, 1,4-benzodioxanyl, or 1,3-benzodioxolyl. In another aspect, the alkyl group is C₁-C₄alkyl. In still another aspect, the alkyl group is C₂-C₅alkyl. In yet still another aspect, the alkyl group is C₃-C₅alkyl. In another aspect, R₂is C₃-C₈alkyl. In yet another aspect, R₂is C₅-C₈alkyl. In still another aspect, R₂is C₇-C₈alkyl. In still another aspect, R₂is C₅-C₈alkyl.

Embodiment 8B

Compounds according to embodiment 8, wherein

R₂is C₁-C₈alkyl substituted with 1,4-benzodioxanyl, or 1,3-benzodioxolyl. In another aspect, the alkyl group is C₁-C₄alkyl. In still another aspect, the alkyl group is C₂-C₅alkyl. In yet still another aspect, the alkyl group is C₃-C₅alkyl. In another aspect, R₂is C₃-C₈alkyl. In yet another aspect, R₂is C₃-C₈alkyl. In still another aspect, R₂is C₇-C₈alkyl. In still another aspect, R₂is C₅-C₇alkyl.

In embodiment 9, the invention provides compounds according to embodiment 8, wherein

R₂is C₁-C₈alkyl substituted with phenyl, wherein the phenyl is optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₆alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl, —C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl, C₁-C₄alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein
- x is 0, 1, or 2;
- R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇;
- R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl; or
- R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl.

Embodiment 9A

Compounds according to embodiment 9, wherein

R₂is C₁-C₄alkyl (in another aspect, C₁-C₂alkyl) substituted with phenyl, wherein the phenyl is optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₆alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₂-C₆)alkyl, —C(O)N(C₂-C₆)alkyl(C₁-C₆)alkyl, C₁-C₄alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein
- x is 0, 1, or 2;
- R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇;
- R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl; or
- R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl.

Embodiment 9B

Compounds according to embodiment 9, wherein

R₂is C₃-C₆alkyl (in another aspect, C₃-C₅alkyl) substituted with phenyl, wherein the phenyl is optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₆alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₂-C₆)alkyl, —C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl, C₁-C₄alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein
- x is 0, 1, or 2;
- R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇;
- R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl; or
- R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl.

Embodiment 9C

Compounds according to embodiment 9, wherein

R₂is C₅-C₈alkyl (in another aspect, C₅-C₇alkyl) substituted with phenyl, wherein the phenyl is optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₆alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₂-C₆)alkyl, —C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl, C₁-C₄alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein
- x is 0, 1, or 2;
- R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇;
- R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl; or
- R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl.

In embodiment 10, the invention provides compounds according to embodiment 9, wherein

R₁is C₁-C₈hydroxyalkyl;
R₃is H, halogen, C₁-C₄alkyl, C₁-C₄alkoxy, CF₂, CN;
R₄is H, halogen, C₁-C₄alkoxy, CF₂, OCF₃, CN, phenyloxy, —SO₂—(C₁-C₆alkyl), —NHR′, —NR′R″, C₁-C₄alkanoyl, pyridyl, furanyl or thienyl, phenyl, or C₁-C₆alkyl optionally substituted with —CO₂—(C₁-C₆alkyl);
R_3′ is H, or halogen;
- R′ is H, C₁-C₄alkyl, benzyl, C₁-C₆alkanoyl, phenyl(C₁-C₄)alkanoyl, pyridyl(C₁-C₄)alkyl, —SO₂-alkyl, —SO₂-phenyl, —SO₂-pyridyl, pyridyl(C₁-C₆)alkanoyl, wherein the alkyl portion of the alkyl and alkanoyl groups are optionally substituted with halogen or C₁-C₄alkoxy,
  - wherein the phenyl and pyridyl groups are optionally substituted with C₁-C₄alkyl, C₁-C₄alkoxy, halogen, CF₃, OCF₃;
- R″ is H or C₁-C₆alkyl, wherein the alkyl group is optionally substituted with halogen.

In embodiment 11, the invention provides compounds according to embodiment 10, wherein

R₁is

R₃is H, halogen, methyl, methoxy, CF₃, or CN;
R₄is H, halogen, methyl, methoxy, CF₃, OCF₃, CN, —NHR′, or —NR′R″;
R_3′ is H, or halogen;
- R′ is H, or C₁-C₄alkyl; and
- R″ is H or C₁-C₆alkyl, wherein the alkyl group is optionally substituted with halogen.

Embodiment 11A

Compounds according to embodiment 11, wherein

R₂is C₁-C₂alkyl substituted with phenyl, wherein the phenyl is optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₆alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl, —C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl, C₁-C₄alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein
- x is 0, 1, or 2;
- R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇;
- R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl; or
- R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl.

Embodiment 11B

Compounds according to Embodiment 11A, wherein R₂is C₁-C₂alkyl substituted with phenyl, wherein the phenyl is unsubstituted.

Embodiment 11C

Compounds according to embodiment 11A, wherein R₂is C₁-C₂alkyl substituted with phenyl, wherein the phenyl is substituted with 1, or 2 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, C₁-C₃alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein x is 0, 1, or 2; R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇; R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl; or R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl.

Embodiment 11D

Compounds according to embodiment 11C, wherein R₂is C₁-C₂alkyl substituted with phenyl, wherein the phenyl is substituted with 1 or 2 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, C₁-C₂alkoxy, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein x is 0, 1, or 2; R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇; R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl; or R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl.

Embodiment 11D1

Compounds according to embodiment 11c, wherein R₂is C₁-C₂alkyl substituted with phenyl, wherein the phenyl is substituted with 1 group that is halogen (in one aspect, F, Cl or Br), C₁-C₄alkoxy (in one aspect, methoxy), or C₁-C₄alkyl (in one aspect, methyl.) In another embodiment, the substituent is in the para position.

Embodiment 11E

Compounds according to embodiment 11D, wherein R₂is C₁-C₂alkyl substituted with phenyl, wherein the phenyl is substituted with 2 groups, one of which is a halogen or a methoxy group. In another aspect, the second group is a halogen or a methoxy group. In still another aspect, the phenyl is substituted with two halogens or two methoxy groups.

Embodiment 11F

Compounds according to embodiment 11D, wherein R₂is C₁-C₂alkyl substituted with phenyl, wherein the phenyl is substituted with 1, or 2 groups that are independently halogen, CO₂H, C₁-C₆alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl, —C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl, methoxy, or C₁-C₂alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl. In another aspect, the phenyl is di-substituted and one of the groups is methoxy. In yet another aspect, the phenyl is di-substituted, one of the groups is methoxy and the other group is C₁-C₂alkoxy substituted with pyridyl, thiazolyl, methyl thiazol-5-yl. In one aspect, the other group is C₁alkoxy substituted with pyridyl, or methyl thiazol-5-yl. In yet another aspect, the other group is C₂alkoxy substituted with pyridyl, or methyl thiazol-5-yl.

Embodiment 11G

Compounds according to Embodiment 11, wherein

R₂is C₃-C₅alkyl substituted with phenyl, wherein the phenyl is optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₆alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl, —C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl, C₁-C₄alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein
- x is 0, 1, or 2;
- R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇;
- R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl; or
- R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl.

Embodiment 11H

Compounds according to Embodiment 11G, wherein

R₂is C₃-C₄alkyl substituted with phenyl, wherein the phenyl is optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₆alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl, —C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl, C₁-C₄alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein
- x is 0, 1, or 2;
- R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇;
- R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl; or
- R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl.

Embodiment 11I

Compounds according to Embodiment 11H, wherein R₂is C₃-C₄alkyl substituted with phenyl, wherein the phenyl is unsubstituted. In one aspect, the C₃alkyl group is a straight chained alkyl group. In another aspect, the C₄alkyl group is a straight chained C₃alkyl group substituted with a methyl group.

Embodiment 11J

Compounds according to embodiment 11H, wherein

R₂is C₃-C₄alkyl substituted with phenyl, wherein the phenyl is substituted with 1, or 2 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, C₁-C₃alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein
- x is 0, 1, or 2;
- R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇;
- R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl; or
- R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl.

Embodiment 11K

Compounds according to embodiment 11J, wherein

R₂is C₃-C₄alkyl substituted with phenyl, wherein the phenyl is substituted with 1, or 2 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, C₁-C₂alkoxy, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein
- x is 0, 1, or 2;
- R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇;
- R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl; or
- R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl.

Embodiment 11L

Compounds according to embodiment 11K, wherein R₂is C₃-C₄alkyl substituted with phenyl, wherein the phenyl is substituted with 2 groups, one of which is a halogen or a methoxy group. In another aspect, the second group is a halogen or a methoxy group. In still another aspect, the phenyl is substituted with two halogens or two methoxy groups.

Embodiment 11M

Compounds according to embodiment 11J, wherein R₂is C₃-C₄alkyl substituted with phenyl, wherein the phenyl is substituted with 1, or 2 groups that are independently halogen, methoxy, or C₁-C₂alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl. In another aspect, the phenyl is di-substituted and one of the groups is methoxy. In yet another aspect, the phenyl is di-substituted, one of the groups is methoxy and the other group is C₁-C₂alkoxy substituted with pyridyl, thiazolyl, methyl thiazol-5-yl. In one aspect, the other group is C₁alkoxy substituted with pyridyl, or methyl thiazol-5-yl. In yet another aspect, the other group is C₂alkoxy substituted with pyridyl, or methyl thiazol-5-yl.

Embodiment 11N

Compounds according to any one of embodiments 11A, 11B, 11C, 11D, 11E, 11F, 11G, 11H, 11I, 11J, 11K, or 11L wherein R₃is H, or halogen; R₄is halogen, methyl, CF₃, or methoxy; and R_3′ is H, or halogen.

Embodiment 11O

Compounds according to embodiment 11N, wherein R₃is H; R₄is halogen (preferably F or Cl, more preferably Cl), methyl of CF₃; and R_3′ is H. In another aspect, R₄is methyl. In still another aspect, R₄is CF₃. In yet another aspect, R₄is Cl.
In embodiment 12, the invention provides compounds according to embodiment 5, wherein R₁is C₁-C₈alkyl;

R₂is C₁-C₈alkyl substituted with a phenyl group, benzofuranyl, 1,4-benzodioxanyl, or 1,3-benzodioxolyl, wherein the phenyl group is optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₆alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl, —C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl, C₁-C₄alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein
- x is 0, 1, or 2;
- R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇;
- R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl; or
- R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl;
R₃is H, halogen, C₁-C₄alkyl, C₁-C₄alkoxy, CF₃, CN;
R₄is H, halogen, C₁-C₄alkoxy, CF₃, OCF₃, CN, phenyloxy, —SO₂—(C₁-C₆alkyl), —NHR′, —NR′R″, C₁-C₄alkanoyl, pyridyl, furanyl or thienyl, phenyl, or C₁-C₄alkyl optionally substituted with —CO₂—(C₁-C₆alkyl);
R_3′ is H, or halogen;
- R′ is H, C₁-C₄alkyl, benzyl, C₁-C₆alkanoyl, phenyl(C₁-C₄)alkanoyl, pyridyl(C₁-C₄)alkyl, —SO₂-alkyl, —SO₂-phenyl, —SO₂-pyridyl, pyridyl(C₁-C₆)alkanoyl, wherein the alkyl portion of the alkyl and alkanoyl groups are optionally substituted with halogen or C₁-C₄alkoxy,
  - wherein the phenyl and pyridyl groups are optionally substituted with C₁-C₄alkyl, C₁-C₄alkoxy, halogen, CF₃, OCF₃;
- R″ is H or C₁-C₆alkyl, wherein the alkyl group is optionally substituted with halogen.

In embodiment 13, the invention provides compounds according to embodiment 12, wherein

R₁is C₂-C₈alkyl;
R₃is H, halogen, methyl, methoxy, CF₃, or CN;
R₄is halogen, methyl, methoxy, CF₃, OCF₃, CN, —NHR′, or —NR′R″;
R_3′ is H, or halogen;
- R′ is H, or C₁-C₄alkyl; and
- R″ is H or C₁-C₆alkyl, wherein the alkyl group is optionally substituted with halogen.

Embodiment 13A

Compounds according to embodiment 13, wherein

Embodiment 13B

Compounds according to Embodiment 13A, wherein R₂is C₁-C₂alkyl substituted with phenyl, wherein the phenyl is unsubstituted.

Embodiment 13C

Compounds according to embodiment 13A, wherein R₂is C₁-C₂alkyl substituted with phenyl, wherein the phenyl is substituted with 1, or 2 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, C₁-C₃alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein

- x is 0, 1, or 2;
- R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇;
- R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl; or
- R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl.

Embodiment 13D

Compounds according to embodiment 13C, wherein

R₂is C₁-C₂alkyl substituted with phenyl, wherein the phenyl is substituted with 1, or 2 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, C₁-C₂alkoxy, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein
- x is 0, 1, or 2;
- R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇;
- R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl; or
- R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl.

Embodiment 13E

Compounds according to embodiment 13D, wherein R₂is C₁-C₂alkyl substituted with phenyl, wherein the phenyl is substituted with 2 methoxy groups.

Embodiment 13E1

Compounds according to Embodiment 13D, wherein R₂is C₁-C₂alkyl substituted with phenyl, wherein the phenyl is substituted with 1 or 2 groups that are independently CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, or —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl. In another aspect, the C₁-C₄alkoxycarbonyl is a methoxy carbonyl or ethoxycarbonyl. More preferably, it is ethoxycarbonyl.

Embodiment 13E2

Compounds according to Embodiment 13D, wherein R₂is C₁-C₂alkyl substituted with phenyl, wherein the phenyl is substituted with 1 or 2 groups that are independently CO₂H, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, or —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl. In another aspect, the phenyl group is substituted with 1 group selected that is CO₂H, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, or —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl.

Embodiment 13E3

Compounds according to embodiment 13D, wherein

R₂is C₁-C₂alkyl substituted with phenyl, wherein the phenyl is substituted with 1 or 2 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein
- x is 0, 1, or 2;
- R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇;
- R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl; or
- R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl.

Embodiment 13E4

Compounds according to embodiment 13D, wherein R₂is C₁-C₂alkyl substituted with phenyl, wherein the phenyl is substituted with 1 or 2 groups that are independently halogen, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, or OH.

Embodiment 13E5

Compounds according to Embodiment 13D, wherein R₂is C₁-C₂alkyl substituted with phenyl, wherein the phenyl is substituted with 1 or 2 groups that are independently —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein

Embodiment 13E6

Compounds according to Embodiment 13D, wherein

R₂is C₁-C₂alkyl substituted with phenyl, wherein the phenyl is substituted with 1 or 2 groups that are independently —S(O)_x—R₂₅, or —(C₁-C₄alkyl)-S(O)_x—R₂₅; wherein
- x is 0, or 2; and
- R₂₅is C₁-C₆alkyl, or OH.

Embodiment 13E7

Compounds according to Embodiment 13D, wherein R₂is C₁-C₂alkyl substituted with phenyl, wherein the phenyl is substituted with NR₂₆R₂₇; wherein

- R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl; or
- R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl.

Embodiment 13E8

- R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl.

Embodiment 13E9

- R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl.

Embodiment 13F

Compounds according to embodiment 13D, wherein R₂is C₁-C₂alkyl substituted with phenyl, wherein the phenyl is substituted with 1, or 2 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, methoxy, or C₁-C₂alkoxy optionally substituted with pyridyl, thiazolyl, methyl thiazol-5-yl. In another aspect, the phenyl is di-substituted and one of the groups is methoxy. In yet another aspect, the phenyl is di-substituted, one of the groups is methoxy and the other group is C₁-C₂alkoxy substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl. In one aspect, the other group is C₁alkoxy substituted with pyridyl, or methyl thiazol-5-yl. In yet another aspect, the other group is C₂alkoxy substituted with pyridyl, or methyl thiazol-5-yl.

Embodiment 13G

Compounds according to Embodiment 13, wherein

R₂is C₃-C₅alkyl substituted with phenyl, wherein the phenyl is optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, C₁-C₄alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein
- x is 0, 1, or 2;
- R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇;
- R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl; or
- R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl.

Embodiment 13G1

Compounds according to Embodiment 13G, wherein

R₂is C₃-C₅alkyl substituted with phenyl, wherein the phenyl is substituted with 1 or 2 groups that are independently —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein
- x is 0, 1, or 2;
- R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇;
- R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl; or
- R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl.

Embodiment 13G2

Compounds according to Embodiment 13G, wherein

R₂is C₃-C₅alkyl substituted with phenyl, wherein the phenyl is substituted with 1 or 2 groups that are independently —S(O)_x—R₂₅, or —(C₁-C₄alkyl)-S(O)_x—R₂₅; wherein
- x is 0, or 2; and
- R₂₅is C₁-C₆alkyl, or OH.

Embodiment 13G3

Compounds according to Embodiment 13G, wherein

R₂is C₃-C₅alkyl substituted with phenyl, wherein the phenyl is substituted with NR₂₆R₂₇; wherein
- R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl; or
- R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl.

Embodiment 13G4

Compounds according to Embodiment 13G, wherein

R₂is C₃-C₅alkyl substituted with phenyl, wherein the phenyl is substituted with NR₂₆R₂₇; wherein
- R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl.

Embodiment 13G5

Compounds according to Embodiment 13G, wherein R₂is C₃-C₅alkyl substituted with phenyl, wherein the phenyl is substituted with NR₂₆R₂₇; wherein

Embodiment 13H

Compounds according to Embodiment 13G, wherein R₂is C₃-C₄alkyl substituted with phenyl, wherein the phenyl is optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, C₁-C₄alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, or OH.

Embodiment 13I

Compounds according to Embodiment 13H, wherein R₂is C₃-C₄alkyl substituted with phenyl, wherein the phenyl is unsubstituted. In one aspect, the C₃alkyl group is a straight chained alkyl group. In another aspect, the C₄alkyl group is a straight chained C₃alkyl group substituted with a methyl group.

Embodiment 13J

Compounds according to embodiment 13H, wherein R₂is C₃-C₄alkyl substituted with phenyl, wherein the phenyl is substituted with 1, or 2 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, C₁-C₃alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, or OH.

Embodiment 13K

Compounds according to embodiment 13J, wherein R₂is C₃-C₄alkyl substituted with phenyl, wherein the phenyl is substituted with 1 or 2 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, C₁-C₂alkoxy, C₁-C₄alkyl, or OH.

Embodiment 13L

Compounds according to embodiment 13J, wherein R₂is C₃-C₄alkyl substituted with phenyl, wherein the phenyl is substituted with 2 methoxy groups.

Embodiment 13L1

Compounds according to Embodiment 13K, wherein R₂is C₃-C₄alkyl substituted with phenyl, wherein the phenyl is substituted with 1 or 2 groups that are independently CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, or —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl. In another aspect, the C₁-C₄alkoxycarbonyl is a methoxy carbonyl or ethoxycarbonyl. More preferably, it is ethoxycarbonyl.

Embodiment 13L2

Compounds according to Embodiment 13K, wherein R₂is C₃-C₄alkyl substituted with phenyl, wherein the phenyl is substituted with 1 or 2 groups that are independently CO₂H, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, or —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl. In another aspect, the phenyl group is substituted with 1 group selected that is CO₂H, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, or —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl.

Embodiment 13L3

Compounds according to embodiment 13K, wherein R₂is C₃-C₄alkyl substituted with phenyl, wherein the phenyl is substituted with 1 or 2 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, or OH.

Embodiment 13L4

Compounds according to embodiment 13K, wherein R₂is C₃-C₄alkyl substituted with phenyl, wherein the phenyl is substituted with 1 or 2 groups that are independently halogen, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, or OH.

Embodiment 13M

Compounds according to embodiment 13J, wherein R₂is C₃-C₄alkyl substituted with phenyl, wherein the phenyl is substituted with 1, or 2 groups that are independently halogen, methoxy, or C₁-C₂alkoxy optionally substituted with pyridyl, thiazolyl, methyl thiazol-5-yl. In another aspect, the phenyl is di-substituted and one of the groups is methoxy. In yet another aspect, the phenyl is di-substituted, one of the groups is methoxy and the other group is C₁-C₂alkoxy substituted with pyridyl, thiazolyl, methyl thiazol-5-yl. In one aspect, the other group is C₁alkoxy substituted with pyridyl, or methyl thiazol-5-yl. In yet another aspect, the other group is C₂alkoxy substituted with pyridyl, or methyl thiazol-5-yl.

Embodiment 13N

Compounds according to embodiment 12, wherein R₂is C₁-C₆alkyl substituted with benzofuranyl, 1,4-benzodioxanyl, or 1,3-benzodioxolyl. In another aspect, the alkyl group is C₁-C₄alkyl. In still another aspect, the alkyl group is C₂-C₅alkyl. In yet still another aspect, the alkyl group is C₃-C₅alkyl.

Embodiment 13O

Compounds according to any one of embodiments 13A, 13B, 13C, 13D, 13E, 13E1, 13E2, 13E3, 13E4, 13E5, 13E6, 13E7, 13E8, 13E9, 13F, 13G, 13H, 13H1, 13H2, 13H3, 13H4, 13H5, 13I, 13J, 13K, 13L, 13L1, 13L2, 13L3, 13L4, 13M, or 13N wherein

R₃is H, or halogen;
R₄is halogen, methyl, CF₃, or methoxy; and
R_3′ is H, or halogen.

Embodiment 13P

Compounds according to embodiment 13O, wherein R₃is H; R₄is halogen (preferably F or Cl, more preferably Cl), methyl, or CF₃; and R_3′ is H. In another aspect, R₄is methyl. In still another aspect, R₄is CF₃. In yet another aspect, R₄is Cl.
In embodiment 14, the invention provides compounds according to embodiment 6, wherein

R₂is C₃-C₈alkenyl, optionally substituted with 1 or 2 groups that are independently phenyl, halogen, 2H-chromenyl, 1,2,3,4-tetrahydronaphthalenyl, indolyl, 3,4-dihydronaphthalenyl, naphthyl, C₃-C₈cycloalkyl, benzofuranyl, indolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, pyridyl, C₁-C₄alkyl, halogen, —CO₂—(C₁-C₄alkyl), pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, triazolyl, or pyrimidyl;
- wherein the cyclic portions of each of the above are optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(G)NH₂, —C(G)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, C₁-C₄alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, —S(C))_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein
- x is 0, 1, or 2;
- R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇;
- R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl; or
- R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl.

Embodiment 14A

Compounds according to embodiment 14, wherein R₂is C₃-C₈alkenyl, which is optionally substituted with 2H-chromenyl, 1,2,3,4-tetrahydronaphthalenyl, indolyl, 3,4-dihydronaphthalenyl, naphthyl, C₃-C₈cycloalkyl, benzofuranyl, indolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, pyridyl, triazolyl, or pyrimidyl; wherein the cyclic portions of each of the above are optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(G)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₂-C₄)alkyl(C₁-C₄)alkyl, C₁-C₄alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein

In another aspect, R₂is C₃-C₆alkenyl, which is optionally substituted as above. In yet another aspect, R₂is C₃-C₅alkenyl, which is optionally substituted as above. In another aspect, R₂is C₄-C₇alkenyl, which is optionally substituted as above.

Embodiment 14B

Compounds according to embodiment 14, wherein R₂is C₃-C₈alkenyl, which is substituted with 1 or 2 groups which are independently C₁-C₄alkyl, halogen, —CO₂—(C₁-C₄alkyl), pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, pyridyl, triazolyl, or pyrimidyl; wherein the cyclic portions of each of the above are optionally substituted with 1, or 2 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, C₁-C₄alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein

In another aspect, R₂is C₃-C₆alkenyl, which is optionally substituted as above. In yet another aspect, R₂is C₃-C₅alkenyl, which is optionally substituted as above. In another aspect, the C₃-C₅alkenyl is substituted with a halogen (preferably Cl or Br.) In still another aspect, R₂is C₄-C₇alkenyl, which is optionally substituted as above. In another aspect, the C₄-C₇alkenyl is substituted with a halogen (preferably Cl or Br.)

Embodiment 14C

Compounds according to embodiment 14, wherein R₂is C₃-C₆alkenyl, which is substituted with 2H-chromenyl, 1,2,3,4-tetrahydronaphthalenyl, 3,4-dihydronaphthalenyl, naphthyl, or C₃-C₈cycloalkyl, wherein the cyclic portions of each of the above are optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, C₁-C₄alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein

Embodiment 14D

Compounds according to embodiment 14, wherein R₂is C₃-C₄alkenyl, which is substituted with 2H-chromenyl, 1,2,3,4-tetrahydronaphthalenyl, 3,4-dihydronaphthalenyl, naphthyl, or C₃-C₈cycloalkyl.

Embodiment 14E

Compounds according to embodiment 14, wherein R₂is C₃-C₄alkenyl, which substituted with 1,2,3,4-tetrahydronaphthalenyl, 3,4-dihydronaphthalenyl, or naphthyl.

Embodiment 14F

Compounds according to embodiment 14, wherein R₂is C₃-C₆alkenyl, substituted with C₃-C₈cycloalkyl. In another aspect, the C₃-C₈cycloalkyl group is substituted with one or two methyl groups. In still another aspect, the C₃-C₈cycloalkyl group is substituted with only —CH₂—OH. In yet still another aspect, the C₃-C₈cycloalkyl group is substituted with one methyl group and one —CH₂—OH.

Embodiment 14G

Compounds according to embodiment 14, wherein R₂is C₃-C₆alkenyl, substituted with C₃-C₆cycloalkyl. In another aspect, the C₃-C₆cycloalkyl group is substituted with one or two methyl groups. In still another aspect, the C₃-C₆cycloalkyl group is substituted with only —CH₂—OH. In yet still another aspect, the C₃-C₆cycloalkyl group is substituted with one methyl group and one —CH₂—OH.

Embodiment 14H

Compounds according to embodiment 14, wherein R₂is C₃-C₄alkenyl, substituted with C₅-C₆cycloalkyl. In another aspect, the C₅-C₆cycloalkyl group is substituted with one or two methyl groups. In still another aspect, the C₅-C₆cycloalkyl group is substituted with only —CH₂—OH. In yet still another aspect, the C₅-C₆cycloalkyl group is substituted with one methyl group and one —CH₂—OH. In one aspect, the methyl group and the —CH₂—OH group are in a 1, 2 relationship relative to each other. In another aspect, the methyl group and the —CH₂—OH group are in a 1, 3 relationship relative to each other.

Embodiment 14I

Compounds according to embodiment 14, wherein R₂is C₃-C₄alkenyl, substituted with C₆cycloalkyl. In another aspect, the C₆cycloalkyl group is substituted with one or two methyl groups. In still another aspect, the C₆cycloalkyl group is substituted with only —CH₂—OH. In yet still another aspect, the C₆cycloalkyl group is substituted with one methyl group and one —CH₂—OH. In one aspect, the methyl group and the —CH₂—OH group are in a 1, 2 relationship relative to each other. In another aspect, the methyl group and the —CH₂—OH group are in a 1, 3 relationship relative to each other.

Embodiment 14J

Compounds according to embodiment 14, wherein R₂is C₃-C₆alkenyl, substituted with 2H-chromenyl, indolyl, benzofuranyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, pyridyl, triazolyl, or pyrimidyl; wherein the cyclic portions of each of the above are optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, C₁-C₄alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein

In another aspect, the cyclic portion of R₂is not substituted.

Embodiment 14K

Compounds according to embodiment 14, wherein R₂is C₃-C₆alkenyl, substituted with 2H-chromenyl, indolyl, benzofuranyl, 1,4-benzodioxanyl, or 1,3-benzodioxolyl; wherein the cyclic portions of each of the above are optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, C₁-C₄alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein

In another aspect, the cyclic portion of R₂is not substituted.

Embodiment 14L

Compounds according to embodiment 14, wherein R₂is C₃-C₆alkenyl, substituted with pyridyl, or pyrimidyl; wherein the cyclic portions of each of the above are optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, C₁-C₄alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein x is 0, 1, or 2; R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇;

R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl; or R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl. In another aspect, the cyclic portion of R₂is not substituted. In still another aspect, the pyridyl group is pyrid-2-yl, pyrid-3-yl, which is optionally substituted with one group that is methyl, methoxy, or halogen.

Embodiment 14M

Compounds according to embodiment 14, wherein

R₂is C₃-C₈alkenyl. In another aspect, R₂is C₃-C₆alkenyl. In still another aspect, R₂is C₃-C₅alkenyl. In yet still another aspect, R₂is C₄-C₆alkenyl.

Embodiment 14N

Compounds according to embodiment 14, wherein R₂is C₃-C₆alkenyl, substituted with benzofuranyl, 1,4-benzodioxanyl, or 1,3-benzodioxolyl.

Embodiment 14N1

Compounds according to Embodiment 14N, wherein R₂is C₃-C₆alkenyl, substituted with 1,4-benzodioxanyl, or 1,3-benzodioxolyl.

Embodiment 14N2

Compounds according to Embodiment 14, wherein R₂is C₃-C₆alkenyl, substituted with halogen or —CO₂—(C₁-C₃alkyl).

Embodiment 14N3

Compounds according to embodiment 14, wherein R₂is C₃-C₆alkenyl, substituted with at least one triazolyl, which is optionally substituted as described in embodiment 14. In another aspect, the triazolyl group is unsubstituted. In still another aspect, the triazolyl group is substituted with only one group.

Embodiment 14O

Compounds according to embodiments 14 14A, 14B, 14C, 14D, 14E, 14F, 14, G, 14H, 14I, 14J, 14K, 14L, 14M, 14N, 14N1, 14N2, or 14N3, wherein R₁is C₁-C₈alkyl. In another aspect, R₁is C₂-C₈alkyl. In still another aspect, R₁is C₃-C₆alkyl. In yet still another aspect, R₁is C₂-C₅alkyl. In another aspect, R₁is C₆-C₈alkyl. In still another aspect, C₇-C₈alkyl.

Embodiment 14P

Compounds according to embodiments 14 14A, 14B, 14C, 14D, 14E, 14F, 14G, 14H, 14I, 14J, 14K, 14L, 14M, or 14N wherein R₁is C₁-C₈hydroxyalkyl. In another aspect, R₁is C₂-C₆hydroxyalkyl. In still another aspect, R₁is C₃-C₆hydroxyalkyl. In yet still another aspect, R₁is C₄-C₆hydroxyalkyl. In yet still another aspect, R₁is C₅-C₆hydroxyalkyl. In another aspect, R₁is C₂-C₈hydroxyalkyl.

Embodiment 14Q

Compounds according to Embodiment 14N, wherein

R₁is

Embodiment 14R

Compounds according to Embodiment 14O, Embodiment 14P, or Embodiment 14Q wherein R₃is H, or halogen;

R₄is halogen, methyl, CF₃, or methoxy; and R_3′ is H, or halogen.

Embodiment 14S

Compounds according to Embodiment 140 Embodiment 14P, or Embodiment 14Q wherein R₃is H; R₄is halogen (preferably F or Cl, more preferably Cl), methyl or CF₃; and R_3′ is H. In another aspect, R₄is methyl. In still another aspect, R₄is CF₃. In yet another aspect, R₄is Cl.
In embodiment 15, the invention provides compounds according to embodiment 14, wherein

R₂is C₃-C₆alkenyl, optionally substituted with 1 or 2 groups that are phenyl, halogen, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, triazolyl, or pyrimidyl; wherein the phenyl group is optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₂-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₂-C₄)alkyl, C₁-C₄alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein
- x is 0, 1, or 2;
- R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇;
- R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl; or
- R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl.

Embodiment 15A

Compounds according to embodiment 15, wherein R₂is C₃-C₆alkenyl substituted with phenyl; wherein the phenyl group is optionally substituted with 1, 2, or 3 groups that are independently halogen (in one aspect, F or Cl), CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, C₁-C₄alkoxy, C₁-C₄alkyl, or OH.

Embodiment 15B

Compounds according to embodiment 15, wherein R₂is C₃-C₆alkenyl.

Embodiment 15C

Compounds according to embodiment 15, wherein R₂is C₃-C₅alkenyl substituted with phenyl; wherein the phenyl group is optionally substituted with 1 or 2 groups that are independently halogen (in one aspect, F or Cl), CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, C₁-C₄alkoxy, or C₁-C₄alkoxy substituted with pyridyl, thiazolyl, methyl thiazol-5-yl, —S(O)_x—R₂₅, or —(C₁-C₄alkyl)-S(O)_x—R₂₅; wherein

Embodiment 15D

Compounds according to embodiment 15, wherein R₂is C₃-C₅alkenyl substituted with phenyl; wherein the phenyl group is substituted with 2 methoxy groups. In one aspect, the methoxy groups are in a 1, 2 relationship relative to each other. In another aspect, the methoxy groups are in a 1, 3 relationship relative to each other.

Embodiment 15D1

Compounds according to Embodiment 15C, wherein R₂is C₃-C₅alkenyl substituted with phenyl, wherein the phenyl is substituted with 1 or 2 groups that are independently CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, or —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl. In another aspect, the C₁-C₄alkoxycarbonyl is a methoxy carbonyl or ethoxycarbonyl. More preferably, it is ethoxycarbonyl.

Embodiment 15D2

Compounds according to Embodiment 15C, wherein R₂is C₃-C₅alkenyl substituted with phenyl, wherein the phenyl is substituted with 1 or 2 groups that are independently CO₂H, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, or —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl. In another aspect, the phenyl group is substituted with 1 group selected that is CO₂H, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, or —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl.

Embodiment 15D3

Compounds according to embodiment 15C, wherein R₂is C₃-C₅alkenyl substituted with phenyl, wherein the phenyl is substituted with 1 or 2 groups that are independently halogen (in one aspect, F, Cl, or Br in another aspect, Br or F), CO₂H, C₁-C₄alkoxycarbonyl, or OH. In one aspect, the halogen is meta relative to the point of attachment of the alkenyl group to the phenyl group. In another aspect, the halogen is ortho relative to the point of attachment of the alkenyl group to the phenyl group.

Embodiment 15D4

Compounds according to embodiment 15C, wherein R₂is C₃-C₅alkenyl substituted with phenyl, wherein the phenyl is substituted with 1 or 2 groups that are independently halogen (in one aspect, F, Cl, or Br in another aspect, Br or F), —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, or OH. In one aspect, the halogen is meta relative to the point of attachment of the alkenyl group to the phenyl group. In another aspect, the halogen is ortho relative to the point of attachment of the alkenyl group to the phenyl group.

Embodiment 15D5

Compounds according to embodiment 15C, wherein R₂is C₃-C₅alkenyl substituted with phenyl, wherein the phenyl is substituted with 1 or 2 groups that are independently —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein

Embodiment 15D6

- x is 0, 1, or 2;
- R₂₅is C₁-C₆alkyl, or OH.

Embodiment 15D7

Compounds according to embodiment 15C, wherein R₂is C₃-C₅alkenyl substituted with phenyl, wherein the phenyl is substituted with 1 group that is NR₂₆R₂₇; wherein

R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl.

Embodiment 15D8

R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl.

Embodiment 15E

Compounds according to embodiment 15, wherein R₂is C₃-C₅alkenyl substituted with phenyl; wherein the phenyl group is substituted with 1 methoxy group. In another aspect, the phenyl group is substituted with 1 methoxy group and C₂-C₃alkoxy substituted with pyridyl, thiazolyl, methyl thiazol-5-yl.

Embodiment 15F

Compounds according to embodiment 15, wherein R₂is C₃-C₅alkenyl substituted with phenyl, which is unsubstituted.

Embodiment 15G

Compounds according to embodiment 15, wherein R₂is C₃-C₅alkenyl substituted with phenyl; wherein the phenyl group is substituted with 1 halogen and 1 methoxy group.

Embodiment 15G1

Compounds according to embodiment 15, wherein R₂is C₃-C₅alkenyl substituted with phenyl, wherein the phenyl is substituted with 1 or 2 groups that are independently halogen, CO₂H, or C₁-C₄alkoxycarbonyl.

Embodiment 15H

Compounds according to embodiment 15, wherein

R₂is

wherein

R₁₀is C₁-C₄alkyl (in one aspect, methyl), halogen (in one aspect, Cl or Br), phenyl, pyridyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl; and the phenyl group is unsubstituted or substituted as in any one of Embodiments 15A, 15C, 15D, 15D1, 15D2, 15D3, 15D4, 15D5, 15D6, 15D7, 15D8, 15E, or 15G. In one aspect, R₁₀is methyl chloro or bromo. In another aspect, R₁₀is phenyl or pyridyl. In still another aspect, R₁₀is pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, or thiadiazolyl. In yet another aspect, R₁₀is pyrazolyl or imidazolyl. In another aspect, R₁₀is oxazolyl, isoxazolyl, or oxadiazolyl. In another aspect, R₁₀is thiazolyl or thiadiazolyl.

Embodiment 15I

Compounds according to any one of embodiments 15, 15A, 15B, 15C, 15D, 15D1, 15D2, 15D3, 15D4, 15D5, 15D6, 15D7, 15D8, 15E, 15F, 15G, 15G1, or 15H wherein R₁is C₁-C₈hydroxyalkyl. In another aspect, R₁is a C₃-C₆hydroxyalkyl. In still another aspect, R₁is a C₅-C₆hydroxyalkyl. In another aspect, R₁is C₇-C₈hydroxyalkyl.

Embodiment 15J

Compounds according to Embodiment 15I,
wherein

R₁is

Embodiment 15K

Compounds according to any one of embodiments 15, 15A, 15B, 15C, 15D, 15E, 15F, 15G, 15G1, or 15H wherein R₁is C₁-C₈alkyl. In another aspect, R₁is a C₃-C₆alkyl. In still another aspect, R₁is a C₅-C₆alkyl. In another aspect, R₁is C₇-C₈alkyl.

Embodiment 15L

Compounds according to any one of embodiments 15, 15A, 15B, 15C, 15D, 15D1, 15D2, 15D3, 15D4, 15E, 15F, 15G, 15G1, 15H, 15I, 15J, or 15K, wherein

R₃is H, halogen, C₁-C₄alkyl, C₁-C₄alkoxy, CF₂, CN;
R₄is H, halogen, C₁-C₄alkoxy, CF₃, OCF₃, CN, phenyloxy, —SO₂—(C₁-C₆alkyl), —NHR′, —NR′R″, C₁-C₄alkanoyl, pyridyl, furanyl or thienyl, phenyl, or C₁-C₄alkyl optionally substituted with —CO₂—(C₁-C₆alkyl);
R_3′ is H, or halogen;
- R′ is H, C₁-C₄alkyl, benzyl, C₁-C₆alkanoyl, phenyl(C₁-C₄)alkanoyl, pyridyl(C₁-C₄)alkyl, —SO₂-alkyl, —SO₂-phenyl, —SO₂-pyridyl, pyridyl(C₁-C₆)alkanoyl, wherein the alkyl portion of the alkyl and alkanoyl groups are optionally substituted with halogen or C₁-C₄alkoxy,
  - wherein the phenyl and pyridyl groups are optionally substituted with C₁-C₄alkyl, C₁-C₄alkoxy, halogen, CF₂, OCF₃;
- R″ is H or C₁-C₆alkyl, wherein the alkyl group is optionally substituted with halogen.

Embodiment 15M

Compounds according to Embodiment 15L, wherein

R₃is H, halogen, methyl, methoxy, CF₂, or CN;
R₄is halogen, methyl, methoxy, CF₂, OCF₃, CN, —NHR′, or —NR′R″; and
R_3′ is H, or halogen;
- R′ is H, or C₁-C₄alkyl; and
- R″ is H or C₁-C₆alkyl, wherein the alkyl group is optionally substituted with halogen.

Embodiment 15N

Compounds according to Embodiment 15M wherein R₃is H, or halogen; R₄is halogen, methyl, CF₃, or methoxy; and R_3′ is H, or halogen.

Embodiment 15O

Compounds according to Embodiment 15N wherein R₃is H; R₄is halogen (preferably F or Cl, more preferably Cl), methyl or CF₃; and R_3′ is H. In another aspect, R₄is methyl. In still another aspect, R₄is CF₃. In yet another aspect, R₄is Cl.
In embodiment 16, the invention provides compounds according to Formula I, wherein

R₁is C₃-C₈cycloalkyl optionally substituted with 1 or 2 groups that are independently C₁-C₄alkyl, C₁-C₄hydroxyalkyl, or OH; or
R₁is heterocycloalkyl or heterocycloalkyl(C₁-C₄)alkyl wherein the heterocycloalkyl group is piperidinyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolyl, or morpholinyl, wherein the heterocycloalkyl groups are optionally substituted with 1 or 2 groups that are independently C₁-C₄alkyl, C₁-C₄alkoxy, phenyl, phenyl(C₁-C₄)alkyl, OH, halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, or C₁-C₄alkoxycarbonyl; or
R₁is heteroaryl(C₈-C₄)alkyl, wherein the heteroaryl group is pyridyl, pyrimidyl, furanyl, or thienyl and the heteroaryl group is optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₈-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, C₁-C₄alkyl, C₁-C₄alkoxy or OH.

Embodiment 16A

Compounds according to any one of embodiments 15H, 15I, 15J, 15K, 15L, 15M, 15N, 15O, or 16, wherein R₁₀is methyl, chloro, or bromo.
In embodiment 17, the invention provides compounds according to embodiment 16, wherein

R₂is C₁-C₈alkyl, or C₂-C₈alkenyl, each of which is optionally substituted with 1 or 2 groups that are independently, 2H-chromenyl, 1,2,3,4-tetrahydronaphthalenyl, indolyl, 3,4-dihydronaphthalenyl, phenyl, naphthyl, C₃-C₈cycloalkyl, benzofuranyl, indolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, pyridyl, pyrimidyl, C₁-C₄alkyl, halogen, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, furanyl, triazolyl, or CN,
- wherein the cyclic portions of each of the above are optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, C₁-C₄alkoxy, C₁-C₄alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, NO₂, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein
- x is 0, 1, or 2;
- R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇;
- R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl; or
- R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl.

Embodiment 17A

Compounds according to embodiment 17, wherein

R₂is C₁-C₂alkyl substituted with phenyl, wherein the phenyl is optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, C₁-C₄alkoxy, C₁-C₄alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein
- x is 0, 1, or 2;
- R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇;
- R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl; or
- R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl.

Embodiment 17B

Compounds according to Embodiment 17A, wherein R₂is C₁-C₂alkyl substituted with phenyl, wherein the phenyl is unsubstituted.

Embodiment 17C

Compounds according to embodiment 17A, wherein

R₂is C₁-C₂alkyl substituted with phenyl, wherein the phenyl is substituted with 1, or 2 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, C₁-C₄alkoxy, C₁-C₃alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein
- x is 0, 1, or 2;
- R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇;
- R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl; or
- R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl.

Embodiment 17C1

Compounds according to embodiment 17C, wherein R₂is C₁-C₂alkyl substituted with phenyl, wherein the phenyl is substituted with 1, or 2 groups that are independently —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein

Embodiment 17C2

Compounds according to embodiment 17C, wherein R₂is C₁-C₂alkyl substituted with phenyl, wherein the phenyl is substituted with 1, or 2 groups that are independently —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein x is 0, 1, or 2; R₂₅is C₁-C₆alkyl, or OH.

Embodiment 17C3

Compounds according to embodiment 17C, wherein R₂is C₁-C₂alkyl substituted with phenyl, wherein the phenyl is substituted with 1 group that is NR₂₆R₂₇; wherein R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl.

Embodiment 17C4

Compounds according to embodiment 17C, wherein R₂is C₁-C₂alkyl substituted with phenyl, wherein the phenyl is substituted with 1 group that is NR₂₆R₂₇; wherein R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl.

Embodiment 17D

Compounds according to embodiment 17C, wherein R₂is C₁-C₂alkyl substituted with phenyl, wherein the phenyl is substituted with 1, or 2 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, C₁-C₄alkoxy, C₁-C₂alkoxy, C₁-C₄alkyl, or OH.

Embodiment 17E

Compounds according to embodiment 17D, wherein R₂is C₁-C₂alkyl substituted with phenyl, wherein the phenyl is substituted with 2 methoxy groups.

Embodiment 17E1

Compounds according to Embodiment 17D, wherein R₂is C₁-C₂alkyl substituted with phenyl, wherein the phenyl is substituted with 1 or 2 groups that are independently CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, or —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl. In another aspect, the C₁-C₄alkoxycarbonyl is a methoxy carbonyl or ethoxycarbonyl. More preferably, it is ethoxycarbonyl.

Embodiment 17E2

Compounds according to Embodiment 17D, wherein R₂is C₁-C₂alkyl substituted with phenyl, wherein the phenyl is substituted with 1 or 2 groups that are independently CO₂H, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, or —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl. In another aspect, the phenyl group is substituted with 1 group selected that is CO₂H, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, or —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl.

Embodiment 17E3

Compounds according to embodiment 17D, wherein R₂is C₁-C₂alkyl substituted with phenyl, wherein the phenyl is substituted with 1 or 2 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, or OH.

Embodiment 17E4

Compounds according to embodiment 17D, wherein R₂is C₁-C₂alkyl substituted with phenyl, wherein the phenyl is substituted with 1 or 2 groups that are independently halogen, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, or OH.

Embodiment 17F

Compounds according to embodiment 17D, wherein

R₂is C₁-C₂alkyl substituted with phenyl, wherein the phenyl is substituted with 1, or 2 groups that are independently halogen, methoxy, or C₁-C₂alkoxy optionally substituted with pyridyl, thiazolyl, methyl thiazol-5-yl. In another aspect, the phenyl is di-substituted and one of the groups is methoxy. In yet another aspect, the phenyl is di-substituted, one of the groups is methoxy and the other group is C₁-C₂alkoxy substituted with pyridyl, thiazolyl, methyl thiazol-5-yl. In one aspect, the other group is C₁alkoxy substituted with pyridyl, or methyl thiazol-5-yl. In yet another aspect, the other group is C₂alkoxy substituted with pyridyl, or methyl thiazol-5-yl.

Embodiment 17G

Compounds according to Embodiment 17, wherein

R₂is C₃-C₅alkyl substituted with phenyl, wherein the phenyl is optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, C₁-C₄alkoxy, C₁-C₄alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein
- x is 0, 1, or 2;
- R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇;
- R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl; or
- R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl.

Embodiment 17H

Compounds according to Embodiment 17G, wherein

R₂is C₃-C₄alkyl substituted with phenyl, wherein the phenyl is optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, C₁-C₄alkoxy, C₁-C₄alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein
- x is 0, 1, or 2;
- R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇;
- R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl; or
- R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl.

Embodiment 17H1

Compounds according to embodiment 17H, wherein R₂is C₃-C₄alkyl substituted with phenyl, wherein the phenyl is substituted with 1, or 2 groups that are independently

—S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein
- x is 0, 1, or 2;
- R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇;
- R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl; or
- R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl.

Embodiment 17H2

—S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein
- x is 0, 1, or 2;
- R₂₅is C₁-C₆alkyl, or OH.

Embodiment 17H3

Compounds according to embodiment 17H, wherein R₂is C₃-C₄alkyl substituted with phenyl, wherein the phenyl is substituted with 1 group that is NR₂₆R₂₇: wherein R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl.

Embodiment 17H4

Compounds according to embodiment 17H, wherein R₂is C₃-C₄alkyl substituted with phenyl, wherein the phenyl is substituted with 1 group that is NR₂₆R₂₇; wherein R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl.

Embodiment 17I

Compounds according to Embodiment 17H, wherein R₂is C₃-C₄alkyl substituted with phenyl, wherein the phenyl is unsubstituted. In one aspect, the C₃alkyl group is a straight chained alkyl group. In another aspect, the C₄alkyl group is a straight chained C₃alkyl group substituted with a methyl group.

Embodiment 17J

Compounds according to embodiment 17H, wherein

R₂is C₃-C₄alkyl substituted with phenyl, wherein the phenyl is substituted with 1, or 2 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, C₁-C₄alkoxy, C₁-C₃alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, or OH.

Embodiment 17K

Compounds according to embodiment 17J, wherein

R₂is C₃-C₄alkyl substituted with phenyl, wherein the phenyl is substituted with 1, or 2 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, C₁-C₄alkoxy, C₁-C₂alkoxy, C₁-C₄alkyl, or OH.

Embodiment 17K1

Compounds according to Embodiment 17K, wherein R₂is C₃-C₄alkyl substituted with phenyl, wherein the phenyl is substituted with 1 or 2 groups that are independently CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, or —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl. In another aspect, the C₁-C₄alkoxycarbonyl is a methoxy carbonyl or ethoxycarbonyl. More preferably, it is ethoxycarbonyl.

Embodiment 17K2

Compounds according to Embodiment 17K, wherein R₂is C₃-C₄alkyl substituted with phenyl, wherein the phenyl is substituted with 1 or 2 groups that are independently CO₂H, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, or —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl. In another aspect, the phenyl group is substituted with 1 group selected that is CO₂H, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, or —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl.

Embodiment 17K3

Compounds according to embodiment 17K, wherein R₂is C₃-C₄alkyl substituted with phenyl, wherein the phenyl is substituted with 1 or 2 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, or OH.

Embodiment 17K4

Compounds according to embodiment 17K, wherein R₂is C₃-C₄alkyl substituted with phenyl, wherein the phenyl is substituted with 1 or 2 groups that are independently halogen, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, or OH.

Embodiment 17L

Compounds according to embodiment 17J, wherein

R₂is C₃-C₄alkyl substituted with phenyl, wherein the phenyl is substituted with 2 methoxy groups.

Embodiment 17M

Compounds according to embodiment 17J, wherein R₂is C₃-C₄alkyl substituted with phenyl, wherein the phenyl is substituted with 1, or 2 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, methoxy, or C₁-C₂alkoxy optionally substituted with pyridyl, thiazolyl, methyl thiazol-5-yl. In another aspect, the phenyl is di-substituted and one of the groups is methoxy. In yet another aspect, the phenyl is di-substituted, one of the groups is methoxy and the other group is C₁-C₂alkoxy substituted with pyridyl, thiazolyl, methyl thiazol-5-yl. In one aspect, the other group is C₁alkoxy substituted with pyridyl, or methyl thiazol-5-yl. In yet another aspect, the other group is C₂alkoxy substituted with pyridyl, or methyl thiazol-5-yl.

Embodiment 17N

Compounds according to embodiment 17, wherein R₂is C₁-C₆alkyl substituted with 1,4-benzodioxanyl, or 1,3-benzodioxolyl. In another aspect, the alkyl group is C₁-C₄alkyl. In still another aspect, the alkyl group is C₂-C₅alkyl. In yet still another aspect, the alkyl group is C₃-C₅alkyl. In another aspect, R₂is C₃-C₈alkyl. In yet another aspect, R₂is C₅-C₈alkyl. In still another aspect, R₂is C₇-C₈alkyl. In still another aspect, R₂is C₅-C₇alkyl.

Embodiment 17O

Compounds according to embodiment 17, wherein R₂is C₃-C₈alkenyl, which is optionally substituted with 2H-chromenyl, 1,2,3,4-tetrahydronaphthalenyl, indolyl, 3,4-dihydronaphthalenyl, naphthyl, C₃-C₈cycloalkyl, benzofuranyl, indolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, pyridyl, or pyrimidyl; wherein the cyclic portions of each of the above are optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, C₁-C₄alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein x is 0, 1, or 2; R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇; R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl; or R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl.

Embodiment 17P

Compounds according to embodiment 17, wherein R₂is C₃-C₈alkenyl, which is substituted with 2H-chromenyl, 1,2,3,4-tetrahydronaphthalenyl, indolyl, 3,4-dihydronaphthalenyl, naphthyl, C₃-C₈cycloalkyl, benzofuranyl, indolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, pyridyl, or pyrimidyl; wherein the cyclic portions of each of the above are optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, C₁-C₄alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, or OH.

Embodiment 17Q

Compounds according to embodiment 17, wherein R₂is C₃-C₆alkenyl, which is substituted with 2H-chromenyl, 1,2,3,4-tetrahydronaphthalenyl, 3,4-dihydronaphthalenyl, naphthyl, or C₃-C₈cycloalkyl, wherein the cyclic portions of each of the above are optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, C₁-C₄alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein

x is 0, 1, or 2;
R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇; R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl; or R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl.

Embodiment 17Q1

Compounds according to embodiment 17Q, wherein R₂is C₃-C₅alkenyl which is substituted with 2H-chromenyl, 1,2,3,4-tetrahydronaphthalenyl, 3,4-dihydronaphthalenyl, naphthyl, or C₃-C₈cycloalkyl, wherein the cyclic portions of each of the above are optionally substituted with 1 or 2 groups that are independently —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein

Embodiment 17Q2

- x is 0, 1, or 2;
- R₂₅is C₁-C₆alkyl, or OH.

Embodiment 17Q3

Compounds according to embodiment 17Q, wherein R₂is C₃-C₅alkenyl which is substituted with 2H-chromenyl, 1,2,3,4-tetrahydronaphthalenyl, 3,4-dihydronaphthalenyl, naphthyl, or C₃-C₈cycloalkyl, wherein the cyclic portions of each of the above are optionally substituted with 1 group that is NR₂₆R₂₇; wherein

Embodiment 17Q4

Compounds according to embodiment 17Q, wherein R₂is C₃-C₅alkenyl which is substituted with 2H-chromenyl, 1,2,3,4-tetrahydronaphthalenyl, 3,4-dihydronaphthalenyl, naphthyl, or C₃-C₈cycloalkyl, wherein the cyclic portions of each of the above are optionally substituted with 1 group that is NR₂₆R₂₇; wherein R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl.

Embodiment 17R

Compounds according to embodiment 17, wherein R₂is C₃-C₄alkenyl, which is substituted with 2H-chromenyl, 1,2,3,4-tetrahydronaphthalenyl, 3,4-dihydronaphthalenyl, naphthyl, or C₃-C₈cycloalkyl.

Embodiment 17S

Compounds according to embodiment 17, wherein R₂is C₃-C₄alkenyl, which is substituted with 1,2,3,4-tetrahydronaphthalenyl, 3,4-dihydronaphthalenyl, or naphthyl.

Embodiment 17S1

Compounds according to embodiment 17, wherein R₂is C₃-C₅alkenyl, substituted with naphthyl, which is optionally substituted with two groups that are independently C₁-C₄alkyl, C₁-C₄alkoxy, or halogen. In another aspect, the naphthyl is unsubstituted.

Embodiment 17T

Compounds according to embodiment 17, wherein R₂is C₃-C₆alkenyl, substituted with C₃-C₈cycloalkyl. In another aspect, the C₃-C₈cycloalkyl group is substituted with one or two methyl groups. In still another aspect, the C₃-C₈cycloalkyl group is substituted with only —CH₂—OH. In yet still another aspect, the C₃-C₈cycloalkyl group is substituted with one methyl group and one —CH₂—OH.

Embodiment 17U

Compounds according to embodiment 17, wherein R₂is C₃-C₆alkenyl, substituted with C₃-C₆cycloalkyl. In another aspect, the C₃-C₆cycloalkyl group is substituted with one or two methyl groups. In still another aspect, the C₃-C₆cycloalkyl group is substituted with only —CH₂—OH. In yet still another aspect, the C₃-C₆cycloalkyl group is substituted with one methyl group and one —CH₂—OH.

Embodiment 17V

Compounds according to embodiment 17, wherein R₂is C₃-C₄alkenyl, substituted with C₅-C₆cycloalkyl. In another aspect, the C₅-C₆cycloalkyl group is substituted with one or two methyl groups. In still another aspect, the C₅-C₆cycloalkyl group is substituted with only —CH₂—OH. In yet still another aspect, the C₅-C₆cycloalkyl group is substituted with one methyl group and one —CH₂—OH. In one aspect, the methyl group and the —CH₂—OH group are in a 1, 2 relationship relative to each other. In another aspect, the methyl group and the —CH₂—OH group are in a 1, 3 relationship relative to each other.

Embodiment 17W

Compounds according to embodiment 17, wherein R₂is C₃-C₄alkenyl, substituted with C₆cycloalkyl. In another aspect, the C₆cycloalkyl group is substituted with one or two methyl groups. In still another aspect, the C₆cycloalkyl group is substituted with only —CH₂—OH. In yet still another aspect, the C₆cycloalkyl group is substituted with one methyl group and one —CH₂—OH. In one aspect, the methyl group and the —CH₂—OH group are in a 1, 2 relationship relative to each other. In another aspect, the methyl group and the —CH₂—OH group are in a 1, 3 relationship relative to each other.

Embodiment 17X

Compounds according to embodiment 17, wherein R₂is C₃-C₆alkenyl, substituted with 2H-chromenyl, indolyl, benzofuranyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, pyridyl, or pyrimidyl; wherein the cyclic portions of each of the above are optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, C₁-C₄alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein

In another aspect, the cyclic portion of R₂is not substituted.

Embodiment 17Y

Compounds according to embodiment 17, wherein R₂is C₃-C₆alkenyl, substituted with 2H-chromenyl, indolyl, benzofuranyl, 1,4-benzodioxanyl, or 1,3-benzodioxolyl; wherein the cyclic portions of each of the above are optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, C₁-C₄alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein

In another aspect, the cyclic portion of R₂is not substituted.

Embodiment 17Y1

Compounds according to embodiment 17Y, wherein R₂is C₃-C₅alkenyl which is substituted with 2H-chromenyl, indolyl, benzofuranyl, 1,4-benzodioxanyl, or 1,3-benzodioxolyl; wherein the cyclic portions of each of the above are optionally substituted with 1 or 2 groups that are independently

Embodiment 17Y2

Compounds according to embodiment 17Y, wherein R₂is C₃-C₅alkenyl which is substituted with 2H-chromenyl, indolyl, benzofuranyl, 1,4-benzodioxanyl, or 1,3-benzodioxolyl; wherein the cyclic portions of each of the above are optionally substituted with 1 or 2 groups that are independently —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein

- x is 0, 1, or 2;
- R₂₅is C₁-C₆alkyl, or OH.

Embodiment 17Y3

Compounds according to embodiment 17Y, wherein R₂is C₃-C₅alkenyl which is substituted with 2H-chromenyl, indolyl, benzofuranyl, 1,4-benzodioxanyl, or 1,3-benzodioxolyl; wherein the cyclic portions of each of the above are optionally substituted with 1 group that is NR₂₆R₂₇; wherein

Embodiment 17Y4

Embodiment 17Z

Compounds according to embodiment 17, wherein R₂is C₃-C₆alkenyl, substituted with pyridyl, or pyrimidyl, wherein the cyclic portions of each of the above are optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, C₁-C₄alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein x is 0, 1, or 2; R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇; R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl; or R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl. In another aspect, the cyclic portion of R₂is not substituted.

Embodiment 17Z1

Compounds according to embodiment 17Z, wherein R₂is C₃-C₅alkenyl which is substituted with pyridyl, or pyrimidyl, wherein the cyclic portions of each of the above are optionally substituted with 1 or 2 groups that are independently —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein x is 0, 1, or 2; R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇; R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl; or R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl.

Embodiment 17Z2

Compounds according to embodiment 17Z, wherein R₂is C₃-C₅alkenyl which is substituted with pyridyl, or pyrimidyl, wherein the cyclic portions of each of the above are optionally substituted with 1 or 2 groups that are independently —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein x is 0, 1, or 2; R₂₅is C₁-C₆alkyl, or OH.

Embodiment 17Z3

Compounds according to embodiment 17Z, wherein R₂is C₃-C₅alkenyl which is substituted with pyridyl, or pyrimidyl, wherein the cyclic portions of each of the above are optionally substituted with 1 group that is NR₂₆R₂₇; wherein

Embodiment 17Z4

Embodiment 17Z5

Compounds according to embodiment 17Z, wherein R₂is C₃-C₅alkenyl which is substituted with pyridyl, or pyrimidyl, wherein the cyclic portions of each of the above are optionally substituted with one halogen.

Embodiment 17AA

Compounds according to embodiment 17, wherein R₂is C₃-C₈alkenyl. In another aspect, R₂is C₃-C₇alkenyl. In still another aspect, R₂is C₃-C₅alkenyl. In yet still another aspect, R₂is C₄-C₆alkenyl.

Embodiment 17BB

Compounds according to embodiment 17, wherein R₂is C₃-C₆alkenyl, substituted with 1,4-benzodioxanyl, or 1,3-benzodioxolyl.

Embodiment 17CC

Compounds according to embodiment 17, wherein R₂is C₃-C₆alkenyl substituted with phenyl; wherein the phenyl group is optionally substituted with 1, 2, or 3 groups that are independently halogen, C₁-C₄alkoxy, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein

In another aspect, the cyclic portion of R₂is not substituted.

Embodiment 17CC1

Compounds according to embodiment 17CC, wherein R₂is C₃-C₅alkenyl substituted with phenyl, wherein the cyclic portions of each of the above are optionally substituted with 1 or 2 groups that are independently

Embodiment 17CC2

Embodiment 17CC3

Compounds according to embodiment 17CC, wherein R₂is C₃-C₅alkenyl substituted with phenyl, wherein the cyclic portions of each of the above are optionally substituted with 1 group that is NR₂₆R₂₇; wherein R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl.

Embodiment 17CC4

Compounds according to embodiment 17CC, wherein R₂is C₃-C₅alkenyl substituted with phenyl, wherein the cyclic portions of each of the above are optionally substituted with 1 group that is NR₂₆R₂₇; wherein R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl.

Embodiment 17DD

Compounds according to embodiment 17, wherein R₂is C₃-C₆alkenyl.

Embodiment 17EE

Compounds according to embodiment 17, wherein R₂is C₃-C₅alkenyl substituted with phenyl; wherein the phenyl group is optionally substituted with 1 or 2 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, C₁-C₄alkoxy, C₁-C₄alkoxy substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl.

Embodiment 17FF

Compounds according to embodiment 17, wherein R₂is C₃-C₅alkenyl substituted with phenyl; wherein the phenyl group is substituted with 2 methoxy groups. In one aspect, the methoxy groups are in a 1, 2 relationship relative to each other. In another aspect, the methoxy groups are in a 1, 3 relationship relative to each other.

Embodiment 17GG

Compounds according to embodiment 17, wherein R₂is C₃-C₅alkenyl substituted with phenyl; wherein the phenyl group is substituted with 1 methoxy group. In another aspect, the phenyl group is substituted with 1 methoxy group and C₂-C₃alkoxy substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl.

Embodiment 17HH

Compounds according to embodiment 17, wherein R₂is C₃-C₅alkenyl substituted with phenyl.

Embodiment 17II

Compounds according to embodiment 17, wherein R₂is C₃-C₅alkenyl substituted with phenyl; wherein the phenyl group is substituted with 1 halogen and 1 methoxy group.

Embodiment 17JJ

Compounds according to embodiment 17, wherein

R₂is

wherein

R₁₀is C₁-C₄alkyl (in one aspect, methyl), halogen (in one aspect, Cl or Br), phenyl, pyridyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl; and the phenyl group is unsubstituted or substituted as in any one of Embodiments 17CC, 17CC1, 17CC2, 17CC3, 17CC4, 17EE, 17FF, 17GG, 17HH, or 17II. In one aspect, R₁₀is methyl chloro or bromo. In another aspect, R₁₀is phenyl or pyridyl. In still another aspect, R₁₀is pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, or thiadiazolyl. In yet another aspect, R₁₀is pyrazolyl or imidazolyl. In another aspect, R₁₀is oxazolyl, isoxazolyl, or oxadiazolyl. In another aspect, R₁₀is thiazolyl or thiadiazolyl.

Embodiment 17KK

Compounds according to any one of embodiments 15, 17A, 17B, 17C, 17C1, 17C2, 17C3, 17C4, 17D, 17E, 17E1, 17E2, 17E3, 17E4, 17F, 17G, 17H, 17H1, 17H2, 17H3, 17H4, 17I, 17J, 17K, 17L, 17M, 17N, 17O, 17P, 17Q, 17Q1, 17Q2, 17Q3, 17Q4, 17R, 17S, 17T, 17U, 17V, 17W, 17X, 17Y, 17Y1, 17Y2, 17Y3, 17Y4, 17Z, 17Z1, 17Z2, 17Z3, 17Z4, 17Z5, 17AA, 17BB, 17CC, 17CC1, 17CC2, 17CC3, 17CC4, 17DD, 17EE, 17FF, 17GG, 17HH, 17II, or 17JJ wherein

R₃is H, halogen, C₁-C₄alkyl, C₁-C₄alkoxy, CF₃, CN;
R₄is H, halogen, C₁-C₄alkoxy, CF₃, OCF₃, CN, phenyloxy, —SO₂—(C₁-C₆alkyl), —NHR′, —NR′R″, C₁-C₄alkanoyl, pyridyl, furanyl or thienyl, phenyl, or C₁-C₄alkyl optionally substituted with —CO₂— (C₁-C₆alkyl);
R_3′ is H, or halogen;
- R′ is H, C₁-C₄alkyl, benzyl, C₁-C₆alkanoyl, phenyl(C₁-C₄)alkanoyl, pyridyl(C₁-C₄)alkyl, —SO₂-alkyl, —SO₂-phenyl, —SO₂-pyridyl, pyridyl(C₁-C₆)alkanoyl, wherein the alkyl portion of the alkyl and alkanoyl groups are optionally substituted with halogen or C₁-C₄alkoxy,
  - wherein the phenyl and pyridyl groups are optionally substituted with C₁-C₄alkyl, C₁-C₄alkoxy, halogen, CF₃, OCF₃;
- R″ is H or C₁-C₆alkyl, wherein the alkyl group is optionally substituted with halogen.

Embodiment 17LL

Compounds according to Embodiment 17KK, wherein

R₃is H, halogen, methyl, methoxy, CF₃, or CN;
R₄is halogen, methyl, methoxy, CF₃, OCF₃, CN, —NHR′, or —NR′R″;
R_3′ is H, or halogen;
- R′ is H, or C₁-C₄alkyl; and
- R″ is H or C₁-C₆alkyl, wherein the alkyl group is optionally substituted with halogen.

Embodiment 17MM

Compounds according to Embodiment 17LL wherein R₃is H, or halogen; R₄is halogen, methyl, CF₃, or methoxy; and R_3′ is H, or halogen.

Embodiment 17NN

Compounds according to Embodiment 17MM wherein R₃is H; R₄is halogen (preferably F or Cl, more preferably Cl), methyl, or CF₃; and R_3′ is H. In another aspect, R₄is methyl. In still another aspect, R₄is CF₃. In yet another aspect, R₄is Cl.

Embodiment 18

Compounds according to any one of Embodiments 17A, 17B, 17C, 17C1, 17C2, 17C3, 17C4, 17D, 17E, 17E1, 17E2, 17E3, 17E4, 17F, 17G, 17H, 17H1, 17H2, 17H3, 17H4, 17I, 17J, 17K, 17L, 17M, 17N, 17O, 17P, 17Q, 17Q1, 17Q2, 17Q3, 17Q4, 17R, 17S, 17T, 17U, 17V, 17W, 17X, 17Y, 17Y1, 17Y2, 17Y3, 17Y4, 17Z, 17Z1, 17Z2, 17Z3, 17Z4, 17AA, 17BB, 17CC, 17CC1, 17CC2, 17CC3, 17CC4, 17DD, 17EE, 17FF, 17GG, 17HH, 17II, 17JJ, 17KK, 17LL, 17MM, or 17NN, wherein R₁is C₃-C₈cycloalkyl optionally substituted with 1 or 2 groups that are independently C₁-C₄alkyl, C₁-C₄hydroxyalkyl, or OH.

Embodiment 18A

Compounds according to Embodiment 18, wherein the C₃-C₈cycloalkyl group is substituted with one or two methyl groups. In still another aspect, the C₃-C₈cycloalkyl group is substituted with only —CH₂—OH. In yet still another aspect, the C₃-C₈cycloalkyl group is substituted with one methyl group and one —CH₂—OH.

Embodiment 18B

Compounds according to Embodiment 18, wherein the cycloalkyl group is a C₃-C₆cycloalkyl group. In another aspect, the cycloalkyl group is substituted with one or two methyl groups. In still another aspect, the C₃-C₆cycloalkyl group is substituted with only —CH₂—OH. In yet still another aspect, the C₃-C₆cycloalkyl group is substituted with one methyl group and one —CH₂—OH. In another aspect, the cycloalkyl group is substituted with at least one OH group. In still another aspect, the cycloalkyl group is substituted with only one OH group. In still another aspect, the cycloalkyl group is a cyclopropyl group.

Embodiment 18C

Compounds according to Embodiment 18, wherein the cycloalkyl group is a C₅-C₆cycloalkyl. In another aspect, the C₅-C₆cycloalkyl group is substituted with one or two methyl groups. In one aspect, the cycloalkyl group is substituted with one methyl group. In another aspect, the cycloalkyl group is substituted with two methyl groups. In still another aspect, the C₅-C₆cycloalkyl group is substituted with only —CH₂—OH. In yet still another aspect, the C₅-C₆cycloalkyl group is substituted with one methyl group and one —CH₂—OH or one OH group. In another aspect, the cycloalkyl group is substituted with at least one OH group. In still another aspect, the cycloalkyl group is substituted with only one OH group. In one aspect, the methyl group and (the —CH₂—OH group or the OH group) are in a 1, 2 relationship relative to each other. In another aspect, the methyl group and (the —CH₂—OH group or the OH group) are in a 1, 3 relationship relative to each other. In still another aspect, the methyl group and (the —CH₂—OH group or the OH group) are in a 1,4 relationship relative to each other.

Embodiment 18D

Compounds according to Embodiment 18, wherein the cycloalkyl group is a C₆cycloalkyl. In another aspect, the C₆cycloalkyl group is substituted with one or two methyl groups. In one aspect, the cycloalkyl group is substituted with one methyl group. In still another aspect, the C₆cycloalkyl group is substituted with only —CH₂—OH. In yet still another aspect, the C₆cycloalkyl group is substituted with one methyl group and one —CH₂—OH. In another aspect, the cycloalkyl group is substituted with at least one OH group. In one aspect, the methyl group and (the —CH₂—OH group or the OH group) are in a 1, 2 relationship relative to each other. In another aspect, the methyl group and (the —CH₂—OH group or the OH group) are in a 1, 3 relationship relative to each other. In still another aspect, the methyl group and (the —CH₂—OH group or the OH group) are in a 1,4 relationship relative to each other.

Embodiment 18E

Compounds according to Embodiment 18D, wherein

R₁is

Embodiment 18E1

Compounds according to embodiment 18E, wherein

R₁is

Embodiment 18F

Compounds according to Embodiment 18, wherein the cycloalkyl group is a C₇-C₈cycloalkyl.

Embodiment 19

Compounds according to any one of Embodiments 17A, 17B, 17C, 17C1, 17C2, 17C3, 17C4, 17D, 17E, 17E1, 17E2, 17E3, 17E4, 17F, 17G, 17H, 17H1, 17H2, 17H3, 17H4, 17I, 17J, 17K, 17L, 17M, 17N, 17O, 17P, 17Q, 17Q1, 17Q2, 17Q3, 17Q4, 17R, 17S, 17T, 17U, 17V, 17W, 17X, 17Y, 17Y1, 17Y2, 17Y3, 17Y4, 17Z, 17Z1, 17Z2, 17Z3, 17Z4, 17Z5, 17AA, 17BB, 17CC, 17CC1, 17CC2, 17CC3, 17CC4, 17DD, 17EE, 17FF, 17GG, 17HH, 17II, 17JJ, 17KK, 17LL, 17MM, or 17NN, wherein R₁is heterocycloalkyl or heterocycloalkyl(C₁-C₄)alkyl wherein the heterocycloalkyl group is piperidinyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolyl, or morpholinyl, wherein the heterocycloalkyl groups are optionally substituted with 1 or 2 groups that are independently C₁-C₄alkyl, C₁-C₄alkoxy, phenyl, phenyl(C₁-C₄)alkyl, OH, halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, or C₁-C₄alkoxycarbonyl.

Embodiment 19A

Compounds according to Embodiment 19, wherein R₁is heterocycloalkyl, which is piperidin-3-yl, piperidin-4-yl, pyrrolidin-2-yl, tetrahydrofuranyl, pyrazolyl, or morpholinyl, wherein the heterocycloalkyl groups are optionally substituted with 1 or 2 groups that are independently C₁-C₄alkyl, C₁-C₄alkoxy, phenyl, phenyl(C₁-C₄)alkyl, OH, halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, or C₁-C₄alkoxycarbonyl.

Embodiment 19B

Compounds according to Embodiment 19, wherein R₁is heterocycloalkyl, which is piperidin-3-yl, piperidin-4-yl, pyrrolidinyl, pyrazolyl, or morpholinyl, wherein the heterocycloalkyl groups are optionally substituted with 1 or 2 groups that are independently C₁-C₄alkyl, C₁-C₄alkoxy, phenyl, phenyl(C₁-C₄)alkyl, OH, halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, or C₁-C₄alkoxycarbonyl.

Embodiment 19C

Compounds according to Embodiment 19, wherein the heterocycloalkyl groups are optionally substituted with 1 or 2 groups that are independently methyl, methoxy, phenyl, benzyl, OH, halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, or tert-butylcarbonyl. In another embodiment, the heterocycloalkyl group is substituted with methyl.

Embodiment 19D

Compounds according to Embodiment 19, wherein R₁is tetrahydrofuranyl, which is optionally substituted with a methyl group.

Embodiment 19E

Compounds according to Embodiment 19, wherein

R₁is heterocycloalkyl(C₁-C₄)alkyl, which is piperidinyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolyl, or morpholinyl, wherein the heterocycloalkyl groups are optionally substituted with 1 or 2 groups that are independently C₁-C₄alkyl, C₁-C₄alkoxy, phenyl, phenyl(C₁-C₄)alkyl, halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, or C₁-C₄alkoxycarbonyl.

Embodiment 19F

Compounds according to Embodiment 19, wherein

R₁is heterocycloalkyl(C₁-C₄)alkyl, which is piperidinyl, pyrrolidinyl, pyrazolyl, or morpholinyl, wherein the heterocycloalkyl groups are optionally substituted with 1 or 2 groups that are independently C₁-C₄alkyl, C₁-C₄alkoxy, phenyl, phenyl(C₁-C₄)alkyl, halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, or C₁-C₄alkoxycarbonyl.

Embodiment 19G

Compounds according to Embodiment 19, wherein the heterocycloalkyl groups are optionally substituted with 1 or 2 groups that are independently methyl, methoxy, phenyl, benzyl, halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, or tert-butylcarbonyl.

Embodiment 19H

Compounds according to Embodiment 19, wherein R₁is tetrahydrofuranyl(C₁-C₄)alkyl, which is optionally substituted with a methyl group.

Embodiment 19I

Compounds according to any one of Embodiments 19, 19B, 19D, 19E, 19F, or 19H, wherein the heterocycloalkyl groups are unsubstituted.

Embodiment 19J

Compounds according to any one of Embodiments 19, 19E, 19F, 19G, 19H, or 19I, wherein the alkyl group is a C₁-C₂alkyl group. In another aspect, the alkyl group is a C₁alkyl group.

Embodiment 20

Compounds according to any one of Embodiments 17A, 17B, 17C, 17C1, 17C2, 17C3, 17C4, 17D, 17E, 17E1, 17E2, 17E3, 17E4, 17F, 17G, 17H, 17H1, 17H2, 17H3, 17H4, 17I, 17J, 17K, 17L, 17M, 17N, 17O, 17P, 17Q, 17Q1, 17Q2, 17Q3, 17Q4, 17R, 17S, 17T, 17U, 17V, 17W, 17X, 17Y, 17Y1, 17Y2, 17Y3, 17Y4, 17Z, 17Z1, 17Z2, 17Z3, 17Z4, 17AA, 17BB, 17CC, 17CC1, 17CC2, 17CC3, 17CC4, 17DD, 17EE, 17FF, 17GG, 17HH, 17II 17JJ, 17KK, 17LL, 17MM, or 17NN, wherein R₁is heteroaryl(C₂-C₄)alkyl, wherein the heteroaryl group is pyridyl, pyrimidyl, furanyl, or thienyl and the heteroaryl group is optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, C₁-C₄alkyl, C₁-C₄alkoxy or OH.

Embodiment 20A

Compounds according to Embodiment 20, wherein R₁is heteroaryl(C₁-C₄)alkyl, wherein the heteroaryl group is pyridyl, or pyrimidyl, each of which is optionally substituted with 1, or 2 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, C₁-C₄alkyl, C₁-C₄alkoxy or OH.

Embodiment 20B

Compounds according to Embodiment 20A, wherein the heteroaryl group is substituted with 1, or 2 groups that are independently halogen, methyl, methoxy, or OH.

Embodiment 20C

Compounds according to Embodiment 20A, wherein R₁is heteroaryl(C₂-C₄)alkyl, wherein the heteroaryl group is furanyl, or thienyl each is optionally substituted with 1, 2, or 3 groups that are independently halogen, C₁-C₄alkyl, C₁-C₄alkoxy or OH.

Embodiment 20D

Compounds according to any one of Embodiments 20, 20A, 20B, or 20C, wherein the alkyl group is a C₁-C₂alkyl group. In another aspect, the alkyl group is a C₁alkyl group.

Embodiment 20E

Compounds according to any one of Embodiments 20, 20A, 20B, 20C, or 20D, wherein the heteroaryl group is un-substituted.

Embodiment 21

In another aspect, the invention provides compounds of Formula X
or pharmaceutically acceptable salts thereof, wherein

L is C₁-C₆alkylene or C₂-C₆alkenylene;
R₁is C₂-C₆alkynyl, C₂-C₆alkenyl, or C₁-C₈alkyl wherein each is optionally substituted with 1, 2, or 3 groups that are independently C₁-C₆alkoxy, OH, halogen, CN, C₁-C₆thioalkoxy, phenyl, naphthyl, pyridyl, pyrimidyl, furanyl, thienyl, C₃-C₈cycloalkyl, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆alkyl), —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl, —C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl, —C(O) phenyl, or C₁-C₆alkoxycarbonyl,
- wherein each of the cyclic groups is optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, C₁-C₄alkyl, C₁-C₄alkoxy, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆alkyl), —SO₂—(C₁-C₆)alkyl, or OH;
  or
R₁is C₃-C₈cycloalkyl optionally substituted with 1 or 2 groups that are independently C₁-C₄alkyl, C₁-C₄hydroxyalkyl, or OH; or
R₁is heterocycloalkyl or heterocycloalkyl(C₁-C₄)alkyl wherein the heterocycloalkyl group is piperidinyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolyl, or morpholinyl, wherein the heterocycloalkyl groups are optionally substituted with C₁-C₄alkyl, C₁-C₄alkoxy, phenyl, phenyl(C₁-C₄)alkyl, halogen or C₁-C₄alkoxycarbonyl; or
R₁is heteroaryl(C₁-C₄)alkyl, wherein the heteroaryl group is pyridyl, pyrimidyl, furanyl, or thienyl and the heteroaryl group is optionally substituted with 1, 2, or 3 groups that are independently halogen, C₁-C₄alkyl, C₁-C₄alkoxy or OH;
R₃is H, halogen, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, CN,
R₄is H, halogen, C₁-C₄alkyl optionally substituted with —CO₂—(C₁-C₆alkyl), C₁-C₆alkoxy, C₁-C₆haloalkyl, C₁-C₆haloalkoxy, CN, aryloxy, isocyanato, —SO₂—(C₁-C₆alkyl), —NHR′, —NR′R″, C₁-C₆alkanoyl, pyridyl, phenyl, or
R₃and R₄and the carbons to which they are attached form a heterocycloalkyl ring which is optionally substituted with 1, 2, or 3 groups that are independently C₁-C₄alkyl, C₁-C₄alkoxy, halogen, or C₁-C₄alkanoyl wherein the alkanoyl group is optionally substituted with up to 3 halogen atoms;
R_3′ is H, —SO₂—NR′R″, halogen, or
R₄and R_3′ and the carbons to which they are attached form a phenyl ring; or
R₄and R_3′ and the carbons to which they are attached form a 1-oxa-2,3-diazacyclopentyl ring;
R₅is H, halogen, C₁-C₆alkoxy, CF₃, CO₂H, C₁-C₄alkoxycarbonyl, —O—(C₁-C₄alkyl)-CO₂—(C₁-C₄alkyl), —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, morpholinyl, oxazolyl, pyrazolyl, thiomorpholinyl, thiomorpholinyl S,S-dioxide, piperidinyl, pyrrolidinyl, halogen, C₁-C₆alkyl, phenyl optionally substituted with 1, 2, 3, 4 or 5 groups that are independently halogen, C₁-C₆alkyl, or C₁-C₄alkoxy, CN, or —(C₁-C₄alkyl)-SO₂-phenyl,
R₆is H, C₁-C₆alkoxy, halogen, C₁-C₆alkyl, CF₃, OCF₃, phenyl(C₁-C₄)alkoxy, phenyloxy, CO₂H, C₁-C₆alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl, —C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl, CN, C₂-C₆alkenyl, or C₁-C₆alkyl,
- wherein the above phenyl groups are optionally substituted with 1, 2, 3, 4 or 5 groups that are independently halogen, C₁-C₆alkyl, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, or C₁-C₄alkoxy, or
R₅, R₆, and the carbons to which they are attached form a phenyl ring, which is optionally substituted with 1 or 2 groups that are independently halogen, C₁-C₄alkyl, C₁-C₄alkoxy, CF₃, or OCF₃;
R₇is H, OH, C₁-C₆alkoxy, —O—SO₂-phenyl where the phenyl is optionally substituted with halogen, halogen, C₁-C₆alkyl, phenyloxy, benzyloxy, CF₃, CO₂H, OH, —O—C(O)—(C₁-C₄alkyl), C₁-C₆alkoxycarbonyl, —C(O)NR₃OR₃₁, —NHR′, —NR′R″, —N(R₁₆)C(O)—R₁₇, thiazolyl, thiazolyl(C₁-C₆)alkoxy, pyridyl(C₁-C₆)alkoxy, oxazolyl(C₁-C₄)alkoxy, pyrazolyl(C₁-C₄)alkoxy, wherein the thiazolyl, pyridyl, oxazolyl, and pyrazolyl groups are optionally substituted with 1, 2, or 3 groups that are independently C₁-C₆alkyl, C₁-C₆alkoxy, or halogen, phenyl optionally substituted with 1, 2, 3, 4 or 5 groups that are independently halogen, C₁-C₆alkyl, C₁-C₄alkoxy, OCF₃, CN, or C₁-C₆thioalkoxy, —S(O)_x—R₂₅, or —(C₁-C₄alkyl)-S(O)_x—R₂₅; wherein
- x is 0, 1, or 2;
- R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇;
- R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl; or
- R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl;
- R₃₀and R₃₁are independently H, C₁-C₆alkyl, phenyl, benzyl, pyridyl, imidazolyl, thiazolyl, oxazolyl, or indolyl, or
- R₃₀, R₃₁, and the nitrogen to which they are attached form a heterocycloalkyl ring containing from 3 to 7 ring members;
- R₁₆is H or C₁-C₆alkyl;
- R₁₇is C₁-C₆alkyl, phenyl, pyridyl, pyrimidyl, pyridazyl, pyrazinyl, thienyl, C₁-C₆alkoxy, OH, phenyloxy, pyridyloxy, pyrimidyloxy, pyridazyloxy, pyrazinyloxy, thienyloxy, phenyl(C₁-C₄)alkoxy, or —NR₁₈R₁₉;
- R₁₈and R₁₉are independently H, C₁-C₆alkyl, phenyl, pyridyl, thienyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, tetrahydro-thiopyranyl 1,1-dioxide, or phenyl(C₁-C₄)alkyl; or
R₆, R₇, and the carbons to which they are attached form a phenyl ring, which is optionally substituted with 1 or 2 groups that are independently halogen, C₁-C₄alkyl, C₁-C₄alkoxy, CF₂, or OCF₃; or
R₆and R₇are —O—CH₂CH₂—O—, or —O—CH₂—O—;
R₈is H, halogen, C₁-C₆alkoxy, C₁-C₆alkyl, cyano, —O-phenyl wherein the phenyl group is optionally substituted with halogen, C₂-C₄alkenyl, C₁-C₄alkoxycarbonyl, benzyloxy, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or CO₂H, or
R₇and R₈are —O—CH₂CH₂—O—, or —O—CH₂—O—;
R₉is H, halogen, C₁-C₆alkyl optionally substituted with —SO2-phenyl, cyano, C₁-C₆alkoxy, or phenyl;
- R′ is H, C₁-C₆alkyl, or C₁-C₆alkanoyl, wherein the alkyl portion of the alkyl and alkanoyl groups are optionally substituted with halogen,
- R″ is H or C₁-C₆alkyl, wherein the alkyl group is optionally substituted with halogen.

Embodiment 21A

Compounds according to Embodiment 21, wherein R₅, R₆, R₇, R₈, and R₉are independently hydrogen, halogen, C₁-C₄alkyl, C₁-C₄alkoxy, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆alkyl), —SO₂—(C₁-C₆)alkyl, or OH.

Embodiment 21B

Compounds according to either Embodiment 21 or Embodiment 21A wherein

R₁is

wherein

R₂₁and R₂₂are independently H or C₁-C₆alkyl;
R₂₃is H, —C(O)NR₃₀R₃₁, C₁-C₆alkyl, CO₂H, halogen, C₁-C₆alkoxycarbonyl, phenyl, naphthyl, benzyl, pyridyl, pyrimidyl, furanyl, or thienyl;
- R₃₀and R₃₁are independently H, C₁-C₆alkyl, phenyl, benzyl, pyridyl, thiazolyl, oxazolyl, or indolyl, or
- R₃₀, R₃₁, and the nitrogen to which they are attached form a azepanyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, or thiomorpholinyl 1,1-dioxide.

Embodiment 21B1

Compounds according to Embodiment 21B, wherein R₂₃is H, or —C(O)NR₃OR₃₁, and R₃₀and R₃₁are independently H, C₁-C₆alkyl, phenyl, or benzyl.

Embodiment 21B2

Compounds according to Embodiment 21B, wherein R₂₃is H, or —C(O)NR₃OR₃₁, and R₃₀and R₃₁are independently H, methyl, pyridyl, thiazolyl, oxazolyl, or indolyl.

Embodiment 21B2

Compounds according to Embodiment 21B, wherein R₂₃is H, or —C(O)NR₃OR₃₁, and R₃₀, R₃₁, and the nitrogen to which they are attached form a azepanyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, or thiomorpholinyl 1,1-dioxide.

Embodiment 21B3

Compounds according to any one of Embodiments 21B, 21B1, or 21B2, wherein R₂₃is H, C₁-C₆alkyl, CO₂H, or C₁-C₆alkoxycarbonyl.

Embodiment 21B4

Compounds according to any one of Embodiments 21B, 21B1, or 21B2, wherein R₂₃is H, phenyl, naphthyl, benzyl, pyridyl, pyrimidyl, furanyl, or thienyl.

Embodiment 21C

Compounds according to either Embodiment 21 or Embodiment 21A wherein

R₁is

wherein

m is 0, 1, 2, or 3;
R₂₀is H or methyl; and
cycloalkyl is C₃-C₇cycloalkyl wherein the cyclic portion is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, C₁-C₆alkyl, OH, or C₁-C₆alkoxy.

Embodiment 21D

Compounds according to Embodiment 21, wherein cycloalkyl is cyclopropyl, cyclopentyl, or cyclohexyl, wherein the cyclic portion is optionally substituted with 1, or 2 groups that are independently halogen, C₁-C₄alkyl, OH, or C₁-C₄alkoxy.

Embodiment 21E

Compounds according to either Embodiment 21 or Embodiment 21A wherein

R₁is of the formula:

wherein

m is 0, 1, 2, or 3;
R₂₀is H or methyl; and
heterocycloalkyl is 4-oxo-4H-chromen-3-yl, 2H-chromen-3-yl, pyrrolidinonyl dione, isoindol-2-yl dione, 1,3-dioxolan-2-yl, dioxanyl, or tetrahydropyran-2-yl, wherein the cyclic portion of each is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently C₁-C₄alkyl, C₁-C₄alkoxy, or halogen.

Embodiment 21F

Compounds according to Embodiment 21E, wherein m is 0 or 1. In another aspect, m is 0 or 1 and heterocycloalkyl is isoindol-2-yl dione, 4-oxo-4H-chromen-3-yl, or 2H-chromen-3-yl.

Embodiment 21G

Compounds according to Embodiment 21E, wherein m is 1 or 2. In another aspect, m is 1 or 2 and heterocycloalkyl is isoindol-2-yl dione, 4-oxo-4H-chromen-3-yl, or 2H-chromen-3-yl.

Embodiment 21H

Compounds according to any one of Embodiments 21, 21A, 21B, 21C, 21D, 21E, 21F, or 21G, wherein

R5 is H, C₁-C₆alkoxy, CF₃, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, morpholinyl, oxazolyl, pyrazolyl, thiomorpholinyl, thiomorpholinyl S,S-dioxide, piperidinyl, pyrrolidinyl, halogen, C₁-C₆alkyl, phenyl optionally substituted with 1, 2, 3, 4 or 5 groups that are independently halogen, C₁-C₆alkyl, or C₁-C₄alkoxy, CN, —(C₁-C₄alkyl)-SO₂-phenyl,
R₆is H, C₁-C₆alkoxy, halogen, C₁-C₆alkyl, CF₃, OCF₃, phenyl(C₁-C₄)alkoxy, phenyloxy, CO₂H, C₁-C₆alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl, —C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl, CN, C₂-C₆alkenyl, wherein the above phenyl groups are optionally substituted with 1, 2, 3, 4 or 5 groups that are independently halogen, C₁-C₆alkyl, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, or C₁-C₄alkoxy;
R₇is H, OH, C₁-C₆alkoxy, —O—SO₂-phenyl, halogen, C₁-C₆alkyl, phenyloxy, CF₃, CO₂H, C₁-C₆alkoxycarbonyl, —C(O)NR₃₀R₃₁, —NHR′, —NR′R″, —N(R₁₆) C(O)—R₁₇, thiazolyl(C₁-C₆)alkoxy, pyridyl(C₁-C₆)alkoxy, oxazolyl(C₁-C₄)alkoxy, pyrazolyl(C₁-C₄)alkoxy, wherein the thiazolyl, pyridyl, oxazolyl, and pyrazolyl groups are optionally substituted with 1, 2, or 3 groups that are independently C₁-C₆alkyl, C₁-C₆alkoxy, or halogen, phenyl optionally substituted with 1, 2, 3, 4 or 5 groups that are independently halogen, C₁-C₆alkyl, C₁-C₄alkoxy, OCF₃, CN, CO₂H, C₁-C₆alkoxycarbonyl, C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, —S(O)_x—R₂₅, or —(C₁-C₄alkyl)-S(O)_x—R₂₅or C₁-C₆thioalkoxy, wherein
- R₃₀and R₃₁are independently H, C₁-C₆alkyl, phenyl, benzyl, pyridyl, imidazolyl, thiazolyl, oxazolyl, or indolyl, or
- R₃₀, R₃₁, and the nitrogen to which they are attached form a heterocycloalkyl ring containing from 3 to 7 ring members;
- R₁₆is H or C₁-C₆alkyl;
- R₁₇is C₁-C₆alkyl, phenyl, pyridyl, pyrimidyl, pyridazyl, pyrazinyl, thienyl, C₁-C₆alkoxy, OH, phenyloxy, pyridyloxy, pyrimidyloxy, pyridazyloxy, pyrazinyloxy, thienyloxy, phenyl(C₁-C₄)alkoxy, or —NR₁₈R₁₉;
R₁₈and R₁₉are independently H, C₁-C₆alkyl, phenyl, pyridyl, thienyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, tetrahydro-thiopyranyl 1,1-dioxide, or phenyl(C₁-C₄)alkyl;
R₈is H, halogen, C₁-C₆alkoxy, C₁-C₆alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅or CO₂H;
R₉is H, halogen, C₁-C₆alkoxy, C₁-C₆alkyl,
- R′ is H, C₁-C₆alkyl, or C₁-C₆alkanoyl, wherein the alkyl portion of the alkyl and alkanoyl groups are optionally substituted with halogen,
- R″ is H or C₁-C₆alkyl, wherein the alkyl group is optionally substituted with halogen.

Embodiment 21I

Compounds according to Embodiment 21H, wherein

R₅is H, C₁-C₄alkoxy, CF₃, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, or —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl;
R₆is H, C₁-C₄alkoxy, halogen, C₁-C₄alkyl, CF₃, OCF₃, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, CN, or C₂-C₆alkenyl;
R₈is H, halogen, C₁-C₄alkoxy, C₁-C₄alkyl, or CO₂H; and
R₉is H, halogen, C₁-C₄alkoxy, or C₁-C₄alkyl.

Embodiment 21J

Compounds according to Embodiment 21I, wherein R₃is H, halogen, methyl, methoxy, CF₃, or CN; R₄is halogen, methoxy, methyl, CF₃, OCF₃, or CN; R_3′ is H, or halogen.

Embodiment 21K

Compounds according to Embodiment 21J, wherein R₇is H, OH, C₁-C₄alkoxy, halogen, C₁-C₄alkyl, CF₃, CO₂H, C₁-C₆alkoxycarbonyl, —C(O)NR₃OR₃₁, thiazolyl(C₁-C₆)alkoxy, pyridyl(C₁-C₆)alkoxy, oxazolyl(C₁-C₄)alkoxy, pyrazolyl(C₁-C₄)alkoxy, wherein the thiazolyl, pyridyl, oxazolyl, and pyrazolyl groups are optionally substituted with 1, 2, or 3 groups that are independently C₁-C₆alkyl, C₁-C₆alkoxy, or halogen, or phenyl optionally substituted with 1, 2, 3, 4 or 5 groups that are independently halogen, C₁-C₆alkyl, C₁-C₄alkoxy, OCF₃, CO₂H, C₁-C₆alkoxycarbonyl, CN, or C₁-C₆thioalkoxy; and

R₃₀and R₃₁are independently H, C₁-C₆alkyl, phenyl, or benzyl.

Embodiment 21K1

Compounds according to Embodiment 21J, wherein R₇is —S(O)_x—R₂₅, or —(C₁-C₄alkyl)-S(O)_x—R₂₅

- R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇;
- R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl; or
- R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl.

Embodiment 21K2

Compounds according to Embodiment 21K1, wherein R₂₅is C₁-C₆alkyl or OH.

Embodiment 21K3

Compounds according to Embodiment 21K1, wherein R₂₅is C₁-C₄alkyl or NR₂₆R₂₇; and R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl.

Embodiment 21K4

Compounds according to Embodiment 21K1, wherein R₂₅is C₁-C₄alkyl or NR₂₆R₂₇; and R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl.

Embodiment 21L

Compounds according to Embodiment 21K, wherein R₇is H, OH, C₁-C₄alkoxy, halogen, C₁-C₄alkyl, CF₃, CO₂H, —C(O)NR₃OR₃₁, or C₁-C₄alkoxycarbonyl; and R₃₀and R₃₁are independently H or C₁-C₆alkyl.

Embodiment 21M

Compounds according to Embodiment 21L, wherein R₇is H, OH, methoxy, halogen, methyl, CF₃, CO₂H, —C(O)NR₃OR₃₁, or C₁-C₂alkoxycarbonyl; and R₃₀and R₃₁are independently H or C₁-C₄alkyl.

Embodiment 21N

Compounds according to Embodiment 21M, wherein R₇is CO₂H, —C(O)NR₃₀R₃₁, or C₁-C₂alkoxycarbonyl.

Embodiment 21O

Compounds according to Embodiment 21M, wherein R₇is OH, methoxy, halogen, methyl, or CF₃.

Embodiment 21P

Compounds according to any one of Embodiments 21K, 21K1, 21K2, 21K3, 21K4, 21L, 21M, 21N or 21O, wherein R₃is H, or halogen;

R₄is halogen, methyl, CF₃, or methoxy; and R_3′ is H or halogen.

Embodiment 21Q

Compounds according to Embodiment 21P, wherein R₅is H, methoxy, CF₃, CO₂H, C₁-C₂alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, or —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl;

R₆is H, C₁-C₂alkoxy, halogen, C₁-C₂alkyl, CF₃, OCF₃, CO₂H, C₁-C₂alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, or —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl;
R₈is H or halogen (preferred halogens are F or Cl); and
R₉is H or halogen (preferred halogens are F or Cl).

Embodiment 21R

Compounds according to Embodiment 21Q wherein R₃is H; R₄is halogen (preferably F or Cl, more preferably Cl); and R_3′ is H. In another aspect, R₄is methyl. In still another aspect, R₄is CF₃. In yet another aspect, R₄is Cl.

Embodiment 21S

Compounds according to Embodiment 21R, wherein R₅is H, methoxy, CF₃, CO₂H, or C₁-C₂alkoxycarbonyl; R₆is H, methoxy, halogen, methyl, CF₃, OCF₃, CO₂H, or C₁-C₂alkoxycarbonyl (in one aspect, C₂alkoxycarbonyl); R₈is H, F or Cl; and R₉is H, F or Cl.

Embodiment 21T

Compounds according to Embodiment 21J, wherein R₇is H, —NHR′, —NR′R″ or —N(R₁₆)C(O)—R₁₇; R₁₆is H or C₁-C₄alkyl; R₁₇is C₁-C₆alkyl, phenyl, pyridyl, pyrimidyl, pyridazyl, pyrazinyl, thienyl, C₁-C₆alkoxy, phenyloxy, pyridyloxy, pyrimidyloxy, pyridazyloxy, pyrazinyloxy, thienyloxy, phenyl(C₁-C₄)alkoxy, or —NR₁₈R₁₉; and R₁₈and R₁₉are independently H, C₁-C₆alkyl, phenyl, pyridyl, thienyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, tetrahydro-thiopyranyl 1,1-dioxide, or phenyl(C₁-C₄)alkyl; wherein R′ is H, C₁-C₄alkyl, or C₁-C₄alkanoyl; R″ is C₁-C₄alkyl, wherein the alkyl group is optionally substituted with halogen.

Embodiment 21U

Compounds according to Embodiment 21T, wherein R₃is H, or halogen; R₄is halogen, methyl, CF₃, or methoxy; and R_3′ is H or halogen. In another aspect, R₄is methyl. In still another aspect, R₄is CF₃. In yet another aspect, R₄is Cl.

Embodiment 21V

Compounds according to Embodiment 21U, wherein R₅is H, methoxy, CF₃, CO₂H, C₁-C₂alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, or —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl;

Embodiment 21W

Compounds according to Embodiment 21V wherein R₃is H; R₄is halogen (preferably F or Cl, more preferably Cl), methyl, or CF₃; and R_3′ is H.

Embodiment 21X

Compounds according to Embodiment 21W, wherein R₅is H, methoxy, CF₃, CO₂H, or C₁-C₂alkoxycarbonyl;

R₆is H, methoxy, halogen, methyl, CF₃, OCF₃, CO₂H, or C₁-C₂alkoxycarbonyl (in one aspect, C₂alkoxycarbonyl);
R₈is H, F or Cl; and
R₉is H, F or Cl.

Embodiment 21Y

Compounds according to any one of Embodiments 21U, 21V, 21W, or 21X, wherein R₇is H or —N(R₁₆)C(O)—R₁₇; wherein R₁₆is H or C₁-C₄alkyl; R₁₇is C₁-C₆alkyl, phenyl, pyridyl, pyrimidyl, pyridazyl, pyrazinyl, thienyl, C₁-C₆alkoxy, phenyloxy, pyridyloxy, pyrimidyloxy, pyridazyloxy, pyrazinyloxy, thienyloxy, phenyl(C₁-C₄)alkoxy, or —NR₁₈R₁₉; and R₁₈and R₁₉are independently H, C₁-C₆alkyl, phenyl, pyridyl, thienyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, tetrahydro-thiopyranyl 1,1-dioxide, or phenyl(C₁-C₄)alkyl.

Embodiment 21Z

Compounds according to Embodiment 21Y, wherein R₁₇is C₁-C₄alkyl, phenyl, pyridyl, pyrimidyl, pyridazyl, pyrazinyl, thienyl, C₁-C₄alkoxy, phenyloxy, pyridyloxy, pyrimidyloxy, pyridazyloxy, pyrazinyloxy, thienyloxy, phenyl(C₁-C₄)alkoxy.

Embodiment 21AA

Compounds according to Embodiment 21Z, wherein R₁₇is C₁-C₄alkyl, C₁-C₄alkoxy, phenyl, phenyloxy, or phenyl(C₁-C₂)alkoxy.

Embodiment 21BB

Compounds according to Embodiment 21Z, wherein R₁₇is pyridyl, pyrimidyl, pyridazyl, pyrazinyl, thienyl, pyridyloxy, pyrimidyloxy, pyridazyloxy, pyrazinyloxy, or thienyloxy.

Embodiment 21BB

Compounds according to Embodiment 21Z, wherein R₁₇is —NR₁₈R₁₉; and R₁₈and R₁₉are independently H, C₁-C₆alkyl, phenyl, pyridyl, thienyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, tetrahydro-thiopyranyl 1,1-dioxide, or phenyl(C₁-C₄)alkyl.

Embodiment 21CC

Compounds according to Embodiment 21Y, wherein R₁₇is —NR₁₈R₁₉; and R₁₈and R₁₉are independently H, C₁-C₆alkyl, phenyl, pyridyl, thienyl, piperidinyl, pyrrolidinyl, morpholinyl, or phenyl(C₁-C₄)alkyl.

Embodiment 21DD

Compounds according to Embodiment 21CC, wherein R₁₈and R₁₉are independently H, C₁-C₄alkyl, phenyl, or phenyl(C₁-C₂)alkyl.

Embodiment 21EE

Compounds according to Embodiment 21CC, wherein R₁₈and R₁₉are independently H, pyridyl, thienyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, or tetrahydro-thiopyranyl 1,1-dioxide. In another aspect, one of R₁₈and R₁₉is H.

Embodiment 21EE1

Compounds according to Embodiment 21CC, wherein R₁₈and R₁₉are independently H, pyridyl, piperidinyl, pyrrolidinyl, or morpholinyl. In another aspect, one of R₁₈and R₁₉is H. In another aspect, only one of R₁₈and R₁₉is H.

Embodiment 21EE2

Compounds according to Embodiment 21CC, wherein R₁₈and R₁₉are independently H, thienyl, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, or tetrahydro-thiopyranyl 1,1-dioxide. In another aspect, one of R₁₈and R₁₉is H. In another aspect, only one of R₁₈and R₁₉is H.

Embodiment 21FF

Compounds according to any one of Embodiments 21U, 21V, 21W, or 21X, wherein R₇is H, —NHR′, or —NR′R″; wherein R′ is H, C₁-C₄alkyl, or C₁-C₄alkanoyl; R″ is C₁-C₄alkyl, wherein the alkyl group is optionally substituted with halogen.

Embodiment 21GG

Compounds according to Embodiment 21K, wherein R₇is thiazolyl(C₁-C₄)alkoxy, pyridyl(C₁-C₄)alkoxy, oxazolyl(C₁-C₄)alkoxy, pyrazolyl(C₁-C₄)alkoxy, wherein the thiazolyl, pyridyl, oxazolyl, and pyrazolyl groups are optionally substituted with 1, 2, or 3 groups that are independently C₁-C₄alkyl, C₁-C₄alkoxy, or halogen.

Embodiment 21HH

Compounds according to Embodiment 21GG, wherein R₇is thiazolyl(C₁-C₂)alkoxy, pyridyl(C₁-C₂)alkoxy, oxazolyl(C₁-C₂)alkoxy, or pyrazolyl(C₁-C₂)alkoxy, wherein the thiazolyl, pyridyl, oxazolyl, and pyrazolyl groups are optionally substituted with 1, or 2 groups that are independently methyl, methoxy, or halogen.

Embodiment 21II

Compounds according to Embodiment 21K, wherein R₇is phenyl optionally substituted with 1, 2, 3, 4 or 5 groups that are independently halogen, C₁-C₄alkyl, C₁-C₄alkoxy, OCF₃, CN, CO₂H, C₁-C₄alkoxycarbonyl, C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, or C₁-C₄thioalkoxy. In another aspect, the phenyl is optionally substituted with 1, 2, or 3 groups, which are independently halogen, C₁-C₄alkyl, C₁-C₄alkoxy, OCF₃, CN, CO₂H, C₁-C₄alkoxycarbonyl, C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, or —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl.

Embodiment 21III

Compounds according to Embodiment 21K, wherein R₇is phenyl optionally substituted with 1, 2, or 3 groups that are independently halogen, C₁-C₂alkyl, C₁-C₂alkoxy, OCF₃, CN, CO₂H, C₁-C₂alkoxycarbonyl, C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, or —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl. In another aspect, the phenyl is optionally substituted with 1 or 2 groups, which are independently halogen, methyl, methoxy, CO₂H, C₁-C₂alkoxycarbonyl, C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, or —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl.

Embodiment 21JJ

Compounds according to any one of Embodiments 21, 21A, 21B, 21C, 21D, 21E, 21F, or 21G, wherein R₅, R₆, and the carbons to which they are attached form a phenyl ring, which is optionally substituted with 1 or 2 groups that are independently halogen, C₁-C₄alkyl, C₁-C₄alkoxy, CF₃, or OCF₃; and R₇, R₈, and R₉are H.

Embodiment 21KK

Compounds according to any one of Embodiments 21, 21A, 21B, 21C, 21D, 21E, 21F, or 21G, wherein R₅, R₈, and R₉are H; and R₆, R₇, and the carbons to which they are attached form a phenyl ring, which is optionally substituted with 1 or 2 groups that are independently halogen, C₁-C₄alkyl, C₁-C₄alkoxy, CF₃, or OCF₃;

Embodiment 21LL

Compounds according to any one of Embodiments 21, 21A, 21B, 21C, 21D, 21E, 21F, or 21G, wherein R₅, R₆, and R₉are H; and R₇and R₈are —O—CH₂CH₂—O—, or —O—CH₂—O—.

Embodiment 21MM

Compounds according to any one of Embodiments 21JJ, 21KK, or 21LL wherein R₃is H, halogen, methyl, methoxy, CF₃, or CN; R₄is halogen, methoxy, methyl, CF₃, OCF₃, or CN; R_3′ is H, or halogen.

Embodiment 21NN

Compounds according to Embodiment 21MM, wherein R₃is H, or halogen (in one aspect F or Cl); R₄is halogen (in one aspect F or Cl), methyl, CF₃, or methoxy; and R_3′ is H or halogen (in one aspect F or Cl). In another aspect, R₄is methyl. In still another aspect, R₄is CF₃. In yet another aspect, R₄is Cl.

Embodiment 21OO

Compounds according to either Embodiment 21MM or Embodiment 21NN, wherein L is a C₁-C₄alkyl. In another aspect, L is C₁-C₂alkyl. In yet another aspect, L is C₃-C₄alkyl.

Embodiment 21PP

Compounds according to either Embodiment 21MM or Embodiment 21NN, wherein L is a C₂-C₅alkenyl. In another aspect, L is C₂-C₄alkenyl. In yet another aspect, L is C₃-C₄alkenyl.

Embodiment 22

Compounds according to either Embodiment 21 or 21A, of the formula:
wherein R₂₀is H or methyl;

R₅₀is H, or C₁-C₆alkyl; and
R₅₅is H, C₁-C₄alkyl, phenyl, heteroaryl selected from the group consisting of pyridyl, pyrimidyl, benzofuranyl, furanyl or indolyl, or C₃-C₆cycloalkyl.

Embodiment 22A

Compounds according to Embodiment 22, wherein

R₅is H, C₁-C₆alkoxy, CF₃, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, morpholinyl, oxazolyl, pyrazolyl, thiomorpholinyl, thiomorpholinyl S,S-dioxide, piperidinyl, pyrrolidinyl, halogen, C₁-C₆alkyl, phenyl optionally substituted with 1, 2, 3, 4 or 5 groups that are independently halogen, C₁-C₆alkyl, or C₁-C₄alkoxy, CN, —(C₁-C₄alkyl)-SO₂-phenyl,
R₆is H, C₁-C₆alkoxy, halogen, C₁-C₆alkyl, CF₃, OCF₃, phenyl(C₁-C₄)alkoxy, phenyloxy, CO₂H, C₁-C₆alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl, —C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl, CN, C₂-C₆alkenyl, wherein the above phenyl groups are optionally substituted with 1, 2, 3, 4 or 5 groups that are independently halogen, C₁-C₆alkyl, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, or C₁-C₄alkoxy;
R₇is H, OH, C₁-C₆alkoxy, —O—SO₂-phenyl, halogen, C₁-C₆alkyl, phenyloxy, CF₃, CO₂H, C₁-C₆alkoxycarbonyl, —C(O)NR₃₀R₃₁, —NHR′, —NR′R″, —N(R₁₆)C(O)—R₁₇, thiazolyl(C₁-C₆)alkoxy, pyridyl(C₁-C₆)alkoxy, oxazolyl(C₁-C₄)alkoxy, pyrazolyl(C₁-C₄)alkoxy, wherein the thiazolyl, pyridyl, oxazolyl, and pyrazolyl groups are optionally substituted with 1, 2, or 3 groups that are independently C₁-C₆alkyl, C₁-C₆alkoxy, or halogen, phenyl optionally substituted with 1, 2, 3, 4 or 5 groups that are independently halogen, C₁-C₆alkyl, C₁-C₄alkoxy, OCF₃, CN, CO₂H, C₁-C₆alkoxycarbonyl, C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, C₁-C₆thioalkoxy, —S(O)_x—R₂₅, or —(C₁-C₄alkyl)-S(O)_x—R₂₅; wherein
- x is 0, 1, or 2;
- R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇;
- R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl; or
- R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl
- R₃₀and R₃₁are independently H, C₁-C₆alkyl, phenyl, benzyl, pyridyl, imidazolyl, thiazolyl, oxazolyl, or indolyl, or
- R₃₀, R₃₁, and the nitrogen to which they are attached form a heterocycloalkyl ring containing from 3 to 7 ring members;
- R₁₆is H or C₁-C₆alkyl;
- R₁₇is C₁-C₆alkyl, phenyl, pyridyl, pyrimidyl, pyridazyl, pyrazinyl, thienyl, C₁-C₆alkoxy, OH, phenyloxy, pyridyloxy, pyrimidyloxy, pyridazyloxy, pyrazinyloxy, thienyloxy, phenyl(C₁-C₄)alkoxy, or —NR₁₈R₁₉;
R₁₈and R₁₉are independently H, C₁-C₆alkyl, phenyl, pyridyl, thienyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, tetrahydro-thiopyranyl 1,1-dioxide, or phenyl(C₁-C₄)alkyl;
R₈is H, halogen, C₁-C₆alkoxy, C₁-C₆alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or CO₂H;
R₉is H, halogen, C₁-C₆alkoxy, C₁-C₆alkyl,
- R′ is H, C₁-C₆alkyl, or C₁-C₆alkanoyl, wherein the alkyl portion of the alkyl and alkanoyl groups are optionally substituted with halogen,
- R″ is H or C₁-C₆alkyl, wherein the alkyl group is optionally substituted with halogen.

Embodiment 22B

Compounds according to Embodiment 22A, wherein

R₅is H, C₁-C₄alkoxy, CF₃, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, or —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl;
R₆is H, C₁-C₄alkoxy, halogen, C₁-C₄alkyl, CF₃, OCF₃, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, CN, or C₂-C₆alkenyl;
R₈is H, halogen, C₁-C₄alkoxy, C₁-C₄alkyl, —S(O)_x—R₂₅, or —(C₁-C₄alkyl)-S(O)_x—R₂₅or CO₂H; and
R₉is H, halogen, C₁-C₄alkoxy, or C₁-C₄alkyl.

Embodiment 22C

Compounds according to Embodiment 22B, wherein R₃is H, halogen, methyl, methoxy, CF₃, or CN; R₄is halogen, methoxy, methyl, CF₃, OCF₃, or CN; R_3′ is H, or halogen.

Embodiment 22D

Compounds according to Embodiment 22C, wherein R₇is H, OH, C₁-C₄alkoxy, halogen, C₁-C₄alkyl, CF₃, CO₂H, C₁-C₆alkoxycarbonyl, —C(O)NR₃OR₃₁, thiazolyl(C₁-C₆)alkoxy, pyridyl(C₁-C₆)alkoxy, oxazolyl(C₁-C₄)alkoxy, pyrazolyl(C₁-C₄)alkoxy, wherein the thiazolyl, pyridyl, oxazolyl, and pyrazolyl groups are optionally substituted with 1, 2, or 3 groups that are independently C₁-C₆alkyl, C₁-C₆alkoxy, or halogen, or phenyl optionally substituted with 1, 2, 3, 4 or 5 groups that are independently halogen, C₁-C₆alkyl, C₁-C₄alkoxy, OCF₃, CO₂H, C₁-C₆alkoxycarbonyl, CN, or C₁-C₆thioalkoxy; and

R₃₀and R₃₁are independently H, C₁-C₆alkyl, phenyl, or benzyl.

Embodiment 22D1

Compounds according to Embodiment 22C, wherein R₇is —S(O)_x—R₂₅, or —(C₁-C₄alkyl)-S(O)_x—R₂₅

Embodiment 22D2

Compounds according to Embodiment 21D1, wherein R₂₅is C₁-C₆alkyl or OH.

Embodiment 22D3

Compounds according to Embodiment 21D1, wherein R₂₅is C₁-C₄alkyl or NR₂₆R₂₇; and R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl.

Embodiment 22D4

Compounds according to Embodiment 22D1, wherein

R₂₅is C₁-C₄alkyl or NR₂₆R₂₇; and R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl;
R₅is H, C₁-C₄alkoxy, CF₃, CO₂H, C₁-C₄alkoxycarbonyl;
R₆is H, C₁-C₄alkoxy, halogen, C₁-C₄alkyl, CF₃, OCF₃, CO₂H, C₁-C₄alkoxycarbonyl, CN, or C₂-C₆alkenyl;
R₈is H, halogen, C₁-C₄alkoxy, C₁-C₄alkyl, —S(O)_x—R₂₅, or —(C₁-C₄alkyl)-S(O)_x—R₂₅; and
R₉is H, halogen, C₁-C₃alkoxy, or C₁-C₃alkyl.

Embodiment 22E

Compounds according to Embodiment 22D, wherein R₇is H, OH, C₁-C₄alkoxy, halogen, C₁-C₄alkyl, CF₃, CO₂H, —C(O)NR₃OR₃₂, or C₁-C₄alkoxycarbonyl; and R₃₀and R₃₁are independently H or C₁-C₆alkyl.

Embodiment 22F

Compounds according to Embodiment 22E, wherein R₇is H, OH, methoxy, halogen, methyl, CF₃, CO₂H, —C(O)NR₃OR₃₁, or C₁-C₂alkoxycarbonyl; and R₃₀and R₃₁are independently H or C₁-C₄alkyl.

Embodiment 22G

Compounds according to Embodiment 22F, wherein R₇is CO₂H, —C(O)NR₃OR₃₈, or C₁-C₂alkoxycarbonyl.

Embodiment 22H

Compounds according to Embodiment 22F, wherein R₇is OH, methoxy, halogen, methyl, or CF₃.

Embodiment 22I

Compounds according to any one of Embodiments 22E, 22F, 22G or 22H, wherein R₃is H, or halogen; R₄is halogen, methyl, CF₃, or methoxy; and R_3′ is H or halogen.

Embodiment 22J

Compounds according to Embodiment 22I, wherein R₅is H, methoxy, CF₃, CO₂H, C₁-C₂alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, or —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl;

Embodiment 22K

Compounds according to Embodiment 22J wherein R₃is H; R₄is halogen (preferably F or Cl, more preferably Cl); and R_3′ is H. In another aspect, R₄is methyl. In still another aspect, R₄is CF₃. In yet another aspect, R₄is Cl.

Embodiment 22L

Compounds according to Embodiment 22K, wherein R₅is H, methoxy, CF₃, CO₂H, or C₁-C₂alkoxycarbonyl; R₆is H, methoxy, halogen, methyl, CF₃, OCF₃, CO₂H, or C₁-C₂alkoxycarbonyl (in one aspect, C₂alkoxycarbonyl); R₈is H, F or Cl; and R₉is H, F or Cl.

Embodiment 22M

Compounds according to Embodiment 22C, wherein R₇is H, —NHR′, —NR′R″ or —N(R₁₆) C(O)—R₁₇; R₁₆is H or C₁-C₄alkyl; R₁₇is C₁-C₆alkyl, phenyl, pyridyl, pyrimidyl, pyridazyl, pyrazinyl, thienyl, C₁-C₆alkoxy, phenyloxy, pyridyloxy, pyrimidyloxy, pyridazyloxy, pyrazinyloxy, thienyloxy, phenyl(C₁-C₄)alkoxy, or —NR₁₈R₁₉; and R₁₈and R₁₉are independently H, C₁-C₆alkyl, phenyl, pyridyl, thienyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, tetrahydro-thiopyranyl 1,1-dioxide, or phenyl(C₁-C₄)alkyl; wherein R′ is H, C₁-C₄alkyl, or C₁-C₄alkanoyl; R″ is C₁-C₄alkyl, wherein the alkyl group is optionally substituted with halogen.

Embodiment 22N

Compounds according to Embodiment 22M, wherein R₃is H, or halogen; R₄is halogen, methyl, CF₃, or methoxy; and R_3′ is H or halogen. In another aspect, R₄is methyl. In still another aspect, R₄is CF₃. In yet another aspect, R₄is Cl.

Embodiment 22O

Compounds according to Embodiment 22N, wherein R₅is H, methoxy, CF₃, CO₂H, C₁-C₂alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, or —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl; R₆is H, C₁-C₂alkoxy, halogen, C₁-C₂alkyl, CF₃, OCF₃, CO₂H, C₁-C₂alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, or —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl; R₈is H or halogen (preferred halogens are F or Cl); and R₉is H or halogen (preferred halogens are F or Cl).

Embodiment 22P

Compounds according to Embodiment 22O wherein R₃is H; R₄is halogen (preferably F or Cl, more preferably Cl), methyl, or CF₃; and R_3′ is H.

Embodiment 22Q

Compounds according to Embodiment 22P, wherein R₅is H, methoxy, CF₃, CO₂H, or C₁-C₂alkoxycarbonyl;

Embodiment 22R

Compounds according to any one of Embodiments 22N, 22O, 22P, or 22Q, wherein R₇is H or —N(R₁₆)C(O)—R₁₇; wherein R₁₆is H or C₁-C₄alkyl; R₁₇is C₁-C₆alkyl, phenyl, pyridyl, pyrimidyl, pyridazyl, pyrazinyl, thienyl, C₁-C₆alkoxy, phenyloxy, pyridyloxy, pyrimidyloxy, pyridazyloxy, pyrazinyloxy, thienyloxy, phenyl(C₂-C₄)alkoxy, or —NR₁₈R₁₉; and R₁₈and R₁₉are independently H, C₁-C₆alkyl, phenyl, pyridyl, thienyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, tetrahydro-thiopyranyl 1,1-dioxide, or phenyl(C₁-C₄)alkyl.

Embodiment 22S

Compounds according to Embodiment 22R, wherein R₁₇is C₁-C₄alkyl, phenyl, pyridyl, pyrimidyl, pyridazyl, pyrazinyl, thienyl, C₁-C₄alkoxy, phenyloxy, pyridyloxy, pyrimidyloxy, pyridazyloxy, pyrazinyloxy, thienyloxy, phenyl(C₁-C₄)alkoxy.

Embodiment 22T

Compounds according to Embodiment 22S, wherein R₁₇is C₁-C₄alkyl, C₁-C₄alkoxy, phenyl, phenyloxy, or phenyl(C₁-C₂)alkoxy.

Embodiment 22U

Compounds according to Embodiment 22S, wherein R₁₇is pyridyl, pyrimidyl, pyridazyl, pyrazinyl, thienyl, pyridyloxy, pyrimidyloxy, pyridazyloxy, pyrazinyloxy, or thienyloxy.

Embodiment 22V

Compounds according to Embodiment 22R, wherein R₁₇is —NR₁₈R₁₉; and R₁₈and R₁₉are independently H, C₁-C₆alkyl, phenyl, pyridyl, thienyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, tetrahydro-thiopyranyl 1,1-dioxide, or phenyl(C₁-C₄)alkyl.

Embodiment 22W

Compounds according to Embodiment 22V, wherein R₁₇is —NR₁₈R₁₉; and R₁₈and R₁₉are independently H, C₁-C₆alkyl, phenyl, pyridyl, thienyl, piperidinyl, pyrrolidinyl, morpholinyl, or phenyl(C₁-C₄)alkyl.

Embodiment 22X

Compounds according to Embodiment 22W, wherein R₁₈and R₁₉are independently H, C₁-C₄alkyl, phenyl, or phenyl(C₁-C₂)alkyl.

Embodiment 22Y

Compounds according to Embodiment 22V, wherein R₁₈and R₁₉are independently H, pyridyl, thienyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, or tetrahydro-thiopyranyl 1,1-dioxide. In another aspect, one of R₁₈and R₁₉is H.

Embodiment 22Z

Compounds according to Embodiment 22V, wherein R₁₈and R₁₉are independently H, pyridyl, piperidinyl, pyrrolidinyl, or morpholinyl. In another aspect, one of R₁₈and R₁₉is H. In another aspect, only one of R₁₈and R₁₉is H.

Embodiment 22AA

Compounds according to Embodiment 21V, wherein R₁₈and R₁₉are independently H, thienyl, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, or tetrahydro-thiopyranyl 1,1-dioxide. In another aspect, one of R₁₈and R₁₉is H. In another aspect, only one of R₁₈and R₁₉is H.

Embodiment 22BB

Compounds according to any one of Embodiments 22I, 22J, 22K, or 22L, wherein R₇is H, —NHR′, or —NR′R″; wherein R′ is H, C₁-C₄alkyl, or C₁-C₄alkanoyl; R″ is C₁-C₄alkyl, wherein the alkyl group is optionally substituted with halogen.

Embodiment 22CC

Compounds according to Embodiment 22D, wherein R₇is thiazolyl(C₁-C₄)alkoxy, pyridyl(C₁-C₄)alkoxy, oxazolyl(C₁-C₄)alkoxy, pyrazolyl(C₁-C₄)alkoxy, wherein the thiazolyl, pyridyl, oxazolyl, and pyrazolyl groups are optionally substituted with 1, 2, or 3 groups that are independently C₁-C₄alkyl, C₁-C₄alkoxy, or halogen.

Embodiment 22DD

Compounds according to Embodiment 21CC, wherein R₇is thiazolyl(C₁-C₂)alkoxy, pyridyl(C₁-C₂)alkoxy, oxazolyl(C₁-C₂)alkoxy, or pyrazolyl(C₁-C₂)alkoxy, wherein the thiazolyl, pyridyl, oxazolyl, and pyrazolyl groups are optionally substituted with 1, or 2 groups that are independently methyl, methoxy, or halogen.

Embodiment 22EE

Compounds according to Embodiment 22D, wherein R₇is phenyl optionally substituted with 1, 2, 3, 4 or 5 groups that are independently halogen, C₁-C₄alkyl, C₁-C₄alkoxy, OCF₃, CN, CO₂H, C₁-C₄alkoxycarbonyl, C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, or C₁-C₄thioalkoxy. In another aspect, the phenyl is optionally substituted with 1, 2, or 3 groups, which are independently halogen, C₁-C₄alkyl, C₁-C₄alkoxy, OCF₃, CN, CO₂H, C₁-C₄alkoxycarbonyl, C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, or —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl.

Embodiment 22FF

Compounds according to Embodiment 22D, wherein R₇is phenyl optionally substituted with 1, 2, or 3 groups that are independently halogen, C₁-C₂alkyl, C₁-C₂alkoxy, OCF₃, CN, CO₂H, C₁-C₂alkoxycarbonyl, C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, or —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl. In another aspect, the phenyl is optionally substituted with 1 or 2 groups, which are independently halogen, methyl, methoxy, CO₂H, C₁-C₂alkoxycarbonyl, C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, or —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl.

Embodiment 22GG

Compounds according to Embodiment 22, wherein R₅, R₆, and the carbons to which they are attached form a phenyl ring, which is optionally substituted with 1 or 2 groups that are independently halogen, C₁-C₄alkyl, C₁-C₄alkoxy, CF₃, or OCF₃; and R₇, R₈, and R₉are H.

Embodiment 22HH

Compounds according to Embodiment 22, wherein R₅, R₈, and R₉are H; and R₆, R₇, and the carbons to which they are attached form a phenyl ring, which is optionally substituted with 1 or 2 groups that are independently halogen, C₁-C₄alkyl, C₁-C₄alkoxy, CF₃, or OCF₃.

Embodiment 22II

Compounds according to Embodiment 22, wherein R₅, R₆, and R₉are H; and R₇and R₈are —O—CH₂CH₂—O—, or —O—CH₂—O—.

Embodiment 22JJ

Compounds according to Embodiment 22, wherein R₅, R₆, and R₉are H; and R₇and R₈are —O—CH₂CH₂—O—.

Embodiment 22KK

Compounds according to Embodiment 22, wherein R₅, R₆, and R₉are H; and R₇and R₈are —O—CH₂—O—.

Embodiment 22LL

Compounds according to any one of Embodiments 22GG, 22HH, 22II, 22JJ, or 22KK wherein R₃is H, halogen, methyl, methoxy, CF₃, or CN; R₄is halogen, methoxy, methyl, CF₃, OCF₃, or CN; R_3′ is H, or halogen.

Embodiment 22MM

Compounds according to Embodiment 22LL, wherein R₃is H, or halogen (in one aspect F or Cl); R₄is halogen (in one aspect F or Cl), methyl, CF₃, or methoxy; and R_3′ is H or halogen (in one aspect F or Cl). In another aspect, R₄is methyl. In still another aspect, R₄is CF₃. In yet another aspect, R₄is Cl.

Embodiment 22NN

Compounds according to any one of Embodiments 22A, 22B, 22C, 22D, 22D1, 22D2, 22D3, 22D4, 22E, 22F, 22G, 22H, 22I, 22J, 22K, 22L, 22M, 22N, 22O, 22P, 22Q, 22R, 22S, 22T, 22U, 22V, 22X, 22Y, 22Z, 22AA, 22BB, 22CC, 22DD, 22EE, 22FF, 22GG, 22HH, 22II, 22JJ, 22KK, 22LL, or 22MM wherein R₅₀is H, methyl, ethyl, n-propyl, isopropyl, sec-butyl, or isobutyl; and R₅₅is H, methyl, ethyl or cyclopropyl.

Embodiment 22OO

Compounds according to Embodiment 22NN, wherein R₅₅is H.

Embodiment 22PP

Compounds according to Embodiment 22NN, wherein R₅₀is methyl, ethyl, or n-propyl.

Embodiment 22RR

Compounds according to Embodiment 22NN, wherein R₅₀is isopropyl, sec-butyl, or isobutyl.

Embodiment 22SS

Compounds according to Embodiment 22NN, wherein R₅₀is n-propyl, isopropyl, or isobutyl.

Embodiment 22TT

Compounds according to Embodiment 22NN, wherein R₅₅is methyl.

Embodiment 22UU

Embodiment 22VV

Embodiment 22WW

Embodiment 22XX

Compounds according to Embodiment 22NN, wherein R₅₅is ethyl.

Embodiment 22YY

Embodiment 22ZZ

Embodiment 22AAA

Embodiment 22BBB

Compounds according to Embodiment 22NN, wherein R₅₅is cyclopropyl.

Embodiment 22CCC

Embodiment 22DDD

Embodiment 22EEE

Embodiment 22FFF

Compounds according to Embodiment 22N of the formula:

Embodiment 22GGG

Compounds according to Embodiment 22M, wherein R₅, R₉, R₃and R_3′ are H.

Embodiment 22HHH

Compounds according to Embodiment 22N, wherein R₄is halogen (in one aspect, F or Cl), methyl, or CF₃. In another aspect, R₄is methyl. In still another aspect, R₄is CF₃. In yet another aspect, R₄is Cl.
In embodiment 23, the invention provides pharmaceutical compositions comprising at least one compound of Formula I and at least one pharmaceutically acceptable carrier, solvent, adjuvant or excipient, or a combination thereof.
In embodiment 24, the invention provides a method of treating a patient who has, or in preventing a patient from getting, a disease or condition selected from the group consisting of Alzheimer's disease, for helping prevent or delay the onset of Alzheimer's disease, for treating patients with mild cognitive impairment (MCI) and preventing or delaying the onset of Alzheimer's disease in those who would progress from MCI to AD, for treating Down's syndrome, for treating humans who have Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treating cerebral amyloid angiopathy and preventing its potential consequences, i.e. single and recurrent lobar hemorrhages, for treating other degenerative dementias, including dementias of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, age related macular degeneration, or diffuse Lewy body type of Alzheimer's disease and who is in need of such treatment which comprises administration of a therapeutically effective amount of at least one compound of Formula I.
The following list is presented to give the reader an understanding of the compounds that are encompassed within the invention.

(S)-4-chloro-N-cinnamyl-N-(1-hydroxy-4-methylpentan-2-yl)benzenesulfonamide;
[(4-Chloro-benzenesulfonyl)-methyl-amino]-acetic acid ethyl ester;
[2-(4-Chloro-benzenesulfonylimino)-imidazolidin-1-yl]-acetic acid;
2-(4-Chloro-benzenesulfonylamino)-N-methyl-propionamide;
2-[(4-Chloro-benzenesulfonyl)-(3,4-dimethoxy-benzyl)-amino]-3-phenyl-propionamide;
2-[(4-Chloro-benzenesulfonyl)-(3-phenyl-propyl)-amino]-3-hydroxy-N-methyl-butyramide;
3-[(4-Chloro-benzenesulfonyl)-(3,4-dimethoxy-benzyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester;
4-Chloro-N-(1,2-dimethyl-propyl)-N-(3-phenyl-allyl)-benzenesulfonamide;
4-Chloro-N-(1,2-dimethyl-propyl)-N-(3-phenyl-propyl)-benzenesulfonamide;
4-Chloro-N-(1,3-dimethyl-butyl)-N-(3-phenyl-allyl)-benzenesulfonamide;
4-Chloro-N-(1,3-dimethyl-butyl)-N-(3-phenyl-propyl)-benzenesulfonamide;
4-Chloro-N-(1-chloro-3,4-dihydro-naphthalen-2-ylmethyl)-N-(1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;
4-Chloro-N-(1-ethyl-propyl)-N-(3-phenyl-allyl)-benzenesulfonamide;
4-Chloro-N-(1-ethyl-propyl)-N-(3-phenyl-propyl)-benzenesulfonamide;
4-Chloro-N-(1-hydroxymethyl-3-methyl-butyl)-N-(1,2,3,4-tetrahydro-naphthalen-2-yl)-benzenesulfonamide;
4-Chloro-N-(1-hydroxymethyl-3-methyl-butyl)-N-(1-methyl-1H-indol-2-ylmethyl)-benzenesulfonamide;
4-Chloro-N-(1-hydroxymethyl-3-methyl-butyl)-N-(1-methyl-3-phenyl-allyl)-benzenesulfonamide;
4-Chloro-N-(1-hydroxymethyl-3-methyl-butyl)-N-(1-methyl-3-phenyl-propyl)-benzenesulfonamide;
4-Chloro-N-(1-hydroxymethyl-3-methyl-butyl)-N-(2-methyl-3-phenyl-allyl)-benzenesulfonamide;
4-Chloro-N-(1-hydroxymethyl-3-methyl-butyl)-N-(2-pentyl-3-phenyl-allyl)-benzenesulfonamide;
4-Chloro-N-(1-hydroxymethyl-3-methyl-butyl)-N-(3-phenyl-butyl)-benzenesulfonamide;
4-Chloro-N-(1-hydroxymethyl-3-methyl-butyl)-N-(3-phenyl-propyl)-benzenesulfonamide;
4-Chloro-N-(1-hydroxymethyl-3-methyl-butyl)-N-(4-methoxy-benzyl)-benzenesulfonamide;
4-Chloro-N-(1-hydroxymethyl-3-methyl-butyl)-N-[3-(2-methoxy-phenyl)-allyl]-benzenesulfonamide;
4-Chloro-N-(1-hydroxymethyl-3-methyl-butyl)-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-benzenesulfonamide;
4-Chloro-N-(1-hydroxymethyl-3-methyl-butyl)-N-methyl-benzenesulfonamide;
4-Chloro-N-(1-hydroxymethyl-3-methyl-butyl)-N-propyl-benzenesulfonamide;
4-Chloro-N-(1-hydroxymethyl-pentyl)-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-benzenesulfonamide;
4-Chloro-N-(1-hydroxymethyl-pentyl)-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-benzenesulfonamide;
4-Chloro-N-(1-hydroxymethyl-propyl)-N-(3-phenyl-allyl)-benzenesulfonamide;
4-Chloro-N-(1-hydroxymethyl-propyl)-N-(3-phenyl-propyl)-benzenesulfonamide;
4-Chloro-N-(1-methyl-butyl)-N-(3-phenyl-allyl)-benzenesulfonamide;
4-Chloro-N-(1-methyl-butyl)-N-(3-phenyl-propyl)-benzenesulfonamide;
4-chloro-N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-N-[(1S)-1-(hydroxymethyl)-3-methylbutyl]benzenesulfonamide;
4-Chloro-N-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-N-(1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;
4-Chloro-N-(2,3-dihydroxy-propyl)-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-benzenesulfonamide;
4-Chloro-N-(2,3-dihydroxy-propyl)-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-benzenesulfonamide;
4-Chloro-N-(2,4-dichloro-benzyl)-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-benzenesulfonamide;
4-Chloro-N-(2,4-dichloro-benzyl)-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-benzenesulfonamide;
4-Chloro-N-(2,4-difluoro-benzyl)-N-(1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;
4-chloro-N-(2,4-difluorobenzyl)-N-[(1R)-1-(hydroxymethyl)-3-methylbutyl]benzenesulfonamide;
4-Chloro-N-(2-cyano-ethyl)-N-cyclopropyl-benzenesulfonamide;
4-Chloro-N-(2-cyano-ethyl)-N-cyclopropyl-benzenesulfonamide;
4-Chloro-N-(2-cyano-ethyl)-N-ethyl-benzenesulfonamide;
4-Chloro-N-(2-cyano-ethyl)-N-ethyl-benzenesulfonamide;
4-Chloro-N-(2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-benzenesulfonamide;
4-Chloro-N-(2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-benzenesulfonamide;
4-Chloro-N-(2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-benzenesulfonamide;
4-Chloro-N-(2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-benzenesulfonamide;
4-Chloro-N-(2-hydroxy-cyclohexylmethyl)-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-benzenesulfonamide;
4-Chloro-N-(2-hydroxy-propyl)-N-(3-phenyl-allyl)-benzenesulfonamide;
4-Chloro-N-(2-hydroxy-propyl)-N-(3-phenyl-propyl)-benzenesulfonamide;
4-Chloro-N-(2-hydroxy-propyl)-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-benzenesulfonamide;
4-Chloro-N-(2-hydroxy-propyl)-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-benzenesulfonamide;
4-Chloro-N-(2-methoxy-1-methyl-ethyl)-N-(3-phenyl-allyl)-benzenesulfonamide;
4-Chloro-N-(2-methoxy-1-methyl-ethyl)-N-(3-phenyl-propyl)-benzenesulfonamide;
4-Chloro-N-(2-methyl-cyclohexyl)-N-(3-phenyl-allyl)-benzenesulfonamide;
4-Chloro-N-(2-methyl-cyclohexyl)-N-(3-phenyl-propyl)-benzenesulfonamide;
4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(1-hydroxymethyl-2-methyl-propyl)-benzenesulfonamide;
4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(1-hydroxymethyl-2-methyl-propyl)-benzenesulfonamide;
4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(1-hydroxymethyl-2-phenyl-ethyl)-benzenesulfonamide;
4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(1-hydroxymethyl-2-phenyl-ethyl)-benzenesulfonamide;
4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;
4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(1-hydroxymethyl-propyl)-benzenesulfonamide;
4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(1-naphthalen-1-yl-ethyl)-benzenesulfonamide;
4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(1-naphthalen-1-yl-ethyl)-benzenesulfonamide;
4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(1-phenyl-4,5-dihydro-1H-pyrazol-3-yl)-benzenesulfonamide;
4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(1-phenyl-4,5-dihydro-1H-pyrazol-3-yl)-benzenesulfonamide;
4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(1-phenyl-ethyl)-benzenesulfonamide;
4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(1-phenyl-ethyl)-benzenesulfonamide;
4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(2,3-dimethyl-cyclohexyl)-benzenesulfonamide;
4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(2,3-dimethyl-cyclohexyl)-benzenesulfonamide;
4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(2-hydroxy-1-hydroxymethyl-2-phenyl-ethyl)-benzenesulfonamide;
4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(2-hydroxy-1-methyl-2-phenyl-ethyl)-benzenesulfonamide;
4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(2-hydroxy-1-phenyl-ethyl)-benzenesulfonamide;
4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(2-methyl-cyclohexyl)-benzenesulfonamide;
4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(3-hydroxy-2,2-dimethyl-propyl)-benzenesulfonamide;
4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(3-hydroxymethyl-bicyclo[2.2.1]hept-2-yl)-benzenesulfonamide;
4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(4-methyl-cyclohexyl)-benzenesulfonamide;
4-chloro-N-(3,4-dimethoxybenzyl)-N-[(1R,2S)-2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]benzenesulfonamide;
4-chloro-N-(3,4-dimethoxybenzyl)-N-[(1S)-1-(hydroxymethyl)-3-methylbutyl]benzenesulfonamide;
4-chloro-N-(3,4-dimethoxybenzyl)-N-[(1S)-1-(hydroxymethyl)propyl]benzenesulfonamide;
4-chloro-N-(3,4-dimethoxybenzyl)-N-[(1S)-2-hydroxy-1-phenylethyl]benzenesulfonamide;
4-chloro-N-(3,4-dimethoxybenzyl)-N-[(1S,2R)-2-hydroxy-1-methyl-2-phenylethyl]benzenesulfonamide;
4-chloro-N-(3,4-dimethoxybenzyl)-N-[(1S,3R,4R)-3-(hydroxymethyl)bicyclo[2.2.1]hept-2-yl]benzenesulfonamide;
4-Chloro-N-(3,4-dimethoxy-benzyl)-N-[1-(4-methanesulfonyl-phenyl)-ethyl]-benzenesulfonamide;
4-Chloro-N-(3,4-dimethoxy-benzyl)-N-[1-(4-methanesulfonyl-phenyl)-ethyl]-benzenesulfonamide;
4-Chloro-N-(3-fluoro-4-methoxy-benzyl)-N-(1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;
4-chloro-N-(3-fluoro-4-methoxybenzyl)-N-[(1S)-1-(hydroxymethyl)-3-methylbutyl]benzenesulfonamide;
4-Chloro-N-(3-hydroxy-butyl)-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-benzenesulfonamide;
4-Chloro-N-(4-chloro-6-fluoro-2H-chromen-3-ylmethyl)-N-(1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;
4-Chloro-N-(4-chloro-benzyl)-N-(1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;
4-chloro-N-(4-chlorobenzyl)-N-[(1R)-1-(hydroxymethyl)-3-methylbutyl]benzenesulfonamide;
4-Chloro-N-(4-diethylamino-1-methyl-butyl)-N-(3,4-dimethoxy-benzyl)-benzenesulfonamide;
4-Chloro-N,N-dicyclohexyl-benzenesulfonamide;
4-Chloro-N,N-diisopropyl-benzenesulfonamide;
4-Chloro-N,N-divinyl-benzenesulfonamide;
4-chloro-N-[(1R)-1-(hydroxymethyl)-3-methylbutyl]-N-(3-phenylpropyl)benzenesulfonamide;
4-chloro-N-[(1R)-1-(hydroxymethyl)-3-methylbutyl]-N-(4-methoxybenzyl)benzenesulfonamide;
4-chloro-N-[(1R,2S)-2-hydroxy-1-methyl-2-phenylethyl]-N-methylbenzenesulfonamide;
4-chloro-N-[(1S)-1-(hydroxymethyl)-3-methylbutyl]-N-[(2E)-2-methyl-3-phenylprop-2-en-1-yl]benzenesulfonamide;
4-chloro-N-[(1S)-1-(hydroxymethyl)-3-methylbutyl]-N-[(2E)-3-phenylprop-2-en-1-yl]benzenesulfonamide;
4-chloro-N-[(1S)-1-(hydroxymethyl)-3-methylbutyl]-N-{3-methoxy-4-[2-(4-methyl-1,3-thiazol-5-yl)ethoxy]benzyl}benzenesulfonamide;
4-chloro-N-[(1S,2S)-2-hydroxy-1-methyl-2-phenylethyl]-N-methylbenzenesulfonamide;
4-Chloro-N-[2-(3,4-dihydroxy-phenyl)-2-oxo-ethyl]-N-methyl-benzenesulfonamide;
4-chloro-N-{[(1R,2S)-2-hydroxycyclohexyl]methyl}-N-{3-methoxy-4-[2-(4-methyl-1,3-thiazol-5-yl)ethoxy]benzyl}benzenesulfonamide;
4-Chloro-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-N-(2-methyl-cyclohexyl)-benzenesulfonamide;
4-Chloro-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-N-(2-methyl-butyl)-benzenesulfonamide;
4-Chloro-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-N-(3-methylsulfanyl-propyl)-benzenesulfonamide;
4-Chloro-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-N-(4-methyl-cyclohexyl)-benzenesulfonamide;
4-Chloro-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-N-pyridin-2-ylmethyl-benzenesulfonamide;
4-Chloro-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-N-prop-2-ynyl-benzenesulfonamide;
4-Chloro-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-N-(3-methyl-butyl)-benzenesulfonamide;
4-Chloro-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-N-(tetrahydro-furan-2-ylmethyl)-benzenesulfonamide;
4-Chloro-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-N-(3-methoxy-propyl)-benzenesulfonamide;
4-Chloro-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-N-(1-phenyl-ethyl)-benzenesulfonamide;
4-Chloro-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-N-(2-methyl-allyl)-benzenesulfonamide;
4-Chloro-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-N-(2-methyl-cyclohexyl)-benzenesulfonamide;
4-Chloro-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-N-(2-methyl-butyl)-benzenesulfonamide;
4-Chloro-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-N-(3-methylsulfanyl-propyl)-benzenesulfonamide;
4-Chloro-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-N-(4-methyl-cyclohexyl)-benzenesulfonamide;
4-Chloro-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-N-pyridin-2-ylmethyl-benzenesulfonamide;
4-Chloro-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-N-prop-2-ynyl-benzenesulfonamide;
4-Chloro-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-N-(3-methyl-butyl)-benzenesulfonamide;
4-Chloro-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-N-(tetrahydro-furan-2-ylmethyl)-benzenesulfonamide;
4-Chloro-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-N-(3-methoxy-propyl)-benzenesulfonamide;
4-Chloro-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-N-(1-phenyl-ethyl)-benzenesulfonamide;
4-Chloro-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-N-(2-methyl-allyl)-benzenesulfonamide;
4-Chloro-N-cyanomethyl-N-methyl-benzenesulfonamide;
4-Chloro-N-cyclohexyl-N-(2-hydroxy-ethyl)-benzenesulfonamide;
4-Chloro-N-cyclohexyl-N-(2-hydroxy-ethyl)-benzenesulfonamide;
4-Chloro-N-cyclohexyl-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-benzenesulfonamide;
4-Chloro-N-cyclohexyl-N-isopropyl-benzenesulfonamide;
4-Chloro-N-cyclooctyl-N-(3,4-dimethoxy-benzyl)-benzenesulfonamide;
4-Chloro-N-cyclopentyl-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-benzenesulfonamide;
4-Chloro-N-cyclopentyl-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-benzenesulfonamide;
4-Chloro-N-cyclopropylmethyl-N-(1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;
4-Chloro-N-cyclopropylmethyl-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-benzenesulfonamide;
4-Chloro-N-cyclopropylmethyl-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-benzenesulfonamide;
4-Chloro-N-ethyl-N-(2-pyridin-2-yl-ethyl)-benzenesulfonamide;
4-Chloro-N-ethyl-N-[2-hydroxy-2-(3-hydroxy-phenyl)-ethyl]-benzenesulfonamide;
4-Chloro-N-ethyl-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-benzenesulfonamide;
4-Chloro-N-isopropyl-N-(2-pyridin-4-yl-ethyl)-benzenesulfonamide;
4-Chloro-N-methyl-N-(1-methyl-piperidin-4-yl)-benzenesulfonamide;
4-Chloro-N-methyl-N-(1-methyl-piperidin-4-yl)-benzenesulfonamide;
4-Chloro-N-methyl-N-(2-pyridin-4-yl-ethyl)-benzenesulfonamide;
4-Chloro-N-pyrrolidin-3-yl-benzenesulfonamide;
N-(1,3-benzodioxol-5-ylmethyl)-4-chloro-N-[(1S)-1-(hydroxymethyl)-3-methylbutyl]benzenesulfonamide;
N-(1-Benzyl-pyrrolidin-3-yl)-4-chloro-N-ethyl-benzenesulfonamide;
N-(2-Amino-benzyl)-4-chloro-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-benzenesulfonamide;
N-(2-Benzyl-cyclohexyl)-4-chloro-N-(1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;
N-(4-Bromo-benzyl)-4-chloro-N-(1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;
N-(4-bromobenzyl)-4-chloro-N-[(1R)-1-(hydroxymethyl)-3-methylbutyl]benzenesulfonamide;
N,N-Di-sec-butyl-4-chloro-benzenesulfonamide;
N-[(1R)-1-benzyl-2-hydroxyethyl]-4-chloro-N-(3,4-dimethoxybenzyl)benzenesulfonamide;
N-[(1S)-1-benzyl-2-hydroxyethyl]-4-chloro-N-(3,4-dimethoxybenzyl)benzenesulfonamide;
N-[(4-chlorophenyl)sulfonyl]-N-(3,4-dimethoxybenzyl)-L-phenylalaninamide;
N-[3-(4-tert-Butyl-phenyl)-2-methyl-propyl]-4-chloro-N-(1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;
N2-[(4-chlorophenyl)sulfonyl]-N-1-methyl-L-alaninamide;
N-Allyl-4-chloro-N-cyclohexyl-benzenesulfonamide;
N-Benzo[1,3]dioxol-5-ylmethyl-4-chloro-N-(1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;
N-Benzofuran-2-ylmethyl-4-chloro-N-(1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;
N-Benzofuran-2-ylmethyl-N-sec-butyl-4-chloro-benzenesulfonamide;
N-Benzyl-4-chloro-N-(1-hydroxymethyl-propyl)-benzenesulfonamide;
N-Benzyl-4-chloro-N-(2-hydroxy-cyclohexyl)-benzenesulfonamide;
N-Benzyl-4-chloro-N-(2-hydroxymethyl-cyclohexyl)-benzenesulfonamide;
N-benzyl-4-chloro-N-[(1R)-1-(hydroxymethyl)propyl]benzenesulfonamide;
N-benzyl-4-chloro-N-[(1S,2R)-2-(hydroxymethyl)cyclohexyl]benzenesulfonamide;
N-benzyl-4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]benzenesulfonamide;
N-Benzyl-N-sec-butyl-4-chloro-benzenesulfonamide;
N-sec-Butyl-4-chloro-N-(1-chloro-3,4-dihydro-naphthalen-2-ylmethyl)-benzenesulfonamide;
N-sec-Butyl-4-chloro-N-(1-methyl-1H-indol-2-ylmethyl)-benzenesulfonamide;
N-sec-Butyl-4-chloro-N-(1-methyl-3-phenyl-allyl)-benzenesulfonamide;
N-sec-Butyl-4-chloro-N-(1-methyl-3-phenyl-propyl)-benzenesulfonamide;
N-sec-Butyl-4-chloro-N-(2-pentyl-3-phenyl-allyl)-benzenesulfonamide;
N-sec-Butyl-4-chloro-N-(3,3-diphenyl-allyl)-benzenesulfonamide;
N-sec-Butyl-4-chloro-N-(3-phenyl-allyl)-benzenesulfonamide;
N-sec-Butyl-4-chloro-N-(3-phenyl-butyl)-benzenesulfonamide;
N-sec-Butyl-4-chloro-N-(3-phenyl-propyl)-benzenesulfonamide;
N-sec-Butyl-4-chloro-N-(4,6-dichloro-2H-chromen-3-ylmethyl)-benzenesulfonamide;
N-sec-Butyl-4-chloro-N-(4-chloro-6-fluoro-2H-chromen-3-ylmethyl)-benzenesulfonamide;
N-sec-Butyl-4-chloro-N-[3-(2-methoxy-phenyl)-allyl]-benzenesulfonamide;
N-tert-Butyl-2-(4-chloro-benzenesulfonylamino)-3-methyl-butyramide; or pharmaceutically acceptable salts thereof.

Specific representative examples of compounds of the invention are the following.

4-Chloro-N-cyclooctyl-N-(3,4-dimethoxy-benzyl)-benzenesulfonamide;
4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(2,3-dimethyl-cyclohexyl)-benzenesulfonamide;
4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(4-methyl-cyclohexyl)-benzenesulfonamide;
4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(1-phenyl-ethyl)-benzenesulfonamide;
4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(1-hydroxymethyl-2-methyl-propyl)-benzenesulfonamide;
4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(3-hydroxy-2,2-dimethyl-propyl)-benzenesulfonamide;
4-Chloro-N-(3,4-dimethoxy-benzyl)-N-[1-(4-methanesulfonyl-phenyl)-ethyl]-benzenesulfonamide;
3-[(4-Chloro-benzenesulfonyl)-(3,4-dimethoxy-benzyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester;
4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(3-hydroxymethyl-bicyclo[2.2.1]hept-2-yl)-benzenesulfonamide;
4-Chloro-N-(3,4-dimethoxy-benzyl)-N—(R-2-hydroxy-1-phenyl-ethyl)-benzenesulfonamide;
4-Chloro-N-(3,4-dimethoxy-benzyl)-N—(R-1-hydroxymethyl-2-phenyl-ethyl)-benzenesulfonamide;
N-Benzyl-4-chloro-N-(1S,2S-2-hydroxy-cyclohexyl)-benzenesulfonamide;
4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-(3-phenyl-allyl)-benzenesulfonamide;
4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-(2-methyl-3-phenyl-allyl)-benzenesulfonamide;
N-Benzo[1,3]dioxol-5-ylmethyl-4-chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;
4-Chloro-N-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;
4-Chloro-N-(3-fluoro-4-methoxy-benzyl)-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;
4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-(4-methoxy-benzyl)-benzenesulfonamide;
4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-(3-phenyl-propyl)-benzenesulfonamide;
4-Chloro-N-(4-chloro-benzyl)-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;
N-(4-Bromo-benzyl)-4-chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;
4-Chloro-N-(2,4-difluoro-benzyl)-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;
R—N-sec-Butyl-4-chloro-N-(3-phenyl-allyl)-benzenesulfonamide;
4-Chloro-N—(R-1,2-dimethyl-propyl)-N-(3-phenyl-allyl)-benzenesulfonamide;
4-Chloro-N-(1-ethyl-propyl)-N-(3-phenyl-allyl)-benzenesulfonamide;
4-Chloro-N-(1-hydroxymethyl-propyl)-N-(3-phenyl-allyl)-benzenesulfonamide;
4-Chloro-N-(2-hydroxy-propyl)-N-(3-phenyl-allyl)-benzenesulfonamide;
4-Chloro-N-(1,3-dimethyl-butyl)-N-(3-phenyl-allyl)-benzenesulfonamide;
4-Chloro-N-(1-methyl-butyl)-N-(3-phenyl-allyl)-benzenesulfonamide;
4-Chloro-N-(2-methoxy-1-methyl-ethyl)-N-(3-phenyl-allyl)-benzenesulfonamide;
4-Chloro-N-(2-methyl-cyclohexyl)-N-(3-phenyl-allyl)-benzenesulfonamide;
3-[(4-Chloro-benzenesulfonyl)-(3-phenyl-allyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester;
4-[(4-Chloro-benzenesulfonyl)-(3-phenyl-allyl)-amino]-piperidine-1-carboxylic acid ethyl ester;
R—N-sec-Butyl-4-chloro-N-(3-phenyl-propyl)-benzenesulfonamide;
4-Chloro-N—(R-1,2-dimethyl-propyl)-N-(3-phenyl-propyl)-benzenesulfonamide;
4-Chloro-N-(1-ethyl-propyl)-N-(3-phenyl-propyl)-benzenesulfonamide;
4-Chloro-N-(1-hydroxymethyl-propyl)-N-(3-phenyl-propyl)-benzenesulfonamide;
4-Chloro-N-(2-hydroxy-propyl)-N-(3-phenyl-propyl)-benzenesulfonamide;
4-Chloro-N-(1,3-dimethyl-butyl)-N-(3-phenyl-propyl)-benzenesulfonamide;
4-Chloro-N-(1-methyl-butyl)-N-(3-phenyl-propyl)-benzenesulfonamide;
4-Chloro-N-(2-methoxy-1-methyl-ethyl)-N-(3-phenyl-propyl)-benzenesulfonamide;
2S,3R-2-[(4-Chloro-benzenesulfonyl)-(3-phenyl-propyl)-amino]-3-hydroxy-N-methyl-butyramide;
4-Chloro-N-(1S,2S-2-hydroxy-cyclopentyl)-N-(3-phenyl-propyl)-benzenesulfonamide;
4-Chloro-N-(2-methyl-cyclohexyl)-N-(3-phenyl-propyl)-benzenesulfonamide;
4-[(4-Chloro-benzenesulfonyl)-(3-phenyl-propyl)-amino]-piperidine-1-carboxylic acid ethyl ester;
N-[3-(4-tert-Butyl-phenyl)-2-methyl-propyl]-4-chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;
4-Chloro-N-(4-chloro-6-fluoro-2H-chromen-3-ylmethyl)-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;
4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-(2-pentyl-3-phenyl-allyl)-benzenesulfonamide;
4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-[3-(2-methoxy-phenyl)-allyl]-benzenesulfonamide;
N-Benzofuran-2-ylmethyl-4-chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;
4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-(3-phenyl-butyl)-benzenesulfonamide;
4-Chloro-N-cyclopropylmethyl-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;
R—N-sec-Butyl-4-chloro-N-(1-methyl-3-phenyl-allyl)-benzenesulfonamide;
R—N-sec-Butyl-4-chloro-N-[3-(2-methoxy-phenyl)-allyl]-benzenesulfonamide;
R—N-Benzofuran-2-ylmethyl-N-sec-butyl-4-chloro-benzenesulfonamide;
R—N-sec-Butyl-4-chloro-N-(1-methyl-1H-indol-2-ylmethyl)-benzenesulfonamide;
R—N-sec-Butyl-4-chloro-N-(1-methyl-3-phenyl-propyl)-benzenesulfonamide;
4-Chloro-N-(2,5-dimethyl-cyclohexyl)-N-(3-fluoro-4-methoxy-benzyl)-benzenesulfonamide;
4-Chloro-N-(2,4-difluoro-benzyl)-N-(2,5-dimethyl-cyclohexyl)-benzenesulfonamide;
4-Chloro-N-(2,5-dimethyl-cyclohexyl)-N-(3-phenyl-allyl)-benzenesulfonamide;
4-Chloro-N-(2,5-dimethyl-cyclohexyl)-N-(4-methoxy-benzyl)-benzenesulfonamide;
4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(2,5-dimethyl-cyclohexyl)-benzenesulfonamide;
N-(4-Bromo-benzyl)-4-chloro-N-(2,5-dimethyl-cyclohexyl)-benzenesulfonamide;
4-Chloro-N-(2,5-dimethyl-cyclohexyl)-N-(3-phenyl-propyl)-benzenesulfonamide;
4-Chloro-N-(2,5-dimethyl-cyclohexyl)-N-(2-methyl-3-phenyl-allyl)-benzenesulfonamide;
4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(1R,2S,5R-2-isopropyl-5-methyl-cyclohexyl)-benzenesulfonamide;
4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-(1-methyl-3-phenyl-allyl)-benzenesulfonamide;
N-(2-Benzyl-cyclohexyl)-4-chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;
4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-(1,2,3,4-tetrahydro-naphthalen-2-yl)-benzenesulfonamide;
4-Chloro-N-(4,6-dichloro-2H-chromen-3-ylmethyl)-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;
4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-(1-methyl-1H-indol-2-ylmethyl)-benzenesulfonamide;
4-Chloro-N-(1-chloro-3,4-dihydro-naphthalen-2-ylmethyl)-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;
4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-(1-methyl-3-phenyl-propyl)-benzenesulfonamide;
4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-propyl-benzenesulfonamide;
4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-methyl-benzenesulfonamide;
R—N-sec-Butyl-4-chloro-N-(1-chloro-3,4-dihydro-naphthalen-2-ylmethyl)-benzenesulfonamide;
4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;
4-Chloro-N—(R-1,2-dimethyl-propyl)-benzenesulfonamide;
4-Chloro-N—(S-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;
4-[(4-Chloro-benzenesulfonyl)-(R-1-hydroxymethyl-3-methyl-butyl)-amino]-3-methyl-but-2-enoic acid ethyl ester;
4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-naphthalen-2-ylmethyl-benzenesulfonamide;
4-Chloro-N-furan-2-ylmethyl-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;
4-Chloro-N-furan-3-ylmethyl-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;
4-Chloro-N—(S-1-hydroxymethyl-3-methyl-butyl)-N-(3-phenyl-allyl)-benzenesulfonamide;
4-Chloro-N—(S-1,2-dimethyl-propyl)-N-(3-phenyl-allyl)-benzenesulfonamide;
N-(2-Bromo-3-phenyl-allyl)-4-chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;
N-But-2-enyl-4-chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;
4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-pentyl-benzenesulfonamide;
4-Chloro-N-(3-furan-2-yl-2-methyl-allyl)-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;
4-Chloro-N-(3-furan-2-yl-allyl)-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;
4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-(2-methyl-pentyl)-benzenesulfonamide;
4-Chloro-N-(2-ethyl-allyl)-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;
4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-(3-methyl-butyl)-benzenesulfonamide;
4-Chloro-N-(2-ethyl-butyl)-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;
4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-(3-methyl-but-2-enyl)-benzenesulfonamide;
4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-(3-pyridin-3-yl-allyl)-benzenesulfonamide;
4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-[3-(2-nitro-phenyl)-allyl]-benzenesulfonamide;
4-[(4-Chloro-benzenesulfonyl)-(R-1-hydroxymethyl-3-methyl-butyl)-amino]-but-2-enoic acid ethyl ester;
4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-(2-methyl-4-phenyl-pentyl)-benzenesulfonamide;
4-Chloro-N-cyclohexylmethyl-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;
4-Chloro-N-(2-chloro-3-phenyl-allyl)-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;
4-Chloro-N-[3-(3-chloro-phenyl)-allyl]-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;
4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-(3-p-tolyl-allyl)-benzenesulfonamide;
4-Chloro-N-[3-(4-dimethylamino-phenyl)-allyl]-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;
4-Chloro-N-[3-(4-fluoro-phenyl)-allyl]-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;
4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-(3-m-tolyl-allyl)-benzenesulfonamide;
4-Chloro-N-[3-(3-fluoro-phenyl)-allyl]-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;
4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-(3-o-tolyl-allyl)-benzenesulfonamide;
4-Chloro-N-[3-(4-chloro-phenyl)-allyl]-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;
4-Chloro-N-[3-(2-fluoro-phenyl)-allyl]-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;
4-Chloro-N-(6-methoxy-pyridin-3-ylmethyl)-N-(2-methyl-cyclohexyl)-benzenesulfonamide;
4-Chloro-N-(6-chloro-pyridin-3-ylmethyl)-N-(2-methyl-cyclohexyl)-benzenesulfonamide;
N-(6-Bromo-pyridin-3-ylmethyl)-4-chloro-N-(2-methyl-cyclohexyl)-benzenesulfonamide; and
4-Chloro-N-(2-methyl-cyclohexyl)-N-(3-pyridin-3-yl-allyl)-benzenesulfonamide.

In another aspect, the compounds of the invention have minimal interaction or preferably, no interaction with Notch.

DEFINITIONS

The definitions and explanations below are for the terms as used throughout this entire document including both the specification and the claims.
It should be noted that, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to a composition containing “a compound” includes a mixture of two or more compounds. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.
Where multiple substituents are indicated as being attached to a structure, it is to be understood that the substituents can be the same or different. Thus for example “R_moptionally substituted with 1, 2 or 3 R_qgroups” indicates that R_mis substituted with 1, 2, or 3 R_qgroups where the R_qgroups can be the same or different.
APP, amyloid precursor protein, is defined as any APP polypeptide, including APP variants, mutations, and isoforms, for example, as disclosed in U.S. Pat. No. 5,766,846. A beta, amyloid beta peptide, is defined as any peptide resulting from beta-secretase mediated cleavage of APP, including peptides of 39, 40, 41, 42, and 43 amino acids, and extending from the beta-secretase cleavage site to amino acids 39, 40, 41, 42, or 43.
Pharmaceutically acceptable refers to those properties and/or substances that are acceptable to the patient from a toxicological and/or safety point of view.
A therapeutically effective amount is defined as an amount effective to reduce or lessen at least one symptom of the disease being treated or to reduce or delay onset of one or more clinical markers or symptoms of the disease.
By “alkyl” and “C₁-C₆alkyl” in the present invention is meant straight or branched chain alkyl groups having 1-6 carbon atoms, such as, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. It is understood that in cases where an alkyl chain of a substituent (e.g. of an alkyl, alkoxy or alkenyl group) is shorter or longer than 6 carbons, it will be so indicated in the second “C” as, for example, “C₁-C₁₀” indicates a maximum of 10 carbons.
By “alkoxy” and “C₁-C₆alkoxy” in the present invention is meant straight or branched chain alkyl groups having 1-6 carbon atoms, attached through at least one divalent oxygen atom, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, neopentoxy, hexoxy, and 3-methylpentoxy.
By the term “halogen” in the present invention is meant fluorine, bromine, chlorine, and/or iodine.
“Alkenyl” and “C₂-C₆alkenyl” means straight and branched hydrocarbon radicals having from 2 to 6 carbon atoms and from one to three double bonds and includes, for example, ethenyl, propenyl, 1-but-3-enyl, 1-pent-3-enyl, 1-hex-5-enyl and the like.
“Alkynyl” and “C₂-C₆alkynyl” means straight and branched hydrocarbon radicals having from 2 to 6 carbon atoms and one or two triple bonds and includes ethynyl, propynyl, butynyl, pentyn-2-yl and the like.
As used herein, the term “cycloalkyl” refers to saturated carbocyclic radicals having three to twelve carbon atoms. The cycloalkyl can be monocyclic, a polycyclic fused system, or a bi or polycyclic bridged system, such as adamantyl or bicyclo[2.2.1]heptyl. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Preferred cycloalkyl groups are cyclopentyl, cyclohexyl, and cycloheptyl. The cycloalkyl groups herein are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups. For example, such cycloalkyl groups may be optionally substituted with, for example, C₁-C₆alkyl, C₁-C₆alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl, C₁-C₆haloalkoxy, amino(C₁-C₆)alkyl, mono(C₁-C₆)alkylamino(C₁-C₆)alkyl or di(C₁-C₆)alkylamino(C₁-C₆)alkyl.
By “aryl” is meant an aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings in which at least one is aromatic, (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl), which is optionally mono-, di-, or trisubstituted. Preferred aryl groups of the present invention are phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl, fluorenyl, tetralinyl or 6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl. The aryl groups herein are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups. For example, such aryl groups may be optionally substituted with, for example, C₁-C₆alkyl, C₁-C₆alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl, C₁-C₆haloalkoxy, amino(C₁-C₆)alkyl, mono(C₁-C₆)alkylamino(C₁-C₆)alkyl or di(C₁-C₆)alkylamino(C₁-C₆)alkyl.
By “heteroaryl” is mean at least one or more aromatic ring systems of 5-, 6-, or 7-membered rings which includes fused ring systems of 9-11 atoms containing at least one and up to four heteroatoms selected from nitrogen, oxygen, or sulfur. Preferred heteroaryl groups of the present invention include pyridinyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl, pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, isothiazolyl, naphthyridinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, chromonyl, chromanonyl, pyridinyl-N-oxide, tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl, dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinyl N-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide, quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide, imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, triazolyl N-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide, benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide, benzothiopyranyl S-oxide, benzothiopyranyl S,S-dioxide. The heteroaryl groups herein are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups. For example, such heteroaryl groups may be optionally substituted with, for example, C₁-C₆alkyl, C₁-C₆alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl, C₁-C₆haloalkoxy, amino(C₁-C₆)alkyl, mono(C₁-C₆)alkylamino(C₁-C₆)alkyl or di(C₁-C₆)alkylamino(C₁-C₆)alkyl.
By “heterocycle”, “heterocycloalkyl” or “heterocyclyl” is meant one or more carbocyclic ring systems of 4-, 5-, 6-, or 7-membered rings which includes fused ring systems of 9-11 atoms containing at least one and up to four heteroatoms selected from nitrogen, oxygen, or sulfur. Preferred heterocycles of the present invention include morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, piperazinyl, homopiperazinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydrofuranyl, tetrahydrothienyl, homopiperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothienyl S-oxide, tetrahydrothienyl S,S-dioxide and homothiomorpholinyl S-oxide. The heterocycle groups herein are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups. For example, such heterocycle groups may be optionally substituted with, for example, C₁-C₆alkyl, C₁-C₆alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl, C₁-C₆haloalkoxy, amino(C₁-C₆)alkyl, mono(C₁-C₆)alkylamino(C₁-C₆)alkyl, di(C₁-C₆)alkylamino(C₁-C₆)alkyl or ═O.
Structures were named using Name Pro IUPAC Naming Software, version 5.09, available from Advanced Chemical Development, Inc., 90 Adelaide Street West, Toronto, Ontario, M5H 3V9, Canada or using ChemDraw v. 6.02 or ChemDraw v. 8.03, both of which are available from Cambridgesoft at 100 Cambridge Park Drive, Cambridge, Mass. 02140 (www.cambridgesoft.com).
The compounds of this invention may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms. These compounds can be, for example, racemates, chiral non-racemic or diastereomers. In these situations, the single enantiomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent; chromatography, using, for example a chiral HPLC column; or derivatizing the racemic mixture with a resolving reagent to generate diastereomers, separating the diastereomers via chromatography, and removing the resolving agent to generate the original compound in enantiomerically enriched form. Any of the above procedures can be repeated to increase the enantiomeric purity of a compound.
Non-toxic pharmaceutically acceptable salts include, but are not limited to salts of inorganic acids such as hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic, and nitric or salts of organic acids such as formic, citric, malic, maleic, fumaric, tartaric, succinic, acetic, lactic, methanesulfonic, p-toluenesulfonic, 2-hydroxyethylsulfonic, salicylic and stearic. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts. The invention also encompasses prodrugs of the compounds of Formula I.
The invention also encompasses the acylated prodrugs of the compounds of Formula I. Those skilled in the art will recognize various synthetic methodologies, which may be employed to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by Formula I.
When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, it is intended that the compounds include the cis, trans, Z- and E-configurations. Likewise, all tautomeric forms are also intended to be included.
The invention also encompasses the prodrugs of the compounds of Formula I. Those skilled in the art will recognize various synthetic methodologies that may be employed to prepare non-toxic pharmaceutically acceptable prodrugs of the compounds encompassed by Formula I. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable solvates, such as water, ethanol, mineral oil, vegetable oil, and dimethylsulfoxide.
The compounds of general Formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes percutaneous, subcutaneous, intravascular (e.g., intravenous), intramuscular, or intrathecal injection or infusion techniques and the like. In addition, there is provided a pharmaceutical formulation comprising a compound of general Formula I and a pharmaceutically acceptable carrier. One or more compounds of general Formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants, and if desired other active ingredients. The pharmaceutical compositions containing compounds of general Formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservative agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques. In some cases such coatings may be prepared by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
Formulations for oral use may also be presented as hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Formulations for oral use may also be presented as lozenges.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents or suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil or a mineral oil or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol, glucose or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parentally 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.
The compounds of general Formula I may also be administered in the form of suppositories, e.g., for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols.
Compounds of general Formula I may be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
For disorders of the eye or other external tissues, e.g., mouth and skin, the formulations are preferably applied as a topical gel, spray, ointment or cream, or as a suppository, containing the active ingredients in a total amount of, for example, 0.075 to 30% w/w, preferably 0.2 to 20% w/w and most preferably 0.4 to 15% w/w. 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 dimethylsulfoxide and related analogs. The compounds of this invention can also be administered by a transdermal device. Preferably topical 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 transdermal patch may include the compound in a suitable solvent system with an adhesive system, such as an acrylic emulsion, and a polyester patch. 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 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. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate, among others. 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 anti-inflammatory 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. For therapeutic purposes, the active compounds of this combination 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. 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 having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day). The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient. The daily dose can be administered in one to four doses per day. In the case of 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.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
For administration to non-human animals, the composition may also be added to the animal feed or drinking water. It may be convenient to formulate the animal feed and drinking water compositions so that the animal takes in a therapeutically appropriate quantity of the composition along with its diet. It may also be convenient to present the composition as a premix for addition to the feed or drinking water.
The disclosures in this document of all articles and references, including patents, are incorporated herein by reference in their entirety.
The invention is illustrated further by the following examples, which are not to be construed as limiting the invention in scope or spirit to the specific procedures described in them.
The starting materials and various intermediates may be obtained from commercial sources, prepared from commercially available compounds, or prepared using known synthetic methods.

General Synthetic Procedures

The compounds of the invention can be prepared using methods well known in the art of organic synthesis. Representative procedures suitable for preparing compounds of the invention are outlined in the following schemes.
Compounds of the invention can be prepared by various methods known to those skilled in the art. For example, the compounds of the invention, as well as all intermediates, can be synthesized by known processes using either solution or solid phase techniques, as shown below.
In scheme 1, the definitions of the variables are as defined above, except that R4 is an optionally substituted phenyl, wherein the phenyl is optionally substituted with R₃, R_3′ and/or R₄, wherein R₃, R_3′ and R₄are as defined above.
Using standard methods familiar to those skilled in the art, a reductive alkylation is performed by treating primary amine 1.0 with appropriate aldehydes or ketones in a suitable solvent such as methanol. Upon treatment with a reducing agent such as sodium borohydride, sodium cyanoborohydride, or polystyrene bound borohydride, intermediate amines 2.0 are formed. Amines 2.0 are further functionalized by treatment with an appropriate sulfonylhalide 3.0 (where X is a halogen) in a suitable solvent, such as dichloromethane, THF or chloroform, in the presence of a base such as diisopropylethylamine, triethylamine or pyridine at a decreased temperature, resulting in compounds of formula Ia.
Certain compounds of this invention are prepared from other compounds listed in this invention via well-known functional group transformations. Such transformations include ester hydrolysis, amide formation, reductive alkylation, with examples of such described in the preparations. Starting materials are prepared by known methods and are described in the examples below.
Compounds included in this invention are exemplified by the following examples, which should not be construed as limiting the scope of this disclosure. Analogous structures and alternative mechanistic pathways within the scope of the invention may be apparent to those skilled in the art.
In the following examples, MH⁺ refers to the mass as determined by LC/MS carried out on a ThermoHypersil-Keystone BDS Hypersil C18 column (50 mm×3 mm, 5 micron particle size). MNa⁺ is used to identify the product based on its sodium adduct. Elution conditions for LC/MS are as follows: Solvents: A. Water with 0.05% TFA (v/v); B. Acetonitrile with 0.05% TFA (v/v); Flow rate: 3 mL/min

Gradient Method


	Time
	(min)	% B Conc

	0	5
	0.25	5
	2.75	95
	3.5	95
	3.6	5
	4.0	STOP

In isolating the following examples, it was necessary to employ a Varian reverse-phase preparative HPLC, utilizing a Phenomenex Aqua C₁₈column (60 mm×21.2 mm, 5 micron particle size). Elution conditions for the HPLC are as follows: Solvents: A. Water with 0.05% TFA (v/v); B. Acetonitrile with 0.05% TFA (v/v); Flow rate: 25 mL/min

Gradient Method


	Time
	(min)	% B Conc

	0	5
	0.75	5
	9.5	100
	10.5	100
	11.5	5
	12.0	STOP

Example 1

Step 1:

A mixture of 3-phenylpropionaldehyde (215 mg; 1.6 mmol) and R-(−)-leucinol (187 mg; 1.6 mmol) in methanol was stirred at room temperature for 3 h. The reaction was treated with polystyrene bound borohydride (640 mg; 1.6 mmol) and stirred at room temperature overnight. The final mixture was filtered, treated with polystyrene bound sulfonic acid (923 mg; 4.8 mmol) and stirred at room temperature for 1 h. The mixture was filtered, leaving the desired product isolated on the resin. Subsequent treatment with 2.0M methanolic ammonia (8 ml) liberated the desired product, which was concentrated under nitrogen overnight.

Step 2

A mixture of the secondary amine from Step 1 (259 mg; 1.1 mmol) and diisopropylethylamine (568 ul; 4.4 mmol) was stirred in CH₂Cl₂at 0° C. for 1 h. A solution of 4-chlorobenzenesulfonylchloride (232 mg; 1.1 mmol) in CH₂Cl₂was added and subsequently stirred at 10° C. for 18 h. The crude reaction mixture was then purified on a Varian reverse-phase preparative HPLC to afford the desired product.

Example 2

Step 1

A mixture of R-(−)-2-benzylamino-1-butanol (36 mg; 0.2 mmol), 4-chlorobenzenesulfonylchloride (51 mg; 0.24 mmol) and pyridine (126 ul; 1.6 mmol) was stirred in CH₂Cl₂at room temperature for 48 h. The crude reaction mixture was then purified on a Varian reverse-phase preparative HPLC to afford the desired product.
The following compounds were prepared essentially according to the methods and procedures described above.


Ex.
No.	Name	M + H+	M + Na+

1	N-benzyl-4-chloro-N-[(1S,2R)-2-	393.9
	(hydroxymethyl)cyclohexyl]benzenesulfonamide
2	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(2-	438.1
	methyl-cyclohexyl)-benzenesulfonamide (one
	isomer)
3	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(2-	438.1
	methyl-cyclohexyl)-benzenesulfonamide (second
	isomer)
4	4-Chloro-N-cyclooctyl-N-(3,4-dimethoxy-		474.1
	benzyl)-benzenesulfonamide
5	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-		474.1
	(2,3-dimethyl-cyclohexyl)-benzenesulfonamide
6	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(4-		460.1
	methyl-cyclohexyl)-benzenesulfonamide
7	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(1-		468.1
	phenyl-ethyl)-benzenesulfonamide
8	4-chloro-N-(3,4-dimethoxybenzyl)-N-		498.1
	[(1S,2R)-2-hydroxy-1-methyl-2-
	phenylethyl]benzenesulfonamide
9	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(1-		450.0
	hydroxymethyl-2-methyl-propyl)-
	benzenesulfonamide
10	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(1-		518.0
	naphthalen-1-yl-ethyl)-benzenesulfonamide
11	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(1-		508.0
	phenyl-4,5-dihydro-1H-pyrazol-3-yl)-
	benzenesulfonamide
12	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(3-		450.0
	hydroxy-2,2-dimethyl-propyl)-
	benzenesulfonamide
13	4-Chloro-N-(4-diethylamino-1-methyl-	483.2
	butyl)-N-(3,4-dimethoxy-benzyl)-
	benzenesulfonamide
14	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-[1-		546.0
	(4-methanesulfonyl-phenyl)-ethyl]-
	benzenesulfonamide
15	3-[(4-Chloro-benzenesulfonyl)-(3,4-		547.2
	dimethoxy-benzyl)-amino]-piperidine-1-
	carboxylic acid tert-butyl ester
16	4-chloro-N-(3,4-dimethoxybenzyl)-N-		490.0
	[(1S,3R,4R)-3-
	(hydroxymethyl)bicyclo[2.2.1]hept-2-
	yl]benzenesulfonamide
17	4-chloro-N-(3,4-dimethoxybenzyl)-N-		484.0
	[(1S)-2-hydroxy-1-
	phenylethyl]benzenesulfonamide
18	N-[(1R)-1-benzyl-2-hydroxyethyl]-4-		498.0
	chloro-N-(3,4-
	dimethoxybenzyl)benzenesulfonamide
19	N-[(4-chlorophenyl)sulfonyl]-N-(3,4-		511.1
	dimethoxybenzyl)-L-phenylalaninamide
20	4-chloro-N-(3,4-dimethoxybenzyl)-N-		514.1
	[(1R,2S)-2-hydroxy-1-(hydroxymethyl)-2-
	phenylethyl]benzenesulfonamide
21	N-[(1S)-1-benzyl-2-hydroxyethyl]-4-		498.1
	chloro-N-(3,4-
	dimethoxybenzyl)benzenesulfonamide
22	N-benzyl-4-chloro-N-[(1S,2S)-2-		402.0
	hydroxycyclohexyl]benzenesulfonamide
23	4-chloro-N-[(1R)-1-(hydroxymethyl)-3-		434.1
	methylbutyl]-N-(4-
	methoxybenzyl)benzenesulfonamide
24	4-chloro-N-(4-chlorobenzyl)-N-[(1R)-1-	416.0
	(hydroxymethyl)-3-
	methylbutyl]benzenesulfonamide
25	N-(4-bromobenzyl)-4-chloro-N-[(1R)-1-	462.0
	(hydroxymethyl)-3-
	methylbutyl]benzenesulfonamide
26	4-chloro-N-(2,4-difluorobenzyl)-N-[(1R)-	418.1
	1-(hydroxymethyl)-3-
	methylbutyl]benzenesulfonamide
27	N-benzyl-4-chloro-N-[(1S)-1-	354.0
	(hydroxymethyl)propyl]benzenesulfonamide
28	4-chloro-N-[(1R)-1-(hydroxymethyl)-3-	410.1
	methylbutyl]-N-(3-
	phenylpropyl)benzenesulfonamide
29	N2-[(4-chlorophenyl)sulfonyl]-N1-methyl-	277.0
	L-alaninamide
30	N-tert-Butyl-2-(4-chloro-	347.0
	benzenesulfonylamino)-3-methyl-butyramide
31	4-Chloro-N-ethyl-N-[2-hydroxy-2-(3-	356.0
	hydroxy-phenyl)-ethyl]-benzenesulfonamide
32	4-Chloro-N-(2-hydroxy-1-methyl-2-phenyl-		362.0
	ethyl)-N-methyl-benzenesulfonamide
33	4-Chloro-N-methyl-N-(1-methyl-piperidin-	303.1
	4-yl)-benzenesulfonamide
34	4-Chloro-N-cyclohexyl-N-(2-hydroxy-2-		416.1
	phenyl-ethyl)-benzenesulfonamide
35	4-Chloro-N-ethyl-N-(2-pyridin-2-yl-	325.1
	ethyl)-benzenesulfonamide
36	N,N-Di-sec-butyl-4-chloro-	304.1
	benzenesulfonamide
37	4-Chloro-N-(2-cyano-ethyl)-N-	285.0
	cyclopropyl-benzenesulfonamide
38	4-Chloro-N-methyl-N-(2-pyridin-4-yl-	311.1
	ethyl)-benzenesulfonamide
39	[(4-Chloro-benzenesulfonyl)-methyl-	292.0
	amino]-acetic acid ethyl ester
40	4-chloro-N-[(1S,2S)-2-hydroxy-1-methyl-		362.0
	2-phenylethyl]-N-methylbenzenesulfonamide
41	4-chloro-N-[(1R,2S)-2-hydroxy-1-methyl-		362.0
	2-phenylethyl]-N-methylbenzenesulfonamide
42	4-Chloro-N-cyclohexyl-N-(2-hydroxy-	318.0
	ethyl)-benzenesulfonamide
43	4-Chloro-N-cyanomethyl-N-methyl-		266.9
	benzenesulfonamide
44	4-Chloro-N-(2-cyano-ethyl)-N-ethyl-	273.0
	benzenesulfonamide
45	4-Chloro-N-isopropyl-N-(2-pyridin-4-yl-	339.0
	ethyl)-benzenesulfonamide
46	4-Chloro-N-[2-(3,4-dihydroxy-phenyl)-2-	356.0
	oxo-ethyl]-N-methyl-benzenesulfonamide
47	N-Allyl-4-chloro-N-cyclohexyl-	314.0
	benzenesulfonamide
48	4-Chloro-N,N-dicyclohexyl-	356.7
	benzenesulfonamide
49	4-Chloro-N-cyclohexyl-N-isopropyl-	315.8
	benzenesulfonamide
50	4-Chloro-N,N-diisopropyl-	275.5
	benzenesulfonamide
51	4-Chloro-N,N-divinyl-benzenesulfonamide	243.8
52	N-(1-Benzyl-pyrrolidin-3-yl)-4-chloro-N-	379.0
	ethyl-benzenesulfonamide
53	4-Chloro-N-{3-methoxy-4-[2-(4-methyl-	508
	thiazol-5-yl)-ethoxy]-benzyl}-N-(2-methyl-
	allyl)-benzenesulfonamide
54	4-Chloro-N-(2-hydroxy-propyl)-N-{3-	512
	methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-
	benzyl}-benzenesulfonamide
55	4-Chloro-N-{3-methoxy-4-[2-(4-methyl-	550.1
	thiazol-5-yl)-ethoxy]-benzyl}-N-(2-methyl-
	cyclohexyl)-benzenesulfonamide
56	4-Chloro-N-(2,3-dihydroxy-propyl)-N-{3-	528.9
	methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-
	benzyl}-benzenesulfonamide
57	4-Chloro-N-(1-hydroxymethyl-pentyl)-N-	554.1
	{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-
	ethoxy]-benzyl}-benzenesulfonamide
58	4-Chloro-N-cycloheptyl-N-{3-methoxy-4-	550
	[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-
	benzenesulfonamide
59	4-chloro-N-[(1S)-1-(hydroxymethyl)-3-	554
	methylbutyl]-N-{3-methoxy-4-[2-(4-methyl-1,3-
	thiazol-5-yl)ethoxy]benzyl}benzenesulfonamide
60	N-(2-Amino-benzyl)-4-chloro-N-{3-	559
	methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-
	benzyl}-benzenesulfonamide
61	4-Chloro-N-{3-methoxy-4-[2-(4-methyl-	542
	thiazol-5-yl)-ethoxy]-benzyl}-N-(3-
	methylsulfanyl-propyl)-benzenesulfonamide
62	4-Chloro-N-(3-hydroxy-butyl)-N-{3-	526
	methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-
	benzyl}-benzenesulfonamide
63	4-Chloro-N-{3-methoxy-4-[2-(4-methyl-	544.9
	thiazol-5-yl)-ethoxy]-benzyl}-N-pyridin-2-
	ylmethyl-benzenesulfonamide
64	4-Chloro-N-(2,4-dichloro-benzyl)-N-{3-	612.9
	methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-
	benzyl}-benzenesulfonamide
65	4-chloro-N-{[(1R,2S)-2-	566
	hydroxycyclohexyl]methyl}-N-{3-methoxy-4-[2-
	(4-methyl-1,3-thiazol-5-
	yl)ethoxy]benzyl}benzenesulfonamide
66	4-Chloro-N-cyclohexyl-N-{3-methoxy-4-[2-	535.8
	(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-
	benzenesulfonamide
67	4-Chloro-N-{3-methoxy-4-[2-(4-methyl-	549.8
	thiazol-5-yl)-ethoxy]-benzyl}-N-(4-methyl-
	cyclohexyl)-benzenesulfonamide
68	4-Chloro-N-cyclobutyl-N-{3-methoxy-4-[2-	507.8
	(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-
	benzenesulfonamide
69	4-Chloro-N-cyclopentyl-N-{3-methoxy-4-	521.8
	[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-
	benzenesulfonamide
70	4-Chloro-N-{3-methoxy-4-[2-(4-methyl-	525.8
	thiazol-5-yl)-ethoxy]-benzyl}-N-(3-methoxy-
	propyl)-benzenesulfonamide
71	4-Chloro-N-{3-methoxy-4-[2-(4-methyl-	491.8
	thiazol-5-yl)-ethoxy]-benzyl}-N-prop-2-ynyl-
	benzenesulfonamide
72	4-Chloro-N-{3-methoxy-4-[2-(4-methyl-	537.8
	thiazol-5-yl)-ethoxy]-benzyl}-N-(tetrahydro-
	furan-2-ylmethyl)-benzenesulfonamide
73	4-Chloro-N-cyclopropylmethyl-N-{3-	507.8
	methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-
	benzyl}-benzenesulfonamide
74	4-Chloro-N-{3-methoxy-4-[2-(4-methyl-	523.8
	thiazol-5-yl)-ethoxy]-benzyl}-N-(2-methyl-
	butyl)-benzenesulfonamide
75	4-Chloro-N-{3-methoxy-4-[2-(4-methyl-	557.9
	thiazol-5-yl)-ethoxy]-benzyl}-N-(1-phenyl-
	ethyl)-benzenesulfonamide
76	4-Chloro-N-{3-methoxy-4-[2-(4-methyl-	523.8
	thiazol-5-yl)-ethoxy]-benzyl}-N-(3-methyl-
	butyl)-benzenesulfonamide
77	4-Chloro-N-ethyl-N-{3-methoxy-4-[2-(4-	481.8
	methyl-thiazol-5-yl)-ethoxy]-benzyl}-
	benzenesulfonamide
78	4-chloro-N-(3,4-dimethoxybenzyl)-N-		437
	[(1S)-1-
	(hydroxymethyl)propyl]benzenesulfonamide
79	4-chloro-N-(3,4-dimethoxybenzyl)-N-		465.1
	[(1S)-1-(hydroxymethyl)-3-
	methylbutyl]benzenesulfonamide
80	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(2-		475.1
	methyl-cyclohexyl)-benzenesulfonamide
81	N-Benzyl-N-sec-butyl-4-chloro-		361
	benzenesulfonamide
82	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(2-	438.8
	methyl-cyclohexyl)-benzenesulfonamide
83	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(2-	438.8
	methyl-cyclohexyl)-benzenesulfonamide
84	N-(1,3-benzodioxol-5-ylmethyl)-4-chloro-		449.1
	N-[(1S)-1-(hydroxymethyl)-3-
	methylbutyl]benzenesulfonamide
85	4-chloro-N-(2,3-dihydro-1,4-benzodioxin-		463.1
	6-ylmethyl)-N-[(1S)-1-(hydroxymethyl)-3-
	methylbutyl]benzenesulfonamide
86	4-chloro-N-(3,4-dimethylbenzyl)-N-[(1S)-		433.1
	1-(hydroxymethyl)-3-
	methylbutyl]benzenesulfonamide
87	4-chloro-N-(3-fluoro-4-methoxybenzyl)-N-		453.1
	[(1S)-1-(hydroxymethyl)-3-
	methylbutyl]benzenesulfonamide
88	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(2-		461.1
	methyl-cyclohexyl)-benzenesulfonamide
89	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(2-		461.1
	methyl-cyclohexyl)-benzenesulfonamide
90	4-chloro-N-[(1S)-1-(hydroxymethyl)-3-		431.1
	methylbutyl]-N-[(2E)-3-phenylprop-2-en-1-
	yl]benzenesulfonamide
91	4-chloro-N-[(1S)-1-(hydroxymethyl)-3-		445.1
	methylbutyl]-N-[(2E)-2-methyl-3-phenylprop-2-
	en-1-yl]benzenesulfonamide
92	4-Chloro-N-(1-hydroxymethyl-3-methyl-		444
	butyl)-N-(1-methyl-3-phenyl-allyl)-
	benzenesulfonamide
93	N-(2-Benzyl-cyclohexyl)-4-chloro-N-(1-		486.2
	hydroxymethyl-3-methyl-butyl)-
	benzenesulfonamide
94	4-Chloro-N-(1-hydroxymethyl-3-methyl-		444
	butyl)-N-(1,2,3,4-tetrahydro-naphthalen-2-
	yl)-benzenesulfonamide
95	4-Chloro-N-(4,6-dichloro-2H-chromen-3-		527
	ylmethyl)-N-(1-hydroxymethyl-3-methyl-butyl)-
	benzenesulfonamide
96	4-Chloro-N-(1-hydroxymethyl-3-methyl-	435.1
	butyl)-N-(1-methyl-1H-indol-2-ylmethyl)-
	benzenesulfonamide
97	4-Chloro-N-(1-chloro-3,4-dihydro-		490.1
	naphthalen-2-ylmethyl)-N-(1-hydroxymethyl-3-
	methyl-butyl)-benzenesulfonamide
98	4-Chloro-N-(1-hydroxymethyl-3-methyl-	424.1
	butyl)-N-(1-methyl-3-phenyl-propyl)-
	benzenesulfonamide
99	4-Chloro-N-(1-hydroxymethyl-3-methyl-	334
	butyl)-N-propyl-benzenesulfonamide
100	4-Chloro-N-(1-hydroxymethyl-3-methyl-	306.1
	butyl)-N-methyl-benzenesulfonamide
101	N-sec-Butyl-4-chloro-N-(4-chloro-6-		466
	fluoro-2H-chromen-3-ylmethyl)-
	benzenesulfonamide
102	N-sec-Butyl-4-chloro-N-(4,6-dichloro-2H-	460
	chromen-3-ylmethyl)-benzenesulfonamide
103	N-sec-Butyl-4-chloro-N-(2-pentyl-3-		456.1
	phenyl-allyl)-benzenesulfonamide
104	N-sec-Butyl-4-chloro-N-(3,3-diphenyl-		462.1
	allyl)-benzenesulfonamide
105	N-Benzofuran-2-ylmethyl-N-sec-butyl-4-		400
	chloro-benzenesulfonamide
106	N-sec-Butyl-4-chloro-N-(1-methyl-1H-	391.1
	indol-2-ylmethyl)-benzenesulfonamide
107	N-sec-Butyl-4-chloro-N-(1-chloro-3,4-		445.9
	dihydro-naphthalen-2-ylmethyl)-
	benzenesulfonamide
108	4-Chloro-N-(1-hydroxymethyl-3-methyl-		460.1
	butyl)-N-[3-(2-methoxy-phenyl)-allyl]-
	benzenesulfonamide
109	N-Benzofuran-2-ylmethyl-4-chloro-N-(1-		444.0
	hydroxymethyl-3-methyl-butyl)-
	benzenesulfonamide
110	4-Chloro-N-cyclopropylmethyl-N-(1-	346.0
	hydroxymethyl-3-methyl-butyl)-
	benzenesulfonamide
111	4-Chloro-N-(2-methyl-cyclohexyl)-N-(3-		426.1
	phenyl-allyl)-benzenesulfonamide
112	4-Chloro-N-(1-hydroxymethyl-3-methyl-	424.1
	butyl)-N-(3-phenyl-butyl)-benzenesulfonamide
113	4-Chloro-N-(1-methyl-butyl)-N-(3-phenyl-		400.1
	allyl)-benzenesulfonamide
114	4-Chloro-N-(1,3-dimethyl-butyl)-N-(3-		414.1
	phenyl-allyl)-benzenesulfonamide
115	4-Chloro-N-(2-methyl-cyclohexyl)-N-(3-		428.1
	phenyl-propyl)-benzenesulfonamide
116	4-Chloro-N-(1-methyl-butyl)-N-(3-phenyl-	380.1
	propyl)-benzenesulfonamide
117	4-Chloro-N-(1-ethyl-propyl)-N-(3-phenyl-		400.1
	allyl)-benzenesulfonamide
118	N-[3-(4-tert-Butyl-phenyl)-2-methyl-	480.2
	propyl]-4-chloro-N-(1-hydroxymethyl-3-methyl-
	butyl)-benzenesulfonamide
119	4-Chloro-N-(1,3-dimethyl-butyl)-N-(3-	394.1
	phenyl-propyl)-benzenesulfonamide
120	4-Chloro-N-(2-methoxy-1-methyl-ethyl)-N-	382.1
	(3-phenyl-propyl)-benzenesulfonamide
121	4-Chloro-N-(4-chloro-6-fluoro-2H-		510.1
	chromen-3-ylmethyl)-N-(1-hydroxymethyl-3-
	methyl-butyl)-benzenesulfonamide
122	4-Chloro-N-(2-methoxy-1-methyl-ethyl)-N-		402.0
	(3-phenyl-allyl)-benzenesulfonamide
123	4-Chloro-N-(1-ethyl-propyl)-N-(3-phenyl-	380.0
	propyl)-benzenesulfonamide
124	4-Chloro-N-(1,2-dimethyl-propyl)-N-(3-		400.1
	phenyl-allyl)-benzenesulfonamide
125	N-sec-Butyl-4-chloro-N-(1-methyl-3-		402.1
	phenyl-propyl)-benzenesulfonamide
126	N-sec-Butyl-4-chloro-N-(3-phenyl-allyl)-		386.0
	benzenesulfonamide
127	4-Chloro-N-(1-hydroxymethyl-propyl)-N-	382.1
	(3-phenyl-propyl)-benzenesulfonamide
128	4-Chloro-N-(2-hydroxy-propyl)-N-(3-	368.1
	phenyl-propyl)-benzenesulfonamide
129	4-Chloro-N-(1-hydroxymethyl-propyl)-N-		402.0
	(3-phenyl-allyl)-benzenesulfonamide
130	4-Chloro-N-(1,2-dimethyl-propyl)-N-(3-	380.1
	phenyl-propyl)-benzenesulfonamide
131	N-sec-Butyl-4-chloro-N-[3-(2-methoxy-		416.1
	phenyl)-allyl]-benzenesulfonamide
132	4-Chloro-N-(2-hydroxy-propyl)-N-(3-		388.0
	phenyl-allyl)-benzenesulfonamide
133	N-sec-Butyl-4-chloro-N-(3-phenyl-	366.1
	propyl)-benzenesulfonamide
134	N-sec-Butyl-4-chloro-N-(1-methyl-3-		400.1
	phenyl-allyl)-benzenesulfonamide
135	2-[(4-Chloro-benzenesulfonyl)-(3-phenyl-	426.1
	propyl)-amino]-3-hydroxy-N-methyl-butyramide
136	4-Chloro-N-(1-hydroxymethyl-3-methyl-		500.1
	butyl)-N-(2-pentyl-3-phenyl-allyl)-
	benzenesulfonamide
137	N-sec-Butyl-4-chloro-N-(3-phenyl-butyl)-	380.1
	benzenesulfonamide
138	(S)-4-chloro-N-cinnamyl-N-(1-hydroxy-4-		431.1
	methylpentan-2-yl)benzenesulfonamide
139	4-Chloro-N-(1-hydroxymethyl-3-methyl-	410.1
	butyl)-N-(3-phenyl-propyl)-benzenesulfonamide
140	4-Chloro-N-(1-hydroxymethyl-3-methyl-		445.1
	butyl)-N-(2-methyl-3-phenyl-allyl)-
	benzenesulfonamide
141	4-Chloro-N-(2,3-dihydro-benzo[1,4]dioxin-		463.1
	6-ylmethyl)-N-(1-hydroxymethyl-3-methyl-
	butyl)-benzenesulfonamide
142	N-Benzo[1,3]dioxol-5-ylmethyl-4-chloro-N-		449.1
	(1-hydroxymethyl-3-methyl-butyl)-
	benzenesulfonamide
143	4-Chloro-N-(3-fluoro-4-methoxy-benzyl)-N-		453.1
	(1-hydroxymethyl-3-methyl-butyl)-
	benzenesulfonamide
144	4-Chloro-N-(2,4-difluoro-benzyl)-N-(1-	418.1	—
	hydroxymethyl-3-methyl-butyl)-
	benzenesulfonamide
145	4-Chloro-N-(1-hydroxymethyl-3-methyl-		434.1
	butyl)-N-(4-methoxy-benzyl)-benzenesulfonamide
146	4-Chloro-N-(4-chloro-benzyl)-N-(1-	416.0	—
	hydroxymethyl-3-methyl-butyl)-
	benzenesulfonamide
147	N-(4-Bromo-benzyl)-4-chloro-N-(1-	462.0	—
	hydroxymethyl-3-methyl-butyl)-
	benzenesulfonamide
148	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(2-	438.1	—
	methyl-cyclohexyl)-benzenesulfonamide
149	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(2-	438.8
	methyl-cyclohexyl)-benzenesulfonamide
150	N-Benzyl-4-chloro-N-(1-hydroxymethyl-	354.0	—
	propyl)-benzenesulfonamide
151	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(2-		475.1
	methyl-cyclohexyl)-benzenesulfonamide
152	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(1-		465.1
	hydroxymethyl-3-methyl-butyl)-
	benzenesulfonamide
153	N-Benzyl-4-chloro-N-(2-hydroxy-		402.0
	cyclohexyl)-benzenesulfonamide
154	N,N-Di-sec-butyl-4-chloro-	304.1	—
	benzenesulfonamide
155	4-Chloro-N-(1-hydroxymethyl-3-methyl-	554
	butyl)-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-
	yl)-ethoxy]-benzyl}-benzenesulfonamide
156	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(2-		461.1
	methyl-cyclohexyl)-benzenesulfonamide
157	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(1-		450.0
	hydroxymethyl-2-methyl-propyl)-
	benzenesulfonamide
158	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(1-		437
	hydroxymethyl-propyl)-benzenesulfonamide
159	4-Chloro-N-cyclohexyl-N-isopropyl-	315.8
	benzenesulfonamide
160	4-Chloro-N-{3-methoxy-4-[2-(4-methyl-	550.1
	thiazol-5-yl)-ethoxy]-benzyl}-N-(2-methyl-
	cyclohexyl)-benzenesulfonamide
161	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(2-		461.1
	methyl-cyclohexyl)-benzenesulfonamide
162	4-Chloro-N,N-diisopropyl-	275.5	—
	benzenesulfonamide
163	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(2-	438.1	—
	methyl-cyclohexyl)-benzenesulfonamide
164	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(2-	438.8
	methyl-cyclohexyl)-benzenesulfonamide
165	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(2,3-		474.1
	dimethyl-cyclohexyl)-benzenesulfonamide
166	N-Benzyl-N-sec-butyl-4-chloro-		361
	benzenesulfonamide
167	4-Chloro-N-(1-hydroxymethyl-pentyl)-N-{3-	554.1
	methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-
	benzyl}-benzenesulfonamide
168	4-Chloro-N-cyclooctyl-N-(3,4-dimethoxy-		474.1
	benzyl)-benzenesulfonamide
169	4-Chloro-N-cyclohexyl-N-{3-methoxy-4-[2-	535.8
	(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-
	benzenesulfonamide
170	N-Allyl-4-chloro-N-cyclohexyl-	314.0	—
	benzenesulfonamide
171	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(2-		484.0
	hydroxy-1-phenyl-ethyl)-benzenesulfonamide
172	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(4-		460.1
	methyl-cyclohexyl)-benzenesulfonamide
173	4-Chloro-N-(3-hydroxy-butyl)-N-{3-methoxy-	526
	4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-
	benzenesulfonamide
174	4-Chloro-N-(2-hydroxy-cyclohexylmethyl)-N-	566
	{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-
	ethoxy]-benzyl}-benzenesulfonamide
175	4-Chloro-N,N-divinyl-benzenesulfonamide	243.8	—
176	4-Chloro-N,N-dicyclohexyl-	356.7	—
	benzenesulfonamide
177	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(3-		450.0
	hydroxy-2,2-dimethyl-propyl)-
	benzenesulfonamide
178	4-Chloro-N-cyclopentyl-N-{3-methoxy-4-[2-	521.8
	(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-
	benzenesulfonamide
179	N-(2-Amino-benzyl)-4-chloro-N-{3-methoxy-	559
	4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-
	benzenesulfonamide
180	4-Chloro-N-cyclohexyl-N-(2-hydroxy-2-	—	416.1
	phenyl-ethyl)-benzenesulfonamide
181	4-Chloro-N-{3-methoxy-4-[2-(4-methyl-	523.8
	thiazol-5-yl)-ethoxy]-benzyl}-N-(2-methyl-
	butyl)-benzenesulfonamide
182	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(3-		490.0
	hydroxymethyl-bicyclo[2.2.1]hept-2-yl)-
	benzenesulfonamide
183	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(1-		498.0
	hydroxymethyl-2-phenyl-ethyl)-
	benzenesulfonamide
184	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-[1-(4-		546.0
	methanesulfonyl-phenyl)-ethyl]-
	benzenesulfonamide
185	4-Chloro-N-(2-hydroxy-propyl)-N-{3-	512
	methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-
	benzyl}-benzenesulfonamide
186	3-[(4-Chloro-benzenesulfonyl)-(3,4-		547.2
	dimethoxy-benzyl)-amino]-piperidine-1-
	carboxylic acid tert-butyl ester
187	4-Chloro-N-cycloheptyl-N-{3-methoxy-4-[2-	550
	(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-
	benzenesulfonamide
188	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(1-		468.1
	phenyl-ethyl)-benzenesulfonamide
189	4-Chloro-N-{3-methoxy-4-[2-(4-methyl-	542
	thiazol-5-yl)-ethoxy]-benzyl}-N-(3-
	methylsulfanyl-propyl)-benzenesulfonamide
190	4-Chloro-N-{3-methoxy-4-[2-(4-methyl-	549.8
	thiazol-5-yl)-ethoxy]-benzyl}-N-(4-methyl-
	cyclohexyl)-benzenesulfonamide
191	4-Chloro-N-ethyl-N-{3-methoxy-4-[2-(4-	481.8
	methyl-thiazol-5-yl)-ethoxy]-benzyl}-
	benzenesulfonamide
192	4-Chloro-N-{3-methoxy-4-[2-(4-methyl-	544.9
	thiazol-5-yl)-ethoxy]-benzyl}-N-pyridin-2-
	ylmethyl-benzenesulfonamide
193	4-Chloro-N-{3-methoxy-4-[2-(4-methyl-	491.8
	thiazol-5-yl)-ethoxy]-benzyl}-N-prop-2-ynyl-
	benzenesulfonamide
194	4-Chloro-N-{3-methoxy-4-[2-(4-methyl-	523.8
	thiazol-5-yl)-ethoxy]-benzyl}-N-(3-methyl-
	butyl)-benzenesulfonamide
195	4-Chloro-N-{3-methoxy-4-[2-(4-methyl-	537.8
	thiazol-5-yl)-ethoxy]-benzyl}-N-(tetrahydro-
	furan-2-ylmethyl)-benzenesulfonamide
196	4-Chloro-N-cyclopropylmethyl-N-{3-methoxy-	507.8
	4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-
	benzenesulfonamide
197	4-Chloro-N-{3-methoxy-4-[2-(4-methyl-	525.8
	thiazol-5-yl)-ethoxy]-benzyl}-N-(3-methoxy-
	propyl)-benzenesulfonamide
198	4-Chloro-N-(2,4-dichloro-benzyl)-N-{3-	612.9
	methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-
	benzyl}-benzenesulfonamide
199	4-Chloro-N-(2,3-dihydroxy-propyl)-N-{3-	528.9
	methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-
	benzyl}-benzenesulfonamide
200	4-Chloro-N-isopropyl-N-(2-pyridin-4-yl-	339.0	—
	ethyl)-benzenesulfonamide
201	4-Chloro-N-cyclobutyl-N-{3-methoxy-4-[2-	507.8
	(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-
	benzenesulfonamide
202	4-Chloro-N-cyclohexyl-N-(2-hydroxy-ethyl)-	318.0	—
	benzenesulfonamide
203	N-Benzyl-4-chloro-N-(2-hydroxymethyl-	393.9	—
	cyclohexyl)-benzenesulfonamide
204	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(2-		498.1
	hydroxy-1-methyl-2-phenyl-ethyl)-
	benzenesulfonamide
205	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(1-		518.0
	naphthalen-1-yl-ethyl)-benzenesulfonamide
206	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(1-		508.0
	phenyl-4,5-dihydro-1H-pyrazol-3-yl)-
	benzenesulfonamide
207	4-Chloro-N-(4-diethylamino-1-methyl-	483.2	—
	butyl)-N-(3,4-dimethoxy-benzyl)-
	benzenesulfonamide
208	2-[(4-Chloro-benzenesulfonyl)-(3,4-		511.1
	dimethoxy-benzyl)-amino]-3-phenyl-propionamide
209	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(2-		514.1
	hydroxy-1-hydroxymethyl-2-phenyl-ethyl)-
	benzenesulfonamide
210	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(1-		498.1
	hydroxymethyl-2-phenyl-ethyl)-
	benzenesulfonamide
211	2-(4-Chloro-benzenesulfonylamino)-N-	277.0
	methyl-propionamide
212	N-tert-Butyl-2-(4-chloro-	347.0
	benzenesulfonylamino)-3-methyl-butyramide
213	4-Chloro-N-ethyl-N-[2-hydroxy-2-(3-	356.0
	hydroxy-phenyl)-ethyl]-benzenesulfonamide
214	4-Chloro-N-(2-hydroxy-1-methyl-2-phenyl-		362.0
	ethyl)-N-methyl-benzenesulfonamide
215	4-Chloro-N-methyl-N-(1-methyl-piperidin-4-	303.1
	yl)-benzenesulfonamide
216	4-Chloro-N-ethyl-N-(2-pyridin-2-yl-ethyl)-	325.1
	benzenesulfonamide
217	4-Chloro-N-(2-cyano-ethyl)-N-cyclopropyl-	285.0
	benzenesulfonamide
218	4-Chloro-N-methyl-N-(2-pyridin-4-yl-	311.1
	ethyl)-benzenesulfonamide
219	[(4-Chloro-benzenesulfonyl)-methyl-amino]-	292.0
	acetic acid ethyl ester
220	4-Chloro-N-(2-hydroxy-1-methyl-2-phenyl-		362.0
	ethyl)-N-methyl-benzenesulfonamide
221	4-Chloro-N-(2-hydroxy-1-methyl-2-phenyl-		362.0
	ethyl)-N-methyl-benzenesulfonamide
222	4-Chloro-N-cyanomethyl-N-methyl-		266.9
	benzenesulfonamide
223	4-Chloro-N-(2-cyano-ethyl)-N-ethyl-	273.0
	benzenesulfonamide
224	4-Chloro-N-[2-(3,4-dihydroxy-phenyl)-2-	356.0
	oxo-ethyl]-N-methyl-benzenesulfonamide
225	N-(1-Benzyl-pyrrolidin-3-yl)-4-chloro-N-	379.0
	ethyl-benzenesulfonamide
226	4-Chloro-N-{3-methoxy-4-[2-(4-methyl-	557.9
	thiazol-5-yl)-ethoxy]-benzyl}-N-(1-phenyl-
	ethyl)-benzenesulfonamide
227	4-Chloro-N-{3-methoxy-4-[2-(4-methyl-	508
	thiazol-5-yl)-ethoxy]-benzyl}-N-(2-methyl-
	allyl)-benzenesulfonamide
228	[2-(4-Chloro-benzenesulfonylimino)-	318.0
	imidazolidin-1-yl]-acetic acid
229	4-Chloro-N-pyrrolidin-3-yl-	261.0
	benzenesulfonamide
230	4-Chloro-N-(2-chloro-3-phenyl-allyl)-N-	—	464
	(R-1-hydroxymethyl-3-methyl-butyl)-
	benzenesulfonamide
231	4-Chloro-N-[3-(3-fluoro-phenyl)-allyl]-	—	447.9
	N-(R-1-hydroxymethyl-3-methyl-butyl)-
	benzenesulfonamide
232	4-Chloro-N-(R-1-hydroxymethyl-3-methyl-	410.1	—
	butyl)-N-(3-phenyl-propyl)-benzenesulfonamide
233	4-Chloro-N-(R-1-hydroxymethyl-3-methyl-	—	431
	butyl)-N-(3-phenyl-allyl)-benzenesulfonamide
234	4-Chloro-N-(2,3-dihydro-	—	463
	benzo[1,4]dioxin-6-ylmethyl)-N-(R-1-
	hydroxymethyl-3-methyl-butyl)-
	benzenesulfonamide
235	N-Benzofuran-2-ylmethyl-4-chloro-N-(R-1-	—	444
	hydroxymethyl-3-methyl-butyl)-
	benzenesulfonamide
236	4-[(4-Chloro-benzenesulfonyl)-(R-1-	—	440
	hydroxymethyl-3-methyl-butyl)-amino]-3-
	methyl-but-2-enoic acid ethyl ester
237	4-Chloro-N-(R-1-hydroxymethyl-3-methyl-	409	—
	butyl)-N-(3-pyridin-3-yl-allyl)-
	benzenesulfonamide
238	4-Chloro-N-cyclohexylmethyl-N-(R-1-	388	—
	hydroxymethyl-3-methyl-butyl)-
	benzenesulfonamide
239	4-Chloro-N-[3-(2-fluoro-phenyl)-allyl]-	—	447.9
	N-(R-1-hydroxymethyl-3-methyl-butyl)-
	benzenesulfonamide
240	N-(2-Bromo-3-phenyl-allyl)-4-chloro-N-	—	509.9
	(R-1-hydroxymethyl-3-methyl-butyl)-
	benzenesulfonamide
241	N-Benzo[1,3]dioxol-5-ylmethyl-4-chloro-	—	449
	N-(R-1-hydroxymethyl-3-methyl-butyl)-
	benzenesulfonamide
242	4-Chloro-N-(3-fluoro-4-methoxy-benzyl)-	—	453
	N-(R-1-hydroxymethyl-3-methyl-butyl)-
	benzenesulfonamide
243	4-Chloro-N-[3-(3-chloro-phenyl)-allyl]-	—	463.9
	N-(R-1-hydroxymethyl-3-methyl-butyl)-
	benzenesulfonamide
244	4-Chloro-N-(R-1-hydroxymethyl-3-methyl-	—	445
	butyl)-N-(2-methyl-3-phenyl-allyl)-
	benzenesulfonamide
245	4-Chloro-N-(2,4-difluoro-benzyl)-N-(R-1-	418.1	—
	hydroxymethyl-3-methyl-butyl)-
	benzenesulfonamide
246	4-Chloro-N-(R-1-hydroxymethyl-3-methyl-	—	434.1
	butyl)-N-(4-methoxy-benzyl)-
	benzenesulfonamide
247	4-Chloro-N-(4-chloro-benzyl)-N-(R-1-	416	—
	hydroxymethyl-3-methyl-butyl)-
	benzenesulfonamide
248	N-(4-Bromo-benzyl)-4-chloro-N-(R-1-	—	483.1
	hydroxymethyl-3-methyl-butyl)-
	benzenesulfonamide
249	4-Chloro-N-[3-(4-fluoro-phenyl)-allyl]-	—	447.9
	N-(R-1-hydroxymethyl-3-methyl-butyl)-
	benzenesulfonamide
250	4-Chloro-N-(R-1-hydroxymethyl-3-methyl-	455	—
	butyl)-N-[3-(2-nitro-phenyl)-allyl]-
	benzenesulfonamide
251	4-Chloro-N-(2-methyl-cyclohexyl)-N-(3-	406	—
	pyridin-3-yl-allyl)-benzenesulfonamide
252	N-(6-Bromo-pyridin-3-ylmethyl)-4-chloro-	459	—
	N-(2-methyl-cyclohexyl)-benzenesulfonamide
253	4-Chloro-N-(R-1-hydroxymethyl-3-methyl-	—	444
	butyl)-N-(3-m-tolyl-allyl)-benzenesulfonamide
254	4-Chloro-N-(R-1-hydroxymethyl-3-methyl-	—	444
	butyl)-N-(3-o-tolyl-allyl)-benzenesulfonamide
255	4-Chloro-N-(R-1-hydroxymethyl-3-methyl-	—	460.1
	butyl)-N-[3-(2-methoxy-phenyl)-allyl]-
	benzenesulfonamide
256	4-Chloro-N-(6-chloro-pyridin-3-	414	—
	ylmethyl)-N-(2-methyl-cyclohexyl)-
	benzenesulfonamide
257	4-Chloro-N-(6-methoxy-pyridin-3-	410	—
	ylmethyl)-N-(2-methyl-cyclohexyl)-
	benzenesulfonamide
258	4-Chloro-N-cyclopropylmethyl-N-(R-1-	346	—
	hydroxymethyl-3-methyl-butyl)-
	benzenesulfonamide
259	4-Chloro-N-(R-1-hydroxymethyl-3-methyl-	334	—
	butyl)-N-propyl-benzenesulfonamide
260	4-Chloro-N-furan-3-ylmethyl-N-(R-1-	—	393.9
	hydroxymethyl-3-methyl-butyl)-
	benzenesulfonamide
261	4-Chloro-N-(R-1-hydroxymethyl-3-methyl-	362	—
	butyl)-N-pentyl-benzenesulfonamide
262	4-Chloro-N-(R-1-hydroxymethyl-3-methyl-	—	454
	butyl)-N-naphthalen-2-ylmethyl-
	benzenesulfonamide
263	4-Chloro-N-(R-1-hydroxymethyl-3-methyl-	—	446
	butyl)-N-(1-methyl-3-phenyl-propyl)-
	benzenesulfonamide
264	4-Chloro-N-(2-ethyl-allyl)-N-(R-1-	360	—
	hydroxymethyl-3-methyl-butyl)-
	benzenesulfonamide
265	N-(4-Bromo-benzyl)-4-chloro-N-(2,5-	—	494
	dimethyl-cyclohexyl)-benzenesulfonamide
266	4-Chloro-N-furan-2-ylmethyl-N-(R-1-	—	393.9
	hydroxymethyl-3-methyl-butyl)-
	benzenesulfonamide
267	N-Benzyl-4-chloro-N-(1S,2S-2-hydroxy-	—	402
	cyclohexyl)-benzenesulfonamide
268	4-Chloro-N-(2-methyl-cyclohexyl)-N-(3-	—	426.1
	phenyl-allyl)-benzenesulfonamide
269	4-Chloro-N-(3-furan-2-yl-2-methyl-	412	—
	allyl)-N-(R-1-hydroxymethyl-3-methyl-butyl)-
	benzenesulfonamide
270	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-	—	475
	(2,5-dimethyl-cyclohexyl)-benzenesulfonamide
271	4-Chloro-N-(R-1-hydroxymethyl-3-methyl-	—	444
	butyl)-N-(3-p-tolyl-allyl)-benzenesulfonamide
272	4-Chloro-N-(2,5-dimethyl-cyclohexyl)-N-	—	445
	(4-methoxy-benzyl)-benzenesulfonamide
273	4-Chloro-N-[3-(4-chloro-phenyl)-allyl]-	—	464
	N-(R-1-hydroxymethyl-3-methyl-butyl)-
	benzenesulfonamide
274	4-Chloro-N-(R-1-hydroxymethyl-3-methyl-	424.1	—
	butyl)-N-(3-phenyl-butyl)-benzenesulfonamide
275	4-Chloro-N-(2,5-dimethyl-cyclohexyl)-N-	—	463
	(3-fluoro-4-methoxy-benzyl)-
	benzenesulfonamide
276	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(1-	—	450
	hydroxymethyl-2-methyl-propyl)-
	benzenesulfonamide
277	4-Chloro-N-(1-methyl-butyl)-N-(3-phenyl-	—	400.1
	allyl)-benzenesulfonamide
278	4-Chloro-N-(1,3-dimethyl-butyl)-N-(3-	—	414.1
	phenyl-allyl)-benzenesulfonamide
279	4-Chloro-N-(R-1-hydroxymethyl-3-methyl-	376	—
	butyl)-N-(2-methyl-pentyl)-benzenesulfonamide
280	4-Chloro-N-(2,5-dimethyl-cyclohexyl)-N-	—	455
	(2-methyl-3-phenyl-allyl)-benzenesulfonamide
281	4-[(4-Chloro-benzenesulfonyl)-(R-1-	404	—
	hydroxymethyl-3-methyl-butyl)-amino]-but-2-
	enoic acid ethyl ester
282	4-Chloro-N-(R-1-hydroxymethyl-3-methyl-	—	444
	butyl)-N-(1-methyl-3-phenyl-allyl)-
	benzenesulfonamide
283	4-Chloro-N-(1-chloro-3,4-dihydro-	—	490
	naphthalen-2-ylmethyl)-N-(R-1-hydroxymethyl-
	3-methyl-butyl)-benzenesulfonamide
284	4-Chloro-N-(R-1-hydroxymethyl-3-methyl-	452.1	—
	butyl)-N-(2-methyl-4-phenyl-pentyl)-
	benzenesulfonamide
285	4-Chloro-N-(2,4-difluoro-benzyl)-N-(2,5-	—	451
	dimethyl-cyclohexyl)-benzenesulfonamide
287	4-Chloro-N-(2-methyl-cyclohexyl)-N-(3-	—	428.1
	phenyl-propyl)-benzenesulfonamide
288	4-Chloro-N-(1-methyl-butyl)-N-(3-phenyl-	380.1	—
	propyl)-benzenesulfonamide
289	4-Chloro-N-(1-ethyl-propyl)-N-(3-phenyl-	—	400.1
	allyl)-benzenesulfonamide
290	4-Chloro-N-(2,5-dimethyl-cyclohexyl)-N-	—	441
	(3-phenyl-allyl)-benzenesulfonamide
291	4-Chloro-N-[3-(4-dimethylamino-phenyl)-	451	—
	allyl]-N-(R-1-hydroxymethyl-3-methyl-butyl)-
	benzenesulfonamide
292	N-[3-(4-tert-Butyl-phenyl)-2-methyl-	480.2	—
	propyl]-4-chloro-N-(R-1-hydroxymethyl-3-
	methyl-butyl)-benzenesulfonamide
293	4-Chloro-N-(1,3-dimethyl-butyl)-N-(3-	394.1	—
	phenyl-propyl)-benzenesulfonamide
294	4-Chloro-N-(R-1-hydroxymethyl-3-methyl-	—	382
	butyl)-N-(3-methyl-but-2-enyl)-
	benzenesulfonamide
295	4-Chloro-N-(R-1-hydroxymethyl-3-methyl-	362	—
	butyl)-N-(3-methyl-butyl)-benzenesulfonamide
296	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-	—	474.1
	(2,3-dimethyl-cyclohexyl)-benzenesulfonamide
297	4-Chloro-N-(4,6-dichloro-2H-chromen-3-	—	526.9
	ylmethyl)-N-(R-1-hydroxymethyl-3-methyl-
	butyl)-benzenesulfonamide
298	4-Chloro-N-(2,5-dimethyl-cyclohexyl)-N-	—	443
	(3-phenyl-propyl)-benzenesulfonamide
299	N-But-2-enyl-4-chloro-N-(R-1-	346	—
	hydroxymethyl-3-methyl-butyl)-
	benzenesulfonamide
300	4-Chloro-N-(S-1,2-dimethyl-propyl)-N-(3-	—	400
	phenyl-allyl)-benzenesulfonamide
301	4-Chloro-N-(R-1-hydroxymethyl-3-methyl-	306.1	—
	butyl)-N-methyl-benzenesulfonamide
302	4-Chloro-N-cyclooctyl-N-(3,4-dimethoxy-	—	474.1
	benzyl)-benzenesulfonamide
303	4-Chloro-N-(2-methoxy-1-methyl-ethyl)-N-	—	402
	(3-phenyl-allyl)-benzenesulfonamide
304	4-Chloro-N-(2-methoxy-1-methyl-ethyl)-N-	382.1	—
	(3-phenyl-propyl)-benzenesulfonamide
305	4-Chloro-N-(4-chloro-6-fluoro-2H-	—	510.1
	chromen-3-ylmethyl)-N-(R-1-hydroxymethyl-3-
	methyl-butyl)-benzenesulfonamide
306	4-Chloro-N-(R-1-hydroxymethyl-3-methyl-	435	—
	butyl)-N-(1-methyl-1H-indol-2-ylmethyl)-
	benzenesulfonamide
307	4-Chloro-N-(1-ethyl-propyl)-N-(3-phenyl-	380.1	—
	propyl)-benzenesulfonamide
308	4-Chloro-N-(R-1-hydroxymethyl-3-methyl-	—	444
	butyl)-N-(1,2,3,4-tetrahydro-naphthalen-2-
	yl)-benzenesulfonamide
309	4-Chloro-N-(R-1,2-dimethyl-propyl)-N-(3-	—	400.1
	phenyl-allyl)-benzenesulfonamide
310	4-Chloro-N-(2-ethyl-butyl)-N-(R-1-	376	—
	hydroxymethyl-3-methyl-butyl)-
	benzenesulfonamide
311	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(R-	—	484
	2-hydroxy-1-phenyl-ethyl)-benzenesulfonamide
312	R-N-sec-Butyl-4-chloro-N-(1-methyl-3-	—	402.1
	phenyl-propyl)-benzenesulfonamide
313	R-N-sec-Butyl-4-chloro-N-(3-phenyl-	—	386
	allyl)-benzenesulfonamide
314	R-N-Benzofuran-2-ylmethyl-N-sec-butyl-4-	—	400
	chloro-benzenesulfonamide
315	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(4-	—	460.1
	methyl-cyclohexyl)-benzenesulfonamide
316	4-Chloro-N-(1-hydroxymethyl-propyl)-N-	382.1	—
	(3-phenyl-propyl)-benzenesulfonamide
317	N-(2-Benzyl-cyclohexyl)-4-chloro-N-(R-1-	—	486.2
	hydroxymethyl-3-methyl-butyl)-
	benzenesulfonamide
318	4-Chloro-N-(2-hydroxy-propyl)-N-(3-	368	—
	phenyl-propyl)-benzenesulfonamide
319	4-Chloro-N-(1-hydroxymethyl-propyl)-N-	—	402
	(3-phenyl-allyl)-benzenesulfonamide
320	4-Chloro-N-(R-1,2-dimethyl-propyl)-N-(3-	380.1	—
	phenyl-propyl)-benzenesulfonamide
321	R-N-sec-Butyl-4-chloro-N-[3-(2-methoxy-	—	416.1
	phenyl)-allyl]-benzenesulfonamide
322	4-Chloro-N-(3-furan-2-yl-allyl)-N-(R-1-	—	419.9
	hydroxymethyl-3-methyl-butyl)-
	benzenesulfonamide
323	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(3-	—	450
	hydroxy-2,2-dimethyl-propyl)-
	benzenesulfonamide
324	4-Chloro-N-(2-hydroxy-propyl)-N-(3-	—	388
	phenyl-allyl)-benzenesulfonamide
325	R-N-sec-Butyl-4-chloro-N-(3-phenyl-	—	388.1
	propyl)-benzenesulfonamide
326	R-N-sec-Butyl-4-chloro-N-(1-methyl-1H-	391.1	—
	indol-2-ylmethyl)-benzenesulfonamide
328	R-N-sec-Butyl-4-chloro-N-(1-methyl-3-	—	400.1
	phenyl-allyl)-benzenesulfonamide
329	2S,3R-2-[(4-Chloro-benzenesulfonyl)-(3-	426.1	—
	phenyl-propyl)-amino]-3-hydroxy-N-methyl-
	butyramide
330	4-Chloro-N-(R-1-hydroxymethyl-3-methyl-	—	500.1
	butyl)-N-(2-pentyl-3-phenyl-allyl)-
	benzenesulfonamide
331	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-	—	503
	(1R,2S,5R-2-isopropyl-5-methyl-cyclohexyl)-
	benzenesulfonamide
332	R-N-sec-Butyl-4-chloro-N-(1-chloro-3,4-	—	446.9
	dihydro-naphthalen-2-ylmethyl)-
	benzenesulfonamide
333	3-[(4-Chloro-benzenesulfonyl)-(3-phenyl-	—	513.1
	allyl)-amino]-piperidine-1-carboxylic acid
	tert-butyl ester
334	4-[(4-Chloro-benzenesulfonyl)-(3-phenyl-	—	485.1
	allyl)-amino]-piperidine-1-carboxylic acid
	ethyl ester
335	4-Chloro-N-(1S,2S-2-hydroxy-	394.1	—
	cyclopentyl)-N-(3-phenyl-propyl)-
	benzenesulfonamide
336	4-[(4-Chloro-benzenesulfonyl)-(3-phenyl-	465.1	—
	propyl)-amino]-piperidine-1-carboxylic acid
	ethyl ester
337	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(3-	—	490
	hydroxymethyl-bicyclo[2.2.1]hept-2-yl)-
	benzenesulfonamide
338	4-Chloro-N-(S-1-hydroxymethyl-3-methyl-	292	—
	butyl)-benzenesulfonamide
339	4-Chloro-N-(R-1-hydroxymethyl-3-methyl-	292	—
	butyl)-benzenesulfonamide
340	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(R-	—	498
	1-hydroxymethyl-2-phenyl-ethyl)-
	benzenesulfonamide
341	4-Chloro-N-(S-1-hydroxymethyl-3-methyl-	—	430
	butyl)-N-(3-phenyl-allyl)-benzenesulfonamide
342	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-[1-	524	—
	(4-methanesulfonyl-phenyl)-ethyl]-
	benzenesulfonamide
343	3-[(4-Chloro-benzenesulfonyl)-(3,4-	—	547.2
	dimethoxy-benzyl)-amino]-piperidine-1-
	carboxylic acid tert-butyl ester
344	4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(1-	—	468.1
	phenyl-ethyl)-benzenesulfonamide
345	4-Chloro-N-(R-1,2-dimethyl-propyl)-	262	—
	benzenesulfonamide

Notch Signaling Assay for Selective Inhibitors of Gamma Secretase.

A convergence of evidence indicates that the gamma secretase complex, comprised of the presenilin subunits, mediates the intra-membrane cleavage of Amyloid precursor protein (APP), and the Notch family of proteins (De Strooper, B., P. Saftig, K. Craessaerts, H. Vanderstichele, G. Guhde, W. Annaert, K. Von Figura and F. Van Leuven (1998). “Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein.” Nature 391(6665): 387-90; De Strooper, B., W. Annaert, P. Cupers, P. Saftig, K. Craessaerts, J. S. Mumm, E. H. Schroeter, V. Schrijvers, M. S. Wolfe, W. J. Ray et al. (1999). “A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain.” Nature 398(6727): 518-22; Mumm, J. S., E. H. Schroeter, M. T. Saxena, A. Griesemer, X. Tian, D. J. Pan, W. J. Ray and R. Kopan (2000). “A ligand-induced extracellular cleavage regulates gamma-secretase-like proteolytic activation of Notch1.” Mol Cell 5(2): 197-206; Zhang, Z., P. Nadeau, W. Song, D. Donoviel, M. Yuan, A. Bernstein and B. A. Yankner (2000). “Presenilins are required for gamma-secretase cleavage of beta-APP and transmembrane cleavage of Notch-1.” Nat Cell Biol 2(7): 463-5). Cleavage of APP by gamma secretase leads to β-amyloid synthesis. Cleavage of Notch1 by gamma secretase results in release of the Notch intracellular domain (NICD), which translocates to the nucleus and activates gene expression (Jarriault, S., C. Brou, F. Logeat, E. H. Schroeter, R. Kopan and A. Israel (1995). “Signalling downstream of activated mammalian Notch.” Nature 377(6547): 355-8; Kopan, R., E. H. Schroeter, H. Weintraub and J. S, Nye (1996). “Signal transduction by activated Notch: importance of proteolytic processing and its regulation by the extracellular domain.” Proc Natl Acad Sci USA 93(4): 1683-8; Schroeter, E. H., J. A. Kisslinger and R. Kopan (1998). “Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain.” Nature 393(6683): 382-6). In particular, Notch signaling activates transcription of the mammalian homolog of the Drosophila transcription factor hairy-enhancer of split (Hes). Transcriptional activation of Hesl is mediated by de-repression of CBF1/RBPJk upon binding by NICD in the nucleus. These facts have been exploited to develop a reporter gene assay for Notch Signaling Hsieh, J. J., T. Henkel, P. Salmon, E. Robey, M. G. Peterson and S. D. Hayward (1996). “Truncated mammalian Notch1 activates CBF1/RBPJk-repressed genes by a mechanism resembling that of Epstein-Barr virus EBNA2.” Mol Cell Biol 16(3): 952-9; Lu, F. M. and S. E. Lux (1996). “Constitutively active human Notch1 binds to the transcription factor CBF1 and stimulates transcription through a promoter containing a CBF1-responsive element.” Proc Natl Acad Sci USA 93(11): 5663-7).
Gamma secretase inhibitors have been observed to block NICD formation, and inhibit Notch signaling (De Strooper, B., W. Annaert, P. Cupers, P. Saftig, K. Craessaerts, J. S. Mumm, E. H. Schroeter, V. Schrijvers, M. S. Wolfe, W. J. Ray et al. (1999). “A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain.” Nature 398(6727): 518-22). Due to the importance of Notch signaling in cell fate determination, and tissue differentiation during both development and in the adult, inhibition of Notch signaling by gamma secretase inhibitors is postulated to be a limiting factor in their therapeutic utility. In order to identify selective gamma secretase inhibitors, we have employed a reporter gene based Notch signaling assay using a constitutively active rat Notch1 construct (ZEDN1) provided by Dr Gerry Weinmaster, who is at the University of California at Los Angeles (UCLA) as described in Shawber, C., D. Nofziger, J. J. Hsieh, C. Lindsell, O. Bogler, D. Hayward and G. Weinmaster (1996). “Notch signaling inhibits muscle cell differentiation through a CBF1-independent pathway.” Development 122(12): 3765-73 in combination with the CBF1 repressible Luciferase reporter gene 4xwtCBFlLuc (Hsieh, J. J., T. Henkel, P. Salmon, E. Robey, M. G. Peterson and S. D. Hayward (1996). “Truncated mammalian Notch1 activates CBF1/RBPJk-repressed genes by a mechanism resembling that of Epstein-Barr virus EBNA2.” Mol Cell Biol 16(3): 952-9).
When 4xwtCBF1 Luciferase is co-transfected with NotchΔE (ZEDN1), γ-secretase cleavage of NotchΔE releases the Notch intracellular domain (NICD), which translocates to the nucleus and de-represses CBFlmediated transcriptional repression, leading to transcription of the Luciferase reporter gene. Luciferase activity is easily assayed in cell extracts using commercially available kits. The activity of the reporter gene is directly correlated with gamma secretase cleavage of NotchΔE, and as such, a reduction in Luciferase activity provides a convenient measure of inhibition of gamma secretase cleavage of NotchΔE. A comparison of the IC50 values of compounds for inhibition of Notch signaling versus inhibition of β-amyloid production in 293sw cells is employed to guide in the selection of compounds that have the desired property of potent inhibition of β-amyloid synthesis with minimal inhibition of Notch Signaling.
Compounds 84, 91, 139, 147, 237, 244, and 252, exhibit IC50 values within the range of about 0.1 to 25 nM; compounds 2, 9, 22, 28, 80, 110, 149, 151, 256, and 262, exhibit IC50 values within the range of about 25 to 100 nM; an compounds 3, 5, 36, 49, 78, 115, 156, 264, 272, and 292, exhibit IC50 values within the range of about 100 to 1000 nM.
It will be apparent that the starting materials may be varied and additional steps employed to produce the varied compounds encompassed by the present invention. In some cases, protection of reactive functionalities may be necessary to achieve some of the above transformations. In general, such need for protecting groups, as well as the conditions necessary to attach and remove such groups, will be apparent to those skilled in the art of organic synthesis.
The invention and the manner and process of making and using it, are now described in such full, clear, concise and exact terms as to enable any person skilled in the art to which it pertains, to make and use the same. It is to be understood that the foregoing describes preferred embodiments of the invention and that modifications may be made therein without departing from the spirit or scope of the invention as set forth in the claims. To particularly point out and distinctly claim the subject matter regarded as invention, the following claims conclude this specification.

Claims

1. A compound of the formula:

or pharmaceutically acceptable salts thereof, wherein

R₁is C₂-C₆alkynyl, C₂-C₆alkenyl, or C₁-C₈alkyl wherein each is optionally substituted with 1, 2, or 3 groups that are independently C₁-C₆alkoxy, OH, halogen, CN, C₁-C₆thioalkoxy, phenyl, naphthyl, C₃-C₈cycloalkyl, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆alkyl), —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl, —C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl, —C(O) phenyl, or C₁-C₆alkoxycarbonyl,

wherein each of the cyclic groups is optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, C₁-C₄alkyl, C₁-C₄alkoxy, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆alkyl), —SO₂—(C₁-C₆)alkyl, or OH; or

R₁is C₃-C₈cycloalkyl optionally substituted with 1 or 2 groups that are independently C₁-C₄alkyl, C₁-C₄hydroxyalkyl, or OH; or

R₁is heterocycloalkyl or heterocycloalkyl(C₁-C₄)alkyl wherein the heterocycloalkyl group is piperidinyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolyl, or morpholinyl, wherein the heterocycloalkyl groups are optionally substituted with 1 or 2 groups that are independently C₁-C₄alkyl, C₁-C₄alkoxy, phenyl, phenyl(C₁-C₄)alkyl, OH, halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, or C₁-C₄alkoxycarbonyl; or

R₁is heteroaryl(C₁-C₄)alkyl, wherein the heteroaryl group is pyridyl, pyrimidyl, furanyl, or thienyl and the heteroaryl group is optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₂-C₄)alkyl, —C(O)N(C₂-C₄)alkyl(C₁-C₄)alkyl, C₁-C₄alkyl, C₁-C₄alkoxy or OH;

R₂is C₁-C₈alkyl, C₁-C₆hydroxyalkyl, or C₂-C₈alkenyl, each of which is optionally substituted with 1, 2, or 3 groups that are independently 2H-chromenyl, 1,2,3,4-tetrahydronaphthalenyl, indolyl, 3,4-dihydronaphthalenyl, phenyl, naphthyl, C₃-C₈cycloalkyl, benzofuranyl, indolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, pyridyl, pyrimidyl, C₁-C₄alkyl, halogen, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, NO₂, thiadiazolyl, furanyl, triazolyl, or CN,

wherein the cyclic portions of each of the above are optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₆alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl, —C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl, C₁-C₄alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, NO₂, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein

x is 0, 1, or 2;

R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇;

R₂₆and R₂₇are independently H, C₁-C₆alkyl, phenyl(C₁-C₄alkyl), phenyl, or pyridyl; or

R₂₆, R₂₇and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl;

R₃is H, halogen, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, or CN,

R₄is H, halogen, C₁-C₆alkyl optionally substituted with —CO₂—(C₁-C₆alkyl), C₁-C₆alkoxy, C₁-C₆haloalkyl, C₁-C₆haloalkoxy, CN, aryloxy, isocyanato, —SO₂—(C₁-C₆alkyl), —NHR′, —NR′R″, C₁-C₆alkanoyl, pyridyl, or phenyl; or

R₃and R₄and the carbons to which they are attached form a heterocycloalkyl ring which is optionally substituted with 1, 2, or 3 groups that are independently C₁-C₄alkyl, C₁-C₄alkoxy, halogen, or C₁-C₄alkanoyl wherein the alkanoyl group is optionally substituted with up to 3 halogen atoms;

R_3′ is H, —SO₂—NR′R″, halogen, or

R₄and R_3′ and the carbons to which they are attached form a phenyl ring; or

R₄and R_3′ and the carbons to which they are attached form a 1-oxa-2,3-diazacyclopentyl ring;

R′ is H, C₁-C₆alkyl, phenyl(C₁-C₄)alkyl, C₁-C₆alkanoyl, phenyl(C₁-C₆)alkanoyl, pyridyl(C₁-C₄)alkyl, pyrimidyl(C₁-C₄)alkyl, pyridazyl(C₁-C₄)alkyl, pyrazinyl(C₁-C₄)alkyl, thienyl(C₁-C₄)alkyl, oxazolyl(C₁-C₄)alkyl, thiazolyl(C₁-C₄)alkyl, furanyl(C₁-C₄)alkyl, —SO₂-alkyl, —SO₂-phenyl, —SO₂-pyridyl, —SO₂-pyrimidyl, —SO₂-pyridazyl, —SO₂-pyrazinyl, —SO₂-thienyl, —SO₂-oxazolyl, —SO₂-thiazolyl, —SO₂-furanyl, pyridyl(C₁-C₆)alkanoyl, pyrimidyl(C₁-C₆)alkanoyl, pyridazyl(C₁-C₆)alkanoyl, pyrazinyl(C₁-C₆)alkanoyl, thienyl(C₁-C₆)alkanoyl, oxazolyl(C₁-C₆)alkanoyl, thiazolyl(C₁-C₆)alkanoyl, or furanyl(C₁-C₆)alkanoyl, wherein the alkyl portion of the alkyl and alkanoyl groups are optionally substituted with halogen or C₁-C₆alkoxy, wherein the aryl, and heteroaryl groups are optionally substituted with alkyl, alkoxy, halogen, haloalkyl, haloalkoxy,

R″ is H, or C₁-C₆alkyl, wherein the alkyl group is optionally substituted with halogen.

2. A compound according to claim 1, wherein

R₁is C₁-C₈alkyl which is optionally substituted with 1, 2, or 3 groups that are independently C₁-C₆alkoxy, OH, halogen, CN, C₁-C₆thioalkoxy, phenyl, naphthyl, C₃-C₈cycloalkyl, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆alkyl), —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl, —C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl, —C(O)phenyl, or C₁-C₆alkoxycarbonyl,

wherein each of the cyclic groups is optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, C₁-C₄alkyl, C₁-C₄alkoxy, NH₂, NH(C₁-C₆)alkyl, N(C₁-C₆)alkyl(C₁-C₆alkyl), —SO₂—(C₁-C₆)alkyl, or OH.

3. A compound according to claim 2, wherein

R₃is H, halogen, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, CN;

R₄is H, halogen, C₁-C₆alkyl optionally substituted with —CO₂—(C₁-C₆alkyl), C₁-C₆alkoxy, C₁-C₄haloalkyl, C₁-C₆haloalkoxy, CN, aryloxy, isocyanato, —SO₂—(C₁-C₆alkyl), —NHR′, —NR′R″, C₁-C₆alkanoyl, oxazolyl, pyrazolyl, thiazolyl, pyridyl, furanyl or thienyl, phenyl; and

R_3′ is H, or halogen.

4. A compound according to claim 3, wherein

R₂is C₁-C₈alkyl, or C₂-C₈alkenyl, each of which is optionally substituted with 1, 2, or 3 groups that are independently, 2H-chromenyl, 1,2,3,4-tetrahydronaphthalenyl, indolyl, 3,4-dihydronaphthalenyl, phenyl, naphthyl, C₃-C₈cycloalkyl, benzofuranyl, indolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, pyridyl, pyrimidyl, C₁-C₄alkyl, halogen, —CO₂—(C₁-C₆alkyl), pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, triazolyl, or CN,

wherein the cyclic portions of each of the above are optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₆alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl, —C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl, C₁-C₄alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein

x is 0, 1, or 2;

R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇;

5. A compound according to claim 4, wherein

R₁is C₁-C₈alkyl which is optionally substituted with OH.

6. A compound according to claim 5, wherein

R₃is H, halogen, C₁-C₆alkyl, C₁-C₆alkoxy, CF₃, CN;

R₄is H, halogen, C₁-C₆alkoxy, C₁-C₆alkyl, CF₃, OCF₃, CN, phenyloxy, —SO₂—(C₁-C₆alkyl), —NHR′, —NR′R″, C₁-C₄alkanoyl, pyridyl, furanyl or thienyl, phenyl, or C₁-C₆alkyl optionally substituted with —CO₂—(C₁-C₆alkyl);

R_3′ is H, or halogen;

R′ is H, C₁-C₆alkyl, phenyl(C₁-C₄)alkyl, C₁-C₆alkanoyl, phenyl(C₁-C₄)alkanoyl, pyridyl(C₁-C₄)alkyl, —SO₂-alkyl, —SO₂-phenyl, —SO₂-pyridyl, pyridyl(C₁-C₆)alkanoyl, wherein the alkyl portion of the alkyl and alkanoyl groups are optionally substituted with halogen or C₁-C₄alkoxy,

wherein the phenyl and pyridyl groups are optionally substituted with C₁-C₄alkyl, C₁-C₄alkoxy, halogen, CF₃, OCF₃;

R″ is H or C₁-C₆alkyl, wherein the alkyl group is optionally substituted with halogen.

7. A compound according to claim 6, wherein

R₂is C₁-C₈alkyl which is optionally substituted with 1 or 2 phenyl groups, 2H-chromenyl, 1,2,3,4-tetrahydronaphthalenyl, indolyl, 3,4-dihydronaphthalenyl, phenyl, naphthyl, C₃-C₈cycloalkyl, benzofuranyl, indolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, pyridyl, pyrimidyl, triazolyl, or CN,

x is 0, 1, or 2;

R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇;

8. A compound according to claim 7, wherein

R₂is C₁-C₈alkyl which is optionally substituted with phenyl, benzofuranyl, 1,4-benzodioxanyl, or 1,3-benzodioxolyl,

wherein the cyclic portions of each of the above are optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₆alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl, —C(O)N(C₈-C₆)alkyl(C₁-C₆)alkyl, C₁-C₄alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein

x is 0, 1, or 2;

R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇;

9. A compound according to claim 8, wherein

R₂is C₁-C₈alkyl substituted with phenyl, wherein the phenyl is optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₆alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl, —C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl, C₁-C₄alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein

x is 0, 1, or 2;

R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇;

10. A compound according to claim 9, wherein

R₁is C₁-C₈hydroxyalkyl;

R₃is H, halogen, C₁-C₄alkyl, C₁-C₄alkoxy, CF₃, CN;

R₄is H, halogen, C₁-C₄alkoxy, CF₃, OCF₃, CN, phenyloxy, —SO₂—(C₁-C₆alkyl), —NHR′, —NR′R″, C₁-C₄alkanoyl, pyridyl, furanyl or thienyl, phenyl, or C₁-C₆alkyl optionally substituted with —CO₂—(C₁-C₆alkyl);

R_3′ is H, or halogen;

R′ is H, C₁-C₄alkyl, benzyl, C₁-C₆alkanoyl, phenyl(C₁-C₄)alkanoyl, pyridyl(C₁-C₄)alkyl, —SO₂-alkyl, —SO₂-phenyl, —SO₂-pyridyl, pyridyl(C₁-C₆)alkanoyl, wherein the alkyl portion of the alkyl and alkanoyl groups are optionally substituted with halogen or C₁-C₄alkoxy,

11. A compound according to claim 10, wherein

R₁is

R₃is H, halogen, methyl, methoxy, CF₃, or CN;

R₄is H, halogen, methyl, methoxy, CF₃, OCF₃, CN, —NHR′, or —NR′R″;

R_3′ is H, or halogen;

R′ is H, or C₁-C₄alkyl; and

12. A compound according to claim 5, wherein

R₁is C₁-C₈alkyl;

R₂is C₁-C₈alkyl substituted with a phenyl group, benzofuranyl, 1,4-benzodioxanyl, or 1,3-benzodioxolyl, wherein the phenyl group is optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₆alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₆)alkyl, —C(O)N(C₁-C₆)alkyl(C₁-C₆)alkyl, C₁-C₄alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein

x is 0, 1, or 2;

R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇;

R₃is H, halogen, C₁-C₄alkyl, C₁-C₄alkoxy, CF₃, CN;

R₄is H, halogen, C₁-C₄alkoxy, CF₃, OCF₃, CN, phenyloxy, —SO₂—(C₁-C₆alkyl), —NHR′, —NR′R″, C₁-C₄alkanoyl, pyridyl, furanyl or thienyl, phenyl, or C₁-C₄alkyl optionally substituted with —CO₂—(C₁-C₆alkyl);

R_3′ is H, or halogen;

13. A compound according to claim 12, wherein

R₁is C₂-C₆alkyl;

R₃is H, halogen, methyl, methoxy, CF₃, or CN;

R₄is halogen, methyl, methoxy, CF₃, OCF₃, CN, —NHR′, or —NR′R″;

R_3′ is H, or halogen;

R′ is H, or C₁-C₄alkyl; and

14. A compound according to claim 6, wherein

R₂is C₃-C₈alkenyl, optionally substituted with 1 or 2 groups that are independently phenyl, halogen, 2H-chromenyl, 1,2,3,4-tetrahydronaphthalenyl, indolyl, 3,4-dihydronaphthalenyl, naphthyl, C₃-C₈cycloalkyl, benzofuranyl, indolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, pyridyl, C₁-C₄alkyl, halogen, —CO₂—(C₁-C₄alkyl), pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, triazolyl, or pyrimidyl;

wherein the cyclic portions of each of the above are optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, C₁-C₄alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein

x is 0, 1, or 2;

R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇;

15. A compound according to claim 14, wherein

R₂is C₃-C₆alkenyl, optionally substituted with 1 or 2 groups that are phenyl, halogen, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, or pyrimidyl; wherein the phenyl group is optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, C₁-C₄alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein

x is 0, 1, or 2;

R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇;

16. A compound according to claim 1, wherein

R₁is heteroaryl(C₁-C₄)alkyl, wherein the heteroaryl group is pyridyl, pyrimidyl, furanyl, or thienyl and the heteroaryl group is optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, C₁-C₄alkyl, C₁-C₄alkoxy or OH.

17. A compound according to claim 16, wherein

R₂is C₁-C₈alkyl, or C₂-C₈alkenyl, each of which is optionally substituted with 1 or 2 groups that are independently, 2H-chromenyl, 1,2,3,4-tetrahydronaphthalenyl, indolyl, 3,4-dihydronaphthalenyl, phenyl, naphthyl, C₃-C₈cycloalkyl, benzofuranyl, indolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, pyridyl, pyrimidyl, C₁-C₄alkyl, halogen, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, furanyl, triazolyl, or CN,

wherein the cyclic portions of each of the above are optionally substituted with 1, 2, or 3 groups that are independently halogen, CO₂H, C₁-C₄alkoxycarbonyl, —C(O)NH₂, —C(O)NH(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl(C₁-C₄)alkyl, C₁-C₄alkoxy, C₁-C₄alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, NO₂, C₁-C₄alkyl, —S(O)_x—R₂₅, —(C₁-C₄alkyl)-S(O)_x—R₂₅, or OH; wherein

x is 0, 1, or 2;

R₂₅is C₁-C₆alkyl, OH, NR₂₆R₂₇;

18. A pharmaceutical composition comprising a compound of claim 1 and at least one pharmaceutically acceptable carrier, solvent, adjuvant or excipient, or a combination thereof.

19. A method of treating a patient who has, or in preventing a patient from getting, a disease or condition selected from the group consisting of Alzheimer's disease, for helping prevent or delay the onset of Alzheimer's disease, for treating patients with mild cognitive impairment (MCI) and preventing or delaying the onset of Alzheimer's disease in those who would progress from MCI to AD, for treating Down's syndrome, for treating humans who have Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treating cerebral amyloid angiopathy and preventing its potential consequences, i.e. single and recurrent lobar hemorrhages, for treating other degenerative dementias, including dementias of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, age related macular degeneration, or diffuse Lewy body type of Alzheimer's disease and who is in need of such treatment which comprises administration of a therapeutically effective amount of a compound of claim 1.

20. A compound according to claim 1 that is

(S)-4-chloro-N-cinnamyl-N-(1-hydroxy-4-methylpentan-2-yl)benzenesulfonamide;

[(4-Chloro-benzenesulfonyl)-methyl-amino]-acetic acid ethyl ester;

[2-(4-Chloro-benzenesulfonylimino)-imidazolidin-1-yl]-acetic acid;

2-(4-Chloro-benzenesulfonylamino)-N-methyl-propionamide;

2-[(4-Chloro-benzenesulfonyl)-(3,4-dimethoxy-benzyl)-amino]-3-phenyl-propionamide;

2-[(4-Chloro-benzenesulfonyl)-(3-phenyl-propyl)-amino]-3-hydroxy-N-methyl-butyramide;

3-[(4-Chloro-benzenesulfonyl)-(3,4-dimethoxy-benzyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester;

4-Chloro-N-(1,2-dimethyl-propyl)-N-(3-phenyl-allyl)-benzenesulfonamide;

4-Chloro-N-(1,2-dimethyl-propyl)-N-(3-phenyl-propyl)-benzenesulfonamide;

4-Chloro-N-(1,3-dimethyl-butyl)-N-(3-phenyl-allyl)-benzenesulfonamide;

4-Chloro-N-(1,3-dimethyl-butyl)-N-(3-phenyl-propyl)-benzenesulfonamide;

4-Chloro-N-(1-chloro-3,4-dihydro-naphthalen-2-ylmethyl)-N-(1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;

4-Chloro-N-(1-ethyl-propyl)-N-(3-phenyl-allyl)-benzenesulfonamide;

4-Chloro-N-(1-ethyl-propyl)-N-(3-phenyl-propyl)-benzenesulfonamide;

4-Chloro-N-(1-hydroxymethyl-3-methyl-butyl)-N-(1,2,3,4-tetrahydro-naphthalen-2-yl)-benzenesulfonamide;

4-Chloro-N-(1-hydroxymethyl-3-methyl-butyl)-N-(1-methyl-1H-indol-2-ylmethyl)-benzenesulfonamide;

4-Chloro-N-(1-hydroxymethyl-3-methyl-butyl)-N-(1-methyl-3-phenyl-allyl)-benzenesulfonamide;

4-Chloro-N-(1-hydroxymethyl-3-methyl-butyl)-N-(1-methyl-3-phenyl-propyl)-benzenesulfonamide;

4-Chloro-N-(1-hydroxymethyl-3-methyl-butyl)-N-(2-methyl-3-phenyl-allyl)-benzenesulfonamide;

4-Chloro-N-(1-hydroxymethyl-3-methyl-butyl)-N-(2-pentyl-3-phenyl-allyl)-benzenesulfonamide;

4-Chloro-N-(1-hydroxymethyl-3-methyl-butyl)-N-(3-phenyl-butyl)-benzenesulfonamide;

4-Chloro-N-(1-hydroxymethyl-3-methyl-butyl)-N-(3-phenyl-propyl)-benzenesulfonamide;

4-Chloro-N-(1-hydroxymethyl-3-methyl-butyl)-N-(4-methoxy-benzyl)-benzenesulfonamide;

4-Chloro-N-(1-hydroxymethyl-3-methyl-butyl)-N-[3-(2-methoxy-phenyl)-allyl]-benzenesulfonamide;

4-Chloro-N-(1-hydroxymethyl-3-methyl-butyl)-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-benzenesulfonamide;

4-Chloro-N-(1-hydroxymethyl-3-methyl-butyl)-N-methyl-benzenesulfonamide;

4-Chloro-N-(1-hydroxymethyl-3-methyl-butyl)-N-propyl-benzenesulfonamide;

4-Chloro-N-(1-hydroxymethyl-pentyl)-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-benzenesulfonamide;

4-Chloro-N-(1-hydroxymethyl-propyl)-N-(3-phenyl-allyl)-benzenesulfonamide;

4-Chloro-N-(1-hydroxymethyl-propyl)-N-(3-phenyl-propyl)-benzenesulfonamide;

4-Chloro-N-(1-methyl-butyl)-N-(3-phenyl-allyl)-benzenesulfonamide;

4-Chloro-N-(1-methyl-butyl)-N-(3-phenyl-propyl)-benzenesulfonamide;

4-chloro-N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-N-[(1S)-1-(hydroxymethyl)-3-methylbutyl]benzenesulfonamide;

4-Chloro-N-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-N-(1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;

4-Chloro-N-(2,3-dihydroxy-propyl)-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-benzenesulfonamide;

4-Chloro-N-(2,4-dichloro-benzyl)-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-benzenesulfonamide;

4-Chloro-N-(2,4-difluoro-benzyl)-N-(1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;

4-chloro-N-(2,4-difluorobenzyl)-N-[(1R)-1-(hydroxymethyl)-3-methylbutyl]benzenesulfonamide;

4-Chloro-N-(2-cyano-ethyl)-N-cyclopropyl-benzenesulfonamide;

4-Chloro-N-(2-cyano-ethyl)-N-ethyl-benzenesulfonamide;

4-Chloro-N-(2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-benzenesulfonamide;

4-Chloro-N-(2-hydroxy-cyclohexylmethyl)-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-benzenesulfonamide;

4-Chloro-N-(2-hydroxy-propyl)-N-(3-phenyl-allyl)-benzenesulfonamide;

4-Chloro-N-(2-hydroxy-propyl)-N-(3-phenyl-propyl)-benzenesulfonamide;

4-Chloro-N-(2-hydroxy-propyl)-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-benzenesulfonamide;

4-Chloro-N-(2-methoxy-1-methyl-ethyl)-N-(3-phenyl-allyl)-benzenesulfonamide;

4-Chloro-N-(2-methoxy-1-methyl-ethyl)-N-(3-phenyl-propyl)-benzenesulfonamide;

4-Chloro-N-(2-methyl-cyclohexyl)-N-(3-phenyl-allyl)-benzenesulfonamide;

4-Chloro-N-(2-methyl-cyclohexyl)-N-(3-phenyl-propyl)-benzenesulfonamide;

4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(1-hydroxymethyl-2-methyl-propyl)-benzenesulfonamide;

4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(1-hydroxymethyl-2-phenyl-ethyl)-benzenesulfonamide;

4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;

4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(1-hydroxymethyl-propyl)-benzenesulfonamide;

4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(1-naphthalen-1-yl-ethyl)-benzenesulfonamide;

4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(1-phenyl-4,5-dihydro-1H-pyrazol-3-yl)-benzenesulfonamide;

4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(1-phenyl-ethyl)-benzenesulfonamide;

4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(2,3-dimethyl-cyclohexyl)-benzenesulfonamide;

4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(2-hydroxy-1-hydroxymethyl-2-phenyl-ethyl)-benzenesulfonamide;

4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(2-hydroxy-1-methyl-2-phenyl-ethyl)-benzenesulfonamide;

4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(2-hydroxy-1-phenyl-ethyl)-benzenesulfonamide;

4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(2-methyl-cyclohexyl)-benzenesulfonamide;

4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(3-hydroxy-2,2-dimethyl-propyl)-benzenesulfonamide;

4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(3-hydroxymethyl-bicyclo[2.2.1]hept-2-yl)-benzenesulfonamide;

4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(4-methyl-cyclohexyl)-benzenesulfonamide;

4-chloro-N-(3,4-dimethoxybenzyl)-N-[(1R,2S)-2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]benzenesulfonamide;

4-chloro-N-(3,4-dimethoxybenzyl)-N-[(1S)-1-(hydroxymethyl)-3-methylbutyl]benzenesulfonamide;

4-chloro-N-(3,4-dimethoxybenzyl)-N-[(1S)-1-(hydroxymethyl)propyl]benzenesulfonamide;

4-chloro-N-(3,4-dimethoxybenzyl)-N-[(1S)-2-hydroxy-1-phenylethyl]benzenesulfonamide;

4-chloro-N-(3,4-dimethoxybenzyl)-N-[(1S,2R)-2-hydroxy-1-methyl-2-phenylethyl]benzenesulfonamide;

4-chloro-N-(3,4-dimethoxybenzyl)-N-[(1S,3R,4R)-3-(hydroxymethyl)bicyclo[2.2.1]hept-2-yl]benzenesulfonamide;

4-Chloro-N-(3,4-dimethoxy-benzyl)-N-[1-(4-methanesulfonyl-phenyl)-ethyl]-benzenesulfonamide;

4-Chloro-N-(3-fluoro-4-methoxy-benzyl)-N-(1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;

4-chloro-N-(3-fluoro-4-methoxybenzyl)-N-[(1S)-1-(hydroxymethyl)-3-methylbutyl]benzenesulfonamide;

4-Chloro-N-(3-hydroxy-butyl)-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-benzenesulfonamide;

4-Chloro-N-(4-chloro-6-fluoro-2H-chromen-3-ylmethyl)-N-(1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;

4-Chloro-N-(4-chloro-benzyl)-N-(1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;

4-chloro-N-(4-chlorobenzyl)-N-[(1R)-1-(hydroxymethyl)-3-methylbutyl]benzenesulfonamide;

4-Chloro-N-(4-diethylamino-1-methyl-butyl)-N-(3,4-dimethoxy-benzyl)-benzenesulfonamide;

4-Chloro-N,N-dicyclohexyl-benzenesulfonamide;

4-Chloro-N,N-diisopropyl-benzenesulfonamide;

4-Chloro-N,N-divinyl-benzenesulfonamide;

4-chloro-N-[(1R)-1-(hydroxymethyl)-3-methylbutyl]-N-(3-phenylpropyl)benzenesulfonamide;

4-chloro-N-[(1R)-1-(hydroxymethyl)-3-methylbutyl]-N-(4-methoxybenzyl)benzenesulfonamide;

4-chloro-N-[(1R,2S)-2-hydroxy-1-methyl-2-phenylethyl]-N-methylbenzenesulfonamide;

4-chloro-N-[(1S)-1-(hydroxymethyl)-3-methylbutyl]-N-[(2E)-2-methyl-3-phenylprop-2-en-1-yl]benzenesulfonamide;

4-chloro-N-[(1S)-1-(hydroxymethyl)-3-methylbutyl]-N-[(2E)-3-phenylprop-2-en-1-yl]benzenesulfonamide;

4-chloro-N-[(1S)-1-(hydroxymethyl)-3-methylbutyl]-N-{3-methoxy-4-[2-(4-methyl-1,3-thiazol-5-yl)ethoxy]benzyl}benzenesulfonamide;

4-chloro-N-[(1S,2S)-2-hydroxy-1-methyl-2-phenylethyl]-N-methylbenzenesulfonamide;

4-Chloro-N-[2-(3,4-dihydroxy-phenyl)-2-oxo-ethyl]-N-methyl-benzenesulfonamide;

4-chloro-N-{[(1R,2S)-2-hydroxycyclohexyl]methyl}-N-{3-methoxy-4-[2-(4-methyl-1,3-thiazol-5-yl)ethoxy]benzyl}benzenesulfonamide;

4-Chloro-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-N-(2-methyl-cyclohexyl)-benzenesulfonamide;

4-Chloro-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-N-(2-methyl-butyl)-benzenesulfonamide;

4-Chloro-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-N-(3-methylsulfanyl-propyl)-benzenesulfonamide;

4-Chloro-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-N-(4-methyl-cyclohexyl)-benzenesulfonamide;

4-Chloro-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-N-pyridin-2-ylmethyl-benzenesulfonamide;

4-Chloro-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-N-prop-2-ynyl-benzenesulfonamide;

4-Chloro-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-N-(3-methyl-butyl)-benzenesulfonamide;

4-Chloro-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-N-(tetrahydro-furan-2-ylmethyl)-benzenesulfonamide;

4-Chloro-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-N-(3-methoxy-propyl)-benzenesulfonamide;

4-Chloro-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-N-(1-phenyl-ethyl)-benzenesulfonamide;

4-Chloro-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-N-(2-methyl-allyl)-benzenesulfonamide;

4-Chloro-N-cyanomethyl-N-methyl-benzenesulfonamide;

4-Chloro-N-cyclohexyl-N-(2-hydroxy-ethyl)-benzenesulfonamide;

4-Chloro-N-cyclohexyl-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-benzenesulfonamide;

4-Chloro-N-cyclohexyl-N-isopropyl-benzenesulfonamide;

4-Chloro-N-cyclooctyl-N-(3,4-dimethoxy-benzyl)-benzenesulfonamide;

4-Chloro-N-cyclopentyl-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-benzenesulfonamide;

4-Chloro-N-cyclopropylmethyl-N-(1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;

4-Chloro-N-cyclopropylmethyl-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-benzenesulfonamide;

4-Chloro-N-ethyl-N-(2-pyridin-2-yl-ethyl)-benzenesulfonamide;

4-Chloro-N-ethyl-N-[2-hydroxy-2-(3-hydroxy-phenyl)-ethyl]-benzenesulfonamide;

4-Chloro-N-ethyl-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-benzenesulfonamide;

4-Chloro-N-isopropyl-N-(2-pyridin-4-yl-ethyl)-benzenesulfonamide;

4-Chloro-N-methyl-N-(1-methyl-piperidin-4-yl)-benzenesulfonamide;

4-Chloro-N-methyl-N-(2-pyridin-4-yl-ethyl)-benzenesulfonamide;

4-Chloro-N-pyrrolidin-3-yl-benzenesulfonamide;

N-(1,3-benzodioxol-5-ylmethyl)-4-chloro-N-[(1S)-1-(hydroxymethyl)-3-methylbutyl]benzenesulfonamide;

N-(1-Benzyl-pyrrolidin-3-yl)-4-chloro-N-ethyl-benzenesulfonamide;

N-(2-Amino-benzyl)-4-chloro-N-{3-methoxy-4-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzyl}-benzenesulfonamide;

N-(2-Benzyl-cyclohexyl)-4-chloro-N-(1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;

N-(4-Bromo-benzyl)-4-chloro-N-(1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;

N-(4-bromobenzyl)-4-chloro-N-[(1R)-1-(hydroxymethyl)-3-methylbutyl]benzenesulfonamide;

N,N-Di-sec-butyl-4-chloro-benzenesulfonamide;

N-[(1R)-1-benzyl-2-hydroxyethyl]-4-chloro-N-(3,4-dimethoxybenzyl)benzenesulfonamide;

N-[(1S)-1-benzyl-2-hydroxyethyl]-4-chloro-N-(3,4-dimethoxybenzyl)benzenesulfonamide;

N-[(4-chlorophenyl)sulfonyl]-N-(3,4-dimethoxybenzyl)-L-phenylalaninamide;

N-[3-(4-tert-Butyl-phenyl)-2-methyl-propyl]-4-chloro-N-(1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;

N2-[(4-chlorophenyl)sulfonyl]-N-1-methyl-L-alaninamide;

N-Allyl-4-chloro-N-cyclohexyl-benzenesulfonamide;

N-Benzo[1,3]dioxol-5-ylmethyl-4-chloro-N-(1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;

N-Benzofuran-2-ylmethyl-4-chloro-N-(1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;

N-Benzofuran-2-ylmethyl-N-sec-butyl-4-chloro-benzenesulfonamide;

N-Benzyl-4-chloro-N-(1-hydroxymethyl-propyl)-benzenesulfonamide;

N-Benzyl-4-chloro-N-(2-hydroxy-cyclohexyl)-benzenesulfonamide;

N-Benzyl-4-chloro-N-(2-hydroxymethyl-cyclohexyl)-benzenesulfonamide;

N-benzyl-4-chloro-N-[(1R)-1-(hydroxymethyl)propyl]benzenesulfonamide;

N-benzyl-4-chloro-N-[(1S,2R)-2-(hydroxymethyl)cyclohexyl]benzenesulfonamide;

N-benzyl-4-chloro-N-[(1S,2S)-2-hydroxycyclohexyl]benzenesulfonamide;

N-Benzyl-N-sec-butyl-4-chloro-benzenesulfonamide;

N-sec-Butyl-4-chloro-N-(1-chloro-3,4-dihydro-naphthalen-2-ylmethyl)-benzenesulfonamide;

N-sec-Butyl-4-chloro-N-(1-methyl-1H-indol-2-ylmethyl)-benzenesulfonamide;

N-sec-Butyl-4-chloro-N-(1-methyl-3-phenyl-allyl)-benzenesulfonamide;

N-sec-Butyl-4-chloro-N-(1-methyl-3-phenyl-propyl)-benzenesulfonamide;

N-sec-Butyl-4-chloro-N-(2-pentyl-3-phenyl-allyl)-benzenesulfonamide;

N-sec-Butyl-4-chloro-N-(3,3-diphenyl-allyl)-benzenesulfonamide;

N-sec-Butyl-4-chloro-N-(3-phenyl-allyl)-benzenesulfonamide;

N-sec-Butyl-4-chloro-N-(3-phenyl-butyl)-benzenesulfonamide;

N-sec-Butyl-4-chloro-N-(3-phenyl-propyl)-benzenesulfonamide;

N-sec-Butyl-4-chloro-N-(4,6-dichloro-2H-chromen-3-ylmethyl)-benzenesulfonamide;

N-sec-Butyl-4-chloro-N-(4-chloro-6-fluoro-2H-chromen-3-ylmethyl)-benzenesulfonamide;

N-sec-Butyl-4-chloro-N-[3-(2-methoxy-phenyl)-allyl]-benzenesulfonamide;

N-tert-Butyl-2-(4-chloro-benzenesulfonylamino)-3-methyl-butyramide; or pharmaceutically acceptable salts thereof.

21. A compound according to claim 1 that is

4-Chloro-N-cyclooctyl-N-(3,4-dimethoxy-benzyl)-benzenesulfonamide;

4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(4-methyl-cyclohexyl)-benzenesulfonamide;

4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(1-phenyl-ethyl)-benzenesulfonamide;

4-Chloro-N-(3,4-dimethoxy-benzyl)-N—(R-2-hydroxy-1-phenyl-ethyl)-benzenesulfonamide;

4-Chloro-N-(3,4-dimethoxy-benzyl)-N—(R-1-hydroxymethyl-2-phenyl-ethyl)-benzenesulfonamide;

N-Benzyl-4-chloro-N-(1S,2S-2-hydroxy-cyclohexyl)-benzenesulfonamide;

4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-(3-phenyl-allyl)-benzenesulfonamide;

4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-(2-methyl-3-phenyl-allyl)-benzenesulfonamide;

N-Benzo[1,3]dioxol-5-ylmethyl-4-chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;

4-Chloro-N-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;

4-Chloro-N-(3-fluoro-4-methoxy-benzyl)-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;

4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-(4-methoxy-benzyl)-benzenesulfonamide;

4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-(3-phenyl-propyl)-benzenesulfonamide;

4-Chloro-N-(4-chloro-benzyl)-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;

N-(4-Bromo-benzyl)-4-chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;

4-Chloro-N-(2,4-difluoro-benzyl)-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;

R—N-sec-Butyl-4-chloro-N-(3-phenyl-allyl)-benzenesulfonamide;

4-Chloro-N—(R-1,2-dimethyl-propyl)-N-(3-phenyl-allyl)-benzenesulfonamide;

4-Chloro-N-(1-ethyl-propyl)-N-(3-phenyl-allyl)-benzenesulfonamide;

4-Chloro-N-(1-hydroxymethyl-propyl)-N-(3-phenyl-allyl)-benzenesulfonamide;

4-Chloro-N-(2-hydroxy-propyl)-N-(3-phenyl-allyl)-benzenesulfonamide;

4-Chloro-N-(1,3-dimethyl-butyl)-N-(3-phenyl-allyl)-benzenesulfonamide;

4-Chloro-N-(1-methyl-butyl)-N-(3-phenyl-allyl)-benzenesulfonamide;

4-Chloro-N-(2-methoxy-1-methyl-ethyl)-N-(3-phenyl-allyl)-benzenesulfonamide;

4-Chloro-N-(2-methyl-cyclohexyl)-N-(3-phenyl-allyl)-benzenesulfonamide;

3-[(4-Chloro-benzenesulfonyl)-(3-phenyl-allyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester;

4-[(4-Chloro-benzenesulfonyl)-(3-phenyl-allyl)-amino]-piperidine-1-carboxylic acid ethyl ester;

R—N-sec-Butyl-4-chloro-N-(3-phenyl-propyl)-benzenesulfonamide;

4-Chloro-N—(R-1,2-dimethyl-propyl)-N-(3-phenyl-propyl)-benzenesulfonamide;

4-Chloro-N-(1-ethyl-propyl)-N-(3-phenyl-propyl)-benzenesulfonamide;

4-Chloro-N-(1-hydroxymethyl-propyl)-N-(3-phenyl-propyl)-benzenesulfonamide;

4-Chloro-N-(2-hydroxy-propyl)-N-(3-phenyl-propyl)-benzenesulfonamide;

4-Chloro-N-(1,3-dimethyl-butyl)-N-(3-phenyl-propyl)-benzenesulfonamide;

4-Chloro-N-(1-methyl-butyl)-N-(3-phenyl-propyl)-benzenesulfonamide;

4-Chloro-N-(2-methoxy-1-methyl-ethyl)-N-(3-phenyl-propyl)-benzenesulfonamide;

2S,3R-2-[(4-Chloro-benzenesulfonyl)-(3-phenyl-propyl)-amino]-3-hydroxy-N-methyl-butyramide;

4-Chloro-N-(1S,2S-2-hydroxy-cyclopentyl)-N-(3-phenyl-propyl)-benzenesulfonamide;

4-Chloro-N-(2-methyl-cyclohexyl)-N-(3-phenyl-propyl)-benzenesulfonamide;

4-[(4-Chloro-benzenesulfonyl)-(3-phenyl-propyl)-amino]-piperidine-1-carboxylic acid ethyl ester;

N-[3-(4-tert-Butyl-phenyl)-2-methyl-propyl]-4-chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;

4-Chloro-N-(4-chloro-6-fluoro-2H-chromen-3-ylmethyl)-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;

4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-(2-pentyl-3-phenyl-allyl)-benzenesulfonamide;

4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-[3-(2-methoxy-phenyl)-allyl]-benzenesulfonamide;

N-Benzofuran-2-ylmethyl-4-chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;

4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-(3-phenyl-butyl)-benzenesulfonamide;

4-Chloro-N-cyclopropylmethyl-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;

R—N-sec-Butyl-4-chloro-N-(1-methyl-3-phenyl-allyl)-benzenesulfonamide;

R—N-sec-Butyl-4-chloro-N-[3-(2-methoxy-phenyl)-allyl]-benzenesulfonamide;

R—N-Benzofuran-2-ylmethyl-N-sec-butyl-4-chloro-benzenesulfonamide;

R—N-sec-Butyl-4-chloro-N-(1-methyl-1H-indol-2-ylmethyl)-benzenesulfonamide;

R—N-sec-Butyl-4-chloro-N-(1-methyl-3-phenyl-propyl)-benzenesulfonamide;

4-Chloro-N-(2,5-dimethyl-cyclohexyl)-N-(3-fluoro-4-methoxy-benzyl)-benzenesulfonamide;

4-Chloro-N-(2,4-difluoro-benzyl)-N-(2,5-dimethyl-cyclohexyl)-benzenesulfonamide;

4-Chloro-N-(2,5-dimethyl-cyclohexyl)-N-(3-phenyl-allyl)-benzenesulfonamide;

4-Chloro-N-(2,5-dimethyl-cyclohexyl)-N-(4-methoxy-benzyl)-benzenesulfonamide;

4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(2,5-dimethyl-cyclohexyl)-benzenesulfonamide;

N-(4-Bromo-benzyl)-4-chloro-N-(2,5-dimethyl-cyclohexyl)-benzenesulfonamide;

4-Chloro-N-(2,5-dimethyl-cyclohexyl)-N-(3-phenyl-propyl)-benzenesulfonamide;

4-Chloro-N-(2,5-dimethyl-cyclohexyl)-N-(2-methyl-3-phenyl-allyl)-benzenesulfonamide;

4-Chloro-N-(3,4-dimethoxy-benzyl)-N-(1R,2S,5R-2-isopropyl-5-methyl-cyclohexyl)-benzenesulfonamide;

4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-(1-methyl-3-phenyl-allyl)-benzenesulfonamide;

N-(2-Benzyl-cyclohexyl)-4-chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;

4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-(1,2,3,4-tetrahydro-naphthalen-2-yl)-benzenesulfonamide;

4-Chloro-N-(4,6-dichloro-2H-chromen-3-ylmethyl)-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;

4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-(1-methyl-1H-indol-2-ylmethyl)-benzenesulfonamide;

4-Chloro-N-(1-chloro-3,4-dihydro-naphthalen-2-ylmethyl)-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;

4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-(1-methyl-3-phenyl-propyl)-benzenesulfonamide;

4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-propyl-benzenesulfonamide;

4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-methyl-benzenesulfonamide;

R—N-sec-Butyl-4-chloro-N-(1-chloro-3,4-dihydro-naphthalen-2-ylmethyl)-benzenesulfonamide;

4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;

4-Chloro-N—(R-1,2-dimethyl-propyl)-benzenesulfonamide;

4-Chloro-N—(S-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;

4-[(4-Chloro-benzenesulfonyl)-(R-1-hydroxymethyl-3-methyl-butyl)-amino]-3-methyl-but-2-enoic acid ethyl ester;

4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-naphthalen-2-ylmethyl-benzenesulfonamide;

4-Chloro-N-furan-2-ylmethyl-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;

4-Chloro-N-furan-3-ylmethyl-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;

4-Chloro-N—(S-1-hydroxymethyl-3-methyl-butyl)-N-(3-phenyl-allyl)-benzenesulfonamide;

4-Chloro-N—(S-1,2-dimethyl-propyl)-N-(3-phenyl-allyl)-benzenesulfonamide;

N-(2-Bromo-3-phenyl-allyl)-4-chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;

N-But-2-enyl-4-chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;

4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-pentyl-benzenesulfonamide;

4-Chloro-N-(3-furan-2-yl-2-methyl-allyl)-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;

4-Chloro-N-(3-furan-2-yl-allyl)-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;

4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-(2-methyl-pentyl)-benzenesulfonamide;

4-Chloro-N-(2-ethyl-allyl)-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;

4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-(3-methyl-butyl)-benzenesulfonamide;

4-Chloro-N-(2-ethyl-butyl)-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;

4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-(3-methyl-but-2-enyl)-benzenesulfonamide;

4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-(3-pyridin-3-yl-allyl)-benzenesulfonamide;

4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-[3-(2-nitro-phenyl)-allyl]-benzenesulfonamide;

4-[(4-Chloro-benzenesulfonyl)-(R-1-hydroxymethyl-3-methyl-butyl)-amino]-but-2-enoic acid ethyl ester;

4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-(2-methyl-4-phenyl-pentyl)-benzenesulfonamide;

4-Chloro-N-cyclohexylmethyl-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;

4-Chloro-N-(2-chloro-3-phenyl-allyl)-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;

4-Chloro-N-[3-(3-chloro-phenyl)-allyl]-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;

4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-(3-p-tolyl-allyl)-benzenesulfonamide;

4-Chloro-N-[3-(4-dimethylamino-phenyl)-allyl]-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;

4-Chloro-N-[3-(4-fluoro-phenyl)-allyl]-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;

4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-(3-m-tolyl-allyl)-benzenesulfonamide;

4-Chloro-N-[3-(3-fluoro-phenyl)-allyl]-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;

4-Chloro-N—(R-1-hydroxymethyl-3-methyl-butyl)-N-(3-o-tolyl-allyl)-benzenesulfonamide;

4-Chloro-N-[3-(4-chloro-phenyl)-allyl]-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;

4-Chloro-N-[3-(2-fluoro-phenyl)-allyl]-N—(R-1-hydroxymethyl-3-methyl-butyl)-benzenesulfonamide;

4-Chloro-N-(6-methoxy-pyridin-3-ylmethyl)-N-(2-methyl-cyclohexyl)-benzenesulfonamide;

4-Chloro-N-(6-chloro-pyridin-3-ylmethyl)-N-(2-methyl-cyclohexyl)-benzenesulfonamide;

N-(6-Bromo-pyridin-3-ylmethyl)-4-chloro-N-(2-methyl-cyclohexyl)-benzenesulfonamide; and

4-Chloro-N-(2-methyl-cyclohexyl)-N-(3-pyridin-3-yl-allyl)-benzenesulfonamide.