MX2008006806A - 5-(arylsulfonyl)-pyrazolopiperidines - Google Patents

Abstract

The invention provides N-cyclic sulfonamido compounds of Formula (I) wherein A, B, R1, R1a, R2, R2a, R3and R3aare as described in the specification. Compounds of Formula (I) are useful in treating or preventing cognitive disorders, such as Alzheimer's disease. The invention also encompasses pharmaceutical compositions comprising compounds of Formula (I), methods of preparing compounds of formula (I), and methods of treating cognitive disorders, such as Alzheimer's disease.

Description

- (ARILSULFONIL) -PIRAZOLOPIPERIDINAS FIELD OF THE INVENTION The invention relates to compounds of 5- (arylsulonyl) -pyrazolopiperidine, which inhibit the release of the gamma secretase and beta-amyloid peptide and / or its synthesis. Therefore, N-cyclic sulfonamide compounds are useful in the prevention of cognitive disorders in patients susceptible to cognitive disorders and / or in the treatment of patients with cognitive disorders to inhibit further deterioration in their aiection.

BACKGROUND OF THE INVENTION Alzheimer's disease (AD) is a degenerative brain disorder characterized clinically by the progressive loss of memory, cognition, reasoning, judgment and emotional stability that leads gradually to a serious mental deterioration and finally death. AD is a very common cause of progressive mental impairment (dementia) in adult humans and is thought to be the fourth most common cause of medical death in the United States. AD has been observed in races and ethnic groups in the world and presents a major public health problem in the present and future. The disease is currently estimated to affect approximately REF .: 191660 two to three million individuals in the United States alone. The AD in the present is incurable. No treatment is currently known that effectively prevents AD or reverses its symptoms and course. The brains of individuals with AD exhibit characteristic lesions called senile plaques (or amyloid), amyloid angiopathy (amyloid deposits in blood vessels), and neurofibrillary tangles. Most of these lesions, particularly amyloid plaques and neurofibrillary networks, are generally found in several areas of the human brain important for memory and cognitive function in patients with AD. The smaller numbers of these lesions in a more restrictive anatomical distribution are also found in the brains of most adult humans who do not have clinical AD. Amyloid plaques and amyloid angiopathy also characterize the brains of individuals with Trisomy 21 (Down syndrome) and hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D). Currently, a definitive diagnosis of AD usually requires observation of the lesions mentioned above in the brain tissue of patients who have died with the disease or, rarely, in small samples of brain tissue biopsies taken during an invasive neurosurgical procedure. The main chemical constituent of the plates amyloid and vascular amyloid deposits (amyloid angiopathy) characteristic of AD and other disorders mentioned above is a protein of approximately 4.2 kilodalton (kD) of approximately 39-43 amino acids designated the β-amyloid peptide (βAP) or often Aβ, AβP or ß / A4. The 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 biology and protein chemistry analyzes have shown that the β-amyloid peptide is a small fragment of a larger precursor protein called the amyloid precursor protein (APP), which is normally produced by cells in many different tissues. animals, including humans. Knowledge of the structure of the APP-encoding gene has shown that the β-amyloid peptide arises as a peptide fragment that is split from APP by the protease enzyme (s). The sequential processing of the precursor protein by enzymes generically referred to as beta and gamma-secretases, gives rise to the ß-amyloid peptide fragment. Both enzymes have now been cloned in a molecular manner and characterized at different levels.

Several lines of evidence indicate that progressive cerebral deposition of β-amyloid peptide plays a seminal role in the pathogenesis of AD and may 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 in amino acid 717 of the amino acid isoform 770 of APP can be found in affected members, but not in unaffected members of different families with a form genetically determined (family) of AD (Goate et al., Nature, 349: 704-706 (1990); Chartier Harian 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 that changes lysine595-methionine596 to asparagine595-leucine596 (with reference to the 695 isoform found in a Swedish family) was reported in 1992 (Mullan et al., Nature Genet., 1: 345-347 (1992).) Gene binding analysis has shown that these mutations, as well as some other mutations in the APP gene, are the specific molecular cause of AD in affected members of such families. A mutation in amino acid 693 of the amino acid isoform 770 of APP has been identified as the cause of the deposition disease of the β-amyloid peptide, HCHWA-D and a change of alanine to glycine in the amino acid 692 which causes a phenotype that looks like AD is some patients, but HCHWA-D in others. The discovery of these and other mutations in APP in genetically-based cases of AD demonstrate that alteration of APP metabolism and subsequent deposition of its β-amyloid peptide fragment can cause AD. Despite the progress that has been made in understanding the fundamental mechanisms of AD and other diseases related to β-amyloid peptide, there is a need to develop methods and compositions for the treatment of the disease (s). Ideally, the methods of treatment would advantageously be based on drugs that are capable of inhibiting the release of the β-amyloid peptide and / or its synthesis in vivo. One method for the inhibition of amyloid peptide synthesis in vivo is by the inhibition of gamma secretase, the enzyme responsible for the carboxy-terminal division resulting in the production of β-amyloid peptide fragments of 40 or 42 residues in length . The immediate substrates for the gamma secretase are divided as well as divided carboxy-terminal (CTF) fragments of APP. The cleavage site of the gamma secretase in the β and a-CTF fragments occurs in the predicted transmembrane domain of APP. Inhibitors of gamma secretase have been shown to effect amyloid pathology in models of transgenic mice (Dovey, HF, V. John, JP Anderson, LZ Chen, P. de Saint Andrieu, LY Fang, SB Freedman, B. Folmer, E. Goldbach, EJ Holsztynska et al. (2001). secretase inhibitors reduce beta-amyloid peptide levéis in brain. "J Neurochem 76 (1): 173-81). The gamma secretase is recognized to be a multi-subunit complex comprised of presenilins (PS1 or PS2), Nicastrin, Aph-1 and Pen 2 (De Strooper, B. (2003). "Aph-1, Pen-2, and Nicastrin with Presenilin genérate 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 Nati Acad Sci USA 100 (11): 6382-7). Most evidence indicates that PS comprises the catalytic radical of the complex, while other identified subunits are necessary for appropriate maturation and sub-cellular localization of the active enzyme complex (reviewed in De Strooper, B. (2003). "Aph. -1, Pen-2, and Nicastrin with Presenilin genérate an active gamma-Secretase complex. "Neuron 38 (1): 9-12). Consistent with this hypothesis: genetically altered mice exhibit significant reductions in β-amyloid production (De Strooper, B., P. Saftig, K. Craessaerts, H. Vanderstichele, G. Guhde, W. Annaert, K. Von Figure 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 DJ 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 the putative active aspartate residues in the PS trans-membrane domains inhibit the production of β-amyloid in cells in the dominant negative manner (Wolfe, MS, W. Xia, BL Ostaszewski, TS Diehl, WT Kimberly and DJ Selkoe (1999). "Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity." Nature 398 (6727): 513-7; Kimberly, WT, W. Xia, T. Rahmati, MS Wolfe and DJ 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); istesters of transition state based on active directed site substrate designed to inhibit gamma secretase directly conjugated 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, likewise, the allostatic gamma secretase inhibitors have been shown to bind directly to PS (Seiffert, D., JD Bradley, Rominger CM, DH Rominger, Yang F., JE Meredith, Jr., Q. Wang, AH Roach, LA Thompson, SM Spitz et al. (2000). "Presenilin-1 and -2 are molecular targets for gamma-secretase inhibitors." J Biol Chem 275 (44): 34086-91). Current evidence indicates that in addition to the processing of APP leading to the synthesis of β-amyloid, gamma secretase also mediates the intra-membrane division of other type I transmembrane proteins (reviewed in Fortini, ME (2002). secretase-mediated proteolysis in cell-surface-receptor signaling. "Nat Rev Mol Cell Biol 3 (9): 673-84, see also Struhl, G. and A. Adachi (2000)." Requirements for presenilin-dependent cleavage of notch and other transmembrane proteins. "Mol Cell 6 (3): 625-36). Worthy of mention among the known substrates of the gamma secretase It's Notch 1 of a mammal. The Notch 1 protein is important for the determination of cell death during tissue development and homeostasis in adults. Due to ligand coupling via the Notch ecto-domain, Notch undergoes an extra-cellular and sequential intra-membrane processing analogous to APP. Intramembranal processing of Notch mediated by gamma secretase leads to the release of the intracellular Notch domain (NICD). The fragment of NICD mediates Notch signaling through translocation to the nucleus, where it regulates the expression of genes that mediate cell differentiation in many tissues during development, as well as in adults. The disruption of Notch signaling by genetically altered mice (KO) results in the embryonic lethal phenotype in mice (Swiatek, PJ, CE Lindsell, FF del Amo, G. Weinmaster and T. Gridley (1994). "Notch 1 is essential for postimplantation development in mice. "Genes Dev 8 (6): 707-19; Conlon, RA, AG Reaume and J. Rossant (1995)." Notch 1 is required for the coordination segmentation of somites. "Development 121 ( 5): 1533-45). The Notch KO phenotype is very similar to the phenotype observed in KO PS1 mice, and reproduces precisely by PSO / 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. Semeels, W. Annaert, D. Collen, L. Schoonjans and B. De Strooper (2000). "Total inactivation of gamma-secretase activity in presenilin-deicient embryonic stem cells." Nat Cell Biol 2 (7): 461-2). This convergence of the phenotypes observed in mice genetically altered from the substrate (Notch) or the enzyme (PS) suggests that gamma secretase inhibitors that also inhibit Notch function can be limited as therapeutic agents due to the importance of the Notch function in adult tissues (Fortini, ME (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 over-phenotype Zheng, H., M. Jiang, M. Trumbauer, R. Hopkins, D. Sirinathsinghji, K. Stevens, M. Conner, H. Slunt, S. Sisodta, H. Y. Chen et al. (nineteen ninety six). "Mice deficient for the amyloid precursor protein gene." Ann N and 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. (nineteen ninety five). "beta-Amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity. "Cell 81 (4): 525-31, therefore, the accumulated evidence suggests that the gamma secretase inhibitors would have a selectivity to inhibit the processing of the gamma secretase of APP on the processing of the Notch range secretase.

BRIEF DESCRIPTION OF THE INVENTION In a broad aspect, the invention provides compounds of Formula I: Compounds of Formula I (Formula I) stereoisomers, tautomers, mixtures of stereoisomers and / or tautomers or pharmaceutically acceptable salts thereof, wherein ring A is aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein each ring is optionally substituted in a halogen-replaceable position, Ci- Cß, C2-C6 alkenyl, C -Cd alkynyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, C? -C6 haloalkoxy, hydroxyl, hydroxyalkyl, CN, aploxy, arylalkyloxy, -S02- (CX-C6 alkyl), -NR'R ", C? -C6 alkanoyl, C0-C3-C (0) OR 'alkyl, heteroaryl, heterocycloalkyl, aryl, arylalkyl or -S02-NR'R ", wherein each of R 'and R" is independently H or Ci-Cß alkyl or R' and R "with the atom to which they are attached can form a 3-8 membered ring including optionally an additional heteroatom, such as N, 0 or S; Ring B is a hetero-tile or heterocycloalkyl ring, each of which is optionally substituted in a substitutable position with a group that is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkyl, C 1 -C 6 alkoxy, amino, alkylamino Ci-Ce, dialkylamino C? -C6, -S (O) 0-2R ', hydroxyl, hydroxyalkyl, halo, haloalkyl C? -C2, haloalkoxy C? -C2, -NR'C (0) R " , -NR'S02R ", -C (0) R ', -C02R', -C (0) alkylC0 (0) R ', -C (0) NR'R", oxo, CN or alkylanol Co- Ci, wherein the aplo is optionally substituted with 1-5 groups independently selected from halogen, Ci-Cß alkyl, -C (0) 0R ', C?-C6 alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, N02, aploxy, -S (O) 0-2- (C? -C6 alkyl), C (0) NR'R ", -NR'R", C? -C6 alkanoyl, pyridyl, phenyl, and -S02NR'R "; and Ri / Ria R2 and 2az are independently hydrogen, halogen, Ci-C? Alkyl, C-C alkenyl, wherein the alkenyl group is optionally substituted with one or more halogens; C2-Ce alkynyl, C3-Cs cycloalkyl, C3-Cg cycloalkyl C? -C6 alkyl, aryl, C? -C6 arylalkyl, heteroaryl, -C02R?, CONR? R ?, Ci-Ce haloalkyl, wherein the haloalkyl group is optionally substituted with C 1 -C 4 -alkoxy, C 1 -C 6 -haloalkoxyalkyl, C -C 6 -hydroxyalkyl, C -Ce alkanoyl, C 6 -C 6 aryloxyalkyl, C 6 -C 6 -heteroaryloxyalkyl, C 0 -C 6 -alkyl (0) NR 'R ", hydroxyl or alkyl-Co-C6-OC (0) -heterocycloalkyl, wherein each aryl, heteroaryl and heterocycloalkyl group is optionally substituted with one or more groups that are independently halogen, Ci-Cß alkyl, Ci-Cß alkoxy, alkanoyl C? -C6, haloalkyl C? -C, haloalkoxy C? ~ C4, C (0) NR'R ", -NR'R", hydroxyl, -0- (CH2)? -2-0-, -C ( 0) 0R ', phenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl; R3 and 3a are independently hydrogen, halogen, C?-C6 alkyl, OH or NR'R "; Ri and R a or R2 and R2a or R3 and R3a combined form = 0 or = N-0R, wherein R is hydrogen, alkyl C? -C6, aryl (such as phenyl) or arylalkyl (such as benzyl or phenethyl); or Ri and RIA or R2 and R2a or R3 and R3a together with the carbon to which they are attached form a C3-C6 cycloalkyl group wherein one of the carbons is optionally replaced with a heteroatom selected from N, 0 or S and wherein the ring can be optionally substituted with Ci-Cß alkyl; Ri and R iorman a double bond. The compounds of Formula I inhibit the release of β-amyloid peptide 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 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 for treating a patient having, or in preventing a patient from acquiring, a disease or condition selected from the group consisting of Alzheimer's disease, to help prevent or delay the onset of the disease. Alzheimer's disease, for the treatment of patients with moderate cognitive impairment (MCI) and to prevent or delay the onset of Alzheimer's disease in those who progress from MCI to AD, for the treatment of Down syndrome, for the treatment of humans have hereditary cerebral hemorrhage with amyloidosis of the Dutch type, for the treatment of cerebral amyloid angiopathy and to prevent its potential consequences, that is, simple or recurrent lobar hemorrhages, for the treatment of other dementias Degenerative diseases, which include 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 dementia. Alzheimer's disease and who is in need of such treatment comprising the administration of a therapeutically effective amount of a compound of the formula (I). In another aspect, the invention provides methods for preparing the compounds of interest, as well as intermediates useful for preparing the compounds of interest.

DETAILED DESCRIPTION OF THE INVENTION As described above, the invention provides the compounds of Formula I. In another aspect, the invention provides compounds of formula 2, ie, compounds of Formula I wherein ring A is phenyl or naphthyl, which is optionally substituted in a halogen-substitutable position, C? -C6 alkyl, alkoxy Ci-Cβ, C?-C6 haloalkyl, C halo ~ haloalkoxy, hydroxyl, hydroxyalkyl, CN, phenyloxy, benzyloxy, -S02- (Ci-Ce alkyl), -NR'R ", C?-C6 alkanoyl, pyridyl, phenyl , benzyl, or -S02-NR'R ", wherein each R 'and R" is independently H or Ci-Ce alkyl. In still another aspect, the invention provides compounds of formula 3, ie, compounds of Formula I wherein ring B is pyrazolyl, imidazolyl, pyrrolyl, triazolyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, isoxazolyl, indolyl, pyrimidyl or pyridyl, each of which is optionally substituted in a substitutable position with a group which is independently Ci-Cβ alkyl, Ci-Cβ alkoxy, amino, Ci-Ce alkylamino, dialkylamino Ci-Ce, Ci-Cd alkylthio, halo, haloalkyl C? -C2, haloalkoxy C? -C2 or alkylphenyl Co-Ci, are optionally substituted with 1 to 5 groups which are independently halogen, hydroxyl, Ci-C? Alkyl, C? -C6 alkoxy, C? -C4 haloalkyl, haloalkoxy C? C, C?-C6 alkanoyl, -NRR ', -C02R', -CONR'R ", CN or N02 In yet another aspect, the invention provides compounds of formula 4, ie, compounds of Formula I wherein Ri is Ci-Cß alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl Ci-Cß alkyl, phenyl, biphenyl, phenylalkyl C 1 -C 6 alkyl, pyridyl, benzofuranyl, benzothienyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, tetrazolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiazolyl, pyrimidyl, -C02R ', -CONR'R', haloalkyl C? C6, hydroxyalkyl C? -C6, Ci-Ce alkoxy, phenyloxyalkyl Ci-Ce, Ci-Ce naphthyloxyalkyl, Ci-Cβ pyridyloxyalkyl, C? -C6 benzofuranyloxyalkyl, C? -C6 benzothienyloxyalkyl, Ci-Cg quinolinyloxyalkyl, Ci-Ce isoquinolinyloxyalkyl, Ci-Ce quinoxalinyloxyalkyl, Ci-Cβ quinazolinyloxyalkyl, C0-C6-OC alkyl (O) NR 'R ", alkyl -C0-C6-NR' R", hydroxyl, C6-C6-OC (O) -piperidinyl alkyl, C6-C6-OC (O) -pyrrolidinyl alkyl, alkyl- Ci-Cβ-OC (0) -morpholinyl, wherein each aryl, heteroaryl and heterocycloalkyl group is optionally substituted with one or more groups that are independently halogen, Ci-Ce alkyl, Ci-Cβ alkoxy, C?-C haloalkyl, haloalkoxy C? ~ C4, C? -C6 alkanoyl, -C (O) NR'R ", -NR'R", -0- (CH2)? _2-0-, -C02R ', pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl , pyridyl, N-methyl pyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl. In still another aspect, the invention provides compounds of the formula 4a, ie, compounds of the Formula I wherein R2 and 2a / are independently hydrogen, halogen, C? -C6 alkyl, C2-Cd alkenyl, wherein the alkenyl group it is optionally substituted with one or more halogens; C2-C6 alkynyl, C-C6 cycloalkyl, C3-C6 cycloalkyl-C? -C6 alkyl, phenyl, naphthyl, phenylalkyl Ci-C?, naphthylalkyl Ci-C?, pyridyl, thiazolyl, pyrimidyl, pyrazolyl, -C02R ', CONR'R ", haloalkyl Ci-Cg, wherein the haloalkyl group is replaced optionally with C alco-C alkoxy; haloalkoxyalkyl C? ~ C4 hydroxyalkyl, Ci-Ce, C2-C6 alkanoyl, phenyloxy Ci-C ?, C naftiloxialquilo? C6 alkyl, Ci-Ce pyridyloxyalkyl, pirimidiloxialquilo Ci-Css, tieniloxialquilo C? -C6, pirroliloxialquilo C? -C6, thiazolyl oxyalkyl C6-C6 alkyl, C0-C6-OC (O) NR 'R "alkyl, -C0-C6-NR' R" alkyl, hydroxyl or C0-C6-OC (0) -heterocycloalkyl alkyl, wherein the heterocycloalkyl group is piperazinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, S, S-dioxide tiomoríolinilo, tetrahidroíuranilo or imidazolidinyl, wherein each aryl, heteroaryl and heterocycloalkyl is optionally substituted with one or more groups that are independently halogen, Ci-Ce, C6-C6 alkoxy, C6-C6 alkanoyl, C6-Chaloalkyl, C6-C4 haloalkoxy, C (0) NR'R ", -NR'R", hydroxyl, -O- (CH2)? - 2-0-, -C (0) 0R ', íenilo, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-bencilpirazolilo, oxadiazolyl, oxazolyl or imidazolyl. In another aspect, the invention provides compounds of the formula 5, ie, compounds of the formula 4 wherein ring A is either ionyl or naphthyl, each of which is optionally substituted in a halogen-substitutable position, Ci-Cß alkyl alkoxy C? C6 haloalkyl C? -C 6 haloalkoxy C? C6 alkyl, hydroxyl, CN, phenyloxy, benzyloxy, -S02- (alkyl C? -C6) -NR'R "alkanoyl Ci-Css, pyridyl , phenyl, or -S02-NR'R ", wherein each R 'and R" is independently H or C? -C6 alkyl; and ring B is pyrazolyl, imidazolyl, pyrrolyl, triazolyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, triazolopirimidilo, imidazopirimidilo, pirazolopirimidilo, isoxazolyl, indolyl, pyrimidyl or pyridyl, each of which is optionally substituted at a substitutable position with a group that is independently Ci-Ce alkyl, C? -C6 alkoxy, amino, C? -C6 alkylamino, C? -C6 dialkylamino, C? -C6 alkylthio, halo, C? -C2 haloalkyl, C? -C2 haloalkoxy, benzyl or phenyl, wherein the cyclic portions of the benzyl or phenyl are optionally substituted with 1 to 5 groups that are independently halogen, hydroxyl, alkyl Ci-Ce alkoxy, Ci-Cd, haloalkyl C? -C, haloalkoxy C? ~ C4 alkanoyl, C ? -C6, -NR'R ", -C02R ', -CONR'R", CN or N02. In another aspect, the invention provides compounds of formula 6, ie, compounds of formula 5 having the formula Formula 6 where, R 2 is H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl or CN; R13 is H, halogen, Ci-Ce alkyl optionally substituted with -C02- (C? -C6 alkyl), C? -C6 alkoxy, C? -C6 haloalkyl, C? -C6 haloalkoxy, CN, aryloxy, isocyanate, -S02 - (C 1 -C 6 alkyl), -NR'R ", Ci-Cd alkanoyl, pyridyl or lhenyl; or Ri 4 is H, C 1 -C 4 alkyl, -S 0 2 -NR'R", or halogen; wherein R 'and R "are independently H or Ci-C6 alkyl, or R3 and R14 and the carbons to which they are linked form a benzo ring; or Rio and Rn in each case are independently H, halogen or C-alkyl ? C6, wherein the alkyl is optionally substituted with a phenyl, wherein the phenyl is optionally substituted with 1 to 5 groups which are independently halogen, hydroxyl, Ci-Ce alkyl, C? -C6 alkoxy / C? -C haloalkyl , haloalkoxy C i -C 4, CN or N 0 2, or Rio / Ri 4 / and the carbons to which they bind form a benzo ring In yet another aspect, the invention provides compounds of the formula 6-1, i.e. of formula 6 wherein ring B is pyrazolyl, imidazolyl, pyrrolyl, triazolyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, isoxazolyl, pyrimidyl or pyridyl, each of which It is unsubstituted. In yet another aspect, the invention provides compounds of formula 6-2, ie, compounds of formula 6 wherein ring B has the formula: wherein R20 is H, C? -C6 alkyl, Ci-Ce alkoxy, amino, C? -C6 alkylamino, dialkylamino Ci-Ce, C? -C6 alkylthio, halo, CF3 or lenyl. In yet another aspect, the invention provides compounds of formula 6-3, ie, compounds of formula 6 wherein ring B has the formula: wherein R20 is H, C? -C alkyl, C? -C4 alkoxy, amino, C? -C4 alkylamino, C1-C4 dialkylamino, C? -C alkylthio, halo, CF3 or phenyl. In yet another aspect, the invention provides compounds of formula 6-4, ie, compounds of formula 6 wherein ring B has the formula: wherein R2o is H, C? -C4 alkyl, C? -C alkoxy, amino, C? -C4 alkylamino, dialkylamino C? -C, alkylthio C? ~ C4, halo, CF3 or phenyl. In yet another aspect, the invention provides compounds of formula 6-5, ie, compounds of formula 6 wherein ring B has the formula: In still another aspect, the invention provides compounds of the formula 6-6, i.e. compounds of formula 6 wherein ring B has the formula: In still another aspect, the invention provides compounds of the formula 6-6a, ie, compounds according to any of the formulas 6-3, 6-4, 6-5 or 6-6, wherein R2o is H, or C1-C6 alkyl. In another embodiment, R2rj is phenyl. In yet another embodiment, when the R2o group is bonded to a carbon, R2o is C1-C4 alkoxy, C12 alkylthio, halo, CF3 or phenyl. In yet another embodiment, R2o is H. In yet another aspect, the invention provides compounds of formula 6-7, ie, compounds of formula 6 wherein ring B has the formula: wherein R0 is H, C? -C alkyl, C? -C4 alkoxy, amino, C? -C alkylamino, C? -C4 dialkylamino, C? -C4 alkylthio, halo, CF3 or phenyl. In yet another aspect, the invention provides compounds of formula 6-8, ie, compounds of formula 6 wherein ring B has the formula: wherein R30 is H, C? -C4 alkyl, C? -C4 alkoxy, amino, C? -C4 alkylamino, C? -C4 dialkylamino, C? -C4 alkylthio, halo, CF3 or phenyl. In still another aspect, the invention provides compounds of the formula 6-9, ie, compounds of the formula 6 in where ring B has the formula wherein R0 is H, C? -C4 alkyl, C? -C4 alkoxy, amino, C? -C4 alkylamino, C? -C4 dialkylamino, C? -C4 alkylthio, halo, CF3 or phenyl. In still another aspect, the invention provides compounds of formula 6-10, ie, compounds of formula 6 wherein ring B has the formula: wherein R3o is H, C? -C alkyl, C? -C alkoxy, amino, C? -C4 alkylamino, C? -C4 dialkylamino, C? -C4 alkylthio, halo, CF3, or phenyl. In still another aspect, the invention provides compounds of formula 6-11, ie, compounds of formula 6 wherein ring B has the formula: wherein R30 is H, C? -C4 alkyl, C? -C4 alkoxy, amino, C? -C4 alkylamino, dialkylamino C? -C4, alkylthio C?, halo,. CF3 or phenyl. In still another aspect, the invention provides compounds of the formula 6-la, ie, compounds according to any of the formulas 6-8, 6-9 or 6-10, wherein R3o is H, or C? CD. In another embodiment, R3o is phenyl. In yet another embodiment, when the R30 group is bonded to a carbon, R3o is C4-4 alkoxy, C4-4 alkylthio, halo, CF3, or phenyl. In yet another embodiment, Ro is H. In another aspect, the invention provides compounds of the formula 6-llb, ie, compounds according to any of formulas 6-8, 6-9 or 6-10, wherein R3o is amino, alkylamino C? -C, dialkylamino C? -C4. In still another aspect, the invention provides compounds of formula 6-12, ie, compounds of formula 6 wherein ring B has the formula: In yet another aspect, the invention provides compounds of formula 6-13, ie, compounds of formula 6 wherein ring B has the formula: In yet another aspect, the invention provides compounds of formula 6-14, ie, compounds of formula 6 wherein ring B has the formula: In yet another aspect, the invention provides compounds of formula 6-15, ie, compounds of formula 6 wherein ring B has the formula: In yet another aspect, the invention provides compounds of formula 7, ie, compounds of formula 6 or any of formulas 6-1, 6-2, 6-3, 6-4, 6-5, 6-6 , 6-6a, 6-7, 6-8, 6-9, 6-10, 6-11, 6-lla, 6-llb, 6-12, 6-13, 6-14 or 6-15 where Rx is C?-C6 alkyl, C3-Ce cycloalkyl, C3-C6 cycloalkylalkyl, phenyl, biphenyl, C fen-C6 phenylalkyl (such as benzyl or phenethyl), C fen-Cd phenyloxyalkyl, or C na-Cd naphthyloxyalkyl, wherein each aryl group is replaced optionally with 1, 2, 3, 4 or 5 groups which are independently halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, -C (0) NR'R ", -NR'R", hydroxyl, -0- (CH2)? -2-0-, -C02R ', phenyl, pyridazinyl, pyrazyl, pyrimidyl, thiazolyl, pyridyl, N-methyl pyrazolyl, N-benzyl pyrazolyl, oxadiazolyl , oxazolyl or lidozolyl; and R and R2a are both H. In still another aspect, the invention provides compounds of formula 7a, ie, compounds of formula 7, wherein R2 is hydrogen, halogen, Ci-Cß alkyl, C2-C5 alkenyl, wherein the alkenyl group is optionally substituted with one or more halogens; C2-Cg alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl Ci-Ce alkyl, phenyl, naphthyl, phenylalkyl C? -C6, naphthylalkyl C? -C6, wherein each aplo group is optionally substituted with 1, 2 , 3, 4 or 5 groups which are independently halogen, Ci-Cß alkyl, C alco-C alco alkoxy, C?-C alca alkanoyl, C?-C haloalkyl, C?-C4 haloalkoxy, C (O) NR'R ", -NR'R ", hydroxyl, -0- (CH2)? -2-0-, -C (0) 0R ', phenyl, pipdazinyl, pyrazyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl , oxazolyl or lidozolyl. In still another aspect, the invention provides compounds of the formula 7b, ie, compounds of the formula 7, wherein R 2 is hydrogen, pyridyl, thiazolyl, pyrimidyl, pyrazolyl, pipdyloxyalkyl C 6 -C 6, pydydyloxyalkyl C x C ?, C 1 -C 6 thienyloxyalkyl, C 1 -C 6 pyrrolyloxyalkyl, or C 1 -C 6 thiazolyloxyalkyl, or C 0 -C 6 -OC (O) -heterocycloalkyl alkyl, wherein the heterocycloalkyl group is piperazyl, pyrrolidinyl, morpholyl, thiomorpholinyl, S , Sodium thiomorpholinyl, tetrahydrofuranyl or imidazolidinyl, wherein each heteroaryl and heterocycloalkyl group is optionally substituted with one or more groups which are independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 4 haloalkyl , haloalkoxy C? -C4, -C (0) NR'R ", -NR'R", hydroxyl, -0- (CH2)? -2-0-, -C (0) 0R ', phenyl, pyridazomyl, pyrazyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl. In still another aspect, the invention provides compounds of the formula 7c, ie, compounds of the formula 7, wherein R 2 is hydrogen, -C02R ', CONR'R ", haloalkyl C? -C6, wherein the haloalkyl group is optionally substituted with C 1 -C-alkoxy, C 1 -C 4 haloalkoxyalkyl, C -Cβ hydroxyalkyl, C 2 -C 6 alkanoyl, Ci-Cd phenyloxyalkyl, Ci-C na naphthyloxyalkyl, C 0 -C 6 -OC (0) NR 'R "alkyl or alkyl C0-C6-NR'R ", wherein each aryl group is optionally substituted with 1, 2, 3, 4 or 5 groups which are independently halogen, Ci-Ce alkyl, Ci-Cß alkoxy, C?-C6 alkanoyl, haloalkyl C? -C4, haloalkoxy C? -C4, -C (0) NR'R ", -NR'R", hydroxyl, -0- (CH2)? -2-0-, -C (0) OR ', phenyl, pyridazinyl, pyrazyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl; and wherein R 'and R "are independently H or Ci-Cd alkyl. In yet another aspect, the invention provides compounds of the formula 7d, ie, compounds of the formula 7, wherein R 2 is hydrogen, or Co-alkyl. C6 ~ OC (0) -heterocycloalkyl, wherein the heterocycloalkyl group is piperazinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, S, S-thiomorpholinyl dioxide, tetrahydrofuranyl or imidazolidinyl, wherein the heterocycloalkyl group is optionally substituted with one or more groups which are independently halogen, C?-C6 alkyl, C-β alkoxy, C?-C6 alkanoyl, C?-C haloalkyl, C?-C4 haloalkoxy, C (0) NR'R ", -NR'R", hydroxyl, - O- (CH2)? -2-0-, -C (0) OR ', phenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl In another aspect, The invention provides compounds of the formula 7-1, ie, compounds of the formula 6 or any of the formulas 6-1, 6-2, 6-3, 6-4, 6-5, 6-6, 6 -6a, 6-7, 6-8, 6-9, 6-10, 6-11, 6-lla, 6-llb, 6-12, 6-13, 6-14 or 6-15, where Ri is pyridyl, thiazolyl, imidazolyl, benzofuranyl, benzothienyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pyridyloxyalkyl C? -C6, benzofuranyloxyalkyl Ci-Ce, C6-C6-benzothienyloxyalkyl, Ci-C5-quinolinyloxyalkyl, C6-C6-isoquinolinyloxyalkyl, Ci-Ce quinoxalinyloxyalkyl, C? -C6 quinazolinyloxyalkyl, C? -C6-OC-O (N) NR 'R' alkyl, C? -C6-alkyl -OC (O) -piperidinyl, C 1 -C 6 -OC (O) -pyrrolidinyl or C 1 -C 6 -OC (O) -moryolinyl alkyl, wherein each heteroaryl and heterocycloalkyl group is optionally substituted with one or more groups which are independently halogen, C?-C6 alkyl, C?-C6 alkoxy, C halo ~C haloalkyl, C?-C4 haloalkoxy, -C (O) NR'R ", -NR'R", hydroxyl, -O - (CH2) -2-0-, -C02R ', iohenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl, and R and R2a are both H. In still another aspect, the invention provides compounds of the formula 7-1 a, ie, compounds of the formula 7-1, wherein R2 is hydrogen, halogen, C?-Cd alkyl, C 2 -C 6 alkenyl, wherein the alkenyl group is optionally substituted with one or more halogens; C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C-C6 alkyl, phenyl, naphthyl, phenylalkyl Ci-Cβ, naphthylalkyl Ci-C ?, wherein each aryl group is optionally substituted with 1, 2, 3, 4 or 5 groups which are independently halogen, C?-C6 alkyl, C?-C6 alkoxy, C?-C6 alkanoyl, C?-C4 haloalkyl, C?-C4 haloalkoxy, C (0) NR'R ", -NR 'R', hydroxyl, -O- (CH2)? -2-0-, -C (0) 0R ', phenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl. In still another aspect, the invention provides compounds of the formula 7-lb, ie, compounds of the formula 7-1, wherein R 2 is hydrogen, pyridyl, thiazolyl, pyrimidyl, pyrazolyl, pyridyloxyalkyl C 6 -C 6, pyrimidyloxyalkyl C 1. ~, thienyloxyalkyl Cx-C ?, pyrrolyloxyalkyl C? -C6, or thiazolyloxyalkyl C? -C6, or C0-C6-C06-OC (0) -heterocycloalkyl, wherein the heterocycloalkyl group is piperazinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, S, S-thiomorpholinyl, tetrahydrofuranyl or imidazolidinyl dioxide, wherein each heteroaryl and heterocycloalkyl group is optionally substituted with one or more groups which are independently halogen, C? -C6 alkyl, C? -C6 alkoxy, C? -C6 alkanoyl, haloalkyl C? -C4, haloalkoxy C? -C4, -C (0) NR'R ", -NR'R", hydroxyl, -0- (CH2)? -2-0-, phenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl. In yet another aspect, the invention provides compounds of the formula 7-lc, ie, compounds of the formula 7-1, wherein R2 is hydrogen, -C02R ', CONRR ", haloalkyl C? -C6, wherein the group haloalkyl is optionally substituted with C-C4 alkoxy, C?-C4 haloalkoxyalkyl, C? -Cs hydroxyalkyl, C 2 -C 6 alkanoyl, C fen-C fen phenyloxyalkyl, C na-C na naphthyloxyalkyl, C0-C6-OC (O) NR 'R "alkyl, or C0-C6-NR' R" alkyl wherein each aryl group is optionally substituted with 1, 2, 3, 4 or 5 groups which are independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkanoyl, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, -C (0) NR'R ", -NR'R", hydroxyl, -0- (CH2) -2-0-, -C (0) 0R ', phenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl; and wherein R 'and R "are independently H or C? -C6 alkyl. In yet another aspect, the invention provides compounds of the formula 7-ld, ie, compounds of the formula 7-1, wherein R2 is hydrogen , or C0-C6-OC (0) -heterocycloalkyl-alkyl, wherein the heterocycloalkyl group is piperazinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, S, S-thiomorpholinyl dioxide, tetrahydrofuranyl or imidazolidinyl, wherein the heterocycloalkyl group is optionally substituted with one or more groups which are independently halogen, Ci-Cg alkyl, Ci-Ce alkoxy, Ci-C alca alkanoyl, C?-C4 haloalkyl, C halo ~C haloalkoxy, C (0) NR'R ", -NR'R" , hydroxyl, -0- (CH2)? -2-0-, -C (0) 0R ', phenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl. In another aspect, the invention provides compounds of the formula 7-2, ie, compounds of the formula 7-1, 7-la, 7-lb, 7-lc or 7-ld, wherein Ri is pyridyl, thiazolyl, imidazolyl, benzofuranyl, benzothienyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl or quinazolinyl, wherein each heteroaryl group is optionally substituted with one or more groups that are independently halogen, C? -Cg alkyl, C? -Cg alkoxy, C? -C4 haloalkyl, C? -C4 haloalkoxy, -C (0) NR'R ", -NR'R", hydroxyl, -0- ( CH2)? -2-0-, -C02R ', phenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl; and R and R2a are both H. In yet another aspect, the invention provides compounds of the formula 7-3, ie, compounds of the formula 7-1, 7-la, 7-1 b, 7-lc or 7 -ld, wherein Ri is pyridyloxyalkyl C? -Cg, benzofuranyloxyalkyl C? -Cg, benzothienyloxyalkyl C? -Cg, quinolinyloxyalkyl C? -C6, isoquinolinyloxyalkyl C? -C6, quinoxalynyloxyalkyl C? -C6 or quinazolinyloxyalkyl C? -Cg, in wherein each heteroaryl group is optionally substituted with one or more groups which are independently halogen, C?-C6 alkyl, C?-C6 alkoxy, C?-C4 haloalkyl, C?-C4 haloalkoxy, -C (0) NR'R " , -NR'R ", hydroxyl, -0- (CH2)? -2-0-, -C02R ', phenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl; and Rla and R2a are both H.

In another aspect, the invention provides compounds of the formula 7-4, ie, compounds of the formula 7-1, 7-la, 7-lb, 7-lc or 7-ld, wherein Rx is C0-C6 alkyl -OC (0) NR 'R ", C0-C6 alkyl-NR'R", C -C6-0C (0) -piperidinyl alkyl, C? -C6-0C (0) -pyrrolidinyl alkyl or C? -C6 alkyl -0C (0) -morpholinyl, wherein each heterocycloalkyl group is optionally substituted with one or more groups which are independently halogen, C? -C6 alkyl, C? -C6 alkoxy, C? -C haloalkyl, C1-C4 haloalkoxy, C (0) NR'R ", -NR'R", hydroxyl, -0- (CH2)? -2-0-, -C02R ', phenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl; and R and R2a are both H. In another aspect, the invention provides compounds of formula 7-5, ie, compounds according to any of formulas 6-1, 6-2, 6-3, 6-4. , 6-5, 6-6, 6-6a, 6-7, 6-8, 6-9, 6-10, 6-11, 6-lla, 6-llb, 6-12, 6-13, 6 -14 or 6-15, wherein Rx is -C02R ', -CONR'R ", haloalkyl C? -C4 or hydroxyalkyl C? -C4; and R? And R2a are both H. In one embodiment, Rx is as defined above and R2 is H. In another embodiment, Ri is as defined above and R2 is methyl, ethyl or cyclopropyl In yet another embodiment, Rx is as defined above and R2 is hydroxyalkyl C? -C. , Rx and R2 are independently -C02-C-C alkyl-In another embodiment, Ri and R2 are independently hydroxyalkyl C? ~ C2. In yet another embodiment, Ri is hydroxyalkyl C? -C2 and R2 is methyl or ethyl. In a further aspect, the invention provides compounds of the formula 7-6, ie, compounds according to any of the formulas 6-1, 6-2, 6-3, 6-4, 6-5, 6-6 , 6-6a, 6-7, 6-8, 6-9, 6-10, 6-11, 6-lla, 6-llb, 6-12, 6-13, 6-14 or 6-15, in where Rx is H or C? -Cg alkoxy, R2 is H or C? -C6 alkoxy, and Rla and R2a are both H. In one embodiment, Rx is C? -C6 alkoxy and R2 is H or C? -C6 alkoxy. . In another embodiment Rx and R2 are independently C6-C6 alkoxy. In yet another embodiment Rx and R2 are both H. In another aspect, the invention provides compounds of formula 7-7, ie, compounds according to any of formulas 6-1, 6-2, 6-3, 6 -4, 6-5, 6-6, 6-6a, 6-7, 6-8, 6-9, 6-10, 6-11, 6-lla, 6-llb, 6-12, 6-13 , 6-14 or 6-15, wherein R and R2 are both C2-C4 alkenyl optionally substituted with one or more halogens (such as F or Cl), and Rla and R2a are both H. In one embodiment, Rx and R2 they are the same. In a further embodiment, R x and R 2 are both C 2 alkenyl substituted with two halogens (such as F). Rx and R2 can be cis or trans to each other. In another aspect, the invention provides compounds of the formula 7-8, ie, compounds according to any of the formulas 6-1, 6-2, 6-3, 6-4, 6-5, 6-6, 6-6a, 6-7, 6-8, 6-9, 6-10, 6-11, 6-lla, 6-llb, 6-12, 6-13, 6-14 or 6-15, wherein Rx and R2 are both haloalkyl C? -C2 and R? a and R2a are both H. Rx and R2 can be cis or trans to each other. In one embodiment, Rx and R2 are the same and are -CH2F, -CH2CF3, CH2CHF2, CF3 or -CF2CH3. In another aspect, the invention provides compounds of the formula 7-9, ie, compounds according to any of the formulas 6-1, 6-2, 6-3, 6-4, 6-5, 6-6, 6-6a, 6-7, 6-8, 6-9, 6-10, 6-11, 6-11a, 6-llb, 6-12, 6-13, 6-14 or 6-15, where Rx and R2 are both benzyl or phenethyl, and Rla and R2a are both H. Rx and R2 can be cis or trans to each other. In one embodiment, Rx and R2 are both benzyl. In another aspect, the invention provides compounds of the formula 7-10, ie, compounds according to any of the formulas 6-1, 6-2, 6-3, 6-4, 6-5, 6-6, 6-6a, 6-7, 6-8, 6-9, 6-10, 6-11, 6-lla, 6-llb, 6-12, 6-13, 6-14 or 6-15, where Rx and R are both H or C? -C4 alkyl and Rla and R2a are both H. Rx and R2 can be cis or trans to each other. In one embodiment, Rx and R2 are both methyl. In another embodiment, Rx and R are both isopropyl. In yet another embodiment, one or R and R2 is methyl while the other is isopropyl. In yet another embodiment, Rx and R2 are ethyl. In another aspect, the invention provides compounds of the formula 7-11, ie, compounds according to any of the formulas 6-1, 6-2, 6-3, 6-4, 6-5, 6-6, 6-6a, 6-7, 6-8, 6-9, 6-10, 6-11, 6-lla, 6-11 b, 6-12, 6-13, 6- 14 or 6-15, wherein R x is H, C 1 -C 4 alkyl, benzyl, phenethyl or phenyl, wherein the xyl portions of R x are optionally substituted with 1, 2 or 3 groups which are independently halogen, C alkyl? -C 4, or C 1 -C 4 alkoxy and R 2 is H or C 1 -C 4 alkyl and R 2 a and R 2a are both H. R x and R 2 can be cis or trans to each other. In one aspect, the invention provides compounds of the formula 7-12, ie, compounds of the formula 7-11 wherein, R 2 is H and R x is methyl, ethyl or propyl (non-iso) or R x is H and R 2 is methyl, ethyl or propyl (non-iso). In one embodiment, only one of Rx and R2 is isopropyl. In another embodiment, only one of Ri and R2 is ethyl. In yet another aspect, the invention provides compounds of the formula 7-13, ie, compounds of the formula 7-11 wherein, R 2 is H and R x is phenyl substituted with one or two halogens (such as F or Cl), or Ri is H and R2 is phenyl substituted with one or two halogens (such as F or Cl). In one aspect, the invention provides compounds of the formula 7-14, ie, compounds of the formula 7-11 wherein, R 2 is H and Ri is benzyl substituted with one or two groups that are independently halogen (such as F or Cl), methyl, ethyl, methoxy or ethoxy. In still another aspect, the invention provides compounds of the formula 7-15, ie, compounds of the formula 7-11 wherein, R 2 is methyl or ethyl, and R x is methyl, ethyl or propyl (n or iso). In one embodiment, Rx and R2 are both ethyl.

In still another aspect, the invention provides compounds of the formula 7-16, ie, compounds of the formula 7-11 wherein, R 2 is methyl or ethyl, and Ri is phenyl substituted with one or two halogens (such as F or Cl). In still another aspect, the invention provides compounds of the formula 7-17, ie, compounds of the formula 7-11 wherein, R 2 is methyl or ethyl, and Ri is benzyl substituted with one or two groups that are independently halogen ( such as F or Cl), methyl, ethyl, methoxy or ethoxy. In another aspect, the invention provides compounds of the formula 7-18, ie, compounds according to any of the formulas 6-1, 6-2, 6-3, 6-4, 6-5, 6-6, 6-6a, 6-7, 6-8, 6-9, 6-10, 6-11, 6-lla, 6-11 b, 6-12, 6-13, 6-14 or 6-15, in where Ri and R2 are independently H or -C02-C1-C4 alkyl, and R? and Ra are both H. Ri and R2 can be cis or trans to each other. In one embodiment, Ri is -C02-C-C2 alkyl and R2 is H. In another embodiment, Rx is -C02-Et and R2 is H. In yet another embodiment, Rx is H and R2 is -C02-C-alkyl. ? -C2. In yet another embodiment, Rx and R2 are both -C02-Et. In another aspect, the invention provides compounds of the formula 7-19, ie, compounds according to any of the formulas 6-1, 6-2, 6-3, 6-4, 6-5, 6-6, 6-6a, 6-7, 6-8, 6-9, 6-10, 6-11, 6-lla, 6-11 b, 6-12, 6-13, 6-14 or 6-15, in where Rx and R3 form a double bond and R13 and R3a they are both H. In one embodiment, R2 is H. In another embodiment, R2 is -C02-C C-C4 alkyl. In yet another embodiment, R2 is -C02-Et. In yet another embodiment, R2 is methyl or ethyl. In yet another embodiment, R2 is thiazolyl, pyridyl or pyrimidyl. In yet another aspect, the invention provides compounds of the formula 7-20, ie, compounds according to any of the formulas 6-1, 6-2, 6-3, 6-4, 6-5, 6-6 , 6-6a, 6-7, 6-8, 6-9, 6-10, 6-11, 6-lla, 6-llb, 6-12, 6-13, 6-14 or 6-15, in where Rx is pyridyl, pyrimidyl, C3-Cg cycloalkyl or thienyl, R2 is H, C? -C4 alkyl or C3-Cg cycloalkyl, and R? and R2a are both H. Ri and R2 can be cis or trans to each other. In still another additional aspect, the invention provides compounds of the formula 7-21, ie, compounds of the formula 7-20 wherein Ri is pyridyl and R2 is H. In yet another aspect, the invention provides compounds of the formula 7-22, ie, compounds of the formula 7-20 wherein Ri is pyridyl and R2 is methyl or ethyl. In a further aspect, the invention provides compounds of the formula 7-23, ie, compounds of the formula 7-20 wherein Ri is pyridyl and R2 is C, C5, or C6 cycloalkyl. In another embodiment, R2 is C3 cycloalkyl. In yet another aspect, the invention provides compounds of the formula 7-24, ie, compounds of the formula 7-20 wherein Ri is pyrimidyl and R2 is H.

In another aspect, the invention provides compounds of the formula 7-25, ie, compounds of the formula 7-20 wherein Ri is pyrimidyl and R2 is methyl or ethyl. In still another aspect, the invention provides compounds of the formula 7-26, ie, compounds of the formula 7-20 wherein Ri is pPrimidyl and R2 is C3, C5, or Cg cycloalkyl. In still another aspect, the invention provides compounds of the formula 7-27, ie, compounds of the formula 7-20 wherein, Ri is C, C5, or C6 cycloalkyl and R2 is H. In yet another aspect, the invention provides compounds of the formula 7-28, ie, compounds of the formula 7-20 wherein, Ri is C3, C5 cycloalkyl, or Cg and R2 is methyl or ethyl. In yet another aspect, the invention provides compounds of the formula 7-29, ie, compounds of the formula 7-20 wherein Ri is C3, C5 cycloalkyl, or C5 and R2 is cycloalkyl C3, C5 or Cg. In a modality one of Ri and R2 is cycloalkyl C3. In another embodiment, both of Rx and R2 are C3 cycloalkyl. In yet another aspect, the invention provides compounds of the formula 7-30, ie, compounds of the formula 7-20 wherein, R x is thienyl and R 2 is H. In yet another aspect, the invention provides compounds of the formula -31, ie, compounds of the formula 7-20 wherein Ri is thienyl and R2 is methyl or ethyl. In still another aspect, the invention provides compounds of the formula 7-32, ie, compounds of the formula 7-20 wherein, Rx is thienyl and R2 is C3, C5, or Cg cycloalkyl. In one embodiment, R2 is C3 cycloalkyl. In a further aspect, the invention provides compounds of the formula 7-33, ie, compounds according to any of the formulas 6-1, 6-2, 6-3, 6-4, 6-5, 6-6 , 6-6a, 6-7, 6-8, 6-9, 6-10, 6-11, 6-lla, 6-llb, 6-12, 6-13, 6-14 or 6-15, in where R 2 is pyridyl, pyrimidyl, -C 0 -C 1 -C 4 alkyl, C 1 -C 4 alkyl, C 1 -C 4 -OC (O) NR 'R "alkyl, benzimidazolyl, thiazolyl or imidazolyl, and R x is H, methyl, or ethyl, wherein R 'and R "are independently H or C? -C alkyl. When Ri is methyl or ethyl, Ri and R2 can be cis or trans to each other. In yet another aspect, the invention provides compounds of the formula 7-34, ie, compounds of the formula 7-33 wherein, R 2 is pyridyl, pyrimidyl, thiazolyl, benzimidazolyl or imidazolyl. In one embodiment, R2 is thiazolyl and Ri is H. In another embodiment, R2 is thiazolyl and Ri is methyl or ethyl. In yet another embodiment, R2 is pyridyl and Ri is H. In another embodiment, R2 is pyridyl and Rx is methyl or ethyl. In yet another embodiment, R2 is pyrimidyl and Ri is H. In another embodiment, R2 is pyrimidyl and Rx is methyl or ethyl. In yet another aspect, the invention provides compounds of the formula 7-35, ie, compounds of the formula 7-33 wherein, R2 is -C02-Me or -C02-Et.

In yet another aspect, the invention provides compounds of the formula 7-36, ie, compounds of the formula 7-33 wherein, R 2 is methyl, ethyl or propyl (either n or iso). In yet another aspect, the invention provides compounds of the formula 7-37, ie, compounds of the formula 7-33 wherein, R2 is -CH2-0C (0) NR 'R ", wherein R' and R" they are independently H or C? -C2 alkyl. In one modality, Rx is H. In another embodiment, Ri is ethyl. In still another aspect, the invention provides compounds of the formula 7-38, ie, compounds according to any of the formulas 6-1, 6-2, 6-3, 6-4, 6-5, 6- 6, 6-6a, 6-7, 6-8, 6-9, 6-10, 6-11, 6-lla, 6-llb, 6-12, 6-13, 6-14 or 6-15, wherein R2 and R2a combine to form oxo. In still another aspect, the invention provides compounds of the formula 7-39, ie, compounds of the formula 7-38 wherein, Rx is H, C1-C4 alkyl, C3-C6 cycloalkyl or C1-C4-OC alkyl (O) NR 'R ", wherein R' and R" are independently H or C 1 -C 4 alkyl and R a is H. In still another aspect, the invention provides compounds of the formula 7-40, ie, compounds of the formula 7-38 wherein, Ri is H, methyl or ethyl. In one embodiment, Ri is H. In another embodiment, Ri is methyl or ethyl. In still another aspect, the invention provides compounds of the formula 7-41, ie, compounds of the formula 7-38 wherein, Ri is C3, C5 or Cg cycloalkyl. In one embodiment, Ri is C3 cycloalkyl. In another embodiment, Ri is C5 or C6 cycloalkyl. In still another aspect, the invention provides compounds of the formula 7-42, ie, compounds of the formula 7-38 wherein, Ri is alkyl -C? -C2-OC (0) NR 'R ", wherein R 'and R' are independently H, methyl or ethyl. In still another aspect, the invention provides compounds of the formula 7-43, ie, compounds according to any of the formulas 6-1, 6-2, 6-3, 6-4, 6-5, 6- 6, 6-6a, 6-7, 6-8, 6-9, 6-10, 6-11, 6-lla, 6-llb, 6-12, 6-13, 6-14 or 6-15, wherein R3 is NR'R ", OH, halogen, R3a is H or halogen, or R3 and R3a combine to form oxo, = N-0H, or = N-0-C? -C alkyl. Rx is H, pyridyl, pyrimidyl, C 1 -C 4 alkyl, R 2 is H, C 1 -C 4 alkyl, pyrimidyl, pyridyl, thiazolyl, or imidazolyl, and Rla and R 2a are both H. In a further aspect, the invention provides compounds of the formula -44, ie, compounds of the formula 7-43 wherein, R3 is NR'R "; R3a is H; and Rx and R2 are independently methyl, ethyl or propyl (n or iso). In one embodiment, Rx and R2 are the same, and are cis, with each other. In another modality, Rx and R2 are the same and are trans, with each other. In another further embodiment R is methyl or ethyl and R 2 is methyl, ethyl or propyl (n or iso). In another embodiment R is methyl and R2 is methyl, ethyl or propyl (n or iso), and Rx and R2 They are cis, each other. In yet another embodiment Rx is methyl and R2 is methyl, ethyl or propyl (n or iso), and Rx and R2 are trans, with each other. In another embodiment Rx is ethyl and R2 is methyl, ethyl or propyl (n or iso), and Rx and R2 are cis, with each other. In yet another embodiment Ri is ethyl and R2 is methyl, ethyl or propyl (n or iso) and Rx and R2 are trans, with each other. In still another aspect, the invention provides compounds of formula 7-45, ie, compounds of formula 7-43 wherein, R3 is NR'R "; R3a is H; and Rx is H, methyl, ethyl or propyl; (non-iso), and R2 is H, pyrimidyl, pyridyl, thiazolyl or imidazolyl In one embodiment, Rx is H and R2 is pyrimidyl or pyridyl In another embodiment, R is H and R is thiazolyl or imidazolyl. Rx is methyl, ethyl or propyl (non-iso) and R2 is pyrimidyl or pyridyl In another embodiment, R is methyl, ethyl or propyl (non-iso) and R2 is thiazolyl or imidazolyl In another aspect, the invention provides compounds of the invention. formula 7-46, ie, compounds of the formula 7-43 wherein, R3 is NR'R "; R3a is H; and R x is pyridyl or pyrimidyl; and R2 is H. In a further aspect, the invention provides compounds of the formula 7-47, ie, compounds of the formula 7-43 wherein, R3 is NR'R "; R3a is H; Rx is pyridyl, or pyrimidyl, and R2 is pyrimidyl, pyridyl, thiazolyl or imidazolyl.

In another aspect, the invention provides compounds of the formula 7-48, ie, compounds of the formula 7-43, wherein Ri is H and R2 is methyl, ethyl or propyl (n or iso). In another embodiment R2 is methyl. In yet another embodiment R2 is ethyl. In another embodiment R2 is propyl (n or iso). In another aspect, the invention provides compounds of the formula 7-49, ie, compounds of the formula 7-43 wherein R 2 is H and R x is methyl, ethyl or propyl (n or iso). In another embodiment Ri is methyl. In yet another embodiment Ri is ethyl. In another embodiment Ri is propyl (n or iso). In still another aspect, the invention provides compounds of the formula 7-50, ie, compounds of the formula 7-43 wherein, R3 is halogen; R3a is H or halogen; and Ri and R2 are independently methyl, ethyl or propyl (n or iso). In one modality, Ri and R2 are the same, and are cis, with each other. In another mode, Ri and R2 are the same, and are trans, with each other. In an additional embodiment Ri is methyl or ethyl and R2 is methyl, ethyl or propyl (n or iso). In another embodiment Rx is methyl and R2 is methyl, ethyl or propyl (n or iso), and Ri and R2 are cis, with each other. In yet another embodiment Rx is methyl and R2 is methyl, ethyl or propyl (n or iso), and Rx and R2 are trans, with each other. In another embodiment Rx is ethyl and R2 is methyl, ethyl or propyl (n or iso), and Rx and R2 are cis, with each other. In yet another embodiment Rx is ethyl and R2 is methyl, ethyl or propyl (n or iso), and Rx and R2 are trans, to each other. In other modality, R3 and R3a are the same. When R3 and R3a are the same, they can both be F. In a further aspect, the invention provides compounds of the formula 7-51, ie, compounds of the formula 7-43 wherein, R3 is OH; R3a is H; and Rx and R2 are independently methyl, ethyl or propyl (n or iso). In one embodiment, Rx and R2 are the same, and are cis, with each other. In another modality, Rx and R2 are the same, and are trans, with each other. In yet another embodiment Rx is methyl or ethyl and R2 is methyl, ethyl or propyl (n or iso). In another embodiment Rx is methyl and R2 is methyl, ethyl or propyl (n or iso), and Rx and R2 are cis, with each other. In yet another embodiment Rx is methyl and R is methyl, ethyl or propyl (n or iso), and Rx and R2 are trans, to each other. In another embodiment Rx is ethyl and R2 is methyl, ethyl or propyl (n or iso), and Rx and R2 are cis, with each other. In yet another embodiment Rx is ethyl and R2 is methyl, ethyl or propyl (n or iso), and Rx and R2 are trans, to each other. In still another aspect, the invention provides compounds of formula 7-52, ie, compounds according to any of formulas 6-1, 6-2, 6-3, 6-4, 6-5, 6- 6, 6-6a, 6-7, 6-8, 6-9, 6-10, 6-11, 6-lla, 6-llb, 6-12, 6-13, 6-14 or 6-15, wherein R 3 and R 3a combine to form oxo, = N-0H or = N-0-C 1 -C 4 alkyl; R x is H, pyridyl, pyrimidyl, C 1 -C 4 alkyl (methyl, ethyl), or C 3 -C g cycloalkyl; R 2 is H, C 1 -C 4 alkyl (methyl, ethyl, isopropyl), pyrimidyl, pyridyl, thiazolyl or imidazolyl; and Ria and R2a are both H. In another aspect, the invention provides compounds of the formula 7-53, ie, compounds of the formula 7-52 wherein, R3 and R3a combine to form oxo; and Ri is C3-C6 cycloalkyl, pyridyl or pyrimidyl. In still another aspect, the invention provides compounds of the formula 7-54, ie, compounds of the formula 7-53 wherein, R 2 is H, C? -C alkyl. In one embodiment, R2 is methyl. In another embodiment, R2 is ethyl. In yet another embodiment, R2 is isopropyl. In yet another mode, Ri and R2 are cis to each other. In another embodiment, Rx and R2 are trans to each other. In yet another embodiment, Ri is pyrimidyl and R2 is H. In yet another embodiment, Rx is pyridyl and R2 is H. In a further embodiment, Ri is cyclopropyl and R2 is H. In a further embodiment, Ri is cyclopropyl and R2 is H. In a further aspect, the invention provides compounds of the formula 7-55, ie, compounds of the formula 7-52 wherein, R3 and Ra combine to form oxo; and Ri is H or C 1 -C 4 alkyl (such as methyl, ethyl or isopropyl). In another aspect, the invention provides compounds of the formula 7-56, ie, compounds of the formula 7-55 wherein, R 2 is H, C 1 -C 4 alkyl. In one embodiment, R2 is methyl. In another embodiment, R2 is ethyl. In yet another mode, R2 is Isopropyl. In yet another embodiment, when Ri is C? -C alkyl, then Ri and R2 are cis to each other. In yet another embodiment, when Ri is C1-C4 alkyl, then Ri and R2 are trans to each other. In another embodiment, Rx and R2 are the same, and are methyl or ethyl. In still another aspect, the invention provides compounds of formula 7-57, ie, compounds of formula 7-52 wherein Ri and R2 are both H. In a further aspect, the invention provides compounds of formula 7- 58, ie, compounds according to any of formulas 7-53 or 7-55 wherein, R2 is pyrimidyl, pyridyl, thiazolyl or imidazolyl. In one embodiment, R2 is pyrimidyl or pyridyl. In another embodiment, R2 is thiazolyl or imidazolyl. In yet another modality, when Rx is not H, then Ri and R2 are cis to each other. In yet another modality, when Rx is not H, then Ri and R2 are trans to each other. In yet another embodiment, Ri is pyrimidyl and R2 is pyrimidyl or pyridyl. In still another embodiment, Ri is pyridyl and R2 is pyrimidyl or pyridyl. In a further embodiment, Ri is cyclopropyl and R2 is pyrimidyl or pyridyl. In a further embodiment, Ri is cyclopropyl and R2 is pyrimidyl or pyridyl. In another aspect, the invention provides compounds of formula 7-59, ie, compounds of formula 7-52 wherein, R3 and R3a combine to form = N-OH; and Ri is C3-C6 cycloalkyl, pyridyl or pyrimidyl.

In yet another aspect, the invention provides compounds of the formula 7-60, ie, compounds of the formula 7-59 wherein, R 2 is H, C 1 -C 4 alkyl. In one embodiment, R2 is methyl. In another embodiment, R2 is ethyl, in yet another embodiment, R2 is isopropyl. In yet another mode, Ri and R2 are cis to each other. In another modality, Ri and R2 are trans to each other. In yet another embodiment, Ri is pyrimidyl and R2 is H. In yet another embodiment, Ri is pyridyl and R2 is H. In a further embodiment, Ri is cyclopropyl and R2 is H. In a further embodiment, Ri is cyclopropyl and R2 is H. In a further aspect, the invention provides compounds of the formula 7-61, ie, compounds of the formula 7-52 wherein, R3 and R3a combine to form = N-OH; and Ri is H or C1-C4 alkyl (such as methyl, ethyl or isopropyl). In another aspect, the invention provides compounds of formula 7-62, ie, compounds of formula 7-61 wherein, R 2 is H, C 1 -C 4 alkyl. In one embodiment, R2 is methyl. In another embodiment, R2 is ethyl. In yet another embodiment, R2 is isopropyl. In yet another embodiment, when Ri is C1-C4 alkyl, then Ri and R2 are cis to each other. In yet another embodiment, when Ri is C? -C4 alkyl, then Rx and R2 are trans to each other. In another embodiment, Rx and R2 are the same, and are methyl or ethyl.

In still another aspect, the invention provides compounds of formula 7-63, ie, compounds according to any of formulas 7-59 or 7-61 wherein, R2 is pyrimidyl, pyridyl, thiazolyl or imidazolyl. In one embodiment, R2 is pyrimidyl or pyridyl. In another embodiment, R2 is thiazolyl or imidazolyl. In yet another embodiment, when Rx is not H, then Rx and R2 are cis to each other. In yet another modality, when Rx is not H, then Rx and R2 are trans to each other. In yet another embodiment, Rx is pyrimidyl and R2 is pyrimidyl or pyridyl. In still another embodiment, Rx is pyridyl and R2 is pyrimidyl or pyridyl. In a further embodiment, Rx is cyclopropyl and R2 is pyrimidyl or pyridyl. In a further embodiment, Rx is cyclopropyl and R2 is pyrimidyl or pyridyl. In another aspect, the invention provides compounds of the formula 7-64, ie, compounds of the formula 7-52 wherein, R 3 and R 3a combine to form = N-0-C 1 -C 4 alkyl; and Rx is C3-Cg cycloalkyl, pyridyl or pyrimidyl. In still another aspect, the invention provides compounds of the formula 7-65, ie, compounds of the formula 7-64 wherein, R 2 is H, C 1 -C 4 alkyl. In one embodiment, R2 is methyl. In another embodiment, R2 is ethyl, in yet another embodiment, R2 is isopropyl. In yet another embodiment, Rx and R2 are cis to each other. In another embodiment, Rx and R2 are trans to each other. In yet another embodiment, Rx is pyrimidyl and R2 is H. In yet another embodiment, Rx is pyridyl and R2 is H. In one embodiment, further embodiment, Rx is cyclopropyl and R2 is H. In a further embodiment, Rx is cyclopropyl and R2 is H. In a further aspect, the invention provides compounds of the formula 7-66, ie, compounds of the formula 7-52 wherein, R3 and R3a combine to form = N-0-C-C4 alkyl; and R x is H or C 1 -C 4 alkyl (such as methyl, ethyl or isopropyl). In another aspect, the invention provides compounds of the formula 7-67, ie, compounds of the formula 7-66 wherein, R 2 is H, C 1 -C 4 alkyl. In one embodiment, R2 is methyl. In another embodiment, R2 is ethyl, in yet another embodiment, R2 is isopropyl. In yet another embodiment, when Ri is C? -C4 alkyl, then Rx and R2 are cis to each other. In yet another embodiment, when Rx is C? -C4 alkyl, then Ri and R2 are trans to each other. In another embodiment, Rx and R2 are the same, and are methyl or ethyl. In still another aspect, the invention provides compounds of the formula 7-68, ie, compounds according to any of the formulas 7-64 or 7-66 wherein, R2 is pyrimidyl, pyridyl, thiazolyl or imidazolyl. In one embodiment, R2 is pyrimidyl or pyridyl. In another embodiment, R2 is thiazolyl or imidazolyl. In yet another embodiment, when Rx is not H, then Rx and R2 are cis to each other. In yet another modality, when Rx is not H, then Rx and R2 are trans to each other. In yet another embodiment, Rx is pyrimidyl and R2 is pyrimidyl or pyridyl. In yet another embodiment, R is pyridyl and R 2 is pyrimidyl or pyridyl. In a further embodiment, Rx is cyclopropyl and R2 is pyrimidyl or pyridyl. In a further embodiment, Rx is cyclopropyl and R2 is pyrimidyl or pyridyl. In a further aspect, the invention provides compounds of the formula 7-69, ie, compounds according to any of the formulas 6-1, 6-2, 6-3, 6-4, 6-5, 6-6 , 6-6a, 6-7, 6-8, 6-9, 6-10, 6-11, 6-lla, 6-llb, 6-12, 6-13, 6-14 or 6-15, in where Rx is pyridyl, pyrimidyl, -C02-C? -C4 alkyl, C? -C4 alkyl, C? -C4-0C (O) NR 'R "alkyl, benzimidazolyl, thiazolyl or imidazolyl, and R2 is H, methyl, or ethyl, when R 'and R "are independently H or C? -C4 alkyl. When R2 is methyl or ethyl, Rx and R2 can be cis or trans to each other. In still another aspect, the invention provides compounds of the formula 7-70, ie, compounds of the formula 7-69 wherein, R x is pyridyl, pyrimidyl, thiazolyl, benzimidazolyl or imidazolyl. In still another aspect, the invention provides compounds of the formula 7-71, ie, compounds of the formula 7-69 wherein, Rx is -C02-Me or -C02-Et. In yet another aspect, the invention provides compounds of the formula 7-72, ie, compounds of the formula 7-69 wherein Ri is methyl, ethyl, or propyl (either n or iso). In still another aspect, the invention provides compounds of formula 7-73, ie, compounds of formula 7-69 wherein, Rx is -CH2-0C (0) NR 'R ", wherein R' and R" are independently H or C? -C2 alkyl . In one embodiment, R2 is H. In another embodiment, R2 is ethyl. In a further aspect, the invention provides compounds of the formula 7-74, ie, compounds according to any of the formulas 6-1, 6-2, 6-3, 6-4, 6-5, 6-6 , 6-6a, 6-7, 6-8, 6-9, 6-10, 6-11, 6-lla, 6-llb, 6-12, 6-13, 6-14 or 6-15, in where Ri is alkyl -C1-C4-OC (0) NR 'R ", R2 is H or alkyl -C? -C4-0C (0) NR' R"; and Ria, R2, R3 and R3a are H; wherein R 'and R "are independently H or C? -C3 alkyl In one embodiment, Ri and R2 are both -CH2-0C (0) NR' R". In yet another embodiment, R 'and R "are both H, methyl or ethyl In yet another embodiment, at least one of R' and R" is isopropyl. In still another aspect, the invention provides compounds of formula 8, ie, compounds according to any of formulas 7 up to and including 7-74, wherein R 10, R n, R 2, R 3 and Ri. they are independently H, halo, CF3, CHF2 or methyl independently. In still another aspect, the invention provides compounds of formula 8-1, ie, compounds of formula 8, wherein R 2 and R 4 are independently H, halo, or methyl. In still another aspect, the invention provides compounds of the formula 8-2, ie, compounds of the formula 8, wherein R13 is H, halogen (in one aspect, F or Cl), C? -C6 alkyl optionally substituted with -C02- (C? -C6 alkyl), C? -C6 alkoxy, CF3, 0CF3 or CN . In still another aspect, the invention provides compounds of formula 8-3, ie, compounds of formula 8 wherein R13 is phenyloxy, -S02- (C? -Cg alkyl), NR'R ", C? Alkanoyl? C6, oxazolyl, pyrazolyl, thiazolyl, imidazolyl, pyridyl, furanyl thienyl or phenyl In a further aspect, the invention provides compounds of formula 8-4, ie, compounds of formula 8, wherein R13 is -NR'R " In still another aspect, the invention provides compounds of the formula 8-5, ie, compounds of the formula 8, 8-1, 8-2 or 8-5, wherein Ri3 is chloro. In still another aspect, the invention provides compounds of the formula 8-6, ie, compounds of the formula 8, 8-1, 8-2 or 8-5, wherein R 3 is fluorine. In still another aspect, the invention provides compounds of the formula 8-7, ie, compounds of the formula 8, 8-1, 8-2 or 8-5, wherein Ri3 is CF3. In still another aspect, the invention provides compounds of the formula 8-8, ie, compounds of the formula 8, 8-1, 8-2 or 8-5, wherein Rx3 is OCF3. In still another aspect, the invention provides compounds of the formula 8-9, ie, compounds according to with any of the formulas 8, 8-2, 8-3, 8-4, 8-5, 8-6, 8-7, or 8-8, where Ri2, R? 4, Rio, and Rn are H. In another aspect, the invention provides compounds of formula 9, ie, compounds of formula 4, wherein ring A is C3-C8 cycloalkyl, which is optionally substituted in a halogen-substituted position, C? -C6 alkyl, Ci-Cg alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, aryloxy, -S02- (C?-C8 alkyl), -NR'R ", C alca-Cg alkanoyl, pyridyl, phenyl or -S02-NR'R", wherein each R 'and R "is independently H or C? -C6 alkyl, and ring B is pyrazolyl, imidazolyl, pyrrolyl, triazolyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, isoxazolyl, pyrimidyl or pyridyl, each of which is substituted optionally in a substitutable position with a group that is independently C?-C6 alkyl, C?-Cg alkoxy, amino, C alqu-Cg alkylamino, C dial-Cg dialkylamino, C?-C6-alkylthio, halo, C?-C2 haloalkyl , haloalkoxy C? -C2 or phenyl. In yet another aspect, the inve tion provides compounds of formula 10, ie, compounds of formula 9 having the following formulas: (formula 10) the cycloalkyl group is optionally substituted in a halogen-substitutable position, C? -C6 alkyl, C? -Cg alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, phenyloxy, benzyloxy, -S02- (C? -C6 alkyl), -NR "R", C?-C6 alkanoyl, pyridyl, phenyl or -S02-NR'R ", wherein each of R 'and R" is independently H or C?-C6 alkyl, In yet another aspect, the invention provides compounds of formula 10-1, ie, compounds of formula 10, wherein ring B is pyrazolyl, imidazolyl, pyrrolyl, triazolyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, isoxazolyl, pyrimidyl or pyridyl, each of which is unsubstituted In still another aspect, the invention provides compounds of formula 10-2, ie, compounds of formula 10, wherein ring B has the formula: wherein R20 is H, C? -C6 alkyl, C? -Cg alkoxy, amino, C? -C6 alkylamino, dialkylamino C? ~ Cg, alkylthio C? -Cg, halo, CF3 or phenyl. In still another aspect, the invention provides compounds of formula 10-3, ie, compounds of formula 10, wherein ring B has the formula: wherein R2o is H, C? -C4 alkyl, C? -C4 alkoxy, amino, C? -C4 alkylamino, C? -C4 dialkylamino, C? -C4 alkylthio, halo, CF3 or phenyl. In yet another aspect, the invention provides compounds of formula 10-4, ie, compounds of formula 10, wherein ring B has the formula: wherein R2o is H, C? -C4 alkyl, C? -C4 alkoxy, amino, C? -C4 alkylamino, C? -C4 dialkylamino, C? -C4 alkylthio, halo, CF3 or phenyl. In yet another aspect, the invention provides compounds of formula 10-5, ie, compounds of formula 10, wherein ring B has the formula: wherein R2o is H, C? -C4 alkyl, C? -C4 alkoxy, amino, C? -C4 alkylamino, C? -C4 dialkylamino, C? -C4 alkylthio, halo, CF3 or phenyl. In yet another aspect, the invention provides compounds of formula 10-6, ie, compounds of formula 10, wherein ring B has the formula: wherein R2o is H, C? -C4 alkyl, C? -C4 alkoxy, amino, C? -C alkylamino, C? -C4 dialkylamino, C? -C4 alkylthio, halo, CF3 or phenyl. In still another aspect, the invention provides compounds of the formula 10-6a, ie, compounds according to any of the formulas 10-3, 10-4, 10-5 or 10-6, wherein R2o is H, or alkyl C? -C6. In another embodiment, R20 is phenyl. In yet another embodiment, when the R2o group is bonded to a carbon, R2o is C?-C4 alkoxy, Cilt-C 4 alkylthio, halo, CF or phenyl. In yet another embodiment, R2o is H. In yet another aspect, the invention provides compounds of formula 10-7, ie, compounds of formula 10, wherein ring B has the formula: wherein R30 is H, C? -C4 alkyl, C? -C4 alkoxy, amino, C? -C4 alkylamino, C? -C4 dialkylamino, C? -C alkylthio, halo, CF3 or phenyl. In still another aspect, the invention provides compounds of formula 10-8, ie, compounds of formula 10, wherein ring B has the formula: In still another aspect, the invention provides compounds of formula 10-9, ie, compounds of formula 10, wherein ring B has the formula: In yet another aspect, the invention provides compounds of formula 10-10, ie, compounds of formula 10, wherein ring B has the formula: In still another aspect, the invention provides compounds of formula 10-11, ie, compounds of formula 10, wherein ring B has the formula: In yet another aspect, the invention provides compounds of formula 10-la, ie, compounds according to any of formulas 10-8, 10-9 or 10-10, wherein R30 is H, or C alquilo alkyl. Cg. In another embodiment, R3o is phenyl. In yet another embodiment, when the R3o group is bonded to a carbon, R3o is C?-C4 alkoxy, Cilt-C4 alkylthio, halo, CF3 or phenyl. In yet another embodiment, R30 is H. In another aspect, the invention provides compounds of formula 10-llb, ie, compounds according to any of formulas 10-8, 10-9 or 10-10, wherein R3o is amino, alkylamino C? -C, dialkylamino C? -C4. In yet another aspect, the invention provides compounds of formula 10-12, ie, compounds of formula 10, wherein ring B has the formula: In still another aspect, the invention provides compounds of formula 10-13, ie, compounds of formula 10, wherein ring B has the formula: In yet another aspect, the invention provides compounds of formula 10-14, ie, compounds of formula 10, wherein ring B has the formula: In yet another aspect, the invention provides compounds of formula 10-15, ie, compounds of formula 10, wherein ring B has the formula: In yet another aspect, the invention provides compounds of formula 11, ie, compounds of formulas 10, 10-1, 10-2, 10-3, 10-4, 10-5, 10-6, 10-6a , 10-7, 10-8, 10-9, 10-10, 10-11, 10-lla, 10-llb, 10-12, 10-13, 10-14, 10-15, where Ri is alkyl Ci-Cg, C3-Cg cycloalkyl, cycloalkylalkyl C-Cg, phenyl, biphenyl, phenylalkyl C? -Cg (such as benzyl or phenethyl), phenyloxyalkyl Ci-C or naphthyloxyalkyl C? -C6, wherein each aryl group is substituted optionally with 1, 2, 3, 4 or 5 groups which are independently halogen, Ci-Cg alkyl, Ci-Cd alkoxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, -C (0) NR'R ", -NR 'R', hydroxyl, -0- (CH2) 1-2- O- / -C02R ', phenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methyl pyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl; and R and R2a are both H. In yet another aspect, the invention provides compounds of the formula lia, ie, compounds of the formula 11, wherein R2 is hydrogen, halogen, Ci-Cg alkyl, C2-Cg alkenyl, wherein the alkenyl group is optionally substituted with one or more halogens; C2-C6 alkynyl, C3-Cg cycloalkyl, C? -C6 alkyl, phenyl, naphthyl, phenylalkyl C? -Cg, naphthylalkyl C? -C6, wherein each aryl group is optionally substituted with 1, 2, 3, 4 or 5 groups which are independently halogen, C? -Cg alkyl, C? -Cg alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, -C (O) NR'R ", -NR'R", hydroxyl, -O- (CH2)? _2-0-, -C (0) 0R ', phenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl. In yet another aspect, the invention provides compounds of the formula 11b, ie, compounds of the formula 11, wherein R 2 is hydrogen, pyridyl, thiazolyl, pyrimidyl, pyrazolyl, pyridyloxyalkyl C? -Ce, pyrimidyloxyalkyl C? C6, thienyloxyalkyl C? ~ Cg, pyrrolyloxyalkyl C? -Cg or thiazolyloxyalkyl C? -Cg, or alkyl -C0-C6-OC (0) -heterocycloalkyl, wherein the heterocycloalkyl group is piperazinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, S, S-thiomorpholinyl, tetrahydrofuranyl or imidazolidinyl dioxide, wherein each heteroaryl and heterocycloalkyl group is optionally substituted with one or more groups that are independently halogen, C? -Cg alkyl, C? -C6 alkoxy, C? -Cg alkanoyl, haloalkyl C? -C4, haloalkoxy C? -C4, -C (0) NR'R ", -NR'R", hydroxyl, -0- (CH2)? -2-0-, -C (0) OR ', phenyl , pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl. In yet another aspect, the invention provides compounds of the formula 11c, ie, compounds of the formula 11, wherein R 2 is hydrogen, -C02R ', CONR'R ", haloalkyl C? -C6, wherein the haloalkyl group is optionally substituted with C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxyalkyl, C 6 -C 6 -hydroxyalkyl, C 2 -C 6 -alkanoyl, C fen-C fen-phenyloxyalkyl, C na-C na-naphthyloxyalkyl, C 0 -C 6 -OC (0) NR alkyl R ", or alkyl -C0-C6-NR 'R", wherein each aryl group is optionally substituted with 1, 2, 3, 4, or 5 groups which are independently halogen, C? -Cg alkyl, C? Alkoxy? C6, C?-C6 alkanoyl, C?-C4 haloalkyl, C?-C4 haloalkoxy, -C (0) NR'R ", -NR'R", hydroxyl, -0- (CH 2) -2 -2-0- , -C (0) 0R ', phenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl; and wherein R 'and R "are independently H or C? -Cg alkyl. In yet another aspect, the invention provides compounds of the formula lid, ie, compounds of the formula 11, wherein R2 is hydrogen, or alkyl- Co-Cg-OC (0) -heterocycloalkyl, wherein the heterocycloalkyl group is piperazinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, S, S-thiomorpholinyl dioxide, tetrahydrofuranyl or imidazolidinyl, wherein the heterocycloalkyl group is optionally substituted with one or more groups which are independently halogen, C?-Cg alkyl, C?-Cg alkoxy, C?-Cg alkanoyl, C?-C4 haloalkyl, C?-C4 haloalkoxy, C (0) NR'R ", -NR'R", hydroxyl, -0- (CH2)? -2-0-, -C (0) 0R ', phenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl. Still another aspect, the invention provides compounds of the formula 11-1, ie, compounds of the formulas 10, 10-1, 10-2, 10-3, 10-4, 10-5, 10-6, 10- 6a, 10-7, 10-8, 10-9, 10-10, 10-11, 10-lla, 10-llb, 10-12, 10-13, 10-14 or 10-15, wherein Rx is pyridyl, thiazolyl, imidazolyl, benzofuranyl, benzothienyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pyridyloxyalkyl C? -Cg, benzofuranyloxyalkyl C? -Cg, benzothienyloxyalkyl C? -Cg, C 1 -C 6 -quinolinyloxyalkyl, C 1 -C 6 -isoquinolinyloxyalkyl, quinoxalinyloxyalkyl C 1 -Cg, quinazolinyloxyalkyl C 1 -Cg, C alquilo-Cg-OC alkyl (O) NR'R ", C?-C 6 -C 0 alkyl (0) - piperidinyl, -alkyl C? -C6-0C (0) -pyrrolidinyl, or C? -Cg-OC (O) -morpholinyl alkyl, wherein each heteroaryl group, and heterocycloalkyl is optionally substituted with one or more groups that are independently halogen , C? -Cg alkyl, C? -C5 alkoxy, C? -C4 haloalkyl, C -C4 haloalkoxy, -C (0) NR'R ", -NR'R", hydroxyl, -0- (CH2)? - 2-0-, -C02R ', phenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl, and R and R2a are both H. In yet another aspect, the invention provides compounds of the formula 11-la, ie, compounds of the formula 11-1, wherein R2 is hydrogen, halogen, C? -Cg alkyl, C2-Cg alkenyl, wherein the alkenyl group is optionally substituted with one or more halogens: C2-Cg alkynyl, C3-C cycloalkyl g, C3-C6 cycloalkyl-C6-C6 alkyl, phenyl, naphthyl, phenylalkyl C6-C6, naphthylalkyl C6-C6, wherein each aryl group is optionally substituted with 1, 2, 3, 4 or 5 groups which are independently halogen, Ci-Cg alkyl, C?-C6 alkoxy, C?-C6 alkanoyl, C?-C4 haloalkyl, C?-C4 haloalkoxy, C (0) NR'R ", -NR'R", hydroxyl, - 0- (CH2)? -2-0-, -C (0) 0R ", phenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl. In yet another aspect, the invention provides compounds of the formula 11-lb, ie, compounds of the formula 11-1, wherein R 2 is hydrogen, pyridyl, thiazolyl, pyrimidyl, pyrazolyl, pyridyloxyalkyl C? -C6, pyrimidyloxyalkyl C? ~ Cg, thienyloxyalkyl Ci-Cg, pyrrolyloxyalkyl C? -C6 or thiazolyloxyalkyl C? -C6 or C0-C6 alkyl-OC (0) -heterocycloalkyl, wherein the heterocycloalkyl group is piperazinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, S, S -thiomorpholinyl dioxide, tetrahydrofuranyl or imidazolidinyl, wherein each heteroaryl and heterocycloalkyl group is optionally substituted with one or more groups which are independently halogen, C 1 -Cg alkyl, Ci-Cg alkoxy, C?-Cg alkanoyl, C halo haloalkyl C, haloalkoxy C? -C4, -C (0) NR'R ", -NR'R", hydroxyl, -0- (CH2)? -2-0-, -C (0) 0R ', phenyl, pyridazinyl , pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl. In still another aspect, the invention provides compounds of the formula 11-lc, ie, compounds of the formula 11-1, wherein R 2 is hydrogen, -C02R ', CONR'R ", haloalkyl C? -C6, wherein the haloalkyl group is optionally substituted with C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxyalkyl, C 1 -C 6 hydroxyalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 phenyloxyalkyl, C 1 -C 6 naphthyloxyalkyl, C 0 -C 6 -OC alkyl (0) NR'R ", or alkyl-C0-C6-NR 'R", wherein each aryl group is optionally substituted with 1, 2, 3, 4 or 5 groups which are independently halogen, Ci-Cg alkyl, Ci-Cg alkoxy, C?-C alca alkanoyl, C?-C4 haloalkyl, C?-C4 haloalkoxy, - C (0) NR'R ", -NR'R", hydroxyl, -0- (CH2)? _2-0-, -C (0) 0R ', phenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N -methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl; and wherein R 'and R "are independently H or C?-Cg alkyl. In yet another aspect, the invention provides compounds of the formula 11-ld, ie, compounds of the formula 11-1, wherein R 2 is hydrogen , or C0-C6-OC (0) -heterocycloalkyl-alkyl, wherein the heterocycloalkyl group is piperazinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, S, S-thiomorpholinyl dioxide, tetrahydrofuranyl or imidazolidinyl, wherein the heterocycloalkyl group is optionally substituted with one or more groups which are independently halogen, C?-C6 alkyl, C?-C6 alkoxy, C?-C6 alkanoyl, C?-C4 haloalkyl, C?-C4 haloalkoxy, C (0) NR'R ", -NR 'R', hydroxyl, -0- (CH2)? -2-0-, -C (0) 0R ', phenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or in another aspect, the invention provides compounds of the formula 11-2, ie, compounds of the formula 11-1, 11-la, 11-lb, 11-lc or 11-ld, wherein Ri is pyridyl, thiazolyl, imidazolyl, benzofuranyl, benzothienyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, or quinazolinyl, wherein each heteroaryl group is optionally substituted with one or more groups that are independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, haloalkyl C1-C4, haloalkoxy C? -C4, -C (0) NR'R ", -NR'R", hydroxyl, -0- (CH2)? -2-0-, -C02R ', phenyl, pyridazinyl, pyrazinyl , pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl; and Rla and R2a are both H. In yet another aspect, the invention provides compounds of the formula 11-3, ie, compounds of the formula 11-1, 11-la, 11-lb, 11-1 cu 11-1 d, wherein Rx is Ci-Cg pyridyloxyalkyl, Ci-Cg benzofuranyloxyalkyl, Ci-Cg benzothienyloxyalkyl, C quin-Cg quinolinyloxyalkyl, C?-Cg isoquinolinyloxyalkyl, C qu-C qu quinoxalinyloxyalkyl or C?-C6 quinazolinyloxyalkyl, wherein each heteroaryl group is optionally substituted with one or more groups which are independently halogen, C? -Cg alkyl, C? -Cg alkoxy, C? -C4 haloalkyl, C? -C4 haloalkoxy, -C (0) NR'R ", -NR ' R ", hydroxyl, -0- (CH2)? _2-0-, -C02R ', phenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl; and Rla and R2a are both H. In still another aspect, the invention provides compounds of the formula 11-4, ie, compounds of the formula 11-1, 11-la, 11-lb, 11-lc or 11-ld, wherein Ri is -OC-C6-OC (0) NR 'alkyl R ", alkyl-Co-Cg-NR'R", alkyl-Ci-Cg-OC (0) -piperidinyl, alkyl-Ci-Cg-OC (0) -pyrrolidinyl or alkyl-Ci-Cg-OC (0) -morpholinyl, wherein each heterocycloalkyl group is optionally substituted with one or more groups that are independently halogen, Ci-Cg alkyl, C 1 -Cg alkoxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, -C (0) NR'R ", -NR'R", hydroxyl, -0- (CH2)? -2-0-, -C02R ', phenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methyl pyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl; and R and R2a are both H. In yet another aspect, the invention provides compounds of formula 11-5, ie, compounds according to any of formulas 10, 10-1, 10-2, 10-3, 10-4, 10-5, 10-6, 10-6a, 10-7, 10-8, 10-9, 10-10, 10-11, 10-lla, 10-llb, 10-12, 10- 13, 10-14 or 10-15, where R? is -C02R ', -CONR'R ", haloalkyl C? -C4, or hydroxyalkyl C? -C4; and Rla and R2a are both H. In one embodiment, Rx is as defined above and R2 is H. In another embodiment , Rx is as defined above and R 2 is methyl, ethyl or cyclopropyl In yet another embodiment, R x is as defined above and R 2 is C 1 -C 4 hydroxyalkyl In a further embodiment, R x and R 2 are independently -C 0 2 -alkyl C? -C4 In another embodiment, Rx and R2 are independently C? -C2 hydroxyalkyl. embodiment, Ri is hydroxyalkyl C? -C2 and R2 is methyl or ethyl. In a further aspect, the invention provides compounds of formula 11-6, ie, compounds according to any of formulas 10, 10-1, 10-2, 10-3, 10-4, 10-5, 10 -6, 10-6a, 10-7, 10-8, 10-9, 10-10, 10-11, 10-lla, 10-llb, 10-12, 10-13, 10-14 or 10-15 wherein Ri is H or Ci-Cg alkoxy, R 2 is H or C 1 -Ce alkoxy, and Rla and R 2a are both H. In one embodiment, Ri is C 1 -C 6 alkoxy and R 2 is H or C 1 alkoxy C6 In another embodiment Rx and R2 are independently C6-C6 alkoxy. In yet another embodiment Ri and R2 are both H. In another aspect, the invention provides compounds of formula 11-7, ie, compounds according to any of formulas 10, 10-1, 10-2, 10-3 , 10-4, 10-5, 10-6, 10-6a, 10-7, 10-8, 10-9, 10-10, 10-11, 10-lla, 10-llb, 10-12, 10 -13, 10-14 or 10-15, wherein Rx and R2 are both C2-C4 alkenyl optionally substituted with one or more halogens (such as F or Cl), and R and R2a are both H. In one embodiment, Ri and R2 are the same. In a further embodiment, Ri and R are both C2 alkenyl substituted with two halogens (such as F). Ri and R2 can be cis or trans to each other. In another aspect, the invention provides compounds of formula 11-8, ie, compounds according to any of formulas 10, 10-1, 10-2, 10-3, 10-4, 10-5, 10- 6, 10-6a, 10-7, 10-8, 10-9, 10-10, 10-11, 10-lla, 10-llb, 10-12, 10-13, 10-14 or 10-15, where Rx and R2 are both haloalkyl C? -C2 and R? a and R2a are both H. Rx and R2 can be cis or trans to each other. In one embodiment, Ri and R2 are the same and are -CH2F, -CH2CF3, -CH2CHF2, CF3 or -CF2CH3. In another aspect, the invention provides compounds of formula 11-9, ie, compounds according to any of formulas 10, 10-1, 10-2, 10-3, 10-4, 10-5, 10- 6, 10-6a, 10-7, 10-8, 10-9, 10-10, 10-11, 10-lla, 10-llb, 10-12, 10-13, 10-14 or 10-15, wherein Rx and R2 are both benzyl or phenethyl, and R and R2a are both H. Ri and R2 may be cis or trans to each other. In one embodiment, Ri and R2 are both benzyl. In another aspect, the invention provides compounds of formula 11-10, ie, compounds according to any of formulas 10, 10-1, 10-2, 10-3, 10-4, 10-5, 10- 6, 10-6a, 10-7, 10-8, 10-9, 10-10, 10-11, 10-lla, 10-llb, 10-12, 10-13, 10-14 or 10-15, wherein Rx and R2 are both H or C? -C4 alkyl and R? and R2a are both H. Rx and R2 may be cis or trans to each other. In one embodiment, Ri and R2 are both methyl. In another embodiment, Ri and R2 are both isopropyl. In yet another embodiment, one or Ri and R2 is methyl, while the other is isopropyl. In yet another embodiment, Ri and R2 are ethyl. In another aspect, the invention provides compounds of the formula 11-11, ie, compounds according to any of the formulas 10, 10-1, 10-2, 10-3, 10-4, 10-5, 10- 6, 10-6a, 10-7, 10-8, 10-9, 10-10, 10-11, 10-lla, 10-llb, -12, 10-13, 10-14 or 10-15, wherein Rx is H, C1-C4 alkyl, benzyl, phenethyl or phenyl, wherein the phenyl portions of Ri are optionally substituted with 1, 2 or 3 groups which are independently halogen, C? -C4 alkyl or C? -C alkoxy, and R2 is H or C? -C alkyl and R? a and R2a are both H. Ri and R2 can be cis or trans to each other. In one aspect, the invention provides compounds of the formula 11-12, ie, compounds of the formula 11-11 wherein, R 2 is H and R x is methyl, ethyl or propyl (non-iso), or Ri is H and R 2 it is methyl, ethyl or propyl (non-iso). In one embodiment, only one of Ri and R2 is isopropyl. In another embodiment, only one of Rx and R2 is ethyl. In yet another aspect, the invention provides compounds of the formula 11-13, ie, compounds of the formula 11-11 wherein, R2 is H and Ri is phenyl substituted with one or two halogens (such as F or Cl), or Ri is H and R2 is phenyl substituted with one or two halogens (such as F or Cl). In one aspect, the invention provides compounds of formula 11-14, ie, compounds of formula 11-11 wherein, R2 is H and Ri is benzyl substituted with one or two groups that are independently halogen (such as F or Cl), methyl, ethyl, methoxy or ethoxy. In still another aspect, the invention provides compounds of the formula 11-15, ie, compounds of the formula 11-11 wherein, R 2 is methyl or ethyl, and R x is methyl, ethyl or propyl (n or iso). In one embodiment, Ri and R2 are both ethyl.

In still another aspect, the invention provides compounds of the formula 11-16, ie, compounds of the formula 11-11 wherein, R 2 is methyl or ethyl, and R x is phenyl substituted with one or two halogens (such as F or Cl). In still another aspect, the invention provides compounds of the formula 11-17, ie, compounds of the formula 11-11 wherein, R 2 is methyl or ethyl, and Ri is benzyl substituted with one or two groups that are independently halogen ( such as F or Cl), methyl, ethyl, methoxy or ethoxy. In another aspect, the invention provides compounds of formula 11-18, ie, compounds according to any of formulas 10, 10-1, 10-2, 10-3, 10-4, 10-5, 10- 6, 10-6a, 10-7, 10-8, 10-9, 10-10, 10-11, 10-lla, 10-llb, 10-12, 10-13, 10-14 or 10-15, wherein Ri and R2 are independently H or -C02-C? -C4 alkyl, and R? and R2a are both H. Rx and R2 can be cis or trans to each other. In one embodiment, Ri is -C02-C C-C2 alkyl and R2 is H. In another embodiment, Ri is -C02-Et and R2 is H. In yet another embodiment, Rx is H and R2 is -C02-C-alkyl. ? -C2. In yet another embodiment, Rx and R2 are both -C02-Et. In another aspect, the invention provides compounds of formula 11-19, ie, compounds according to any of formulas 10, 10-1, 10-2, 10-3, 10-4, 10-5, 10- 6, 10-6a, 10-7, 10-8, 10-9, 10-10, 10-11, 10-lla, 10-llb, -12, 10-13, 10-14 or 10-15, where Rx and R3 form a double bond and Ria and R3a are both H. In one embodiment, R2 is H. In another embodiment, R2 is -C02- C? -C alkyl. In yet another embodiment, R2 is -C02-Et. In yet another embodiment, R2 is methyl or ethyl. In yet another embodiment, R2 is thiazolyl, pyridyl or pyrimidyl. In yet another aspect, the invention provides compounds of formula 11-20, ie, compounds according to any of formulas 10, 10-1, 10-2, 10-3, 10-4, 10-5, 10. -6, 10-6a, 10-7, 10-8, 10-9, 10-10, 10-11, 10-lla, 10-llb, 10-12, 10-13, 10-14 or 10-15 , wherein Rx is pyridyl, pyrimidyl, C3-Cg cycloalkyl or thienyl, R2 is H, C? -C4 alkyl, or C3-C6 cycloalkyl and Ria and R2a are both H. Rx and R2 may be cis or trans to each other. In still another aspect, the invention provides compounds of the formula 11-21, ie, compounds of the formula 11-20 wherein Ri is pyridyl and R2 is H. In yet another aspect, the invention provides compounds of the formula 11-22, ie, compounds of the formula 11-20 wherein Ri is pyridyl and R2 is methyl or ethyl. In a further aspect, the invention provides compounds of the formula 11-23, ie, compounds of the formula 11-20 wherein Ri is pyridyl and R2 is C3, C5 or Cg cycloalkyl. In another embodiment, R2 is C3 cycloalkyl. In still another aspect, the invention provides compounds of the formula 11-24, ie, compounds of the formula 11-20 wherein Ri is pyrimidyl and R2 is H. In another aspect, the invention provides compounds of the formula 11-25, ie, compounds of the formula 11-20 wherein, Ri is pyrimidyl and R2 is methyl or ethyl. In still another aspect, the invention provides compounds of the formula 11-26, ie, compounds of the formula 11-20 wherein Ri is pyrimidyl and R2 is C3, C5 or Cg cycloalkyl. In still another aspect, the invention provides compounds of the formula 11-27, ie, compounds of the formula 11-20 wherein Ri is C3, C5 or Cg cycloalkyl and R2 is H. In yet another aspect, the invention provides compounds of the formula 11-28, ie, compounds of the formula 11-20 wherein, Ri is C3, C5 or Cg cycloalkyl and R2 is methyl or ethyl. In still another aspect, the invention provides compounds of the formula 11-29, ie, compounds of the formula 11-20 wherein, Ri is C3, C5 or Cg cycloalkyl and R2 is cycloalkyl.

C3, C5 or Cg. In one embodiment, one of Ri and R2 is C3 cycloalkyl. In another embodiment, Ri and R2 are C3 cycloalkyl. In yet another aspect, the invention provides compounds of the formula 11-30, ie, compounds of the formula 11-20 wherein Ri is thienyl and R2 is H. In yet another aspect, the invention provides compounds of the formula -31, ie, compounds of the formula 11-20 wherein, Ri is thienyl and R2 is methyl or ethyl. In yet another aspect, the invention provides compounds of the formula 11-32, ie, compounds of the formula 11-20 wherein, Rx is thienyl and R2 is C3, C5 or Cg cycloalkyl. In one embodiment, R2 is C3 cycloalkyl. In a further aspect, the invention provides compounds of formula 11-33, ie, compounds according to any of formulas 10, 10-1, 10-2, 10-3, 10-4, 10-5, 10 -6, 10-6a, 10-7, 10-8, 10-9, 10-10, 10-11, 10-la, 10-llb, 10-12, 10-13, 10-14 or 10-15 , wherein R2 is pyridyl, pyrimidyl, -C02-C?-C4 alkyl, C?-C4 alkyl, C 1 -C 4 -alkyl (O) NR 'R ", benzimidazolyl, thiazolyl or imidazolyl, and Rx is H, methyl or ethyl, wherein R 'and R "are independently H or C? -C4 alkyl. When Rx is methyl or ethyl, Rx and R2 may be cis or trans to each other. In still another aspect, the invention provides compounds of the formula 11-34, ie, compounds of the formula 11-33 wherein, R2 is pyridyl, pyrimidyl, thiazolyl, benzimidazolyl, or imidazolyl. In one embodiment, R2 is thiazolyl and Rx is H. In another embodiment, R2 is thiazolyl and Rx is methyl or ethyl. In yet another embodiment, R2 is pyridyl and Rx is H. In another embodiment, R2 is pyridyl and Rx is methyl or ethyl. In yet another embodiment, R 2 is pyrimidyl and R x is H. In another embodiment, R 2 is pyrimidyl and R x is methyl or ethyl. In still another aspect, the invention provides compounds of the formula 11-35, ie, compounds of the formula 11-33 wherein, R2 is -C02-Me or -C02-Et. In yet another aspect, the invention provides compounds of the formula 11-36, ie, compounds of the formula 11-33 wherein, R 2 is methyl, ethyl or propyl (either n or iso). In still another aspect, the invention provides compounds of formula 11-37, ie, compounds of formula 11-33 wherein, R2 is -CH2-0C (0) NR 'R ", wherein R' and R" they are independently H or C? -C2 alkyl. In one embodiment, Ri is H. In another embodiment, Rx is ethyl. In still another aspect, the invention provides compounds of formula 11-38, ie, compounds according to any of formulas 10, 10-1, 10-2, 10-3, 10-4, 10-5, 10-6, 10-6a, 10-7, 10-8, 10-9, 10-10, 10-11, 10-la, 10-llb, 10-12, 10-13, 10-14 or 10- 15, wherein R2 and R2a combine to form oxo. In still another aspect, the invention provides compounds of the formula 11-39, ie, compounds of the formula 11-38 wherein Ri is H, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl or C 1 -C 4 alkyl (O) NR 'R ", wherein R' and R" are independently H or C? -C alkyl, and Rla is H. In yet another aspect, the invention provides compounds of the formula 11-40, ie, compounds of the formula 11-38 wherein, Rx is H, methyl or ethyl. In one embodiment, Rx is H. In another embodiment, Rx is methyl or ethyl.

In still another aspect, the invention provides compounds of the formula 11-41, ie, compounds of the formula 11-38 wherein, Rx is C3, C5 or Cg cycloalkyl. In one embodiment, Rx is C3 cycloalkyl. In another embodiment, Rx is C5 or C6 cycloalkyl. In still another aspect, the invention provides compounds of formula 11-42, ie, compounds of formula 11-38 wherein, Rx is C alquilo-C2-OC (0) NR 'R "alkyl, wherein R' and R "are independently H, methyl or ethyl. In still another aspect, the invention provides compounds of the formula 11-43, ie, compounds according to any of the formulas 10, 10-1, 10-2, 10-3, 10-4, 10-5, 10-6, 10-6a, 10-7, 10-8, 10-9, 10-10, 10-11, 10-lla, 10-llb, 10-12, 10-13, 10-14 or 10- 15, wherein R3 is NR'R ", OH, halogen, R3a is H or halogen, or R3 and R3a combine to form oxo, = N-OH, or = N-0-C? -C4 alkyl. H, pyridyl, pyrimidyl, C 1 -C 4 alkyl, R 2 is H, C 1 -C 4 alkyl, pyrimidyl, pyridyl, thiazolyl or imidazolyl, and R 2 and R 2a are both H. In a further aspect, the invention provides compounds of the formula 11-44, ie, compounds of formula 11-43 wherein, R3 is NR'R "; R3a is H; and Rx and R2 are independently methyl, ethyl or propyl (n or iso). In one embodiment, Rx and R2 are the same, and are cis, with each other. In another modality, Rx and R2 are the same, and are trans, with each other.

In yet another embodiment Rx is methyl or ethyl and R2 is methyl, ethyl or propyl (n or iso). In another embodiment Rx is methyl and R2 is methyl, ethyl or propyl (n or iso), and Ri and R2 are cis, with each other. In yet another embodiment Ri is methyl and R2 is methyl, ethyl or propyl (n or iso), and Ri and R2 are trans, with each other. In another embodiment Rx is ethyl and R2 is methyl, ethyl or propyl (n or iso), and Rx and R2 are cis, with each other. In yet another embodiment Ri is ethyl and R2 is methyl, ethyl or propyl (n or iso), and Ri and R2 are trans, with each other. In still another aspect, the invention provides compounds of the formula 11 -45, ie, compounds of the formula 11-43 wherein, R3 is NR'R "; R3a is H; and Rx is H, methyl, ethyl or propyl; (non-iso), and R2 is H, pyrimidyl, pyridyl, thiazolyl or imidazolyl In one embodiment, Ri is H and R2 is pyrimidyl or pyridyl In another embodiment, Ri is H and R2 is thiazolyl or imidazolyl. Ri is methyl, ethyl or propyl (non-iso) and R2 is pyrimidyl or pyridyl In another embodiment, Ri is methyl, ethyl or propyl (non-iso) and R2 is thiazolyl or imidazolyl In another aspect, the invention provides compounds of the invention. formula 11-46, ie, compounds of formula 11-43 wherein, R is NR'R "; R3a is H; and Ri is pyridyl or pyrimidyl; and R2 is H. In a further aspect, the invention provides compounds of the formula 11-47, ie, compounds of the formula 11-43 wherein, R3 is NR'R ", R3a is H, Rx is pyridyl, or pyrimidyl, and R2 is pyrimidyl, pyridyl, thiazolyl or imidazolyl, In another aspect, the invention provides compounds of the formula 11-48. , i.e., compounds of the formula 11-43 wherein Ri is H and R2 is methyl, ethyl or propyl (non-iso) In another embodiment R2 is methyl In yet another embodiment R2 is ethyl In another embodiment R2 is propyl (Non-iso) In another aspect, the invention provides compounds of the formula 11-49, ie, compounds of the formula 11-43 wherein R 2 is H and Ri is methyl, ethyl or propyl (non-iso). Rx modality is methyl In yet another embodiment Ri is ethyl, in another embodiment Rx is propyl (non-iso) In a further aspect, the invention provides compounds of formula 11-50, ie, compounds of formula 11-43 wherein, R3 is halogen, R3a is H or halogen, and Ri and R2 are independently methyl, ethyl or propyl (non-iso) In one embodiment, Rx and R2 are the isms, and they are cis, with each other. In another mode, Ri and R2 are the same, and are trans, with each other. In yet another embodiment Ri is methyl or ethyl and R2 is methyl, ethyl or propyl (n or iso). In another embodiment Ri is methyl and R2 is methyl, ethyl or propyl (n or iso), and Ri and R2 are cis, with each other. In yet another embodiment Ri is methyl and R2 is methyl, ethyl or propyl (n or iso), and Ri and R2 are trans, with each other. In another embodiment Ri is ethyl and R2 is methyl, ethyl or propyl (n or iso), and Ri and R2 are cis, with each other. In yet another embodiment Ri is ethyl and R2 is methyl, ethyl or propyl (n or iso), and Rx and R2 are trans, to each other. In yet another embodiment R3 and R3a are the same. When R3 and R3a are the same, they can both be F. In still another aspect, the invention provides compounds of the formula 11-51, ie, compounds of the formula 11-43 wherein, R3 is OH; R3a is H; and Rx and R2 are independently methyl, ethyl or propyl (n or iso). In one embodiment, Rx and R2 are the same, and are cis, with each other. In another modality, Rx and R2 are the same, and are trans, with each other. In yet another embodiment Rx is methyl or ethyl and R2 is methyl, ethyl or propyl (n or iso). In another embodiment Rx is methyl and R2 is methyl, ethyl or propyl (n or iso), and Rx and R2 are cis, with each other. In yet another embodiment Rx is methyl and R2 is methyl, ethyl or propyl (n or iso), and Rx and R are trans, with each other. In another embodiment Rx is ethyl and R2 is methyl, ethyl or propyl (n or iso), and R and R2 are cis, with each other. In yet another embodiment Rx is ethyl and R2 is methyl, ethyl or propyl (n or iso), and Rx and R2 are trans, to each other. In still another aspect, the invention provides compounds of the formula 11-52, ie, compounds according to any of the formulas 10, 10-1, 10-2, 10-3, 10-4, 10-5, 10-6, 10-6a, 10-7, 10-8, 10-9, 10-10, 10-11, 10-la, 10-llb, 10-12, 10-13, 10-14 or 10- 15, where R3 and R3a are combine to form oxo, = N-0H, or N-0-alkyl C? -C4; R x is H, pyridyl, pyrimidyl, C 1 -C 4 alkyl (methyl, ethyl), or C 3 -C g cycloalkyl; R 2 is H, C 1 -C 4 alkyl (methyl, ethyl, isopropyl), pipmidyl, pyridyl, thiazolyl or imidazolyl; and Rla and R2a are both H. In another aspect, the invention provides compounds of formula 11-53, ie, compounds of formula 11-52 wherein, R3 and R3a combine to form oxo; and Rx is C3-Cg cycloalkyl, pyridyl or pipmidyl. In still another aspect, the invention provides compounds of formula 11-54, ie, compounds of formula 11-53 wherein, R 2 is H, C 1 -C 4 alkyl. In one embodiment, R2 is methyl. In another embodiment, R2 is ethyl, in yet another embodiment, R2 is isopropyl. In yet another modality, Rx and R2 are cis to each other. In another modality, Rx and R2 are trans to each other. In yet another embodiment, Rx is pyrimidyl and R2 is H. In yet another embodiment, Rx is pipdyl and R2 is H. In a further embodiment, Rx is cyclopropyl and R2 is H. In a further embodiment, R? is cyclopropyl and R2 is H. In a further aspect, the invention provides compounds of formula 11-55, ie, compounds of formula 11-52 wherein, R3 and R3a combine to form oxo; and R x is H or C 1 -C 4 alkyl (such as methyl, ethyl or isopropyl). In another aspect, the invention provides compounds of Formula 11-56, ie, compounds of formula 11-55 wherein, R2 is H, Cj-C4 alkyl. In one embodiment, R2 is methyl. In another embodiment, R2 is ethyl, in yet another embodiment, R2 is isopropyl. In yet another embodiment, when Rx is C? -C4 alkyl, then Rx and R2 are cis to each other. In yet another embodiment, when Rx is C? -C4 alkyl, then Rx and R2 are trans to each other. In another embodiment, Rx and R2 are the same, and are methyl or ethyl. In still another aspect, the invention provides compounds of the formula 11-57, ie, compounds of the formula 11-52 wherein, Rx and R2 are both H. In a further aspect, the invention provides compounds of the formula 11- 58, ie, compounds according to any of formulas 11-53 or 11-55 wherein, R2 is pyrimidyl, pyridyl, thiazolyl, or imidazolyl. In one embodiment, R2 is pyrimidyl or pyridyl. In another embodiment, R2 is thiazolyl, or imidazolyl. In yet another embodiment, when Rx is not H, then Rx and R2 are cis to each other. In yet another mode, when R is not H, then Rx and R2 are trans to each other. In yet another embodiment, Rx is pyrimidyl and R2 is pyrimidyl or pyridyl. In still another embodiment, Rx is pyridyl and R2 is pyrimidyl or pyridyl. In a further embodiment, Ri is cyclopropyl and R2 is pyrimidyl or pyridyl. In a further embodiment, Rx is cyclopropyl and R2 is pyrimidyl or pyridyl.

In another aspect, the invention provides compounds of the formula 11-59, ie, compounds of the formula 11-52 wherein, R3 and R3a combine to form = N-0H; and Rx is C3-C5 cycloalkyl, pyridyl or pyrimidyl. In still another aspect, the invention provides compounds of the formula 11-60, ie, compounds of the formula 11-59 wherein, R2 is H, C? -C alkyl. In one embodiment, R2 is methyl. In another embodiment, R2 is ethyl, in yet another embodiment, R2 is isopropyl. In yet another embodiment, Rx and R2 are cis to each other. In another embodiment, Rx and R2 are trans to each other. In yet another embodiment, Rx is pyrimidyl and R2 is H. In yet another embodiment, Rx is pyridyl and R2 is H. In a further embodiment, Rx is cyclopropyl and R2 is H. In a further embodiment, Rx is cyclopropyl and R2 is H. In a further aspect, the invention provides compounds of the formula 11-61, ie, compounds of the formula 11-52 wherein, R3 and R3a combine to form = N-OH; and Rx is H or C? -C alkyl (such as methyl, ethyl or isopropyl). In another aspect, the invention provides compounds of the formula 11-62, ie, compounds of the formula 11-61 wherein, R 2 is H, C 1 -C 4 alkyl. In one embodiment, R2 is methyl. In another embodiment, R2 is ethyl, in yet another embodiment, R2 is isopropyl. In yet another embodiment, when Rx is C? -C4 alkyl, then Rx and R2 are cis to each other. In yet another modality, when Rx is C? -C4 alkyl, then Rx and R2 are trans to each other. In another embodiment, Rx and R2 are the same, and are methyl or ethyl. In still another aspect, the invention provides compounds of formula 11-63, ie, compounds according to any of formulas 11-59 or 11-61 wherein, R2 is pyrimidyl, pyridyl, thiazolyl, or imidazolyl. In one embodiment, R2 is pyrimidyl or pyridyl. In another embodiment, R2 is thiazolyl, or imidazolyl. In yet another embodiment, when Rx is not H, then Rx and R2 are cis to each other. In yet another modality, when Rx is not H, then Rx and R2 are trans to each other. In yet another embodiment, R is pyrimidyl and R2 is pyrimidyl or pyridyl. In still another embodiment, Rx is pyridyl and R2 is pyrimidyl or pyridyl. In a further embodiment, Rx is cyclopropyl and R2 is pyrimidyl or pyridyl. In a further embodiment, Ri is cyclopropyl and R2 is pyrimidyl or pyridyl. In another aspect, the invention provides compounds of the formula 11-64, ie, compounds of the formula 11-52 wherein, R3 and R3a combine to form = N-0-C? -C alkyl, and Rx is C3-C3 cycloalkyl, pyridyl or pyrimidyl. In yet another aspect, the invention provides compounds of the formula 11-65, ie, compounds of the formula 11-64 wherein, R 2 is H, C 1 -C 4 alkyl. In one embodiment, R2 is methyl. In another modality, R2 is ethyl, in yet another modality, R2 is isopropyl. In yet another embodiment, Rx and R2 are cis to each other. In another modality, Ri and R2 are trans to each other. In yet another embodiment, Ri is pyrimidyl and R2 is H. In yet another embodiment, Ri is pyridyl and R2 is H. In a further embodiment, Ri is cyclopropyl and R2 is H. In a further embodiment, Ri is cyclopropyl and R2 is H. In a further aspect, the invention provides compounds of the formula 11-66, ie, compounds of the formula 11-52 wherein, R and R3a combine to form = N-0-C1-C alkyl; and R x is H or C 1 -C 4 alkyl (such as methyl, ethyl or isopropyl). In another aspect, the invention provides compounds of formula 11-67, ie, compounds of formula 11-66 wherein, R 2 is H, C 1 -C 4 alkyl. In one embodiment, R2 is methyl. In another embodiment, R2 is ethyl, in yet another embodiment, R2 is isopropyl. In yet another embodiment, when Ri is C1-C4 alkyl, then Ri and R2 are cis to each other. In yet another embodiment, when Ri is C? -C4 alkyl, then Ri and R2 are trans to each other. In another embodiment, Ri and R2 are the same, and are methyl or ethyl. In still another aspect, the invention provides compounds of formula 11-68, ie, compounds according to any of formulas 11-64 or 11-66 wherein, R2 is pyrimidyl, pyridyl, thiazolyl, or imidazolyl. In one embodiment, R2 is pyrimidyl or pyridyl. In other embodiment, R is thiazolyl, or imidazolyl. In yet another modality, when Rx is not H, then Ri and R2 are cis to each other. In yet another mode, when Ri is not H, then Ri and R2 are trans to each other. In yet another embodiment, Ri is pyrimidyl and R2 is pyrimidyl or pyridyl. In still another embodiment, Ri is pyridyl and R2 is pyrimidyl or pyridyl. In a further embodiment, Ri is cyclopropyl and R2 is pyrimidyl or pyridyl. In a further embodiment, Ri is cyclopropyl and R2 is pyrimidyl or pyridyl. In a further aspect, the invention provides compounds of formula 11-69, ie, compounds according to any of formulas 10, 10-1, 10-2, 10-3, 10-4, 10-5, 10. -6, 10-6a, 10-7, 10-8, 10-9, 10-10, 10-11, 10-lla, 10-llb, 10-12, 10-13, 10-14 or 10-15 , wherein Rx is pyridyl, pyrimidyl, -C? 2 ~ C1-C4 alkyl, C? -C4 alkyl, C1-C4 alkyl-OC (O) NR 'R ", benzimidazolyl, thiazolyl or imidazolyl, and R2 is H, methyl or ethyl, when R 'and R "are independently H or C 1 -C 4 alkyl. When R2 is methyl or ethyl, Ri and R2 can be cis or trans to each other. In still another aspect, the invention provides compounds of the formula 11-70, ie, compounds of the formula 11-69 wherein Ri is pyridyl, pyrimidyl, thiazolyl, benzimidazolyl or imidazolyl. In yet another aspect, the invention provides compounds of the formula 11-71, ie, compounds of the formula 11-69 wherein, Ri is -C02-Me or -C02-Et. In still another aspect, the invention provides compounds of formula 11-72, ie, compounds of formula 11-69 wherein, Rx is methyl, ethyl or self (either n or iso). In still another aspect, the invention provides compounds of formula 11-73, ie, compounds of formula 11-69 wherein, Rx is -CH2-OC (0) NR 'R ", wherein R' and R" they are independently H or C? -C2 alkyl. In one embodiment, R2 is H. In another embodiment, R2 is ethyl. In a further aspect, the invention provides compounds of formula 11-74, ie, compounds according to any of formulas 10, 10-1, 10-2, 10-3, 10-4, 10-5, 10 -6, 10-6a, 10-7, 10-8, 10-9, 10-10, 10-11, 10-lla, 10-llb, 10-12, 10-13, 10-14 or 10-15 wherein R x is C 1 -C 4 -CO (O) NR 'R "alkyl; R 2 is H or C 1 -C 4 -OC (O) NR' R" alkyl; and ía 2 / R3 and R3a are H; wherein R 'and R "are independently H or C? -C3 alkyl In one embodiment, Rx and R2 are both -CH2-OC (O) NR' R". In yet another embodiment, R 'and R "are both H, methyl or ethyl In yet another embodiment, at least one of R' and R" is isopropyl. In yet another aspect, the invention provides compounds of formula 11-75, ie, compounds according to any of formulas 10, up to and including 10-15, or any of formulas 11, up to and including 11- 74, wherein the C3-C8 cycloalkyl group is cyclopropyl.

In yet another aspect, the invention provides compounds of formula 11-76, ie, compounds according to any of formulas 10, up to and including 10-15, or any of formulas 11, up to and including 11- 74, wherein the C3-C8 cycloalkyl group is cyclobutyl. In still another aspect, the invention provides compounds of formula 11-77, ie, compounds according to any of formulas 10, up to and including 10-15, or any of formulas 11, up to and including 11- 74, wherein the C-C8 cycloalkyl group is cyclopentyl. In still another aspect, the invention provides compounds of formula 11-78, ie, compounds according to any of formulas 10, up to and including 10-15, or any of formulas 11, up to and including 11- 74, wherein the C-C8 cycloalkyl group is cyclohexyl. In still another aspect, the invention provides compounds of formula 11-79, ie, compounds according to any of formulas 10, up to and including 10-15, or any of formulas 11, up to and including 11- 74, wherein the C3-C8 cycloalkyl group is cycloheptyl. In still another aspect, the invention provides compounds of the formula 11-80, ie, compounds according to any of the formulas formulas 10, up to and including 10-15, or any of the formulas 11, up to and including 11 -74, wherein the C3-C8 cycloalkyl group is cyclooctyl. In another aspect, the invention provides compounds of formula 12, ie, compounds of formula 4, wherein ring A is heteroaryl, which is optionally substituted in a halogen-substitutable position, C? -C6 alkyl, C? Alkoxy? -C6, haloalkyl, haloalkoxy, hydroxyl, CN, aryloxy, arylalkyloxy, -S02- (C? -C6 alkyl), -NR'R ", C? -C6 alkanoyl, heteroaryl, aryl, or -S02-NR'R" wherein each R 'and R "is independently H or C? -Cg alkyl, and ring B is pyrazolyl, imidazolyl, pyrrolyl, triazolyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, isoxazolyl, pyrimidyl or pyridyl each of which is substituted optionally in a substitutable position with a group that is independently C? -Cg alkyl, C? -Cg alkoxy, amino, C? -Cy alkylamino, dialkylamino C? -Cg, alkylthio C? -Cg, halo, haloalkyl C? -C2 , haloalkoxy C? ~ C2, or phenyl In another aspect the invention provides compounds of formula 13, ie, compounds of formula 12, of the mules: (formula 13) where the heteroaryl group is optionally substituted in a halogen-substitutable position, C? -Cg alkyl, C? -Cg alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, aryloxy, arylalkyloxy, -S02- (C? -C6 alkyl), -NR "R", C?-C6 alkanoyl, pyridyl, phenyl or -S02-NR'R ", wherein each R 'and R" is independently H or C?-Cg alkyl. In yet another aspect, the invention provides compounds of Formula 13-1, ie, compounds according to formula 13, wherein ring B is pyrazolyl, imidazolyl, pyrrolyl, triazolyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, isoxazolyl, pyrimidyl or pyridyl, each of which is unsubstituted In still another aspect, the invention provides compounds of formula 13-2, ie, compounds according to formula 13, wherein ring B has the formula: wherein R2o is H, C? -C6 alkyl, C? -C6 alkoxy, amino, C? -Cy alkylamino, dialkylamino C? -Cg, alkylthio C? -Cg, halo, CF3 or phenyl. In still another aspect, the invention provides compounds of formula 13-3, ie, compounds according to formula 13, wherein ring B has the formula: wherein R2o is H, C? -C4 alkyl, C? -C4 alkoxy, amino, C? -C4 alkylamino, C? -C4 dialkylamino, C? -C4 alkylthio, halo, CF3 or phenyl. In still another aspect, the invention provides compounds of formula 13-4, ie, compounds according to formula 13, wherein ring B has the formula: wherein R2o is H, C? -C4 alkyl, C? -C4 alkoxy, amino, C? -C alkylamino, C? -C4 dialkylamino, C? -C4 alkylthio, halo, CF3 or phenyl. In still another aspect, the invention provides compounds of formula 13-5, ie, compounds according to formula 13, wherein ring B has the formula: wherein R2o is H, C? -C4 alkyl, C? -C4 alkoxy, amino, C? -C4 alkylamino, C? -C4 dialkylamino, C? -C4 alkylthio, halo, CF3 or phenyl. In still another aspect, the invention provides compounds of formula 13-6, ie, compounds according to formula 13, wherein ring B has the formula: wherein R2o is H, C? -C4 alkyl, C? -C4 alkoxy, amino, C? -C4 alkylamino, C? -C4 dialkylamino, C? -C4 alkylthio, halo, CF3 or phenyl. In still another aspect, the invention provides compounds of the formula 13-6a, ie, compounds according to any of the formulas 13-3, 13-4, 13-5 or 13-6, wherein R20 is H, or alkyl C? -C6. In another embodiment, Ro is phenyl. In yet another embodiment, when the R2o group is bonded to a carbon, R20 is C? -C alkoxy, C? -C4 alkylthio, halo, CF3 or phenyl. In yet another mode, R2o is H.

In still another aspect, the invention provides compounds of formula 13-7, ie, compounds according to formula 13, wherein ring B has the formula: wherein R30 is H, C? -C4 alkyl, C? -C4 alkoxy, amino, C? -C4 alkylamino, C? -C4 dialkylamino, C? -C4 alkylthio, halo, CF3 or phenyl. In still another aspect, the invention provides compounds of formula 13-8, ie, compounds according to formula 13, wherein ring B has the formula: In still another aspect, the invention provides compounds of formula 13-9, ie, compounds according to formula 13, wherein ring B has the formula: In still another aspect, the invention provides compounds of formula 13-10, ie, compounds according to formula 13, wherein ring B has the formula: In still another aspect, the invention provides compounds of formula 13-11, ie, compounds according to formula 13, wherein ring B has the formula: In yet another aspect, the invention provides compounds of the formula 13-la, ie, compounds according to any of the formulas 13-8, 13-9 or 13-10, wherein R30 is H, or C alquilo-alkyl Cg. In another embodiment, R30 is phenyl. In yet another embodiment, when the R30 group is bonded to a carbon, R3o is C4-4 alkoxy, C4-4 alkylthio, halo, CF3 or phenyl. In yet another embodiment, R30 is H.

In another aspect, the invention provides compounds of formula 13-llb, ie, compounds according to any of formulas 13-8, 13-9 or 13-10, wherein Ro is amino, C 1 -C 4 alkylamino, dialkylamino C? -C4. In still another aspect, the invention provides compounds of formula 13-12, ie, compounds according to formula 13, wherein ring B has the formula: In still another aspect, the invention provides compounds of formula 13-13, ie, compounds according to formula 13, wherein ring B has the formula: In still another aspect, the invention provides compounds of formula 13-14, ie, compounds according to formula 13, wherein ring B has the formula: In still another aspect, the invention provides compounds of formula 13-15, ie, compounds according to formula 13, wherein ring B has the formula: In still another aspect, the invention provides compounds of formula 14, ie, compounds according to any of formulas 13, 13-1, 13-2, 13-3, 13-4, 13-5, 13- 6, 13-7, 13-8, 13-9, 13-10, 13-11, 13-12, 13-13, 13-14 or 13-15, where Rx is C alco-Cg alkoxy, C3 cycloalkyl - Cg, C3-Cg cycloalkylalkyl, phenyl, biphenyl, phenylalkyl C? -Cg (such as benzyl or phenethyl), phenyloxyalkyl C? -C6, or naphthyloxyalkyl C? -Cg, wherein each aryl group is optionally substituted with 1, 2 , 3, 4 or 5 groups which are independently halogen, C?-Cg alkyl, C alco-Cg alkoxy, C ^ ^ haloalkyl, C?-C4 haloalkoxy, -C (0) NR'R ", -NR'R" , hydroxyl, -O- (CH2)? -2-0-, -C02R ', phenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methyl pyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl; and R and R2a are both H. In yet another aspect, the invention provides compounds of formula 14a, ie, compounds of formula 14, wherein R2 is hydrogen, halogen, C? -Cg alkyl, C2-Cg alkenyl , wherein the alkenyl group is optionally substituted with one or more halogens; C2-Cg alkynyl, C3-Cg cycloalkyl, C3-C6 cycloalkyl-C? -Cg alkyl, phenyl, naphthyl, phenylalkyl C? -Cg, naphthylalkyl C? -C6, wherein each aryl group is optionally substituted with 1, 2, 3, 4 or 5 groups which are independently halogen, C?-Cg alkyl, C alco-Cg alkoxy, C?-C6 alkanoyl, C?-C4 haloalkyl, C?-C4 haloalkoxy, C (0) NR'R ", -NR'R ", hydroxyl, -0- (CH2)? -2-0-, -C (0) 0R ', phenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methyl pyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl. In yet another aspect, the invention provides compounds of formula 14, ie, compounds of formula 14, wherein R 2 is hydrogen, pyridyl, thiazolyl, pyrimidyl, pyrazolyl, pyridyloxyalkyl C? -C3, pyrimidyloxyalkyl C? -Cg alkyl, thienyloxyalkyl C? -Cg, pyrrolyloxyalkyl C? -Cg alkyl or thiazolyloxyalkyl C? -C6 or C0-Cg-OC (O) -heterocycloalkyl alkyl, wherein the heterocycloalkyl group is piperazinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, S, S-dioxide of thiomorpholinyl, tetrahydrofuranyl or imidazolidinyl, wherein each heteroaryl and heterocycloalkyl group is optionally substituted with one or more groups which are independently halogen, C? -Cg alkyl, C? -C6 alkoxy, C? -C6 alkanoyl, C? -C4 haloalkyl , haloalkoxy C? -C4, -C (0) NR'R ", -NR'R", hydroxyl, -0- (CH2)? -2-0-, -C (0) 0R ', phenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl. In yet another aspect, the invention provides compounds of formula 14c, ie, compounds of formula 14, wherein R 2 is hydrogen, -C02R ', CONR'R ", haloalkyl C? -Cd, wherein the haloalkyl group is optionally substituted with C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxyalkyl, C?-C hidro hydroxyalkyl, C 2 -C 6 -alkanoyl, C fen-C fen-phenyloxyalkyl, C?-C6-naphthyloxyalkyl, C 0 -C 6 -OC (0) NR 'R alkyl ", alkyl C0-C6-NR'R", wherein each aryl group is optionally substituted with 1, 2, 3, 4 or 5 groups that are independently halogen, C? -Cg alkyl, C? -Cg alkoxy, C-alkanoyl -C6, haloalkyl C? -C, haloalkoxy C? -C4, -C (0) NR'R ", -NR'R", hydroxyl, -0- (CH2)? -2-0-, -C ( 0) 0R ', phenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl, and wherein R' and R "are independently H or C? -Cg alkyl. In yet another aspect, the invention provides compounds of formula 14d, ie, compounds of formula 14, wherein R 2 is hydrogen, or alkyl Co-Cg-OC (O) -heterocycloalkyl, wherein the heterocycloalkyl group is piperazinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, S, S-thiomorpholinyl dioxide, tetrahydrofuranyl or imidazolidinyl, wherein the heterocycloalkyl group is optionally substituted with one or more groups which are independently halogen, C alquilo-C alquilo alkyl, C?-Cg alkoxy, C?-Cg alkanoyl, C?-C4 haloalkyl, C?-C4 haloalkoxy, C (O) NR'R ", -NR'R", hydroxyl, -O- (CH2)? -2-0-, -C (0) OR ', phenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl. In still another aspect, the invention provides compounds of formula 14-1, ie, compounds according to any of formulas 13, 13-1, 13-2, 13-3, 13-4, 13-5, 13-6, 13-7, 13-8, 13-9, 13-10, 13-11, 13-12, 13-13, 13-14 or 13-15, wherein R is pyridyl, thiazolyl, imidazolyl, benzofuranyl, benzothienyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pyridyloxyalkyl C? -Cg, benzofuranyloxyalkyl C? -C6, benzothienyloxyalkyl C? -C6, quinolinyloxyalkyl C? -Cg, isoquinolinyloxyalkyl C? -Cg, quinoxalynyloxyalkyl C? -Cg, quinazolinyloxyalkyl C? -C6, C? -C6-OC (O) NR 'R "alkyl, C? -C6-OC (O) -piperidinyl alkyl, C? -Cg-OC (O) -pyrrolidinyl alkyl, or C-alkyl ? -Cg-OC (O) -morpholinyl, wherein each heteroaryl and heterocycloalkyl group is optionally substituted with one or more groups which are independently halogen, C? -C6 alkyl, C? -Ce alkoxy, C? -C4 haloalkyl, haloalkoxy C? -C4, -C (0) NR'R ", -NR'R", hydroxyl, -O- (CH2)? -2- 0-, -C02R ', phenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl, or imidazolyl; and R a and R 2a are both H. In still another aspect, the invention provides compounds of the formula 14-la, ie, compounds of the formula 14-1, wherein R 2 is hydrogen, halogen, C 1 -C 6 alkyl, alkenyl C2-C6, wherein the alkenyl group is optionally substituted with one or more halogens; C2-Cg alkynyl, C3-Cg cycloalkyl, C3-C6 cycloalkyl-C6-C6 alkyl, phenyl, naphthyl, phenylalkyl Ci-Cg, naphthylalkyl Ci-Cg, wherein each aryl group is optionally substituted with 1, 2, 3, 4 or 5 groups which are independently halogen, Ci-Cg alkyl, Ci-Cg alkoxy, Cx-Cg alkanoyl, C?-C4 haloalkyl, C?-C4 haloalkoxy, -C (O) NR'R ", -NR ' R ", hydroxyl, -O- (CH2)? -2-0-, -C (0) OR ', phenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl. In still another aspect, the invention provides compounds of the formula 14-lb, ie, compounds of the formula 14-1, wherein R 2 is hydrogen, pyridyl, thiazolyl, pyrimidyl, pyrazolyl, pyridyloxyalkyl, C 1 -C 6, pyrimidyloxyalkyl C? ~ C6, thienyloxyalkyl C? -C6, pyrrolyloxyalkyl Ci-Cg, or thiazolyloxyalkyl C? ~ Cg, or C0-C6-OC (O) -heterocycloalkyl alkyl, wherein the heterocycloalkyl group is piperazinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, S, S-thiomorpholinyl dioxide, tetrahydrofuranyl or imidazolidinyl, wherein each heteroaryl and heterocycloalkyl group is optionally substituted with one or more groups that are independently halogen, Ci-Cg alkyl, Ci-Cg alkoxy, C?-C4 haloalkyl, C?-C4 haloalkoxy, -C (O) NR 'R', -NR'R ", hydroxyl, -O- (CH2)? _2-0-, -C (0) OR ', phenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N- benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl. In still another aspect, the invention provides compounds of the formula 14-lc, ie, compounds of the formula 14-1, wherein R2 is hydrogen, -C02R ', CONR'R ", haloalkyl C? -C6, wherein the haloalkyl group is optionally substituted with C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxyalkyl, Ci-Cg hydroxyalkyl, C 2 -Cg alkanoyl, C 1 -C 6 phenyloxyalkyl, C 6 -C 6 naphthyloxyalkyl, C 0 -C 5 alkyl OC (O) NR 'R ", alkyl-C0-C6-NR' R", wherein each aryl group is optionally substituted with 1, 2, 3, 4 or 5 groups which are independently halogen, Ci-Cg alkyl, Ci-Cg alkoxy, C? -Cg alkanoyl, C? -C4 haloalkyl, C? -C4 haloalkoxy, -C (O) NR'R ", -NR'R", hydroxyl, -O- (CH2)? -2-0-, - C (0) OR ', phenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl, and wherein R' and R "are independently H or C? -Cg alkyl? . In yet another aspect, the invention provides compounds of the formula 14-ld, ie, compounds of the formula 14-1, wherein R2 is hydrogen, or C0-C3-OC (O) -heterocycloalkyl alkyl, wherein the heterocycloalkyl group is piperazinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, S, S-thiomorpholinyl dioxide, tetrahydrofuranyl or imidazolidinyl, wherein the heterocycloalkyl group optionally substituted with one or more groups which are independently halogen, C? -Cg alkyl, C? -Cg alkoxy, Cx-Cg alkanoyl, C? -C4 haloalkyl, C? -C4 haloalkoxy, C (0) NR? R. , -NR'R ", hydroxyl, -O- (CH2)? _2-0-, -C (0) OR ', phenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl , oxazolyl or imidazolyl. In still another aspect, the invention provides compounds of formula 14-2, ie, compounds according to any of formulas 14-1, 14-la, 14-lb, 14-lc or 14-ld, wherein R 1 is pyridyl, thiazolyl, imidazolyl, benzofuranyl, benzothienyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl or quinazolinyl, wherein each heteroaryl group is optionally substituted with one or more groups that are independently halogen, C 1 -C 6 alkyl, C 1 alkoxy; Cg, haloalkyl C? -C4, haloalkoxy C? ~ C4, -C (O) NR'R ", -NR'R", hydroxyl, -O- (CH2)? -2-0-, -C02R ', phenyl , pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl; and Rla and R2a are both H. In still another aspect, the invention provides compounds of formula 14-3, ie, compounds according to any of formulas 14-1, 14-la, 14-lb, 14-lc or 14-ld, wherein Rx is C? -Cg pyridyloxyalkyl, C? -C6 benzofuranyloxyalkyl, C? -Cg benzothienyloxyalkyl, C? -Cg quinolinyloxyalkyl, C? -Cg isoquinolinyloxyalkyl, C? -C6 quinoxalinyloxyalkyl or C? -Cg quinazolinyloxyalkyl, wherein each group heteroaryl is optionally substituted with one or more groups which are independently halogen, C? -Cg alkyl, C? -C6 alkoxy, C? -C4 haloalkyl, C? -C4 haloalkyl, -C (O) NR'R ", -NR 'R', hydroxyl, -O- (CH2)? -2-0-, -C02R ', phenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl; and Rla and R2a are both H. In yet another aspect, the invention provides compounds of formula 14-4, ie, compounds according to formula 14-1, 14-la, 14-lb, 14-lc or 14-ld, wherein Rx is C0-C6-OC (O) NR 'R "alkyl, C0-C6-NR'R alkyl, C? -C6-0C (O) -piperidinyl alkyl, C? -Cg alkyl -OC (O) -pyrrolidinyl or C? -Cg-OC (O) -morpholinyl alkyl, wherein each heterocycloalkyl group is optionally substituted with one or more groups which are independently halogen, C? -Cg alkyl, C? -C6 alkoxy , C? -C4 haloalkyl, C? -C4 haloalkoxy, -C (O) NR'R ", -NR'R ", hydroxyl, -0- (CH2)? -2-O-, -C02R ', phenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl, or imidazolyl; and Rla and R2a are both H. In yet another aspect, the invention provides compounds of formula 14-5, ie, compounds according to any of formulas 13, 13-1, 13-2, 13- 3, 13-4, 13-5, 13-6, 13-6a, 13-7, 13-8, 13-9, 13-10, 13-11, 13-lla, 13-llb, 13-12, 13-13, 13-14 or 13-15 wherein Rx is -C02R ', -CONR'R ", haloalkyl C? -C4, or hydroxyalkyl C? -C4; and R a and R 2a are both H. In one embodiment, R x is as defined above and R 2 is H. In another embodiment, R x is as defined above and R 2 is methyl, ethyl or cyclopropyl. In yet another embodiment, Rx is as defined above and R2 is hydroxyalkyl C? -C4. In a further embodiment, Rx and R2 are independently -C02-C?-C4 alkyl. In another embodiment, Ri and R 2 are independently C 1 -C 2 hydroxyalkyl. In yet another embodiment, Rx is hydroxyalkyl C? -C2 and R2 is methyl or ethyl. In a further aspect, the invention provides compounds of the formula 14-6, ie, compounds according to any of the formulas 13, 13-1, 13-2, 13-3, 13-4, 13-5, 13 -6, 13-6a, 13-7, 13-8, 13-9, 13-10, 13-11, 13-lla, 13-llb, 13-12, 13-13, 13-14 or 13-15 wherein Rx is H or C? -Cg alkoxy, R2 is H or C? -C6 alkoxy, and Rla and R2a are both H.

In one embodiment, Rx is C6-C6 alkoxy and R2 is H or C6-C6 alkoxy. In another embodiment Rx and R2 are independently C6-C6 alkoxy. In yet another embodiment Rx and R2 are both H. In another aspect, the invention provides compounds of the formula 14-7, ie, compounds according to any of the formulas 13, 13-1, 13-2, 13-3 , 13-4, 13-5, 13-6, 13-6a, 13-7, 13-8, 13-9, 13-10, 13-11, 13-lla, 13-llb, 13-12, 13 -13, 13-14 or 13-15 wherein Rx and R2 are both C2-C4 alkenyl optionally substituted with one or more halogens (such as F or Cl), and Rla and R2a are both H. In one embodiment, Rx and R2 are the same. In a further embodiment, Ri and R2 are both C2 alkenyl substituted with two halogens (such as F). Ri and R2 can be cis or trans to each other. In another aspect, the invention provides compounds of formula 14-8, ie, compounds according to any of formulas 13, 13-1, 13-2, 13-3, 13-4, 13-5, 13- 6, 13-6a, 13-7, 13-8, 13-9, 13-10, 13-11, 13-lla, 13-llb, 13-12, 13-13, 13-14 or 13-15 in where Ri and R2 are both haloalkyl C -C2 and R a and R2a are both H. Rx and R2 can be cis or trans to each other. In one embodiment, Rx and R2 are the same and are -CH2F, -CH2CF3, -CH2CHF2, CF3, or -CF2CH3. In another aspect, the invention provides compounds of the formula 14-9, ie, compounds according to any of the formulas 13, 13-1, 13-2, 13-3, 13-4, 13-5, 13- 6, 13-6a, 13-7, 13-8, 13-9, 13-10, 13-11, 13-lla, 13-llb, 13-12, 13-13, 13-14 or 13-15 where Rx and R2 are both benzyl or phenethyl, and R a and R2a are both H. Ri and R2 can be cis or trans to each other. In one embodiment, Ri and R2 are both benzyl. In another aspect, the invention provides compounds of formula 14-10, ie, compounds according to any of formulas 13, 13-1, 13-2, 13-3, 13-4, 13-5, 13- 6, 13-6a, 13-7, 13-8, 13-9, 13-10, 13-11, 13-lla, 13-llb, 13-12, 13-13, 13-14 or 13-15 in where Ri and R2 are both H or C? -C alkyl and R? and R2a are both H. Ri and R2 can be cis or trans to each other. In one embodiment, Ri and R2 are both methyl. In another embodiment, both Ri and R2 are isopropyl. In yet another embodiment, one or Ri and R2 is methyl, while the other is isopropyl. In yet another embodiment, Ri and R2 are ethyl. In another aspect, the invention provides compounds of formula 14-11, ie, compounds according to any of formulas 13, 13-1, 13-2, 13-3, 13-4, 13-5, 13- 6, 13-6a, 13-7, 13-8, 13-9, 13-10, 13-11, 13-llat 13-llb, 13-12, 13-13, 13-14 or 13-15 where R x is H, C 1 -C 4 alkyl, benzyl, phenethyl or phenyl, wherein the phenyl portions of Ri are optionally substituted with 1, 2 or 3 groups which are independently halogen, C 1 -C 4 alkyl, or C 1 alkoxy; C4 and R2 is H or C?-C4 alkyl and R a and R 2a are both H. Ri and R 2 can be cis or trans to each other. In one aspect, the invention provides compounds of the formula 14-12, ie, compounds of the formula 14-11 in 10Í where R 'is H and Ri is methyl, ethyl or propyl (n or iso), or Rx is H and R2 is methyl, ethyl or propyl (n or iso). In one embodiment, only one of Ri and R2 is isopropyl. In another embodiment, only one of Ri and R2 is ethyl. In yet another aspect, the invention provides compounds of formula 14-13, ie, compounds of formula 14-11 wherein, R 2 is H and R x is phenyl substituted with one or two halogens (such as F or Cl), or Ri is H and R2 is phenyl substituted with one or two halogens (such as F or Cl). In one aspect, the invention provides compounds of the formula 14-14, ie, compounds of the formula 14-11 wherein, R is H and Ri is benzyl substituted with one or two groups that are independently halogen (such as F or Cl), methyl, ethyl, methoxy or ethoxy. In yet another aspect, the invention provides compounds of the formula 14-15, ie, compounds of the formula 14-11 wherein, R 2 is methyl or ethyl, and Ri is methyl, ethyl or propyl (n or iso). In one embodiment, Ri and R2 are ethyl. In still another aspect, the invention provides compounds of formula 14-16, ie, compounds of formula 14-11 wherein, R 2 is methyl or ethyl, and Ri is phenyl substituted with one or two halogens (such as F or Cl). In still another aspect, the invention provides compounds of the formula 14-17, ie, compounds of the formula 14-11 wherein, R 2 is methyl or ethyl, and Ri is benzyl substituted with one or two groups which are independently halogen (such as F or Cl), methyl, ethyl, methoxy or ethoxy. In another aspect, the invention provides compounds of the formula 14-18, ie, compounds according to any of the formulas 13, 13-1, 13-2, 13-3, 13-4, 13-5, 13- 6, 13-6a, 13-7, 13-8, 13-9, 13-10, 13-11, 13-lla, 13-llb, 13-12, 13-13, 13-14 or 13-15 in where Rx and R2 are independently H or -C0-C? -C alkyl, and Rla and R2a are both H. Ri and R2 can be cis or trans to each other. In one embodiment, Ri is -C02-C-C2 alkyl and R2 is H. In another embodiment, Rx is -C02-Et and R2 is H. In yet another embodiment, Rx is H and R2 is -C02-C-alkyl. ? -C2. In yet another embodiment, Ri and R are both -C02-Et. In another aspect, the invention provides compounds of the formula 14-19, ie, compounds according to any of the formulas 13, 13-1, 13-2, 13-3, 13-4, 13-5, 13- 6, 13-6a, 13-7, 13-8, 13-9, 13-10, 13-11, 13-lla, 13-llb, 13-12, 13-13, 13-14 or 13-15 in where Rx and R3 form a double bond and R? and R3a are both H. In one embodiment, R2 is H. In another embodiment, R2 is -C02-C? -C4 alkyl. In yet another embodiment, R2 is -C02-Et. In yet another embodiment, R2 is methyl or ethyl. In yet another embodiment, R2 is thiazolyl, pyridyl or pyrimidyl. In still another aspect, the invention provides compounds of the formula 14-20, ie, compounds in accordance with any of the formulas 13, 13-1, 13-2, 13-3, 13-4, 13-5, 13-6, 13-6a, 13-7, 13-8, 13-9, 13-10, 13-11, 13-lla, 13-llb, 13-12, 13-13, 13-14 or 13-15 wherein Ri is pyridyl, pyrimidyl, C3-C6 cycloalkyl, or thienyl, R2 is H, alkyl C? -C4 or C3-C6 cycloalkyl, and Rla and R2a are both H. R and R2 can be cis or trans to each other. In still another additional aspect, the invention provides compounds of the formula 14-21, ie, compounds of the formula 14-20 wherein, Rx is pyridyl and R2 is H. In yet another aspect, the invention provides compounds of the formula 14-22, ie, compounds of the formula 14-20 wherein, Rx is pyridyl and R2 is methyl or ethyl. In a further aspect, the invention provides compounds of the formula 14-23, ie, compounds of the formula 14-20 wherein, Rx is pyridyl and R2 is C3, C5 or C6 cycloalkyl. In another embodiment, R2 is C3 cycloalkyl. In yet another aspect, the invention provides compounds of the formula 14-24, ie, compounds of the formula 14-20 wherein, Rx is pyrimidyl and R2 is H. In another aspect, the invention provides compounds of the formula 14- 25, ie, compounds of the formula 14-20 wherein, Rx is pyrimidyl and R2 is methyl or ethyl. In yet another aspect, the invention provides compounds of the formula 14-26, ie, compounds of the formula 14-20 wherein, Rx is pyrimidyl and R2 is C3, C5 or Cg cycloalkyl.

In still another aspect, the invention provides compounds of the formula 14-27, ie, compounds of the formula 14-20 wherein, Rx is C3, C5 or Cg cycloalkyl and R2 is H. In yet another aspect, the invention provides compounds of the formula 14-28, ie, compounds of the formula 14-20 wherein, Rx is C3, C5 or Cg cycloalkyl and R2 is methyl or ethyl. In yet another aspect, the invention provides compounds of the formula 14-29, ie, compounds of the formula 14-20 wherein, Rx is C3, C5 or Cg cycloalkyl and R2 is cycloalkyl C3, C5 or Cg. In a modality one of Ri and R2 is cycloalkyl C3. In another embodiment, Rx and R2 are C3 cycloalkyl. In still another aspect, the invention provides compounds of the formula 14-30, ie, compounds of the formula 14-20 wherein Ri is thienyl and R2 is H. In still another aspect, the invention provides compounds of the formula -31, ie, compounds of the formula 14-20 wherein Ri is thienyl and R2 is methyl or ethyl. In still another aspect, the invention provides compounds of the formula 14-32, ie, compounds of the formula 14-20 wherein Ri is thienyl and R2 is C3, C5 or C6 cycloalkyl. In one embodiment, R2 is C3 cycloalkyl. In a further aspect, the invention provides compounds of formula 14-33, ie, compounds according to any of formulas 13, 13-1, 13-2, 13-3, 13-4, 13-5, 13-6, 13-6a, 13-7, 13-8, 13-9, 13-10, 13-11, 13-lla, 13-llb, 13-12, 13- 13, 13-14 or 13-15 wherein R2 is pyridyl, pyrimidyl, -C02-C alquilo-C4 alkyl, C?-C alkyl, C 1 -C 4 -alkyl (O) NR 'R ", benzimidazolyl, thiazolyl or imidazolyl and Ri is H, methyl or ethyl, wherein R 'and R "are independently H or C 1 -C 4 alkyl. When Ri is methyl or ethyl, Ri and R2 can be cis or trans to each other. In yet another aspect, the invention provides compounds of the formula 14-34, ie, compounds of the formula 14-33 wherein, R 2 is pyridyl, pyrimidyl, thiazolyl, benzimidazolyl or imidazolyl. In one embodiment, R2 is thiazolyl and Ri is H. In another embodiment, R2 is thiazolyl and Rx is methyl or ethyl. In yet another embodiment, R 2 is pyridyl and R x is H. In another embodiment, R is pyridyl and R x is methyl or ethyl. In yet another embodiment, R 2 is pyrimidyl and R x is H. In another embodiment, R 2 is pyrimidyl and R x is methyl or ethyl. In yet another aspect, the invention provides compounds of formula 14-35, ie, compounds of formula 14-33 wherein, R2 is -C02-Me or -C02-Et. In yet another aspect, the invention provides compounds of the formula 14-36, ie, compounds of the formula 14-33 wherein, R 2 is methyl, ethyl or propyl (either n or iso). In still another aspect, the invention provides compounds of the formula 14-37, ie, compounds of the formula 14-33 wherein, R2 is -CH2-OC (O) NR 'R ", wherein R' and R" They are independently H or C? -C2 alkyl. In one embodiment, Rx is H. In another embodiment, Ri is ethyl. In still another aspect, the invention provides compounds of formula 14-38, ie, compounds according to any of formulas 13, 13-1, 13-2, 13-3, 13-4, 13-5, 13-6, 13-6a, 13-7, 13-8, 13-9, 13-10, 13-11, 13-lla, 13-llb, 13-12, 13-13, 13-14 or 13- Where R2 and R2a combine to form oxo. In yet another aspect, the invention provides compounds of the formula 14-39, ie, compounds of the formula 14-38 wherein, Rx is H, C? -C4 alkyl, C3-Cg cycloalkyl, or alkyl C1-C4-OC (O) NR 'R ", wherein R' and R" are independently H or C? -C4 alkyl and Ri3 is H. In yet another aspect, the invention provides compounds of the formula 14-40, that is, compounds of the formula 14-38 wherein, Rx is H, methyl or ethyl. In one embodiment, Ri is H. In another embodiment, Ri is methyl or ethyl. In still another aspect, the invention provides compounds of the formula 14-41, ie, compounds of the formula 14-38 wherein Ri is C3, C5 or Cg cycloalkyl. In one embodiment, Ri is C3 cycloalkyl. In another embodiment, Rx is C5 cycloalkyl or Cs. In still another aspect, the invention provides compounds of the formula 14-42, ie, compounds of the formula 14-38 wherein, Rx is C -C2-OC-C (O) NR 'R "alkyl, in where R 'and R "are independently H, methyl or ethyl In yet another aspect, the invention provides compounds of the formula 14-43, ie, compounds according to any of the formulas 13, 13-1, 13- 2, 13-3, 13-4, 13-5, 13-6, 13-6a, 13-7, 13-8, 13-9, 13-10, 13-11, 13-lla, 13-llb, 13-12, 13-13, 13-14 or 13-15 wherein R3 is NR'R ", OH, halogen, R3a is H or halogen; or R3 and R3a combine to form oxo, = N-0H or = N-0-C C-C alkyl. Ri is H, pyridyl, pyrimidyl, C 1 -C 4 alkyl; R 2 is H, C 1 -C 4 alkyl, pyrimidyl, pyridyl, thiazolyl or imidazolyl; and R and R2a are both H. In a further aspect, the invention provides compounds of formula 14-44, ie, compounds of formula 14-43 wherein, R3 is NR'R "; R3a is H; Rx and R2 are independently methyl, ethyl or propyl (non-iso) In one embodiment, Ri and R2 are the same, and are cis, with each other In another embodiment, Rx and R2 are the same, and are trans, with each other In yet another embodiment Rx is methyl or ethyl and R2 is methyl, ethyl or propyl (non-iso) In another embodiment Rx is methyl and R2 is methyl, ethyl or propyl (non-iso), and Ri and R2 are cis, In yet another mode Ri is methyl and R2 is methyl, ethyl or propyl (non-iso), and Ri and R2 are trans, each other In another embodiment Ri is ethyl and R2 is methyl, ethyl or propyl (non-iso) and Ri and R2 are cis, each other In another embodiment Ri is ethyl and R2 is methyl, ethyl or propyl (non-iso), and Ri and R2 are trans, each other. In still another aspect, the invention provides compounds of formula 14-45, ie, compounds of formula 14-43 wherein, R3 is NR'R "; R3a is H; and Rx is H, methyl, ethyl or propyl; (non-iso), and R2 'is H, pyrimidyl, pyridyl, thiazolyl, or imidazolyl In one embodiment, Rx is H and R2 is pyrimidyl or pyridyl In another embodiment, Ri is H and R2 is thiazolyl or imidazolyl. RI is methyl, ethyl or propyl (non-iso) and R2 is pyrimidyl or pyridyl In another embodiment, Ri is methyl, ethyl or propyl (non-iso) and R2 is thiazolyl or imidazolyl In another aspect, the invention provides compounds of the formula 14-46, ie, compounds of the formula 14-43 wherein, R3 is NR'R "; R3a is H; and Ri is pyridyl or pyrimidyl; and R2 is H. In a further aspect, the invention provides compounds of the formula 14-47, ie, compounds of the formula 14-43 wherein, R3 is NR'R "; R3a is H; Rx is pyridyl, or pyrimidyl, and R2 is pyrimidyl, pyridyl, thiazolyl, or imidazolyl In another aspect, the invention provides compounds of the formula 14-48, ie, compounds of the formula 14-43 wherein Ri is H and R2 is methyl, ethyl or propyl (non-iso) In another embodiment R2 is methyl In yet another embodiment R2 is ethyl In another embodiment R2 is propyl (non-iso).

In another aspect, the invention provides compounds of formula 14-49, ie, compounds of formula 14-43 wherein R 2 is H and R is methyl, ethyl or propyl (n or iso). In another embodiment, Rx is methyl. In yet another embodiment Rx is ethyl. In another embodiment Rx is propyl (n or iso). In still another aspect, the invention provides compounds of the formula 14-50, ie, compounds of the formula 14-43 wherein, R3 is halogen; R3a is H or halogen; and Rx and R2 are independently methyl, ethyl or propyl (n or iso). In one embodiment, R and R2 are the same, and are cis, with each other. In another modality, Rx and R2 are the same, and are trans, with each other. In yet another embodiment Rx is methyl or ethyl and R2 is methyl, ethyl or propyl (n or iso). In another embodiment Rx is methyl and R2 is methyl, ethyl or propyl (n or iso), and Rx and R2 are cis, with each other. In yet another embodiment Rx is methyl and R2 is methyl, ethyl or propyl (n or iso), and Ri and R2 are trans, with each other. In another embodiment Ri is ethyl and R2 is methyl, ethyl or propyl (n or iso), and Rx and R2 are cis, with each other. In yet another embodiment Rx is ethyl and R2 is methyl, ethyl or propyl (n or iso), and Rx and R2 are trans, to each other. In yet another modality R3 and Ra are the same. When R3 and R3a are the same, they may both be F. In a further aspect, the invention provides compounds of the formula 14-51, ie, compounds of the formula 14-43 wherein, R is OH; R3a is H; and Rx and R2 are independently methyl, ethyl or propyl (n or iso). In one embodiment, Rx and R2 are the same, and are cis, with each other. In another modality, Rx and R2 are the same, and are trans, with each other. In yet another embodiment Rx is methyl or ethyl and R2 is methyl, ethyl or propyl (n or iso). In another embodiment R is methyl and R2 is methyl, ethyl or propyl (n or iso), and Rx and R2 are cis, with each other. In yet another embodiment Rx is methyl and R2 is methyl, ethyl or propyl (n or iso), and Rx and R2 are trans, with each other. In another embodiment Rx is ethyl and R2 is methyl, ethyl or propyl (n or iso), and Rx and R2 are cis, with each other. In yet another embodiment Rx is ethyl and R2 is methyl, ethyl or propyl (n or iso), and R and R2 are trans, to each other. In still another aspect, the invention provides compounds of the formula 14-52, ie, compounds according to any of the formulas 13, 13-1, 13-2, 13-3, 13-4, 13-5, 13-6, 13-6a, 13-7, 13-8, 13-9, 13-10, 13-11, 13-lla, 13-llb, 13-12, 13-13, 13-14 or 13- Wherein R 3 and R 3a combine to form oxo, = N-OH or SN-O-C 1 -C 4 alkyl; R x is H, pyridyl, pyrimidyl, C 1 -C 4 alkyl (methyl, ethyl), or C 3 -C 6 cycloalkyl; R 2 is H, C 1 -C 4 alkyl (methyl, ethyl, isopropyl), pyrimidyl, pyridyl, thiazolyl or imidazolyl; and Ria and 2a are both H. In another aspect, the invention provides compounds of the formula 14-53, ie, compounds of the formula 14-52 wherein, R3 and R3a combine to form oxo; and Rx is C3-C6 cycloalkyl, pyridyl or pyrimidyl.

In yet another aspect, the invention provides compounds of the formula 14-54, ie, compounds of the formula 14-53 wherein, R 2 is H, C 1 -C 4 alkyl. In one embodiment, R2 is methyl. In another embodiment, R2 is ethyl, in yet another embodiment, R2 is isopropyl. In yet another embodiment, Rx and R2 are cis to each other. In another embodiment, Rx and R2 are trans to each other. In yet another embodiment, Rx is pyrimidyl and R2 is H. In yet another embodiment, Ri is pyridyl and R2 is H. In a further embodiment, Ri is cyclopropyl and R2 is H. In a further embodiment, Ri is cyclopropyl and R2 is H. In a further aspect, the invention provides compounds of the formula 14-55, ie, compounds of the formula 14-52 wherein, R3 and R3a combine to form oxo; and Ri is H or C 1 -C 4 alkyl (such as methyl, ethyl or isopropyl). In another aspect, the invention provides compounds of the formula 14-56, ie, compounds of the formula 14-55 wherein, R 2 is H, C 1 -C 4 alkyl. In one embodiment, R2 is methyl. In another embodiment, R2 is ethyl, in yet another embodiment, R2 is isopropyl. In yet another embodiment, when Ri is C1-C4 alkyl, then Ri and R2 are cis to each other. In yet another embodiment, when Ri is C1-C4 alkyl, then Ri and R2 are trans to each other. In another embodiment, Ri and R2 are the same, and are methyl or ethyl. In still another aspect, the invention provides compounds of the formula 14-57, ie, compounds of the formula 14-52 wherein, Ri and R2 are both H. In a further aspect, the invention provides compounds of the formula 14-58, ie, compounds according to with any of the formulas 14-53 or 14-55 wherein, R2 is pyrimidyl, pyridyl, thiazolyl or imidazolyl. In one embodiment, R2 is pyrimidyl or pyridyl. In another embodiment, R2 is thiazolyl, or imidazolyl. In yet another modality, when Rx is not H, then Ri and R2 are cis to each other. In yet another modality, when Rx is not H, then Ri and R2 are trans to each other. In yet another embodiment, Ri is pyrimidyl and R2 is pyrimidyl or pyridyl. In still another embodiment, Ri is pyridyl and R2 is pyrimidyl or pyridyl. In a further embodiment, Ri is cyclopropyl and R2 is pyrimidyl or pyridyl. In a further embodiment, Ri is cyclopropyl and R2 is pyrimidyl or pyridyl. In another aspect, the invention provides compounds of the formula 14-59, ie, compounds of the formula 14-52 wherein, R3 and R3a combine to form = N-OH; and Ri is C3-C6 cycloalkyl, pyridyl or pyrimidyl. In yet another aspect, the invention provides compounds of formula 14-60, ie, compounds of formula 14-59 wherein, R 2 is H, C 1 -C 4 alkyl. In one embodiment, R2 is methyl. In another embodiment, R2 is ethyl, in yet another embodiment, R2 is isopropyl. In yet another mode, Ri and R2 They are cis to each other. In another modality, Ri and R2 are trans to each other. In yet another embodiment, Rx is pyrimidyl and R2 is H. In yet another embodiment, R is pyridyl and R2 is H. In a further embodiment, Rx is cyclopropyl and R2 is H. In a further embodiment, Rx is cyclopropyl and R2 is H. In a further aspect, the invention provides compounds of the formula 14-61, ie, compounds of the formula 14-52 wherein, R3 and R3a combine to form = N-OH; and R is H or C? -C alkyl (such as methyl, ethyl or isopropyl). In another aspect, the invention provides compounds of the formula 14-62, ie, compounds of the formula 14-61 wherein, R 2 is H, C 1 -C 4 alkyl. In one embodiment, R2 is methyl. In another embodiment, R2 is ethyl, in yet another embodiment, R2 is isopropyl. In yet another embodiment, when R x is C 1 -C 4 alkyl, then R x and R 2 are cis to each other. In yet another embodiment, when Rx is C? -C4 alkyl, then Rx and R2 are trans to each other. In another embodiment, Rx and R2 are the same, and are methyl or ethyl. In still another aspect, the invention provides compounds of formula 14-63, ie, compounds according to any of formulas 14-59 or 14-61 wherein, R2 is pyrimidyl, pyridyl, thiazolyl, or imidazolyl. In one embodiment, R2 is pyrimidyl or pyridyl. In another embodiment, R2 is thiazolyl, or imidazolyl. In yet another modality, when Rx is not H, then Rx and R2 are cis to each other. In yet another embodiment, when Rx is not H, then R and R2 are trans to each other. In yet another embodiment, R is pyrimidyl and R2 is pyrimidyl or pyridyl. In still another embodiment, Rx is pyridyl and R2 is pyrimidyl or pyridyl. In a further embodiment, Rx is cyclopropyl and R2 is pyrimidyl or pyridyl. In a further embodiment, Rx is cyclopropyl and R2 is pyrimidyl or pyridyl. In another aspect, the invention provides compounds of the formula 14-64, ie, compounds of the formula 14-52 wherein, R3 and R3a combine to form = N-0-C? -C4 alkyl; and Rx is C3-C6 cycloalkyl, pyridyl or pyrimidyl. In yet another aspect, the invention provides compounds of the formula 14-65, ie, compounds of the formula 14-64 wherein, R 2 is H, C 1 -C 4 alkyl. In one embodiment, R is methyl. In another embodiment, R2 is ethyl, in yet another embodiment, R is isopropyl. In yet another embodiment, Rx and R2 are cis to each other. In another embodiment, Rx and R2 are trans to each other. In yet another embodiment, Rx is pyrimidyl and R2 is H. In yet another embodiment, Rx is pyridyl and R2 is H. In a further embodiment, Rx is cyclopropyl and R2 is H. In a further embodiment, R is cyclopropyl and R2 is H. In a further aspect, the invention provides compounds of the formula 14-66, ie, compounds of the formula 14-52 wherein, R3 and R3a combine to form I rent; and R x is H or C 1 -C 4 alkyl (such as methyl, ethyl or isopropyl). In another aspect, the invention provides compounds of the formula 14-67, ie, compounds of the formula 14-66 wherein, R2 is H, C? -C alkyl. In one embodiment, R2 is methyl. In another embodiment, R2 is ethyl, in yet another embodiment, R2 is isopropyl. In yet another embodiment, when Rx is C? -C4 alkyl, then Ri and R2 are cis to each other. In yet another embodiment, when Ri is C? -C4 alkyl, then Ri and R2 are trans to each other. In another embodiment, Rx and R2 are the same, and are methyl or ethyl. In still another aspect, the invention provides compounds of formula 14-68, ie, compounds according to any of formulas 14-64 or 14-66 wherein, R2 is pyrimidyl, pyridyl, thiazolyl, or imidazolyl. In one embodiment, R2 is pyrimidyl or pyridyl. In another embodiment, R2 is thiazolyl, or imidazolyl. In yet another embodiment, when Rx is not H, then Rx and R2 are cis to each other. In yet another modality, when Rx is not H, then Rx and R2 are trans to each other. In yet another embodiment, Rx is pyrimidyl and R2 is pyrimidyl or pyridyl. In still another embodiment, Rx is pyridyl and R2 is pyrimidyl or pyridyl. In a further embodiment, Rx is cyclopropyl and R2 is pyrimidyl or pyridyl. In a further embodiment, Rx is cyclopropyl and R2 is pyrimidyl or pyridyl.

In a further aspect, the invention provides compounds of the formula 14-69, ie, compounds according to any of the formulas 13, 13-1, 13-2, 13-3, 13-4, 13-5, 13 -6, 13-6a, 13-7, 13-8, 13-9, 13-10, 13-11, 13-lia, 13-llb, 13-12, 13-13, 13-14 or 13-15 wherein Rx is pyridyl, pyrimidyl, -C02-C? -C4 alkyl, C? -C4 alkyl, C? -C0C (O) NR 'R "alkyl, benzimidazolyl, thiazolyl or imidazolyl, and R2 is H, methyl or ethyl, wherein R 'and R "are independently H or C? -C4 alkyl. When R2 is methyl or ethyl, Rx and R2 can be cis or trans to each other. In still another aspect, the invention provides compounds of the formula 14-70, ie, compounds of the formula 14-69 wherein, Rx is pyridyl, pyrimidyl, thiazolyl, benzimidazolyl, or imidazolyl. In still another aspect, the invention provides compounds of the formula 14-71, ie, compounds of the formula 14-69 wherein, Rx is -C02-Me or -C02-Et. In still another aspect, the invention provides compounds of the formula 14-72, ie, compounds of the formula 14-69 wherein, Rx is methyl, ethyl or propyl (either n or iso). In yet another aspect, the invention provides compounds of the formula 14-73, ie, compounds of the formula 14-69 wherein, Rx is -CH2-OC (O) NR 'R ", wherein R' and R" they are independently H or C? -C2 alkyl. In one embodiment, R2 is H. In another embodiment, R2 is ethyl.

In a further aspect, the invention provides compounds of the formula 14-74, ie, compounds according to any of the formulas 13, 13-1, 13-2, 13-3, 13-4, 13-5, 13 -6, 13-6a, 13-7, 13-8, 13-9, 13-10, 13-11, 13-lia, 13-llb, 13-12, 13-13, 13-14 or 13-15 wherein R x is C 1 -C 4 -CO (O) NR 'R "alkyl; R 2 is H or C 1 -C 4 -OC (O) NR' R" alkyl; and Ria / R2 / R3 and R3a are H; wherein R 'and R "are independently H or C? -C3 alkyl In one embodiment, Rx and R2 are both -CH2-OC (O) NR' R". In yet another embodiment, R 'and R "are both H, methyl or ethyl In yet another embodiment, at least one of R' and R" is isopropyl. In still another aspect, the invention provides compounds of formula 14-75, ie, compounds according to any of formulas 13, 13-1, 13-2, 13-3, 13-4, 13-5, 13-6, 13-6a, 13-7, 13-8, 13-9, 13-10, 13-11, 13-lla, 13-llb, 13-12, 13-13, 13-14 or 13- Wherein the heteroaryl group is pyridyl optionally substituted with 1 or 2 groups which are independently halogen, C? -C alkyl, C? -C4 alkoxy, CF3, OCF3, OH, amino or mono or di (C? -C4 alkyl) Not me. In still another additional aspect, the invention provides compounds of the formula 14-76, ie, compounds 14-75, wherein the pyridyl is substituted with a group that is halogen, C? -C alkyl, C? -C4 alkoxy, CF3, OCF3, OH, amino or mono or di (C? -C alkyl) amino.

In still another aspect, the invention provides compounds of the formula 14-77, ie, compounds of the formula 14-76, wherein the pyridyl is substituted at the 4-position. In yet another aspect, the invention provides Formula 14-78, ie, compounds of formula 14-77, wherein the pyridyl is substituted with a group which is halogen (preferably chlorine). In still another aspect, the invention provides compounds of the formula 14-79, ie, compounds of the formula 14-78, wherein the heteroaryl group has the following structure: In still another aspect, the invention provides compounds of formula 14-80, ie, compounds according to any of formulas 13, 13-1, 13-2, 13-3, 13-4, 13-5, 13-6, 13-6a, 13-7, 13-8, 13-9, 13-10, 13-11, 13-lia, 13-llb, 13-12, 13-13, 13-14 or 13- Wherein the heteroaryl group is an unsaturated pyridyl. In one embodiment, the pyridyl is a pyrid-2-yl. In another embodiment, the pyridyl is a pyrid-3-yl. In yet another embodiment, the pyridyl is a pyrid-4-yl. In still another additional aspect, the invention provides compounds of the formula 14-81, ie, the compounds according to any of the formulas, 13-1, 13-2, 13-3, 13-4, 13-5, 13-6, 13-6a, 13-7, 13-8, 13-9, 13-10, 13-11, 13 -, 13-llb, 13-12, 13-13, 13-14 or 13-15 wherein the heteroaryl group is thienyl optionally substituted with 1 or 2 groups that are independently halogen, C?-C4 alkyl, C alco alkoxy? ~ C4, CF3, OCF3, OH, amino, or mono or di (C? -C alkyl) amino. In yet a further aspect, the invention provides compounds of the formula 14-82, ie, compounds of the formula 14-81 wherein the thienyl group is substituted with a group that is halogen, C?-C4 alkyl, C alco alkoxy? -C4, CF3, OCF3, OH, amino or mono or di (C? -C4 alkyl) amino. In still another aspect, the invention provides compounds of the formula 14-83, ie, compounds of the formula 14-82, wherein the thienyl group is replaced with a halogen (preferably Cl). In still another aspect, the invention provides compounds of the formula 14-84, ie, compounds of the formula 14-83, wherein the thienyl group has the formula: k f r ?. In still another aspect, the invention provides compounds of the formula 14-85, ie, compounds of the formula 14-81, wherein the thienyl group is unsubstituted. In still another aspect, the invention provides compounds of the formula 14-86, ie, compounds of the formula 14-85, wherein the thienyl group has the formula: In another aspect, the invention provides compounds of formula 15, ie, compounds of formula 4, wherein ring A is heterocycloalkyl, which is optionally substituted in a halogen-substitutable position, C? -Cg alkyl, C? Alkoxy? ~ Cg, haloalkyl, haloalkoxy, hydroxyl, CN, aryloxy, arylalkyloxy,, -S02- (C? -Cg alkyl), -NR'R ", C? -C6 alkanoyl, heteroaryl, aryl or -S02- NR'R" wherein each R 'and R "is independently H or Ci-Cg alkyl, and ring B is pyrazolyl, imidazolyl, pyrrolyl, triazolyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, isoxazolyl, pyrimidyl or pyridyl, each of which is substituted optionally in a substitutable position with a group which is independently Ci-Cß alkyl, Ci-Cg alkoxy, amino, C alqu-C alqu alkylamino, Ci-Cg dialkylamino, Cilt-Cg alkylthio, halo, C?-C 2 haloalkyl, haloalkoxy C C2 or phenyl In another aspect, the invention provides compounds of the formula 16, ie, the compounds of the formula 4 or formula 15, where: rQ heterocycloalkyl (formula 16) wherein the heterocycloalkyl group is optionally substituted in a halogen-substitutable position, C? -C6 alkyl, Ci-Cg alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, aryloxy, arylalkyloxy, -S02- (C? -Cg alkyl), - NR'R ", C?-C6 alkanoyl, pyridyl, phenyl or -S02-NR'R", wherein each R 'and R "is independently H or C alquilo-Cg alkyl. In another aspect, the invention provides compounds of Formula 16-1, ie, compounds of formula 16, wherein ring B is pyrazolyl, imidazolyl, pyrrolyl, triazolyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, isoxazolyl, pyrimidyl or pyridyl, each of which is unsubstituted. In another aspect, the invention provides compounds of formula 16-2, ie, compounds of formula 16, wherein ring B has the formula: wherein R20 is H, C? -C6 alkyl, Ci-Cg alkoxy, amino, C? -Cy alkylamino, dialkylamino Ci-Cg, alkylthio C? -C6, halo, CF3 or phenyl. In another aspect, the invention provides compounds of formula 16-3, ie, compounds of formula 16, wherein ring B has the formula: wherein R2o is H, C? -C4 alkyl, C? -C4 alkoxy, amino, C? -C alkylamino, dialkylamino C? -C, alkylthio C? ~ C, halo, CF3 or phenyl. In another aspect, the invention provides compounds of formula 16-4, ie, compounds of formula 16, wherein ring B has the formula: wherein R2o is H, C? -C alkyl, C? -C4 alkoxy, amino, C? -C4 alkylamino, dialkylamino C? ~ C, alkylthio C? ~ C, halo, CF3 or phenyl. In another aspect, the invention provides compounds of formula 16-5, ie, compounds of formula 16, wherein ring B has the formula: wherein R 20 is H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, amino, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, C 1 -C 4 alkylthio, halo, CF 3 or phenyl. In another aspect, the invention provides compounds of formula 16-6, ie, compounds of formula 16, wherein ring B has the formula: wherein R 2 is H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, amino, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, C 1 -C 4 alkylthio, halo, CF 3 or phenyl. In still another aspect, the invention provides compounds of the formula 16-6a, ie, compounds according to any of the formulas 16-3, 16-4, 16-5 or 16-6, wherein R20 is H, or alkyl C? ~ Cg. In another embodiment, R2o is phenyl. In yet another embodiment, when the R20 group is bonded to a carbon, R20 is C1-C4 alkoxy, C1-C4 alkylthio, halo, CF3 or phenyl. In yet another embodiment, R2o is H. In another aspect, the invention provides compounds of Formula 16-7, ie, compounds of formula 16, wherein ring B has the formula: wherein R 3o is H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, amino, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, C 1 -C 4 alkylthio, halo, CF 3 or phenyl. In another aspect, the invention provides compounds of formula 16-8, ie, compounds of formula 16, wherein ring B has the formula: In another aspect, the invention provides compounds of formula 16-9, ie, compounds of formula 16, wherein ring B has the formula: In another aspect, the invention provides compounds of the formula 16-10, ie, compounds of the formula 16, in where ring B has the formula In another aspect, the invention provides compounds of formula 16-11, ie, compounds of formula 16, wherein ring B has the formula: In yet another aspect, the invention provides compounds of formula 16-la, ie, compounds according to any of formulas 16-8, 16-9 or 16-10, wherein R30 is H, or C alquilo alkyl. Cg. In another embodiment, R30 is phenyl. In yet another embodiment, when the R30 group is bonded to a carbon, R30 is C1-C4 alkoxy, C1-C4 alkyl, halo, CF3, or phenyl. In yet another embodiment, R30 is H. In another aspect, the invention provides compounds of formula 16-llb, ie, compounds according to any of formulas 16-8, 16-9 or 16-10, wherein R30 it is amino, C1-C4 alkylamino, dialkylamino C1-C4. In another aspect, the invention provides compounds of the formula 16-12, ie, compounds of the formula 16, where ring B has the formula: In another aspect, the invention provides compounds of formula 16-13, ie, compounds of formula 16, wherein ring B has the formula: In another aspect, the invention provides compounds of formula 16-14, ie, compounds of formula 16, wherein ring B has the formula: In another aspect, the invention provides compounds of formula 16-15, ie, compounds of formula 16, wherein ring B has the formula: In another aspect, the invention provides compounds of formula 17, ie, compounds of formulas 16, 16-1, 16-2, 16-3, 16-4, 16-5, 16-6, 16-6a, 16-7, 16-8, 16-9, 16-10, 16-11, 16-, 16- llb, 16-12, 16-13, 16-14 or 16-15 wherein Ri is Ci-Cg alkyl, C3-C6 cycloalkyl, C3-Cg cycloalkylalkyl, phenyl, biphenyl, alkyl (such as benzyl or phenethyl), alkyl or naphthyloxyalkyl C? -Cg, wherein each aryl group is optionally substituted with 1, 2, 3, 4 or 5 groups which are independently halogen, Ci-Cg alkyl, Ci-Cg alkoxy, C? -C4 haloalkyl, haloalkoxy C? -C4, -C (0) NR'R ", -NR'R", hydroxyl, -O- (CH2)? -2-0-, -C02R ', phenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl, or imidazolyl; and R and R2a are both H. In still another aspect, the invention provides compounds of the formula 17a, ie, compounds of the formula 17, wherein R2 is hydrogen, halogen, C?-C6 alkyl, C2-C6 alkenyl , wherein the alkenyl group is optionally substituted with one or more halogens; C2-C6 alkynyl, C3-C6 cycloalkyl, C3-Cg cycloalkyl-C6-C6 alkyl, phenyl, naphthyl, phenylalkyl C6-6, naphthylalkyl C6-C6, wherein each aryl group is optionally substituted with 1, 2, 3, 4 or 5 groups which are independently halogen, C?-C6 alkyl, C alco-Cg alkoxy, C?-Cg alkanoyl, C?-C4 haloalkyl, C?-C4 haloalkoxy, C (0) NR'R ", -NR'R ", hydroxyl, -O- (CH2)? -2-0-, -C (0) OR ', phenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl. In yet another aspect, the invention provides compounds of formula 17b, ie, compounds of formula 17, wherein R 2 is hydrogen, pyridyl, thiazolyl, pyrimidyl, pyrazolyl, pyridyloxyalkyl C 6 -C 6, pyrimidyloxyalkyl C 6 -C 6, thienyloxyalkyl C? -C6, pyrrolyloxyalkyl C? -Cg or thiazolyoxyalkyl C? -C6 or C0-C6-OC (O) -heterocycloalkyl alkyl, wherein the heterocycloalkyl group is piperazinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, S, S-thiomorpholinyl dioxide, tetrahydrofuranyl or imidazolidinyl , wherein each heteroaryl and heterocycloalkyl group is optionally substituted with one or more groups that are independently halogen, C? -Cg alkyl, C? -C6 alkoxy, C? -C6 alkanoyl, C? -C4 haloalkyl, C? -C4 haloalkoxy? , -C (0) NR'R ", -NR'R", hydroxyl, -O- (CH2)? -2-0-, -C (0) OR ', phenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl. In yet another aspect, the invention provides compounds of the formula 17c, ie, compounds of the formula 17, wherein R 2 is hydrogen, -C02R ", CONR'R", haloalkyl C? -C6, wherein the haloalkyl group is optionally substituted with C? -C4 alkoxy; C 1 -C 4 haloalkoxyalkyl, C 1 -Cg hydroxyalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 phenyloxyalkyl, C 1 -C 6 naphthyloxyalkyl, C 0 -C 6 -alkyl (O) NR 'R', C 0 -C 6 -NR alkyl R ", where each aryl group is optionally substituted with 1, 2, 3, 4 or 5 groups which are independently halogen, C?-C6 alkyl, C?-C6 alkoxy, C?-Cg alkanoyl, C?-C4 haloalkyl, C?-C4 haloalkoxy , -C (0) NR'R ", -NR'R", hydroxyl, -0- (CH2) 1-2-O-, -C (0) 0R ', phenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl; and wherein R 'and R "are independently H or C? -C6 alkyl. In yet another aspect, the invention provides compounds of formula 17d, ie, compounds of formula 17, wherein R2 is hydrogen or Co-alkyl. Cg-OC (O) -heterocycloalkyl, wherein the heterocycloalkyl group is piperazinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, S, S-thiomorpholinyl dioxide, tetrahydrofuranyl or imidazolidinyl, wherein the heterocycloalkyl group is optionally substituted with one or more groups which are independently halogen, C?-Cg alkyl, C?-Cg alkoxy, C?-C6 alkanoyl, C?-C4 haloalkyl, C?-C4 haloalkoxy, C (0) NR'R ", -NR'R", hydroxyl, -0- (CH2)? -2-0-, -C (0) 0R ', phenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl. , the invention provides compounds of the formula 17-1, ie, compounds of the formulas 16, 16-1, 16-2, 16-3, 16-4, 16-5, 16-6, 16-6a, 16 -7, 16-8, 16-9, 16- , 16-11, 16-lla, 16-llb, 16-12, 16-13, 16-14 or 16-15 where Rx is pyridyl, thiazolyl, imidazolyl, benzofuranyl, benzothienyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl , quinazolinyl, pyridyloxyalkyl C? -Cg, benzofuranyloxyalkyl C? -C6, benzothienyloxyalkyl C? -Cg, quinolinyloxyalkylC? -C6, isoquinolinyloxyalkylC? -Cg, quinoxalinyloxyalkylC? -C6, quinazolinyloxyalkylC? -C6, alkylC? -C6 -OC (O) NR 'R ", C? -C6-OC (O) -piperidinyl alkyl, C? -C6-OC (O) -pyrrolidinyl alkyl or C? -C6-OC alkyl (OJmorpholinyl, wherein each group heteroaryl and heterocycloalkyl is optionally substituted with one or more groups which are independently halogen, C?-Cg alkyl, C?-C6 alkoxy, C?-C4 haloalkyl, haloalkoxy - ^, -C (0) NR'R ", -NR 'R', hydroxyl, -O- (CH2)? _2-0-, -C02R ', phenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl; and R2a are both H. In yet another aspe Accordingly, the invention provides compounds of the formula 17-la, ie, compounds of the formula 17-1, wherein R2 is hydrogen, halogen, C? -Cg alkyl, C2-Cg alkenyl, wherein the alkenyl group is substituted optionally with one or more halogens; C2-Cg alkynyl, C-Cg cycloalkyl, C? -Cg cycloalkyl C? -C6 alkyl, phenyl, naphthyl, phenylalkyl? C6, naphthylalkyl C? -C6, wherein each aryl group is optionally substituted with 1, 2, 3, 4 or 5 groups 13Í which are independently halogen, C? -Cg alkyl, Cx-C6 alkoxy, C? -C6 alkanoyl, C? -Cg haloalkyl, C? -C4 haloalkoxy, C (0) NR'R ", -NR'R", hydroxyl , -0- (CH2)? -2-0-, phenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl. In yet another aspect, the invention provides compounds of the formula 17-lb, ie, compounds of the formula 17-1, wherein R 2 is hydrogen, pyridyl, thiazolyl, pyrimidyl, pyrazolyl, pyridyloxyalkyl, C 1 -C 6, pyrimidyloxyalkyl C? ~ C6, thienyloxyalkyl C? -C6, pyrrolyloxyalkylC? -C6 or thiazolyloxyalkylC? -Cg or C0-C6alkyl-OC (O) -heterocycloalkyl, wherein the heterocycloalkyl group is piperazinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, S, S -thiomorpholinyl dioxide, tetrahydrofuranyl or imidazolidinyl, wherein each heteroaryl and heterocycloalkyl group is optionally substituted with one or more groups which are independently halogen, C? -Cg alkyl, C? -C6 alkoxy, C? -C6 alkanoyl, C haloalkyl? -C4, haloalkoxy C? -C4, -C (0) NR'R ", -NR'R", hydroxyl, -0- (CH2)? _2-0-, -C (0) OR ', phenyl, pyridazinyl , pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl. In still another aspect, the invention provides compounds of the formula 17-lc, ie, compounds of the formula 17-1, wherein R2 is hydrogen, -C02R ', CONR'R ", haloalkyl C? -C6, wherein the haloalkyl group is optionally substituted with C? -C4 alkoxy, C? -C haloalkoxyalkyl, C? -C6 hydroxyalkyl, C2 alkanoyl -C6, C? -C6 phenyloxyalkyl, C? -C3 naphthyloxyalkyl, C0-C6-OC (0) NR 'R "alkyl, C0-C6 alkyl-NR'R", wherein each aryl group is optionally substituted with 1, 2, 3, 4 or 5 groups which are independently halogen, C? -C6 alkyl, C? -Cg alkoxy, C? -Cg alkanoyl, C? -C4 haloalkyl, C? -C4 haloalkoxy, -C (0) NR? R ", -NR'R", hydroxyl, -0- (CH2)? -2-0-, -C (0) 0R ', phenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N- benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl, and wherein R 'and R "are independently H or C? -Cg alkyl. In yet another aspect, the invention provides compounds of the formula 17-ld, ie, compounds of the formula 17-1, wherein R 2 is hydrogen, or C 0 -Ce-OC (O) -heterocycloalkyl, wherein the group heterocycloalkyl is piperazinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, S, S-thiomorpholinyl dioxide, tetrahydrofuranyl or imidazolidinyl, wherein the heterocycloalkyl group is optionally substituted with one or more groups which are independently halogen, C 1 -C 6 alkyl, C 1 alkoxy C6, C?-C6 alkanoyl, C?-C4 haloalkyl, C?-C4 haloalkoxy, C (0) NR'R ", -NR'R", hydroxyl, -0- (CH 2) -2 -2-0-, -C (0) 0R ', phenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl. In still another aspect, the invention provides compounds of the formula 17-2, ie, compounds of the formula 17-1, 17-la, 17-lb, 17-lc or 17-ld, wherein Rx is pyridyl, thiazolyl , imidazolyl, benzofuranyl, benzothienyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, or quinazolinyl, wherein each heteroaryl group is optionally substituted with one or more groups which are independently halogen, C? -C6 alkyl, C? -C6 alkoxy, haloalkyl C? -C4, haloalkoxy C? -C4, -C (O) NR'R ", -NR'R", hydroxyl, -O- (CH2)? -2-0-, -C02R ', phenyl, pyridazinyl, pyrazinyl , pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl; and Rla and R2a are both H. In still another aspect, the invention provides compounds of the formula 17-3, ie, compounds of the formula 17-1, 17-la, 17-lb, 17-lc or 17-ld , wherein R x is C 1 -C 6 pyridyloxyalkyl, C 1 -C 6 -benzofuranyloxyalkyl, C 1 -C 6 -benzothienyloxyalkyl, C 1 -C 6 -quinolinyloxyalkyl, C 1 -C 6 -quinolinynyloxyalkyl, C 1 -C 6 -quinolyalkyloxyalkyl or C 1 -C 6 -quinolinnylaxyalkyl; wherein each heteroaryl group is optionally substituted with one or more groups which are independently halogen, C? -C6 alkyl, C? -Cg alkoxy, C? -C4 haloalkyl, C? -C4 haloalkoxy, -C (0) NR'R ", -NR'R", hydroxyl, -O- (CH2)? -2-0-, -C02R ', phenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl; and R and R2a are both H. In still another aspect, the invention provides compounds of the formula 17-4, ie, compounds of the formula 17-1, 17-la, 17-lb, 17-lc or 17- ld, wherein Rx is C0-C6-OC (0) NR'R "alkyl, -C0-C6-NR 'R" alkyl, C? -Cg-OC (O) -piperidinyl alkyl, C-Cg-alkyl -OC (0) -pyrrolidinyl or C? -Cg-OC (0) -morpholinyl alkyl, wherein each heterocycloalkyl group is optionally substituted with one or more groups that are independently halogen, C? -C6 alkyl, C? -Cg alkoxy , haloalkyl C? -C4, haloalkoxy C? -C4, -C (0) NR'R ", -NR'R", hydroxyl, -0- (CH2)? _2-0-, -C02R ", phenyl, pyridazinyl , pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl, or imidazolyl, and Rla and R2a are both H. In another aspect, the invention provides compounds of the formula 17-5, ie, compounds of the formulas 16, 16-1, 16-2, 16-3, 16-4, 16-5, 16-6, 16-6a, 16-7, 16-8, 16-9, 16-10, 16-11, 16-lla, 16-llb, 16-12, 16-13, 16-14 or 16-15 where Rx is -CONR'R ", haloalkyl C? -C4, or hydroxyalkyl C? -C4; and R? And R2a are both H. In one embodiment, Rx is as defined above and R2 is H. In another embodiment, Rx is as it was previously defined and R2 is methyl, ethyl or cyclopropyl. In yet another embodiment, Rx is as defined above and R2 is hydroxyalkyl C? -C. In a further embodiment, Rx and R2 are independently -C02-C?-C4 alkyl. In another embodiment, R x and R 2 are independently C 1 -C 2 hydroxyalkyl. In yet another embodiment, Rx is hydroxyalkyl C? -C2 and R2 is methyl or ethyl. In a further aspect, the invention provides compounds of formula 17-6, ie, compounds according to any of formulas 16, 16-1, 16-2, 16-3, 16-4, 16-5, 16 -6, 16-6a, 16-7, 16-8, 16-9, 16-10, 16-11, 16-11a, 16-11 b, 16-12, 16-13, 16-14 or 16- 15, wherein Rx is H or C? -Cg alkoxy, R2 is H or C? -Cg alkoxy, and Rla and R2a are both H. In one embodiment, Rx is C? -Cg alkoxy and R2 is H or C alkoxy? ? -Cg. In another embodiment Rx and R2 are independently C alco-Cg alkoxy. In yet another embodiment Rx and R2 are both H. In another aspect, the invention provides compounds of the formula 17-7, ie, compounds according to any of the formulas 16, 16-1, 16-2, 16-3 , 16-4, 16-5, 16-6, 16-6a, 16-7, 16-8, 16-9, 16-10, 16-11, 16-lla, 16-llb, 16-12, 16 -13, 16-14 or 16-15 wherein Rx and R2 are both C -C4 alkenyl optionally substituted with one or more halogens (such as F or Cl), and R and R2a are both H. In one embodiment, Rx and R2 are the same. In a further embodiment, Rx and R2 are both C2 alkenyl substituted with two halogens (such as F). Rx and R2 can be cis or trans to each other.

In another aspect, the invention provides compounds of formula 17-8, ie, compounds according to any of formulas 16, 16-1, 16-2, 16-3, 16-4, 16-5, 16- 6, 16-6a, 16-7, 16-8, 16-9, 16-10, 16-11, 16-lla, 16-llb, 16-12, 16-13, 16-14 or 16-15 in where Rx and R2 are both haloalkyl C? ~ C2 and R? and R2a are both H. Ri and R2 may be cis or trans to each other. In one embodiment, Ri and R2 are the same and are -CH2F, -CH2CF3, -CH2CHF2, CF3 or -CF2CH3. In another aspect, the invention provides compounds of the formula 17-9, ie, compounds according to any of the formulas 16, 16-1, 16-2, 16-3, 16-4, 16-5, 16- 6, 16-6a, 16-7, 16-8, 16-9, 16-10, 16-11, 16-lla, 16-llb, 16-12, 16-13, 16-14 or 16-15 in where Ri and R2 are benzyl or phenethyl and Ria and R2a are both H. Ri and R2 may be cis or trans to each other. In one embodiment, Ri and R2 are both benzyl. In another aspect, the invention provides compounds of the formula 17-10, ie, compounds according to any of formulas 16, 16-1, 16-2, 16-3, 16-4, 16-5, 16- 6, 16-6a, 16-7, 16-8, 16-9, 16-10, 16-11, 16-lla, 16-llb, 16-12, 16-13, 16-14 or 16-15 in where Rx and R2 are both H or C1-C alkyl and R and R2a are both H. Rx and R2 may be cis or trans to each other. In one embodiment, Ri and R2 are both methyl. In another embodiment, Ri and R2 are both isopropyl. In yet another embodiment, one or Rx and R2 is methyl while the other is isopropyl. In yet another embodiment, Ri and R2 are ethyl.

In another aspect, the invention provides compounds of the formula 17-11, ie, compounds according to any of the formulas 16, 16-1, 16-2, 16-3, 16-4, 16-5, 16- 6, 16-6a, 16-7, 16-8, 16-9, 16-10, 16-11, 16-lla, 16-llb, 16-12, 16-13, 16-14 or 16-15 in where R x is H, C 1 -C 4 alkyl, benzyl, phenethyl or phenyl, wherein the phenyl portions of R x are optionally substituted with 1, 2 or 3 groups which are independently halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy and R2 is H or C? -C4 alkyl, and Rla and R2a are both H. Rx and R2 can be cis or trans to each other. In one aspect, the invention provides compounds of the formula 17-12, ie, compounds of the formula 17-11 wherein, R 2 is H and R x is methyl, ethyl or propyl (non-iso), or R x is H and R 2 it is methyl, ethyl or propyl (non-iso). In one embodiment, only one of Rx and R2 is isopropyl. In another embodiment, only one of Rx and R2 is ethyl. In yet another aspect, the invention provides compounds of formula 17-13, ie, compounds of formula 17-11 wherein, R 2 is H and R x is phenyl substituted with one or two halogens (such as F or Cl), or R x is H and R2 is phenyl substituted with one or two halogens (such as F or Cl). In one aspect, the invention provides compounds of formula 17-14, ie, compounds of formula 17-11 wherein, R 2 is H and R x is benzyl substituted with one or two groups that are independently halogen (such as F or Cl), methyl, ethyl, methoxy or ethoxy. In yet another aspect, the invention provides compounds of the formula 17-15, ie, compounds of the formula 17-11 wherein, R 2 is methyl or ethyl, and R x is methyl, ethyl or propyl (n or iso). In one embodiment, Ri and R2 are both ethyl. In still another aspect, the invention provides compounds of the formula 17-16, ie, compounds of the formula 17-11 wherein, R 2 is methyl or ethyl, and R x is phenyl substituted with one or two halogens (such as F or Cl). In yet another aspect, the invention provides compounds of the formula 17-17, ie, compounds of the formula 17-11 wherein, R is methyl or ethyl, and Rx is benzyl substituted with one or two groups that are independently halogen ( such as F or Cl), methyl, ethyl, methoxy or ethoxy. In another aspect, the invention provides compounds of the formula 17-18, ie, compounds according to any of formulas 16, 16-1, 16-2, 16-3, 16-4, 16-5, 16- 6, 16-6a, 16-7, 16-8, 16-9, 16-10, 16-11, 16-lla, 16-llb, 16-12, 16-13, 16-14 or 16-15 in where R? and R2 are independently H or C02-C? -C4 alkyl, and Rla and R2a are both H. Rx and R2 can be cis or trans to each other. In one embodiment, Rx is -C02-C C-C2 alkyl and R2 is H. In another embodiment, Rx is -C02-Et and R2 is H. In yet another embodiment, Rx is H and R2 is -C02-C-alkyl. ? -C2. In yet another embodiment, Rx and R2 are both -C02-Et.

In another aspect, the invention provides compounds of the formula 17-19, ie, compounds according to any of the formulas 16, 16-1, 16-2, 16-3, 16-4, 16-5, 16- 6, 16-6a, 16-7, 16-8, 16-9, 16-10, 16-11, 16-lla, 16-llb, 16-12, 16-13, 16-14 or 16-15 in where Rx and R3 form a double bond and R? and R3a are both H. In one embodiment, R2 is H. In another embodiment, R2 is -C02-C? -C4 alkyl. In yet another embodiment, R is -C02-Et. In yet another embodiment, R2 is methyl or ethyl. In yet another embodiment, R2 is thiazolyl, pyridyl or pyrimidyl. In yet another aspect, the invention provides compounds of the formula 17-20, ie, compounds according to any of the formulas 16, 16-1, 16-2, 16-3, 16-4, 16-5, 16 -6, 16-6a, 16-7, 16-8, 16-9, 16-10, 16-11, 16-lla, 16-llb, 16-12, 16-13, 16-14 or 16-15 wherein Rx is pyridyl, pyrimidyl, C3-Cg cycloalkyl, or thienyl, R2 is H, C? -C4 alkyl, or C3-C6 cycloalkyl, and Ria and R2a are both H. R1 and R2 may be cis or trans to each other . In yet another additional aspect, the invention provides compounds of the formula 17-21, ie, compounds of the formula 17-20 wherein Ri is pyridyl and R2 is H. In yet another aspect, the invention provides compounds of the formula 17-22, ie, compounds of the formula 17-20 wherein Ri is pyridyl and R2 is methyl or ethyl. In a further aspect, the invention provides compounds of the formula 17-23, ie, compounds of the formula 17-20 wherein Ri is pyridyl and R2 is C3, C5 or Cg cycloalkyl. In another embodiment, R2 is C3 cycloalkyl. In yet another aspect, the invention provides compounds of the formula 17-24, ie, compounds of the formula 17-20 wherein Ri is pyrimidyl and R2 is H. In another aspect, the invention provides compounds of the formula 17- 25, ie, compounds of the formula 17-20 wherein Ri is pyrimidyl and R is methyl or ethyl. In still another aspect, the invention provides compounds of the formula 17-26, ie, compounds of the formula 17-20 wherein Ri is pyrimidyl and R2 is C3, C5 or Cg cycloalkyl. In still another aspect, the invention provides compounds of the formula 17-27, ie, compounds of the formula 17-20 wherein, Rx is C3, C5 or Cg cycloalkyl and R2 is H. In yet another aspect, the invention provides compounds of the formula 17-28, ie, compounds of the formula 17-20 wherein, Rx is C3, C5 or Cg cycloalkyl and R is methyl or ethyl. In yet another aspect, the invention provides compounds of the formula 17-29, ie, compounds of the formula 17-20 wherein Ri is C3, C5 or Cg cycloalkyl and R2 is C3, C5 or C5 cycloalkyl. In one embodiment one of Ri and R2 is C3 cycloalkyl. In another embodiment, Ri and R2 are C3 cycloalkyl. 14! In still another aspect, the invention provides compounds of the formula 17-30, ie, compounds of the formula 17-20 wherein Ri is thienyl and R2 is H. In yet another aspect, the invention provides compounds of the formula -31, ie, compounds of the formula 17-20 wherein, Rx is thienyl and R2 is methyl or ethyl. In still another aspect, the invention provides compounds of the formula 17-32, ie, compounds of the formula 17-20 wherein, Rx is thienyl and R2 is C3, C5 or Cg cycloalkyl. In one embodiment, R2 is C3 cycloalkyl. In a further aspect, the invention provides compounds of the formula 17-33, ie, compounds according to any of the formulas 16, 16-1, 16-2, 16-3, 16-4, 16-5, 16 -6, 16-6a, 16-7, 16-8, 16-9, 16-10, 16-11, 16-lia, 16-llb, 16-12, 16-13, 16-14 or 16-15 wherein R2 is pyridyl, pyrimidyl, -C02-C? -C4 alkyl, C? -C4 alkyl, C? -C4-OC (O) NR 'R "alkyl, benzimidazolyl, thiazolyl or imidazolyl, and Rx is H, methyl or ethyl, wherein R 'and R "are independently H or C? -C4 alkyl. When Rx is methyl or ethyl, Rx and R2 may be cis or trans to each other. In yet another aspect, the invention provides compounds of the formula 17-34, ie, compounds of the formula 17-33 wherein, R2 is pyridyl, pyrimidyl, thiazolyl, benzimidazolyl, or imidazolyl. In one embodiment, R2 is thiazolyl and Ri is H. In another embodiment, R2 is thiazolyl and Ri it is methyl or ethyl. In yet another embodiment, R2 is pyridyl and Rx is H. In another embodiment, R is pyridyl and Ri is methyl or ethyl. In yet another embodiment, R2 is pyrimidyl and Ri is H. In another embodiment, R2 is pyrimidyl and Ri is methyl or ethyl. In still another aspect, the invention provides compounds of the formula 17-35, ie, compounds of the formula 17-33 wherein, R2 is -C02-Me or -C02-Et. In yet another aspect, the invention provides compounds of the formula 17-36, ie, compounds of the formula 17-33 wherein, R 2 is methyl, ethyl or propyl (either n or iso). In still another aspect, the invention provides compounds of the formula 17-37, ie, compounds of the formula 17-33 wherein, R2 is -CH2-OC (O) NR 'R ", wherein R' and R" they are independently H or C? -C2 alkyl. In one embodiment, Ri is H. In another embodiment, Ri is ethyl. In still another aspect, the invention provides compounds of the formula 17-38, ie, compounds according to any of the formulas 16, 16-1, 16-2, 16-3, 16-4, 16-5, 16-6, 16-6a, 16-7, 16-8, 16-9, 16-10, 16-11, 16-lia, 16-llb, 16-12, 16-13, 16-14 or 16- Where R2 and R2a combine to form oxo. In yet another aspect, the invention provides compounds of the formula 17-39, ie, compounds of the formula 17-38 wherein, Ri is H, C?-C4 alkyl, C3-C6 cycloalkyl, or C alquilo-alkyl C4-OC (0) NR'R ", where R 'and R" are independently H or C? -C4 alkyl and Rla is H. In still another aspect, the invention provides compounds of formula 17-40, ie, compounds of formula 17-38 wherein, Rx is H, methyl or ethyl. In one embodiment, Rx is H. In another embodiment, Rx is methyl or ethyl. In yet another aspect, the invention provides compounds of the formula 17-41, ie, the compounds of the formula 17-38 wherein, Rx is C3, C5, or Cg cycloalkyl. In one embodiment, Rx is C3 cycloalkyl. In another embodiment, Rx is C5 or C6 cycloalkyl. In still another aspect, the invention provides compounds of the formula 17-42, ie, compounds of the formula 17-38 wherein, R x is C 1 -C 2 -CO (O) NR 'R "alkyl, wherein R 'and R' are independently H, methyl or ethyl. In still another aspect, the invention provides compounds of the formula 17-43, ie, compounds according to any of the formulas 16, 16-1, 16-2, 16-3, 16-4, 16-5, 16-6, 16-6a, 16-7, 16-8, 16-9, 16-10, 16-11, 16-lla, 16-llb, 16-12, 16-13, 16-14 or 16- Where R3 is NR'R ", OH, halogen, R3a is H or halogen, or R3 and R3a combine to form oxo, = N-OH or = N-0-C? -C4 alkyl Ri is H, pyridyl, pyrimidyl, C? -C4 alkyl, R2 is H, C? -C4 alkyl, pyrimidyl, pyridyl, thiazolyl or imidazolyl, and R? and R2a are both H. In a further aspect, the invention provides compounds of formula 17-44, ie, compounds of formula 17-43 wherein, R is NR'R "; Ra is H; and Rx and R2 are independently methyl, ethyl or propyl (non-iso). modality, Rx and R2 are the same, and are cis, to each other In another embodiment, Rx and R2 are the same, and are trans, to each other In yet another embodiment Rx is methyl or ethyl and R2 is methyl, ethyl or propyl (non-iso) In another embodiment Rx is methyl and R2 is methyl, ethyl or propyl (non-iso), and Rx and R2 are cis, each other In yet another embodiment Rx is methyl and R2 is methyl, ethyl or propyl (not iso), and Rx and R2 are trans, each other In another embodiment Rx is ethyl and R2 is methyl, ethyl or propyl (non-iso), and Rx and R are cis, with each other. ethyl and R2 is methyl, ethyl or propyl (non-iso), and Rx and R2 are trans, to each other In a further aspect, the invention provides compounds of the formula 17-45, ie, compounds of the formula 17-43 wherein, R3 is NR'R "; R3a is H; and Rx is H, methyl, ethyl or propyl (n or iso); and R2 is H, pyrimidyl, pyridyl, thiazolyl or imidazolyl. In one embodiment, Rx is H and R2 is pyrimidyl or pyridyl. In another embodiment, Rx is H and R2 is thiazolyl, or imidazolyl. In one embodiment, Rx is methyl, ethyl or propyl (n or iso) and R2 is pyrimidyl or pyridyl. In another embodiment, Rx is methyl, ethyl or propyl (n or iso) and R2 is thiazolyl, or imidazolyl. In another aspect, the invention provides compounds of formula 17-46, ie, compounds of formula 17-43 wherein, R3 is NR'R "; R3a is H; and Rx is pyridyl or pyrimidyl, and R2 is H. In a further aspect, the invention provides compounds of the formula 17-47, ie, compounds of the formula 17-43 wherein, R3 is NR'R "; R3a is H; Rx is pyridyl, or pyrimidyl; and R2 is pyrimidyl, pyridyl, thiazolyl, or imidazolyl. In another aspect, the invention provides compounds of the formula 17-48, ie, compounds of the formula 17-43 wherein Rx is H and R2 is methyl, ethyl or propyl (n or iso). In another embodiment R2 is methyl. In yet another embodiment R2 is ethyl. In another embodiment R2 is propyl (n or iso). In another aspect, the invention provides compounds of the formula 17-49, ie, compounds of the formula 17-43 wherein R 2 is H and R x is methyl, ethyl or propyl (n or iso). In another embodiment, Rx is methyl. In yet another embodiment Rx is ethyl. In another embodiment Rx is propyl (n or iso). In still another aspect, the invention provides compounds of the formula 17-50, ie, compounds of the formula 17-43 wherein, R3 is halogen; R3a is H or halogen; and Rx and R2 are independently methyl, ethyl or propyl (n or iso). In one embodiment, Rx and R2 are the same, and are cis, with each other. In another modality, Rx and R2 are the same, and are trans, with each other. In yet another embodiment Rx is methyl or ethyl and R2 is methyl, ethyl or propyl (n or iso). In another embodiment Rx is methyl and R2 is methyl, ethyl or propyl (n or iso), and Rx and R2 are cis, with each other. In yet another embodiment Rx is methyl and R2 is methyl, ethyl or propyl (n or iso), and Rx and R2 are trans, with each other. In another embodiment R is ethyl and R2 is methyl, ethyl or propyl (n or iso), and Rx and R2 are cis, with each other. In yet another embodiment Rx is ethyl and R2 is methyl, ethyl or propyl (n or iso), and Rx and R2 are trans, to each other. In yet another embodiment R3 and R3a are the same. When R3 and R3a are the same, they can both be F. In a further aspect, the invention provides compounds of the formula 17-51, ie, compounds of the formula 17-43 wherein, R3 is OH; R3a is H; and Rx and R2 are independently methyl, ethyl or propyl (n or iso). In one modality, Ri and R2 are the same, and are cis, with each other. In another mode, Ri and R2 are the same, and are trans, with each other. In yet another embodiment Ri is methyl or ethyl and R2 is methyl, ethyl or propyl (n or iso). In another embodiment Ri is methyl and R2 is methyl, ethyl or propyl (n or iso), and Ri and R2 are cis, with each other. In yet another embodiment Ri is methyl and R2 is methyl, ethyl or propyl (n or iso), and Ri and R2 are trans, with each other. In another embodiment Ri is ethyl and R2 is methyl, ethyl or propyl (n or iso), and Ri and R2 are cis, with each other. In yet another embodiment Ri is ethyl and R2 is methyl, ethyl or propyl (n or iso), and Ri and R2 are trans, with each other.

In still another aspect, the invention provides compounds of the formula 17-52, ie, compounds according to any of the formulas 16, 16-1, 16-2, 16-3, 16-4, 16-5, 16-6, 16-6a, 16-7, 16-8, 16-9, 16-10, 16-11, 16-lia, 16-llb, 16-12, 16-13, 16-14 or 16- Wherein R 3 and R 3a combine to form oxo, = N-0H, or = N-0-C 1 -C 4 alkyl; Ri is H, pyridyl, pyrimidyl, C 1 -C 4 alkyl (methyl, ethyl), or C 3 -C 6 cycloalkyl; R 2 is H, C 1 -C 4 alkyl (methyl, ethyl, isopropyl), pyrimidyl, pyridyl, thiazolyl or imidazolyl; and R a and R 2a are both H. In another aspect, the invention provides compounds of the formula 17-53, ie, compounds of the formula 17-52 wherein, R 3 and R 3a combine to form oxo; and Rx is C3-Cg cycloalkyl, pyridyl or pyrimidyl. In still another aspect, the invention provides compounds of the formula 17-54, ie, compounds of the formula 17-53 wherein, R 2 is H, C 1 -C 4 alkyl. In one embodiment, R2 is methyl. In another embodiment, R2 is ethyl, in yet another embodiment, R2 is isopropyl. In yet another embodiment, Rx and R2 are cis to each other. In another embodiment, Rx and R2 are trans to each other. In yet another embodiment, Rx is pyrimidyl and R2 is H. In yet another embodiment, Rx is pyridyl and R2 is H. In a further embodiment, Rx is cyclopropyl and R2 is H. In a further embodiment, Rx is cyclopropyl and R2 is H. In a further aspect, the invention provides compounds of the formula 17-55, ie, compounds of the formula 17-52 wherein, R3 and R3a combine to form oxo; and R x is H or C 1 -C 4 alkyl (such as methyl, ethyl or isopropyl). In another aspect, the invention provides compounds of the formula 17-56, ie, compounds of the formula 17-55 wherein, R 2 is H, C 1 -C 4 alkyl. In one embodiment, R2 is methyl. In another embodiment, R2 is ethyl, in yet another embodiment, R2 is isopropyl. In yet another embodiment, when Rx is C? -C4 alkyl, then Rx and R2 are cis to each other. In still another embodiment, when Rx is C? -C4 alkyl, then R and R2 are trans to each other. In another embodiment, Rx and R2 are the same, and are methyl or ethyl. In still another aspect, the invention provides compounds of the formula 17-57, ie, compounds of the formula 17-52 wherein, Rx and R2 are both H. In a further aspect, the invention provides compounds of the formula 17- 58, ie, compounds according to any of formulas 17-53 or 17-55 wherein, R 2 is pipmidyl, pyridyl, thiazolyl, or iimidazolyl. In one embodiment, R2 is pipmidyl or pipdyl. In another embodiment, R2 is thiazolyl, or imidazolyl. In yet another embodiment, when Rx is not H, then Rx and R2 are cis to each other. In yet another modality, when Rx is not H, then Rx and R2 are trans to each other. In yet another embodiment, Rx is pyrimidyl and R2 is pyrimidyl or pipdyl. In still another embodiment, Rx is pyridyl and R2 is pipmidyl or pyridyl. In a further embodiment, Rx is cyclopropyl and R2 is pyrimidyl or pyridyl. In a further embodiment, Rx is cyclopropyl and R2 is pipmidyl or pipdyl. In another aspect, the invention provides compounds of formula 17-59, ie, compounds of formula 17-52 wherein, R3 and R3a combine to form = N-OH; and Rx is C3-C6 cycloalkyl, pyridyl or pyrimidyl. In still another aspect, the invention provides compounds of formula 17-60, ie, compounds of formula 17-59 wherein, R 2 is H, C 1 -C 4 alkyl. In one embodiment, R2 is methyl. In another embodiment, R2 is ethyl, in yet another embodiment, R2 is isopropyl. In yet another modality, Rx and R2 are cis to each other. In another modality, Rx and R2 are trans to each other. In yet another embodiment, R2 is pyrimidyl and R2 is H. In yet another embodiment, Rx is pipdyl and R2 is H. In a further embodiment, Rx is cyclopropyl and R2 is H. In a further embodiment, Rx is cyclopropyl and R2 is H. In a further aspect, the invention provides compounds of formula 17-61, ie, compounds of formula 17-52 wherein, R3 and R3a combine to form = N-OH; and R x is H or C 1 -C 4 alkyl (such as methyl, ethyl or isopropyl). In another aspect, the invention provides compounds of Formula 17-62, ie, compounds of formula 17-61 wherein, R 2 is H, C 1 -C 4 alkyl. In one embodiment, R2 is methyl. In another embodiment, R2 is ethyl, in yet another embodiment, R2 is isopropyl. In yet another embodiment, when Rx is C? -C4 alkyl, then Rx and R2 are cis to each other. In yet another embodiment, when Rx is C? -C4 alkyl, then Rx and R2 are trans to each other. In another embodiment, Rx and R2 are the same, and are methyl or ethyl. In still another aspect, the invention provides compounds of formula 17-63, ie, compounds according to any of formulas 17-59 or 17-61 wherein, R2 is pyrimidyl, pyridyl, thiazolyl, or imidazolyl. In one embodiment, R2 is pyrimidyl or pyridyl. In another embodiment, R2 is thiazolyl, or imidazolyl. In yet another embodiment, when Rx is not H, then R and R2 are cis to each other. In yet another modality, when Rx is not H, then Rx and R2 are trans to each other. In yet another embodiment, Rx is pyrimidyl and R2 is pyrimidyl or pyridyl. In still another embodiment, Rx is pyridyl and R2 is pyrimidyl or pyridyl. In a further embodiment, Rx is cyclopropyl and R2 is pyrimidyl or pyridyl. In a further embodiment, Rx is cyclopropyl and R2 is pyrimidyl or pyridyl. In another aspect, the invention provides compounds of the formula 17-64, ie, compounds of the formula 17-52 wherein, R and R 3a combine to form = N-0-C 1 -C 4 alkyl; Y Rx is C3-Cg cycloalkyl, pyridyl or pyrimidyl. In yet another aspect, the invention provides compounds of the formula 17-65, ie, compounds of the formula 17-64 wherein, R 2 is H, C 1 -C 4 alkyl. In one embodiment, R2 is methyl. In another embodiment, R2 is ethyl, in yet another embodiment, R2 is isopropyl. In yet another embodiment, Rx and R2 are cis to each other. In another embodiment, R and R2 are trans to each other. In yet another embodiment, Rx is pyrimidyl and R2 is H. In yet another embodiment, Rx is pyridyl and R2 is H. In a further embodiment, Rx is cyclopropyl and R2 is H. In a further embodiment, Rx is cyclopropyl and R2 is H. In a further aspect, the invention provides compounds of the formula 17-66, ie, compounds of the formula 17-52 wherein, R3 and R3a combine to form = N-0-C-C4 alkyl; and R x is H or C 1 -C 4 alkyl (such as methyl, ethyl or isopropyl). In another aspect, the invention provides compounds of the formula 17-67, ie, compounds of the formula 17-66 wherein, R 2 is H, C 1 -C 4 alkyl. In one embodiment, R2 is methyl. In another embodiment, R2 is ethyl, in yet another embodiment, R2 is isopropyl. In yet another embodiment, when Rx is C? -C4 alkyl, then Rx and R2 are cis to each other. In yet another embodiment, when Rx is C? -C alkyl, then Rx and R2 are trans to each other. In another embodiment, Rx and R2 are the same, and are methyl or ethyl.

In still another aspect, the invention provides compounds of formula 17-68, ie, compounds according to any of formulas 17-64 or 17-66 wherein, R2 is pyrimidyl, pyridyl, thiazolyl, or imidazolyl. In one embodiment, R2 is pyrimidyl or pyridyl. In another embodiment, R2 is thiazolyl, or imidazolyl. In yet another embodiment, when Rx is not H, then R and R2 are cis to each other. In yet another mode, when Ri is not H, then Ri and R2 are trans to each other. In yet another embodiment, Ri is pyrimidyl and R2 is pyrimidyl or pyridyl. In still another embodiment, Rx is pyridyl and R2 is pyrimidyl or pyridyl. In a further embodiment, Ri is cyclopropyl and R2 is pyrimidyl or pyridyl. In a further embodiment, Rx is cyclopropyl and R2 is pyrimidyl or pyridyl. In a further aspect, the invention provides compounds of formula 17-69, ie, compounds according to any of formulas 16, 16-1, 16-2, 16-3, 16? 4, 16-5, 16 -6, 16-6a, 16-7, 16-8, 16-9, 16-10, 16-11, 16-lla, 16-11 b, 16-12, 16-13, 16-14 or 16- Wherein Rx is pyridyl, pyrimidyl, -C02-C? -C4 alkyl, C? -C4 alkyl, C? -C4-OC (O) NR 'R "alkyl, benzimidazolyl, thiazolyl or imidazolyl and R2 is H, methyl, or ethyl, wherein R 'and R "are independently H or C? -C4 alkyl. When R2 is methyl or ethyl, Ri and R2 can be cis or trans to each other. In still another aspect, the invention provides compounds of the formula 17-70, ie, compounds of the formula 17-69 wherein Ri is pyridyl, pyrimidyl, thiazolyl, benzimidazolyl or imidazolyl. In still another aspect, the invention provides compounds of the formula 17-71, ie, compounds of the formula 17-69 wherein, Rx is -C02-Me or -C02-Et. In yet another aspect, the invention provides compounds of the formula 17-72, ie, compounds of the formula 17-69 wherein Ri is methyl, ethyl or propyl (either n or iso). In still another aspect, the invention provides compounds of formula 17-73, ie, compounds of formula 17-69 wherein, Rx is -CH2-0C (O) NR 'R ", wherein R' and R" they are independently H or C? -C2 alkyl. In one embodiment, R2 is H. In another embodiment, R2 is ethyl. In a further aspect, the invention provides compounds of formula 17-74, ie, compounds according to any of formulas 16, 16-1, 16-2, 16-3, 16-4, 16-5, 16 -6, 16-6a, 16-7, 16-8, 16-9, 16-10, 16-11, 16-lla, 16-llb, 16-12, 16-13, 16-14, or 16- Wherein R x is C 1 -C 4 -OC (O) NR 'R "alkyl; R 2 is H or C 1 -C 4 -OC (O) NR' R" alkyl; and R2 / R3 and R3a are both H; wherein R 'and R "are independently H or C? -C3 alkyl.In one embodiment, Ri and R2 are both -CH2-OC (O) NR' R". In yet another embodiment, R 'and R "are both H, methyl or ethyl In yet another embodiment, at least one of R' and R" is isopropyl.

In yet another aspect, the invention provides compounds of formula 17-75, ie, compounds according to either Formula 16 up to and including 16 to 15, or any of formulas 17, up to and including 17-74 wherein the heterocycloalkyl group is morpholinyl optionally substituted by one or more groups that are independently halogen, C alkyl? C6 alkoxy C? C6 alkyl, haloalkyl, haloalkoxy, hydroxyl, CN, aryloxy, arylalkyloxy, -S02- (alkyl C ? -C6) -NR'R "alkanoyl C? C6 alkyl, pyridyl, phenyl or -S02-NR'R", wherein each R 'and R "is independently H or C? ~ Cg. in yet another aspect, the invention provides compounds of formula 17-75a, ie compounds of formula 17-75 wherein the morpholinyl group not bound to the sulfur group S02 via the ring nitrogen. in yet another aspect, the invention provides compounds of the formula 17-75b, ie, compounds of the formula 17-75 wherein the morpholinyl group is to the sulfur of the S02 group by means of the ring nitrogen. In yet another aspect, the invention provides compounds of formula 17-76, ie, compounds according to either Formula 16 up to and including 16 to 15, or any of formulas 17, up to and including 17-74 , wherein the heterocycloalkyl group is thiomorpholinyl optionally substituted with one or more groups which are independently halogen, C?-Cg alkyl, C?-C6 alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, aryloxy, arylalkyloxy-S02- (C?-C6 alkyl), -NR'R ", C?-C6 alkanoyl, pyridyl phenyl or -S02-NR'R ", wherein each R 'and R" is independently H or C? C6 alkyl. in yet another aspect, the invention provides compounds of formula 17-76a, ie compounds Formula 17-76 wherein the thiomorpholinyl group is not bonded to the sulfur of the S02 group by ring nitrogen In yet another aspect, the invention provides compounds of the formula 17-76b, ie, compounds of the formula 17- 76 wherein the thiomorpholinyl group is bonded to the sulfur of the group S02 by means of the ring nitrogen In yet another aspect, the invention provides compounds of the formula 17-77, ie, compounds according to any of the formulas 16 to and which includes 16-15, or any of formulas 17, up to and including 17-74, wherein the heterocycloalkyl group is s S, thiomorpholinyl S-dioxide optionally substituted with one or more groups which are independently halogen, C?-Cg alkyl, C?-Cg alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, aryloxy, arylalkyloxy, -S02- (C-alkyl) ? -Cg), -NR'R ", C? -Cg alkanoyl, pyridyl, phenyl or -S02-NR'R", wherein each R 'and R "is independently H or C? -Cg alkyl. In still another aspect, the invention provides compounds of the formula 11 -11 a, ie, compounds of the formula 17-77 wherein the thiomorpholinyl group is not bonded to the sulfur of the group S02 via the ring nitrogen. In still another aspect, the invention provides compounds of the formula 17-77b, ie, compounds of the formula 17-77 wherein the thiomorpholinyl group is bonded to the sulfur of the S02 group by means of the ring nitrogen. In still another aspect, the invention provides compounds of the formula 17-78, ie, compounds according to any of the formulas 16 up to and including 16-15, or any of the formulas 17, up to and including 17-74 , wherein the heterocycloalkyl group is piperidinyl optionally substituted with one or more groups which are independently halogen, C? -Cg alkyl, C? -Cg alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, aryloxy, arylalkyloxy, -S02- (C-alkyl) ? -Cg), -NR'R ", C? -Cg alkanoyl, pyridyl, phenyl or -S02-NR'R", wherein each R 'and R "is independently H or C? -C6 alkyl. aspect, the invention provides compounds of the formula 17-78a, ie, compounds of the formula 17-78 wherein the thiomorpholinyl group is not bonded to the sulfur of the group S02 by means of the nitrogen of the ring In yet another aspect, the invention provides compounds of the formula 17-78b, ie, compounds of the formula 17-78 wherein the thiomorpholine group binds it to the sulfur of S02 group by means of the ring nitrogen. In still another aspect, the invention provides compounds of formula 17-79, ie, compounds according to any of formulas 16 up to and including 16-15, or any of formulas 17, up to and including 17-74 , wherein the heterocycloalkyl group is piperazinyl optionally substituted with one or more groups which are independently halogen, C? -C6 alkyl, C? -C6 alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, aryloxy, arylalkyloxy, -S02- (C-alkyl) ? -C6), -NR'R ", C? -C6 alkanoyl, pyridyl, phenyl, or -S02-NR'R", wherein each R 'and R "is independently H or C? -C6 alkyl. In another aspect, the invention provides compounds of the formula 17-79a, ie, compounds of the formula 17-79 wherein the thiomorpholinyl group is not bonded to the sulfur of the S02 group by the ring nitrogen. invention provides compounds of the formula 17-79b, ie, compounds of the formula 17-79 wherein the thiomorpholinyl group it is bonded to the sulfur of the S02 group by means of the ring nitrogen. In another aspect, the invention provides compounds of formula 18, ie, compounds of formulas 1 or 2, wherein R x is phenyl, benzyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl, C02R ', -CONR'R ", methyl, ethyl, i-propyl, i-butyl, s-butyl, wherein Het in each occurrence is independently pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl; Ph is phenyl; Py is pyridyl; ring B is pyrazolyl, imidazolyl, pyrrolyl, triazolyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, isoxazolyl, pyrimidyl or pyridyl, each of which is optionally substituted in a substitutable position with a group that is independently C?-Cg alkyl, C-alkoxy ? -Cg, amino, alkylamino C? -C3, dialkylamino C? -C6, alkylthio C? -Cg, halo, C? -C2 haloalkyl, C? -C2 haloalkoxy or phenyl; R8 = H or C? -Cg alkyl (such as methyl); R2 = methyl, ethyl, isopropyl, vinyl or allyl; and R '= H or methyl. In another aspect, the invention provides compounds of formula 18-1, ie, compounds of formula 18 wherein ring B has the formula: wherein R2o is H, C? -C4 alkyl, C? -C4 alkoxy, amino, C? -C alkylamino, C? -C4 dialkylamino, C? -C4 alkylthio, halo, CF3 or phenyl. In yet another aspect, the invention provides compounds of the formula 18-2, ie, compounds of the formula 18-1 wherein R20 is H, or C? -C3 alkyl. In another embodiment, R20 is phenyl. In yet another embodiment, R2o is H. In yet another embodiment, R2o is methyl or ethyl. In another aspect, the invention provides compounds of formula 18-3, ie, compounds of formula 18 wherein ring B has the formula: wherein R30 is H, C? -C4 alkyl, C? -C4 alkoxy, amino, C? -C4 alkylamino, C? -C4 dialkylamino, C? -C4 alkylthio, halo, CF or phenyl. In another aspect, the invention provides compounds of the formula 18-4, ie, compounds of the formula 18-3 wherein, R30 is H, or C6-C6 alkyl. In another embodiment, R30 is phenyl. In yet another embodiment, when the R30 group is bonded to a carbon, R30 is C? -C4 alkoxy, C? -C4 alkylthio, halo, CF3, or phenyl. In yet another embodiment, R 30 is H. In another aspect, the invention provides compounds of the formula 18-5, ie, compounds of the formula 18-4, wherein R 30 is amino, C 1-4 alkylamino, dialkylamino C? -C4. In another aspect, unless otherwise defined, the invention provides compounds according to any of the above formulas wherein R3 and R3a are H. In another aspect, the invention provides compounds selected from: 5- (4-chlorophenylsulfonyl) -4,6-dicyclopropyl-4,5,6,7-tetrahydro-lH-pyrazolo [4, 3-c] pyridine; cis- (5- (4-chlorophenylsulfonyl) -4-ethyl-4,5,6,7-tetrahydro-lH-pyrazolo [4, 3-c] pyridin-6-yl) methanol; 5- (4-chlorophenylsulfonyl) -6- (pyrimidin-5-yl) -5,6-dihydro-1H-pyrazolo [4, 3-c] pyridin-7 (4H) -one; 5- (4-chlorophenylsulfonyl) -4- (pyrimidin-5-yl) -5,6-dihydro-1H-pyrazolo [4, 3-c] pyridin-7 (4H) -one; - (4-chlorophenylsulfonyl) -6-cyclopropyl-6,7-dihydro-1H-pyrazolo [4, 3-c] pyridin-4 (5H) -one; 4- (pyrimidin-5-yl) -5-. { 4- (trifluoromethyl) phenylsulfonyl) -4,5,6,7-tetrahydro-lH-pyrazolo [4, 3-c] pyridine; 6-methy1-4- (pyrimidin-5-yl) -5- (4- (trifluoromethyl) phenylsulfonyl) -4,5,6,7,7-tetrahydro-lH-pyrazolo [4, 3-c] pyridine; 4,6-dimethyl-5- (4- (trifluoromethyl) phenylsulfonyl) -5,6-dihydro-1H-pyrazolo [4,3-c] pyridin-7 (4H) -one; (4- (pyrimidin-5-yl) -5- (4- (trifluoromethyl) phenylsulfonyl) -4,5,6,7-tetrahydro-lH-pyrazolo [4, 3-c] pyridin-6-yl) methanol; 5- (4-chlorophenylsulfonyl) -6-methyl-4- (pyrimidin-5-yl) -4,5,6,7,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 5- (4-chlorophenylsulfonyl) -6-cyclopropyl-4- (pyrimidin-5-yl) -4,5,6,7-tetrahydro-lH-pyrazolo [4, 3-c] pyridine, • 5- (4- fluorophenylsulfonyl) -4,6-dimethyl-5,6-dihydro-lH-pyrazolo [4, 3-c] pyridin-7 (4H) -one; 4,6-dimethyl-5- (pyridin-2-ylsulfonyl) -5,6-dihydro-lH-pyrazolo [4, 3-c] pyridin-7 (4H) -one; 5- (4-chlorophenylsulfonyl) -4,6-bis (1,1-difluoroethyl) -4,5,6,7,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 5- (4-chlorophenylsulfonyl) -4,6-bis (difluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 1, 1 '- (5- (4-chlorophenylsulfonyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridin-4,6-diyl) dietanone; - (4-chlorophenylsulfonyl) -4,6-bis (2,2-difluorovinyl) -4,5,6,7,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 5- (4-chlorophenylsulfonyl) -4,6-bis (2,2-difluoroethyl) -4,5,6,7-tetrahydro-lH-pyrazolo [4, 3-c] pyridine; 5- (4-chlorophenylsulfonyl) -4,6-bis (fluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 5- (4-chlorophenylsulfonyl) -4,6-bis (difluoro (methoxy) methyl) 4,5,6,6-7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 5- (4-chlorophenylsulfonyl) -4,6-bis ((trifluoromethoxy) methyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 5- (4-chlorophenylsulfonyl) -4,6-bis (2,2,2-trifluoroethyl) -4,5,6,7,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 5- (4-chlorophenylsulfonyl) -4,6-diisopropyl-4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine, • 5 '- (4-chlorophenylsulfonyl) -l', ', 6', 7'-tetrahydrospiro [cyclopropan-1,4'-pyrazolo [4,3-c] pyridine]; 6-methyl-4- (pyrimidin-5-yl) -5- (4- (trifluoromethyl) phenylsulfonyl) -5,6-dihydro-lH-pyrazolo [4, 3-c] pyridin-7 (4H) -one; 6-methyl-4- (pyridin-3-yl) -5- (4- (trifluoromethyl) phenylsulfonyl) -5,6-dihydro-lH-pyrazolo [4,3-c] pyridin-7 (4H) -one; 6-methyl-4- (pyridin-4-yl) -5- (4- (trifluoromethyl) phenylsulfonyl) -5,6-dihydro-1H-pyrazolo [4, 3 c] pyridin-7 (4H) -one; 5- (4-chlorophenylsulfonyl) -4,6-diethyl-5,6-dihydro-lH-pyrazolo [4, 3-c] pyridin-7 (4H) -one O-methyl oxime; 5- (4-chlorophenylsulfonyl) -4,6-diethyl-N, N-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridin-7-amine; 5- (4-chlorophenylsulfonyl) -4,6-diethyl-4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridin-7-amine; 5- (4-chlorophenylsulfonyl) -4,6-diethyl-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridin-7-ol; 5- (4-chlorophenylsulfonyl) -4,6-diethyl-1-fluoro-, 5,6-7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 5- (4-chlorophenylsulfonyl) -4,6-diethyl-7,7-difluoro-4,5,6,6-7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 6-methyl-4- (thiazol-2-yl) -5- (4- (trifluoromethyl) phenylsulfonyl) -5,6-dihydro-lH-pyrazolo [4,3-c] pyridin-7 (4H) -one; 4- (1H-imidazol-5-yl) -6-methyl-5- (4- (trifluoromethyl) phenylsulfonyl) -5,6-dihydro-1H-pyrazolo [4,3-c] pyridine-7 (4H) - ona; 4- (1H-imidazol-2-yl) -6-methyl-5- (4- (trifluoromethyl) phenylsulfonyl) -5,6-dihydro-1H-pyrazolo [4,3-c] pyridin-7 (4H) - ona; 5- (4-chlorophenylsulfonyl) -4,6-bis (trifluoromethyl) -4,5,6,7,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 5- (4-chlorophenylsulfonyl) -4-isopropyl-5,6-dihydro-lH- pyrazolo [4, 3-c] pyridin-7 (4H) -one; 5- (chlorophenylsulfonyl) -6-pheny1-4,5,6,6-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 6-benzyl-5- (4-chlorophenylsulfonyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 5- (4-chlorophenylsulfonyl) -6-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyrridine; 5- (4-chlorophenylsulfonyl) -6- (4-fluorophenyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 6- (4-chlorophenyl) -5- (4-chlorophenylsulfonyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 5- (4-chlorophenylsulfonyl) -6- (3, 5-difluorophenyl) -4,5,6,7,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 4- (4-chlorophenyl) -5- (4-chlorophenylsulfonyl) -6-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 6- (4-chlorophenyl) -5- (4-chlorophenylsulfonyl) -3- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine; 6- (4-chlorophenyl) -5- (4-chlorophenylsulfonyl) -4-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 5- (4-chlorophenylsulfonyl) -4,6-dimethyl-4,5,6,6-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 5- (4-chlorophenylsulfonyl) -6- (pyridin-3-yl) -4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine, • 5- (4-chlorophenylsulfonyl) -6 - (pyridin-4-yl) -4,5,6,7- tetrahydro-lH-pyrazolo [4, 3-c] pyridine; 5- (4-chlorophenylsulfonyl) -4,6-diethyl-4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 5- (4-chlorophenylsulfonyl) -6- (pyrimidin-5-yl) -4,5,6,7,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 5- (Chloro-benzenesulfonyl) -4-pyrimidin-5-yl-4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 5- (4-chlorophenylsulfonyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine-carboxylic acid ethyl ester; 5- (4-chlorophenylsulfonyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine-6-carboxylic acid ethyl ester; 5- (4-chlorophenylsulfonyl) -6-ethyl-6,7-dihydro-lH-pyrazolo [4,3-c] pyridin-4 (5H) -one; (5- (4-chlorophenylsulfonyl) -4,5,6,7-tetrahydro-lH-pyrazolo [4, 3-c] pyridin-6-yl) methanol; 5- (4-chlorophenylsulfonyl) -4,6-diethyl-5,6-dihydro-lH-pyrazolo [4, 3-c] pyridin-7 (4H) -one; 5-. { 4-chlorophenylsulfonyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridin-4,6-dicarboxylate diethyl ester; 5- (4-chlorophenylsulfonyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridin-diyl) dimethanol; dimethylcarbamate (5- (4-chlorophenylsulfonyl) -4,5,6,7-tetrahydro-lH-pyrazolo [4,3-c] pyridin-4-yl) methyl; 5- (4-chlorophenylsulfonyl) -4,6-diethyl-5,6-dihydro-lH-pyrazolo [4, 3-c] pyridin-7 (4H) -one; (5- (4-chlorophenylsulfonyl) -1- (dimethylcarbamoyl) -4,5,6,7-tetrahydro-lH-pyrazolo [4, 3-c] pyridin-4-yl) methyl dimethylcarbamate; 4,6-diethyl-5- (pyridin-2-ylsulfonyl) -4,5,6,7,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 4- (1H-benzoimidazol-2-yl) -5- (4-chloro-benzenesulfonyl) -4,5,6,7,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 5- (4-chlorophenylsulfonyl) -4,6-diethyl-5,6-dihydro-1H-pyrazolo [4,3-c] pyridin-7 (4H) -one oxime; 5- (4-chlorophenylsulfonyl) -6-ethyl-4,5,6,6-7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine-4-carboxylic acid ethyl ester; 4,6-diethyl-5- (4-fluorophenylsulfonyl) -4,5,6,7-tetrahydro-2H-pyrazolo [4, 3-c] pyridine; 5- (4-chlorophenylsulfonyl) -6-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridin-4-yl) methyl dimethylcarbamate; 5- (4-chlorophenylsulfonyl) -4-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridin-6-yl) methyl dimethylcarbamate; 2- (5- (4-chlorophenylsulfonyl) -4,5,6,6> 7-tetrahydro-2H-pyrazolo [4, 3-c] pyridin-6-yl) thiazole; 2- (5- (4-chlorophenylsulfonyl) -4,5,6,7-tetrahydro-2H-pyrazolo [4, 3-c] pyridin-4-yl) thiazole; 5- (4-chlorophenylsulphonyl) -ethyl-4,5,6,7-tetrahydro-lH-pyrazolo [4, 3-c] pyridin-6-yl) methanol, • 4? 6-diethyl-5- (pyridine -2-ylsulfonyl) -4,5,6,7-tetrahydro-2H-pyrazolo [, 3-c] pyridine; 4,6-diethyl-5- (pyridin-2-ylsulfonyl) -4,5,6,7,7-tetrahydro-2H-pyrazolo [4 > 3-c] pyridine; 4,6-dimethyl-5- (4- (trifluoromethyl) phenylsulfonyl) -5,6-dihydro-2H-pyrazolo [4,3-c] pyridin-7 (4H) -one; and stereoisomers, tautomers, mixture of stereoisomers and / or tautomers or pharmaceutically acceptable salts thereof. In another aspect, the invention provides a method for the treatment of Alzheimer's disease which comprises administering a therapeutically effective amount of a compound or a salt of the formula I to a patient in need of such treatment. In another aspect, the invention provides a method for the treatment of Alzheimer's disease comprising administering a therapeutically effective amount of a compound or a salt of the formula la to a patient in need of such treatment. In yet another aspect, the invention provides a composition comprising a compound or a salt of formula 1 and at least one pharmaceutically acceptable solvent, adjuvant, excipient, vehicle, binder or disintegrant. In yet another aspect, the invention provides a composition comprising a compound or a salt of the formula I and at least one pharmaceutically solvent acceptable, adjuvant, excipient, vehicle, binder or disintegrant. In still another aspect, the invention provides a composition comprising a compound or a salt of the formula la and at least one pharmaceutically acceptable solvent, adjuvant, excipient, vehicle, binder or disintegrant. In yet another aspect, the invention provides a method for the treatment of Alzheimer's disease which comprises administering a therapeutically effective amount of a compound or salt of formula I to a patient in need of such treatment. In still another aspect, the invention provides a method for the treatment of Alzheimer's disease which comprises administering a therapeutically effective amount of a compound or salt of formula la to a patient in need of such treatment. In another aspect, the compounds of the invention have a minimal interaction or, preferably, have no interaction with Notch.

Definitions The following definitions and explanations are for the terms as used throughout this document including the specification and the claims.

It should be noted that, as used in this specification and the appended claims, the singular forms "a", "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to a composition containing "a compound" includes a mixture of two or more compounds. It should also be noted that the term "or" in general is used in its sense including "and / or" unless the content clearly dictates otherwise. When the multiple substituents are indicated as linked to a structure, it will be understood that the substituents may be the same or different. Thus, for example, "Rm optionally substituted with 1, 2 or 3 Rq groups" indicates that Rm is substituted with 1, 2 or 3 Rq groups in which the Rq groups may be the same or different. It will be understood by those skilled in the art with respect to any group containing one or more substituents in which such groups are not intended to introduce any substitution or substitution patterns that are spherically impractical and / or synthetically unfeasible. APP, amyloid precursor protein, is defined as any APP polypeptide, which includes variants of APP, mutations and isoforms, for example, as described in U.S. Pat. No. 5,766,846. A beta amyloid peptide, beta, it is defined as any peptide that results from the cleavage mediated by the beta secretase of APP, which includes the peptides of 39, 40, 41, 42 and 43 amino acids and which extends from the cleavage site of beta secrecase to amino acids 39 , 40, 41, 42 or 43. Pharmaceutically acceptable refers to the properties and / or substances that are acceptable to the patient from a toxicological and / or safety point of view. A therapeutically effective amount is defined as an amount effective to reduce or decrease at least one symptom of the disease being treated or to reduce or delay the onset of one or more clinical markers or symptoms of the disease. By "alkanoyl" is meant an acyl radical Alq-C (O) -, wherein Alk is an alkyl radical as defined herein. Examples of alkanoyl include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, 2-methyl-butyryl, 2,2-dimethylpropionyl, valeryl, hexanoyl, heptanoyl, octanoyl and the like. By "alkyl" and "C" -Cg alkyl "in the present invention is meant straight or branched chain alkyl groups having 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, sec- butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3-methylpentyl. It is understood that in cases where an alkyl chain of a substituent (eg, of an alkyl, alkoxy or alkenyl group) is shorter or longer than 6 carbons, in this way it will be indicated in the second "C" as, for example, "C? -C? o" indicates a maximum of 10 carbons. The term also includes substituted alkyl groups, and refers to an alkyl group in which 1 or more hydrogen atoms is replaced by a substituent independently selected from the group: acyl, acyloxy, alkoxy, amino (wherein the amino group may be a cyclic amine), aryl, heteroaryl, heterocyclyl, carboxyl, oxo, amido, cyano, cycloalkyl, cycloalkenyl, halogen, hydroxyl, nitro, sulfamoyl, sulfanyl, sulfinyl, sulfonyl and sulfonic acid. By "alkylene" is meant a di-radical of alkyl group, whereby alkyl is as defined above.

By "alkoxy" and "C alco-C alco alkoxy" in the present invention is meant straight or branched chain alkyl groups having 1-6 carbon atoms, linked at least through a divalent oxygen atom, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, neopentoxy, hexoxy and 3-methylpentoxy. "Alkenyl" and "C2-C6 alkenyl" means straight and branched hydrocarbon radicals having from 2 to 6 carbon atoms and from one to three double bonds and includes, by example, ethenyl, propenyl, l-but-3-enyl, l-pent-3-enyl, l-hex-5-enyl and the like. The term also includes substituted alkenyl groups, and refers to an alkenyl group in which 1 or more hydrogen atoms is replaced by a substituent independently selected from the group: acyl, acyloxy, alkoxy, amino (wherein the amino group may be a cyclic amine), aryl, heteroaryl, heterocyclyl, carboxyl, oxo, amido, cyano, cycloalkyl, cycloalkenyl, halogen, hydroxyl, nitro, sulfamoyl, sulfanyl, sulfinyl, sulfonyl and sulfonic acid, for example lH-pyrrol-2-ylmethylene. "Alkynyl" and "C2-Cg alkynyl" means straight or branched chain hydrocarbon radicals having from 2 to 6 carbon atoms and one or two triple bonds and includes ethynyl, propynyl, butynyl, pentin-2-yl and the like. The term also includes substituted alkynyl groups, and refers to an alkynyl group in which 1 or more hydrogen atoms is replaced by a substituent independently selected from the group: acyl, acyloxy, alkoxy, amino (wherein the amino group may be a cyclic amine), aryl, heteroaryl, heterocyclyl, carboxyl, oxo, amido, cyano, cycloalkyl, cycloalkenyl, halogen, hydroxyl, nitro, sulfamoyl, sulfanyl, sulfinyl, sulfonyl and sulfonic acid. By "aryl" is meant an aromatic carbocyclic group having a single ring (eg, phenyl) or multiple condensed ring in which at least one is aromatic, (eg, 1, 2, 3, 4-tetrahydronaphthyl, naphthyl), which is optionally mono-, di-, or trisubstituted. Preferred aryl groups of the present invention are phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl, fluorenyl, tetralinyl or 6,7,8,8-tetrahydro-5H-benzo [a] cycloheptenyl. The aryl groups herein are unsubstituted or substituted in one or more substitutable positions with several groups. For example, such aryl groups can be optionally substituted with, for example, C? -C6 alkyl, C? -Cg alkoxy, halogen, hydroxyl, cyano, nitro, amino, mono (C? -Cg) alkylamino, di (C? -C6) alkylamino, C2-C6 alkenyl, C2-C6 alkynyl, haloalkyl C? -Cg, haloalkoxy C? -C6, amino (C? -Cg) alkyl, mono (C? -Cg) alkylamino (C? -C6) alkyl or di (C? -C6) alkylamino (Ci-Cg) alkyl. By "arylalkyl" or "aralkyl" is meant the -alkylene-aryl group, wherein alkylene and aryl are defined herein. By "aryloxy" is meant the group -O-aryl wherein the term "aryl" is as defined herein. By "arylalkyloxy" or "arylalkyloxy" is meant the group -O-C? -4-alkylene-aryl wherein the terms "aryl" and "alkylene" are as defined herein. An example of arylalkyloxy is benzyloxy (or -0-CH2-phenyl). By "cycloalkyl" is meant carbocyclic radicals saturated ones that have three to twelve carbon atoms. The cycloalkyl can be a monocyclic, fused polycyclic system, or a bi-or polycyclic bridge system, such as adamantyl or bicyclo [2.2.1] heptyl. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Preferred cycloalkyl groups are cyclopentyl, cyclohexyl and cycloheptyl. The cycloalkyl groups herein are unsubstituted or substituted in one or more substitutable positions with several groups. For example, such cycloalkyl groups can be optionally substituted with, for example, Ci-Cg alkyl, C alco-Cg alkoxy, halogen, hydroxyl, cyano, nitro, amino, mono (C? -Cg) alkylamino, di (Ci-Cg) alkylamino, C2-Cg alkenyl, C2-Cg alkynyl, C? -C6 haloalkyl, C? -C6 haloalkoxy, amino ( Ci-Cg) alkyl, mono (Ci-Cg) alkylamino (C? -C6) alkyl or di- (Ci-Cg) -alkylamino- (C? -Cg) alkyl. By the term "halogen" or "halo" in the present invention is meant fluorine, bromine, chlorine and / or iodine. By "haloalkyl" is meant an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced by a halogen. Examples of such haloalkyls include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl and the like. By "heteroaryl" is meant at least one or more rings 5-6- or 7-membered aromatic ring systems including fused ring systems of 9-11 atoms containing at least one and up to four heteroatoms selected from nitrogen, oxygen or sulfur. The heteroaryl groups of the present invention include pyridyl, pyrimidyl, quinolinyl, benzothienyl, indolyl, indolinyl, pyridazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, isothiazolyl, naphthyridinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl, pyridopyridyl, benzotetrahydrofuranyl, benzotetrahidrotienilo, purinyl, benzodioxolyl, triazinyl, pteridinyl, benzothiazolyl, imidazopyridyl, imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, chromonyl, chromanonyl, pyridyl-N-oxide, tetrahydroquinolinyl, dihydroquinolinyl, dihydroquin nolinonyl, dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocumarinyl, isoindolinonyl, benzodioxanil, benzoxazolinonyl, N-oxide pyrrolyl, N- Pyrimidyl oxide, N-oxide of pyridazinyl, N-oxide of pyrazinyl, N-oxide of quinolinyl, N-oxide of indolyl, N-oxide of indolinyl, N-oxide of isoquinolyl, N-oxide of quinazolinyl, N-oxide of quinoxalinyl, phthalazinyl N-oxide, imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolyl N-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide, Benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide, benzothiopyranyl S-oxide, S, S-benzothiopyranyl dioxide. Preferred heteroaryl groups include pyridyl, pyrimidyl, quinolinyl, benzothienyl, indolyl, pyridazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, furanyl, thienyl and pyrrolyl. More preferred heteroaryl groups include pyridyl, pyrimidyl, thienyl, pyrazolyl, oxazolyl, thiazolyl and pyrrolyl. More preferred are pyridyl, pyrimidyl, thienyl, pyrrolyl and thiazolyl. The heteroaryl groups herein are unsubstituted or substituted in one or more positions substitutable with several groups. For example, such heteroaryl groups can be optionally substituted with, for example, C?-Cg alkyl, C alco-Cg alkoxy, halogen, hydroxyl, cyano, nitro, amino, mono (C? -C6) alkylamino, di (Ci-Cs) alkylamino, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Cg haloalkyl, C? -C6 haloalkoxy, amino- (C? C6) alkyl, mono (C? -Cg) alkylamino (Ci-Cg) alkyl or di (Ci-Cg) alkylamino (C? -Cg) alkyl. By "heterocycle", "heterocycloalkyl" or "heterocyclyl" is meant one or more 4-, 5-, 6- or 7-membered ring carbocyclic ring systems which includes fused ring systems of 9-11 atoms containing minus one and up to four heteroatoms selected from nitrogen, oxygen or sulfur. Preferred heterocycles of the present invention include morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, S, S-thiomorpholinyl dioxide, piperazinyl, homopiperazinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydrofuranyl, tetrahydrothienyl, homopiperidinyl, homomorpholinyl, homothiomorpholinyl, S, S-homothiomorpholinyl, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazolyl, dihydropyridyl, dihydropyrimidyl, dihydrofuryl, dihydropyranyl, tetrahydrothienyl S-oxide, S, S-tetrahydrothienyl dioxide and homothiomorpholinyl S-oxide. More preferred are piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, S, S-thiomorpholinyl dioxide, tetrahydrofuranyl or imidazolidinyl. The heterocycle groups in the present are unsubstituted or substituted in one or more substitutable positions in several groups. For example, such heterocycle groups may be optionally substituted with, for example, C? -Cg alkyl, C? -Cg alkoxy, halogen, hydroxyl, cyano, nitro, amino, mono (C? -C6) alkylamino, di (C? Ce) alkylamino, C2-Cg alkenyl, C2-C6 alkynyl, C? -Cg haloalkyl, C? -C6 haloalkoxy, amino (C? -Cg) alkyl, mono (C? -C6) alkylamino (C? -Cg) alkyl , di (C? -C6) alkylamino (C? ~ Cg) alkyl or = 0. By "hydroxyalkyl" is meant an alkyl substituted with a hydroxyl, such as hydroxymethyl, 1-hydroxypropyl, 2-hydroxyethyl, 3-hydroxyethyl or 3-hydroxybutyl. Most of the compounds were named using Autonom 2000 4.01.305, which is available from Beilstein Information Systems, Inc., Englewood, Colorado, or ChemDraw v. 9.0.1 or 10.0, (available at Cambridgesoft at 100 Cambridge Park Drive, Cambridge, MA 02140). Alternatively, the names were generated based on the IUPAC rules. The term "laugh" is used to represent the relative configuration of any asymmetric center with respect to another stereocenter within the same molecule or, alternatively, to represent the relative configuration of any asymmetric center in a molecule with respect to the same stereocenter in its enantiomer when the absolute configurations have not been determined.

The compounds of this invention may contain one or more asymmetric carbon atoms, so that the compounds may exist in different stereoisomeric forms. These compounds can be, for example, racemates, non-racemic chirals or diastereomers. In these situations, simple enantiomers, that is, optically active forms can be obtained by asymmetric synthesis or by resolution of the racemates. The resolution of the racemates can be carried out, for example, by conventional methods, such as crystallization in the presence of a resolving agent; chromatography, using, for example, a chiral HPLC column or derivation of the racemic mixture with a resolving agent to generate diastereomers, separation of the diastereomers by means of chromatography and removal of the resolving agent to generate the original compound in the enantiomerically form enriched Any of the above procedures can be repeated to increase the enantiomeric purity of a compound. Non-toxic pharmaceutically acceptable salts include, but are not limited to the salts of inorganic acids, such as hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic and nitric or the salts of organic acids, such as formic, citric, malic, maleic, fumaric , tartaric, succinic, acetic, lactic, methanesulfonic, p-toluenesulfonic, 2-hydroxyethylsulfonic, salicilico and stearic. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium. Those skilled in the art will recognize a wide variety of pharmaceutically acceptable, non-toxic addition salts. The invention also encompasses prodrugs of the compounds of formula I. The invention also encompasses the acylated prodrugs of the compounds of the formula I. Those skilled in the art will recognize the various synthetic methodologies, which may be employed to prepare pharmaceutically acceptable non-toxic addition salts and the acylated prodrugs of the compounds encompassed by the Formula I. The term "acid prodrug group" represents a radical that is converted into an active carboxylic acid compound of the formula I in vivo. Such prodrug groups are generally known in the art and include the ester forming groups, to form an ester prodrug, such as benzyloxy, di (C? -Cg) alkylammoyethyloxy, acetoxymethyl, pivaloyloxymethyl, phthalidoyl, ethoxycarbonyloxyethyl, 5-met? l-2-oxo-l, 3-d? oxo-4-? methyl and (C? -C6) alkoxy optionally substituted by N-morpholmo and amide forming groups such as di (C? -Cg) alkylamino. Preferred prodrug groups include C alco-Cg alkoxy which forms an ester, and 0 ~ M + where M + represents a cation for form an acid salt. Preferred cations include sodium, potassium and ammonium. Other canes include magnesium and calcium. Preferred additional prodrug groups include 0"M ++ where M ++ is a divalent cation such as magnesium or calcium When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, It is intended that the compounds include the cis, trans, Z-, and E. Also, all tautomeric forms are also intended to be included The invention also encompasses prodrugs of the compounds of Formula I. Those skilled in the art will recognize different Synthesis methodologies that can be used to prepare pharmaceutically acceptable non-toxic prodrugs of the compounds encompassed by Formula I. Those skilled in the art will recognize a wide variety of pharmaceutically acceptable non-toxic solvates, such as water, ethanol, mineral oil, vegetable oil and Dimethylsulfoxide The compounds of Formula I p they can be administered orally, topically, parenterally, by inhalation or atomization or rectally in unit dosage formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes percutaneous, subcutaneous, intravascular (e.g., intravenous), intramuscular or intrathecal injection or infusion techniques and the like. In addition, a pharmaceutical formulation comprising a compound of the general Formula I and a pharmaceutically acceptable carrier is provided. One or more compounds of the general formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and / or diluents and / or adjuvants, and if desired other active ingredients. The pharmaceutical compositions containing the compounds of the general formula I can be in the form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservatives. to provide pharmaceutically elegant and edible preparations. The tablets contain the active ingredient in admixture with excipients pharmaceutically acceptable non-toxic which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulation and disintegration agents, for example, corn starch or alginic acid; agglomerating agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques. In some cases such coatings can be prepared by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a prolonged action for a longer period. For example, a time delay material, such as glyceryl monostearate or glyceryl distearate, may be employed. Formulations for oral use may also be presented as hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules, wherein the active ingredient is mixed with water or an oily medium, for example, peanut oil, liquid paraffin or olive oil. Formulations for oral use can also be presented as pills.

Aqueous suspensions contain active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and acacia gum; The dispersing agents or humectants may be a naturally occurring phosphatide, for example, lecithin or condensation products of an alkylene oxide with fatty acids, for example, polyoxyethylene stearate or condensation products of ethylene oxide with aliphatic alcohols of long chain, for example, heptadecaethyleneoxycetanol or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and anhydrides of hexitol, for example, polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin. Oily suspensions can be formulated by suspending the active ingredients in a vegetable oil, for example, peanut oil, olive oil, oil sesame or coconut oil or in a mineral oil, such as liquid paraffin. Oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol. Sweetening agents and flavoring agents may be added to provide edible oral preparations. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid. Dispersible powders and granules suitable for the preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing agents or humectants or suspending agents are exemplified by those already mentioned above. Additional excipients may also be present, for example, sweetening, flavoring and coloring agents. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil or a mineral oil or mixtures of these. Suitable emulsifying agents may be naturally occurring gums, for example, acacia gum or tragacanth gum, naturally occurring phosphatides, for example, soy, lecithin and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example, sorbitan monooleate and condensation products of the partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents. The syrups and elixirs can be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol, glucose or sucrose. Such formulations may also contain an emollient, a preservative and flavoring and coloring agents. The pharmaceutical compositions can be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using the appropriate dispersing agents or humectants and suspending agents mentioned above. The sterile injectable preparation can also be an injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, fixed, sterile oils are conventionally employed as a solvent or suspension medium. For this purpose, any soft fixed oil may be used, including synthetic mono- or diglycerides. In addition, fatty acids, such like oleic acid have use in the preparation of injectables. The compounds of the general formula I can also be administered in the form of suppositories, for example, for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures, but liquid at the rectal temperature and, therefore, will melt in the rectum to release the drug. These materials include cocoa butter and polyethylene glycols. The compounds of the general formula I can be administered parenterally in a sterile medium. The drug, depending on the vehicle and the concentration used, can be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle. For disorders of ocular and other external tissues, for example, mouth and skin, the formulations are preferably applied as a topical gel, spray, ointment or cream or as a suppository, containing the active ingredients in a total amount of, for example, 0.075 to 30% w / w, preferably 0.2 to 20% w / w and more preferably 0.4 to 15% w / w. When formulated in an ointment, the active ingredients can be used with a paraffinic or irascible ointment base in water. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of a cream base may include, for example, at least 30% w / w of polyhydric alcohol, such as propylene glycol, butan-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof. The topical formulation may desirably include a compound that improves the absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulfoxide and related analogs. The compounds of this invention can also be administered by a transdermal device. Preferably, topical administration will be performed using a patch either of the reservoir type and of the porous membrane or of a variety of solid matrix. In any case, the active agent is continuously released from the reservoir or microcapsules through a membrane in the permeable adhesive of active agent, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the patient. In the case of microcapsules, the encapsulating agent can also function as the membrane.

The transdermal patch can include the compound in a suitable solvent system with an adhesive system, such as an acrylic emulsion and a polyester patch. The oily phase of the emulsions of this invention may be constituted of the known ingredients in a known manner. While the phase may exclusively comprise an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or oil or with a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier, which acts as a stabilizer. It is also preferred to include an oil and a fat. Together, the emulsifier (s) with or without the stabilizer (s) form the so-called emulsifying wax and the wax together with the oil and the fat form the so-called emulsifying ointment base, which forms the dispersed oily phase of the cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the invention include Tween 60, Span 80, cetearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium laupl sulfate, among others. The choice of oils or fats suitable for the formulation is based on obtaining the desired cosmetic properties, since the solubility of the active compound in most of the oils that will probably be used in the pharmaceutical emulsion is very low. In this way, the cream should preferably be a non-greasy, non-dyed and washable product with an appropriate consistency to avoid spilling the tubes or other containers. Straight or branched, mono or dibasic alkyl chain esters, such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, may be used. , 2-ethylhexyl palmitate or a mixture of branched chain esters. These can be used alone or in combination depending on the properties required. Alternatively, high-melting lipids, such as white soft paraffin and / or liquid paraffin or other mineral oils, may be used. Formulations suitable for topical administration to the eye also include eye drops, wherein the active ingredients are dissolved or suspended in an appropriate vehicle, especially an aqueous solvent for the active ingredients. Anti-inflammatory active ingredients are preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% and particularly about 1.5% w / w. For therapeutic purposes, the active compounds of this combination of the invention are ordinarily combined with one or more adjuvants appropriate for the indicated route of administration. The compounds can be mixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum , sodium alginate, polyvinylpyrrolidone and / or polyvinyl alcohol, and then formed into tablets or encapsulated for convenient administration. Such capsules or tablets may contain a controlled release formulation as may be provided in a dispersion of active compound in hydroxypropylmethylcellulose. Formulations for parenteral administration may be in the form of sterile, isotonic, aqueous or non-aqueous injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the mentioned carriers or diluents for use in the formulations for oral administration. The compounds can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride and / or different buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art. Dosage levels in the order of about 0.1 mg to about 140 mg per kilogram of weight per day are useful in the treatment of the conditions indicated above (approximately 0.5 mg to approximately 7 g per patient per day). The amount of active ingredient that can be combined with the carrier materials to produce a simple dosage form will vary depending on the host treated and the particular mode of administration. In general, the unit dosage forms contain between about 1 to about 500 mg of an active ingredient. The daily dose can be administered in one to four doses per day. In the case of skin conditions, it may be preferable to apply a topical preparation of the compounds of this invention to the affected area two to four times per day. It will be understood, however, that the specific dosage level for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration , route of administration and the rate of excretion, combination of the drug and the severity of the particular disease that undergoes therapy. For administration to non-human animals, the composition can also be added to the animal feed or drinking water. It may be convenient to formulate animal feed compositions and water for drink so that the al takes in a therapeutically appropriate amount of the composition along with its diet. It may also be convenient to present the composition as a premix for addition to the food or drinking water. Descriptions in this document of all articles and references, including patents, are hereby incorporated by reference in their entirety. The invention is further illustrated by the following examples, which will not be construed to limit the invention in scope or spirit to the specific procedures described therein. The initiator materials and the different intermediates can be obtained from commercial sources, prepared from the commercially available compounds and / or prepared using the known synthesis methods.

General Synthesis Methods The compounds of the invention can be prepared using methods known in the art of org synthesis. For example, the compounds of the invention, as well as all intermediates, can be synthesized by known processes using the solid phase or solution techniques as shown below. The representative procedures to prepare the compounds of the invention are represented in the following reaction schemes. In addition, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent some functional groups from experiencing unwanted reactions. Appropriate protecting groups for the different functional groups, as well as the appropriate conditions for protecting and deprotecting the particular functional groups are well known in the art. For example, the numerous protecting groups are described in T. W. Greene and G. M. Wuts, Protecting Groups in Org Synthesis, Second Edition, Wiley, New York, 1991 and the references cited therein. Some abbreviations used throughout the specification have the following megs: BiNAP refers to 2, 2'-bis-diphenylphosphanyl- [1, 1 '] binaphthalenyl. conc. it refers to concentrate. DBU refers to 1,8-diazabicyclo [5.4.0] undec-7-ene. DCM refers to dichloromethane. DDC refers to dicyclohexylcarbodiimide. DIEA refers to N, N-diisopropylamine. DMA refers to N, N-dimethylacetamide. DMAP refers to dimethylaminopyridine. DMF refers to dimethylformamide.

DMF-DMA refers to dimethylformamide dimethylacetal. DMSO refers to dimethyl sulfoxide. EDC refers to l- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride. Et20 or ether refers to diethyl ether. EtOAc refers to ethyl acetate. HATU refers to 0- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate. HBTU refers to 1-hydroxybenztriazolyltetramethyl uronium. HPLC refers to high pressure liquid chromatography.

IC 50 refers to the molar concentration of a drug, which produces 50% of the maximum possible inhibition for such a drug. LCMS refers to liquid chromatography / mass spectrometer. MeOH refers to methanol. MMNG refers to l-methyl-3-nitro-l-nitrosoguine. MP-TsOH refers to a structure of crosslinked macroporous polystyrene (10-25%) with divinylbenzene that has been functionalized with a sulfonic acid group. MS represents mass spectrum. m / z refers to the mass to load ratio. NMR refers to nuclear magnetic resonance. RT refers to room temperature. sat it refers to saturated. THF refers to tetrahydrofuran. TMS refers to tetramethylsilane. TMS-CI refers to trimethylchlorosilane REACTION SCHEME 1 Method 7 T T Deprotection. »• 1-iN-Ñ Method 8 G = NH, N?, O p = protective groups X = Halogen or other leaving group, such as OMs, OTs, etc.

In the above reaction scheme, each of the variables independently contains the definitions as described above. One skilled in the art will appreciate that the above reaction scheme can be used to selectively produce a single diastereomer and / or a single enantiomer.

Method 1. Sulfonyl glyoxaldehyde imines 1 (prepared according to Lit: Synlet t, (1991), pp. 29-30) was condensed with the Danishefsky diene in a refluxing solvent (eg, 50-250 ° C in toluene) , xylene, etc.), or at a lower temperature (-78 to 50 ° C) in a solvent (tetrahydrofuran, dichloromethane, acetonitrile, etc.) with a metal catalyst and ligand (for example, Cu (C104) (MeCN) 4 and S-di (p-tolyl) BiNAP). The reaction can be made and purified according to the literature to provide the enone ester sulfonamides 2.

Method 2. The reaction of ester enones 2 with an organocopper or organocuprate (for example, vinyl (Me) CuCN example in Lit: J.

Am. Chem. Soc. (2003), Vol. 68, pp. 8867-8878 or J. Org. Chem. (1996), Vol. 61, 4594-4599) at low temperature (-100 to 25 ° C) gives the enolate that can be trapped as an enol ether using TMS-Cl or another electrophile. After turning off the reaction, the The product of enol ethers 3 are isolated after typical processing.

Method 3 The. Enol ethers 3 can generate the enolate by the addition of methyllithium or another nucleophile in a solvent, such as tetrahydrofuran. The enolate can be reacted with different electrophiles including ethyl formate, formyl pivalate, ethyl trifluoroacetate, pyruvonitrile and others to produce enol ketones 4 in typical processing and purification.

Method 4. The enol-ketones 4 were condensed with hydrazine or a substituted hydrazine (solution or hydrazine-free salt) in a single solvent or combination of ethanol, acetic acid, tetrahydrofuran, toluene or others with or without an added base such as acetate of sodium. After typical processing, the pyrazole 5 product can be purified by chromatography or crystallization.

Method 5. The pyrazole ester group 5 (or alternatively, the pyrazole acid 5 which is formed by hydrolysis of the ester), under a typical polar solvent (tetrahydrofuran, tetrahydropyran, etc.) and low temperature conditions (-100 to 25 ° C) can be optionally reacted with one or more nucleophiles, sequentially with or without the preparation of the intermediate. Nucleophiles, such as lithium tri-s-butylborohydride, lithium and tri-t-butoxyaluminum hydride, alkyl or aryl magnesium reagents, organozier reagents or organozinc can be reacted to produce the secondary or tertiary alcohol products 6 after the elaboration and purification. Alternatively, the pyrazole acid 5 can be converted to a Weinreb amide and further processed to generate, for example, an acid ketone. Alternatively, the pyrazole acid 5 can be reacted with some coupling or activation reagent (such as DCC, EDC, HATU, HBTU etc.) to generate a species that can be further elaborated to generate, for example, an acid amide .

Method 6. The products of the pyrazole alcohol 6 can be alkylated in the OH position using different electrophilic reagents such as alkyl halides, benzylic halides and heterosubstituted alkyl and arylalkyl halides using a typical solvent (acetonitrile, etc.) and base (triethylamine). - dimethylaminopyridine, cesium carbonate, silver oxide (1), etc.), or using the conditions of activation and displacement (ie, Mitsunobu conditions with an acidic nucleophilic group such as a sulfonamide, acylated amine, etc.). The alcohols 6 can also be acylated using the typical conditions (acylation Lit. WO 2003/014075 or US 20050085506). After typical processing and purification by chromatography or crystallization, pyrazoles substituted with ether or amine can be obtained.

Method 7. In the case of pyrazole products 7 with a protective group in one of the pyrazole nitrogens, this group can be removed by the oxidative or reductive, acidic, nucleophilic conditions common to the protecting group to produce free NH pyrazoles 8 Method 8. In the case of pyrazole products 7 or 8 with a carbon substituent (R2o = H), this position C-H can be halogenated by reactants, such as N-chlorosuccinimide, bromine, etc. (bromination Lit. WO 2003/066634). After typical processing and purification by chromatography or crystallization of the halogenated pyrazoles 9, it can also be substituted in this position by nucleophiles or palladium-mediated couplings.

REACTION SCHEME 2 17 18 In the above reaction scheme, each of the variables independently contains the definitions as described above, while alq is a C? -Cg alkyl group. One of ordinary skill in the art will appreciate that the above reaction scheme can be used to selectively produce a single diastereomer and / or a single enantiomer.

Method 9. 4-Methoxypyridine 10 can be reacted according to Lit. (Tetrahedron Lett., (1986), Vol. 27 (38), pp. 4549-4552 or J. Am. Chem. Soc. (2003), Vol. 68, pp. 8867-8878.) With an organomagnesium reagent and a chloroformate (e.g., benzyl chloroformate or phenyl chloroformate) at a lower temperature (-78 to 50 ° C) in a solvent (tetrahydrofuran, dichloromethane, acetonitrile, etc.). The reaction can be worked up and purified according to Lit. to provide the enone carbamate 11.

Method 10. The reaction of the enone carbamate 11 according to Method 2 gives the product carbamate enol ether 12.

Method 11. Enol ether 12 can generate the enolate by adding methyllithium or other nucleophile as in Method 3 and reacted to generate enol ketone 13. Alternatively, enol ether 12 can be reacted with different electrophiles (e.g. , dichloromethyl methyl ether, trimethyl orthoformate, etc.) and a Lewis acid (tin chloride, titanium chloride, etc.) to produce an enol ketone 13 once the typical work up and purification.

Method 12. Enol-ketone 13 can be treated as in Method 4 to produce pyrazole carbamate 14 which can be purified by chromatography or crystallization.

Method 13. Pyrazole carbamate 14 can be deprotected by standard means as appropriate for the protection used (treatment with trimethylsilyl iodide, catalytic hydrogenation, sodium alkoxide, etc.) as described in Greene, Theodora W.; Wuts, Peter G. M. Protective Groups in Organic Synthesis. 2nd Ed. (1991), p. 473. After typical work up and optional purification by chromatography or crystallization, pyrazole piperidine 15 can be obtained as the free amine or as a salt form.

Method 14. Pyrazole piperidine 15 can be sulfonylated with a sulfonyl chloride and an organic or inorganic base (e.g., triethylamine, pyridine, aqueous sodium hydroxide, etc.) with or without a solvent such as dichloromethane or tetrahydrofuran at temperatures of 0. at 25 ° C. After typical work-up and optional purification by chromatography or crystallization, pyrazole sulfonamide 16 can be obtained.

Method 15. In the case of pyrazole products 16 with a protecting group in one of the pyrazole nitrogens, this group can be removed by the oxidizing or reductive, acidic, nucleophilic conditions common to the protecting group to produce the free NH pyrazole. .

Method 16. In the case of pyrazole products 17 without a carbon substituent (R2o = H), this position C-H can be halogenated by reactants, such as N-chlorosuccinimide, bromine, etc. (bromination Lit. WO 2003/066634). After typical processing and purification by chromatography or crystallization, the halogenated pyrazole 18 can be further substituted in this position by nucleophiles or couplings mediated by palladium.

REACTION SCHEME 3 2 In the above reaction scheme, each of the variables independently contains the definitions as described above, while each alq is independently C?-Cg alkyl (preferably, methyl, ethyl, isopropyl or tert-butyl). One skilled in the art will appreciate that the above reaction scheme can be used to selectively produce a single diastereomer and / or a single enantiomer.

Method 20. The aplimins 22 are prepared by refluxing 21 with an appropriate aldehyde of aplo and a Lewis acid, such as T? Cl4 in an appropriate solvent, such as toluene, benzene, etc. according to the procedure: W. Bpan Jennings, et al., Tetrahedron (1991), Vol 47, No. 29, pp. 5561-5568.

METHOD 21. Compounds 23 are prepared from compounds 22 by Diels Alder reaction according to the literature procedure: Geoffrey R. Heintzelman, et al., J. Org. Chem., (1996), Vol. 61, pp. 4594-4599.

METHOD 22 Compounds 24 are prepared from compounds 23 by hydrogenation with H2 and an appropriate catalyst such as Pd on carbon in a suitable solvent, such as methanol or ethanol etc. Compounds 24 can also be prepared using L-select method by the procedure: Williams, Alfred L.; Abbot Grillo, Teresa; Comins, Daniel L. Department of Chemistry, North Carolina State University, Raleigh; NC, USA. Journal of Organic Chemistry (2002), No. 67 (6), pp. 1972-1973. Alternatively, Compounds 24 can be prepared according to Method 2 above, or the Method 32 as shown below. The compounds 25 can be prepared by subjecting the compounds 24 to Method 3 and Method 4 as depicted above.

REACTION SCHEME 4 31 32 33 40 39 In the above reaction scheme, each of the variables independently contains the definitions as described above, while P is a protecting group. One skilled in the art will appreciate that the The above reaction scheme can be used to selectively produce a single diastereomer and / or a single enantiomer.

Method 30. Benzyl 4-oxo-l-piperidinecarboxylate 31 (purchased from Aldrich, St. Louis, MO) was treated with bromine in ethylene glycol to produce compound 32.

Method 31. The elimination of compounds 32 with a base such as DBU, DIEA, etc. in a suitable solvent such as DMSO DMF, DMA, etc. followed by hydrolysis of the compounds 33.

Method 32. 1.4 addition of the aryl Grignard reagents to 33 with a BFOEt2 / organocopper complex formed in situ yielded the compounds 34. Alternatively, the compounds 34 can be prepared according to Method 2 above. Alternatively, compounds 34 can be prepared asymmetrically by rhodium-catalyzed addition 1-4 of organozinc reagents to compounds 33 as described by Hayashi JACS. (2004), Vol. 125, pp. 6240-41. Alternatively, the compounds 34 can be prepared asymmetrically by the addition of the catalyzed conjugate by rhodium / phosphoramidite of the arylboronic acids to compounds 33 as described by de Vries, Feringa, and Minnaard. Org. Let t. (2005), Vol. 7, pp. 2433-35. The compounds 36 are prepared by formylation or acylation of the ketones 34 using Method 3 and Method 4.

Method 33. Compounds 36 can be deprotected by standard means appropriate for the type of protection used as described in Greene, Theodora W .; Wuts, Peter G. M. Protective Groups in Organic Syn thesis. 2nd Ed. (1991), 473 pp. (treatment with trimethylsilyl iodide, catalytic hydrogenation, sodium alkoxide, etc.).

Method 34. The sulfonylation is carried out with a sulfonyl chloride and an organic or inorganic base (for example, triethylamine, pyridine, aqueous sodium hydroxide, DIEA, etc.) with or without a solvent such as dichloromethane or tetrahydrofuran at temperatures of 0 at 25 ° C. After typical work-up and optional purification by chromatography or crystallization, di-sulfonylated products 37 and 38 are obtained.

Method 35. The di-sulfonylated products 37 and 38 were divided selectively hydrolytically with a base such as NaOH, NaOMe, etc. in a suitable solvent such as THF, MeOH, dioxane, H20, etc. to provide the products 39.

Experimental procedures Some compounds of this invention are prepared from other compounds of this invention by means of the known reactions and the transformations of the functional groups. Examples of such transformations are ester hydrolysis, amide formation and reductive alkylation; examples of these are described in the following preparations. The initiator materials are obtained from commercial sources or prepared by known methods as described in the following examples. The compounds included in this invention are exemplified by the following examples, which should not be construed as limiting the scope of this description. Analogous structures and alternative synthesis routes within the scope of the invention will be apparent to those skilled in the art. Reagents and solvents obtained from commercial suppliers were used without further purification unless otherwise stated. Thin layer chromatography was performed on pre-coated 0.25 mm silica gel plates (silica gel 60 from E. Merck, F254). Visualization was achieved using UV illumination or staining with phosphomolybdic acid, ninhydrin or other common dyeing reagents. Flash chromatography was performed using a Biotage Flash 40 system and pre-packaged silica gel columns or hand-packed columns (E. Merck silica gel 60, 230-400 mesh). Preparative HPLC was performed on a Varian Prepstar high resolution chromatograph. The 1 H NMR spectra were recorded on a Varian Gemini 300 MHz spectrometer or a Bruker Avance 300 MHz spectrometer. The chemical changes are reported in ppm (d) and were calibrated using the resonance of the non-deuterated solvent as an internal standard. The mass spectra were recorded on an Agilent 1100 series mass spectrometer connected to an Agilent 1100 series HPLC. The purity of the compounds was determined by HPLC / MS analysis by a variety of analytical methods: [1] = gradient 20% [ B]: 80% [A] to 70% [B]: 30% [A] in 1.75 min, then retention, to 2 mL / min, where [A] = 0.1% trifluoroacetic acid in water; [B] = 0.1% trifluoroacetic acid in acetonitrile on a Phenomenex Luna C18 (2) 4.6 mm x 30 cm column, 3 micron packing, 210 nm detection, at 35 ° C. [2]: An isocratic gradient that employs 10-20% EtOH or isopropanol in hexane on a Chiralcel OD or Chiralcel OJ column of 2 cm X 25 cm, 220 nm detection at room temperature.

Example 1 Preparation of 5- (4-chlorophenylsulfonyl) -6-phenyl-4,5,6,7-tetrahydro-2H-pyrazolo [4, 3-c] pyridine (55) 53 54 55 Synthesis of 5-hydroxymethylene-4-oxo-2-phenyl-piperidine-1-carboxylic acid tert-butyl ester (51). To a suspension of piperidin-4-one (50) (442 mg, 1.61 mmol) and 75 mg of NaH (60% suspension in mineral oil, 1.77 mmol) in 10 ml of benzene were added 1.3 ml of ethyl formate. and 40 μl of methanol The mixture was stirred at room temperature overnight. Water (5 ml) was added and the organic layer was separated. NaHS04 (10% aq) was added to the aqueous layer to adjust the pH to the range of 3-4 and then extracted with EtOAc twice (2 x 10 ml). The combined organic layers were washed with brine (5 ml) once, and dried (MgSO4). After evaporation of the solvent, the yellow oil was used for the next reaction without further purification. LCMS 326.1 (M + 23).

Synthesis of 6-phenyl-1,4,6,7-tetrahydro-pyrazolo [4, 3-c] pyridine-5-carboxylic acid tert-butyl ester (52). Compound 51 (310 mg, 1.02 mmol) from the previous step was dissolved in MeOH (3 mL). Hydrazine monohydrate (0.1 ml, 2.04 mmol) was added to the solution and then stirred at room temperature for 1 hour. The solvent was removed under reduced pressure to provide a yellow gel as the desired product. LCMS 300.2 (M + 1).

Synthesis of 1,5-bis- (4-chloro-benzenesulfonyl) -6-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine (53) and its regioisomer (54) . Compound 52 from the previous step (1.1 g, 3.67 mmol) was dissolved in ethyl acetate (15 ml). HCl (g) was bubbled into the solution for 5 minutes. The solvent was removed under reduced pressure and the residue was redissolved in pyridine (15 ml). 4-Chlorophenylsulfonyl chloride (1.55 g, 2. 2 eq.) Was added to the solution at zero degrees. The mixture was stirred at zero degrees and rose slowly to room temperature with stirring overnight. Ethyl acetate (100 ml) was added to the reaction mixture, and the solution was washed with saturated NaHCO 3 (2 x 25 ml), 10% HCl solution (2 x 25 ml) and brine (10 ml). The sample was dried on (MgSO4), and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography, eluted with EtOAc / hexane (15:85) to give a white solid as the mixture of two regioisomers. LCMS 569.9 (M + 23).

Synthesis of 5- (4-chloro-benzenesulfonyl) -6-phenyl-4,5,6,7-tetrahydro-2H-pyrazolo [4, 3-c] pyridine (55). Regioisomers 53 and 54 of the previous stage (197 mg, 0.36 mmol) were dissolved in a mixture of THF and water (2: 1, 4.5 ml). NaOH (1.1 ml, 1.0 M) was added to the solution and the mixture was stirred at 75 ° C for 3 hours. After cooling to room temperature, ethyl acetate (50 ml) was added and the mixture was washed with brine twice. The solvent was removed under reduced pressure to give an almost white solid as the pure product. LCMS 374.0 (M + 1). XH NMR (CDC13) d 7.72 (d, J = 7.5 Hz, 2H), 7.38 (d, J = 7.5 Hz, 2H), 7.29-7.19 (m, 6H), 5.61 (d, J = 6.9 Hz, 1H) , 4. 77 (d, J = 16.2 Hz, 1H), 3.84 (d, J = 16.2 Hz, 1H), 3.24 (d, J = 16.8 Hz, 1H), 2.92 (dd, J = 16.8, 6.9 Hz, 1H). The isomers were separated into chiral isomers using the enantiomer A of the HPLC method [2]: γRI NMR (CDC13) d 7.72 (d, J = 7.5 Hz, 2H), 7.38 (d, J = 7.5 Hz, 2H), 7.29- 7.19 (m, 6H), 5.61 (d, J = 6.9 Hz, 1H), 4.77 (d, J = 16.2 Hz, 1H), 3.84 (d, J = 16.2 Hz, 1H), 3.24 (d, J) = 16.8 Hz, 1H), 2.92 (dd, J = 16.8, 6.9 Hz, 1H). Enantiomer B: XH NMR (CDC13) d 7.72 (d, J = 7.5 Hz, 2H), 7.38 (d, J = 7.5 Hz, 2H), 7.29- 7.19 (m, 6H), 5.61 (d, J = 6.9 Hz , 1H), 4.77 (d, J = 16.2 Hz, 1H), 3.84 (d, J = 16.2 Hz, 1H), 3.24 (d, J = 16.8 Hz, 1H), 2.92 (dd, J = 16.8, 6.9 Hz , 1 HOUR) .

Example 2 Cl CIO? S 58 9 NHj DC xM. TErA ** - * • ** • N C OaMe NH 57 P 3P, DIAD, THF e02C COjMe 66 S9 62 63 Synthesis of methyl 2- (4-chlorophenylsulfonamido) butanoate (57). Methyl 2-aminobutanoate hydrochloride 56 (25 g, 0.163 mol) was suspended in CH2C12 (100 ml) and triethylamine (50 mL) and 4-chlorobenzenesulfonyl chloride (37.8 g, 1.1 eq) were added to the mixture. The mixture was stirred at room temperature overnight. It was diluted with 200 mL of CH2Cl2 and washed with water (3 x 50 mL), sat. NaHCO3. (2 x 50 mL), brine (50 mL) and dried (MgSO4). The solvent was removed by rotary evaporation to give the product 57 as a yellow oil. LCMS 292.0 (M + H).

Synthesis of methyl 2- (4-chloro-N- (penty-l-in-3-yl) phenylsulfonamido) butanoate (59). To a dry, cooled flask was added compound 57 (5.0 g, 17.14 mmol), triphenylphosphine (4.25 g, 16.34 mmol) and THF (50 mL). The flask was cooled to 0 ° C and 1-pentyl-3-ol 58 (1.35 mL, 15.59 mmol) in THF (50 mL) was added to the above solution. Then diisopropyl azodicarboxylate (3.2 mL, 16.24 mmol) was added and the reaction mixture was warmed to room temperature and stirred over the weekend. The solvent was removed by rotary evaporation and the residue was redissolved in EtOAc, washed with water, saturated NaHCO3, brine and dried (MgSO4). After in va cuo concentration, the crude material was purified by flash chromatography to give the product 59 as a solid white. LCMS 380.0 (M + 23).

Synthesis of 2- (4-chloro-N- (penty-l-in-3-yl) phenylsulfonamido) -butanoic acid (60). Compound 59 (584 mg, 1.63 mmol) was dissolved in THF (10 mL). Lithium hydroxide monohydrate (134 mg, 2.0 eq) was added followed by 10 mL of water. The mixture was stirred at room temperature overnight. The solvent was removed and the solution was adjusted to pH 3-4 using 3N HCl. The mixture was then extracted with EtOAc (4 x 20 mL). The combined organic layers were washed with brine and dried (MgSO). After removal of the solvent, a white solid was obtained as the product 60. LCMS 366.0 (M + 23).

Synthesis of 4-chloro-N- (l-diazo-2-oxopentan-3-yl) -N- (penty-l-in-3-yl) benzenesulfonamide (61). To a solution of compound 60 (498 mg, 1.45 mmol) in 7.5 mL of Et20 was added sequentially 0.24 mL of triethylamine (1.2 eq), 0.23 mL of isobutyl chloroformate (1.2 eq) at -30 ° C. After stirring at -30 ° C for 15 min, diazomethane (prepared by mixing MNNG and KOH in diethyl ether) (excess) was added to the above mixture at 0 ° C and stirred for 5 hours. Glacial HOAc (1.5 mL) was added to destroy the excess diazomethane and the solution was extracted with EtOAc. The organic phase was washed with saturated NaHCO 3, water, brine and dried (MgSO4). LCMS 368.1 (M + 1).

Synthesis of (4R, 6S) -5- (4-chlorophenylsulfonyl) -4,6-diethyl-5,6-dihydro-1H-pyrazolo [4, 3-c] pyridin-7 (4H) -one (62). The above solution of 61 was stirred at room temperature for four days. The cis isomer was subjected to a 2 + 3 cycloaddition to give the desired product, which was separated from the non-cyclized trans product by flash chromatography. 1 H NMR (CDC13) d 7.58 (d, J = 7.5 Hz, 2 H), 7.54 (s, 1 H), 7.25 (d, J = 8.2 Hz, 2 H), 5.09 (t, J = 7.5 Hz, 1 H), 4. 50 (dd, J = 6.6, 9.9 Hz, 1H), 2.11-1.75 (m, 4H), 1.27-1.15 (m, 6H); MS (m / z) 368.1 (M + H) P Synthesis of (4R, 6S, Z) -5- (4-chlorophenylsulfonyl) -4,6-diethyl-5,6-dihydro-lH-pyrazolo [4, 3-c] pyridin-7 (4H) -one oxime (63). To a solution of compound 62 (67 mg, 0.17 mmol) in a mixture of MeOH / H20 (5: 1, 9 mL) was added NaOAc (141 mg, 1. 7 mmol) followed by hydroxylamine hydrochloride (131.6 mg, 1. 9 mmol). The resulting solution was stirred at room temperature over a weekend. The solvent was removed by rotary evaporation and the residue was placed in EtOAc. The organic phase was washed with water, brine and dried (MgSO4).

After removal of the solvent under reduced pressure, the crude product was purified by flash chromatography to give a white solid as the product 63. - * H NMR (CDC13) d . 28 (bs, 1H), 7.56 (d, J = 9.0 Hz, 2H), 7.45 (s, 1H), 7.20 (d, J = 9.0 Hz, 2H), 5.48 (dd, J = 4.5, 10.5 Hz, 1H ), 4.97 (t, J = 7.5 Hz, 1H), 2.06-1.96 (m, 1H), 1.91-1.77 (m, 2H), 1.68-1.57 (m, 1H), 1.22 (t, J = 6.9 Hz, 3H), 1.14 (t, J = 7.2 Hz, 3H); MS (m / z) 383.0 (M + H) P Example 3 Synthesis of 6-bromo-l, 4-dioxa-8-azaspiro [4.5] decan-8-carboxylic acid benzyl (65). A stirred solution of compound 64 (5.0 g, 21.43 mmol) in 40 ml of dry ethylene glycol was treated with bromine (27 ml, 52 mmol) in a small portion for 3 hours at 35-40 ° C under a balloon filled with nitrogen. Bromine was added at a rate that was sufficient to maintain a red-orange color. The resulting mixture was stirred for an additional 2 hours. Anhydrous potassium carbonate (4.15 g, 21.43 mmol) was added to the reaction mixture, and stirring was continued until bubbling ceased. The mixture was diluted with water (40 mL) and extracted with diethyl ether (5 X 100 ml). The combined organic layers were dried over MgSO4, filtered and concentrated by rotary evaporation. Chromatography of the residue on silica gel with 20% EtOAc / hexanes gave the desired product 65.

Synthesis of 4-oxo-3,4-dihydropyridin-l (2H) -benzylcarboxylate (66). Compound 65 from the previous step (2.1 g, 5.8 mmol) was dissolved in DMSO (30 ml). Under a nitrogen atmosphere, DBU (0.98 mL, 1.14 eq.) Was added and the mixture was heated at 80 ° C overnight. Water was added and the mixture was extracted with diethyl ether (5 X 60 mL). The combined organic layers were washed with brine and dried (MgSO 4). The solvent was removed by rotary evaporation and the white oil was purified by flash chromatography to give product 67 as a white oil.

Synthesis of benzyl 2- (4-chlorophenyl) -4-oxopiperidine-l-carboxylate (67). The CuBr-SMe2 complex (1.49 g, 7.26 mmol) was added to 25 mL of anhydrous THF and cooled to -78 ° C. 4-Chlorophenylmagnesium bromide (7.26 mL, 1.0 M in THF, 7.26 mmol) was slowly added with a syringe. Stirring at -78 ° C for 1 hour produced an orange suspension similar to green. Boron trifluoride dimethyl boron (0.92 mL, 7.26 mmol) was added and stirred for 5 minutes. To the complex formed again, a solution of compound 66 (1.0 g, 4.32 mmol) in 15 mL of anhydrous THF was added over 1 hour. After stirring for 2 hours at -78 ° C, 16 mL of 20% 20% aqueous NH4CI / concentrated NHOH (1: 1) was added, and the mixture was allowed to warm to room temperature. EtOAc was used to extract (3 x 100 mL) and the combined organic layers were washed with brine and dried (MgSO4). The solvent was removed by rotary evaporation and the residue was purified by flash chromatography to give product 67 as a colorless oil.

Example 4 Synthesis of (E) -4-chloro-N- (pyrimidin-5-ylmethylene) benzenesulfonamide (69). To a solution of 5-formyl pyrimidine (68, 1.0 g, 9.3 mmol) and 4-chlorobenzenesulfonamide (1.95 g, 10.2 mmol) in toluene (20 mL) were added molecular sieves of 4 Á (1.0 g) and MP-TsOH (1.0 g). A Dean-Stark apparatus with reflux condenser was attached to the reaction vessel and the reaction was heated to reflux for 18 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was placed in EtOAc and filtered through Celite. The filtrate was concentrated in vacuo to yield 2.12 g (81%) 69 as a light brown solid. XH NMR (CDC13) d 9.42 (s, 1H), 9.25 (s, 2H), 9.15 (s, 1H), 7.98 (d, 2H), 7.57 (d, 2H).

Synthesis of 1- (4-chlorophenylsulfonyl) -2- (pyrimidin-5-yl) piperidin-4-one (71). To a solution of 69 (2.12 g, 7.5 mmol) in THF (15 mL) was added 2- (trimethylsilyl) -1,3-butadiene (70.2.18 g, 15 mmol). The reaction was heated to reflux for 36 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to yield 3.33 g of crude material. The residue was purified by flash chromatography (3: 1 hexanes / EtOAc) to yield 1.05 g (40%) 71 as a yellow solid. H NMR (CDC13) d 9.16 (s, 1H), 8.63 (s, 2H), 7.85 (d, 2H), 7.55 (d, 2H), 5.65 (d, 1H), 4.11-4.04 (m, 1H) , 3. 24-3.14 (m, 1H), 2.96-2.82 (m, 2H), 2.55-2.49 (m, 1H), 2.40-2.34 (m, 1H).

Synthesis of 1- (4-chlorophenylsulfonyl) -5- ((dimethylamino) methylene) -2- (pyrimidin-5-yl) piperidin-4-one and 1- (4-chlorophenylsulfonyl) -3- ((dimethylamino) methylene) -2- (pyrimidin-5-yl) piperidin-4-one (72a, 72b). Compound 71, (0.20 g, 0.57 mmol) was dissolved in DMF-DMA (1 ml) and heated at 70 ° C for 4 hours. The reaction mixture was concentrated in vacuo to yield 230 mg (99%) 72 as a yellow oil which was used without further purification. MS (m / z) 407. (M + H) +.

Synthesis of (re S) -5- (4-chlorophenylsulphonyl) -4- (pyrimidin-5-yl) -4,5,6,7-tetrahydro-lH-pyrazolo [4, 3-c] pyridine, (R) ) -5- (4-chlorophenylsulphonyl) -4- (pyrimidin-5-yl) -4,5,6,7-tetrahydro-lH-pyrazolo [4, 3-c] pyridine, (re S) -5- ( 4-chlorophenylsulfonyl) -6- (pyrimidin-5-yl) -4,5,6,7,7-tetrahydro-lH-pyrazolo [4, 3-c] pyridine and (R, R) -5- (4-chlorophenylsulfonyl) - 6- (pyrimidin-5-yl) -4,5,6,7-tetrahydro-lH-pyrazolo [4, 3-c] pyridine (73, 74, 75, 76). A flask was charged with compound 72 (230 mg, 0.55 mmol) and dissolved in acetic acid (2 ml) and methanol (1 ml). Hydrated hydrazine (0.083 mL, 1.7 mmol) was added and the reaction was stirred at room temperature for 18 hours. The reaction mixture The mixture was concentrated in vacuo and the residue was placed in EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4, filtered, and concentrated in vacuo to yield 0.17 g of crude material as a mixture of regioisomers. The residue was purified by chromatography using method [2] to produce four separate compounds. - (4-chlorophenylsulfonyl) -4- (pyrimidin-5-yl) -tetrahydro-1H-pyrazolo [4, 3-c] pyridine (Enantiomers A and B) XH NMR (CD30D) d 9.09 (s, 1H), 8.71 (s, 2H), 7.83 (d, J = 8.7 Hz, 2H), 7.47 (d, J = 8.7 Hz, 2H), 6.49 (s, 1H), 4.16 (dd, J = 14.9, 6.1 Hz, 1H ) 3.24-3.16 (m, 1H), 2.62 (dd, J = 16.4, 4.4 Hz, 1H), 2.50-2.40 (m, 1H); MS (m / z) 376.0 (M + H) P - (4-Chlorophenylsulfonyl) -6- (pyrimidin-5-yl) -4,5,6,7-tetrahydro-lH-pyrazolo [4, 3-c] pyridine (Enantiomers A and B) 1 H NMR (CD3OD) d 9.03 (s, lH), 8.59 (d, J = 4.5 Hz, 2H), 7.88 (d, J = 8.7 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.43 (bs, 1H) , 5.78 (d, J = 6.0 Hz, 1H), 3.96-3.91 (m, 1H), 2.93 (dd, J = 16.8, 6.3 Hz, 1H); MS (m / z) 376.0 (M + H) P Example 5 Synthesis of (5- (4-chlorophenylsulfonyl) -4,5,6,7-tetrahydro-2H-pyrazolo [4, 3-c] pyridin-4-yl) methanol (78).

Compound 77 (1.22 g, 3.3 mmol) was dissolved in THF (25 mL). Lithium borohydride (5.3 mmol) was slowly added and the reaction was stirred at room temperature for 18 hours. The reaction was quenched with water (25 mL) and salt of Rochelle (2.0 g). The mixture was stirred at room temperature for 1 hour. The mixture was extracted with EtOAc and the combined organic layers were washed with brine. The organic layer was dried over Na 2 SO 4, filtered, and concentrated in vacuo to yield 0.9 g of 78 as a white foam (83%).

XH NMR (CD3OD) d 7.81 (m, 2H), 7.46 (m, 3H), 5.09-5.07 (m, 1H), 4.11-4.06 (m, 2H), 3.72-3.63 (m, 2H), 3.52-3.25 (m, 1H), 2.50-2.37 (m, 2H); MS (m / z) 328, (M + H) P Synthesis of 5- (4-chlorophenylsulfonyl) -4,5,6,7-tetrahydro-2H-pyrazolo [4, 3-c] pyridine-4-carbaldehyde (79). The compound 78 (0.50 g, 1.5 mmol) was dissolved in CH2C12 (5 mL). NaHCO3 (0.3 g, 3.6 mmol) was added, followed by Dess-Martin periodinone (0.78 g, 1.8 mmol). The reaction was stirred at room temperature for two hours and quenched with saturated NaHCO3 (10 mL) and 10% w / v sodium bisulfite (10 mL). The mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted with CH2Cl2 and the combined organic layers were washed with brine. The organic layer was dried over Na 2 SO 4, filtered, and concentrated in vacuo to yield 0.4 g of 79 as a white solid which was used without further purification.

Synthesis of 4- (lH-benzo [d] imidazol-2-yl) -5- (4-chlorophenylsulfonyl) -4,5,6,7-tetrahydro-2H-pyrazolo [4, 3-c] pyridine (80) . A flask was charged with silica (0.06 g) and CH2C12 (5 mL). Thionyl chloride (0.015 mL) was added dropwise. After the addition was complete, the reaction was stirred at room temperature for 1 hour. Compound 79 (0.05 g, 0.15 mmol) was added, followed by phenylenediamine (0.017 g, 0.15 mmol). The reaction was stirred at room temperature for 18 hours. The mixture was diluted with EtOH and the resulting suspension was filtered. The filtrate was concentrated in vacuo and the resulting residue was purified by Preparative HPLC using method [1] to produce 7.8 mg (13%) 80 as a white powder. ** H NMR (CD30D) d 9.13 (s, 1H), 8.33 (s, 1H), 8.05-8.01 (m, 2H), 7.85-7.73 (m, 2H), 7.66 (d, J = 8.7 Hz, 2H ), 7.39 (d, J = 9.0 Hz), 3.42-3.34 (m, 3H); MS (m / z) 414.0 (M + H) P Example 6 Synthesis of 2-ethyl-4-oxo-3,4-dihydropyridin-l (2H) -benzylcarboxylate (82). To a solution of 4-methoxylpyridine 81. (4.41 g, 40.5 mmol) in toluene (200 mL) at -20 ° C was added CbzCl (5.7 mL, 40.5 mmol) in toluene (200 mL) dropwise. After 15 min, ethylmagnesium bromide (23 mL, 2M in THF, 46 mmol) was added dropwise. After 1 h, 10% aqueous HCl (100 mL) was added and the mixture was stirred overnight. The mixture was separated and the organic layer was washed with saturated NaHCO 3 and brine. It was dried and concentrated to provide 82 (9 g, 36.4 mmol, 89.9%) which was used directly in the next reaction.

Synthesis of benzyl 2- (4-chlorophenyl) -6-ethyl-4-oxopiperidin-1-carboxylate (83). CuBr-SMe2 (5.6 g, 27.2 mmol) was added to dry THF (64 mL). It was cooled to -78 ° C. 4-Chlorophenylmagnesium bromide (27.2 mL, 1M in THF, 27.2 mmol) was added to the mixture slowly over 1 h at -78 ° C. Then BF3-Et20 (3.44 mL, 27.2 mmol) was added and the mixture was stirred for 5 min. Then ketone 82 (4 g, 8.1 mmol) in THF (55 mL) was slowly added over 1 h at -78 ° C. After 2 h of stirring at -78 ° C, an aqueous solution of NH 4 Cl / concentrated NH 40 H (1: 1, 20%, 60 mL) was added. The mixture was warmed to room temperature and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine, dried and concentrated to a residue and purified by chromatography on silica gel (0-40% EtOAc / hexanes) to provide pure 83 (1 g, 2.7 mmol, 33%) as a mixture of cis stereoisomers.

Synthesis of 4- (4-chlorophenyl) -6-ethyl-6,7-dihydro-lH-pyrazolo [, 3-c] pyridin-5 (4H) -carboxylic acid benzyl ester and 6- (4-chlorophenyl) -4- ethyl-6,7-dihydro-lH-pyrazolo [4,3-c] pyridin-5 (4H) -benzylcarboxylate (84, 85). To compound 83 (0.91 g, 2.4 mmol) in benzene (24 ml) at room temperature was added NaH (193 mg, 60% in mineral oil, 4.8 mmol) and MeOH (10 DL). Ethyl formate (0.44 mL, 5.5 mmol) was added and the reaction was stirred for 3 h. TLC showed the cmption of 83. The mixture was divided between aqueous citric acid (20%, 20 mL) and EtOAc (20 L). The organic layer was washed with brine. It was dried and concentrated to a residue. The residue was dissolved in MeOH (20 mL). Hydrated hydrazine (0.24 mL, 4.9 mmol) was added and the mixture was stirred overnight at room temperature. The mixture was concentrated to a residue and purified by chromatography on silica gel (10% to 50% EtOAc / Hexanes) to provide compounds 84 (0.2 g, 0.5 mmol, 22%) and 85 (0.5 g, 1.3 mmol, 54%).

Example 7 Synthesis of 4- (4-chlorophenyl) -2,5-bis (4-chlorophenylsulfonyl) -6-ethyl-4,5,6,7-tetrahydro-2H-pyrazolo [4, 3-c] pyridine and 4- ( 4-chlorophenyl) -1,5-bis (4-chlorophenylsulfonyl) -6-ethyl-4,5,6,7-tetrahydro-lH- pyrazolo [4, 3-c] pyridine (86, 87). Compound 84 (0.2 g, 0.5 mmol) in CH3CN (3 mL) at -10 ° C in the dark was added TMSI (0.17 mL, 1.2 mmol). The solution was stirred in the dark while heating at room temperature for 1 h. It was stirred at room temperature for 3 h. The reaction mixture was cooled to -10 ° C again and HCl in MeOH (1.25 M) was added., 1.7 mL, 2.1 mmol) and the reaction was warmed to room temperature while stirring for 1.5 h. The mixture was evaporated to dryness then EtOAc (5 mL) was added. It was sonicated for 30 min and the solvent decanted. This process was repeated 2 more times. The solid was dried and dissolved in pyridine (2 mL). P-Chlorophenylsulfonyl chloride (0.27 g, 1.3 mmol) was added and the mixture was stirred at room temperature overnight. The pyridine was removed and the residue was partitioned between EtOAc and H20. The organic layer was washed with 10% citric acid, saturated NaHCO 3 and brine. It was dried and concentrated and purified by chromatography on silica gel (0% to 40% EtOAc / hexanes) to provide compounds 86 and 87 (70 mg, 0.1 mmol, 20%) as a mixture of cis regioisomers.

Synthesis of 4- (4-chlorophenyl) -5- (4-chlorophenylsulfonyl) -6-ethyl-4,5,6,7-tetrahydro-2H-pyrazolo [4, 3-c] pyridine (88). Compounds 86 and 87 (70 mg, 0.1 mmol) in THF (3.4 mL) were added aqueous NaOH (1M, 1.7 mL, 1.7 mmol) and H20 (1.7 mL).

The mixture was heated at 75 ° C for 2 h. The reaction was partitioned between EtOAc and H20. The organic layer was dried and concentrated and purified by chromatography on silica gel (0% to 50% EtOAc / hexanes) to provide compound 88 (50 mg, 0.1 mmol, 100%) as a mixture of cis stereoisomers.

Example 8 Synthesis of cis and trans-1-benzyl-2,6-dimethylpiperidin-4-one (90, 91). The 1 liter 3-necked round bottom flask, equipped with mechanical stirrer, reflux condenser, thermometer and addition funnel was charged with the acetonicarboxylic acid solution (40 g, 0.28 mol) in water (100 ml). The stirred solution was treated with acetaldehyde (25.3 g, 0.55 mol) at room temperature for 10 minutes, then benzylamine (30 ml, 0.28 mol) was added in small portions for 15 min. A vigorous gas evolution was observed and moderated by the use of a cooling bath (ice-water). The resulting yellow solution was stirred at room temperature for 78 h. The stirred reaction mixture was acidified with IN aqueous HCl a pH 2, was stirred for 1 h then neutralized with saturated sodium bicarbonate to pH 7 and extracted with CH2C12 (3 x 250 ml). The combined extracts were washed with brine and dried with anhydrous Na 2 SO 4. The solution was filtered and evaporated to give a brown liquid, 57 g. The isomeric piperidones were separated by flash chromatography, eluting with CH2Cl2-EtOAc (9: 1). The yield of the first eluent compound, identified as the cis isomer was 20 g. The yield of the second eluent compound, identified as the trans isomer was 25 g. A small amount of unresolved material was also collected (ca. 4, 7 g).

Example 9 Cl Synthesis of cis-2, 6-dimethylpiperidin-4-one (91). The cis-N-benzyl-2,6-dimethylpiperidon-4-one 90 (1.85 g) was dissolved in EtOH (15 ml) and catalyst (0.5 g, 5% Pd / C) was added, the suspension stirred vigorously was maintained under a hydrogen atmosphere (60 psi, 413.64 kPa) for 90 h The catalyst was removed by filtration through Celite and the filtrate was evaporated at 3 mmHg / 40 ° C. The residue 91 (ca.12 g) it was used in the following experiment without further purification.

Synthesis of cis-1- (4-chlorophenylsulfonyl) -2,6-dimethylpiperidin-4-one (92). Crude cis-2,6-dimethylpiperidin-4-one 91 from the previous experiment (1.1 g, 8. 6 mmol) was dissolved in CH2C12 (50 ml) and triethylamine (5 ml, 35 mmol) was added. The stirred solution was treated with 4-chlorobenzenesulfonyl chloride (2.2 g, 9.5 mmol). The mixture was stirred for 24 h then it was divided between water (100 mL) and CH2Cl2 (100 mL). The organic layer was washed with 0.2 N citric acid, water, brine and dried over anhydrous Na2SO4.

The solution was filtered and evaporated. The residue was purified by flash chromatography, eluting with a mixture of EtOAc-hexane (1: 3). Yield 60 mg (2% after two stages).

Example 10 Synthesis of trans-2, 6-dimethylpiperidin-4-one (93). trans-N-benzyl-2,6-dimethylpiperidin-4-one (91, 7.5 g) was dissolved in EtOH (20 mL) and the catalyst (0.8 g, 5% Pd / C) was added. The suspension was vigorously stirred and maintained under a hydrogen atmosphere (60 psi, 413.64 kPa) for 90 h. The catalyst was removed by filtration through Celite and the filtrate was evaporated at 3 mmHg / 40 ° C. The residue (ca. 5.2 g) was used without further purification.

Synthesis of trans-1- (4-chlorophenylsulfonyl) -2,6-dimethylpiperidin-4-one (94). trans-2,6-dimethylpiperidin-4-one (93.2.2 g, 39 mmol) was dissolved in CH2C12 (100 mL) and triethylamine (22 mL, 155 mmol) was added. The solution was stirred and treated with 4-chlorobenzenesulfonyl chloride (9.2 g, 43 mmol). The mixture was stirred for 24 h and then partitioned between water (300 mL) and CH2C12 (300 mL). The organic layer was washed with 0.2 N citric acid, water, brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue (6.7 g) was purified by flash chromatography, eluting with a mixture of EtOAc-hexane (1: 3) to yield 3.6 g (35%, 2 steps) of product 94.

Example 11 ?? r r?? c? ?? ra? prc? H2NNH?; H20 Et0j < - N * EíOjC. , r-l. * EtOjC ^ N. To Et02C,.,, N. i! 100 99 HN-N HN'-fj N ~ tAtA N 'H Synthesis of ethyl 1- (4-chlorophenylsulfonyl) -4-oxopiperidine-2-carboxylate (96). A solution of ethyl glyoxalate (4.5 mL, 23 mmol) and 4-chlorobenzene sulfonyl isocyanate (5.0 g, 23 mmol) in toluene (60 mL) was heated to reflux for 36 hours. The reaction mixture was cooled to room temperature and 2- (trimethylsilyl) -1,3-butadiene (3.3 g, 23 mmol) was added. The reaction was heated at 50 ° C for 18 hours. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (5% EtOAc / hexanes) to give 1.05 g (13%) 96 as a beige oil. And NMR (CDC13) d 7.73 (d, 2H), 7.46 (d, 2H), 4. 87 (d, 1H), 4.76-4.75 (m, 1H), 4.17-3.76 (m, 5H), 2.65-2.52 (m, 1H), 2.48-2.41 (m, 1H), 1.12 (t, 3H).

Synthesis of ethyl 1- (4-chlorophenylsulfonyl) -5- ((dimethylamino) methylene) -4-oxopiperidine-2-carboxylate and 1- (4-chlorophenylsulfonyl) -3- ((dimethylamino) methylene) -4-oxopiperidine- Ethyl 2-carboxylate (97, 98). Compound 96 (0.82 g, 2.4 mmol) was dissolved in DMF-DMA (10 mL) and heated at 40 ° C for 2 hours. The reaction mixture was concentrated in vacuo to yield 900 mg (94%) of a mixture of compounds 97 and 98 as a yellow oil which was used without further purification.

Synthesis of 5- (4-chlorophenylsulfonyl) -4,5,6,7-tetrahydro-IH-pyrazolo [4, 3-c] pyridine-6-carboxylate of (re S) -ethyl, 5- (4-chlorophenylsulfonyl) -4, 5, 6, -tetrahydro-lH-pyrazolo [4, 3-c] pyridine-6-carboxylate of (reí R), 5- (4-chlorophenylsulfonyl) -4,5,6,7-tetrahydro-lH -pyrazolo [4, 3-c] -4-pyridine-carboxylate of (re S) -ethyl and 5- (4-chlorophenylsulfonyl) -4,5,6,7-tetrahydro-lH-pyrazolo [4, 3-c] ] pyridine-4-carboxylate of (R-R) -ethyl (99, 100, 101, 102). A flask was charged with compounds 97 and 98 (900 mg, 2.24 mmol) in acetic acid (5 mL). Hydrated hydrazine (0.194 mL, 4.0 mmol) was added and the reaction was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue placed in EtOAc. The organic layer was washed with saturated aqueous NaHCO 3, brine, dried over Na 2 SO 4, filtered and concentrated in vacuo to yield 0.55 g of crude material as a mixture of the regioisomers. The residue was purified by HPLC using method [2] to provide compounds 99, 100, 101 and 102. - (4-chlorophenylsulfonyl) -4,5,6,7-tetrahydro-lH-pyrazolo [4, 3-c] -pyridine-6-carboxylic acid ethyl ester (Enantiomers A and B) and NMR (CDC13) d 7.78 ( d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7.32 (s, 1H), 5.15 (dd, J = 6.6, 1.5 Hz, 1H), 4.76 (d, J = 13.8 Hz, 1H), 4.36 (d, J = 13.8 Hz, 1H), 4.03- 3. 85 (m, 2H), 3.36 (d, J = 15.6 Hz, 1H), 3.08 (dd, J = 15.9, 6.6 Hz, 1H), 1.20 (d, J = 6.0 Hz, 1H), 1.04 (t, J) = 6.9 Hz, 3H); MS (m / z) 376.0 (M + H) P - (4-chlorophenylsulfonyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine-4-carboxylic acid ethyl ester (Enantiomers A and B). And NMR (CDC13) d 7.78 (d, J = 8.6 Hz, 2H), 7.55 (s, 1H), 7.44 (d, J = 8.6 Hz, 2H), 5.67 (s, 1H), 4.11-4.06 (m, 3H), 3.57-3.47 (m, 1H), 2.72-2.70 (m, 2H), 1.19 (t, J = 7.1 Hz, 3H); MS (m / z) 370.0 (M + H) P Example 12 Synthesis of ethyl 1- (4-chlorophenylsulfonyl) -4-oxo-l, 2,3,4-tetrahydropyridine-2-carboxylate (103). A solution of ethyl glyoxalate (27 mL, 0.14 mol) and 4-chlorobenzene sulfonyl isocyanate (20 mL, 0.14 mol) in toluene (300 mL) was heated to reflux for 60 hours. The reaction mixture is cooled to room temperature and l-methoxy-3-trimethylsilyl-1,3-butadiene (27 mL, 0.14 mol) was added. The reaction was heated at 50 ° C for 18 hours. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (20% EtOAc / hexanes) to yield 16.0 g (34%) of compound 103 as a yellow oil. Y NMR (CDC13) d 7.81 (d, 2H), 7.67 (dd, 1H), 7.55 (d, 2H), 5.40 (d, 1H), 5.01-4.97 (m, 1H), 4.13-4.03 (m, 3H ), 2.86-2.81 (m, 2H), 1.16 (t, 3H).

Synthesis of 1- (4-chlorophenylsulfonyl) -3- ((dimethylamino) methylene) -4-oxo-l, 2,3,4-tetrahydropyridine-2-carboxylic acid ethyl ester (104). Compound 103 (5.0 g, 15 mmol) was dissolved in DMF-DMA (20 mL) and heated at 100 ° C for 30 minutes. The reaction mixture was concentrated in vacuo to yield compound 104 as a yellow oil which was used without further purification.

Synthesis of 5- (4-chlorophenylsulfonyl) -4,5-dihydro-1H-pyrazolo [4, 3-c] pyridine-4-carboxylic acid ethyl ester (105). A flask was charged with compound 104 (5.8 g, 14.6 mmol), acetic acid (10 mL) and EtOH (10 mL). Hydrated hydrazine (1.4 mL, 30 mmol) was added and the reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and the residue placed in EtOAc. The organic layer was washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated in vacuo to yield the crude material which was purified by flash chromatography (50% EtOAc / hexanes) to yield 1.63 g (30%) of compound 105 as a yellow foam. Y NMR (CDCl 3) d 7.76 (d, J = 6.3 Hz, 2H), 7.48-7.41 (m, 3H), 6.90-6.87 (m, 1H), 5.96-5.93 (m, 1H), 5.80 (s, 1H ), 4.13-4.11 (m, 2H), 1.24-1.18 (m, 3H, MS (m / z) 368.0 (M + H) P Example 13 Synthesis of 7- (4-chlorophenyl) -6- (4-chlorophenylsulfonyl) -5,6,7,8-tetrahydro-l, 6-naphthyridine and 5- (4-chlorophenyl) -6- (4-chlorophenylsulfonyl) - 5, 6, 7, 8-tetrahydro-l, 6-naphthyridine (107, 108). A sealed tube was charged with compound 106 (177 mg, 0.46 mmol), propargylamine (59 μL, 0.92 mmol), NaAuCl4-H20 (4.5 mg, 0.012 mmol) and EtOH (2 mL). The reaction mixture was heated at 80 ° C for 6.5 hours. The cooled reaction was filtered, concentrated and the residue placed in CH2C12. The organic portion was washed with 1.0 N HCl (3 x 10 mL), water (1 x 10 mL), saturated aqueous NaHCO3 (3 x 10 mL), brine (1 x 10 mL), dried (MgSO), filtered and concentrated to give the raw product. Purification by preparative TLC eluting with hexanes / EtOAc 2: 1 yielded 37 mg of the less polar regioisomer 107 (TLC: EtOAc / hexanes 1: 1, Rf = 0.38) and 34 mg of the more polar regioisomer 108 (TLC: EtOAc / hexanes 1 : 1, Rf = 0.25). 5- (4-Chlorophenyl) -6- (4-chlorophenylsulfonyl) -5,6,7,8-tetrahydro-1,6-naphthyridine Y-NMR (CDC13) d 8.46-8.44 (m, 1H), 7.59 (d , J = 8.80, 2H), 7.31-7.25 (m, 5H), 7.15-7.12 (m, 1H), 7.09 (d, J = 8.2 Hz, 2H), 6.21 (s, 1H), 3.98-3.91 (m , 1H), 3.38-3.28 (m, 1H), 2.86-2.81 (m, 2H); MS (m / z) 419.0 (M + H) P 7- (4-Chlorophenyl) -6- (4-chlorophenylsulfonyl) -5,6,7,8-tetrahydro-1,6-naphthyridine Y-NMR (CDC13) d 8.42 (d, J = 4.4 Hz, 1H), 7.72 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.8 Hz, 2H), 7.28-7.08 (m, 6H), 5.52 (d, J = 5.5 Hz, 1H), 4.73 (d, J = 17.0 Hz, 1H), 4.09 (d, J = 17.0 Hz, 1H), 3.32 (dd, J = 17.4, 2.2 Hz, 1H), 3.13 (dd, J = 17.5, 6.6 Hz, 1H); MS (m / z) 419.0 (M-H-I) P Example 14 Synthesis of ethyl 1- (4-chlorophenylsulfonyl) -6-ethyl-4-oxopiperidine-2-carboxylate (109). CuBr2-SMe2 (19.13 g, 93.1 mmol) was placed in a flame-dried flask together with THF (250 mL). The mixture was cooled to -78 ° C and ethylmagnesium bromide (31 ml, 3.0 M in ether, 93.1 mmol) was added slowly. The reaction was stirred for 45 minutes under nitrogen. Boron trifluoride dimethyl etherate was added (11.7 ml, 93.1 mmol) and the mixture was stirred for 5 minutes. 1- (4-chlorophenylsulfonyl) -4-oxo-l, 2,3,4-tetrahydropyridine-2-carboxylic acid ethyl ester (103; 8.0 g, 23.3 mmol) was added via a syringe pump for a period of 2 hours. hours while maintaining a bath temperature of -78 ° C. The reaction was stirred for 4 hours and quenched with a 1: 1 solution of NH4C1 / 2% NH40H. An equal amount of EtOAc and water was added and the mixture was filtered to remove the solids. The layers were separated and the aqueous layer was extracted with two more portions of EtOAc. The organic layers were combined and dried over Na 2 SO and concentrated to yield a colorless oil (7.74 g). The material was purified by column chromatography using gradients of EtOAc / hexanes to yield 5.84 g (67%) of a mixture of cis / trans isomers (4:96).

Synthesis of ethyl 8- (4-chlorophenylsulfonyl) -9-ethyl-l, 4-dioxa-8-azaspiro [4.5] decan-7-carboxylate (110). ethyl l- (4-chlorophenylsulphonyl) -6-ethyl-4-oxopiperidine-2-carboxylate (109; 5.31 g, 14.2 mmol), TMSCI (5.41 mL, 42.6 mmol), and ethylene glycol (3.96 mL, 71.0 mmol) were added. add CH2C12 (50 mL) and reflux under nitrogen for 3 hours. The reaction mixture was concentrated under reduced pressure, and placed in equal portions of EtOAc and water. The aqueous layer was washed with several more portions of EtOAc, dried over Na 2 SO 4, and concentrated to give 5.67 g (96%) of a mixture of cis / trans isomers (4:96) as a clear oil which solidified on standing. The material was used without further purification.

Synthesis of (8- (4-chlorophenylsulfonyl) -9-ethyl-l, 4-dioxa-8-azaspiro [4.5] decan-7-yl) methanol (111). 8- (4-chlorophenylsulphonyl) -9-ethyl-1,4-dioxa-8-azaspiro [4.5] decan-7-carboxylic acid ethyl ester (110.247 g, 5.92 mmol) and lithium borohydride (4.7 ml, 2.0 M) in THF, 9.48 mmol) were added to THF (15 ml). The mixture was stirred for 18 hours under nitrogen at room temperature which led only to a 25% conversion to the desired alcohol. The solid sodium borohydride was used in equivalent portions and the reaction was monitored until the initiating ester was consumed. The reaction mixture was concentrated under reduced pressure, and equal portions of EtOAc and the Rochelle salt were added. The aqueous layer was washed with several more portions of EtOAc, dried with Na 2 SO 4, and concentrated to give 2.44 g of crude oil. The material was purified by column chromatography using gradients of EtOAc / hexanes to give 1.26 g (57%) of a mixture of cis / trans isomers.

Synthesis of (8- (4-chlorophenylsulfonyl) -9-ethyl-l, 4-dioxa-8-azaspiro [4.5] decan-7-yl) methyl dimethylcarbamate (112). (8- (4-Chlorophenylsulfonyl) -9-ethyl-1,4-dioxa- 8-azaspiro [4.5] decan-7-yl) methanol (111.1.19 g, 3.18 mmol) and triethylamine (2.21 ml, 15.9 mmol) were added to CH2C12 (15 ml) in a flame-dried flask and placed under N2 DMAP (77.8 mg, 0.637 mmol) was added and the mixture was stirred for 5 minutes. Dimethylcarbamoyl chloride (0.88 ml, 1.54 mmol) was added dropwise and the reaction was stirred for 18 hours. The reaction mixture was concentrated under reduced pressure, and equal portions of EtOAc and water were added. The aqueous layer was extracted with several more portions of EtOAc. The combined organic layers were washed with a diluted NaOH solution, 10% citric acid, brine, dried over Na 2 SO and concentrated to yield 940 mg of 112 as a yellow oil. The material was purified by column chromatography using gradients of EtOAc / hexanes to yield 836 mg (59%) of a mixture of cis / trans isomers.

Synthesis of (1- (4-chlorophenylsulfonyl) -6-ethyl-4-oxopiperidin-2-yl) methyl dimethylcarbamate (113). (8- (4-Chlorophenylsulfonyl) -9-ethyl-1,4-dioxa-8-azaspiro [4.5] decan-7-yl) methyl dimethylcarbamate (112.820 mg, 1.83 mmol) was dissolved in 4M HCl in dioxane (4 mL) and stirred for 18 hours. The reaction mixture was concentrated under reduced pressure and compound 113 was isolated as a crude oil 113 (715 mg, 97%). The material was used without purification additional .

Synthesis of (l- (4-chlorophenylsulfonyl) -5- ((dimethylamino) methylene) -6-ethyl-4-oxopiperidin-2-yl) methyl dimethylcarbamate and (1- (4-chlorophenylsulfonyl) -3- dimethylcarbamate ( (dimethylamino) methylene) -6-ethyl-4-oxopiperidin-2-yl) methyl (114, 115). dimethylcarbamate of (1- (4-chlorophenylsulfonyl) -6-ethyl-4-oxopiperidin-2-yl) methyl (113; 0.69 g, 1.71 mmol) was dissolved in DMF-DMA (3.41 mL, 25.6 mmol) and heated to 90 ° C for 1 hour. The reaction mixture was concentrated under reduced pressure and used without further purification.

Synthesis of ((4R, 6R) -5- (4-chlorophenylsulfonyl) -4-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridin-6-yl) dimethylcarbamate methyl, dimethylcarbamate 4R, 6S) -5- (4-chlorophenylsulfonyl) -4-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridin-6-yl) methyl, dimethylcarbamate (( 4R, 6R) -5- (4-chlorophenylsulfonyl) -6-ethyl-4,5,6,6-tetrahydro-1H-pyrazolo [4, 3-c] pyridin-4-yl) methyl and dimethylcarbamate of ((4S, 6R) -5- (4-chlorophenylsulfonyl) -6-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo [, 3-c] pyridin-4-yl) methyl ester (116, 117 , 118, 119). Compounds 114 and 115 (780 mg from the previous step, 1.71 mmol) were dissolved in EtOH (6 mL) and acetic acid (0.25 mL). Hydrazine was added dropwise hydrated (0.41 mL, 8.55 mmol) and the reaction was stirred for 18 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and the crude material (600 mg) was purified by HPLC using Method [1] to give 118 (16.8 mg), 119 (7.6 mg), 116 (49.4 mg) and 117 ( 5.6 mg).

Cis- (5- (4-chlorophenylsulfonyl) -6-ethyl-4,5,6,7-tetrahydro-lH-pyrazolo [4,3-c] pyridin-4-yl) methyl dimethylcarbamate Y-NMR (CDC13) d 7.74 (d, 2H, J = 8.7 Hz), 7.56 (s, 1H), 7.44 (d, 2H, J = 8.7 Hz), 5.41 (t, 1H, J = 6.9 Hz), 4.38 (dd, 1H, J = 11.9 Hz), 4.25-4.10 (m, 2H), 3.05 (s, 3H), 2.99 (s, 3H), 2.91 (m, 1H), 2.60 (d, 1H, J = 16.4 Hz), 2.29 (d, 1H, J = 16.4 Hz), 1.58 (m, 1H, J = 7.2 Hz), 1.47 (m, 1H, J = 7.2 Hz), 1.02 (t, 3H, J = 7.2 Hz ); 427.1.

Cis- (5-4-chlorophenylsulfonyl) -4-ethyl-4,5,6,7-tetrahydro-lH-pyrazolo [4, 3-c] pyridin-6-yl) methyl-Y-NMR (CDCI3) dimetricarbamate 7.74 (d, 2H, J = 8.7 Hz), 7.53 (s, 1H), 7.41 (d, 2H, J = 8.7 Hz), 5.57 (dd, 1H, J = 8.4 Hz), 4.34 (dd, 1H, J = 8.4 Hz), 4.21 (dd, 1H, J = 5.1 Hz), 3.59 (m, 1H), 2.92 (s, 3H), 2.89 (s, 3H), 2.82 (dd, 1H, J = 4.0 Hz), 2.68 (dd, 1H, J = 11.0 Hz), 2.11 (m, 1H, J = 7.0 Hz), 1.87 (m, 1H, J = 7.0 Hz), 0.98 (t, 3H, J = 7.0 Hz); MS (m / z) 427.1 (M + H) P Trans- (5- (4-chlorophenylsulfonyl) -4-ethyl-4,5,6,7-tetrahydro-lH-pyrazolo [4,3-c] pyridin-6-yl) methyl dimethylcarbamate Y-NMR (CDC13) d 7.67 (d, 2H, J = 8.7 Hz), 7.51 (s, 1H), 7.37 (d, 2H, J = 8.7 Hz), 5.85 (dd, 1H, J = 8.4 Hz), 4.32 (dd, 1H, J = 8.4 Hz), 4.19 (dd, 1H, J = 5.1 Hz), 3.63 (m, 1H), 2.94 (s, 3H), 2.94 (s, 3H), 2.84 (dd, 1H) , J = 5.0 Hz), 2.70 (dd, 1H, J = 10.0 Hz), 1.87 (, 2H, J = 7.0 Hz), 0.85 (t, 3H, J = 7.0 Hz); MS (m / z) 427.1 (M + H) P Trans- (5- (4-chlorofennylsulfonyl) -4-ethyl-4,5,6,7-tetrahydro-lH-pyrazolo [4, 3-c] pyridin-4-yl) methyl dimethylcarbamate Y-NMR (CDCl 3) d 7.77 (s, 1 H), 7.64 (d, 2 H, J = 8.7 Hz), 7. 34 (d, 2H, J = 8.7 Hz), 7.19 (d, 1H, J = 7.1 Hz), 6.49 (br s, 1H), 5.33 (d, 1H, J = 7.1 Hz), 3.40 (m, 1H) , 3.13 (s, 3H), 3.07 (s, 3H), 2.96-2.79 (m, 2H), 1.57 (m, 2H, J = 7.2 Hz), 0.86 (t, 3H, J = 7.2 Hz); MS (m / z) 427.0 (M + H) P Example 15 122 not isolated Synthesis of 1- (4-chlorophenylsulfonyl) -3- ((dimethylamino) methylene) -6-ethyl-4-oxopiperidine-2-carboxylic acid ethyl ester and 1- (4-chlorophenylsulfonyl) -5- ((dimethylamino) methylene) - Ethyl 6-ethyl-4-oxopiperidine-2-carboxylate (120. 121). 1- (4-chlorophenylsulfonyl) -6-ethyl-4-oxopiperidine-2-carboxylic acid ethyl ester (109, 0.32 g, 0.86 mmol) was dissolved in DMF-DMA (1.71 mL, 12.8 mmol) and heated to 90 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to produce a mixture of compounds 120 and 121 which was used without further purification.

Synthesis of 5- (4-chlorophenylsulfonyl) -6-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine-4-carboxylate (122). A mixture of compounds 120 and 121 (352 mg, 0.82 mmol) was dissolved in EtOH (3 mL) and acetic acid (0.25 mL). Hydrated hydrazine (0.20 mL, 4.11 mmol) was added dropwise and the reaction was stirred for 18 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and the crude material was purified by HPLC to yield 78 mg (28%) of compound 122. Y-NMR (CDC13) d 7.91 (d, 2H, J = 8.4 Hz), 7.63 (s, 1H), 7.59 (d, 2H, J = 8.4 Hz), 5.75 (s, 1H), 4.24 (m, 4H), 2.65 (d, 1H, J = 15 Hz), 2.42 (dd, 1H, J = 6.8 Hz), 1.53 (m, 1H), 1.32 (t, 3H, J = 6.8 Hz), 1.25 (m, 1H), .90 (t, 3H, J = 6.8 Hz); MS (m / z) 398.0 (M + H) P Example 16 125 Synthesis of l-benzyl-2,6-diethylpiperidin-4-one (123). A round bottom flask from ÍL, 3-neck, equipped with a mechanical stirrer, reflux condenser, thermometer and addition funnel was charged with a propionaldehyde solution (25.3 g, 0.4 mol) in water (150 mL) and stirred. The solution was cooled in an ice bath at 5 ° C. The solution was treated with benzylamine hydrochloride (37.2 g, 0.26 mol) and stirred at 5 ° C for 30 min. The solid acetonicarboxylic acid 89 (31.6 g, 0.2 mol) was added at 5 ° C, followed within 5 minutes with a solution of sodium acetate (7.65 g, 0.093 mol) in water (60 mL). The reaction mixture was stirred at 5 ° C for 1 hour and then allowed to warm to room temperature and stirred for 70 hours. CH2C12 (350 mL) was added and the pH of the mixture was adjusted to 9 by the careful addition of solid sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted with CH2C12 (300 mL). The combined extracts were washed with saturated sodium bicarbonate (200 mL), water (200 mL), brine (200 mL) and dried over anhydrous Na2SO4. The solution was filtered and evaporated to give a brown liquid, ca. 57 g. This was diluted with CH 2 Cl 2 (100 mL) and filtered through a plug of basic alumina (ca. 3 x 2 inches, 7.61 x 5.08 cm), washing with CH 2 Cl 2 (1 L). The combined filtrates were evaporated to give the product 123 as a light orange liquid, 50.1 g, which was used without further purification.

Synthesis of (R 7 R, 9 S) -8-benzyl-7, 9-d? Et? Ll, 4-d? Oxa-8-azaspiro [4.5] decane and (R 7 R, 9 R) -8-benz? l-7, 9-d? et? ll, 4-d? oxa-8-azasp? ro [4.5] decane (124, 125). l-Benzyl-2, 6-d? et? lp? per? dm-4-one (123; 11.5 g, 46.7 mmol) was dissolved in toluene (400 mL) and placed in a round-bottomed flask. 3-neck LED, equipped with a mechanical stirrer, thermometer, Dean-Stark trap and reflux condenser. The solution was treated with anhydrous ethylene glycol (13.5 mL, 240 mmol) and p-toluenesulfonic acid (9.0 g, 53 mmol). The resulting dark solution was refluxed for 8 h, while the trap was drained several times. The solution was cooled, diluted with EtOAc (500 mL) and neutralized with saturated aqueous sodium carbonate to pH 9. The organic layer was separated and the aqueous layer was extracted with EtOAc (250 mL). The combined extracts were washed with brine (250 mL) and dried over Na2SO4. The solution was filtered and evaporated to give 19 g of a dark brown liquid. The isomeric products are separated by flash chromatography on silica gel, eluting with EtOAc-hexane (1: 9). The first eluent was identified as trans-N-benzyl-7,9-diethyl-l, 4-dioxa-8-azaspiro [4.5] decane (125), yield 5.45 g (40%), the second eluent was identified as cis-N-benzyl-7,9-diethyl-l, 4-dioxa-8-azaspiro [4.5] decane (124). yield 7.78 g (57%).

Example 17 Synthesis of (reI 7R, 9S) -7, 9-diethyl-l, 4-dioxa-8-azaspiro [4.5] decane (126). The cis-N-benzyl-, 9-diethyl-l, 4-dioxa-8-azaspiro [4.5] decane (124; 9.1 g, 31 mmol) was dissolved in EtOH (50 mL). The catalyst (5% Pd / C, 3.0 g) was added and the suspension was stirred vigorously under a hydrogen atmosphere (60 psi, 413.64 kPa) at room temperature for 6 h. The catalyst was removed by filtration through Celite (1 x 1 inch, 2.54 x 2.54 cm), rinsing with EtOH (250 mL). The combined filtrates were evaporated to dryness to give the product 126 as a pale yellow viscous liquid, 6.1 g (> 99% yield) which was used without further purification.

Synthesis of (re? 7R, 9S) -8- (4-chlorophenylsulfonyl) -7,9-diethyl-1,4-dioxa-8-azaspiro [4.5] decane (127). The cis-7,9-diethyl-1,4-dioxa-8-azaspiro [4.5] decane 126 (2.48 g, 12.5 mmol) was dissolved in anhydrous pyridine (10 mL). 4-Chlorobenzenesulfonyl chloride (8.3 g, 39.3 mmol) was added and the solution was placed in a 20 mL glass ampoule equipped with a magnetic stir bar, sealed under nitrogen and irradiated in a 150 ° microwave reactor. C for 10 min. The products of the two identical reactions, as described above, were combined, diluted with EtOAc (400 mL), washed with water (2 x 200 mL), 0.2 N citric acid (2 x 200 mL), water (200 mL), saturated aqueous sodium bicarbonate (200 mL) and dried over anhydrous Na2SO4. The solution was filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with a mixture of EtOAc-hexane (1: 9) to give 2.16 g (24%) of product 127.

Synthesis of (re1 2S, 6R) -1- (4-chlorophenylsulfonyl) -2,6-diethylpiperidin-4-one (128). Cis-8- (4-chlorophenylsulfonyl) -7,9-diethyl-l, 4-dioxa-8-azaspiro [4.5] decane (2.2 g, 5.88 mmol) it was dissolved in THF (50 mL) and treated with concentrated aqueous HCl (8 mL) at room temperature for 18 h. EtOAc (250 mL) was added, the organic layer was separated and the aqueous layer was extracted with EtOAc (100 mL). The combined extracts were washed with water (100 mL), saturated aqueous sodium bicarbonate (100 mL) and dried over anhydrous Na2SO4. The solution was filtered and evaporated to give an oily product which solidified on standing, yield 1.85 g (95%) of compound 128.

Example 18 so2c? Synthesis of (reI 7R, 9R) -7, 9-diethyl-l, 4-dioxa-8-azaspiro [4.5] decane (129). The trans-N-benzyl-7,9-diethyl-l, 4-dioxa-8-azaspiro [4.5] decane (125.6.5 g, 22 mmol) was dissolved in EtOH (50 mL). The catalyst (5% Pd / C, 2.4 g) was added and the suspension was stirred vigorously under a hydrogen atmosphere (60 psi, 413.64 kPa) at room temperature for 6 h. The catalyst was removed by filtration through Celite (1 x 1, 2.54 x 2.54 cm), rinsing with EtOH (250 mL). The combined filtrates were evaporated to dryness to give the product as a pale yellow viscous liquid, 4.4 g (> 99% yield) of compounds 129, which was used without further purification.

Synthesis of (re? 7R, 9R) -8- (4-chlorophenylsulfonyl) -7,9-diethyl-1,4-dioxa-8-azaspiro [4.5] decane (130). The trans-7,9-diethyl-1,4-dioxa-8-azaspiro [4.5] decane (129.6.6 g, 18 mmol) was dissolved in anhydrous pyridine (15 mL). 4-Chlorobenzenesulfonyl chloride (9.8 g, 47 mmol) was added and the solution was placed in a 20 mL glass ampoule equipped with a magnetic stir bar, sealed under nitrogen and irradiated in a 150 ° microwave reactor. C for 10 min. The product was diluted with EtOAc (300 mL), washed with water (2 x 200 mL), 0.2 N citric acid (2 x 200 mL), water (200 mL), saturated aqueous sodium bicarbonate (200 mL) and dried with anhydrous Na2SO4. The solution was filtered and evaporated, the residue was purified by chromatography on silica gel, eluting with a mixture of EtOAc-hexane (1: 9) to give 3.8 g (57%) of product 130.

Synthesis of (RI 2R, 6R) -1- (4-chlorophenylsulfonyl) -2,6-diethylpiperidin-4-one (131). The trans-8- (4-chlorophenylsulfonyl) -7,9-diethyl-l, 4-dioxa-8-azaspiro [4.5] decane (130, 3.7 g, 10 mmol) was dissolved in THF (80 mL) and treated with concentrated aqueous HCl (10 mL) at room temperature for 18 h. EtOAc (250 mL) was added, the organic layer was separated and the aqueous layer was extracted with EtOAc (100 mL). The combined extracts were washed with water (100 mL), saturated aqueous sodium bicarbonate (100 mL) and dried over anhydrous Na2SO4. The solution was filtered and evaporated to give an oily product, which solidified on standing to produce 2.55 g (77%) of product.

Example 19 6-Benzyl-5- (4-chlorophenylsulfonyl) -4,5,6,7,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine Prepared as described for compound 55 in Example 1 using 2- (phenylmethyl) -4-piperidinone. And NMR (CDC13) d 7.61 (d, J = 8.1 Hz, 2H), 7.42 (s, 1H), 7.37 (d, J = 8.1 Hz, 2H), 7.28 (m, 3H), 7.10 (m, 2H) , 4.86 (d, J = 15.6 Hz, 1H), 4.68 (q, J = 6.5 Hz, 1H), 4.25 (d, J = 15.6 Hz, 1H), 2.73 (m, 4H), MS (m / z) 388.1 (M + H) P Example 20 5 (4-Chlorophenylsulfonyl) -6-isopropyl-4,5,6-7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine 2-isopropyl-4-oxopiperidine-1-benzyl carboxylate, prepared as was described for compound 67 in Example 3 using isopropylmagnesium chloride, was formed and was treated with hydrated hydrazine as described for compound 50 in Example 1 to give 6-isopropyl-6,7-dihydro-1H-pyrazolo [4,3-c] pyridin-5 (4H) -carboxylic acid benzyl ester. This compound was then deprotected and treated with 4-chlorophenylsulfonyl chloride followed by NaOH as described above for compound 52 in Example 1.

And NMR (CDC13) d 7.72 (d, J = 9.0 Hz, 2H), 7.40 (d, J = 9. 0 Hz, 2H), 7.34 (s, 1H), 4.84 (d, J = 16.6 Hz, 1H), 4.19 (d, J = 16.6 Hz, 1H), 3.96 (dd, J = 10.5, 6.0 Hz, 1H), 2.85 (d, J = 16.2 Hz, 1H), 2.50 (dd, J = 16.2, 6.0 Hz, 1H) , 1.70 (m, 1H), 1.01 (d, J = 6.6 Hz, 3H), 0.95 (d, J = 6.6 Hz, 3H), MS (m / z) 340.0 (M + H) P Example 21 5-. { 4-chlorophenylsulfonyl) -6- (4-fluorophenyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine 2- (4-fluorophenyl) -4-oxopiperidine-1-carboxylate benzyl, prepared as described for compound 67 in the Example, using 4-fluorophenylmagnesium bromide, was formed and treated with hydrazine hydrate as described for compound 50 in Example 1 to give 6-isopropyl-6, 7- dihydro-lH-pyrazolo [4, 3-c] pyridin-5 (4H) -carboxylic acid benzyl ester. This compound was then deprotected and treated with 4-chlorophenylsulfonyl chloride followed by NaOH as described for compound 52 in Example 1.

And NMR (CDCI3) d 7.74 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 8. 7 Hz, 2H), 7.30 (s, 1H), 7.21 (m, 2H), 6.95 (m, 2H), 5.61 (d, J = 6.6 Hz, 1H), 4.78 (d, J = 16.2 Hz, 1H), 3.85 (d, J = 16. 2 Hz, 1H), 3.22 (d, J = 16.5 Hz, 1H), 2.92 (dd, J = 16.5, 6.6 Hz, 1H), MS (m / z) 392.0 (M + H) P Example 22 6- (4-Chlorophenyl) -5- (4-chlorophenylsulfonyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine. 2- (4-chlorophenyl) -4-oxopiperidine-1-carboxylic acid benzyl ester, 67, was formed and treated with hydrazine hydrate as described for compounds 50 and 51 in Example 1 to give 6- (4-chlorophenyl) -6,7-dihydro-1H-pyrazolo [4, 3-c] pyridin-5 (4H) -benzylcarboxylate which was then deprotected and sulfonylized as described for compound 84 in Example 7. And NMR ( CDCI3) d 7.71 (d, J = 8.7 Hz, 2H), 7.37 (d, J = 9.0 Hz, 2H), 7.26 (s, 1H), 7.18 (d, J = 8.7 Hz, 2H), 7.12 (d, J = 8.7 Hz, 2H), 5.56 (d, J = 6.6 Hz, 1H), 4.74 (d, J = 16.5 Hz, 1H), 3.82 (d, J = 15.90 Hz, 1H), 3.18 (d, J = 16.50 Hz, 1H), 2.91 (dd, J = 16.50, 6.6 Hz, 1H), MS (m / z) 408.0, (M + H) P Example 23 6- (4-Chlorophenyl) -5- (4-chlorophenylsulfonyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine (Enantiomers A and B). 2- (4-chlorophenyl) -4-oxopiperidine-1-benzyl carboxylate, 67, it was formed and treated with hydrated hydrazine as described for compounds 50 and 51 in Example 1 to give 6- (4-chlorophenyl) -6,7-dihydro-1H-pyrazolo [4, 3-c] pyridine-5 (4H) -benzylcarboxylate which was then deprotected and sulfonylized as described for compound 84 in Example 7. The enantiomers were separated by HPLC using Method [2]. And NMR (CDC13) d 7.71 (d, J = 8.7 Hz, 2H), 7.37 (d, J = 9.0 Hz, 2H), 7.26 (s, 1H), 7.18 (d, J = 8.7 Hz, 2H), 7.12 (d, J = 8.7 Hz, 2H), 5.56 (d, J = 6.6 Hz, 1H), 4.74 (d, J = 16.5 Hz, 1H), 3.82 (d, J = 15.90 Hz, 1H), 3.18 (d , J = 16.50 Hz, 1H), 2.91 (dd, J = 16.50, 6.6 Hz, 1H); MS (m / z) 408.0, (M + H) P Example 24 5- (4-Chlorophenylsulfonyl) -6- (3,5-difluorophenyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine 2- (3, 5-difluorophenyl) Benzyl 4-oxopiperidine-l-carboxylate, prepared as described for compound 67 in Example 3 using 3,5-difluorophenylmagnesium bromide, was formulated and treated with hydrazine hydrate as described for compound 50 in Example 1 to give 6-isopropyl-6,7-dihydro-1H-pyrazolo [4, 3-c] pyridin-5 (4H) -carboxylic acid benzyl ester. This compound was then deprotected and treated with 4-chlorophenylsulfonyl chloride followed by NaOH as described for compound 52 in Example 1. And NMR (CDC13) d 7.73 (d, J = 8.7 Hz, 2H), 7.41 (d, J = 8. 4 Hz, 2H), 7.29 (s, 1H), 6.76 (d, J = 6.6 Hz, 2H), 6.71-6.65 (m, 1H), 5.56 (d, J = 6.0 Hz, 1H), 4.79 (d, J = 16.5 Hz, 1H), 3.92 (d, J = 15.9 Hz, 1H), 3.17 (d, J = 16.5 Hz, 1H), 2. 90 (dd, J = 16.5, 6.6 Hz, 1H).

EXAMPLE 25 5- (5-Clorot? Ofen-2? -sulfonyl) -6-phen? L-4,5,6,7-L0 tetrahydro-lH-pyrazolo [4, 3-c] pyridine. Prepared as described in Example 1 using 5-chloro-2-thiophenesulfonyl chloride. MS (m / z) 410.0, (M + H) P EXAMPLE 26 L5 5- (4-Chlorophene? Lsulfon? L) -6- (3,5-d? Fluorofeml) -4,5,6,7-tetrahydro-lH-pyrazolo [4,3-c] pyridine (Enantiomeros) A and B). 2- (3,5-d? Fluorophenyl) -4-oxop? Per? Dm-l-carboxyl benzyl, prepared as described for compound 67 in Example 3 using 3,5-d? Fluorophenylmagnesium bromide was treated with hydrazine hydrate as described for compound 50 in Example 1 to give 6-? sopropyl-6,7-dihydro-1H-pyrazole [4, 3-c] p? pd? n-5 (4H) -benzylcarboxylate. This compound was then deprotected and treated with 4-chlorophenylsulfonyl chloride followed by NaOH as described for compound 52 in Example 1.

Enantiomers were separated using the HPLC Method [2]. And NMR (CDCI3) d 7.73 (d, J = 6.0 Hz, 2H), 7.41 (d, J = 9.0 Hz, 2H), 7.29 (s, 1H), 6.76 (d, J = 6.0 Hz, 2H). 6.72-6.65 (m, 1H), 5.56 (d, J = 6 Hz, 1H), 4.79 (d, J = 18.0 Hz, 1H), 3.92 (d, J = 15.0 Hz, 1H), 3.17 (d, J = 15.0 Hz, 1H), 2.90 (dd, J = 15.0, 6.0 Hz, 1H) MS (m / z) 410.0, (M + H) P Example 27 5- (4-Chlorophenylsulfonyl) -6- (3-fluorophenyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine. 2- (3-fluorophenyl) -4-oxopiperidine-1-carboxylic acid benzyl ester, prepared as described for compound 67 in Example 3 using (3-fluorophenyl) magnesium bromide, was formed and treated with hydrazine hydrate as described for compound 50 in Example 1 to give 6-isopropyl-6,7-dihydro-1H-pyrazolo [4, 3-c] pyridin-5 (4H) -carboxylic acid benzyl ester. This compound was then deprotected and treated with 4-chlorophenylsulfonyl chloride followed by NaOH as described for compound 52 in Example 1. And NMR (CDCl 3) d 7.73 (d, J = 6.0 Hz, 2H), 7.39 (d , J = 9.0 Hz, 2H), 7.28 (s, 1H), 7.23-7.18 (m, 1H), 7.02 (d, J = 9.0 Hz, 1H), 6.96-6.90 (m, 2H), 5.60 (d, J = 6.0 Hz, 1H), 4.79 (d, J = 15.0 Hz, 1H), 3.89 (d, J = 15.0 Hz, 1H), 3.22 < d, J = 15.0 Hz, 1H), 2.92 (dd, J = 18.0, 6.0 Hz, 1H); MS (m / z) 392.0, (M + H) P Example 28 5- (4-chlorophenylsulfonyl) -6- (4-fluorophenyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine (Enantiomers A and B). 2- (4-fluorophenyl) -4-oxopiperidine-benzyl carboxylate, prepared as described for compound 67 in the Example using 4-fluorophenylmagnesium bromide, was formulated and treated with hydrazine hydrate as described for the compound 50 in Example 1 to give 6-isopropyl-6,7-dihydro-1H-pyrazolo [4, 3-c] pyridin-5 (4H) -carboxylic acid benzyl ester. This compound was then deprotected and treated with 4-chlorophenylsulfonyl chloride followed by NaOH as described for compound 52 in Example 1. The enantiomers were separated using the HPLC method [2]. And NMR (CDC13) d 7.74 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 8.7 Hz, 2H), 7.30 (s, 1H), 7.21 (m, 2H), 6.95 (m, 2H) , 5.61 (d, J = 6.6 Hz, 1H), 4.78 (d, J = 16.2 Hz, 1H), 3.85 (d, J = 16.2 Hz, 1H), 3.22 (d, J = 16.5 Hz, 1H), 2.92 (dd, J = 16.5, 6.6 Hz, 1H); MS (m / z) 392.0 (M + H) P EXAMPLE 29 5- (4-Chlorophenylsulfonyl) -6-isopropyl-4,5,6-7-tetrahydro-lH-pyrazolo [4, 3-c] pyridine benzyl 2-isopropyl-4-oxopiperidine-l-carboxylate, prepared as described for compound 67 in Example 3 using isopropylmagnesium chloride, it was formed and treated with hydrated hydrazine as described for compound 50 in Example 1 to give 6-isopropyl-6,7-dihydro-1H-pyrazolo [4, 3-c] pyridin-5 (4H) -carboxylic acid benzyl ester. This compound was then deprotected and treated with 4-chlorophenylsulfonyl chloride of NaOH as described for compound 52 in Example 1. The enantiomers were separated using the HPLC Method [2]. And NMR (CDC13) d 7.72 (d, J = 9.0 Hz, 2H), 7.41 (d, J = 9. 0 Hz, 2H), 7.34 (s, 1H), 4.84 (d, J = 16.6 Hz, 1H), 4.19 (d, J = 16.6 Hz, 1H), 3.96 (dd, J = 10.5, 6.0 Hz, 1H) , 2.85 (d, J = 16.2 Hz, 1H), 2.50 (dd, J = 16.2, 6.0 Hz, 1H), 1.70 (m, 1H), 1.01 (d, J = 6.6 Hz, 3H), 0.95 (d, J = 6.6 Hz, 3H); MS (m / z) 436.1 (M + H) P EXAMPLE 30 5- (4-Chlorophenylsulfonyl) -6- (3-fluorophenyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine (Enantiomers A and B) 2-Isopropyl-4 -oxopiperidine-benzyl carboxylate, prepared as described for compound 67 in Example 3 using isopropylmagnesium chloride, was formed and treated with hydrazine hydrate as described for compound 50 in Example 1 to give 6-isopropyl- 6, 7-dihydro-lH-pyrazolo [4, 3-c] pyridin-5 (4H) -carboxylic acid benzyl ester. This compound was then deprotected and treated with 4-chlorophenylsulfonyl chloride followed by NaOH as described for compound 52 in Example 1. The enantiomers were separated using the HPLC method [2]. And NMR (CDC13) d 7.72 (d, J = 9.0 Hz, 2H), 7.40 (d, J = 9.0 Hz, 2H), 7.34 (s, 1H), 4.84 (d, J = 16.6 Hz, 1H), 4.19 (d, J = 16.6 Hz, 1H), 3.96 (dd, J = 10.5, 6.0 Hz, 1H), 2.85 (d, J = 16.2 Hz, 1H), 2.50 (dd, J = 16.2, 6.0 Hz, 1H) , 1.70 (m, 1H), 1.01 (d, J = 6.6 Hz, 3H), 0.95 (d, J = 6.6 Hz, 3H); MS (m / z) 436.1 (M + H) P Example 31 5- (4-Chlorophenylsulfonyl) -6- (3-fluorophenyl) -4, 5, 6, 7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine (Enantiomers A and B) 2- (3-fluorophenyl) -4-oxopiperidine-1-benzyl carboxylate, prepared as described for compound 67 in Example 3 using (3-fluorophenyl) magnesium bromide, was formulated and treated with hydrazine hydrate as described for compound 50 in Example 1 to give 6-isopropyl-6,7-dihydro-1H-pyrazolo [4, 3-c] pyridin-5 (4H) -carboxylic acid benzyl ester. This compound was then deprotected and treated with 4-chlorophenylsulfonyl chloride followed by NaOH as described for compound 52 in Example 1. The enantiomers were separated using the HPLC Method [2]. And NMR (CDC13) d 7.73 (d, J = 8.7 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.28 (s, 1H), 7.22-7.18 (m, 1H), 7.02 (d, J = 7.8 Hz, 1H), 6.95-6.89 (m, 2H), 5.59 (d, J = 6.3 Hz, 1H), 4.78 (d, J = 15.9 Hz, 1H), 3.88 (d, J = 15.9 Hz, 1H), 3.21 (d, J = 16.5 Hz, IH; 2.92 (dd, J 16.8, 6.6 Hz, 1H); MS (m / z) 392.1 : M + H) Example 32 cis-6- (chlorophenyl) -5-chlorophenylsulfonyl) -4-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine Prepared as described for compound 88 in the Example 7 using compound 85. XH NMR (CDC13) d 7.43 (s, 1H), 7.19 (s, 4H), 7.11 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 8.4 Hz, 2H) , 5.30 (t, J = 7.5 Hz, 1H), 4.84 (dd, J = 10.5, 3.9 Hz, 1H), 3.63 (dd, J = 15.5, 10.5 Hz, 1H), 3.05 (dd, J = 15.5, 3.9 Hz, 1H), 2.01 (m, 1H), 1.84 (m, 1H), 1.06 (t, J = 7.2 Hz, 3H); MS (m / z) 436.0 (M + H) Example 33 trans-5- (4-Chlorophenylsulfonyl) -4,6-dimethyl-1,4,6,6,7-tetrahydro-lH-pyrazolo [4, 3-c] pyridine Trans-1- (4-chlorophenylsulfonyl) -2 , 6-dimethylpiperidin-4-one (94) was treated with DMF-DMA followed by hydrazine hydrate as described for compound 71 in Example 4. Y-NMR (CD3OD) d 7.81-7.79 (m, 2H), 7.62 (m, 3H), 5.38 (q, J = 7.1 Hz, 1H), 4.20-4.13, (m, 1H), 2.78 (dd, J = 16.2, 4.4 Hz, 1H), 2.56-2.48 (ra, 1H) , 1.54-1.47 (m, 6H); MS (m / z) 326.0 (M + H) P Example 34 cis-5- (4-Chlorophenylsulfonyl) -4,6-dimethyl-1, 5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine cis-1- (4-chlorophenylsulfonyl) -2, 6-dimethylpiperidin-4-one (92) was treated with DMF-DMA followed by hydrazine hydrate as described for compound 71 in Example 4. Y-NMR (CD3OD) d 7.88-7.79 (m, 2H), 7.58- 7.50 (m, 3H), 5.36 (q, J = 6.6 Hz, 1H), 2.76 (dd, J = 15.9, 4.4 Hz, 1H), 2.53-2.48 (m, 1H), 1.53-1.47 (m, 6H); MS (m / z) 436.0 (M + H) P EXAMPLE 35 5- (4-Chlorophenylsulfonyl) -6- (pyridin-3-yl) -4,5,6,7-tetrahydro-lH-pyrazolo [4, 3-c] pyridine and 5- (4-chlorophenylsulfonyl) - 4- (pyridin-3-yl) -4,5,6,7-tetrahydro-lH-pyrazolo [4, 3-c] pyridine Prepared as described in Example 4 using pyridine-3-carboxaldehyde. And NMR (CD3OD) d 8.93 (Si 1H), 8.68-8.56 (m, 4H, 8.38- 8.35 (ra, 1H), 8.15 (ra, 1H), 7.99-7.98 (m, 1H), 7.86-7.75 (m , 4H), 7.55-7.51 (ra, 5H), 7.40-7.30 (m, 2H), 6.56 (s, 0.5H), . 86-5.83 (m, 1H), 3.98-3.93 (m, 1H), 2.96-2.89 (m, 1H), 2. 58-2.42 (m, 1.5H); MS (m / z) 375.0 (M + H) P Example 36 5- (4-Chlorophenylsulfonyl) -6- (pyridin-4-yl) -4,5,6,7- tetrahydro-lH-pyrazolo [4, 3-c] pipdin and 5- (4-chlorophenylsulfonyl) -4- (p? pd? n-4-? l) -4, 5, 6, 7-tetrahydro-lH -pyrazolo [4, 3-c] p? r? d? na Prepared as described in Example 4 using p? r? d? n-4-carboxaldehyde. And NMR (CD3OD) d 8.44 (bs, 3H), 7.88 (d, J = 8.5 Hz, 2H), 7.53 (d, J = 8.5 Hz, 2H), 7.36-7.30 (m, 3H), 5.71 (d, J = 6.0 Hz, 1H), 3.94 (d, 16.3 Hz, 1H), 2.88 (dd, J = 16.6, 6.3 Hz, 1H), 2.25 (d, J = 21.0 Hz, 1H); MS (m / z) 375.0 (M + H) P Example 37 c? S-5- (4-chlorophen? Lsulfon? L) -4,6-d? Et? L-4,6,6,7-tetrahydro-lH-p? Razolo [4.3- c] p? r? d? na Prepared as described for compound 122 in Example 15 using compound 128. Y NMR (CDC13) 69.05 (bs, 1H), 7.70 (d, J = 8.1 Hz, 2H), 7.46 (s, lH), 7.39 (d, J = 8.1 Hz, 2H), 4.97 (t, J = 7.5 Hz, 1H), 4.18 (dd, J = 6.9, 14.3 Hz, 1H), 2.55 (d, J = 15.9 Hz, 1H), 2.27 (dd, J = 6.6, 16.5 Hz, 1H), 1.93 (septet, J = 7.5 Hz, 1H), 1.78 (septet, J = 6.9 Hz, 1H), 1.58 (septet, J = 7.5 Hz, 1H), 1.44 (septet, J = 6.9 Hz, 1H), 1.18 (t, J = 6.9 Hz, 3H), 0.97 (t, J = 7.5 Hz, 3H); MS (m / z) 354.0 (M + H) P Example 38 c? S-5- (4-Chlorophen? Lsulfon? L) -4,6-d? Et? L-4, 5,6,7- tetrahydro-lH-pyrazolo [4, 3-c] pyridine (Enantiomers A and B) Prepared as described for compound 122 in Example 15 using compound 128 followed by HPLC separation of the enantiomers using Method [2]. Y NMR (CDC13) d 9.05 (bs, 1H), 7.70 (d, J = 8.1 Hz, 2H), 7.46 (s, 1H), 7.39 (d, J = 8.1 Hz, 2H), 4.97 (t, J = 7.5 Hz, 1H), 4.18 (dd, J = 6.9, 14.3 Hz, 1H), 2.55 (d, J = 15.9 Hz, 1H), 2.27 (dd, J = 6.6, 16.5 Hz, 1H), 1.93 (septet, J = 7.5 Hz, 1H), 1.78 (septet, J = 6.9 Hz, 1H), 1.58 (septet, J = 7.5 Hz, 1H), 1.44 (septet, J = 6.9 Hz, 1H), 1.18 (t, J = 6.9 Hz, 3H), 0.97 (t, J = 7.5 Hz, 3H); MS (m / z) 354.0 (M + H) P Example 39 Trans-5- (4-chlorophenylsulfonyl) -4,6-diethyl-4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine. Prepared as described for compound 122 in Example 15 using compound 131. and NMR (CDC13) d 7.66 (d, J = 8.7 Hz, 2H), 7.34-7.30 (m, 3H), 5.11 (t, J = 7.5 Hz, 1H), 3.51- 3.44 (m, 1H), 2.63 (dd, J = 3.9, 15.9 Hz, 1H), 2.40 (dd, J = 11.4, 15.9 Hz, 1H), 2.22 (septet, J = 7.2 Hz, 1H), 1.85-1.65 (m, 3H), 1.02-0.97 (m, 6H); MS (m / z) 354.0 (M + H) P Example 40 5- (4-Chlorophenylsulfonyl) -6-ethyl-6,7-dihydro-1H-pyrazolo [4, 3-c] pyridin-4 (5H) -one Prepared by oxidation of Cr? 3 / H5I? 6 of 5- (4-chlorophenylsulfonyl) -4,6-diethyl-4,5,6,7-tetrahydro-2H-pyrazolo [4, 3-c] pyridine. See Yamazaki, S. Org. Lett. 1999, 1 (13), 2129. And NMR (CDC13) d 8.04 (d, J = 8.7 Hz, 2H), 7.99 (s, 1H), 7.49 (s, J = 8.3 Hz, 2H), 5.02-4.94 ( m, 1H), 3.20 (dd, J = 5.7, 13.5 Hz, 1H), 3.09 (dd, J = 1.5, 16.5 Hz, 1H), 1.79-1.68 (m, 1H), 1.66-1.54 (m, 1H) , 0.96 (t, J = 7.8 Hz, 3H); MS (m / z) 340.0 (M + H) P Example 41 (5- (4-Chlorophenylsulfonyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine) methanol Prepared by reduction of ester 100 as described for compound 110 in Example 14. Y NMR (CD3OD) d 7.82 (d, J = 8.7 Hz, 2H), 7.48-7.45 (m, 3H), 5.10 (t, J = 6.6 Hz, 1H), 4.14 (dd, J = 15.0, 5.7 Hz, 1H), 3.75-3.59 (m, 2H), 3.49-3.35 (m, 1H), 2.52 (dd, J = 16.2, 3.9 Hz, 1H), 2.43-2.32 (m, 1H), 2.15 (s, 1H), MS (m / z) 328.0 (M + H) P Example 42 Trans-5- (4-chlorophenylsulfonyl) -4,6-diethyl-4,5,6,7-tetrahydro-1H-pyrazolo [, 3-c] pyridine (Enantiomers A and B) Prepared as described for compound 122 in Example 15 using compound 131 followed by separation by HPLC of the enantiomers using Method [2]. Y NMR (CDCI3) d7.66 (d, J = 8.7 Hz, 2H), 7.34-7.30 (m, 3H), 5.11 (t, J = 7.5 Hz, 1H), 3.51- 3.44 (m, 1H), 2.63 (dd, J = 3.9, 15.9 Hz, 1H), 2.40 (dd, J = 11.4, 15.9 Hz, 1H), 2.22 (septet, J = 7.2 Hz, 1H), 1.85-1.65 (m, 3H), 1.02- 0.97 (m, 6H); MS (m / z) 354.0 (M + H) P Example 43 5- (4-Chlorophenylsulfonyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridin-4,6-dicarboxylic acid cis-diethyl ester Prepared by sulfonylation of cis-dimethyl ester -4-oxo-2, 6-piperidinedicarboxylic acid (Hermann, K.; Dreiding, AS Helvetica Chimica Acta 1976, 59 (2), 626-42) followed by formylation and pyrazole formation as shown in Example 1. And NMR (CDCl 3) d 7.90 (d, J = 8.4 Hz, 2H), 7.61 ( s, 1H), 7.49 (d, J = 9.0 Hz, 2H), 5.87 (s, 1H), 5.01 (d, J = 6.6 Hz, 1H), 3.68 (s, 3H), 3.54 (s, 3H), 3.18 (d, J = 16.2 Hz, 1H), 2.89 (dd, J = 6.6, 16.2 Hz, 1H); MS (m / z) 413.9 (M + H) P Example 44 cis- (5- (4-Chlorophenylsulfonyl) -4,5,6,7-tetrahydro-lH-pyrazolo [4, 3-c] pyridin-4,6-diyl) dimethanol Prepared by reduction of 5- (4 -chlorophenylsulfonyl) -4,5,6,7-tetrahydro-lH-pyrazolo [4, 3-c] pyridin-4,6- cis-diethyl dicarboxylate using LiBH4 as shown in Example 14. And NMR (DMSO) d 12.49 (bs, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.1 Hz, 2H ), 7.48 (bs, 1H), 5.12 (t, J = 5.0 Hz, 1H), 5.10 (bs, 1H), 4.98-4.79 (m, 1H), 4.24-4.17 (m, 1H), 3.67-3.61 ( m, 1H), 3.21-3.10 (m, 3H), 2.72 (d, J = 16.3 Hz, 1H), 2.15 (dd, J = 5.9, 16.1 Hz, 1H); MS (m / z) 358.1 (M + H) P EXAMPLE 45 (5- (4-Chlorophenylsulfonyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridin-4-yl) methyl dimethylcarbamate Prepared by treatment of (5- (4- chlorophenylsulfonyl) -4,5,6,7,7-tetrahydro-lH-pyrazolo [4, 3-c] pyridin-4-yl) methanol with dimethylcarbamyl chloride as described for compound 111 in Example 14. Y-NMR ( CD3OD) d 7.80 (d, 2H, J = 8.8 Hz), 7.57 (s, 1H), 7.50 (d, 2H, J = 8.8 Hz), 5.41 (dd, 1H, J = 4.6, 8.8 Hz), 4.29- 4.13 (m, 3H), 3.50 (m, 1H), 2.93 (s, 6H), 2.99 (s, 3H), 2.56 (dd, 1H, J = 4.6, 16.3 Hz), 2.32 (m, 1H); MS (m / z) 399.1 (M + H) P Example 46 cis-5- (4-Chlorophenylsulfonyl) -4,6-diethyl-5,6-dihydro-lH-pyrazolo [4, 3-c] pyridin-7 (4H) -one (Enantiomers A and B) Prepared as was described in Example 2 followed by separation of the enantiomers using the HPLC method [2].

And NMR (CDCI3) d 7.58 (d, J = 7.5 Hz, 2H), 7.54 (s, 1H), 7.25 (d, J = 8.2 Hz, 2H), 5.09 (t, J = 7.5 Hz, 1H), 4.50 (dd, J = 6.6, 9.9 Hz, 1H), 2.11-1.75 (m, 4H), 1.27-1.15 (m, 6H); MS (m / z) 368.0 (M + H) P Example 47 cis-4,6-diethyl-5- (pyridin-2-sulfonyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine Prepared by the treatment of 2, 6 diethyl-1- (pyridin-2-ylsulfonyl) piperidin-4-one, which was prepared by sulfonylating compound 126 using pyridine-2-sulfonyl chloride hydrochloride followed by deprotection as shown in Example 17, with DMF-DMA followed by pyrazole formation using hydrated hydrazine as shown in Example 15.

Y-NMR (CDCI3) d 8.52 (d, J = 8.5 Hz, 1H), 7.96 (d, J = 7.7 Hz, 1H), 7.82 (t, J = 7.8 Hz, 1H), 7.40-7.36 (m, 2H ), 4.96 (t, J = 7.1 Hz, 1H), 4.45-4.42 (m, 1H), 2.55-2.54 (m, 2H), 2.07-1.98 (m, 1H), 1.82-1.73 (m, 1H), 1.72-1.62 (m, 1H), 1.51-1.42 (m, 1H), 1.17 (t, J = 7.1 Hz, 3H), 1.01 (t, J = 7.1 Hz, 3H); MS (m / z) 321.1 (M + H) P Example 48 cis-4,6-Diethyl-5- (4-fluorophenylsulfonyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine Prepared by treatment of 2,6-diethyl-1- (4-fluorophenylsulfonyl) piperidin-4-one, which was prepared by sulfonylating compound 126 using 4-fluorobenzenesulfonyl chloride followed by deprotection as shown in Example 17, with DMF -DMA followed by pyrazole formation using hydrated hydrazine as shown in Example 15. Y-NMR (CD3OD) d 7.81-7.76 (m, 2H), 7.42 (s, 1H), 7.12-7.06 (m, 2H), 4.98 (t, J = 6.3 Hz, 1H), 4.21-4.09 (m, 1H), 2.51 (d, J = 18.0 Hz, 1H), 2.16 (m, 1H), 1.95-1.93 (m, 1H), 1.81 -1.78 (m, 1H), 1.64-1.62 (m, 1H), 1.47-1.42 (m, 1H), 1.21 (t, J = 7.1 Hz, 3H), 1.00 (t, J = 7.1 Hz, 3H) MS (m / z) 338.1 (M + H) P Example 49 2- (5- (4-Chlorophenylsulfonyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridin-6-yl) thiazole Prepared as described for compounds 75 and 76 in Example 4 using 2-thiazolecarboxaldehyde. And NMR (CDCI3) d 7.78 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 2. 4 Hz, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.27 (S, 1H), 5.93 (d, J = 6.3 Hz, 2H), 4.89 (d, J = 15.6 Hz, 1H), 4.20 (d, J = 15.9 Hz, 1H), 3.71 (d, J = 16.8 Hz, 1H), 3.19-3.11 (m, 1H); MS (m / z) 381.0 (M + H) P Example 50 2- (5- (4-Chlorophenylsulfonyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridin-yl) thiazole Prepared as described for compounds 73 and 74 in the Example 4 using 2-thiazolecarboxaldehyde. Y NMR (CDC13) d 7.80-7.75 (m, 3H), 7.69 (d, J = 3.3 Hz, 1H), 7.43 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 3.3 Hz, 1H) , 6.54 (s, 1H), 4.23-4.18 (m, 1H), 3.49-3.39 (m, 1H), 2.80 (s, 2H); MS (m / z) 381.0 (M + H) P BIOLOGICAL EXAMPLES Notch signaling test for selective gamma secretase inhibitors A convergence of evidence indicates that the gamma secretase complex, comprised of the presenilin subunits, mediates the intra-membrane division of the amyloid precursor protein (APP) and the Notch family of proteins (De Strooper, B., P. Saftig, K. Craessaerts, H.

Vanderstichele, G. Guhde, W. Annaert, K. Von Figure and F. Van Leuven (1998). "Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein." Nature 391 (6665): 387-90; De Strooper, B., W. Annaert, P. Cupers, P.

Saftig, K. Craessaerts, J. S. Mumm, E. H. Schroeter, V.

Schrijvers, M.S. Wolfe, W.J. Ray et al. (1999). "A presenilin-1-dependent gamma-secretase-like protease mediates relay of Notch intracellular domain. "Nature 398 (6727): 518-22; Mu m, JS, EH Schroeter, MT Saxena, A. Griesemer, X. Tian, DJ Pan, WJ Ray and R. Kopan (2000)." A ligand-induced extracellular cleavage regulates gamma-secretase-like proteolytic activation of Notch 1. "Mol Cell 5 (2): 197-206; Zhang, Z., P. Nadeau, W. Song, D. Donoviel, M. Yuan , A. Bernstein and BA Yankner (2000). "Presenilins are required for gamma-secretase cleavage of beta-APP and transmembrane cleavage of Notch-1." Nat Cell Biol 2 (7): 463-5.) Cleavage of APP by gamma secretase leads to beta-amyloid synthesis Cleavage of Notchl by gamma secretase results in relay of the Notch intracellular domain (NICD), which translocates to the nucleus and activates gene expression (Jarriault, S., C. Brou, F. Logeat, EH Schroeter, R. Kopan and A. Israel (1995). "Signaling downstream of activated mammalian Notch." Nature 377 (6547): 355-8, Kopan, R., EH Schroeter, H. Weintraub and JS Nye (1996) . "Signal transduction by activated Notch: importance of proteolytic processing and its regulation by the extracellular domain." Proc Nati Acad Sci USA 93 (4): 1683-8; Schroeter, E. H., J. A. Kisslinger and R. Kopan (1998). "Notch-1 signalling requires ligand-induced proteolytic relay of intracellular domain." Nature 393 (6683): 382-6). In particular, Notch signaling activates the transcription of the mammalian homolog of the hair splitting enhancer of the transcription factor of the Drosophi la (Hes). The transcriptional activation of Hesl is mediated by the de-repression of CBFl / RBPJk due to the binding by NICD in the nucleus. These have been explained to develop a reporter gene test for the signaling of Notch Hsieh, J. J., T. Henkel, P. Salmon, E. Robey, M. G. Peterson and S. D. Hayward (1996). "Truncated mammalian Notchl activates CBFl / RBPJk-repressed genes by a mechanism resembling of Epstein-Barr virus EBNA2." Mol Cell Biol 16 (3): 952-9; Lu, F. M. and S. E. Lux (1996). "Constitutively active human Notchl binds to the transcription factor CBF1 and stimulates transcription through a promoter containing a CBFl-responsive element." Proc Nati Acad Sci USA 93 (11): 5663-7). Inhibitors of gamma secretase have been observed to block the formation of CIND, and inhibit Notch signaling (De Strooper, B., W. Annaert, P. Cupers, P. Saftig, K. Craessaerts, JS Mu m, EH Schroeter, V. Schrijvers, MS Wolfe, WJ Ray et al. (1999). "A presenilin-1-dependent gamma-secretase-like protease mediates relase of Notch intracellular domain." Nature 398 (6727): 518-22). Due to the importance of Notch signaling in the determination of cell death, and tissue differentiation during development and in the adult, the inhibition of Notch signaling by gamma secretase inhibitors is postulated to be a limiting factor in Its utility therapy. To identify selective gamma secretase inhibitors, a reporter gene based on the Notch signaling test was used using a constitutively active rat Notchl construct (ZEDNl) provided by Dr Gerry Weinmaster, who is at the University of California at Los Angeles (UCLA) as described in Shawber, C, D. Nofziger, JJ Hsieh, C. Lindsell, 0. Bogler, D. Hayward and G. Weinmaster (1996). "Notch signaling inhibits muscle cell differentiation through to CBFl-independent pathway." Development 122 (12): 3765-73 in combination with the CBF1 repressible Luciferase reporter gene 4xwtCBFlLuc (Hsieh, JJ, T. Henkel, P. Salmon, E. Robey, MG Peterson and SD Hayward (1996). "Truncated mammalian Notchl activates CBFl / RBPJk-repressed genes by a mechanism resembling of Epstein-Barr virus EBNA2. "Mol Cell Biol 16 (3): 952-9). When 4xwtCBFl Luciferase is co-transfected with NotchdE (ZEDN 1), the gamma-secretase division of NotchdE releases the intracellular Notch domain (NICD), which translocates to the nucleus and de-represses transcription repression mediated by CBF1, leading to transcription of the luciferase reporter gene. Luciferase activity is easily tested in cell extracts using commercially available kits. The activity of the reporter gene correlates directly with the division of the gamma secretase of NotchdE, and as such, a reduction in the activity of Luciferase provides a convenient measure of the inhibition of the division of the gamma secretase of NotchdE. A comparison of the IC50 values of the compounds for the inhibition of Notch signaling against the inhibition of beta-amyloid production in 293sw cells is used to guide the selection of compounds having the desired property of potent inhibition of beta-amyloid synthesis with minimal inhibition of Notch signaling. Compound 2a has an IC50 value of less 100 nM. Compound 7a has an IC50 value of less 50 nM. Compounds la, 3a, 4a, 5a and 6a have an IC50 value of less 25 nM.

Grasse secretase test The APP gamma secretase enzyme test was designed to measure the specific proteolytic cleavage of an APP substrate (MBP-C125 Swe fusion protein) at the Aβ40 site. The test used a partially purified extract of the IMR-32 cell membranes as the gamma secretase enzyme preparation and a recombinant fusion protein containing the terminal 125 amino acids C of the Swedish APP variant (MBP-C125swe) as the substrate . This test involved two stages start with the enzymatic reaction generates a division product was captured with a immobilized antibody specific for the Aβ40 site of the neo-epitope. The captured split product was then detected in an ELISA test interposed with a biotinylated reporter antibody that is specific to Aβ (17-28). The alkaline phosphatase linked to streptavidin was then added, which would generate a fluorescent signal providing the amount of divided product. This test was used to discover inhibitors of small molecules of secretase-gamma Materials and Methods: Briefly, a solution of 149 mg / ml of BIGCHAP detergent was made with water at 42 ° C and then turned for 30 minutes at the same temperature. This heated solution of detergent BigCHAPS (N, N-Bis (3-D-glucanamidopropyl) colamide) was used to dissolve the brain extract of type V (lipid containing a minimum of 40% phosphatidylethanolamine) from Sigma (St. Louis, Mo.) At a concentration of 8 mg / ml. This solution containing BigCHAPS and lipid at 8 mg / ml is then diluted to 0.53 mg / ml of lipid with preheated solutions of Hepes and sodium chloride. This final solution containing the Hepes buffer, sodium chloride, BigCHAPS detergent and the lipid is used to create working solutions of gamma secretase (25 Units) and MBP-C125 substrate (0.05 mg / ml).

The gamma secretase was then added to a 96-well microtiter plate and then incubated with different concentrations of inhibitor for 30 minutes at 37 ° C. The MBPC125 substrate was then added to initiate the reaction that would run for two hours at 37 ° C. The reaction was quenched with the addition of SDS to a final concentration of 0.1% and then 100 μl of the reaction mixture was transferred to a capture ELISA plate and incubated overnight at 4 ° C. Detection and division of the product were performed using a standard interposed ELISA test and quantified using a standard six point curve.

Results The following compounds when tested as described above exhibited an inhibition with an IC 50 in a range of 300 nM-150 nM (A), in a range of 150 nM-50 nM (B) or of less than 5 nM (C) ).

Structure Name of compound YA PP 6-benzyl-5- (4-chlorophenylsulfonyl] B 4,5,6,7-tetrahydro-lH-pyrazolo [4,3-c] pyridine 5- (4-chlorophenylsulfonyl) -6- isopropyl -4, 5, 6, 7-tetrahydro-lH-pyrazolo [4, 3-c] pyridine 5- (4-chlorophenylsulfonyl) -6- (4- C fluorophenyl) -4, 5, 6, -tetrahydro-lH- pyrazolo [4, 3-c] pyridine 6- (4-chlorophenyl) -5- (4-chlorophenylsulfonyl) -4,5,6-7-tetrahydro-1H-pyrazolo [4,3- c] pyridine Enantiomer AA Enantiomer BC 5- (4-chlorophenylsulfonyl) -6- (3, 5-difluorophenyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine 5- (5 -chlorothiophen-2-ylsulfonyl) -6- C phenyl-4,5,6,7-tetrahydro-lH-pyrazolo [4, 3-c] pyridine The invention and the form and process for the elaboration and use of it, will now be described in complete, clear, concise and exact terms to allow any person experienced in the technique to which it belongs, to make and use it. It will be understood that the foregoing describes the preferred embodiments of the invention and that modifications may be made thereto without departing from the spirit and scope of the invention as set forth in the claims. To particularly visualize and claim in a different manner the related matter considered by the invention, the following claims conclude this specification.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (20)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. Compounds of the formula:
2. (Formula I) stereoisomers, tautomers, mixtures of stereoisomers and / or tautomers or pharmaceutically acceptable salts thereof, characterized in that: ring A is aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein each ring is optionally substituted in a halogen-substituted position, alkyl C ? -C6, C2-C6 alkenyl, C2-C6 alkynyl, Ci-C? Alkoxy, C? -C6 haloalkyl, C? -C6 haloalkoxy, hydroxyl, hydroxyalkyl, CN, aryloxy, arylalkyloxy, -S02- (C? -C6 alkyl) ), -NR'R ", C? -C6 alkanoyl, C0-C3-C (O) OR 'alkyl, heteroaryl, heterocycloalkyl, aryl, arylalkyl or -S02-NR'R", wherein each of R' and R "is independently H or C? -C6 alkyl or R 'and R" with the atom to which they are attached can form a 3-8 member ring optionally including an additional heteroatom, such as N, 0 or S; Ring B is a heteroaryl or heterocycloalkyl ring, each of which is optionally substituted in a substitutable position with a group that is independently Ci-Ce alkyl, C2-Cg alkenyl, C2-C6 alkynyl, C6-C6 alkoxy, amino, alkylamino Ci-C ?, dialkylamino C? -C6, -S (O) 0-2R ', hydroxyl, hydroxyalkyl, halo, haloalkyl C? -C2, haloalkoxy C? -C2, -NR'C (0) R ", -NR'S02R", -C (0) R ', -C02R', -C (0) alkylOC (0) R ', -C (0) NR'R ", oxo, CN or alkylaryn Cn-Ci , wherein the aryl is optionally substituted with 1-5 groups independently selected from halogen, Ci-Ce alkyl, -C (0) OR ', C? -C6 alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, N02, aryloxy, - S (O) 0-2- (C? -C6 alkyl), C (0) NR'R ", -NR'R", C? -C6 alkanoyl, pyridyl, phenyl, and -S02NR'R "; and go Ria R2 and R2a? are independently hydrogen, halogen, C?-C6 alkyl, C-C6 alkenyl, wherein the alkenyl group is optionally substituted with one or more halogens; C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl C? -C6 alkyl, aryl, C? -C6 arylalkyl, heteroaryl, -C02R?, CONR? R ?, Ci-Cd haloalkyl, wherein the haloalkyl group is optionally substituted with C 1 -C-alkoxy, C 1 -C 6 haloalkoxyalkyl, C 6 -C 6 hydroxyalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 aryloxyalkyl, C 1 -C 6 heteroaryloxyalkyl, C 0 -C 6 -alkyl (O) NR 'R " , hydroxyl or C0-C6-OC (O) -heterocycloalkyl alkyl, wherein each aryl, heteroaryl and heterocycloalkyl group is optionally substituted with one or more groups which are independently halogen, C? -C6 alkyl, C? -C6 alkoxy, alkanoyl C? -C6, C? -C4 haloalkyl, C? -C4 haloalkoxy,
3. C (O) NR'R ", -NR'R", hydroxyl, -O- (CH2)? -2-0-, -C (0) OR ', phenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl; R3 and R3a are independently hydrogen, halogen, C? -C6 alkyl, OH or NR'R "; Rx and R? A or R2 and R2a or R and R3a combined form = 0 or = N-OR, where R is hydrogen, C? -C6 alkyl, aryl (such as phenyl) or arylalkyl (such as benzyl or phenethyl); or Rx and Rla or R2 and R? a or R3 and R3a together with the carbon to which they bond form a C3-C6 cycloalkyl group wherein one of the carbons is optionally replaced with a heteroatom selected from N, O or S and wherein the ring can be optionally substituted with C? -C6 alkyl, or Rx and R3 form a double bond. according to claim 1, characterized in that: ring B is pyrazolyl, imidazolyl, pyrrolyl, triazolyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, isoxazolyl, indolyl, pyrimidyl or pyridyl, each of the which is optionally substituted in a substitutable position with a group which is independently Ci-Cß alkyl, Ci-Ce alkoxy, amino, C?-C6 alkylamino, C?-C6 dialkylamino, Cilt-C6 alkylthio, halo, C halo haloalkyl C2, C? -C2 haloalkoxy or C0-C? Alkylphenyl are optionally substituted with 1 to 5 groups which are independently halogen, hydroxyl, C? -C6 alkyl, Ci-Cd alkoxy, C? -C haloalkyl, C? -C4 haloalkoxy, Cx-Ce alkanoyl, -NRR ', -C02R', -CONR'R ", CN or N02. The compounds or salts according to claim 2, characterized in that: Ri is Ci-Cβ alkyl, C3-C6 cycloalkyl, C3-Cβ cycloalkyl C? -C6 alkyl, phenyl, biphenyl, phenylalkyl C? -C6, pyridyl, benzofuranyl benzothienyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, tetrazolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiazolyl, pyrimidyl, -C02R ', -CONR'R', haloalkyl C? -C6, hydroxyalkyl C? -C6, alkoxy C -Cd, C? -C6 phenyloxyalkyl, C? -C6 naphthyloxyalkyl, C? -C6 pyridyloxyalkyl, C? -C6 benzofuranyloxyalkyl, C? -C6 benzothienyloxyalkyl, C? -C6 quinolinyloxyalkyl, C? -C6 isoquinolinyloxyalkyl, quinoxalynyloxyalkyl C? C6, quinazoliniloxyalkyl C? -C6, alkyl -C0-C6-OC (O) NR 'R ", alkyl -C0-C6-NR' R", hydroxyl, alkyl C? -C6-OC (O) -piperidinyl, alkyl -C? -C6-OC (O) -pyrrolidinyl, alkyl -C? -C6-OC (O) -morpholinyl, wherein each aryl, heteroaryl and heterocycloalkyl group is substituted optionally with one or more groups which are independently halogen, Ci-Cß alkyl, C?-C6 alkoxy, C?-C4 haloalkyl, C?-C4 haloalkoxy, C?-C6 alkanoyl, -C (O) NR'R ", -NR'R ", -0- (CH2)? _2-0-, -C02R ', pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methyl pyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl. 4. The compounds or salts according to claim 3, having the following formula:
4. Formula 6 characterized in that: Ri2 is H, halogen, Ci-Ce alkyl, C6-C6 alkoxy, C6-C6 haloalkyl or CN; Ri3 is H, halogen, Ci-Ce alkyl optionally substituted with -C02- (C? -C6 alkyl), C? -C6 alkoxy, C? -C6 haloalkyl, Ci-Ce haloalkoxy, CN, aryloxy, isocyanate, -S02- (C? -C6 alkyl), -NR'R ", C? -C6 alkanoyl, pyridyl or phenyl; or Ri4 is H, C? -C alkyl, -S02-NR'R", or halogen; wherein R 'and R "are independently H or Ci-
5. C6; or R? 3 and Ri. and the carbons to which they bind form a benzo ring; or Rio and Rii in each case are independently H, halogen or C? -C6 alkyl, wherein the alkyl is optionally substituted with a phenyl, wherein the phenyl is optionally substituted with 1 to 5 groups which are independently halogen, hydroxyl, alkyl C? -C6, C? -C6 alkoxy, C? -C4 haloalkyl, C? -C haloalkoxy, CN or N02; or Rio Rii and the carbons to which they are bound form a benzo ring. 5. The compounds or salts according to claim 4, wherein ring B has the following formula: characterized in that R20 is H, C? -C6 alkyl, C? -C6 alkoxy, amino, C? -C6 alkylamino, C? -C6 dialkylamino, C? -C6 alkylthio, halo, CF3 or phenyl.
6. 6. The compounds or salts according to claim 4, characterized in that: Ri is C? -C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylalkyl, phenyl, biphenyl, phenylalkyl Ci-C? (such as benzyl or phenethyl), C? -C6 phenyloxyalkyl, or C? -Ce naphthyloxyalkyl, wherein each aryl group is optionally substituted with 1, 2, 3, 4 or 5 groups which are independently halogen, C? -C6 alkyl , C 1 -C 6 alkoxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, -C (O) NR'R ", -NR'R", hydroxyl, -O- (CH 2)? _ 2-0-, - C02R ', phenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methyl pyrazolyl, N-benzyl pyrazolyl, oxadiazolyl, oxazolyl or imidazolyl; and Rla and R2a, R3 and R3a are H.
7. 7. Compounds or salts according to claim 5, characterized in that: R2 and? a combine to form oxo.
8. 8. Compounds or salts according to claim 1, characterized in that they have the formula:
9. 9. Compounds or salts according to claim 8, characterized in that ring B has the following formula: wherein R3o is H, C? -C4 alkyl, C? -C4 alkoxy, amino, C? -C4 alkylamino, C? -C4 dialkylamino, C? 4 alkylthio, halo, CF3 or phenyl.
10. 10. Compounds or salts according to claim 9, characterized in that: Rx is pyridyl, thiazolyl, imidazolyl, benzofuranyl, benzothienyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pyridyloxyalkylC? -C6, benzofuranyloxyalkylC? -C6, benzothienyloxyalkyl Ci-Ce, C?-C5 quinolinyloxyalkyl, C?-C6 isoquinolinyloxyalkyl, C?-Cg quinoxalinyloxyalkyl, C qu-C qu quinazolinyloxyalkyl, C alquilo-C?-C--OC (O) NR'R "alkyl, C alquilo-C6-alkyl -OC (O) -piperidinyl, C 1 -C 6 -OC (O) -pyrrolidinyl or C 1 -C 6 -OC (O) -morpholinyl alkyl, wherein each heteroaryl and heterocycloalkyl group is optionally substituted with one or more groups which are independently halogen, Ci-Cg alkyl, C?-C6 alkoxy, C halo-C4 haloalkyl, C?-C4 haloalkoxy, -C (0) NR'R ", -NR'R", hydroxyl, -O- (CH2) -2-0-, -C02R ', phenyl, pyridazinyl, pyrazinyl, pyrimidyl, thiazolyl, pyridyl, N-methylpyrazolyl, N-benzylpyrazolyl, oxadiazolyl, oxazolyl or imidazolyl, and R a, R 2a, R 3 and R 3a are H.
11. 11. Compounds of salts according to claim 10, characterized in that R2 is pyridyl, pyrimidyl, -C02-C1-C4 alkyl, C? -C4 alkyl, alkyl -C? -C4-OC (0) NR 'R', benzimidazolyl, thiazolyl or imidazolyl, and Ri is H, methyl, or ethyl; wherein R 'and R "are independently H or C 1 -C 4 alkyl
12. 12. Compounds of salts according to claim 10, characterized in that the heteroaryl group is pyridyl optionally substituted with 1 or 2 groups which are independently halogen, C-alkyl C4, C 1 -C 4 alkoxy, CF 3, OCF 3, OH, amino or mono or di (C 1 -C) alkyl amino
13. 13. Compounds of salts according to claim 10, characterized in that the heteroaryl group is thienyl optionally substituted with 1 or 2 groups which are independently halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, CF 3, OCF 3, OH, amino, or mono or di (C 1 -C 4 alkyl) amino
14. 14. Compounds or salts of according to claim 1, characterized in that they have the formula: wherein: the heterocycloalkyl group is optionally substituted in a substitutable position with halogen, Ci-Ce alkyl, Ci-Ce alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, aryloxy, arylalkyloxy, -S02- (C6-C6 alkyl), NR'R ", C? -C6 alkanoyl, pyridyl, phenyl or -S02-NR'R", wherein each R 'and R "is independently H or C? -C6 alkyl.
15. 15. Compounds of salts according to claim 14, characterized in that: Ri is -C02R ', -CONR'R ", haloalkyl C? -C4 or hydroxyalkyl C? -C; and R? A, Ra, R3 and R3a are H.
16. 16. Compounds of salts according to claim 15, characterized in that the heterocycloalkyl group is morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, S, S-thiomorpholinyl dioxide, tetrahydrofuranyl or imidazolidinyl, each of which is substituted
17. 17. Compounds or salts according to claim 1, characterized in that they have the formula: the cycloalkyl group is optionally substituted in a halogen-substitutable position, C? -C6 alkyl, Ci-Cg alkoxy, haloalkyl, haloalkoxy, hydroxyl, CN, phenyloxy, benzyloxy, -S02- (C? -C6 alkyl), -NR ' R ", C?-C6 alkanoyl, pyridyl, phenyl or -S02-NR'R", wherein each of R 'and R "is independently H or C?-Cg alkyl
18. 18. A method for the treatment of disease Alzheimer's, characterized in that it comprises administering a therapeutically effective amount of a compound or salt according to claim 1 to a patient in need of such treatment.
19. 19. A composition, characterized in that it comprises a compound or salt according to claim 1 and at least one pharmaceutically acceptable solvent, adjuvant, excipient, vehicle, binder or disintegrant.
20. 20. Compounds according to claim 1, characterized in that they are: 5- (4-chlorophenylsulfonyl) -4,6-dicyclopropyl-4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; cis- (5- (4-chlorophenylsulfonyl) -4-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridin-6-yl) methano1; 5- (4-chlorophenylsulfonyl) -6- (pyrimidin-5-yl) -5,6-dihydro-lH-pyrazolo [4, 3-c] pyridin-7 (4H) -one; 5- (4-chlorophenylsulfonyl) -4- (pyrimidin-5-yl) -5,6-dihydro-1H-pyrazolo [4, 3-c] pyridin-7 (4H) -one; 5- (4-chlorophenylsulfonyl) -6-cyclopropyl-6,7-dihydro-1H-pyrazolo [4, 3-c] pyridin-4 (5H) -one; 4- (pyrimidin-5-yl) -5- (4- (trifluoromethyl) phenylsulfonyl) -4,5,6,6-tetrahydro-lH-pyrazolo [4, 3-c] pyridine; 6-methyl-4- (pyrimidin-5-yl) -5- (4- (trifluoromethyl) phenylsulfonyl) -4,5,6,7,7-tetrahydro-lH-pyrazolo [4, 3-c] pyridine; 4,6-dimethyl-5- (4- (trifluoromethyl) phenylsulfonyl) -5,6-dihydro-lH-pyrazolo [4, 3-c] pyridin-7 (H) -one; (4- (pyrimidin-5-yl) -5- (4- (trifluoromethyl) phenylsulfonyl) -4,5,6,7-tetrahydro-lH-pyrazolo [4, 3-c] pyridin-6-yl) methanol; 5- (4-chlorophenylsulfonyl) -6-methyl-4- (pyrimidin-5-yl) -4,5,6,7-tetrahydro-lH-pyrazolo [, 3-c] pyridine; 5- (4-chlorophenylsulfonyl) -6-cyclopropyl-4- (pyrimidin-5-yl) -4,5,6,7,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 5- (4-fluorophenylsulfonyl) -4,6-dimethyl-5,6-dihydro-lH-pyrazolo [4,3-c] pyridin-7 (4H) -one; 4,6-dimethyl-5- (pyridin-2-ylsulfonyl) -5,6-dihydro-lH-pyrazolo [4,3-c] pyridin-7 (4H) -one; 5- (4-chlorophenylsulfonyl) -4,6-bis (1,1-difluoroethyl) -4,5,6,7-tetrahydro-lH-pyrazolo [, 3-c] pyridine; 5- (4-chlorophenylsulfonyl) -4,6-bis (difluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 1, 1 '- (5- (4-chlorophenylsulfonyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridin-4,6-diyl) dietanone; 5- (4-chlorophenylsulphonyl) -4,6-bis (2,2-difluorovinyl) -4,5,6,7,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 5- (4-chlorophenylsulphonyl) -4,6-bis (2,2-difluoroethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 5- (4-chlorophenylsulfonyl) -4,6-bis (fluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 5- (4-chlorophenylsulphonyl) -4,6-bis (difluoro (methoxy) methyl) 4,5,6,7-tetrahydro-lH-p? Razolo [4,3-c] p? R? Dma; 5- (4-chlorophen? Lsulfon? L) -4,6-bis ((tpf luor orne toxi) useful) -4, 5, 6, 7-tetrahydro-lH-p? Razolo [4, 3- c] p? r? dma; 5- (4-chlorophen? Lsulfonyl) -4,6-b? S (2, 2, 2-tpfluoroetyl) - 4, 5, 6, 7-tetrahydro-lH-p? Razolo [4 , 3-c] p? R? D? Na; 5- (4-chlorophen-lysulfonyl) -4,6-d ?? -propyl-4,5,6,7-tetrahydro-lH-pyrazolo [4, 3-c] p? R? D? Na; 5 '- (4-chlorofenylsulfonyl) -l', 5 ', 6', 7'-tetrahydrospiro [c? Clopropan-1, 4'-p? Razolo [4,3-c] p? R? Dma]; 6-met? L-4- (p? Pm? Dm-5-? L) -5- (4- (trifluoromethyl) phenylsulfonyl) -5,6-d? H? Dro-lH-p? Razolo [4 , 3-c] p? Pd? N-7 (4H) -one; 6-met? L-4- (p? Pd? N -3? L) -5- (4- (trifluoromethyl) phenylsulfonyl) -5,6-d? H? Dro-lH-p? Razolo [4 , 3-c] p? Pd? N-7 (4H) -one; 6-met? L-4- (p? R? D? N-4-? L) -5- (4- (tpf luoromethyl) phenylsulfonyl) -5,6-d? H? Dro-lH-p? Razolo [4,3-c] p? R? Dm-7 (4H) -one; 5- (4-chlorophen? Lsulfon? L) -4,6-d? Et? L-5,6-d? H? Dro-lH-pyrazolo [4, 3-c] p? R? D? N- 7 (4H) -one O-methyl oxime; 5- (4-chlorophen? Lsulfon? L) -4,6-d? Et? LN, Nd? Met? L-4, 5,6,7-tetrahydro-lH-pyrazolo [4, 3-c] p? pd? n-7-am? na; 5- (4-chlorophen? Lsulfon? L) -4,6-d? Et? L-4, 5,6,7-tetrahydro-lH-p? Razolo [4,3-c] p? Pd? n-7-am? na; 5- (4-chlorophenylsulfonyl) -4,6-diethyl-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridin-7-ol; 5- (4-chlorophenylsulfonyl) -4,6-diethyl-7-fluoro-4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 5- (4-chlorophenylsulfonyl) -4,6-diethyl-7,7-difluoro-4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 6-methyl-4- (thiazol-2-yl) -5- (4- (trifluoromethyl) phenylsulfonyl) -5,6-dihydro-lH-pyrazolo [4, 3-c] pyridin-7 (4H) -one; 4- (1H-imidazol-5-yl) -6-methyl-5- (4- (trifluoromethyl) phenylsulfonyl) -5,6-dihydro-1H-pyrazolo [4,3-c] pyridin-7 (4H) - ona; 4- (1H-imidazol-2-yl) -6-methyl-5- (4- (trifluoromethyl) phenylsulfonyl) -5,6-dihydro-1H-pyrazolo [4,3-c] pyridin-7 (4H) - ona; 5- (4-chlorophenylsulfonyl) -4,6-bis (trifluoromethyl) -4,5,6,6-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 5- (4-chlorophenylsulphonyl) -4-isopropyl-5,6-dihydro-lH-pyrazolo [4,3-c] pyridin-7 (4H) -one; 5- (chlorophenylsulfonyl) -6-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 6-benzyl-5- (4-chlorophenylsulfonyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 5- (4-chlorophenylsulfonyl) -6-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 5- (-chlorophenylsulfonyl) -6- (4-fluorophenyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 6- (4-chlorophenyl) -5- (4-chlorophenylsulfonyl) -4,5,6) 7-tetrahydro-lH-pyrazolo [4, 3-c] pyridine; 5- (4-chlorophenylsulfonyl) -6- (3,5-difluorophenyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 4- (4-chlorophenyl) -5- (4-chlorophenylsulfonyl) -6-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 6- (4-chlorophenyl) -5- (4-chlorophenylsulfonyl) -3- (trifluoromethyl) -4,5,6,7,7-tetrahydro-lH-pyrazolo [4, 3-c] pyridine; 6- (4-chlorophenyl) -5- (4-chlorophenylsulfonyl) -4-ethyl-4,5,6,6-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 5- (4-chlorophenylsulfonyl) -4,6-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 5- (4-chlorophenylsulfonyl) -6- (pyridin-3-yl) -4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 5- (4-chlorophenylsulfonyl) -6- (pyridin-4-yl) -4,5,6,8,1-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 5- (4-chlorophenylsulphonyl) -4,6-diethi4-4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 5- (4-chlorophenylsulfonyl) -6- (pyrimidin-5-yl) -4,5,6,7,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 5- (chloro-benzenesulfonyl) -4-pyrimidin-5-yl-4, 5,6,7-tetrahydro-lH-pyrazolo [4, 3-c] pyridine; 5- (4-chlorophenylsulfonyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine-carboxylic acid ethyl ester; 5- (4-chlorophenylsulfonyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine-6-carboxylic acid ethyl ester; 5- (4-chlorophenylsulphonyl) -6-ethyl-6,7-dihydro-lH-pyrazolo [4, 3-c] pyridin-4 (5H) -one; (5- (4-chlorophenylsulfonyl) -4,5,6,7-tetrahydro-lH-pyrazolo [4, 3-c] pyridin-6-yl) methanol; 5- (4-chlorophenylsulfonyl) -4,6-diethyl-5,6-dihydro-lH-pyrazolo [4, 3-c] pyridin-7 (4H) -one; 5-. { 4-chlorophenylsulfonyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridin-4,6-dicarboxylate diethyl ester; 5- (4-chlorophenylsulfonyl) -4,5,6,7-tetrahydro-lH-pyrazolo [4,3-c] pyridin-diyl) dimethanol; dimethylcarbamate (5- (4-chlorophenylsulfonyl) -4,5,6,7-tetrahydro-lH-pyrazolo [4,3-c] pyridin-4-yl) methyl; 5- (4-chlorophenylsulfonyl) -4,6-diethyl-5,6-dihydro-lH-pyrazolo [4, 3-c] pyridin- (4H) -one; (5- (4-chlorophenylsulfonyl) -1- (dimethylcarbamoyl) -4,5,6,7-tetrahydro-lH-pyrazolo [4, 3-c] pyridin-4-yl) methyl dimethylcarbamate; 4,6-diethyl-5- (pyridin-2-ylsulfonyl) -4,5,6,7,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine; 4- (1H-benzoimidazol-2-yl) -5- (4-chloro-benzenesulfonyl) -4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine; 5- (4-chlorophenylsulfonyl) -4,6-diethyl-5,6-dihydro-1H-pyrazolo [4, 3-c] pyridin-7 (4H) -one oxime; 5- (4-chlorophenylsulfonyl) -6-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo [4, 3-c] pyridine-4-carboxylic acid ethyl ester; 4,6-diethyl-5- (4-fluorophenylsulfonyl) -4,5,6,7-tetrahydro-2H-pyrazolo [4, 3-c] pyridine; 5- (4-chlorophenylsulfonyl) -6-ethyl-4,5,6,6-tetrahydro-lH-pyrazolo [4, 3-c] pyridin-4-yl) methyl dimethylcarbamate; 5- (4-chlorophenylsulfonyl) -4-ethyl-4,5,6-tetrahydro-1H-pyrazolo [4, 3-c] pyridin-6-yl) methyl dimethylcarbamate; 2- (5- (4-chlorophenylsulfonyl) -4,5,6,6> 7-tetrahydro-2H-pyrazolo [4, 3-c] pyridin-6-yl) thiazole; 2- (5- (4-chlorophenylsulfonyl) -4,5,6,7-tetrahydro-2H-pyrazolo [4, 3-c] pyridin-4-yl) thiazole; 5- (4-chlorophenylsulfonyl) -4-ethyl-4,5,6,6-tetrahydro-1H-pyrazolo [4, 3-c] pyridin-6-yl) methanol; 4? 6-diethyl-5- (pyridin-2-ylsulfonyl) -4,5,6,7-tetrahydro-2H-pyrazolo [4, 3-c] pyridine; 4,6-diethyl-5- (pyridin-2-ylsulfonyl) -4,5,6,7,7-tetrahydro-2H-pyrazolo [4 > 3-c] pyridine; 4,6-dimethyl-5- (4- (trifluoromethyl) phenylsulfonyl) -5,6-dihydro-2H-pyrazolo [4,3-c] pyridin-7 (4H) -one; and stereoisomers, tautomers, mixture of stereoisomers and / or tautomers or pharmaceutically acceptable salts thereof.