N-substituted benzene sulfonamides   

Abstract: Compounds of particular interest are defined by Formula (I), wherein R1, R2, R3, R4, and R3′, 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). The invention provides N-substituted benzenesulfonamides for use in treating or preventing cognitive disorders, such as Alzheimer's Disease.

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-methionine596 to 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

In a broad aspect, the invention provides compounds of Formula I:

and pharmaceutically acceptable salts thereof, wherein R1 is C2-C6 alkynyl, C2-C6 alkenyl, or C1-C8 alkyl wherein each is optionally substituted with 1, 2, or 3 groups that are independently C1-C6 alkoxy, OH, halogen, CN, C1-C6 thioalkoxy, phenyl, naphthyl, C3-C8 cycloalkyl, NH2, NH(C1-C6)alkyl, N(C1-C6)alkyl(C1-C6 alkyl), —C(O)NH2, —C(O)NH(C1-C6)alkyl, —C(O)N(C1-C6)alkyl(C1-C6)alkyl, —C(O)phenyl, or C1-C6 alkoxycarbonyl, wherein each of the cyclic groups is optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, C1-C4 alkyl, C1-C4 alkoxy, NH2, NH(C1-C6)alkyl, N(C1-C6)alkyl(C1-C6 alkyl), —SO2—(C1-C6)alkyl, or OH; or R1 is C3-C8 cycloalkyl optionally substituted with 1 or 2 groups that are independently C1-C4 alkyl, C1-C4 hydroxyalkyl, or OH; or R1 is 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-C4 alkyl, C1-C4 alkoxy, phenyl, phenyl(C1-C4)alkyl, OH, halogen, CO2H, C1-C4 alkoxycarbonyl, —C(O)NH2, —C(O)NH(C1-C4)alkyl, —C(O)N(C1-C4)alkyl(C1-C4)alkyl, or C1-C4 alkoxycarbonyl; or R1 is 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-C4 alkoxycarbonyl, —C(O)NH2, —C(O)NH(C1-C4)alkyl, —C(O)N(C2-C4)alkyl(C1-C4)alkyl, C1-C4 alkyl, C1-C4 alkoxy or OH; R2 is C1-C8 alkyl, C1-C6 hydroxyalkyl, or C2-C8 alkenyl, 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-C8 cycloalkyl, benzofuranyl, indolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, pyridyl, pyrimidyl, C1-C4 alkyl, 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-C6 alkoxycarbonyl, —C(O)NH2, —C(O)NH(C1-C6)alkyl, —C(O)N(C1-C6)alkyl(C1-C6)alkyl, C1-C4 alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, NO2, C1-C4 alkyl, —S(O)x—R25, —(C1-C4 alkyl)-S(O)x—R25, or OH; wherein x is 0, 1, or 2; R25 is C1-C6 alkyl, OH, NR26R27; R26 and R27 are independently H, C1-C6 alkyl, phenyl(C1-C4 alkyl), phenyl, or pyridyl; or R26, R27 and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl; R3 is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or CN, R4 is H, halogen, C1-C6 alkyl optionally substituted with —CO2—(C1-C6 alkyl), C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, CN, aryloxy, isocyanato, —SO2—(C1-C6 alkyl), —NHR′, —NR′R″, C1-C6 alkanoyl, pyridyl, or phenyl; or R3 and R4 and 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-C4 alkyl, C1-C4 alkoxy, halogen, or C1-C4 alkanoyl wherein the alkanoyl group is optionally substituted with up to 3 halogen atoms; R3′ is H, —SO2—NR′R″, halogen, or R4 and R3′, and the carbons to which they are attached form a phenyl ring; or R4 and R3′ and the carbons to which they are attached form a 1-oxa-2,3-diazacyclopentyl ring; R′ is H, C1-C6 alkyl, phenyl(C1-C4)alkyl, C1-C6 alkanoyl, 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-C6 alkoxy, wherein the aryl, and heteroaryl groups are optionally substituted with alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, R″ is H, or C1-C6 alkyl, 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

In embodiment 2, the invention provides compounds of formula I wherein R1 is C1-C8 alkyl which is optionally substituted with 1, 2, or 3 groups that are independently C1-C6 alkoxy, OH, halogen, CN, C1-C6 thioalkoxy, phenyl, naphthyl, C3-C8 cycloalkyl, NH2, NH(C1-C6)alkyl, N(C1-C6)alkyl(C1-C6 alkyl), —C(O)NH2, —C(O)NH(C1-C6)alkyl, —C(O)N(C1-C6)alkyl(C1-C6)alkyl, —C(O)phenyl, or C1-C6 alkoxycarbonyl, wherein each of the cyclic groups is optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, C1-C4 alkyl, C1-C4 alkoxy, NH2, NH(C1-C6)alkyl, N(C1-C6)alkyl(C1-C6 alkyl), —SO2— (C1-C6)alkyl, or OH.

In embodiment 3, the invention provides compounds according to embodiment 2, wherein R3 is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, CN; R4 is H, halogen, C1-C6 alkyl optionally substituted with —CO2—(C1-C6 alkyl), C1-C6 alkoxy, C1-C4 haloalkyl, C1-C6 haloalkoxy, CN, aryloxy, isocyanato, —SO2—(C1-C6 alkyl), —NHR′, —NR′R″, C1-C6 alkanoyl, oxazolyl, pyrazolyl, thiazolyl, pyridyl, furanyl or thienyl, phenyl; and R3′ is H, or halogen.

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

In embodiment 4, the invention provides compounds according to embodiment 3, wherein R2 is C1-C8 alkyl, or C2-C8 alkenyl, 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-C8 cycloalkyl, benzofuranyl, indolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, pyridyl, pyrimidyl, C1-C4 alkyl, halogen, —CO2—(C1-C6 alkyl), 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-C6 alkoxycarbonyl, —C(O)NH2, —C(O)NH(C1-C6)alkyl, —C(O)N(C1-C6)alkyl(C1-C6)alkyl, C1-C4 alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C1-C4 alkyl, —S(O)x—R25, —(C1-C4 alkyl)-S(O)x—R25, or OH; wherein x is 0, 1, or 2; R25 is C1-C6 alkyl, OH, NR26R27; R26 and R27 are independently H, C1-C6 alkyl, phenyl(C1-C4 alkyl), phenyl, or pyridyl; or R26, R27 and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl.

Compounds according to embodiment 4, wherein R1 is C1-C8 alkyl which is optionally substituted with 1, 2, or 3 groups that are independently C1-C4 alkoxy, OH, halogen, CN, C1-C4 thioalkoxy, naphthyl, C3-C8 cycloalkyl, NH2, NH(C1-C6)alkyl, N(C1-C6)alkyl(C1-C6 alkyl), —C(O)NH2, —C(O)NH(C1-C6)alkyl, —C(O)N(C1-C6)alkyl(C1-C6)alkyl, —C(O)phenyl, or C1-C6 alkoxycarbonyl, wherein each of the cyclic groups is optionally substituted with 1, 2, or 3 groups that are independently halogen, C1-C4 alkyl, C1-C4 alkoxy, NH2, NH(C1-C6)alkyl, N(C1-C6)alkyl(C1-C6 alkyl), —SO2—(C1-C6)alkyl, or OH.

Compounds according to Embodiment 4, wherein R1 is C1-C8 alkyl which is optionally substituted with 1, 2, or 3 groups that are independently C1-C4 alkoxy, OH, halogen, CN, C1-C4 thioalkoxy, NH2, NH(C1-C6)alkyl, N(C1-C6)alkyl(C1-C6 alkyl), —C(O)NH2, —C(O)NH(C1-C6)alkyl, —C(O)N(C1-C6)alkyl(C1-C6)alkyl, —C(O) phenyl, or C1-C4 alkoxycarbonyl.

Compounds according to Embodiment 4, wherein R1 is C1-C8 alkyl which is optionally substituted with 1, or 2 groups that are independently C1-C4 alkoxy, OH, halogen, CN, C1-C4 thioalkoxy, NH2, NH(C1-C4)alkyl, N(C1-C4)alkyl(C1-C4 alkyl), —C(O)NH2, —C(O)NH(C1-C4)alkyl, —C(O)N(C1-C4)alkyl(C1-C4)alkyl, or C1-C4 alkoxycarbonyl.

Compounds according to Embodiment 4, wherein R1 is C1-C8 alkyl which is optionally substituted with 1 or 2 groups that are independently C1-C4 alkoxy, OH, halogen, CN, C1-C4 thioalkoxy, NH2, NH(C1-C4)alkyl, or N(C1-C4)alkyl(C1-C4 alkyl).

Compounds according to Embodiment 4, wherein R1 is C1-C8 alkyl which is optionally substituted with 1, or 2 groups that are independently C1-C4 alkoxy, OH, halogen, CN, or C1-C4 thioalkoxy.

Compounds according to Embodiment 4, wherein R1 is C1-C8 alkyl which is optionally substituted with 1, or 2 groups that are independently NH2, NH(C1-C4)alkyl, or N(C1-C4)alkyl(C1-C4 alkyl).

Compounds according to Embodiment 4, wherein R1 is C1-C8 alkyl 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-C4 alkoxycarbonyl.

Compounds according to Embodiment 4, wherein R1 is C1-C8 alkyl substituted with C3-C8 cycloalkyl which is optionally substituted with 1, or 2 groups that are independently halogen, C1-C4 alkyl, C1-C4 alkoxy, NH2, NH(C1-C6)alkyl, N(C1-C6)alkyl(C1-C6 alkyl), or OH.

In embodiment 5, the invention provides compounds according to embodiment 4, wherein R1 is C1-C8 alkyl which is optionally substituted with OH.

In embodiment 6, the invention provides compounds according to embodiment 5, wherein R3 is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, CF3, CN; R4 is H, halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, OCF3, CN, phenyloxy, —SO2—(C1-C6 alkyl), —NHR′, —NR′R″, C1-C4 alkanoyl, pyridyl, furanyl or thienyl, phenyl, or C1-C6 alkyl optionally substituted with —CO2—(C1-C6 alkyl); R3′ is H, or halogen; R′ is H, C1-C6 alkyl, phenyl(C1-C4)alkyl, C1-C6 alkanoyl, 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-C4 alkoxy, wherein the phenyl and pyridyl groups are optionally substituted with C1-C4 alkyl, C1-C4 alkoxy, halogen, CF3, OCF3; R″ is H or C1-C6 alkyl, wherein the alkyl group is optionally substituted with halogen.

Compounds according to embodiment 6, wherein R1 is C1-C8 hydroxyalkyl. In one aspect, R1 is C2-C6 hydroxyalkyl. In another aspect, R1 is a C3-C6 hydroxyalkyl. In still another aspect, R1 is a C5-C6 hydroxyalkyl. In another aspect, R1 is a C7-C8 hydroxyalkyl. In yet another aspect, R1 is

Compounds according to embodiment 6, wherein R1 is C1-C8 alkyl. In another aspect, R1 is a C3-C6 alkyl. In still another aspect, R1 is a C5-C6 alkyl. In another aspect, R1 is C5-C8 alkyl. In still another aspect, R1 is C7-C8 alkyl.

Compounds according to either Embodiment 6A or Embodiment 6B, wherein R2 is C1-C8 alkyl. In another aspect, the R2 is C2-C8 alkyl. In still another aspect, R2 is C2-C6 alkyl. In yet another aspect, R2 is C3-C4 alkyl (preferably, C3 alkyl.) In another aspect, R2 is C1, C3, or C5 alkyl. In still another aspect, R2 is n-propyl or isopropyl. In another aspect, R2 is C3-C8 alkyl. In yet another aspect, R2 is C5-C8 alkyl. In still another aspect, R2 is C7-C8 alkyl. In still another aspect, R2 is C5-C7 alkyl.

Compounds according to Embodiment 6C, wherein R3 is H, halogen, methyl, methoxy, or CF3; R4 is H, halogen (preferably Cl or F, more preferably Cl), methoxy, methyl, or CF3; and R3′ is H, or halogen.

Compounds according to Embodiment 6D, wherein R3 and R8′ are both H; and R4 is halogen (preferably Cl or F, more preferably Cl), methoxy, methyl, or CF3. In one aspect, R4 is Cl. In another aspect, R4 is methyl. In still another aspect, R4 is CF3.

In embodiment 7, the invention provides compounds according to embodiment 6, wherein R2 is C1-C8 alkyl which is optionally substituted with 1 or 2 phenyl groups, 2H-chromenyl, 1,2,3,4-tetrahydronaphthalenyl, indolyl, 3,4-dihydronaphthalenyl, phenyl, naphthyl, C3-C8 cycloalkyl, 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-C6 alkoxycarbonyl, —C(O)NH2, —C(O)NH(C1-C6)alkyl, —C(O)N(C1-C6)alkyl(C1-C6)alkyl, C1-C4 alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C1-C4 alkyl, —S(O)x—R25, —(C1-C4 alkyl)-S(O)x—R25, or OH; wherein x is 0, 1, or 2; R25 is C1-C6 alkyl, OH, NR26R27; R26 and R27 are independently H, C1-C6 alkyl, phenyl(C1-C4 alkyl), phenyl, or pyridyl; or R26, R27 and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl.

Compounds according to embodiment 7, wherein R2 is C1-C8 alkyl which is optionally substituted with 2H-chromenyl, 1,2,3,4-tetrahydronaphthalenyl, indolyl, 3,4-dihydronaphthalenyl, naphthyl, C3-C8 cycloalkyl, 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-C6 alkoxycarbonyl, —C(O)NH2, —C(O)NH(C1-C6)alkyl, —C(O)N(C1-C6)alkyl(C1-C6)alkyl, C1-C4 alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C1-C4 alkyl, —S(O)x—R25, —(C1-C4 alkyl)-S(O)x—R25, or OH; wherein x is 0, 1, or 2; R25 is C1-C6 alkyl, OH, NR26R27; R26 and R27 are independently H, C1-C6 alkyl, phenyl(C1-C4 alkyl), phenyl, or pyridyl; or R26, R27 and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl.

Compounds according to embodiment 7, or embodiment 7A, wherein R2 is C1-C4 alkyl 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-C6 alkoxycarbonyl, —C(O)NH2, —C(O)NH(C1-C6)alkyl, —C(O)N(C1-C6)alkyl(C1-C6)alkyl, C1-C4 alkoxy optionally substituted with pyridyl, thiazolyl, or methyl thiazol-5-yl, C1-C4 alkyl, —S(O)x—R25, —(C1-C4 alkyl)-S(O)x—R25, or OH; wherein x is 0, 1, or 2; R25 is C1-C6 alkyl, OH, NR26R27; R26 and R27 are independently H, C1-C6 alkyl, phenyl(C1-C4 alkyl), phenyl, or pyridyl; or R26, R27 and the nitrogen to which they are attached represent pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or imidazolidinyl. In another aspect, the cyclic portions are unsubstituted.

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