Bridged N-Cyclic Sulfonamido Inhibitors of Gamma Secretase

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to bridged N-cyclic sulfonamido compounds fused with a heteroaryl or heterocycloalkyl ring, which inhibit gamma secretase and β-amyloid peptide release and/or its synthesis. Therefore, the N-cyclic sulfonamido compounds of the present invention 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 βamyloid peptide (βAP) 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 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 11-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, gives 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 8-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 Bid 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 Blot 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 PSI 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:

stereoisomers, tautomers, mixtures of stereoisomers and/or tautomers or pharmaceutically acceptable salts thereof,

wherein,

the A-ring is aryl, cycloalkyl, heteroaryl or heterocycloalkyl, where each ring is optionally substituted at a substitutable position with halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, CN, aryloxy, —S(O)_0-2— (C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, C₀-C₃alkylCO₂R′, heteroaryl, heterocycloalkyl, aryl, arylalkyl, or —SO₂NR₁₀R₁₁;

R₁and R₂combine to form a [3.3.1] or a [3.2.1] ring system, where the nitrogen is attached to the two bridgehead carbons, where 0 or 1 of the carbons in the ring system is optionally replaced with an —O—, —S(O)_0-2—, or —NR₁₅— group, and where the [3.3.1] or [3.2.1] ring system is optionally substituted with 1, 2, 3, or 4 groups that are independently oxo, halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl, C₂-C₆alkynyl, hydroxy, hydroxyalkyl, C₁-C₆alkoxy, haloalkoxy, —(O)OR₁₃, —(C₁-C₄alkyl)—(O)OR₁₃, —OC(O)NR₁₀R₁₁, —NR′C(O)OR″, —NR′S(O)₂R″, —OS(O)₂R″, —NR′C(O)R″, CN, ═N—NR₁₂, or ═N—O—R₁₃;

two adjacent carbons (not including the bridgehead carbons) in the [3.3.1] or [3.2.1] ring system combine to form part of a fused heteroaryl or heterocycloalkyl ring, each of which is optionally substituted at a substitutable position with a group that is independently C₁-C₆alkyl, C₃-C₈cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, amino, C₁-C₆alkylamino, C₁-C₆dialkylamino, —S(O)_0-2R′, hydroxy, hydroxyalkyl, halo, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, —NR′C(O)R″, —NR′SO₂R″, —C(O)R′, —C(O)OR', —C(O)alkylOC(O)R′; —C(O)NR₁₀R₁₁, oxo, CN, or C₀-C₁alkylaryl (such as phenyl or naphthyl, where phenyl is preferred), where the aryl is optionally substituted with 1-5 groups independently selected from halogen, C₁-C₆alkyl, —CO₂R′, C₁-C₆alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, NO₂, aryloxy, —S(O)_0-2—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, and —SO₂NR₁₀R₁₁, and additionally, two adjacent carbons in the [3.3.1] or the [3.2.1] ring system (not including the bridegehead carbons) may combine with one or more —C—, —CH—, and/or —CH₂— groups to form a cycloalkyl ring that may optionally be substituted with one or more groups that are independently halogen, C₁-C₆alkyl or haloalkyl.

R₁₀and R₁₁at each occurrence are independently H or C₁-C₆alkyl, where the alkyl is optionally substituted with an aryl (such as phenyl or naphthyl, where phenyl is preferred), where the aryl is optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO₂; and R₁₀and R₁₁together may form a 3-8 membered ring optionally including an additional heteroatom such as N, O or S;

R₁₂is H, C₁-C₆alkyl or —13 SO₂-aryl (such as phenyl or naphthyl, where phenyl is preferred), where the aryl is optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO₂;

R₁₃is H or C₁-C₆alkyl optionally substituted with aryl (such as phenyl or naphthyl, more preferably, phenyl), hydroxyl, or halogen, where the aryl is optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO₂;

R₁₅is H, aryl, heteroaryl, heterocycloalkyl, —SO₂′, —C(O)R′, —C(O)OR′, or C₁-C₆alkyl optionally substituted with aryl, hydroxyl, or halogen, where the aryl groups are optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN, amino, NH(C₁-C₆alkyl), N(C₁-C₆alkyl) (C₁-C₆alkyl) or NO₂, and

R′ and R″ at each occurrence are independently hydrogen, C₁-C₆alkyl, haloalkyl, C₂-C₆alkenyl or phenyl optionally substituted with 1 to 5 groups that are independently halogen, C₁-C₆alkyl, —C(O)OR′, C₁-C₆alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, aryloxy, —SO₂—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, NO₂, or —SO₂NR₁₀R₁₁.

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

As described above, the invention provides for compounds according to Formula I.

In one aspect, the invention provides compounds of Formula Ia, Ib or Ic, i.e. compounds of Formula I having the following structures:

wherein, no carbons in the ring system are replaced with an —O—, —S(O)_0-2— or —-NR₁₅— group;

B is a heteroaryl or heterocycloalkyl ring, where the heteroaryl and heterocycloalkyl groups are monocyclic or bicyclic, each of which is optionally substituted at a substitutable position with a group that is independently C₁-C₆alkyl, C₃-C₈cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, amino, C₁-C₆alkylamino, C₁-C₆dialkylamino, —S(O)_0-2R′, hydroxy, hydroxyalkyl, halo, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, —NR′C(O)R″, —NR′SO₂R″, —C(O)R′, —C(O)OR′, —C(O)alkylOC(O)R′; —C(O))NR₁₀R₁₁, oxo, CN, or C₀-C₁alkylphenyl, where the phenyl is optionally substituted with 1-5 groups independently selected from halogen, C₁-C₆alkyl, —CO₂R′, C₁-C₆alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, NO₂, aryloxy, —S(O)_0-2—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, and —SO₂NR₁₀R₁₁; and

two adjacent carbons in the [3.3.1] or the [3.2.1] ring system (not including the bridegehead carbons) may combine with one or more —C—, —CH—, and/or —CH₂— groups to form a cycloalkyl ring that may optionally be substituted with one or more groups that are independently halogen, C₁-C₆alkyl or haloalkyl.

In another aspect, the invention provides compounds of Formula Id and Ie, i.e., compounds of Formula I having the following structures:

wherein

R₁and R₂combine to form a [3.3.1] or a [3.2.1] ring system where the ring system is optionally substituted with 1, 2, 3, or 4 groups that are independently oxo, halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl, C₂-C₆alkynyl, hydroxy C₀-C₃-alkyl, C₁-C₆alkoxy, haloalkoxy, —(O)OR₁₃, —(C₁-C₄alkyl)—(O)OR₁₃, —CONR₁₀R₁₁, —OC(O)NR₁₀R₁₁, —NR′C(O)OR″, —NR′S(O)₂R″, −OS(O)₂R″, —NR′C(O)R″, CN, ═N—NR₁₂, or ═N—O—R₁₃; and

X is —C—, —CH—, —CH₂—, —O—, —S(O)_0-2—, or —NR₁₅—.

In another aspect, the invention provides compounds according to any one of Formulas I, Ia, Ib, Ic, Id, or Ie, where the A-ring is phenyl, C₃-C₈, cycloalkyl, heteroaryl that is pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, thienyl, furanyl, pyrrolyl, pyrazolyl, or imidazolyl, or heterocycloalkyl that is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or thiomorpholinyl-S,S-dioxide, where each of the above rings is optionally substituted at a substitutable position with C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, CN, phenyloxy, —S(O)_0-2—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, C₀-C₃alkylCO₂R′, pyridyl, thienyl, furanyl, pyrrolyl, pyrrolidinyl, piperidinyl, piperazinyl, phenyl, phenyl C₁-C₄alkyl, or —SO₂NR₁₀R₁₁.

In another aspect, the invention provides a compound of Formula II, i.e., a compound of Formula I with the structure:

wherein

two adjacent carbons (not including the bridgehead carbons) in the [3.2.1] ring system combine to form part of a fused heteroaryl or heterocycloalkyl ring, each of which is optionally substituted at a substitutable position, as is described above for Formula I,

where two adjacent carbons (not including the bridegehead carbons) may combine to form part of a cycloalkyl ring that may optionally be substituted at a substitutable position with one or more groups that are independently halogen, C₁-C₆alkyl or haloalkyl;

where 0 or 1 of the carbons in the [3.2.1] ring system is optionally replaced with an —O—, —S(O)_0-2—, or —NR₁₅— group;

the [3.2.1] ring system is optionally substituted with 1, 2, 3, or 4 groups that are independently oxo, halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl, C₂-C₆alkynyl, hydroxy, hydroxyalkyl, C₁-C₆alkoxy, haloalkoxy, —(O)OR₁₃, —(C₁-C₄alkyl)—(O)OR₁₃, —CONR₁₀R₁₁, —OC(O)NR₁₀R₁₁, —NR′C(O)OR″, —NR′S(O)₂R″, —OS(O)₂R″, —NR′C(O)R″, CH, ═N—NR₁₂, or ═N—O—R₁₃; and

R₁₅is H, phenyl, pyridyl, pyrimidinyl, oxazolyl, thiazolyl, imidazolyl, thienyl, furanyl, pyrrolyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, indolyl, quinolinyl, —SO₂R′, —C(O)R′, —C(O)OR′, or C₁-C₆alkyl optionally substituted with phenyl, hydroxyl, or halogen, where the above cyclic groups are optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl (such as CF₃or CH₂CF₃), C₁-C₄haloalkoxy (such as OCF₃or OCH₂CF₃), CN, amino, NH(C₁-C₆alkyl), N(C₁-C₆alkyl) (C₁-C₆alkyl) or NO₂.

In still another aspect, the invention provides compounds of Formula III, i.e compounds of Formula II, wherein the A-ring is phenyl or naphthyl (preferably phenyl), which is optionally substituted at a substitutable position with halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, CN, phenyloxy, —S(O)_0-2—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, C₀-C₃alkylCO₂R′, pyridyl, thienyl, furanyl, pyrrolyl, pyrrolidinyl, piperidinyl, piperazinyl, phenyl, phenyl C₁-C₄alkyl, or —SO₂NR₁₀R₁₁.

In another aspect, the invention provides compounds of Formulas IIIa, IIIb, and IIIc, i.e. compounds of Formula III wherein no carbons in the [3.2.1] ring system are replaced with an —O—, —S(O)_0-2—, or —NR₁₅— group, having the following structures:

wherein,

the B-ring is a heteroaryl or heterocycloalkyl ring, each of which is optionally substituted at a substitutable position with a group that is independently C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, amino, C₁-C₆alkylamino, C₁-C₆dialkylamino, —S(O)_0-2R′, hydroxy, hydroxyalkyl, halo, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, —NR′C(O)R″, —NR′SO₂R″, —C(O)R′, —C(O)OR′, —C(O)alkylOC(O)R′, —C(O)NR₁₀R₁₁, oxo, CN, or C₀-C₁alkylphenyl, where the phenyl is optionally substituted with 1-5 groups independently selected from halogen, C₁-C₆alkyl, —CO₂R′, C₁-C₆alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, NO₂, phenyloxy, —S(O)_0-2—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, and —SO₂NR₁₀R₁₁;

the [3.2.1] ring system is optionally substituted with 1, 2, 3, or 4 groups that are independently oxo, halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl, C₂-C₆alkynyl, hydroxy, hydroxyalkyl, C₁-C₆alkoxy, haloalkoxy, —(O)OR₁₃, —(C₁-C₄alkyl)—(O)OR₁₃, —OC(O)NR₁₀R₁₁, —NR′C(O)OR″, —NR′S(O)₂R″, —OS(O)₂R″, —NR′C(O)R″, CN, ═N—NR₁₂, or ═N—O—R₁₃, and additionally, two adjacent carbons (not including the bridegehead carbons) may combine to form a cycloalkyl ring that may optionally be substituted with halogen, C₁-C₆alkyl or haloalkyl;

R₃, R₄, R₅, R₆, R₇are independently of each other H, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆haloalkoxy, CN, hydroxyl, C₁-C₆alkoxy, alkyl-OH, —C₁-C₃alkyl-alkoxy, phenyloxy, —S(O₂)R′, —NR₁₀R₁₁, C₁-C₆alkanoyl, oxazolyl, pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, imidazolyl, indolyl, furanyl, thienyl, phenyl, or phenyl C₁-C₄alkyl, or

R₄and R₅, or R₅and R₆and the carbons to which they are attached form a heterocycloalkyl or a heteroaryl ring which is optionally substituted with 1, 2, 3, or 4 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; or

R₄and R₅, or R₅and R₆and the carbons to which they are attached form a benzo ring which is optionally substituted with optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO₂; and

R′ and R″ are independently of each other hydrogen, C₁-C₆alkyl, haloalkyl, C₂-C₆alkenyl or phenyl optionally substituted with 1 to 5 groups that are independently halogen, C₁-C₆alkyl, —C(O)OR′, C₁-C₆alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, phenyloxy, —SO₂—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, NO₂, or —SO₂NR₁₀R₁₁.

In another aspect, the invention provides compounds of Formulas IIId, IIIe and IIIf, i.e., compounds of Formula III, having the structures:

wherein,

the B-ring is a heteroaryl or heterocycloalkyl ring, each of which is optionally substituted at a substitutable position with a group that is independently C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, amino, C₁-C₆alkylamino, C₁-C₆dialkylamino, —S(O)_0-2R′, hydroxy, hydroxyalkyl, halo, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, —NR′C(O)R″, —NR′SO₂R″, —C(O)R′, —C(O)OR′, —C(O)alkylOC(O)R′; —C(O)NR₁₀R₁₁, oxo, CN, or C₀-C₁alkylphenyl, where the phenyl is optionally substituted with 1-5 groups independently selected from halogen, C₁-C₆alkyl, —CO₂R′, C₁-C₆alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, NO₂, phenyloxy, —S(O)_0-2—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, and —SO₂NR₁₀R₁₁;

R₃, R₄, R₅, R₆, R₇are independently of each other H, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆haloalkoxy, CN, hydroxyl, C₁-C₆alkoxy, —C₁-C₃alkyl-OH, —C₁-C₃alkyl-alkoxy, phenyloxy, —SO₂R′, C₁-C₆alkanoyl, oxazolyl, pyrazolyl,'thiazolyl, pyridyl, pyrimidinyl, imidazolyl, indolyl, furanyl, thienyl, phenyl, or phenyl C₁-C₄alkyl, or

R₄and R₅, or R₅and R₆and the carbons to which they are attached form a benzo ring which is optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO₂;

R′ and R″ are independently of each other hydrogen, C₁-C₆alkyl, haloalkyl, C₂-C₆alkenyl or phenyl optionally substituted with 1 to 5 groups that are independently halogen, C₁-C₆alkyl, —C(O)OR′, C₁-C₆alkoxy, haloalkyl (such as CF₃), haloalkoxy (such as OCF₃), hydroxyl, CN, phenyloxy, —SO₂—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, NO₂, or —SO₂NR₁₀R₁₁; and

R₁₅is H, phenyl, pyridyl, pyrimidinyl, oxazolyl, thienyl, furanyl, pyrrolyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, indolyl, —SO₂R′, —C(O)R′, —C(O)OR′, or C_l-C₆alkyl optionally substituted with phenyl, hydroxyl, or halogen, where the above cyclic groups are optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl (such as CF₃), C₁-C₄haloalkoxy (such as OCF₃), amino, NH(C₁-C₄alkyl), N(C₁-C₄alkyl) (C₁-C₄alkyl), CN or NO₂.

In some aspects, the invention provides compounds of Formulas IIIa, IIIb, IIIc, IIId, IIIe or IIIf wherein the B-ring is pyrazolyl, imidazolyl, pyrrolyl, triazolyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, triazolopyrimidinyl, imidazopyrimidinyl, pyrazolopyrimidinyl, indolyl or pyridyl, each of which is optionally substituted at a substitutable position with a group that is independently C₁-C₆alkyl, C₃-C₈cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, amino, C₁-C₆alkylamino, C₁-C₆dialkylamino, —S(O)_0-2R′, hydroxy, hydroxyalkyl, halo, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, —NR′C(O)R″, —NR′SO₂R″, —C(O)R′, —C(O)OR′, —C(O)alkylOC(O)R′; —C(O)NR₁₀R₁₁, oxo, CN, or C₀-C₁alkylphenyl, where the phenyl is optionally substituted with 1-5 groups independently selected from halogen, C₁-C₆alkyl, —CO₂R′, C₁-C₆alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, NO₂, phenyloxy, —S(O)_0-2-(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, and —SO₂NR₁₀R₁₁.

In some other aspects, the invention provides compounds of Formulas IIIa, IIIb, IIIc, IIId, IIIe or IIIf wherein the B-ring is pyrazolyl, imidazolyl, pyrrolyl, triazolyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl or pyridyl, each of which is optionally substituted at a substitutable position with a group that is independently C₁-C₄alkyl; C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₄alkoxy, amino, C₁-C₄alkylamino, C₁-C₄dialkylamino, —S(O)_0-2R′, hydroxy, hydroxy C₁-C₄alkyl; halo, C₁-C₂haloalkyl (such as CF₃), C₁-C₂haloalkoxy (such as OCF₃), —NR′C(O)R″, —NR′SO₂R″, —C(O)R′, —C(O)OR′, —C(O)alkylOC(O)R′; —C(O)NR₁₀R₁₁, oxo, CN, or C₀-C₁alkylphenyl, where the phenyl is optionally substituted with 1-5 groups independently selected from halogen, C₁-C₄alkyl, —CO₂R′, C₁-C₄alkoxy, C₁-C₂haloalkyl (such as CF₃), C₁-C₂haloalkoxy (such as OCF₃), hydroxyl, CN, NO₂, phenyloxy, —S(O)_0-2—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, and —SO₂NR₁₀R₁₁.

In some other aspects, the invention provides compounds of Formulas IIIa, IIIb, IIIc, IIId, IIIe or IIIf wherein the B-ring is pyrazolyl, imidazolyl, pyrrolyl, triazolyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl or pyridyl, each of which is substituted at a substitutable position with a group that is independently C₁-C₄alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₁-C₄alkoxy, amino, C₁-C₄alkylamino, C₁-C₄dialkylamino, —S(O)_0-2R′, hydroxy, hydroxy C₁-C₄alkyl, halo, C₁-C₂haloalkyl (such as CF₃), C₁-C₂haloalkoxy (such as OCF₃), —C(O)R′, —C(O)OR′, —C(O)alkylOC(O)R′; —C(O)NR₁₀R₁₁, oxo, CN, or C₀-C₁alkylphenyl, where the phenyl is optionally substituted with 1-3 groups independently selected from halogen, C₁-C₄alkyl, —CO₂R′, C₁-C₄alkoxy, C₁-C₂haloalkyl (such as CF₃), C₁-C₂haloalkoxy (such as OCF₃), hydroxyl, —NR₁₀R₁₁, and C₁-C₆alkanoyl.

In some aspects, the invention provides compounds of Formulas IIIa, IIIb, IIIc, IIId, IIIe or IIIf wherein the B-ring is triazolopyrimidinyl, imidazopyrimidinyl, pyrazolopyrimidinyl, or indolyl, each of which is optionally substituted at a substitutable position with a group that is independently C₁-C₄alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₄alkoxy, amino, C₁-C₄alkylamino, C₁-C₄dialkylamino, —S(O)_0-2R′, hydroxy, hydroxy C₁-C₄alkyl, halo, C₁-C₂haloalkyl (such as CF₃), C₁-C₂haloalkoxy (such as OCF₃), —NR′C(O)R″, —NR′SO₂R″, —C(O)R′, —C(O)OR′, —C(O)alkylOC(O)R′; —C(O)NR₁₀R₁₁, oxo, CN, or C₀-C₁alkylphenyl, where the phenyl is optionally substituted with 1-5 groups independently selected from halogen, C₁-C₄alkyl, —CO₂R′, C₁-C₄alkoxy, C₁-C₂haloalkyl (such as CF₃), C₁-C₂haloalkoxy (such as OCF₃), hydroxyl, CN, NO₂, phenyloxy, —S(O)_0-2—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, and —SO₂NR₁₀R₁₁.

In some other aspects, the invention provides compounds of Formulas IIIa, IIIb, IIIc, IIId, IIIe or IIIf wherein the B-ring is triazolopyrimidinyl, imidazopyrimidinyl, pyrazolopyrimidinyl, or indolyl, each of which is substituted at a substitutable position with a group that is independently C₁-C₄alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₁-C₄alkoxy, amino, C₁-C₄alkylamino, C₁-C₄dialkylamino, —S(O)_0-2R′, hydroxy, hydroxy C₁-C₄alkyl, halo, C₁-C₂haloalkyl (such as CF₃), C₁-C₂haloalkoxy (such as OCF₃), —C(O)R′, —C(O)OR′, —C(O)alkylOC(O)R′; —C(O)NR₁₀R₁₁, oxo, CN, or C₀-C₁alkylphenyl, where the phenyl is optionally substituted with 1-3 groups independently selected from halogen, C₁-C₄alkyl, —CO₂R′, C₁-C₄alkoxy, C₁-C₂haloalkyl (such as CF₃), C₁-C₂haloalkoxy (such as OCF₃), hydroxyl, —NR₁₀R₁₁, and C₁-C₆alkanoyl.

In other aspects, the invention provides compounds of Formulas IIIa, IIIb, IIIc, IIId, IIIe or IIIf wherein

R₃is H, halogen, C₁-C₆alkyl, C₁-C₆alkoxy, haloalkyl, or CN;

R₄is H, halogen; C₁-C₆alkyl; C₁-C₆alkoxy; C₁-C₆haloalkyl; haloalkoxy, CN, phenyloxy, —SO₂-(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, oxazolyl, pyrazolyl, thiazolyl, pyridyl, furanyl, thienyl, or phenyl; and

R₅is H, C₁-C₆alkyl, —SO₂—NR₁₀R₁₁, or halogen.

In other aspects, the invention provides compounds of Formulas IIIa, IIIb, IIIc, IIId, IIIe or IIIf, wherein R₆and R₇are independently H or methyl.

In still other aspects, the invention provides compounds of Formulas IIIa, IIIb, IIIc, IIId, IIIe or IIIf, wherein R₃and R₅are independently H, halo, CF₃, CHF₂or methyl.

In still other aspects, the invention provides compounds of Formulas IIIa, IIIb, IIIc, IIId, IIIe or IIIf, wherein R₄, R₆and R₇are independently H, halo, CF₃, CHF₂or methyl.

In other aspects, the invention provides compounds of Formulas IIIa, IIIb, IIIc, IIId, IIIe or IIIf, wherein R₄is H, halogen (in one aspect, I, Br, F or Cl), C₁-C₆alkyl optionally substituted with halogen or hydroxyl, C₁-C₆alkoxy, OCF₃, or CN.

In yet still other aspects, the invention provides compounds of Formulas IIIa, IIIb, IIIc, IIId, IIIe or IIIf, wherein R₄is phenyloxy, —SO₂—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, oxazolyl, pyrazolyl, thiazolyl, pyridyl, furanyl, thienyl, or phenyl.

In still yet another aspect, the invention provides compounds of Formulas IIIa, IIIb, IIIc, IIId, IIIe or IIIf, wherein R₄is —NR₁₀R₁₁..

In still yet another aspect, the invention provides compounds of Formulas IIIa, IIIb, IIIc, IIId, IIIe or IIIf, wherein R₄is —NR₁₀R₁₁, and R₃, R₅, R₆, and R₇are H.

In yet still another aspect, the invention provides compounds of Formulas IIIa, IIIb, IIIc, IIId, IIIe or IIIf, wherein R₃, R₄, R₅, R₅, and R₇are H, halo, CF₃, CHF₂or methyl.

In yet still another aspect, the invention provides compounds of Formulas IIIa, IIIb, IIIc, IIId, IIIe or IIIf, wherein R₃, R₅, R₆, and R₇are H.

In still another aspect, the invention provides compounds of Formulas IIIa, IIIb, IIIc, IIId, IIIe or IIIf, wherein R₄is chloro.

In yet still another aspect, the invention provides compounds of Formulas IIIa, IIIb, IIIc, IIId, IIIe or IIIf, wherein R₄is chloro, and R₃, R₅, R₆, and R₇are H.

In another aspect, the invention provides compounds of Formulas IIIa, IIIb, IIIc, IIId, IIIe or IIIf, wherein at least one of R₃, R₄, or R₅is chloro, and R₆and R₇are H.

In another aspect, the invention provides compounds of Formulas IIIa, IIIb, IIIc, IIId, IIIe or IIIf, wherein R₃is hydrogen, halogen, C₁-C₄alkyl, C₁-C₄alkoxy, CF₃, or CN;

R₄is hydrogen, halogen, C₁-C₄alkyl, C₁-C₄alkoxy, CF₃, OCF₃, CN, phenyloxy, —SO₂—(C₁-C₄alkyl), —NR₁₀R₁₁, C₁-C₄alkanoyl, and

R₅is hydrogen, C₁-C₄alkyl, —SO₂NR₁₀R₁₁or halogen.

In still yet another aspect, the invention provides compounds of Formulas IIIa, IIIb, IIIc, IIId, IIIe or IIIf, wherein R₄is halogen (in one aspect, F or Cl), C₁-C₄alkyl, C₁-C₄alkoxy, CF₃, OCF₃, or CN.

In another aspect, the invention provides compounds of Formulas IIIa, IIIb, IIIc, IIId, IIIe or IIIf, wherein R₄, R₅R₆, and R₇are hydrogen.

In another aspect, the invention provides compounds of Formulas IIIa, IIIb, IIIc, IIId, IIIe or IIIf, wherein R₃is hydrogen, halogen, C₁-C₄alkyl, C₁-C₄alkoxy, CF₃, or CN;

R₄is oxazolyl, pyrazolyl, thiazolyl, pyridyl, furanyl, thienyl, or phenyl; and

R₅is hydrogen, C₁-C₄alkyl, —SO_{2 NR}₁₀R₁₁, or halogen.

In still yet another aspect, the invention provides compounds of Formulas IIIa, IIIb, IIIc, IIId, IIIe or IIIf, wherein R₄is halogen (in one aspect, F or Cl), CH₃, OCH₃, CF₃, or OCF₃.

In another aspect, the invention provides compounds of Formulas IIIa, IIIb, IIIc, IIId, IIIe or IIIf, wherein R₃is hydrogen, halogen, C₁-C₂alkyl, C₁-C₂alkoxy, CF₃, or CN;

R₄is hydrogen, halogen, C₁-C₂alkyl, C₁-C₂alkoxy, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, CN, NR₁₀R₁₁, C₂-C₃alkanoyl, oxazolyl, pyrazolyl, thiazolyl, pyridyl, furanyl, or thienyl;

R₅is hydrogen, CH₃, or F; and

R₆and R₇are independently hydrogen or halogen.

In still yet another aspect, the invention provides compounds of Formulas IIIa, IIIb, IIIc, IIId, IIIe or IIIf, wherein R₄is CF₃, or OCF₃.

In yet another aspect, the invention provides compounds of Formulas IIIa, IIIb, IIIc, IIId, IIIe or IIIf, wherein R₄and R₅, or R₅and R₆and the carbons to which they are attached form a benzo ring which is optionally substituted with optionally substituted with 1 or 2 groups that are independently halogen, hydroxyl, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₃haloalkyl, C₁-C₃haloalkoxy, CN or NO₂.

In still yet another aspect, the invention provides compounds of Formulas IIIa, IIIb, IIIc, IIId, IIIe or IIIf, wherein R₄and R₅, or R₅and R₆and the carbons to which they are attached form a pyridyl, pyrrolyl, thienyl, furanyl, pyrrolidinyl, piperidinyl ring, each of 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 (such as F).

In one aspect, the invention provides compounds of Formulas IIIa, IIIb, IIIc, IIId, IIIe or IIIf, wherein R₆and R₇are independently hydrogen or methyl.

In one aspect, the invention provides compounds of Formulas IIIa, IIIb, IIIc, IIId, IIIe or IIIf, wherein R₃and R₅are independently hydrogen, halo, or methyl.

In another aspect, the invention provides compounds of Formula IV, i.e., compounds of Formula II, wherein the A-ring is C₃-C₈cycloalkyl, which is optionally substituted at a substitutable position with halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₅alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, CN, phenyloxy, —S(O)_0-2—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, C₀-C₃alkylCO₂R′, pyridyl, thienyl, furanyl, pyrrolyl, pyrrolidinyl, piperidinyl, piperazinyl, phenyl, phenyl C₁-C₄alkyl, or —SO₂NR₁₀R₁₁.

In yet another aspect, the invention provides compounds of Formula IVa, IVb or IVc, i.e. compounds of Formula IV wherein no carbons in the [3.2.1] ring system are replaced with an —O—, —S(O)_0-2—, or —NR₁₅— group, having the following structures:

wherein,

the B-ring is a heteroaryl or heterocycloalkyl ring, each of which is optionally substituted at a substitutable position with a group that is independently is independently C₁-C₆alkyl, C₃-C₈cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, amino, C₁-C₆alkylamino, C₁-C₆dialkylamino, —S(O)_0-2R′, hydroxy, hydroxyalkyl, halo, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, —NR′C(O)R″, —NR′SO₂R″, —C(O)R′, —(O)OR′, —C(O)alkylOC(O)R′; —C(O)NR₁₀R₁₁, oxo, CN, or C₀-C₁alkylphenyl, where the phenyl is optionally substituted with 1-5 groups independently selected from halogen, C₁-C₆alkyl, —CO₂R′, C₁-C₆alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, NO₂, phenyloxy, —S(O)_0-2—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, and —SO₂NR₁₀R₁₁; and

In yet another aspect, the invention provides compounds of Formula IVd, IVe or IVf, i.e. compounds of Formula IV having the following structures:

wherein,

the B-ring is a heteroaryl or heterocycloalkyl ring, each of which is optionally substituted at a substitutable position with a group that is independently is independently C₁-C₆alkyl, C₃-C₈cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, amino, C₁-C₆alkylamino, C₁-C₆dialkylamino, —S(O)_0-2R′, hydroxy, hydroxyalkyl, halo, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, —NR′C(O)R″, —NR′SO₂R″, —C(O)R′, —C(O)OR′, —C(O)alkylOC(O)R′; —C(O)NR₁₀R₁₁, oxo, CN, or C₀-C₁alkylphenyl, where the phenyl is optionally substituted with 1-5 groups independently selected from halogen, C₁-C₆alkyl, —CO₂R′, C₁-C₆alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, NO₂, phenyloxy, —S(O)_0-2—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, and —SO₂NR₁₀R₁₁;

R₁₅is H, phenyl, pyridyl, pyrimidinyl, oxazolyl, thienyl, furanyl, pyrrolyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, indolyl, —SO₂R′, —C(O)R′, —C(O)OR′, or C₁-C₆alkyl optionally substituted with phenyl, hydroxyl, or halogen, where the above cyclic groups are optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl (such as CF₃), C₁-C₄haloalkoxy (such as OCF₃), CN, amino, NH(C₁-C₆alkyl), N(C₁-C₆alkyl) (C₁-C₆alkyl), or NO₂.

In some aspects, the invention provides compounds of Formula IVg, i.e., compounds according to any one of Formulas IVa, IVb, IVc, IVd, IVe or IVf wherein the B-ring is pyrazolyl, imidazolyl, pyrrolyl, triazolyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, triazolopyrimidinyl, imidazopyrimidinyl, pyrazolopyrimidinyl, indolyl, or pyridyl, each of which is optionally substituted at a substitutable position with a group that is independently C₁-C₆alkyl, C₃-C₈cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, amino, C₁-C₆alkylamino, C₁-C₆dialkylamino, —S(O)_0-2R′, hydroxy, hydroxyalkyl, halo, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, —NR′C(O)R″, —NR′SO₂R″, —C(O)R′, —C(O)OR′, —C(O)alkylOC(O)R′; —C(O)NR₁₀R₁₁, oxo, CN, or C₀-C₁alkylphenyl, where the phenyl is optionally substituted with 1-5 groups independently selected from halogen, C₁-C₆alkyl, —CO₂R′, C₁-C₆alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, NO₂, phenyloxy, —S(O)_0-2—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, and —SO₂NR₁₀R₁₁.

In yet another aspect, the invention provides compounds of Formula IV-1, i.e, compounds according to any one of Formulas IVa, IVb, IVc, IVd, IVe, IVf, or IVg, wherein the C₃-C₈cycloalkyl group is cyclopropyl.

In yet another aspect, the invention provides compounds of Formula IV-2, i.e, compounds according to any one of Formulas IVa, IVb, IVc, IVd, IVe, IVf, or IVg, wherein the C₃-C₈cycloalkyl group is cyclobutyl. In yet another aspect, the invention provides compounds of Formula IV-3, i.e, compounds according to any one of Formulas IVa, IVb, IVc, IVd, IVe, IVf, or IVg, wherein the C₃-C₈cycloalkyl group is cyclopentyl.

In yet another aspect, the invention provides compounds of Formula IV-4, i.e, compounds according to any one of Formulas IVa, IVb, IVc, IVd, IVe, IVf, or IVg, wherein the C₃-C₈cycloalkyl group is cyclohexyl.

In yet another aspect, the invention provides compounds of Formula IV-5, i.e, compounds according to any one of Formulas IVa, IVb, IVc, IVd, IVe, IVf, or IVg, wherein the C₃-C₈cycloalkyl group is cycloheptyl.

In yet another aspect, the invention provides compounds of Formula IV-6, i.e, compounds according to any one of Formulas IVa, IVb, IVc, IVd, IVe, IVf, or IVg, wherein the C₃-C₈cycloalkyl group is cyclooctyl.

In another aspect, the invention provides compounds of Formula V, i.e., compounds of Formula II, wherein the A-ring is heteroaryl that is pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, thienyl, furanyl, pyrrolyl, pyrazolyl, or imidazolyl, each of which is optionally substituted at one or more substitutable positions with halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, CN, phenyloxy, —S(O)_0-2—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, C₀-C₃alkylCO₂R′, pyridyl, thienyl, furanyl, pyrrolyl, pyrrolidinyl, piperidinyl, piperazinyl, phenyl, phenyl C₁-C₄alkyl or —SO₂NR₁₀R₁₁.

In another aspect, the invention provides compounds of Formulas Va, Vb or Vc, i.e. compounds of Formula V having the following structures:

wherein,

the B-ring is a heteroaryl or heterocycloalkyl ring, each of which is optionally substituted at a substitutable position with a group that is independently C₁-C₆alkyl, C₃-C₈cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, amino, C₁-C₆alkylamino, C₁-C₆dialkylamino, —S(O)_0-2R′, hydroxy, hydroxyalkyl, halo, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, —NR′C(O)R″, —NR′SO₂R″, —C(O)R′, —C(O)OR′, —C(O)alkylOC(O)R′; —C(O)NR₁₀R₁₁, oxo, CN, or C₀-C₁alkylphenyl, where the phenyl is optionally substituted with 1-5 groups independently selected from halogen, C₁-C₆alkyl, —CO₂R′, C₁-C₆alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, NO₂, phenyloxy, —S(O)_0-2—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, phenyl, and —SO₂NR₁₀R₁₁; and

the [3.2.1] ring system is optionally substituted with 1, 2, 3, or 4 groups that are independently oxo, halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C_l-C₆haloalkyl, C₂-C₆alkynyl, hydroxy, hydroxyalkyl, C₁-C₆alkoxy, haloalkoxy, —(O)OR₁₃, —(C₁-C₄alkyl)—(O)OR₁₃, —CONR₁₀R₁₁, —OC(O)NR₁₀R₁₁, —NR′C(O)OR″, —NR′S(O)₂R″, —OS(O)₂R″, —NR′C(O)R″, CN, ═N—NR₁₂, or ═N—O—R₁₃and additionally, two adjacent carbons (not including the bridegehead carbons) may combine to form a cycloalkyl ring that may optionally be substituted with halogen, C₁-C₆alkyl or haloalkyl.

In yet another aspect, the invention provides compounds of Formula Vd, Ve or Vf, i.e. compounds of Formula V wherein one of the carbons in the [3.2.1] ring system is replaced with an —O—, —S(O)_0-2—, or —NR₁₅— group,

with the following structures:

wherein,

the [3.2.1] ring system is optionally substituted with 11, 2, 3, or 4 groups that are independently oxo, halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl, C₂-C₆alkynyl, hydroxy, hydroxyalkyl, C₁-C₆alkoxy, haloalkoxy, —(O)OR₁₃, —(C₁-C₄alkyl)-C(O)OR₁₃, —CONR₁₀R₁₁, —OC(O)NR₁₀R₁₁, —NR′C(O)OR″, —NR′S(O)₂R″, —OS(O)₂R″, —NR′C(O)R″, CN, ═N—NR₁₂, or ═N—O—R₁₃and additionally, two adjacent carbons (not including the bridegehead carbons) may combine to form a cycloalkyl ring that may optionally be substituted with halogen, C₁-C₆alkyl or haloalkyl; and

R₁₅is H, phenyl, pyridyl, pyrimidinyl, oxazolyl, thienyl, furanyl, pyrrolyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, indolyl, —SO₂R′, —C(O)R′, —C(O)OR′, or C₁-C₆alkyl optionally substituted with phenyl, hydroxyl, or halogen, where the above cyclic groups are optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl (such as CF₃), C₁-C₄haloalkoxy (such as OCF₃), CN, amino, NH(C₁-C₆alkyl), N(C₁-C₆alkyl) (C₁-C₆alkyl), or NO₂.

In some aspects, the invention provides compounds of Formula Vg, i.e., compounds according to any one of Formulas Va, Vb, Vc, Vd, Ve or Vf wherein the B-ring is pyrazolyl, imidazolyl, pyrrolyl, triazolyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, triazolopyrimidinyl, imidazopyrimidinyl, pyrazolopyrimidinyl, or indolyl, or pyridyl, each of which is optionally substituted at a substitutable position with a group that is independently C₁-C₆alkyl, C₃-C₈cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, amino, C_l-C₆alkylamino, C₁-C₆dialkylamino, —S(O)_0-2R′, hydroxy, hydroxyalkyl, halo, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, —NR′C(O)R″, —NR′SO₂R″, —C(O)R′, —C(O)OR′, —C(O)alkylOC(O)R′; —C(O)NR₁₀R₁₁, oxo, CN, or C₀-C₁alkylphenyl, where the phenyl is optionally substituted with 1-5 groups independently selected from halogen, C₁-C₆alkyl, —CO₂R′, C₁-C₆alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, NO₂, phenyloxy, —S(O)_0-2—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, and —SO₂NR₁₀R₁₁.

In still another aspect, the invention provides compounds of Formula V-1, i.e, compounds according to any one of Formulas II, Va, Vb, Vc, Vd, Ve, Vf, or Vg, wherein the heteroaryl group is pyridyl, which is optionally substituted at one or more substitutable positions with groups that are independently halogen, C₁-C₆alkyl, C₁-C₆alkoxy, CF₃, OCF₃, hydroxyl, CN, phenyloxy, —SO₂—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, or —SO₂NR₁₀R₁₁, where each R₁₀and R₁₁is independently H or C₁-C₆alkyl. In some embodiments pyridyl is substituted with halogen, for example chloro.

In still another aspect, the invention provides compounds of Formula V-2, i.e, compounds according to any one of Formulas II, Va, Vb, Vc, Vd, Ve, Vf, or Vg, wherein the heteroaryl group is pyrimidyl, which is optionally substituted at one or more substitutable positions with groups that are independently halogen, C₁-C₆alkyl, C₁-C₆alkoxy, CF₃, OCF₃, hydroxyl, CN, phenyloxy, —SO₂—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, or —SO₂NR₁₀R₁₁, where each R₁₀and R₁₁is independently H or C₁-C₆alkyl. In some aspects pyrimidyl is substituted with halogen, for example chloro.

In still another aspect, the invention provides compounds of Formula V-3, i.e, compounds according to any one of Formulas II, Va, Vb, Vc, Vd, Ve, Vf, or Vg, wherein the heteroaryl group is pyridazinyl, which is optionally substituted at one or more substitutable positions with groups that are independently halogen, C₁-C₆alkyl, C₁-C₆alkoxy, CF₃, OCF₃, hydroxyl, CN, phenyloxy, —SO₂—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, or —SO₂NR₁₀R₁₁, where each R₁₀and R₁₁is independently H or C₁-C₆alkyl, In some aspects pyridazinyl is substituted with halogen, for example chloro.

In still another aspect, the invention provides compounds of Formula V-4, i.e, compounds according to any one of Formulas II, Va, Vb, Vc, Vd, Ve, Vf, or Vg, wherein the heteroaryl group is pyrazinyl, which is optionally substituted at one or more substitutable positions with groups that are independently halogen, C₁-C₆alkyl, C₁-C₆alkoxy, CF₃, OCF₃, hydroxyl, CN, phenyloxy, —SO₂—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, or —SO₂NR₁₀R₁₁, where each R₁₀and R₁₁is independently H or C₁-C₆alkyl. In some aspects pyrazinyl is substituted with halogen, for example chloro.

In still another aspect, the invention provides compounds of Formula V-5, i.e. compounds according to any one of Formulas II, Va, Vb, Vc, Vd, Ve, Vf, or Vg, wherein the heteroaryl group is thienyl, which is optionally substituted at one or more substitutable positions with groups that are independently halogen, C₁-C₆alkyl, C₁-C₆alkoxy, CF₃, OCF₃, hydroxyl, CN, phenyloxy, —SO₂—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, or —SO₂NR₁₀R₁₁, where each R₁₀and R₁₁is independently H or C₁-C₆alkyl, In some exemplary compounds the thienyl is substituted with halogen, for example chloro or bromo.

In still another aspect, the invention provides compounds of Formula V-6, i.e. compounds according to any one of Formulas II, Va, Vb, Vc, Vd, Ve, Vf, or Vg, wherein the heteroaryl group is furanyl, which is optionally substituted at one or more substitutable positions with groups that are independently halogen, C₁-C₆alkyl, C₁-C₆alkoxy, CF₃, OCF₃, hydroxyl, CN, phenyloxy, —SO₂—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, or —SO₂NR₁₀R₁₁, where each R₁₀and R₁₁is independently H or C₁-C₆alkyl In some aspects furanyl is substituted with halogen, for example chloro.

In another aspect, the invention provides compounds of Formula VI, Le., compounds of Formula II, wherein the A-ring is heterocycloalkyl that is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or thiomorpholinyl-S,S-dioxide, where each of the above rings is optionally substituted at a substitutable position with halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, CN, phenyloxy, —S(O)_0-2—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, C₀-C₃alkylCO₂R′, pyridyl, thienyl, furanyl, pyrrolyl, pyrrolidinyl, piperidinyl, piperazinyl, phenyl, phenyl C₁-C₄alkyl, or —SO₂NR₁₀R₁₁.

In another aspect, the invention provides compounds of Formulas VIa, VIb or VIc, i.e. compounds of Formula VI wherein no carbons in the [3.2.1] ring system are replaced with an —O—, —S(O)_0-2—, or —NR₁₅— group,

having the following structures:

wherein,

the B-ring is a heteroaryl or heterocycloalkyl ring, each of which is optionally substituted at a substitutable position with a group that is independently C₁-C₆alkyl, C₃-C₈cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, amino, C₁-C₆alkylamino, C₁-C₆dialkylamino, —S(O)_0-2R′, hydroxy, hydroxyalkyl, halo, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, —NR′C(O)R″, —NR′SO₂R″, —C(O)R′, —C(O)OR′, —C(O)alkylOC(O)R′; —C(O)NR₁₀R₁₁, oxo, CN, or C₀-C₁alkylphenyl, where the phenyl is optionally substituted with 1-5 groups independently selected from halogen, C₁-C₆alkyl, —CO₂K, C₁-C₆alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, NO₂, phenyloxy, —S(O)_0-2—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, and —SO₂NR₁₀R₁₁; and

in yet another aspect, the invention provides compounds of Formula VId, VIe or VIf, i.e. compounds of Formula VI wherein one of the carbons in the [3.2.1] ring system is replaced with an —O—, —S(O)_0-2—, or —NR₁₅— group,

In another aspect, the invention provides compounds of Formulas VId, VIe or VIf, i.e. compounds of Formula V having the following structures:

wherein,

the [3.2.1] ring system is optionally substituted with 1, 2, 3, or 4 groups that are independently oxo, halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl, C₂-C₆alkynyl, hydroxy, hydroxyalkyl, C₁-C₆alkoxy, haloalkoxy, —C(O)OR₁₃, —(C₁-C₄alkyl)-C(O)OR₁₃, —CONR₁₀R₁₁, —OC(O)NR₁₀R₁₁, —NR′C(O)OR″, —NR′S(O)₂R″, —OS(O)₂R″, —NR′C(O)R″, CN, ═N—NR₁₂, or ═N—O—R₁₃and additionally, two adjacent carbons (not including the bridegehead carbons) may combine to form a cycloalkyl ring that may optionally be substituted with halogen, C₁-C₆alkyl or haloalkyl; and

R₁₅is H, phenyl, pyridyl, pyrimidinyl, oxazolyl, thienyl, furanyl, pyrrolyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, indolyl, —SO₂R′, —C(O)R′, —C(O)OR′, or C₁-C₆alkyl optionally substituted with phenyl, hydroxyl, or halogen, where the above cyclic groups are optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl (such as CF₃), C₁-C₄haloalkoxy (such as OCF₃), CN, amino, NH(C₁-C₆alkyl), N(C₁-C₆alkyl) (C₁-C₆alkyl), or NO₂.

In some aspects, the invention provides compounds of Formula VIg, i.e., compounds according to any one of Formulas VIa, VIb, VIc, VId, VIe or VIf wherein the B-ring is pyrazolyl, imidazolyl, pyrrolyl, triazolyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, triazolopyrimidinyl, imidazopyrimidinyl, pyrazolopyrimidinyl, or indolyl, or pyridyl, each of which is optionally substituted at a substitutable position with a group that is independently C₁-C₆alkyl, C₃-C₅cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, amino, C₁-C₆alkylamino, C₁-C₆dialkylamino, —S(O)_0-2R′, hydroxy, hydroxyalkyl, halo, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, —NR′C(O)R″, —NR′SO₂R″, —C(O)R′, —C(O)OR′, —C(O)alkylOC(O)R′; —C(O)NR₁₀R₁₁, oxo, CN, or C₀-C₁alkylphenyl, where the phenyl is optionally substituted with 1-5 groups independently selected from halogen, C₁-C₆alkyl, —CO₂R′, C₁-C₆alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, NO₂, phenyloxy, —S(O)_0-2—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, and —SO₂NR₁₀R₁₁.

In another aspect, the invention provides compounds of Formula VI-1, i.e., compounds according to any one of Formulas VI, VIa, VIb, VIc, VId, VIe, VIf, or VIg, where the heterocycloalkyl group is pyrrolidinyl, which is optionally substituted at one or more substitutable positions with groups that are independently halogen, C₁-C₆alkyl, C₁-C₆alkoxy, CF₃, OCF₃, hydroxyl, CN, phenyloxy, —SO₂—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, or —SO₂NR₁₀R₁₁, where each R₁₀and R₁₁is independently H or C₁-C₆alkyl.

In another aspect, the invention provides compounds of Formula VI-2, i.e., compounds according to any one of Formulas VI, VIa, VIb, VIc, VId, VIe, VIf, or VIg, where the heterocycloalkyl group is piperidinyl, which is optionally substituted at one or more substitutable positions with groups that are independently halogen, C₁-C₆alkyl, C₁-C₆alkoxy, CF₃, OCF₃, hydroxyl, CN, phenyloxy, —SO₂—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, or —SO₂NR₁₀R₁₁, where each R₁₀and R₁₁is independently H or C₁-C₆alkyl.

In yet another aspect, the invention provides compounds of Formula VI-3, i.e., compounds according to any one of Formulas VI, VIa, VIb, VIc, VId, VIe, VIf, or VIg, where the heterocycloalkyl group is piperazinyl, which is optionally substituted at one or more substitutable positions with groups that are independently halogen, C₁-C₆alkyl, C₁-C₆alkoxy, CF₃, OCF₃, hydroxyl, CN, phenyloxy, —SO₂—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, or —SO₂NR₁₀R₁₁, where each R₁₀and R₁₁is independently H or C₁-C₆alkyl.

In still another aspect, the invention provides compounds of Formula VI-4, i.e., compounds according to any one of Formulas VI, VIa, VIb, VIc, VId, VIe, VIf, or VIg, where the heterocycloalkyl group is morpholinyl, which is optionally substituted at one or more substitutable positions with groups that are independently halogen, C₁-C₆alkyl, C₁-C₆alkoxy, CF₃, OCF₃, hydroxyl, CN, phenyloxy, —SO₂—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, or —SO₂NR₁₀R₁₁, where each R₁₀and R₁₁is independently H or C₁-C₆alkyl.

In another aspect, the invention provides compounds of Formula VI-5, i.e., compounds according to any one of Formulas VI, VIa, VIb, VIc, VId, VIe, VIf, or VIg, where the heterocycloalkyl group is thiomorpholinyl, which is optionally substituted at one or more substitutable positions with groups that are independently halogen, C₁-C₆alkyl, C₁-C₆alkoxy, CF₃, OCF₃, hydroxyl, CN, phenyloxy, —SO₂—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, or —SO₂NR₁₀R₁₁, where each R₁₀and R₁₁is independently H or C₁-C₆alkyl.

In another aspect, the invention provides compounds of Formula VI-6, i.e., compounds according to any one of Formulas VI, VIa, VIb, VIc, VId, VIe, VIf, or VIg, where the heterocycloalkyl group is thiomorpholinyl-S,S-dioxide, which is optionally substituted at one or more substitutable positions with groups that are independently halogen, C₁-C₆alkyl, C₁-C₆alkoxy, CF₃, OCF₃, hydroxyl, CN, phenyloxy, —SO₂—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, or —SO₂NR₁₀R₁₁, where each R₁₀and R₁₁is independently H or C₁-C₆alkyl.

In another aspect, the invention provides compounds of Formulas IIa or IIb, i.e., compounds of Formula II, with the structures:

including stereoisomers, tautomers and mixtures of steroisomers and/or tautomers, and/or pharmaceutical salts thereof, wherein

A is aryl, cycloalkyl, heteroaryl or heterocycloalkyl, where each ring is optionally substituted at a substitutable position with halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, CN, phenyloxy, —S(O)_0-2—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, C₀-C₃alkylCO₂R′, pyridyl, thienyl, furanyl, pyrrolyl, pyrrolidinyl, piperidinyl, piperazinyl, phenyl, phenyl C₁-C₄alkyl, or —SO₂NR₁₀R₁₁;

the bridged ring including the fused pyrazol ring is optionally substituted at a substitutable position with a group that is independently C₁-C₆alkyl, C₃-C₈, cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, amino, C₁-C₆alkylamino, C₁-C₆dialkylamino, —S(O)_0-2R′, hydroxy, hydroxyalkyl, halo, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, —NR′C(O)R″, —NR′SO₂R″, —C(O)R′, —C(O)OR′, —(C₁-C₄alkyl)-C(O)OR_13,—C(O)alkylOC(O)R′; —C(O)NR₁₀R₁₁, —OC(O)NR₁₀R_11,—NR′C(O)OR′, oxo, CN, or C₀-C₁alkylphenyl, where the phenyl is optionally substituted with 1-5 groups independently selected from halogen, C₁-C₆alkyl, —CO₂R′, C₁-C₆alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, NO₂, phenyloxy, —S(O)_0-2—(C₁-C₅alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, and —SO₂NR₁₀R₁₁;

R₁₀and R₁₁at each occurrence are independently H or C₁-C₆alkyl, where the alkyl is optionally substituted with an aryl, where the aryl is optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO₂; and R₁₀and R₁₁together may form a 3-8 membered ring optionally including an additional heteroatom such as N, O or S; and

R′ is hydrogen, C₁-C₆alkyl, haloalkyl, C₂-C₆alkenyl or phenyl optionally substituted with 1 to 5 groups that are independently halogen, C₁-C₆alkyl, —C(O)OR′, C₁-C₆alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, phenyloxy, —SO₂—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, NO₂, or —SO₂NR₁₀R₁₁.

In some aspects, the invention provides compounds of Formulas IIa or IIb where the A ring is aryl, for example phenyl optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO₂. In some exemplary compounds the ring is a phenyl ring optionally substituted with 1 to 5 groups that are halogen, such as chloro, bromo, iodo or fluoro.

In other aspects, the invention provides compounds of Formulas IIa or IIb where the A ring is heteroaryl, for example furanyl, thienyl or pyridyl, each of which is optionally substituted with 1 to 3 groups that are independently halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, CN or NO₂. In some exemplary compounds the ring is a thienyl ring optionally substituted with 1 to 2 groups that are halogen, such as chloro, or bromo.

In another aspect, the invention provides compounds of Formula VII, i.e., compounds of formula I, having the structure:

where

two adjacent carbons (not including the bridgehead carbons) in the ring system combine to form part of a fused heteroaryl or heterocycloalkyl ring, each of which is optionally substituted at a substitutable position with a group that is independently C₁-C₆alkyl, C₃-C₈cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, amino, C₁-C_talkylamino, C₁-C₆dialkylamino, —S(O)_0-2R′, —C₀-C₃alkyl-OH, halo, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, —NC(O)R′, —C(O)R′, —C(O)OR′, —C(O)alkylOC(O)R′, —C(O)NR₁₀R₁₁, oxo, CN, or C₀-C₁alkylphenyl, where the phenyl is optionally substituted with 1-5 groups independently selected from halogen, C₁-C₆alkyl, —CO₂R′, C₁-C₆alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, NO₂, phenyloxy, —S(O)_0-2—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, and —SO₂NR₁₀R₁₁;

0 or 1 of the carbons in the [3.3.1] ring system is optionally replaced with an —O—, —S(O)_0-2—, or —NR₁₅— group;

the [3.3.1] ring system is optionally substituted with 1, 2, 3, or 4 groups that are independently oxo, halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl, C₂-C₆alkynyl, hydroxy, hydroxyalkyl, C₁-C₆alkoxy, haloalkoxy, —(O)OR₁₃, —(C₁-C₄alkyl)-C(O)OR₁₃, —CONR₁₀R₁₁, —OC(O)NR₁₀R₁₁, —NR′C(O)OR″, —NR′S(O)₂R″, —OS(O)₂R″, —NR′C(O)R″, CN, ═N—NR₁₂, or ═N—O—R₁₃and additionally, two adjacent carbons (not including the bridegehead carbons) may combine to form a cycloalkyl ring that may optionally be substituted with halogen, C₁-C₆alkyl or haloalkyl;

R′ and R″ are independently of each other hydrogen, C₁-C₆alkyl, haloalkyl, C₂-C₆alkenyl or phenyl optionally substituted with 1 to 5 groups that are independently halogen, C₁-C₆alkyl, —C(O)OR′, C₁-C₆alkoxy, haloalkyl (such as CF₃), haloalkoxy (such as OCF₃), hydroxyl, CN, phenyloxy, —SO₂—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, NO₂, or —SO₂NR₁₀R₁₁; and

In another aspect, the invention provides compounds of formula VIII, i.e. compounds of formula VII, wherein the A-ring is phenyl or naphthyl (preferably phenyl) which is optionally substituted at a substitutable position with halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, CN, phenyloxy, —S(O)_0-2—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-06 alkanoyl, C₀-C₃alkylCO₂R′, pyridyl, thienyl, furanyl, pyrrolyl, pyrrolidinyl, piperidinyl, piperazinyl, phenyl, phenyl C₁-C₄alkyl, or —SO₂NR₁₀R₁₁.

In another aspect, the invention provides compounds of Formula VIIIa and VIIIb, i.e., compound of formula VIII, having the following structures:

wherein,

X is —C—, —CH—, —CH₂—, —O—, —S(O)_0-2—, or —NR₁₅—, where the —C— and —CH— groups are optionally substituted with 1 or 2 groups that are independently oxo (oxo can only be a substituent on —C—), halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl, C₂-C₆alkynyl, hydroxy, hydroxyalkyl, C₁-C₆alkoxy, haloalkoxy, —(O)OR₁₃, —(C₁-C₄alkyl)-C(O)OR₁₃, —CONR₁₀R₁₁, —OC(O)NR₁₀R₁₁, —NR′C(O)OR″, —NR′S(O)₂R″, —OS(O)₂R″, —NR′C(O)R″, CN, ═N—NR₁₂, or ═N—O—R₁₃:

the B-ring is a heteroaryl or heterocycloalkyl ring, each of which is optionally substituted at a substitutable position with a group that is independently C₁-C₆alkyl, C₃-C₈cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, amino, C₁-C₆alkylamino, C₁-C₆dialkylamino, —S(O)_0-2R′, hydroxy, hydroxyalkyl, halo, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, —NR′C(O)R″, —NR′SO₂R″, —C(O)R′, —C(O)OR′, —C(O)alkylOC(O)R′; —C(O)NR₁₀R₁₁, oxo, CN, or C₀-C₁alkylphenyl, where the phenyl is optionally substituted with 1-5 groups independently selected from halogen, C₁-C₅alkyl, —CO₂R′, C₁-C₆alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, NO₂, phenyloxy, —S(O)_0-2—(C₁-C₆alkyl), −NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, and —SO₂NR₁₀R₁₁;

the [3.3.1] ring system is optionally substituted with 1, 2, 3, or 4 groups that are independently oxo, halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl, C₂-C₆alkynyl, hydroxy, hydroxyalkyl, C₁-C₆alkoxy, haloalkoxy, —(O)OR₁₃, —(C₁-C₄alkyl)—(O)OR₁₃, —CONR₁₀R₁₁, —OC(O)NR₁₀R₁₁, —NR′C(O)OR′″, —NR′S(O)₂R″, —OS(O)₂R″, —NR′C(O)R″, CN, ═N—NR₁₂, or ═N—O—R₁₃and additionally, two adjacent carbons (not including the bridegehead carbons) may combine to form a cycloalkyl ring that may optionally be substituted with halogen, C₁-C₆alkyl or haloalkyl;

R₃, R₄, R₅, R₆, R₇are independently of each other H, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆haloalkoxy, CN, hydroxyl, C₁-C₆alkoxy, -C₁-C₃alkyl-OH, —C₁-C₃alkyl-alkoxy, phenyloxy, —SO₂R′, —NR₁₀R₁₁, C₁-C₆alkanoyl, oxazolyl, pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, imidazolyl, indolyl, furanyl, thienyl, phenyl, or phenyl C₁-C₄alkyl, or

R′ and R″ are independently of each other hydrogen, C₁-C₆alkyl, haloalkyl, C₂-C₆alkenyl or phenyl optionally substituted with 1 to 5 groups that are independently halogen, C₁-C₆alkyl, —C(O)OR′, C₁-C₆alkoxy, haloalkyl (such as CF₃), haloalkoxy (such as OCF₃), hydroxyl, CN, phenyloxy, —SO₂—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, NO₂, or —SO₂NR₁₀R₁₁; and

R₁₅is H, phenyl, pyridyl, pyrimidinyl, oxazolyl, thienyl, furanyl, pyrrolyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, indolyl, —SO₂R′, —C(O)R′, —C(O)OR′, or C₁-C₆alkyl optionally substituted with phenyl, hydroxyl, or halogen, where the above cyclic groups are optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl (such as CF₃), C₁-C₄haloalkoxy (such as OCF₃), CN, amino, NH(C₁-C₆alkyl), N(C₁-C₆alkyl) (C₁-C₆alkyl), or NO₂.

In some aspects, the invention provides compounds of Formula VIIIe or VIIId, i.e., compounds of formula VIII having the following structures:

where X is —CH₂— and R₃, R₄, R₅, R_s, R₇and the B-ring are as defined for Formulas VIIIa and VIIIb.

In another aspect, the invention provides compounds of Formula VIIIe or VIIIf, i.e., compounds of formula VIII having the following structures:

where X is —O—. and R₃, R₄, R₅, R₆, R₇and the B-ring are as defined for Formulas VIIIa and VIIIb.

In still another aspect, the invention provides compounds of Formula VIIIg or VIIIh, i.e., compounds of formula VIII having the following structures:

where X is —S(O)_0-2—. and R₃, R₄, R₅, R₆, R₇and the B-ring are as defined for Formulas VIIIa and VIIIb.

In still another aspect, the invention provides compounds of Formula VIIIm or VIIIn, i.e., compounds of formula VIII having the following structures:

where X is —NR₁₅—, and R₃, R₄, R₅, R_s, R₇and the B-ring are as defined for Formulas VIIIa and VIIIb.

In some aspects, the invention provides compounds of Formula VIIIo, i.e., compounds according to any one of Formulas VIII, VIIIa, VIIIb, VIIIc, VIIId, VIIIe, VIIIf, VIIIg, VIIIm, or VIIIn wherein the B-ring is pyrazolyl, imidazolyl, pyrrolyl, triazolyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, triazolopyrimidinyl, imidazopyrimidinyl, pyrazolopyrimidinyl, or indolyl or pyridyl, each of which is optionally substituted at a substitutable position with a group that is independently C₁-C₆alkyl, C₃-C₈cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, amino, C₁-C₆alkylamino, C₁-C₆dialkylamino, —S(O)_0-2R′, hydroxy, hydroxyalkyl, halo, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, —NR′C(O)R″, —NR′SO₂R″, —C(O)R′, —C(O)OR′, —C(O)alkylOC(O)R′; —C(ONR₁₀R₁₁, oxo, CN, or C₀-C₁alkylphenyl, where the phenyl is optionally substituted with 1-5 groups independently selected from halogen, C₁-C₆alkyl, —CO₂R′, C₁-C₆alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, NO₂, phenyloxy, —S(O)_0-2—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, and —SO₂NR₁₀R₁₁.

In other aspects, the invention provides compounds according to any one of Formulas VIII, or VIIIa-VIIIo, wherein

R₃is H, halogen, C₁-C₆alkyl, C₁-C₆alkoxy, haloalkyl, or CN;

R₄is H, halogen, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, haloalkoxy, CN, phenyloxy, —SO₂—(C₁-C₆alkyl), —R₁₀R₁₁, C₁-C₆alkanoyl, oxazolyl, pyrazolyl, thiazolyl, pyridyl, furanyl, thienyl, or phenyl; and

R_3′ is H, C₁-C₆alkyl —SO₂NR₁₀R₁₁or halogen.

In other aspects, the invention provides compounds according to any one of Formulas VIII, or VIIIa-VIIIo, wherein R₆and R₇are independently H or methyl.

In other aspects, the invention provides compounds according to any one of Formulas VIII, or VIIIa-VIIIo, wherein R₃and R₅are independently H, halo, or methyl.

In other aspects, the invention provides compounds according to any one of Formulas VIII, or VIIIa-VIIIo, wherein R₄is H, halogen (in one aspect, I, Br, F or Cl), C₁-C₆alkyl optionally substituted with halogen or hydroxy, C₁-C₆alkoxy, CF₃, OCF₃, or CN.

In other aspects, the invention provides compounds according to any one of Formulas VIII, or VIIIa-VIIIo, wherein R₄is phenyloxy, —SO₂—(C₁-C₅alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, oxazolyl, pyrazolyl, thiazolyl, pyridyl, furanyl, thienyl, or phenyl.

In other aspects, the invention provides compounds according to any one of Formulas VIII, or VIIIa-VIIIo, wherein R₄is —NR₁₀R₁₁.

In other aspects, the invention provides compounds according to any one of Formulas VIII, or VIIIa-VIIIo, wherein R₄is —NR₁₀R₁₁, and R₃, R₅, R₆, and R₇are H.

In other aspects, the invention provides compounds according to any one of Formulas VIII, or VIIIa-VIIIo wherein R₃, R₄, R₅, R₆, and R₇are H, halo, CF₃, CHF₂or methyl

In other aspects, the invention provides compounds according to any one of Formulas VIII, or VIIIa-VIIIo, wherein R₃, R_5′, R₆, and R₇are H.

In other aspects, the invention provides compounds according to any one of Formulas VIII, or VIIIa-VIIIo, wherein R₄is chloro.

In other aspects, the invention provides compounds according to any one of Formulas VIII, or VIIIa-VIIIo, wherein R₄is chloro, and R₃, R₅, R₆, and R₇are H.

In another aspect, the invention provides compounds of Formulas VIII, or VIIIa-VIIIo, wherein at least one of R₃, R₄, or R₅is chloro, and R₆and R₇are H.

In yet still another aspect, the invention provides compounds of Formulas VIII, or VIIIa-VIIIo, wherein R₃, R₅, R₆, and R₇are H.

In still another aspect, the invention provides compounds of Formulas VIII, or VIIIa-VIIIo, wherein R₄is chloro.

In yet still another aspect, the invention provides compounds of Formulas VIII, or VIIIa-VIIIo, wherein R₄is chloro, and R₃, R₅, R₆, and R₇are H.

In another aspect, the invention provides compounds of Formulas VIII, or VIIIa-VIIIo, wherein at least one of R₃, R₄, or R₅is chloro, and R₆and R₇are H.

In another aspect, the invention provides compounds of Formulas VIII, or VIIIa-VIIIo, wherein R₃is hydrogen, halogen, C₁-C₄alkyl, C₁-C₄alkoxy, CF₃, or CN;

R₄is hydrogen, halogen, C₁-C₄alkyl, C₁-C₄alkyl, CF₃, OCF₃, CN, phenyloxy, —SO₂—(C₁-C₄alkyl), —NR₁₀R₁₁, C₁-C₄alkanoyl, and

R₅is hydrogen, C₁-C₄alkyl, —SO₂NR₁₀R₁₁or halogen.

In still yet another aspect, the invention provides compounds of Formulas VIII, or VIIIa-VIIIo, wherein R₄is halogen (in one aspect, F or Cl), C₁-C₄alkyl, C₁-C₄alkoxy, CF₃, OCF₃, or CN.

In another aspect, the invention provides compounds of Formulas VIII, or VIIIa-VIIIo, wherein R₄, R₅R₆, and R₇are hydrogen.

In another aspect, the invention provides compounds of Formulas VIII, or VIIIa-VIIIo, wherein R₃is hydrogen, halogen, C₁-C₄alkyl, C₁-C₄alkoxy, CF₃, or CN;

R₄is oxazolyl, pyrazolyl, thiazolyl, pyridyl, furanyl, thienyl, or phenyl; and

R₅is hydrogen, C₁-C₄alkyl, —SO₂NR₁₀R₁₁, or halogen.

In still yet another aspect, the invention provides compounds of Formulas VIII, or VIIIa-VIIIo, wherein R₄is halogen (in one aspect, F or Cl), CH₃, OCH₃, CF₃, or OCF₃.

In another aspect, the invention provides compounds of Formulas VIII, or VIIIa-VIIIo, wherein R₃is hydrogen, halogen, C₁^-C₂alkyl, C₁-C₂alkoxy, CF₃, or CN;

R₄is hydrogen, halogen, C₁-C₂alkyl, C₁-C₂alkoxy, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, CN, —NR₁₀R₁₁, C₂-C₃alkanoyl, oxazolyl, pyrazolyl, thiazolyl, pyridyl, furanyl, or thienyl;

R₅is hydrogen. CH₃, or F; and

R₆and R₇are independently hydrogen or halogen.

In still yet another aspect, the invention provides compounds of Formulas VIII, or VIIIa-VIIIo, wherein R₄is CF₃, or OCF₃.

In yet another aspect, the invention provides compounds of Formulas VIII, or VIIIa-VIIIo, wherein R₄and R₅, or R₅and R₆and the carbons to which they are attached form a benzo ring which is optionally substituted with optionally substituted with 1 or 2 groups that are independently halogen, hydroxyl, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₃haloalkyl, C₁-C₃haloalkoxy, CN or NO₂.

In still yet another aspect, the invention provides compounds of Formulas VIII, or VIIIa-VIIIo, wherein R₄and R₅, or R₅and R₆and the carbons to which they are attached form a pyridyl, pyrrolyl, thienyl, furanyl, pyrrolidinyl, piperidinyl ring, each of 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 (such as F).

In one aspect, the invention provides compounds of Formulas VIII, or VIIIa-VIIIo, wherein R₆and R₇are independently hydrogen or methyl.

In one aspect, the invention provides compounds of Formulas VIII, or VIIIa-VIIIo, wherein R₃and R₅are independently hydrogen, halo, or methyl.

In another aspect, the invention provides compounds of Formula IX, i.e., compounds of Formula VII, wherein the A-ring is C₃-C₈cycloalkyl, which is optionally substituted at a substitutable position with halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, CN, phenyloxy, —S(O)_0-2—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, C₀-C₃alkylCO₂R′, pyridyl, thienyl, furanyl, pyrrolyl, pyrrolidinyl, piperidinyl, piperazinyl, phenyl, phenyl C₁-C₄alkyl, or —SO₂NR₁₀R₁₁.

In yet another aspect, the invention provides compounds of Formula IXa or IXb, i.e. compounds of Formula IX having the following structures:

wherein

X is —C—, —CH—, —CH₂—, —O—, —S(O)_0-2—, or —NR₁₅—, where the —C— and —CH— groups are optionally substituted with 1 or 2 groups that are independently oxo (oxo can only be a substituent on —C—), halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl, C₂-C₆alkynyl, hydroxy, hydroxyalkyl, C₁-C₆alkoxy, haloalkoxy, —(O)OR₁₃, —(C₁-C₄alkyl)—(O)OR₁₃, —CONR₁₀R₁₁, —OC(O)NR₁₀R₁₁, —NR′C(O)OR″, —NR′S(O)₂R″, —OS(O)₂R″, —NR′C(O)R″, CN, ═N—NR₁₂, or ═N—O—R₁₃;

the B-ring is a heteroaryl or heterocycloalkyl ring, each of which is optionally substituted at a substitutable position with a group that is independently is independently C₁-C₆alkyl, C₃-C₈cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, amino, C₁-C₆alkylamino, C₁-C₆dialkylamino, —S(O)_0-2R′, hydroxy, hydroxyalkyl, halo, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, —NR′C(O)R″, —NR′SO₂R″, —C(O)R′, —C(O)OR′, —C(O)alkylOC(O)R′; —C(O)NR₁₀R₁₁, oxo, CN, or C₀-C₁alkylphenyl, where the phenyl is optionally substituted with 1-5 groups independently selected from halogen, C₁-C₆alkyl, —CO₂R′, C₁-C₆alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, NO₂, phenyloxy, —S(O)_0-2—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, and —SO₂NR₁₀R₁₁;

R₁₅is H, phenyl, pyridyl, pyrimidinyl, oxazolyl, thienyl, furanyl, pyrrolyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, indolyl, —SO₂R′, —C(O)R′, —C(O)OR′, or C₁-C₆alkyl optionally substituted with phenyl, hydroxyl, or halogen, where the above cyclic groups are optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl (such as CF₃), C₁-C₄haloalkoxy (such as OCF₃), CN, amino, NH(C₁-C₆alkyl), N(C₁-C₆alkyl) (C₁-C₆alkyl), or NO₂.

In yet another aspect, the invention provides compounds of Formula IXa or IXb, wherein X is NR₁₅.

In yet another aspect, the invention provides compounds of Formula IXa or IXb, wherein X is NR₁₅where R₁₅is H, —SO₂R′, —C(O)R′, or C₁-C₆alkyl, and R′ is C₁-C₆alkyl, haloalkyl, or phenyl optionally substituted with 1 to 3 groups that are independently halogen, C₁-C₆alkyl, —C(O)OR′, C₁-C₆alkoxy, haloalkyl (such as CF₃), haloalkoxy (such as OCF₃), hydroxyl, CN, or NO₂.

In still another aspect, the invention provides compounds of Formula IXa or IXb, wherein X is O.

In another aspect, the invention provides compounds of Formula IXa or IXb, wherein X is —S(O)_0-2—.

In another aspect, the invention provides compounds of Formula IXa or IXb, wherein X is —C—, —CH—, —CH₂—, where the —C— and —CH— groups are optionally substituted with 1 or 2 groups that are independently oxo (oxo can only be a substituent on —C—), halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl, C₂-C₆alkynyl, hydroxy, hydroxyalkyl, C₁-C₆alkoxy, haloalkoxy, —(O)OR₁₃, —(C₁-C₄alkyl)—(O)OR₁₃, —CONR₁₀R₁₁, —OC(O)NR₁₀R₁₁, —NR′C(O)OR″, —NR′S(O)₂R″, —OS(O)₂R″, —NR′C(O)R″, CN, ═N—NR₁₂, or ═N—O—R₁₃.

In some aspects, the invention provides compounds of Formula IXc, i.e., compounds according to any one of Formulas IX, IXa, or IXb, wherein the B-ring is pyrazolyl, imidazolyl, pyrrolyl, triazolyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, triazolopyrimidinyl, imidazopyrimidinyl, pyrazolopyrimidinyl, indolyl, or pyridyl, each of which is optionally substituted at a substitutable position with a group that is independently C₁-C₅alkyl, C₃-C₈cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, amino, C₁-C₆alkylamino, C₁-C₆dialkylamino, —S(O)_0-2R′, hydroxy, hydroxyalkyl, halo, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, —NR′C(O)R″, —NR′SO₂R″, —C(O)R′, —C(O)OR′, —C(O)alkylOC(O)R′; —C(O)NR₁₀R₁₁, oxo, CN, or C₀-C₁alkylphenyl, where the phenyl is optionally substituted with 1-5 groups independently selected from halogen, C₁-C₆alkyl, —CO₂R′, C₁-C₆alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, NO₂, phenyloxy, —S(O)_0-2—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, and —SO₂NR₁₀R₁₁.

In yet still another aspect, the invention provides compounds of Formula IX-1, i.e., compounds according to any one of Formulas IXa, IXb, or IXc where the B-ring is defined as above and where the C₃-C₈cycloalkyl group is cyclopropyl.

In yet still another aspect, the invention provides compounds of Formula IX-2, i.e., compounds according to any one of Formulas IXa, IXb, or IXc where the B-ring is defined as above and where the C₃-C₈cycloalkyl group is cyclobutyl.

In yet still another aspect, the invention provides compounds of Formula IX-3, i.e., compounds according to any one of Formulas IXa, IXb, or IXc where the B-ring is defined as above and where the C₃-C₈cycloalkyl group is cyclopentyl.

In yet still another aspect, the invention provides compounds of Formula IX-4, i.e., compounds according to any one of Formulas IXa, IXb, or IXc where the B-ring is defined as above and where the C₃-C₈cycloalkyl group is cyclohexyl.

In yet still another aspect, the invention provides compounds of Formula IX-5, i.e., compounds according to any one of Formulas IXa, IXb, or IXc where the B-ring is defined as above and where the C₃-C₈cycloalkyl group is cycloheptyl. In yet still another aspect, the invention provides compounds of Formula IX-6, i.e., compounds according to any one of Formulas IXa, IXb, or IXc where the B-ring is defined as above and where the C₃-C₈cycloalkyl group is cyclooctyl.

In another aspect, the invention provides compounds of Formula X, i.e., compounds of Formula VII, where the A-ring is heteroaryl that is pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, thienyl, furanyl, pyrrolyl, pyrazolyl, or imidazolyl, each of which is optionally substituted at one or more substitutable positions with groups that are independently halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, CN, phenyloxy, —S(O)_0-2—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, C₀-C₃alkylCO₂R′, pyridyl, thienyl, furanyl, pyrrolyl, pyrrolidinyl, piperidinyl, piperazinyl, phenyl, phenyl C₁-C₄alkyl, or —SO₂NR₁₀R₁₁.

In another aspect, the invention provides compounds of Formula Xa or Xb, i.e., compounds of Formula X, having the following structures:

wherein,

X is —C—, —CH—, —CH₂—, —O—, —S(O)_0-2—, or —NR₁₅—, where the —C— and —CH— groups are optionally substituted with 1 or 2 groups that are independently oxo (oxo can only be a substituent on —C—), halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl, C₂-C₆alkynyl, hydroxy, hydroxyalkyl, C₁-C₆alkoxy, haloalkoxy, —(O)OR₁₃, —(C₁-C₄alkyl)—(O)OR₁₃, —CONR₁₀R₁₁, —OC(O)NR₁₀R₁₁, —NR′C(O)OR″, —NR′S(O)₂R″, —OS(O)₂R″, —NR′C(O)R″, CN, ═N—NR₁₂, or ═N—O—R₁₃;

the B-ring is a heteroaryl or heterocycloalkyl ring, each of which is optionally substituted at a substitutable position with a group that is independently C₁-C₆alkyl, C₃-C₈cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, amino, C₁-C₆alkylamino, C₁-C₆dialkylamino, —S(O)_0-2—R′, hydroxy, hydroxyalkyl, halo, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, —NR′C(O)R″, —NR′SO₂R″, —C(O)R′, —C(O)OR′, —C(O)alkylOC(O)R′; —C(O)NR₁₀R₁₁, oxo, CN, or C₀-C₁alkylphenyl, where the phenyl is optionally substituted with 1-5 groups independently selected from halogen, C₁-C₆alkyl, —CO₂R′, C₁-C₆alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, NO₂, phenyloxy, —S(O)_0-2—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, and —SO₂NR₁₀R₁₁;

R₁₅is H, phenyl, pyridyl, pyrimidinyl, oxazolyl, thienyl, furanyl, pyrrolyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, indolyl, —SO₂R′, —C(O)R′, —C(O)OR′, or C₁-C₆alkyl optionally substituted with phenyl, hydroxyl, or halogen, where the above cyclic groups are optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl (such as CF₃), C₁-C₄haloalkoxy (such as OCF₃), CN, amino, NH(C₁-C₆alkyl), N(C₁-C₆alkyl) (C₁-C₆alkyl), or NO₂.

In yet another aspect, the invention provides compounds of Formula Xa or Xb, wherein X is NR₁₅.

In yet another aspect, the invention provides compounds of Formula Xa or Xb, wherein X is NR₁₅where R₁₅is H, —SO₂R′, —C(O)R′, or C₁-C₆alkyl, and R′ is C₁-C₆alkyl, haloalkyl, or phenyl optionally substituted with 1 to 3 groups that are independently halogen, C₁-C₆alkyl, —C(O)OR′, C₁-C₆alkoxy, haloalkyl (such as CF₃), haloalkoxy (such as OCF₃), hydroxyl, CN, or NO₂. In still another aspect, the invention provides compounds of Formula Xa or Xb, wherein X is O.

In another aspect, the invention provides compounds of Formula Xa or Xb, wherein X is —S(O)_0-2.

In another aspect, the invention provides compounds of Formula Xa or Xb, wherein X is —C—, —CH—, —CH₂—, where the —C— and —CH— groups are optionally substituted with 1 or 2 groups that are independently oxo (oxo can only be a substituent on —C—), halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl, C₂-C₆alkynyl, hydroxy, hydroxyalkyl, C₁-C₆alkoxy, haloalkoxy, —C(O)OR₁₃, —(C₁-C₄alkyl)-C(O)OR₁₃, —CONR₁₀R₁₁, —OC(O)NR₁₀R₁₁, —NR′C(O)OR″, —NR′S(O)₂R″, —OS(O)₂R″, —NR′C(O)R″, CN, ═N—NR₁₂, or ═N—O—R₁₃.

In some aspects, the invention provides compounds of Formula Xc, i.e., compounds according to any one of Formulas Xa, or Xb, wherein the B-ring is pyrazolyl, imidazolyl, pyrrolyl, triazolyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, triazolopyrimidinyl, imidazopyrimidinyl, pyrazolopyrimidinyl, indolyl, or pyridyl, each of which is optionally substituted at a substitutable position with a group that is independently C₁-C₆alkyl, C₃-C₈cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, amino, C₁-C₆alkylamino, C₁-C₆dialkylamino, —S(O)_0-2R′, hydroxy, hydroxyalkyl, halo, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, —NR′C(O)R″, —NR′SO₂R″, —C(O)R′, —(O)OR′, —C(O)alkylOC(O)R′; —C(O)NR₁₀R₁₁, oxo, CN, or C₀-C₁alkylphenyl, where the phenyl is optionally substituted with 1-5 groups independently selected from halogen, C₁-C₆alkyl, —CO₂R′, C₁-C₆alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, NO₂, phenyloxy, —S(O)_0-2—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, and —SO₂NR₁₀R₁₁.

In another aspect, the invention provides compounds of Formula X-1, i.e, compounds according to any one of Formulas Xa, Xb, or Xc, where the B-ring is as defined above and the heteroaryl group is pyridyl, which is optionally substituted at one or more substitutable positions with groups that are independently halogen, C₁-C₆alkyl, C₁-C₆alkoxy, CF₃, OCF₃, hydroxyl, CN, phenyloxy, —SO₂-(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, or —SO₂—NR₁₀R₁₁where each R₁₀and R₁₁is independently H or C₁-C₆alkyl. In some exemplary compounds the pyridyl is substituted with halogen, for example chloro.

In another aspect, the invention provides compounds of Formula X-2, i.e, compounds according to any one of Formulas Xa, Xb, or Xc, where the B-ring is as defined above and the heteroaryl group is pyrimidyl, which is optionally substituted at one or more substitutable positions with groups that are independently halogen, C₁-C₆alkyl, C₁-C₆alkoxy, CF₃, OCF₃, hydroxyl, CN, phenyloxy, —SO₂—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, or —SO₂NR₁₀R₁₁, where each R₁₀and R₁₁is independently H or C₁-C₆alkyl.

In yet another aspect, the invention provides compounds of Formula X-3, i.e, compounds according to any one of Formulas Xa, Xb, or Xc, where the B-ring is as defined above and the heteroaryl group is pyridazinyl, which is optionally substituted at one or more substitutable positions with groups that are independently halogen, C₁-C₆alkyl, C₁-C₆alkoxy, CF₃, OCF₃, hydroxyl, CN, phenyloxy, —SO₂—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, or —SO₂NR₁₀R₁₁, where each R₁₀and R₁₁is independently H or C₁-C₆alkyl.

In still another aspect, the invention provides compounds of Formula X-4, i.e, compounds according to any one of Formulas Xa, Xb, or Xc, where the B-ring is as defined above and the heteroaryl group is pyrazinyl, which is optionally substituted at one or more substitutable positions with groups that are independently halogen, C₁-C₆alkyl, C₁-C₆alkoxy, CF₃, OCF₃, hydroxyl, CN, phenyloxy, —SO₂—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, or —SO₂NR₁₀R₁₁, where each R₁₀and R₁₁is independently H or C₁-C₆alkyl.

In another aspect, the invention provides compounds of Formula X-5, i.e, compounds according to any one of Formulas Xa, Xb, or Xc, where the B-ring is as defined above and the heteroaryl group is thienyl, which is optionally substituted at one or more substitutable positions with groups that are independently halogen, C₁-C₆alkyl, C₁-C₆alkoxy, CF₃, OCF₃, hydroxyl, CN, phenyloxy, —SO₂—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, or —SO₂NR₁₀R₁₁, where each R₁₀and R₁₁is independently H or C₁-C₆alkyl. In some exemplary compounds the thienyl is substituted with halogen, for example chloro. In yet still another aspect, the invention provides compounds of Formula X-6, i.e, compounds according to any one of Formulas Xa, Xb, or Xc, where the B-ring is as defined above and the heteroaryl group is furanyl, which is optionally substituted at one or more substitutable positions with groups that are independently halogen, C₁-C₆alkyl, C₁-C₆alkoxy, CF₃, OCF₃, hydroxyl, CN, phenyloxy, —SO₂—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, or —SO₂NR₁₀R₁₁, where each R₁₀and R₁₁is independently H or C₁-C₆alkyl.

In another aspect, the invention provides compounds of Formula XI, i.e., compounds of Formula VII where the A-ring is heterocycloalkyl that is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or thiomorpholinyl-S,S-dioxide, where each of the above rings is optionally substituted at a substitutable position with halogen, C₁-C₆alkyl, C_z-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, CN, phenyloxy, —S(O)_0-2-(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, C₀-C₃alkylCO₂R′, pyridyl, thienyl, furanyl, pyrrolyl, pyrrolidinyl, piperidinyl, piperazinyl, phenyl, phenyl C₁-C₄alkyl, or —SO₂NR₁₀R₁₁.

In another aspect, the invention provides compounds of Formula XIa and XIb i.e., compounds of formula XI having the following structures:

where

X is —C—, —CH—, —CH₂—, —O—, S(O)_0-2—, or —N₁₅—, where the —C— and —CH— groups are substituted with 1 or 2 groups that are independently oxo (oxo can only be a substituent on —C—), halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl, C₂-C₆alkynyl, hydroxy, hydroxyalkyl, C₁-C₆alkoxy, haloalkoxy, —(O)OR₁₃, —(C₁-C₄alkyl)—(O)OR₁₃, —CONR₁₀R₁₁, —OC(O)NR₁₀R₁₁, —NR′C(O)OR″, —NR′S(O)₂R″, —OS(O)₂R″, —NR′C(O)R″, CN, ═N—NR₁₂, or ═N—O—R₁₃;

the B-ring is a heteroaryl or heterocycloalkyl ring, each of which is optionally substituted at a substitutable position with a group that is independently C₁-C₈alkyl, C₃-C₈cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₈alkoxy, amino, C₁-C₈alkylamino, C₁-C₆dialkylamino, —S(O)_0-2R′, hydroxy, hydroxyalkyl, halo, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, —NR′C(O)R″, —NR′SO₂R″, —C(O)R′, —C(O)OR′, —C(O)alkylOC(O)R′; —C(O)NR₁₀R₁₁, oxo, CN, or C₀-C₁alkylphenyl, where the phenyl is optionally substituted with 1-5 groups independently selected from halogen, C₁-C₆alkyl, —CO₂R′, C₁-C₆alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, NO₂, phenyloxy, —S(O)_0-2—(C₁-C₈alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, and —SO₂NR₁₀R₁₁; and

R₁₅is H, phenyl, pyridyl, pyrimidinyl, oxazolyl, thienyl, furanyl, pyrrolyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, indolyl, —SO₂R′, —C(O)R′, —C(O)OR′, or C₁-C₆alkyl optionally substituted with phenyl, hydroxyl, or halogen, where the above cyclic groups are optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl (such as CF₃), C₁-C₄haloalkoxy (such as OCF₃), CN, amino, NH(C₁-C₆alkyl), N(C₁-C₆alkyl) (C₁-C₆alkyl), or NO₂.

In yet another aspect, the invention provides compounds of Formula XIa or XIb, wherein X is NR₁₅.

In yet another aspect, the invention provides compounds of Formula XIa or XIb, wherein X is NR₁₅where R₁₅is H, —SO₂R′, —C(O)R′, or C₁-C₆alkyl, and R′ is C₁-C₆alkyl, haloalkyl, or phenyl optionally substituted with 1 to 3 groups that are independently halogen, C₁-C₆alkyl, —C(O)OR′, C₁-C₈alkoxy, haloalkyl (such as CF₃), haloalkoxy (such as OCF₃), hydroxyl, CN, or NO₂.

In still another aspect, the invention provides compounds of Formula XIa or XIb, wherein X is O.

In another aspect, the invention provides compounds of Formula XIa or XIb, wherein X is —S(O)_0-2—.

In another aspect, the invention provides compounds of Formula XIa or XIb, wherein X is —C—, —CH—, —CH₂—, where the —C— and —CH— groups are optionally substituted with 1 or 2 groups that are independently oxo (oxo can only be a substituent on —C—), halogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆haloalkyl, C₂-C₆alkynyl, hydroxy, hydroxyalkyl, C₁-C₆alkoxy, haloalkoxy, —C(O)OR₁₃, —(C₁-C₄alkyl)—(O)OR₁₃, —CONR₁₀R₁₁, —OC(O)NR₁₀R₁₁, —NR′C(O)OR″, —NR′S(O)₂R″, —OS(O)₂R″, —NR′C(O)R″, CN, ═N—NR₁₂, or ═N—O—R₁₃.

In some aspects, the invention provides compounds of Formula XIc, i.e., compounds according to any one of Formulas XIa or XIb, wherein the B-ring is pyrazolyl, imidazolyl, pyrrolyl, triazolyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, triazolopyrimidinyl, imidazopyrimidinyl, pyrazolopyrimidinyl, or pyridyl, each of which is optionally substituted at a substitutable position with a group that is independently C₁-C₆alkyl, C₃-C₈cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, amino, C₁-C₆alkylamino, C₁-C₆dialkylamino, —S(O)R_0-2R′, hydroxy, hydroxyalkyl, halo, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, —NR′C(O)R″, —NR′SO₂R″, —C(O)R′, —C(O)OR′, —C(O)alkylOC(O)R′; —C(O)NR₁₀R₁₁, oxo, CN, or C₀-C₁alkylphenyl, where the phenyl is optionally substituted with 1-5 groups independently selected from halogen, C₁-C₆alkyl, —CO₂R′, C₁-C₆alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, NO₂, phenyloxy, —S(O)_0-2—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, and —SO₂NR₁₀R₁₁.

In another aspect, the invention provides compounds of Formula XI-1, i.e., compounds according to any one of Formulas XIa, XIb, or XIc, where the heterocycloalkyl group is pyrrolidinyl, which is optionally substituted at one or more substitutable positions with groups that are independently halogen, C₁-C₆alkyl, C₁-C₆alkoxy, CF₃, OCF₃, hydroxyl, CN, phenyloxy, —SO₂—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, or —SO₂NR₁₀R₁₁, where each R₁₀and R₁₁is independently H or C₁-C₆alkyl.

In another aspect, the invention provides compounds of Formula XI-2, i.e., compounds according to any one of Formulas XIa, XIb, or XIc, where the heterocycloalkyl group is piperidinyl, which is optionally substituted at one or more substitutable positions with groups that are independently halogen, C₁-C₆alkyl, C₁-C₆alkoxy, CF₃, OCF₃, hydroxyl, CN, phenyloxy, —SO₂—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, or —SO₂NR₁₀R₁₁, where each R₁₀and R₁₁is independently H or C₁-C₆alkyl.

In yet another aspect, the invention provides compounds of Formula XI-3, i.e., compounds according to any one of Formulas XIa, XIb, or XIc, where the heterocycloalkyl group is piperazinyl, which is optionally substituted at one or more substitutable positions with groups that are independently halogen, C₁-C₆alkyl, C₁-C₆alkoxy, CF₃, OCF₃, hydroxyl, CN, phenyloxy, —SO₂—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, or —SO₂NR₁₀R₁₁, where each R₁₀and R₁₁is independently H or C₁-C₆alkyl.

In still another aspect, the invention provides compounds of Formula XI-4, i.e., compounds according to any one of Formulas XIa, XIb, or XIc, where the heterocycloalkyl group is morpholinyl, which is optionally substituted at one or more substitutable positions with groups that are independently halogen, C₁-C₆alkyl, C₁-C₆alkoxy, CF₃, OCF₃, hydroxyl, CN, phenyloxy, —SO₂—(C₁-C₆alkyl), —NR₁₀R₁₁, C_I-C₆alkanoyl, pyridyl, phenyl, or —SO₂NR₁₀R₁₁, where each R₁₀and R₁₁is independently H or C₁-C₆alkyl.

In another aspect, the invention provides compounds of Formula XI-5, i.e., compounds according to any one of Formulas XIa, XIb, or XIc, where the heterocycloalkyl group is thiomorpholinyl, which is optionally substituted at one or more substitutable positions with groups that are independently halogen, C₁-C₆alkyl, C₁-C₆alkoxy, CF₃, OCF₃, hydroxyl, CN, phenyloxy, —SO₂—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, or —SO₂NR₁₀R₁₁, where each R₁₀and R₁₁is independently H or C₁-C₆alkyl.

In another aspect, the invention provides compounds of Formula XI-6, i.e., compounds according to any one of Formulas XIa, XIb, or XIc, where the heterocycloalkyl group is thiomorpholinyl-S,S-dioxide, which is optionally substituted at one or more substitutable positions with groups that are independently halogen, C₁-C₆alkyl, C₁-C₆alkoxy, CF₃, OCF₃, hydroxyl, CN, phenyloxy, —SO₂—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, or —SO₂NR₁₀R₁₁, where each R₁₀and R₁₁is independently H or C₁-C₆alkyl.

In further aspects, the invention provides compounds of Formulas IV-1 to 1V-6, IVa to IVf, V-1 to V-6, Va to Vf, VI-1 to V1-6, VIa to VIf, VIIIa to VIIIg, VIIIh, VIIIm, VIIIn, IX-1 to IX-6, IXa, IXb, IXc, X-1 to X-6, Xa, Xb, Xc, XI-1 to XI-6, XIa, XIb, XIc, wherein the B-ring is pyrazolyl, imidazolyl, pyrrolyl, triazolyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl or pyridyl, each of which is optionally substituted at a substitutable position with a group that is independently C₁-C₄alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₄alkoxy, amino, C₁-C₄alkylamino, C₁-C₄dialkylamino, —S(O)_0-2R′, hydroxy, hydroxy C₁-C₄alkyl, halo, C₁-C₂haloalkyl (such as CF₃), C₁-C₂haloalkoxy (such as OCF₃), —NR′C(O)R″, —NR′SO₂R″, —C(O)R′, —C(O)OR′, —C(O)alkylOC(O)R′; —C(O)NR₁₀R₁₁, oxo, CN, or C₀-C₁alkylphenyl, where the phenyl is optionally substituted with 1-5 groups independently selected from halogen, C₁-C₄alkyl, —CO₂R′, C₁-C₄alkoxy, C₁-C₂haloalkyl (such as CF₃), C₁-C₂haloalkoxy (such as OCF₃), hydroxyl, CN, NO₂, phenyloxy, —S(O)_0-2—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, and —SO₂NR₁₀R₁₁.

In some other aspects, the invention provides compounds of Formulas IV-1 to IV-6, IVa to IVf, V-1 to V-6, Va to Vf, VI-1 to VI-6, VIa to VIf, VIIIa to VIIIg, VIIIh, VIIIm, VIIIn, IX-1 to IX-6, IXa, IXb, IXc, X-1 to X-6, Xa, Xb, Xc, XI-1 to XI-6, XIa, XIb, XIc, wherein the B-ring is pyrazolyl, imidazolyl, pyrrolyl, triazolyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl or pyridyl, each of which is substituted at a substitutable position with a group that is independently C₁-C₄alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₁-C₄alkoxy, amino, C₁-C₄alkylamino, C₁-C₄dialkylamino, —S(O)_0-2R′, hydroxy, hydroxy C₁-C₄alkyl, halo, C₁-C₂haloalkyl (such as CF₃), C₁-C₂haloalkoxy (such as OCF₃), —C(O)R′, —C(O)OR′, —C(O)alkylOC(O)R′; —C(O)NR₁₀R₁₁, oxo, CN, or C₀-C₁alkylphenyl, where the phenyl is optionally substituted with 1-3 groups independently selected from halogen, C₁-C₄alkyl, —CO₂R′, C₁-C₄alkoxy, C₁-C₂haloalkyl (such as CF₃), C₁-C₂haloalkoxy (such as OCF₃), hydroxyl, —NR₁₀R₁₁, and C₁-C₆alkanoyl.

In some aspects, the invention provides compounds of Formulas IV-1 to IV-6, IVa to IVf, V-1 to V-6, Va to Vf, VI-1 to VI-6, VIa to VIf, VIIIa to VIIIg, VIIIh, VIIIm, VIIIn, IX-1 to IX-6, IXa, IXb, IXc, X-1 to X-6, Xa, Xb, Xc, XI-1 to XI-6, XIa, XIb, XIc, wherein the B-ring is triazolopyrimidinyl, imidazopyrimidinyl, pyrazolopyrimidinyl, or indolyl, each of which is optionally substituted at a substitutable position with a group that is independently C₁-C₄alkyl, C_s-C₆cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₄alkoxy, amino, C₁-C₄alkylamino, C₁-C₄dialkylamino, —S(O)_0-2R′, hydroxy, hydroxy C₁-C₄alkyl, halo, C₁-C₂haloalkyl (such as CF₃), C₁-C₂haloalkoxy (such as OCF₃), —NR′C(O)R″, —NR′SO₂R″, —C(O)R′, —C(O)OR′, —C(O)alkylOC(O)R′; —C(O)NR₁₀R₁₁, oxo, CN, or C₀-C₁alkylphenyl, where the phenyl is optionally substituted with 1-5 groups independently selected from halogen, C₁-C₄alkyl, —CO₂R′, C₁-C₄alkoxy, C₁-C₂haloalkyl (such as CF₃), C₁-C₂haloalkoxy (such as OCF₃), hydroxyl, CN, NO₂, phenyloxy, —S(O)_0-2—(C₁-C₆alkyl), —NR₁₀R₁₁, C₁-C₆alkanoyl, pyridyl, phenyl, and —SO₂NR₁₀R₁₁.

In some other aspects, the invention provides compounds of Formulas IV-1 to IV-6, IVa to IVf, V-1 to V-6, Va to Vf, VI-1 to VI-6, VIa to VIf, VIIIa to VIIIg, VIIIh, VIIIm, VIIIn, IX-1 to IX-6, IXa, IXb, IXc, X-1 to X-6, Xa, Xb, Xc, XI-1 to XI-6, XIa, XIb, XIc, wherein the B-ring is triazolopyrimidinyl, imidazopyrimidinyl, pyrazolopyrimidinyl, or indolyl, each of which is substituted at a substitutable position with a group that is independently C₁-C₄alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₁-C₄alkoxy, amino, C₁-C₄alkylamino, C₁-C₄dialkylamino, —S(O)_0-2R′, hydroxy, hydroxy C₁-C₄alkyl, halo, C₁-C₂haloalkyl (such as CF₃), C₁-C₂haloalkoxy (such as OCF₃), —C(O)R′, —C(O)OR′, —C(O)alkylOC(O)R′; —C(O)NR₁₀R₁₁, oxo, CN, or C_0-1alkylphenyl, where the phenyl is optionally substituted with 1-3 groups independently selected from halogen, C₁-C₄alkyl, —CO₂R′, C₁-C₄alkoxy, C₁-C₂haloalkyl (such as CF₃), C₁-C₂haloalkoxy (such as OCF₃), hydroxyl, —NR₁₀R₁₁, and C₁-C₆alkanoyl.

In some aspects, the invention provides compounds of formula XV, i.e., compounds according to any one of Formulas Ia to Ie, II, IIIa to IIIf, IV-1 to IV-6, IVa to IVf, V-1 to V-6, Va to Vf, VI-1 to VI-6, VIa to VIf, VIIIa to VIIIg, VIIIh, VIIIm, VIIIn, IX-1 to IX-6, IXa, IXb, IXc, X-1 to X-6, Xa, Xb, Xc, XI-1 to XI-6, XIa, XIb, XIc, where the B-ring has the formula:

wherein

R₂₀is H, C₁-C₆alkyl, C₁-C₆alkoxy, oxo , amino, C₁-C₆alkylamino, C₁-C₆dialkylamino, —R′C(O)R″, halo, or CF₃; and where the dashed bond represents an optional second bond.