GAMMA SECRETASE MODULATORS
CN06928 WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 GAMMA SECRETASE MODULATORS Reference To Related Application This application claims the benefit of U.S. Provisional Application No. 6!/tt4233 filed November t3, 2008. Field of the Invention The present invention relates to certain heterocyclic compounds useful as gamma secretase modulators (including inhibitors, antagonists and the like), pharmaceutical compositions containing the compounds, and methods of treatment using the compounds and compositions to treat various diseases including central nervous system disorders such as, for example, neürodegenerative diseases such as Alzheimer's disease and other diseases relating to the deposition of amyloid protein. They are especially useful for reducing Amyloid beta (hereinafter referred to as AI3) production which is effective in the treatment of diseases caused by Ap such as, for example, Alzheimers and Down Syndrome. Background of the Invention Alzheimer's disease is a disease characterized by degeneration and loss of neurons and also by the formation of senile plaques and neurofibrillary change. Presently, treatment of Alzheimer's disease is limited to symptomatic therapies with a symptom-improving agent represented by an acetylcholinesterase inhibitor, and the basic remedy which prevents progress of the disease has not been developed. A method of controlling the cause of onset of path.ologic conditions needs to be developed for creation of the basic remedy of AIzheimer's disease. AI3 protein, which is a metabolite of amyJoid precursor protein (hereinafter referred to as APP), is considered to be greatly involved in degeneration and loss of neurons as well as onset of demential conditions (for example, see Klein W L, et ai Proceeding National Academy of Science USA, WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Sep. 2, 2003, 100(18), p. 10417-22, suggest a molecular basis for reversible memory loss. Nitsch R M, and 16 others, Antibodies against -amyloid slow cognitive decline in Alzheimer's disease, Neuron, May 22, 2003, 38(4), p. 547-554) suggest that the main components of At3 protein are At340 consisting of 40 amino acids and Ai 42 having two additional amino acids at the C-terminal. The A#40 and At342 tend to aggregate (for example, see Darrell J T et al, The carboxy terminus of the fl amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of AIzheimer's disease, Biochemistry, May I0 11,1993, 32(18), p. 4693-4697) and constitute main components of senile plaques (for example, (Glenner GG, et al, Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein, Biochemical and Biophysical Research Communications, May 16, 1984, 120(3), p. 885-90. See also Masters C L, et al, Amyloid plaque core protein in Alzheimer disease and Down syndrome, Proceeding National Academy of Science USA, June 1985, 82(12), p. 4245-4249.). Furthermore, it is known that mutations of APP and presenetin genes, which is observed in familial AlzheimeCs disease, increase production of A1840 and Aj342 (for example, see Gouras G K, et al, IntraneuronalA#142 accumulation in human brain, American Journal of Pathology, January 2000, 156(I), p. 15-20. Also, see Scheuner D, et al, Nature Medicine, August 1996, 2(8), p. 864-870; and Forman M S, et al, Differential effects of the Swedish mutant amyloid precursor protein on f}-amyloid accumulation and secretion in neurons and nonneuronaf cells, Journal of Biological Chemistry, Dec. 19, 1997, 272(51), p. 32247-32253.). Therefore, compounds which reduce production of Aí340 and Ai342 are expected as an agent for controlling progress of Atzheimer's disease or for preventing the disease. These At3s are produced when APP is cleaved by beta secretase and subsequently clipped by gamma secretase, tn consideration of this, creation of inhibitors of y secretase and 13 secretase has been attempted for the purpose of WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 reducing production of A#s. Many of these secretase inhibitors already known are peptides or peptidomimetics such as L-685,458. L-685,458, an aspartyl protease transition stale mimic, is a potent inhibitor of amyloid J3-protein precursor y-secretase activity, Biochemistry, Aug. 1, 2000, 39(30), p. 86988704). Also of interest in connection with the present invention are: US 200710117798 (Eisai, published May 24, 2007); US 2007t0117839 (Eisai, published May 24, 2007); US 2006/0004013 (Essai, published January 5, 2006); WO 2005/110422 (Boehringer lngelheim, published November 24, 2005); WO 2006/045554 (Cellzone AG, published may 4, 2006); WO 2004/110350 (Neurogenetics, published December 23, 2004); WO 2004t07143t (Myriad Genetics, published August 26, 2004); US 2005/0042284 (Myriad Genetics, published February 23, 2005) and WO 2006t001877 (Myriad Genetics, published January 5, 2006). !5 There is a need for new compounds, formulations, treatments and therapies to treat diseases and disorders associated with AI3. it is, therefore, an object of this invention to provide compounds useful in the treatment or prevention or amelioration of such diseases and disorders. Summary of the Invention In its many embodiments, the present invention provides a novel class of heterocyclic compounds as gamma secretase modulators (including inhibitors, antagonists and the like), methods of preparing such compounds, pharmaceutical compositions comprising one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition or amelioration of one or more diseases assocïated with the Ai3 using such compounds or pharmaceutical compositions. As used herein, Group A represents compounds Q11, R4, T2, U2, W3; X2, Y3, Z2, Aa2, Ab2, Ac6, Af3, Ag4, Ah2, Ai2, Ai4, Ak2, Al2, Ara3, Am4, An4, Ao5, WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Ap15, Aq7, Ar3, 201-203, 206-215, 220-222, 226-227, 229, 23I, 233, and 245394, identified below. As used herein, Group B represents compounds 201-203, 206-215, 220222, 226-227, 229, 231,233, and 253-394, identified below. The compounds of this invention (Groups A and B) can be useful as gamma secretase modulators and can be useful in the treatment and prevention of diseases such as, for example, Alzheimers disease, mild cognitive impairment (MCl), Downs Syndrome, Glaucoma (Guo et.al., Proc. Natl. Acad. Sci. USA 104, 13444-13449 (2007)), Cerebral amytoid angiopathy, stroke or dementia (Frangione et al., Amyloid: J. Protein folding Disord. 8, suppl. 1, 36-42 (2001), Microgiiosis and brain inflammation (M P Lamber, Proc. Natl. Acad. Sci. USA 95, 6448-53 (1998)), Olfactory function loss (Getchell, et.al. Neurobiology of Aging, 663-673, 24, 2003). This invention provides compounds selected from the group consisting of: the compounds of Group A, or a pharmaceutically acceptable sait, ester, so]vate or prodrug thereof. This invention also provides compounds selected from the group consisting of the compounds of Group A, or a pharmaceutically acceptable salt, ester, or solvate or thereof. This invention also provides compounds selected from the group consisting of the compounds of Group A. This invention also provides compounds selected from the group consisting of the compounds of Group B, or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof. This invention provides compounds selected from the group consisting of the compounds of Group B, or a pharmaceutica!ty acceptable sait, ester, or sotvate thereof. This invention provides compounds selected from the group consisting of the compounds of Group B. WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 The present invention further includes the compounds of the invention in ail its isolated forms. This invention also provides the compounds of Group A or B in pure and isolated form. This invention also provides pharmaceutical compositions comprising an effective amount of one or more (e.g., one) compounds of Group A, or a pharmaceutically acceptable sait, ester or solvate thereof, and a pharmaceutically acceptable carrier. This invention also provides pharmaceutical compositions comprising an t0 effective amount of one or more (e.g., one) compounds of Group B, or a pharmaceutically acceptable salt, ester or solvate thereof, and a pharmaceutically acceptable carrier. This invention also provides pharmaceutical compositions comprising an effective amount of one or more (e.g., one) compounds of Group A, or a pharmaceutically acceptable salt, ester or soldate thereof, and an effective amount of one or more (e.g., one) other pharmaceutically active ingredients (e.g., drugs), and a pharmaceutically acceptable carrier. This invention also provides pharmaceutical compositions comprising an effective amount of one or more (e.g., one) compounds of Group B, or a pharmaceutically acceptable salt, ester or solvate thereof, and an effective amount of one or more (e.g., one) other pharmaceutically active ingredients (e.g., drugs), and a pharmaceutically acceptable carrier. The compounds of Formula A or B can be useful as gamma secretase modulators and can be useful in the treatment and prevention of diseases such as, for example0 central nervous system disorders such as Alzheimers disease and Downs Syndrome. Thus, this invention also provides methods for: (!) method for modulating (including inhibiting, antagonizing and the like) gamma-secretase; (2) treating one or more neurodegenerative diseases: (3) inhibiting the deposition of amyloid protein (e.g., amytoid beta protein} in, on or around neurological tissue (e.g., the WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 brain): (4) Alzheimer's disease; and (5) treating Downs syndrome; wherein each method comprises administering an effective amount of one or more (e.g., one) compounds of Group A to a patient in need of such treatment. Thus, this invention also provides methods for: (1) method for modulating (including inhibiting, antagonizing and the like) gamma-secretase; (2) treating one or more neurodegenerative diseases; (3) inhibiting the deposition of amyloid protein (eg., amyloid beta protein) in, on or around neurological tissue (e.g., the brain); (4) Alzheimer's disease; and (5) treating Downs syndrome; wherein each method comprises administering an effective amount of one or more (e.g., one) compounds of formula B to a patient in need of such treatment. This invention also provides combination therapies for (1) modulating gamma-secretase, or (2) treating one or more neurodegenerative diseases, or (3) inhibiting the deposition of amyloid protein (e.g., amyloid beta protein) in, on or around neurological tíssue (e.g., the brain), or (4) treating Alzheimer's disease. The combination therapies are directed to methods comprising the administration of an effective amount of one or more (e.g. one) compounds of Group A and the administration of an effective amount of one or more (e.g., one) other pharmaceutical active ingredients (e.g., drugs). This invention also provides combination therapies for (1) modulating g amma-secretase, or (2) treating one or more neurodegenerative diseases, or (3) inhibiting the deposition of amyloid protein (e.g., amyloid beta protein) in, on or around neurological tissue (e.g., the brain), or (4) treating Alzheimer's disease. The combination therapies are directed to methods comprising the administration of an effective amount of one or more (e.g. one) compounds of Group B and the administration of an effective amount of one or more (e.g., one) other pharmaceuticaf active ingredients (e.g., drugs). This invention also provides methods for: (1) treating mild cognitive impairment; (2) treating glaucoma; (3) treating cerebral amyloid angiopathy; (4) treating stroke; (5) treating dementia; (6) treating microgliosis; (7) treating brain inflammation: and (8) treating olfactory function loss; wherein wherein each WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 t5 method comprises administering an effective amount of one or more (e.g., one) compounds of Group AI to a patient in need of such treatment. This invention also provides methods for: (t) treating mild cognitive impairment; (2) treating glaucoma; (3) treating cerebral amyloid angiopathy; (4) treating stroke; (5) treating dementia; (6) treating microgiiosis; (7) treating brain inflammation; and (8) treating olfactory function loss; wherein wherein each method comprises administering an effective amount of one or more (e.g., one) compounds of Group B to a patient in need of such treatment. This invention also provides a kit comprising, in separate containers, in a single package, pharmaceutical compositions for use in combination, wherein one container comprises an effective amount of a compound of Group A in a pharmaceutically acceptable carrier, and another container (i.e., a second container) comprises an effective amount of another pharmaceutically active ingredient (as described below), the combined quantities of the compound of Group A and the other pharmaceutically active ingredient being effective to treat the diseases or conditions mentioned in any of the above methods. This invention also provides a kit comprising, in separate containers, in a single package, pharmaceutical compositions for use in combination, wherein one container comprises an effective amount of a compound of Group B in a pharmaceutically acceptable carrier, and another container (i.e., a second container) comprises an effective amount of another pharmaceutically active ingredient (as described below), the combined quantities of the compound of Group BI and the other pharmaceutically active ingredient being effective to treat the diseases or conditions mentioned in any of the above methods. A. Detailed Description Thus one embodiment of thîs invention is directed to compounds of Group Another embodiment of this invention is directed to compounds of Group B. WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 The compounds of this invention are useful for treating central nervous system disorders such as, for example, neurodegenerative diseases such as AIzheime¢s disease and other diseases relating to the deposition of amyloid protein. They are especially useful for reducing Amyloid beta (hereinafter referred to as AI3) production which is effective in the treatment of diseases caused by AI3 such as, for example, Aizheimers and Down Syndrome. Thus, for example, the compounds of this invention can be used to treat the following diseases or conditions: AIzheimers disease, mild cognitive impairment (MCI), Downs Syndrome, Glaucoma (Guo etal., Proc. Natl. Acad. Sci. USA 104, 13444-13449 (2007)), Cerebral amyloid angiopathy, stroke or dementia (Frangione et al., Amytoid: J. Protein folding Distord. 8, suppl. 1, 36-42 (2001), Microgtiosis and brain inflammation (M P Lamber, Proc. Natl. Acad. Sci. USA 95, 6448-53 (1998)), and Olfactory function loss (Getchell, et.al. Neurobiology of Aging, 663-673, 24, 2003). Another embodiment of this invention is directed to compound Q11. Another embodiment of this invention is directed to compound R4. Another embodiment of this invention is directed to compound U2. Another embodiment of this invention is directed to compound W3. Another embodiment of this invention is directed to compound X2. Another embodiment of this invention is directed to compound Y3. Another embodiment of this invention is directed to compound Z2. Another embodiment of this invention is directed to compound Aa2. Another embodiment of this invention is directed to compound Ab2 Another embodiment of this invention is directed to compound Ac6. Another embodiment of this invention is directed to compound Af3. Another embodiment of this invention is directed to compound Ag4. Another embodiment of this invention is directed to compound Ah2. Another embodiment of this invention is directed to compound Ai2. Another embodiment of this invention is directed to compound Ai4. Another embodiment of this invention is directed to compound Ak2. Another embodiment of this invention is directed to compound AI2. Another embodiment of this invention is directed to compound Am3, Another embodiment of this invention is WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 directed to compound Am4, Another embodiment of this invention is directed to compound Ao5. Another embodiment of this invention is directed to compound Apt& Another embodiment of this invention is directed to compound Aq7, Another embodiment of this invention is directed to compound Af3. Another embodiment of this invention is directed to compound 201. Another embodiment of this invention is directed to compound 202, Another embodiment of this invention is directed to compound 203, Another embodiment of this invention is directed to 206. Another embodiment of this ínvention is directed to compound embodiment of this invention is directed to compound 208 Another of this invention is directed to compound 209, Another embodiment invention is directed to compound 210. Another embodiment of this directed to compound 211, Another embodiment of this invention is compound 212. Another embodiment of this invention is directed to 213. Another embodiment of this invention is directed to compound embodiment of this invention is directed to compound 215. Another of this invention is directed to compound 220, Another embodiment invention is directed to compound 221. Another embodiment of this directed to compound 222. Another embodiment of this invention is compound 226, Another embodiment of this invention is directed to 227. Another embodiment of this invention is directed to compound embodiment of this invention is directed to compound 23t. Another of this invention is directed to compound 233, Another embodiment invention is directed to compound 245, Another embodiment of this directed to compound 246. Another embodiment of this invention is compound 247, Another embodiment of this invention is directed to 248, Another embodiment of this invention is directed to compound embodiment of this invention is directed to compound 250. Another of this invention is directed to compound 251. Another embodiment invention is directed to compound 252. Another embodiment of this directed to compound 253, Another embodiment of this invention is compound 207. Another embodiment of this invention is directed to compound 214. Another embodiment of this invention is directed to compound 229. Another embodiment of this invention is directed to compound 249, Another embodiment of this invention is directed to WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 t0 compound 254. Another embodiment of this invention is directed to 255. Another embodîment of this invention is directed to compound embodiment of this invention is directed to compound 257, Another of this invention is directed to compound 258. Another embodiment invention is directed to compound 259. Another embodiment of this directed to compound 260. Another embodiment of this invention is compound 261. Another embodiment of this invention is directed to 262, Another embodiment of this invention is directed to compound embodiment of this invention is directed to compound 264. Another of this invention is directed to compound 265. Another embodiment invention is directed to compound 266. Another embodiment of this directed to compound 267. Another embodiment of this invention is compound 268. Another embodiment of this invention is directed to 269. Another embodiment of this invention is directed to compound embodiment of this invention is directed to compound 271. Another of this invention is directed to compound 272, Another embodiment invention is directed to compound 273. Another embodiment of this directed to compound 274. Another embodiment of this invention is compound 275, Another embodiment of this invention is directed to compound 256. Another embodiment of this invention is directed to compound 263. Another embodiment of this invention is directed to compound 270. Another embodiment of this invention is directed to compound 276. Another embodiment of this invention is directed to compound 277, Another embodiment of this invention is directed to compound 278, Another embodiment of this invention is directed to compound 279, Another embodiment of this invention is directed to compound 280. Another embodiment of this invention is directed to compound 281, Another embodiment of this invention is directed to compound 282, Another embodiment of this invention is directed to compound 283. Another embodiment of this invention is directed to compound 284, Another embodiment of this invention is directed to compound 285. Another embodiment of this invention is directed to compound 286. Another embodiment of this invention is directed to compound 287. Another embodiment of this invention is directed to compound 288, Another embodiment of this invention is directed to WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 compound 289, Another embodiment of this invention is directed to 290. Another embodiment of this invention is directed to compound embodiment of this invention is directed to compound 292. Another of this invention is directed to compound 293, Another embodiment invention is directed to compound 294, Another embodiment of this directed to compound 295, Another embodiment of this invention is compound 296, Another embodiment of this invention is directed to 297, Another embodiment of this invention is directed to compound embodiment of this invention is directed to compound 299. Another of this invention is directed to compound 300. Another embodiment invention is directed to compound 301. Another embodiment of this directed to compound 302. Another embodiment of this invention is compound 303. Another embodiment of this invention is directed to 304. Another embodiment of this invention is directed to compound embodiment of this invention is directed to compound 306. Another of this invention is directed to compound 307. Another embodiment invention is directed to compound 308. Another embodiment of this directed to compound 309. Another embodiment of this invention is compound 310, Another embodiment of this invention is directed to 311. Another embodiment of this invention is directed to compound embodiment of this invention is directed to compound 313. Another of this invention is directed to compound 314. Another embodiment invention is directed to compound 315, Another embodiment of this directed to compound 316, Another embodiment of this invention is compound 317. Another embodiment of this invention is directed to 3t8, Another embodiment of this invention is directed to compound embodiment of this invention is directed to compound 320, Another of this invention is directed to compound 321. Another embodiment invention is directed to compound 322. Another embodiment of this directed to compound 323, Another embodiment of this invention is compound 291, Another embodiment of this invention is directed to compound 298, Another embodiment of this invention is directed to compound 305, Another embodiment of this invention is directed to compound 312. Another embodiment of this invention is directed to compound 319. Another embodiment of this invention is directed to WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 !0 compound 324. Another embodiment of this invention is directed to 325. Another embodiment of this invention is directed to compound embodiment of this invention is directed to compound 327, Another of this invention is directed to compound 328. Another embodiment invention is directed to compound 329. Another embodiment of this directed to compound 330, Another embodiment of this invention is compound 331. Another embodiment of this invention is directed to 332. Another embodiment of this invention is directed to compound embodiment of this invention is directed to compound 334. Another of this invention is directed to compound 335, Another embodiment invention is directed to compound 336. Another embodiment of this directed to compound 337. Another embodiment of this invention is compound 338. Another embodiment of this invention is directed to compound 326. Another embodiment of this invention is directed to compound 333, Another embodiment of this invention is directed to compound 339. Another embodiment of this invention is directed to compound 340. Another embodiment of this invention is directed to compound 341. Another embodiment of this invention is directed to compound 342. Another embodiment of this invention is directed to compound 343, Another embodiment of this directed to compound 344. Another embodiment of this invention is compound 345. Another embodiment of this invention is directed to 346. Another embodiment of this invention is directed to compound embodiment of this invention is directed to compound 348, Another of this invention is directed to compound 349. Another embodiment invention is directed to compound 350. Another embodiment of this directed to compound 351, Another embodiment of this invention is compound 352. Another embodiment of this invention is directed to 353. Another embodiment of this invention is directed to compound embodiment of this invention is directed to compound 355. Another of this invention is directed to compound 356. Another embodiment invention is directed to compound 357, Another embodiment of this directed to compound 358. Another embodiment of this invention is invention is directed to compound 347. Another embodiment of this invention is directed to compound 354. Another embodiment of this invention is directed to WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 compound 359. Another embodiment of this invention is directed to compound 360. Another embodiment of this invention is directed to compound 361, Another embodiment of this invention is directed to compound 362, Another embodiment of this invention is directed to compound 363. Another embodiment of this invention is directed to compound 364. Another embodiment of this directed to compound 365. Another embodiment of this invention is compound 366, Another embodiment of this invention is directed to 367, Another embodiment of this invention is directed to compound embodiment of this invention is directed to compound 369, Another of this invention is directed to compound 370. Another embodiment invention is directed to compound 37t. Another embodiment of this directed to compound 372. Another embodiment of this invention is compound 373. Another embodiment of this invention is directed to 374. Another embodiment of this invention is directed to compound embodiment of this invention is directed to compound 376. Another of this invention is directed to compound 377, Another embodiment invention is directed to compound 378. Another embodiment of this directed to compound 379, Another embodiment of this invention is compound 380, Another embodiment of this invention is directed to 381. Another embodiment of this invention is directed to compound embodiment of this invention is directed to compound 383, Another of this invention is directed to compound 384. Another embodiment invention is directed to compound 385. Another embodiment of this directed to compound 386. Another embodiment of this invention is compound 387. Another embodiment of this invention is directed to 388, Another embodiment of this invention is directed to compound embodiment of this invention is directed to compound 390. Another of this invention is directed to compound 39t. Another embodiment invention is directed to compound 392. Another embodiment of this invention is directed to compound 368. Another embodiment of this invention is directed to compound 375. Another embodiment of this invention is directed to compound 382. Another embodiment of this invention is directed to compound 389. Another embodiment of this invention is WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 directed to compound 393. Another embodiment of this invention is directed to compound 394, Another embodiment of this invention is directed to a pharmaceutically acceptable salt of compound Q11. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound R4. Another embodiment of this invention is directed to a pharmaceutically acceptable salt of compound U2, Another embodiment of this invention is directed to a pharmaceutically acceptable salt of compound W3, Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound X2, Another embodiment of this invention is directed to a pharmaceutically acceptable salt of compound Y3, Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound Z2. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound Aa2, Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound Ab2. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound Ac6. Another embodiment of this invention is directed to a pharmaceutically acceptable salt of compound Af3. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound Ag4. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound Ah2. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound Ai2. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound Aj4. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound Ak2, Another embodiment of this invention is directed to a pharmaceutically acceptable salt of compound AI2. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound Am3, Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound Am4. Another embodiment of this invention is directed to a pharmaceutically acceptable salt of compound Ao5. Another embodiment of this invention is directed to a pharmaceuticaNy acceptable WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 sait of corn found Ap15. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound Aq7, Another embodìment of this invention is directed to a pharmaceutically acceptable sait of compound Ar3. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 201. Another embodiment of this Invention is directed to a pharmaceutically acceptable sait of compound 202. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 203. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of coin found 206. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 207, Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 208. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 209. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 210. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 211. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 212, Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 2t3. Another embodiment of this invention is directed to a pharmaceutically acceptable salt of compound 214. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of corn found 215, Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 220. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 221. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of coin found 222. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 226. Another embodiment of this invention is directed to a pharmaceutically acceptable salt of compound 227. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 229, Another embodiment of this "lvention is directed to a pharmaceutically acceptable sait of compound 231, Another embodiment of this WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 invention is directed to a pharmaceutically acceptable salt of compound 233. Another embodiment of this invention is directed to a pharmaceutically acceptabIe sait of compound 245. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 246. Another embodiment of this invention is directed to a pharmaceutically acceptable satt of compound 247, Another embodiment of this invention is directed to a pharmaceutically acceptable salt of compound 248. Another embodiment of this invention is directed to a pharmaceutically acceptable salt of compound 249. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 250. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 251. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 252. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 253. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 254. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 255. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 256. Another embodiment of this invention is directed to a pharmaceutically acceptable salt of compound 257. Another embodiment of this invention is directed to a pharmaceutically acceptable salt of compound 258. Another embodiment of this invention is directed to a pharmaceutically acceptable salt of compound 259. Another embodiment of this invention is directed to a pharmaceutically acceptable salt of compound 260. Another of embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 261. Another embodiment of this invention is directed to a pharmaceutically acceptable salt of compound 262. Another embodiment of this nventìon is directed to a pharmaceutically acceptable sait of compound 263. Another embodiment of this invention is directed to a pharmaceutically acceptable salt of compound 264. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 265. Another embodiment of this invention is directed to a pharmaceutically acceptable WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 t7 sait of compound 266, Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 267, Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 268, Another embodiment of this invention is directed to a »harmaceutically acceptable sait of compound 269. Another embodiment of this invention is directed to a pharmaceutically acceptable salt of compound 270, Another embodiment of this invention is directed to a pharmaceutically acceptable salt of compound 271, Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 272. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 273, Another embodiment of this invention is directed to a »harmaceutical:ly acceptable sait of compound 274 Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 275. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 276, Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 277. Another embodiment of this invention is directed to a pharmaceutically acceptable salt of compound 278 Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 279. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 280. Another embodiment of this invention is directed to a pharmaceutically acceptable salt of compound 281, Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 282, Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 283, Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 284, Another embodiment of this invention is directed to a pharmaceutically acceptable salt of compound 285. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 286. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 287. Another embodiment of this invention is directed to a pharmaceutically acceptable salt of compound 288, Another embodiment of this WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 I8 invention is directed to a pharmaceutically acceptable sait of compound 289. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 290. Another of embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 291. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 292. Another embodiment of this invention is directed to a pharmaceutically acceptable salt of compound 293. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 294. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 295. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 296. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 297. Another embodiment of this invention is directed to a pharmaceutically acceptable salt of compound 298. Another embodiment of this invention is directed to a pharmaceutically acceptable salt of compound 299. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 300. Another of embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 30I. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 302. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 303. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 304. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 305. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 306. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 307. Another embodiment of this invention is directed to a pharmaceuticaîty acceptable salt of compound 308. Another embodiment of this invention is directed to a pharmaceutically acceptable salt of compound 309. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 310. Another of embodiment of this invention is directed to a pharmaceutically WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 acceptable sait of compound 311. Another embodiment of this invention is directed to a pharmaceutically acceptable salt of compound 312, Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 3t 3. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 314. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 315. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 316. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 3t7. Another embodiment of this !0 invention is directed to a pharmaceutically acceptable sait of compound 318. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 319. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 320. Another of embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 321. t5 Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 322. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 323. Another embodiment of this invention is directed to a pharmaceutically acceptable salt of compound 324 Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 325. Another embodiment of this invention is directed to a pharmaceutically acceptable salt of compound 326, Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 327, Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 328. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 329. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 330. Another of embodiment of this invention is directed to a pharmaceutically acceptable salt of compound 331. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 332. Another embodiment of this invention is directed to a pharmaceutically acceptable salt of WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 compound 333, Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 334. Another embodiment of this invention is directed to a pharmaceutically acceptable salt of compound 335 Another embodiment of this invention is directed to a harmaceutically acceptable sait of compound 336. Another embodiment of this invention is directed to a pharmaceutical y acceptable sait of compound 337, Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 338, Another embodiment of this invention is directed to a »harmaceuticalty acceptable sait of compound 339. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 340, Another of embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 34t, Another embodiment of this inven.ti.on is directed to a pharmaceutically acceptable sait of compound 342. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 343, Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 344, Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 345, Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 346. Another embodiment of this invention is directed to a pharmaceutically acceptable salt of compound 347, Another embodiment of this invention is directed to. a »harmaceuticatly acceptable sait of compound 348. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 349. Another embodiment of this invention is directed to a pharmaceutically acceptable salt of compound 350. Another embodiment of this invention is directed to a harmaceuticalty acceptable sait of compound 351. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 352, Another embodiment of this t.nvention is directed to a pharmaceutically acceptable sait of compound 353, Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 354, Another embodiment of this invention is directed to a pharm.aceüticatiy acceptable salt of compound 355. Another embodiment of this WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 2t i0 t5 invention is directed to a pharmaceutically acceptable salt of compound 356. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 357, Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 358. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 359, Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 360. Another of embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 361. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 362. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 363, Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 364. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 365, Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 366. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 367, Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 368. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 369 Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 370. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 37t, Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 372. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 373, Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 374. Another embodïment of this invention is directed to a pharmaceutically acceptable salt of compound 375. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 376. Another embodiment of this invention is directed to a pharmaceutically acceptable salt of compound 377, Another embodiment of this invention is directed to a pharmaceutically acceptable WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 sait of compound 378, Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 379. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 380, Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 381. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 382. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 383. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 384. Another embodiment of this invention is directed to a pharmaceutically acceptable salt of compound 385. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 386. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 387. Another embodiment of this invention is directed to a pharmaceutically acceptable salt of compound 388. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 389. Another embodiment of this invention is directed to a pharmaceutically acceptable salt of compound 390. Another of embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 391. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 392, Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 393. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 394, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound Q11. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound R4. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound U2, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound W3. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound X2. Another embodiment of this invention is directed to a pharmaceuticalIy acceptable WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 ester of compound Y3. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound Z2. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound Aa2. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound Ab2, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound Ac6, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound Af3. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound Ag4. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound Ah2. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound Ai2. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound Ai4. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound Ak2. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound AI2. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound Am3 Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound Am4, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound Ao5ç Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound Apt5. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound Aq7. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound Ar3. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 201. Another embodiment of this invention is directed to a pharmaceuticaily acceptable ester of compound 202, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 203, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 206. Another embodiment of this invention is directed to a pharmaceuticalíy acceptable ester of compound 207. Another embodiment of this WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 !0 invention is directed to a pharmaceutically acceptable ester of compound 208, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 209. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 210. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 211, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 212. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 213. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 214. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 215. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 220, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 221, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 222. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 226. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 227. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 229, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 231. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 233. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 245. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 246. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 247. Another embodiment of this invention i.s directed to a pharmaceutica fy acceptable ester of compound 248 Another embodiment of this invention is directed to a pharmaceutically acceptable ester compound 249. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 250. Another embodiment of this invention is directed to a pharmaceutically acceptable WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 ester compound 251, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 252. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 253. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 254. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 255, Another embodiment of this învention is directed to a pharmaceutically acceptable ester of compound 256. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 257. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 258. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 259, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 260. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 261, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 262, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 263. Another embodiment of this invention is directed to a pharmaceutically acceptable sait of compound 264. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 265. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 266. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 267, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 268, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 269, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 270. Another of embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 271. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 272, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 273, Another embodiment of this WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 invention is directed to a pharmaceutically acceptable ester of com found 274, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 275. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 276, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 277. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 278. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 279, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of com found 280. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 281, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 282, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of com found 283. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 284, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 285. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 286. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 287. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 288. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of corn found 289. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 290, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 291. Another embodiment of this invention is directed to a pharmaceuticatly acceptable ester of compound 292, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 293, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 294. Another embodiment of this invention is dìrected to a pharmaceutically acceptable ester of compound 295. Another embodiment of this invention is directed to a pharmaceutically acceptable WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 !0 ester of compound 296, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 297. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 298. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 299, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 300. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 30t, Another embodíment of this invention is directed to a pharmaceutically acceptable ester of compound 302. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 303. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 304, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 305. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 306. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 307, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 308. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 309. Another embodiment of this invention is directed fo a pharmaceutically acceptable ester of compound 310. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 311. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 312, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 313, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 314 Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 3!5. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 316. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 317, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 318. Another embodiment of this WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 invention is directed to a pharmaceutically acceptable ester of compound 319. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 320. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 321. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 322, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 323. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 324, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 325. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 326. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 327. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 328, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 329. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 330. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 331. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 332, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 333. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 334. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 335. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 336. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 337. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 338. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 339. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 340, Another of embodiment of this invention is directed to a pharmaceutically WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 i5 acceptable ester of compound 341, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 342, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 343, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 344. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 345, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 346, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 347. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 348. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 349, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 350. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 351. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 352. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 353. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 354. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 355. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 356. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 357. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 358. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 359. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 360° Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 361, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 362, Another embodiment of this ìnvention is directed to a pharmaceutically acceptable ester of compound 363. WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 364. Another embodiment of this inventîon is directed to a pharmaceutically acceptable ester of compound 365. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 366. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 367. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 368, Another embodiment of this invention is directed to a.pharmaceuticalfy acceptable ester of compound 369 Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 370, Another of embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 371. Another embodiment of this nvention is directed to a pharmaceutically acceptable ester of compound 372. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 373, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 374. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 375. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 376. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 377, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 378. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 379. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 380. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 381. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 382. Another embodiment of this inventî.on is directed to a pharmaceutically acceptable ester of compound 383. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 384. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 385. Another embodiment of this invention is directed to a WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 pharmaceutically acceptable ester of compound 386, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 387. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 388, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 389, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 390. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 391, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 392, Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 393. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of compound 394. Another embodiment of this invention is directed to a solvate of compound Q11. Another embodiment of this invention is directed to a sûlvate of compound R4. Another embodiment of this invention is directed to a sûlvate of compound U2. Another embodiment of this invention is directed to a sûlvate of compound W3. Another embodiment of this invention is directed to a solvate of compound X2. Another embodiment of this invention is directed to a solvate of compound Y3. Another embodiment of this invention Another embodiment of this invention Another embodiment of this invention Another embodiment of this invention Another embodiment of this invention Another embodiment of this mvention Another embodiment of this invention Another embodiment of this invention Another embodiment of this invention Another embodiment of th s invention Another embodiment of this invention Another embodiment of this invention is directed to a is directed to a is directed to a is directed to a is directed to a is directed to a is directed to a is directed to a is directed to a is directed to a is directed to a ïs directed to a solvate of corn solvate of corn solvate of corn solvate of com sotvate of com solvate of coin found found found found found found solvate of compound sotvate of compound soivate of compound solvate of compound solvate of compound solvate of compound Z2. Aa2. Ab2. Ac6. Af3. Ag4. Ah2. Ai2. Ai4. Ak2 Al2. Am3, WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment of this of this of this of this of this of this of this of this of this of this of this of this of this of this of this of this of this of this of this of this of this of this of this of this of this of this of this of this of this of this invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to a solvate of compound Am4. a sotvate of compound Ao5. a solvate of compound Apt5. a soldate of compound Aq7. a solvate of compound Ar3. a sotvate of compound 20t. a solvate of compound 202. a solvate of compound 203. a solvate of compound 206. a solvate of compound 207. a soivate of compound 208. a solvate of compound 209. a solvate of compound 2t0. a solvate of compound 211. a solvate of compound 212. a sotvate of compound 213. a solvate of compound 214. a solvate of compound 215. a solvate of corn found 220. a solvate of corn found 221. a solvate of compound 222. a solvate of coin found 226. a solvate of corn found 227. a sotvate of corn found 229. a sotvate of com »oünd 23t. a sotvate of coin found 233. a solvate of coin »ound 245. a solvate of compound 246. a solvate of compound 247. a sotvate of compound 248. WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Another embodiment Another embodiment Another embodiment Another e mbod ment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment of this of this of this of this of this of this of this of this of this of this of this of this of this of this of this of this of this of this of this of this of this of this of this of this of this of this of this of this Another embodiment of this Another embodiment of this invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention is directed to a solvate is directed to a soJvate is directed to a solvate is directed to a solvate is directed to a solvate is directed to a solvate is directed to a sotvate is directed to a solvate is directed to a solvate is directed to a solvate is directed to a solvate is directed to a solvate is directed to a solvate is directed to a solvate is directed to a solvate is directed to a solvate is directed to a solvate is directed to a solvate is directed to a solvate is directed to a solvate is directed to a soJvate is directed to a solvate is directed to a solvate is directed to a solvate is directed to a so]vate is directed to a solvate is directed to a sofvate is directed to a solvate is directed to a sotvate is directed to a soívate of compound of compound of compound of compound of compound of compound of compound of compound of compound of compound of com found of com found of coin found of coin found of corn found of corn found of com found of com ound of compound of compound of compound of compound of corn found of com found of com round of coin found of com »ound of com found of compound of compound 249. 250. 251. 252. 253, 254, 255. 256. 257. 258. 259. 260. 261. 262. 263. 264, 265, 266. 267. 268. 269. 270. 271. 272. 273, 275. 276. 277. WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Another embodiment of this Another embodiment of this Another embodiment of this Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment of this of this of this of this of this of this of this of this of this of this of this of this of this of this of this of this of this of this of this of this of this of this of this of this of this of this of this invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention invention is directed te is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed te is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to a solvate of com found 279. a solvate of com found 280. a solvate of compound 281. a solvate of com »ound 282. a sotvate of com found 283, a solvate of com found 284, a soJvate of cern found 285. a solvate of com found 286. a soivate of corn found 287. a solvate of com found 288. a solvate of compound 289. a solvate of compound 290. a soivate of compound 29t, a solvate of compound 292. a solvate of compound 293, a solvate of compound 294. a solvate of compound 295. a solvate of compound 296. a soldate of compound 297. a solvate of compound 298, a soivate of com pound 299, a sol vate of corn found 300. a solvate of compound 301. a solvate of compound 302, a sotvate of coin found 303, a soldate of corn found 304. a sotvate of corn ound 305. a sotvate of com found 306, a sotvate of com found 307. a solvate of compound 308. WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment Another embodiment of this invention of this invention of this invention of this invention of this invention of this invention of this invention of this invention of this invention of this invention of this invention of this invention of this invention of this invention of this invention of this invention of this invention of this invention of this invention of this invention of this invention of this invention of thts invention of this invention of this Invention of this invention of this invention of this invention of this invention of this invention is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to is directed to ìs directed to is directed to is directed to is directed to a sonate of compound 309. a soivate of compound 310, a solvate of compound 311. a sonate of compound 312, a soivate of compound 313, a soivate of compound 314, a sotvate of compound 315. a soivate of compound 3t6. a soivate of compound 3i7, a soi vate of compound 3!8, a soivate of compound 319. a solvate of compound 320. a so vate of compound 321. a so vate of compound 322. a solvate of compound 323, a soivate of compound 324, a sotvate of compound 325, a sotvate of compound 326, a soivate of compound 327. a sotvate of compound 328. a sotvate of compound 329. a soJvate of compound 330. a soivate of compound 331, a solvate of compound 332, a sotvate of compound 333, a soivate of compound 334, a soivate of compound 335. a soivate of compound 336. a solvate of compound 337. a soJvate of compound 338, WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Another Another Another Another Another Another Another Another Another Another Another Another Another Another Another Another Another Another Another Another Another Another Another Another Another Another Another Another Another Another embodiment of embodiment of embodiment of embodiment of embodiment of embodiment of embodiment of embodiment of embodiment of embodiment of embodiment of embodiment of embodiment of embodiment of embodiment of embodiment of embodiment of embodiment of embodiment of embodiment of embodiment of embodiment of embodiment of embodiment of embodiment of embodiment of embodiment of embodiment of embodiment of embodîment of this invention is this invention is this invention is this invention is this invention is this invention is this invention is this invention is this invention is this invention is this invention is this invention is this invention is this invention is this invention is this invention is this invention is this invention is this invention is this invention is this invention is this invention is this invention is this invention is this invention is this invention is this invention is this invention is this invention is this invention is directed to directed to directed to directed to directed to directed to directed to directed to directed to directed to directed to directed to directed to directed to directed to directed to directed to directed to directed to directed to directed to directed to directed to directed to directed to directed to directed to directed to directed to directed to a soldate of compound 339. a sofvate of compound 340. a solvate of compound 341. a soldate of compound 342. a solvate of compound 343. a solvate of compound 344. a soivate of compound 345. a sofvate of compound 346. a solvate of compound 347. a solvate of coin a solvate of corn a solvate of com a sofvate of com a solvate of coin a solvate of coin a solvate of coin a soldate of corn a sofvate of coin a sofvate of coin a solvate of coin a soldate of corn a solvate of corn a soldate of coin a solvate of corn a sotvate of corn a sofvate of coin a solvate of com a solvate of com a soldate of com a soivate of com found 348. found 349. found 350. found 351, found 352. found 353, found 354. found 355. 3ound 356. found 357, found 358. found 359, found 360, found 361, found 362. found 363. found 364. 3ou.nd 365, found 366, found 367, found 368. WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Another Another Another Another Another Another Another Another Another Another Another Another Another Another Another Another Another Another Another Another Another Another Another Another Another embodiment of this embodiment of this embodiment of this embodiment of this embodiment of this embodiment of this embodiment of this embodiment of this embodiment of this embodiment of this embodiment of this embodiment of this embodiment of this embodiment of this embodiment of this embodiment of this embodiment of this embodiment of this embodiment of this embodiment of this embodiment of this embodiment of this embodiment of this embodiment of this embodiment of this invention is directed invention is directed invention is directed invention is directed invention is directed invention is directed invention is directed invention is directed invention is directed invention is directed invention is directed invention is directed invention is directed invention is directed invention is directed invention is directed invention is directed invention is directed invention is directed invention is directed invention is directed invention is directed invention is directed invention is directed invention is directed to to to to to to to to to to to to to to to to to to to to to to to to to a solvate of compound 369, a solvate of compound 370. a solvate of compound 371. a solvate of compound 372, a solvate of compound 373. a solvate of compound 374. a solvate of compound 375. a solvate of com found 376. a solvate of com found 377. a solvate of com found 378. a soldate of corn found 379. a solvate of corn found 380. a solvate of com found 381. a solvate of com found 382, a solvate of coin found 383. a solvate of com found 384, a solvate of coin found 385. a solvate of corn »ound 386. a solvate of corn found 387. a soldate of coin found 388. a sotvate of com found 389. a soJvate of coin found 390. a solvate of coin found 39! a solvate of compound 392, a solvate of compound 393. Another embodiment of this invention is directed to a sofvate of compound 394, in the embodiments below Groups A and B are as defined above, Another embodiment of this invention is directed to a compound selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Another embodiment of this invention is directed to a pharmaceutically acceptable sait of a compound selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B). Another embodiment of this invention is directed to a pharmaceutically acceptable ester of a compound selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B). Another embodiment of this invention is directed to a solvate of a compound selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B). Another embodiment of this invention is directed to a compound selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B) in pure and isolated form. Another embodiment of this invention is directed to a compound selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B) in pure form. Another embodiment of this invention is directed to a compound selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B) in isolated form. Another embodiment of this invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of at yeast one compound selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B) or a pharmaceutically acceptable sait, solvate, or ester thereof, and at least one pharmaceutically acceptable carrier. WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B) and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of a pharmaceutically acceptable salt of one or more (e.g., one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected t0 from the compounds of Group B) and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of a pharmaceutically acceptable ester of one or more (e.g., one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are t5 selected from the compounds of Group B) and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of a solvate of one or more (eg., one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B) and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B) and an effective amount of one or more (e.g., one) other pharmaceutically active ingredients (e.g., drugs), and a pharmaceutically acceptable carrier. Examples of the other pharmaceutically active ingredients include, but are not limited to drugs selected form the group consisting of: (a) drugs usefut for the treatment of Atzheimer's disease, (b) drugs usefut for WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 inhibiting the deposition of amytoid protein (e.g., amyloid beta protein) in, on or around neurological tissue (e.g., the brain), (c) drugs useful for treating neurodegenerative diseases, and (d) drugs useful for inhibiting gamma-secretase. Another embodiment of this invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of at least one compound selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), or a pharmaceutically acceptable sait, solvate, or ester thereof, and at least one pharmaceutically acceptable carrier, and a therapeutically effective amount of one or more compounds selected from the group consisting of cholinesterase inhibitors, AÇ antibody inhibitors, gamma secretase inhibitors and beta secretase inhibitors. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), and effective amount of one or more 8ACE inhibitors, and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), and effective amount of one or more cholinesterase inhibitors (e.g., acetyiand/or butyrylchlolinesterase inhibitors), and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Group B), and effective amount of one or more muscarinic antagonists (e.g., ml or m2 antagonists), and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), and effective amount of Exelon (rivastigmine), and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), and effective amount of Cognez (tacrine), and a pharmaceutically acceptable carrier, Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), and effective amount of a Tau kinase inhibitor, and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), and effective amount of one or more Tau kinase inhibitor (e.g., GSK3beta inhibitor, cdk5 inhibitor, ERK inhibiting and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds selected from the group consisting of the compounds of Group A (and WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 in another embodiment the compounds are selected from the compounds of Group B), and effective amount of one anti-Abeta vaccine (active immunization), and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), and effective amount of one or more APP ligands, and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), and effective amount of one or more agents that upregulate insulin degrading enzyme and/or neprilysin, and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), and effective amount of one or more cholesterol lowering agents (for example, statins such as Atorvastatin, Fluvastatin, Lovastatin, Mevastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin, and cholesterol absorption inhibitor such as Ezetimibe), and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), and effective amount of one or more fibrates (for example, ctofibrate, Clofibride, Etofibrate, Aluminium Clofibrate), and a pharmaceutically acceptable carrier WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), and effective amount of one or more LXR agonists, and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), and effective amount of one or more LRP mimics, and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), and effective amount of one or more 5-HT6 receptor antagonists, and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), and effective amount of one or more nicotinic receptor agonists, and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), and effective amount of one or more H3 receptor antagonists, and a pharmaceutically acceptable carrier. WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), and effective amount of one or more historie deacetylase inhibitors, and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), and effective amount of one or more hsp90 inhibitors, and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), and effective amount of one or more ml muscarinic receptor agonists, and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to combinations, i.e., a pharmaceutical composition, comprising a pharmaceutically acceptable carrier, an effective (i.e., therapeutically effective) amount of one or more compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), in combination with an effective (i.e., therapeutically effective) amount of one or more compounds selected from the group consisting of cholinesterase inhibitors (such as, for example, (+)-2,3 dihydro-5,6-dimethoxy-2-[[1-(phenyImethyl)-4piperidinyl]methyl]-I H -inden-l-one hydrochloride, i.e., donepezil hydrochloride, available as the Aricept® brand of donepezil hydrochtoride), AI3 antibody inhibitors, gamma secretase inhibitors and beta secretase inhibitors. WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), and effective amount of one or more 5-HT6 receptor antagonists mGluR1 or mGluR5 positive allosteric modulators or agonists, and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) t0 compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), and effective amount of one or more one mGluR2/3 antagonists, and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), and effective amount of one or more anti-inflammatory agents that can reduce neuroinflammation, and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), and effective amount of one or more Prostaglandin EP2 receptor antagonists, and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Group B), and effective amount of one or more PAI-t inhibitors, and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), and effective amount of one or more agents that can induce Abeta efflux such as gelsolin, and a pharmaceutically acceptable carrier. The compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B) can be useful as gamma secretase modulators and can be useful in the treatment and prevention of diseases such as, for example, central nervous system disorders (such as AIzheimers disease and Downs Syndrome), mild cognitive impairment, glaucoma, cerebral amyloid angiopathy, stroke, dementia, microgliosis, brain inflammation, and olfactory function loss. Another embodiment of this invention is directed to a method of treating a central nervous system disorder comprising administering a therapeutically effective amount of at least one compound selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B) to a patient in need of such treatment. Another embodiment of this invention is directed to a method of treating a central nervous system disorder comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of at least one compound selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), or a pharmaceutically acceptable salt, sotvate, or ester thereof, and at least one pharmaceutically acceptable carrier° Another embodiment of this invention is directed to a method of treating a central nervous system disorder comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 effective amount of at least one compound selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), or a pharmaceutically acceptable sait, soIvate, or ester thereof, and at least one pharmaceutically acceptable carrier, and a therapeutically effective amount of one or more compounds selected from the group consisting of cholinesterase inhibitors, Al3 antibody inhibitors, gamma secretase inhibitors and beta secretase inhibitors. Another embodiment of this invention is directed to a method for modulating (including inhibiting, antagonizing and the like) gamma-secretase comprising administering an effective amount of one or more (e.g., one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B) to a patient in need of such treatment. Another embodiment of this invention is directed to a method for modulating (including inhibiting, antagonizing and the like) gamma-secretase, comprising administering an effective amount of a compound selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B) to a patient in need of treatment Another embodiment of this invention is directed to a method of treating one or more neurodegenerative diseases, comprising administering an effective amount of one or more (e.g., one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B) to a patient in need of treatment. Another embodiment of this invention is directed to a method of treating one or more neurodegenerative diseases, comprising administering an effective amount of a compound selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B) to a patient in need of treatment. WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Another embodiment of this invention is directed to a method of inhibiting the deposition of amyloid protein (e.g., amyloid beta protein) in, on or around neurological tissue (e.g., the brain), comprising administering an effective amount of one or more (e.g., one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B) to a patient in need of treatment. Another embodiment of this invention is directed to a method of inhibiting the deposition of amyioid protein (e.g., amyloid beta protein) in, on or around neurological tissue (e.g., the brain), comprising administering an effective amount of a compound selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B) to a patient in need of treatment. Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more t5 (e.g., one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B) to a patient in need of treatment. Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of a compound selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B) to a patient in need of treatment. Another embodiment of this invention is directed to a method of treating mild cognitive impairment, glaucoma, cerebral amyloid angiopathy, stroke, dementia, microgliosis, brain inflammation, or olfactory function toss, comprising administering an effective (i.e., therapeutically effective) amount of one or more (e.g., one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B) to a patient in need of treatment. WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Another embodiment of this invention is directed to a method of treating mild cognitive impairment, glaucoma, cerebral amyloid angiopathy, stroke, dementia, microgliosis, brain inflammation, or olfactory function loss, comprising administering an effective (i.e., therapeutically effective) amount of a compound selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B) to a patient in need of treatment. Another embodiment of this invention is directed to a method of treating mild cognitive impairment, comprising administering an effective amount of one or t0 more (e.g., one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B) to a patient in need of treatment. Another embodiment of this invention is directed to a method of treating glaucoma, comprising administering an effective amount of one or more (e.g., one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B) to a patient in need of treatment. Another embodiment of this invention is directed to a method of treating cerebral amyloid angiopathy, comprising administering an effective amount of one or more (e.g., one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B) to a patient in need of treatment. Another embodiment of this invention is directed to a method of treating stroke, comprising administering an effective amount of one or more (e.g., one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B) to a patient in need of treatment. Another embodiment of this invention is directed to a method of treating dementia, comprising administering an effective amount of one or more (e.g., one) compounds selected from the group consisting of the compounds of Group A (and WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 in another embodiment the compounds are selected from the compounds of Group B) to a patient in need of treatment. Another embodiment of this invention is directed to a method of treating microgliosis, comprising administering an effective amount of one or more (e.g., one) compounds setected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B) to a patient in need of treatment. Another embodiment of this invention is directed to a method of treating brain inflammation, comprising administering an effective amount of one or more (e.g., one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B) to a patient in need of treatment. Another embodiment of this invention is directed to a method of treating olfactory function loss, comprising administering an effective amount of one or more (e.g., one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B) to a patient in need of treatment. Another embodiment of this invention is directed to a method of treating Downs syndrome, comprising administering an effective amount of one or more (e.g., one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B) to a patient in need of treatment. Another embodiment of this invention is directed to a method of treating Downs syndrome, comprising administering an effective amount of a compound selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B) to a patient in need of treatment. This invention also provides combination therapies for (1) modulating gamma-secretase, or (2) treating one or more neurodegenerative diseases, or (3) inhibiting the deposition of amytoid protein (e.g., amytoid beta protein) in, on or WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 5! around neurological tissue (e.g., the brain), or (4) treating Alzheimer's disease. The combination therapies are directed to methods comprising the administration of an effective amount of one or more (e.g. one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B) and the administration of an effective amount of one or more (e.g., one) other pharmaceutical active ingredients (e.g, drugs). The compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B) and the other drugs can be administered separately (i.e., each is in its own separate dosage form), or the compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B) can be combined with the other drugs in the same dosage form. Thus, other embodiments of this invention are directed to any one of the methods of treatment, or methods of inhibiting, described herein, wherein an effective amount of the compound selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B) is used in combination with an effective amount of one or more other pharmaceutically active ingredients (e.g., drugs). The other pharmaceutically active ingredients (i.e., drugs) are selected from the group consisting of: BACE inhibitors (beta secretase inhibitors), muscarinic antagonists (e.g., ml agonists or m2 antagonists), cholinesterase inhibitors (e g., acetylandlor butyrylchlolinesterase inhibitors); gamma secretase inhibitors; gamma secretase modulators; HMG-CoA reductase inhibitors; non-steroidal anti-inflammatory agents; N-methyl-D-aspartate receptor antagonists; anti-amyioid antibodies vitamin E; nicotinic acetylchotine receptor agonists; CB! receptor inverse agonists or CB1 receptor antagonists; an antibiotic; grov,4h hormone secretagogues; histamine H3 antagonists; AMPA agonists; PDE4 inhibitors; GABAA inverse agonists; inhibitors of amyloid aggregation; glycogen synthase kinase beta inhibitors; promoters of alpha secretase activity; PDE-10 inhibitors; Exelon WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 (rivastigmine); Cognex (tacrine); Tau kinase inhibitors (e.g., GSK3beta inhibitors, cdk5 inhibitors, or ERK inhibitors); anti-Abeta vaccine; APP Ligands; agents that upregulate insulin cholesterol lowering agents (for example, statins such as Atorvastatin, Fluvastatin, Lovastatin, Mevastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin); cholesterol absorption inhibitors (such as Ezetimibe); fibrates (such as, for example, for example, clofibrate, Clofibride, Etofibrate, and Aluminium Clofibrate); LXR agonists; LRP mimics; nicotinic receptor agonists; H3 receptor antagonists; historie deacetylase inhibitors; hspg0 inhibitors; mt muscarinic receptor agonists; 5-HT6 receptor antagonists; mGluR1; mGluR5; positive aliosteric modulators or agonists; mGluR2/3 antagonists; antiinflammatory agents that can reduce neuroinflammation; Prostaglandin EP2 receptor antagonists; PAt-1 inhibitors; and agents that can induce Abeta effiux such as gelsolin. Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more (e.g., one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), in combination with an effective (i.e, therapeutically effective) amount of one or more cholinesterase inhibitors (such as, for example, (+)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-pipeddinyl]methyl]- 1 Hinden-l-one hydrochloride, i.e., donepezil hydrochloñde, available as the Aricept® brand of donepezil hydrochloride), to a patient in need of treatment. Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of a compound selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group 8), in combination with an effective amount of one or more (e.g., one) cho inesterase inhibitors (such as, for example, (+)-2,3-dihydro-5,6-dimethoxy-2-[[1- (phenylmethyt)-4-piperidinyl]methyl]-I H-inden-t-one hydrochloride, i.e., WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 donepezil hydrochloride, available as the Aricept® brand of donepezil hydrochloride), to a patient in need of treatment. Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more (e.g., one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), in combination with an effective amount of one or more compounds selected from the group consisting of Ai3 antibody inhibitors, gamma secretase inhibitors and beta secretase inhibitors. Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more (e.g., one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), in combination with an effective amount of one or more BACE inhibitors. Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), in combination with an effective amount of Exelon (rivastigmine). Another embodiment of this invention is directed to a method of treating Atzheimer's disease, comprising administering an effective amount of one or more compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), in combination with an effective amount of Cognex (tacñne). Another embodiment of this invention is directed to a method of treating Afzheimer's disease, comprising administering an effective amount of one or more compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B)» in combination with an effective amount of a Tau kinase inhibitor. WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), in combination with an effective amount of one or more Tau kinase inhibitor (eg., GSK3beta inhibitor, cdk5 inhibitor, ERK inhibitor). This invention also provides a method of treating Alzheimer's disease, comprísing administering, an effective amount of one or more compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), in combination with an effective amount of one anti-Abeta vaccination (active immunization). Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), in combination with an effective amount of one or more APP ligands. Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), in combination with an effective amount of one or more agents that upregulate insulin degrading enzyme andtor neprilysin. Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), in combination with an effective amount of one or more cholesterol lowering agents (for example, stains such as Atorvastatin, Fluvastatin, Lovastatin, WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Mevastatin, P[tavastatin, Pravastatin, Rosuvastatin, Simvastatin, and cholesterol absorption inhibitor such as Ezetimibe). This invention also provides a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), in combination with an effective amount of one or more fibrates (for example, clofibrate, Ctofibride, Etofibrate, Aluminium Clofibrate). Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), in combination with an effective amount of one or more LXR agonists. Another embodiment of this invention is directed to a method of treating i5 Alzheimer's disease, comprising administering an effective amount of one or more compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), in combination with an effective amount of one or more LRP mimics. Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), in combination with an effective amount of one or more 5-HT6 receptor antagonists. Another embodiment of this invention is directed to a method of treating Aizheimer's disease, comprising administering an effective amount of one or more compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), in combination with an effective amount of one or more nicotinic receptor agonists. WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), in combination with an effective amount of one or more H3 receptor antagonists. This invention also provides a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds selected from the group consisting of the compounds of Group A (and in another t0 embodiment the compounds are selected from the compounds of Group B), in combination with an effective amount of one or more historie deacetytase inhibitors. Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), in combination with an effective amount of one or more hsp90 inhibitors. Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), in combination with an effective amount of one or more ml muscarinic receptor agonists. Another embodiment of this invention is directed to a method of treating Aî.zheimer's disease, comprising administering an effective amount of one or more compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), in combination with an effective amount of one or more 5-HT6 receptor antagonists mGiuRl or mGluR5 positive aitosteric modulators or agonists WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Another embodiment of this invention is directed to a method of treating AIzheimer's disease, comprising administering an effective amount of one or more compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), in combination with an effective amount of one or more mGluR2t3 antagonists. Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), in combination with an effective amount of one or more antiinflammatory agents that can reduce neuroinflammation. Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), in combination with an effective amount of one or more Prostaglandin EP2 receptor antagonists. Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), in combination with an effective amount of one or more PAl-1 inhibitors. Another embodiment of this invention is directed to a method of treating Alzheimer:s disease comprising administering an effective amount of one or more compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), in combination with an effective amount of one or more agents that can induce Abeta efftux such as gelsolin. WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Another embodiment of this invention is directed to a method of treating Downs syndrome, comprising administering an effective amount of one or more (e.g., one) compounds selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), in combination with an effective amount of one or more cholinesterase inhibitors (such as, for example, (+)-2,3-dihydro-5,6-dimethoxy-2- [[1-(phenylmethyl)-4-piperidinyl]methyl]-1 H-inden-l-one hydrochloride, i.e., donepezil hydrochloride, available as the Aricept® brand of donepezil hydrochloride), to a patient in need of treatment. Another embodiment of this invention is directed to a method of treating Downs syndrome, comprising administering an effective amount of a compound selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B), in combination with an effective amount of one or more (e.g., one) chotinesterase inhibitors (such as, for example, (+)-2,3-dihydro-5,6-dimethoxy-2-[[1- (phenylmethyl)-4-piperidinyl]methyl]-I H-inden-l-one hydrochloride, i.e., donepezil hydrochloride, available as the Aricept® brand of donepezil hydrochloride), to a patient in need of treatment. This invention also provides a kit comprising, in separate containers, in a single package, pharmaceutical compositions for use in combination, wherein one container comprises an effective amount of a compound selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B) in a pharmaceutically acceptable carrier, and another container (i.e., a second container) comprises an effective amount of another pharmaceutically active ingredient (as described above), the combined quantities of the compound selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B) and the other pharmaceutically active ingredient being effective to: (a) treat Alzheimer's disease, or (b) inhibit the deposition of amyloid protein (eg., amyloid beta protein) in, on or WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 around neurological tissue (e.g., the brain), or (c) treat neurodegenerative diseases, or (d) modulate the actívity of gamma-secretase, or (e) mild cognitive impairment, or (f) glaucoma, or (g) cerebral amytoid angiopathy, or (h) stroke, or (i) dementia, or Ò) microgliosis, or (k) brain inflammation, or (f) olfactory function loss. This invention also provides a kit comprising, in separate containers, in a single package, pharmaceutical compositions for use in combination, wherein one container comprises an effective amount of a compound selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B) in a pharmaceutically acceptable carrier, and another container (i.e., a second container) comprises an effective amount of another pharmaceutically active ingredient (as described above), the combined quantities of the compound selected from the group consisting of the compounds of Group A (and in another embodiment the compounds are selected from the compounds of Group B) and the other pharmaceutically active ingredient being effective to: (a) treat Alzheimer's disease, or (b) inhibit the deposition of amyloid protein (e.g., amytoid beta protein) in, on or around neurological tissue (e.g., the brain), or (c) treat neurodegenerative diseases, or (d) modulate the activity of gamma-secretase. As used herein, the following terms, unless otherwise indicated, shall be understood to have the following meanings: "ADDP" means 1, l'-(azodicarbonyl)dipiperidine. "DCM" means dichloromethane. "(DHQ)2PHAL" means WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 N "»N "DtAD" means di-isopropylazodicarboxytate "DtEA" means di-isopropylethylamine "DMF" means di.methylformamide. "EDCI" means N-ethyI-N'-dimethylaminopropyl carbodiimide "EtOAc" means ethyl acetate "TEA" means triethytamine "TFA" means trifluoroacetic acid "At least one" means one or more than one: for example, 1, 2 or 3, or inanother example, t or 2, or in another example t. "One or more" with reference to the use of the compounds of this invention means that one or more than one compound is used, for example, 1, 2 or 3, or in another example, 1 or 2, or in another example 1. "Patient" includes both human and animals. "Mammal" means humans and other mammalian animals. It is noted that the carbons of the compounds of Group A or B and other formulas herein may be replaced with 1 to 3 silicon atoms so I.ong as ait valency requirements are satisfied. "AikyV means an aliphatic hydrocarbon group which may be straight or branched and comprising about t to about 20 carbon atoms in the chain. Preferred alkyl groups contain about t to about 12 carbon atoms in the chain. More preferred alkyl groups contain about l to about 6 carbon atoms in the chain WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Branched means that one or more lower alkyl groups such as methyl, ethyl or propyt, are attached to a linear alkyl chain. "Lower alkyl" means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. "Alkyl" may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, cycioa]kyl, cyano, hydroxy, alkoxy, atkytthio, amino, oxime (e.g., =N-OH), -NH(alkyl), -NH(cyctoalkyl), -N(alkyl)2, -Or-C(O)-alkyl, -Or-C(O)-aryl, -Or-C(O)-cycloa]kyl, carboxy and -C(O)Oalkyl. Non-limiting examples of suitable alkyl groups include methyl, ethyl, npropyt, isopropyt and t-butyl. "Alkenyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred atkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. "Lower atkenyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. "Alkenyl" may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl. aryl, cycloalkyl, cyano, alkoxy and -S(alkyl). Non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, n-buteny], 3-methytbut-2-enyl, npentenyl, octenyl and decenyl. "Alkylene" means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above. Non-limiting examples of alkyfene include methylene, ethyîene and propylene. "Alkynyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and comprising about 2 to about !5 carbon atoms in the chain. Preferred afkynyl groups have about 2 to about t2 carbon atoms in the chain; and more preferably about 2 to WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyI, are attached to a linear alkynyt chain. "Lower aikynyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyt and 3-methylbutynyl. "Atkynyl" may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of a]ky], aryl and cycloalkyl. "Aryl" means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein. Nonlimiting examples of suitable aryl groups include phenyl and naphthyi. "Heteroaryl" means an aromatic monocyclic or mu]ticycfic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms. The "heteroaryl" can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryt can be optionally oxidized to the corresponding N-oxide. "Heteroaryr' may also include a heteroaryl as defined above fused to an aryl as defined above. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, füranyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazoiyf, isothiazotyl, oxazolyl, thiazoiyl, pyrazolyi, furazany!, pyrroryl, pyrazotyt triazolyl, t,2,4thiadiazolyl, pyrazinyI, pyridazinyL quinoxalinyl, phthalazinyl, oxindolyl, imidazo[t,2-a]pyridinyf, imidazo[2,l-b]thiazolyf, benzofurazanyl, indolyf, azaindolyl, Denzimidazo{yl, benzothienyi, quinoinyl, imidazolyl, thienopyridyi, quinazolinyl, WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 thienopyrimidyl, pyrrotopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like. The term "heteroaryl" also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinotyl, tetrahydroquinolyl and the like. "Aralkyl" or "arylalkyl" means an aryl-alkylgroup in which the aryl and alkyl are as previously described. Preferred araIkyls comprise a lower alkyl group. Nonlimiting examples of suitable aratkyl groups include benzyt, 2-phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl "Alkylaryl" means an alkyl-arylgroup in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. Nonlimiting example of a suitable alkylaryl group is toll. The bond to the parent moiety is through the aryl. "Cycloalkyl" means a non-aromatic monoor multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. The cycloalkyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above. Nonlimiting examples of suitable monocyclic cycloalkyrs include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl, adamantly and the like. "Cycloalkylalkyl" means a cycloa kyl moiety as defined above linked via an alkyi moiety (defined above) to a parent core. Non-limiting examples of suitable cycloalkylalkyls include cyclohexylmethyl, adamantylmethyl and the like. "Cycloalkenyl" means a non-aromatic mono or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about carbon atoms which contains at least one carbon-carbon double bond. Preferred cycloatkenyi rings contain about 5 to about 7 ring atoms. The cycloalkenyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above+ Non-limiting examples of suitable monocyclic cycloalkenyis ínctude cyc openteny cycLohexenyl, cyclohepta-t 3WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 dienyl, and the like. Nonqimiting example of a suitable multicyciic cycloalkenyi is norborny enyi. "Cycloalkenyla]kyl" means a cycloaikenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable cycloalkenyJalkyls include cyclopentenylmethyl, cydohexenylmethyl and the like. "Halogen" means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine and bromine. "Halo" refers to fluoro, chloro, bromo or iodo. "Ring system substituent" means a substituent attached to an aromatic or t0 non-aromatic ring system which, for example, replaces an available hydrogen on the ring system. Ring system substituents may be the same or different, each being independently selected from the group consisting of atkyl, alkenyl, alkynyt, aryl, heteroaryl, aralkyl, alkylaryt, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, atkylsulfonyl, arytsuifonyt, heteroarytsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclyl,-O-C(O)- alkyl, -O-C(O)-aryl, *O-C(O)-cycloalkyl, -C(=N-CN)-NH2 , -C(=NH)-NH2 , -C(=NH)- NH(alkyl), oxime (eg., =N-OH), Y1 Y2 N-, Y1 Y2 N-alkyl-, Y1 Y2 NC(O)-, Y1 Y2 NSO2 - and -SO2 NY1 Y2 , wherein Y1 and Y2 can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycioatkyl, and aralkyl.. "Ring system substituent" may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system. Examples of such moiety are methylene dioxy, ethytenedioxy, -C(CH3 )2 - and the Iike which form moieties such as, for example: and WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 "Heteroarylatkyl" means a heteroaryl moiety as defined above linked via an a JkyJ moiety (defined above) to a parent core. Non-limiting examples of suitable heteroaryls include 2-pyridinytmethyl, quinolinylmethyl and the like. "Heterocyclyl" means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. Any-NH in a heterocyclyl ring may exist protected such as, for example, as an -N(Boc), - N(CBz), -N(Tos) group and the like; such protections are also considered part of this invention. The heterocyclyi can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The nitrogen or sulfur atom of the heterocyclyt can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include p[peridyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like. "Heterocyclyl" may also mean a heterocycly] ring wherein a single moiety (e.g =O) simultaneously replaces two available hydrogens on the same carbon atom on a ring system. An example of such moiety is pyrro]idone: H /N O • WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 "Heterocyclylalkyl" means a heterocyclyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable heterocyciylalkyls include piperidinylmethyl, piperazinylmethyl and the like. "Heterocyctenyr' means a non-aromatic mon ocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur atom, alone or in combination, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclenyt root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclenyl can be optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined above. The nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable h eterocyclenyl groups inctude 1,2,3,4tetrahydropyridinyl, t ,2-dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 1,4,5,6-tetrahydropyrimidinyl, 2pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazoliny dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazoly!, 3,4-dihydro-2H-pyranyl, dihydrofuranyl, fluorodihydrofuranyl, 7-oxabicycto[2.2.1]heptenyl, dihydrothiophenyl, dihydrothiopyranyl, and the like. "Heterocyclenyl" may atso mean a single moiety (e.g., carbonyl) which simultaneously replaces two available hydrogens on the same carbon atom on a ring system. Example of such moiety is pyrrotidinone: H o WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 "Heterocyclenylalkyl" means a heterocyclenyl moiety as defined above linked via an afkyl moiety (defined above) to a parent core. It should be noted that in hetero-atom containing ring systems of this invention, there are no hydroxyl groups on carbon atoms adjacent to a N, O or S, as well as there are no N or S groups on carbon adjacent to another heteroatom. Thus, for example, in the ring: N H there is no -OH attached directly to carbons marked 2 and It should also be noted that tautomeric forms such as, for example, the moieties: and are considered equivalent in certain embodiments of this invention. "Alkynytalkyl" means an alkynyl-alkylgroup in which the alkynyl and alkyl are as previously described. Preferred alkynylalkyls contain a lower alkynyl and a lower alkyl group. The bond to the parent moiety is through the alkyl. Non-limiting examples of suitable aJkynylalkyl groups include propargytmethyl. "Heteroaralkyl" means a heteroaryt-alkylgroup in which the heteroaryl and alkyf are as previously described. Preferred heteroaralkyts contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, and quinol[n-3-ylmethyl. The bond to the parent moiety is through the alkyl. "Hydroxyaiky " means a HO-alkylgroup in which aikyt is as previously defined. Preferred hydroxyalkyls contain iower alkyí. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl. "Acyl" means an H-C(O)-, atkyt-C(O)- or cycloalkyl-C(O)-, group in which the various groups are as previously described. The bond to the parent moiety is WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 through the carbonyle. Preferred acyls contain a lower alkyt. Non-limiting examples of suitable acyl groups include formyl, acetyt and propanoyi. "AroyE" means an aryl-C(O)- group in which the aryl group is as previously described. The bond to the parent moiety is through the carbonyl. Non-limiting examples of suitable groups include benzol and 1naphthoyl. "Alkoxy" means an alkyI-Ogroup in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond to the parent moiety is through the ether oxygen. I0 "Aryloxy" means an aryt-Ogroup in which the aryl group is as previously described. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The bond to the parent moiety is through the ether oxygen. "Aralkytoxy" means an aralkyI-Qgroup in which the aralkyt group is as previously described. Non-limiting examples of suitable aralkyloxy groups include benzyloxy and 1or 2-naphthalenemethoxy. The bond to the parent moiety is through the ether oxygen. "Atkylthio" means an alkyl-Sgroup in which the atkyl group is as previously described. Non-limiting examples of suitable alkylthio groups include methylthio and ethylthio. The bond to the parent moiety is through the sulfur. "Arytthio" means an aryl-Sgroup in which the aryl group is as previously described. Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. The bond to the parent moiety is through the sulfur. "Aralkylthio" means an aralkyt-Sgroup in which the aralkyt group is as previously described. Non-limiting example of a suitable aralkylthio group is benzylthio. The bond to the parent moiety is through the sulfur. "Aikoxycarbonyi" means an alkyl-O-COgroup+ Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl The bond to the parent moiety is through the carbonyle. WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 "Aryloxycarbonyl" means an a ryl-O-C(O)- group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyt and naphthoxycarbonyl. The bond to the parent moiety is through the carbonyle. "Aratkoxycarbonyl" means an aralkyI-O-C(O)- group. Ñonqimiting example of a suitable aratkoxycarbonyl group is benzyloxycarbonyl. The bond to the parent moiety is through the carbonyle. "Alkylsulfonyr' means an alkyI-S(O2 )- group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl. "Arylsulfonyl" means an aryl-S(O2 )- group. The bond to the parent moiety is through the sulfonyl. The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties. The term "purified", "in purified form" or "in isolated and purified form" for a compound refers to the physical state of said compound after being isolated from a synthetic process (e.g. from a reaction mixture), or natural source or combination thereof. Thus, the term "purified", "in purified form" or "in isolated and purified form" for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystallization and the like), in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan. WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and Tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences. When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as welt as by reference to standard textbooks such as, for example, T. W. Greene et af, Protective Groups in organic Synthesis (1991), Wiley, New York. When any variable (e.g., aryl, heterocycle, R2, etc.) occurs more than one time in any constituent (or in a compound of Group A or B), its definition on each occurrence is independent of its definition at every other occurrence. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Prodrugs and soldates of the compounds of the invention are also contemplated herein. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press. The term "prodrug" means a compound (e.g., a drug precursor) that is transformed in vivo to yield a compound of Formula (I) or a pharmaceutically acceptable sait, hydrate or solvate of the compound. The transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for exampte, through hydrolysis in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. I4 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Edward B. Roche, American Pharmaceutical Association and Pergamon Press, I987. For example, if a compound of Group A or B or a pharmaceutically acceptable salt, hydrate or sotvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (C1 - Cs)alkyl, (C2 -C 2 )atkanoyloxymethyl, 1-(atkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-l-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonytoxymethyl having from 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy)ethyt having from 4 to 7 carbon atoms, 1-methyl-1- (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N- (atkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(C1 -C2 )alkylamino(C2 -C3 )atkyl (such as 13-dimethylaminoethyl), carbamoyl-(C1 -C2 )alkyl, N,N-di (CIC2)alkytcarbamoyl-(C1-C2)alkyl and piperidino-, pyrrolidinoor morpholino(C2 - C3)alkyl, and the like. Similarly, if a compound of Group A or B contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (C -C6 )alkanoyloxymethyl, 1- ((CvC6)alkanoyloxy)ethyl, 1-methyl-l-((CvC6 )alkanoyloxy)ethyl, (C1 - C6)alkoxycarbonyloxymethyl, N-(C -C6 )alkoxycarbonylaminomethyl, succinoyl, (C1-C6)alkanoyl, «-amino(C -C4 )alkanyl, arylacyt and -aminoacyl, or -aminoacyl- -aminoacyl, where each ct-aminoacy! group is independently selected from the naturally occurring L-amino acids, P(O)(OH)2 , -P(O)(O(C -C6 )alkyl)2 or gtycosyt (the radical resulting from the removal of a hydroxyl group of the hemiaceta! form of a carbohydrate), and the tike. If a compound of Group A or B incorporates an amine functional group, a prod.rug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyf, NRR'-carbonyl WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 where R and R' are each independently (C -C o)alkyl, (C3 -C7 ) cycloalkyl, benzyl, or R-carbonyl is a natural ù-aminoacyl or natural c -aminoacyl, --C(OH)C(O)OY wherein y1 is H, (C -Ce)alkyl or benzyl, --C(OY2)Y3 wherein y2 is (CvC4 ) alkyt and yS is (C -C6 )alkyl, carboxy (C1 -C6 )alkyl, amincie-C«)alkyl or mono-N---or diN,N-(C -Ce)alkylaminoalkyt, --C(y4)y5 wherein y4 is H or methyl and y5 is monoN-- or di-N,N-(C -C6 )alkylamino morpholino, piperidiml-yl or pyrrolidin-l-yl, and the like. One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, t0 ethanol, and the Iíke, and it is intended that the invention embrace both solvated and unsolvated forms. "Solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanotates, and the like. "Hydrate" is a solvate wherein the solvent molecule is H20. One or more compounds of the invention may optionally be converted to a solvate. Preparation of solvates is generally known. Thus, for example, M. Caira et al, J. Pharmaceutical ScL, 93(3), 601-611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et af, AAPS PharmSciTech., 5(1), article 12 (2004); and A. L. Bingham et al, Chem. Commun. 603-604 (2001). A typical, non*limiting, process involves dissoMng the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example i. WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate). "Effective amount" or "therapeutically effective amount" is meant to describe an amount of compound or a composition of the present invention effective in inhibiting the above-noted diseases and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect. The compounds of Group A or B can form salts which are also within the scope of this invention. Reference to a compound of Group A or 8 herein is understood to include reference to salts thereof, unless otherwise indicated. The t0 term "sait(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as welt as basic salts formed with inorganic and/or organic bases. In addition, when a compound of Group A or B contains both a basic moiety, such as, but not limited to a pyñdJne or Jmidazoie, and an acidic moiety, such as, but not limited to a carboxylic acid, zwittedons ("inner salts") may be formed and are included within the term "sait(s)" as used herein Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the compounds of Group A or B may be formed, for example, by reacting a compound of Group A or B with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the sait precipitates or in an aqueous medium followed by lyophilization. Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsutfonates, fumarates, hydrochloride, hydrobromides, hydroiodides, lactates, mareates, methanesutfonates, naphthatenesulfonates, nitrates, oxalates, phosphates, propionates, calculates süccinate& sulfates tartarates thiocyanates, toluenesutfonates (also known as tosylates,) and the Iike. Additionally,. acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salt& Properties, Selection and Use. (2002)Zurich: Wiley-VCH; WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 S. Berge et al, Journal of Pharmaceutical Sciences (1977) 1-19; P. Gould, lntemationat J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry" (1996), Academic Press, New York; and in The Orange Bûok (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto. Exemplary basic salts ínclude ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as t0 arginine, lysine and the like. Basic nitrogen-containing groups may be quartemized with agents such as lower atkyt halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyi, diethyl, and dibuty! sulfates), long chain halides (e.g. decyJ, lauryl, and stearyl chlorides, bromides and iodides), aratkyt halides (e.g. benzyl and phenethyl bromides), and other& Ail such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and ail acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention. Pharmaceutically acceptable esters of the present compounds include the following groups: (1) carboxy]ic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n-propyt, t-bu.tyr, or n-butyl), alkoxyalkyt (for example, methoxymethyl), aratkyi (for example, benzyi), arytoxyalkyl (for example, phenoxymethyI), aryl (for example: phenyi optionally substituted with, for example, haíogen, C 4 aikyI, or C + «alkoxy or amino); (2) sui.fonate esters, such as aikylor aralkylsulfo.nyl (for example, methanesuIfonyl); (3) amino acid esters (for example, L-valyl or Lisoteucyl); (4) phosphonate esters and (5) mono-, dior triphosphate esters. The WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 phosphate esters may be further esterified by, for example, a 01 -20 alcohol or reactive derivative thereof, or by a 2,3-di (Ce-24 )acyt glycerol. Compounds of Group A or B, and salts, solvates, esters and prodrugs thereof, may exist in their tautomeric form (for example, as an amide, enoi, keto or imino ether). Ail such taütomeric forms are contemplated herein as part of the present invention. The compounds Group A or B may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that ail stereoisomeric forms of the compounds Group A or B as wel! as mixtures thereo:r, t0 including racemic mixtures, form part of the present invention. In addition, the present invention embraces ail geometric and positional isomers. For example, if a compound Group A or B incorporates a double bond or a fused ring, both the cisand trans-forms, as well as mixtures, are embraced within the scope of the invention. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography andtor fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds Group A or B may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can aîso be separated by use of chiral HPLC column. It is also possible that the compounds Group A oç B may exist in different tautomeric forms, and ai! such forms are embraced within the scope of the invention. Also, for example, all keto-enol and amine-enamine forms of the compounds are included in the invention. WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Ail stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example, if a compound of Group A or B incorporates a double bond or a fused ring, both the cisand transforms, as well as mixtures, are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.) individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with al! other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms "sait", "solvate", "ester", "prodrug" and the like, is intended to equally apply to the sait, sotvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds. The present invention also embraces isotopically-labetled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon nitrogen, oxygen, phosphorus, fluorine and chlorine and iodine, such as 2H, sri, 11C SC, ;4C, 15N, SO, 170, S p, S2p, S S SF, 3601 and 123I, respectively. Certain isotopically-labelled compounds of the invention (e.g., those labeled with 3H and 14C) are useful in compound andlor substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon-14 (i.e, 4C) isotopes are WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 particularly preferred for their ease of preparation and detectability. Certain isotopicatlyqabelled compounds of the invention can be useful for medical imaging purposes. E.g., those labeled with positron-emitting isotopes like 11C or I F can be useful for application in Positron Emission Tomography (PET) and those labeled with gamma ray emitting isotopes like 1231 can be useful for application in Single photon emission computed tomography (SPECT). Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo halflife or reduced dosage requirements) and hence may be preferred in some circumstances. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Additionally, isotopic substitution at a site where epimerization occurs may slow or reduce the epimerization process and thereby retain the more active or efficacious form of the compound for a longer period of time. lsotopically labeled compounds of the invention, in particular those containing isotopes with longer half lives (T1/2 >1 day), can generafly be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an appropriate isotopically labeled reagent for a non-isotopica[ly labeled reagent. Polymorphic forms of the compounds of Group A or B, and of the salts, solvates, esters and prodrugs of the compounds of Group A or B, are intended to be included in the present invention. The compounds according to the invention can have pharmacological properties; in particular the compounds of Group A or B can be modulators of gamma secretase (including inhibitors, antagonists and the like). More specifically, the compounds of Group A or B can be useful in the treatment of a variety of disorders of the central nervous system including, for example, including, but not limited to, Alzheimer's disease, AIDS-related WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 dementia, Parkinsons disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration and the like. Another aspect of this invention is a method of treating a mammal (e.g., human) having a disease or condition of the central nervous system by administering a therapeutically effective amount of at least one compound of Group A or B, or a pharmaceutically acceptable sait, soldate, ester or prodrug of said compound to the mamma!. A preferred dosage is about 0.001 to 500 mglkg of body weight/day of the compound of Group A or B. An especially preferred dosage is about 0.01 to mg!kg of body weight/day of a compound of Group A or B, or a pharmaceutically acceptable sait or solvate of said compound. The compounds of this invention may also be useful in combination (administered together or sequentially) with one or more additional agents listed above. The compounds of this invention may also be useful in combination (administered together or sequentially) with one or more compounds selected from the group consisting of Al antibody inhibitors, gamma secretase inhibitors and beta secretase inhibitors. If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active agent or treatment within its dosage range. Accordingly, in an aspect, this invention includes combinations comprising an amount of at least one compound of Group A or B, or a pharmaceutically acceptable sait, solvate, ester or prodrug thereof, and an amount of one or more additional agents listed above wherein the amounts of the compounds/treatments çesult in desired therapeutic effect. The pharmacological properties of the compounds of this invention may be confirmed by a number of pharmacological assays. Certain assays are exemplified later in this document. WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 !5 This invention is also directed to pharmaceutical compositions which comprise at least one compound of Group A or B, or a pharmaceutically acceptable sait solvate, ester or prodrug of said compound and at least one pharmaceutically acceptable carrier, Another embodiment of this invention is directed to a pharmaceutically acceptable sait of a compound of Group A or B. Another embodiment of this invention is directed to a pharmaceutically acceptable ester of a compound of Group A or B, Another embodiment of this invention is directed to a solvate of a compound of Group A or B. Another embodiment of this invention is directed to a compound of Group A or B in isolated form. Another embodment of this invention is directed to a compound of Group A or B in pure form. Another embodiment of this invention is directed to a compound of Group A or B in pure and isolated form. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of Group A or B and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of a pharmaceutically acceptable salt of one or more (e.g., one) compounds of Group A or B and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of a pharmaceutically acceptable ester of one or more (e.g., one) compounds of Group A or B and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of a solvate of one or more (e.g., one) compounds of Group A or B and a pharmaceutically acceptable carrier. WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of Group A or B, and an effective amount of one oç more (e.g., one) other pharmaceutically active ingredients (e.g.,) drugs, and a pharmaceutically acceptable carrier. Examples of the other pharmaceutically active ingredients include, but are not limited to drugs selected form the group consisting of: (a) drugs useful for the treatment of Alzheimer's disease, (b) drugs useful for inhibiting the deposition of amyloid protein (e.g., amytoid beta protein) in, on or around neurological tissue (e.g., the brain), (c) drugs useful for treating neurodegenerative diseases, and (d) drugs useful for inhibiting gamma-secretase. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of Group A or B, and effective amount of one or more BACE inhibitors, and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of Group A or B, and effective amount of one or more cholinesterase inhibitors (e.g., acetytandlor butyrylchlolinesterase inhibitors), and a pharmaceutically acceptable carrier. The compounds of Group A or B can be useful as gamma secretase modu ators and can be useful in the treatment and prevention of diseases such as, for examples central nervous system disorders such as Alzheimers disease and Downs Syndrome. Thus, another embodiment of this invention is directed to a method for modulating (including inhibiting, antagonizing and the fike) gamma-secretase comprising administering an effective amount of one or more (e.g., one) compounds of Group A or B to a patient in need of such treatment. Another embodiment of this invention is directed to a method for modulating (including inhibiting, antagonizing and the like) gamma-secretase, WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 comprising administering an effective amount of a compound of Group A or B to a patient in need of treatment. Another embodiment of this invention is directed to a method of treating one or more neurodegenerative diseases, comprising administering an effective amount of one or more (e.g., one) compounds of Group A or B to a patient in need of treatment. Another embodiment of this invention is directed to a method of treating one or more neurodegenerative diseases, comprising administering an effective amount of a compound of Group A or B to a patient in need of treatment. 1.0 Another embodiment of this invention is directed to a method of inhibiting the deposition of amy!oid protein (e.g., amyloid beta protein) in, on or around neurological tissue (e.g., the. brain), comprising administering an effective amount of one or more (e.g., one) compounds of Group A or B to a patient in need of treatment. Another embodiment of this invention is directed to a method of inhibiting the deposition of amyioid protein (e.g., amy!oid beta protein)in, on or around neurological tissue (e.g., the brain), comprising administering an effective amount of a compound of Group A or 8 to a patient in need of treatment. Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more (e.g., one) compounds of Group A or B to a patient in need of treatment. Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of a compound of Group A or B to a patient in need of treatment. This invention also provides combination therapies for (I) moduiatJng g:amma-secretase, or (2) treating one or more neurodegenerative diseases, or (3) inhibiting the deposition of amyloid protein (e.g.» amyloid beta protein) in, on or around neurological tissue (e.g., the brain), or (4) treating Alzheimer's disease. The combination therapies are directed to methods comprising the administration of an effective amount of one or more (e.g. one) compounds of Group A or B and WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 the administration of an effective amount of one or more (e.g., one) other pharmaceutical active ingredients (e.g., drugs). The compounds of Group A or B and the other drugs can be administered separately (i.e., each is in its own separate dosage form), or the compounds of Group A or B 1 can be combined with the other drugs in the same dosage form. Thus, other embodiments of this invention are directed to any one of the methods of treatment, or methods of inhibiting, described herein, wherein an effective amount of the compound of Group A or B is used in combination with an effective amount of one or more other pharmaceutically active ingredients selected from the group consisting of: BACE inhibitors (beta secretase inhibitors), muscarinic antagonists (e.g., ml agonists or m2 antagonists), cholinesterase inhibitors (e.g., acetyland/or butyrylchlolinesterase inhibitors); gamma secretase inhibitors; gamma secretase modulators; HMG-CoA reductase inhibitors; nonsteroidal anti-inflammatory agents; N-methyl-D-aspartate receptor antagonists; anti-amytoid antibodies; vitamin E; nicotinic acetylchotine receptor agonists; CB1 receptor inverse agonists or CB1 receptor antagonists; an antibiotic; growth hormone secretagogues; histamine H3 antagonists; AMPA agonists; PDE4 inhibitors; GABAA inverse agonists; inhibitors of amyloid aggregation; glycogen synthase kinase beta inhibitors; promoters of alpha secretase activity; PDE-10 inhibitors and cholesterol absorption inhibitors (e.g., ezetimibe). Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more (e.g., one) compounds of Group A or B, in combination with an effective (i.e., therapeutica!ly effective) amount of one or more cholinesterase inhibitors (such as, for example, (+)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyt)-4piperidinyi]methyf]-I H -indent-one hydrochloride, i.e.» donepezii hydrochloride available as the Aricept® brand of donepezil hydrochloride), to a patient in need of treatment. Another embodiment of this invention is directed to a method of treating AtzheimeCs disease, comprising administering an effective amount of a compound WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 of Group A or B, in combination with an effective amount of one or more (e.g., one) cholinesterase iñhibitors (such as, for example, (±)-2,3-dihydro-5,6dimethoxy-2-[[1-(phenylmethyl)-4-pipeñdinyl]methyl]- t H-inden-l-one hydrochloride, i,e., donepezil hydrochloride, available as the AricepL® brand of donepezil hydrochloride), to a patient in need of treatment. Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more (eg,, one) compounds of Group A or B, in combination with an effective amount of one or more compounds selected from the group consisting of Al3 antibody inhibitors, gamma secretase inhibitors and beta secretase inhibitors. Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more (e.g., one) compounds of Group A or B, in combination with an effective amount of one or more BACE inhibitors. Another embodiment of this invention is directed to a method of treating Alzheimer°s disease, comprising administering an effective amount of one or more compounds of Group A or B, in combination with an effective amount of Exelon (rivastigmine). Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Group A or B, in combination with an effective amount of Cognex (taurine). Another embodiment of this invention is directed to a method of treating Aizheimer's disease, comprising administering an effective amount of one or more compounds of Group A or B, in combination with an effective amount of a Tau kinase inhibitor. Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Group A or B, in combination with an effective amount of one or more Tau kinase inhibitor (e.g., GSK3beta inhibitors cdk5 inhibitor, ERK inhibitor)+ WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 This invention also provides a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Group A or B, in combination with an effective amount of one anti-Abeta vaccination (active immunization). Another embodiment of this invention is directed to a method of treating Atzhei.mer's disease, comprising administering an effective amount of one or more compounds of Group A or B, in combination with an effective amount of one or more APP ligands. Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Group A or B, in combination with an effective amount of one or more agents that upregulate insulin degrading enzyme and/or neprilysin. Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Group A or B, in combination with an effective amount of one or more cholesterol lowering agents (for example, statins such as Atorvastatin, Fluvastatin, Lovastatin, Mevastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin, and cholesterol absorption inhibitor such as Ezetimibe). This invention atso provides a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Group A or B, in combination with an effective amount of one or more fibrates (for example, clofibrate, Clofibride, Etofibrate, Aluminium Ctofibrate)ç Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Group A or B, in combination with an effective amount of one or more LXR agonists. Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Group A or B, in combination with an effective amount of one or more LRP mimics. WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Another embodiment of this invention is directed to a method of treating AJzheimer's disease, comprising administering an effective amount of one or more compounds of Group A or B, in combination with an effective amount of one or more 5-HT6 receptor antagonists. Another embodiment of this invention is directed to a method of treating Aizheimer's disease, comprising administering an effective amount of one or more compounds of Group A or B, in combination with an effective amount of one or more nicotinic receptor agonists. Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Group A or B, in combination with an effective amount of one or more H3 receptor antagonists. This invention also provides a method of treating Atzheimer's disease, comprising administering an effective amount of one or more compounds of Group A or B, in combination with an effective amount of one or more histone deacetylase inhibitors. Another embodiment of this invention is directed to a method of treating Atzheimer's disease, comprising administering an effective amount of one or more compounds of Group A or B, in combination with an effective amount of one or more hsp90 inhibitors. Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Group A or B, in combination with an effective amount of one or more rot muscarinic receptor agonists. Another embodiment of this invention is directed to a method of treating Aizheimer's disease, comprising administering an effective amount of one or more compounds of Group A or B, in combination with an effective amount of one or more 5-HT6 receptor antagonists mGluR! or mGiuR5 positive al!osteric modulators or agonists WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Another embodiment of this invention is directed to a method of treating Atzheimer's disease, comprising administering an effective amount of one or more compounds of Group A or B, in combination with an effective amount of one or more mGtuR2/3 antagonists. Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Group A or B, in combination with an effective amount of one or more anti-inflammatory agents that can reduce neuroinflammation. Another embodiment of this invention is directed to a method of treating Atzheimer's disease, comprising administering an effective amount of one or more compounds of Group A or B, in combination with an effective amount of one or more Prostaglandin EP2 receptor antagonists. This invention also provides a method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of I5 Group A or B, in combination with an effective amount of one or more PAl-1 inhibitors. This comprising Group A or can induce This invention also provides a method of treating Alzheimer's disease, administering an effective amount of one or more compounds of B, in combination with an effective amount of one or more agents that Abeta efflux such as gelsotin. invention also provides a method of treating Downs syndrome, comprising administering an effective amount of one or more (e.g., one) compounds of Group A or B to a patient in need of treatment. This invention also provides a method of treating Downs syndrome, comprising administering an effective amount of a compound of Group A or B to a patient in need of treatment. This invention also provides a method of treating Downs syndrome, comprising administering an effective amount of one or more (e.g., one) compounds of Group A or B, in combination with an effective amount of one or more choíinesterase i nhibitors (such as, for example, (+)-2,3-dihydro-5,6WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 dimethoxy-2-[[1-(phenylmethyt)-4-piperidinyt]methyl]-I H-inden-t-one hydrochtoride, i.e., donepezif hydrochloride, available as the Aricept® brand of donepezil hydrochloride), to a patient in need of treatment. This invention also provides a method of treating Downs syndrome, comprising administering an effective amount of a compound of Group A or B, in combination with an effective amount of one or more (e.g., one) cholinesterase inhibitors (such as, for example, (+)-2,3-dihydro-5,6-dimethoxy-2-[[1- (phenylmethyt)-4-piperidinyl]methyl]-I H-inden-l-one hydrochloride, i.e., donepezil hydrochtoride, available as the Aricept® brand of donepezit hydrochtoride), to a patient in need of treatment. This invention also provides a method of treating mild cognitive impairment, comprising administering an effective amount of one or more (e.g., one) compounds of Group A or B to a patient in need of treatment. This invention also provides a method of treating glaucoma, comprising administering an effective amount of one or more (e.g., one) compounds of Group A or B to a patient in need of treatment. This invention also provides a method of treating cerebral amyloid angiopathy, comprising administering an effective amount of one or more (e.g., one) compounds of Group A or B to a patient in need of treatment. This invention also provides a method of treating stroke, comprising administering an effective amount of one or more (e.g., one) compounds of Group A or B to a patient in need of treatment. This invention also provides a method of treating dementia, comprising administering an effective amount of one or more (e.g., one) compounds of Group A or B to a patient in need of treatment. This invention also provides a method of treating microgliosis, comprising administering an effective amount of one or more (e.g, one) compounds of Group A or B to a patient in need of treatment. WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 This invention also provides a method of treating brain inflammation, comprising administering an effective amount of one or more (e.g., one) compounds of Group A or B to a patient in need of treatment. This invention also provides a method of treating olfactory function loss, comprising administering an effective amount of one or more (e.g., one) compounds of Group A or B to a patient in need of treatment. This invention also provides combinations (i.e., pharmaceutical compositions) comprising an effective amount of one or more (e.g., one) compounds of Group A or B, in combination with an effective amount of one or more compounds selected from the group consisting of cholinesterase inhibitors (such as, for example, (+)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4piperidinyl]methyl]-I H-inden-l-one hydrochloride, i.e., donepezil hydrochloride, available as the Aricept® brand of donepezil hydrochloride), Ap antibody inhibitors, gamma secretase inhibitors and beta secretase inhibitors. The pharmaceutical compositions also comprise a pharmaceutically acceptable carrier. This invention also provides a kit comprising, in separate containers, in a single package, pharmaceutical compositions for use in combination, wherein one container comprises an effective amount of a compound of Group A or B in a pharmaceutically acceptable carrier, and another container (i.e., a second container) comprises an effective amount of another pharmaceutically active ingredient (as described above), the combined quantities of the compound of Group A or B and the other pharmaceutically active ingredient being effective to: (a) treat Alzheimer's disease, or (b) inhibit the deposition of amyloid protein (e.g., amyloid beta protein) in, on or around neurological tissue (e.g., the brain), or (c) treat neurodegenerative diseases, or (d) modulate the activity of gammasecretase. Another embodiment of this invention is directed to a compound of Group A or B in isolated form. Another embodment of this invention is directed to a compound of Group A or B in pure form. WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Another embodiment of this invention is directed to a compound of Group A or B in pure and isolated form. Another embodiment is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of Group A or B, and a pharmaceutically acceptable carrier. Another embodiment is directed to a pharmaceutical composition comprising an effective amount of a pharmaceutically acceptable salt of one or more (e.g, one) compounds of Group A or B, and a pharmaceutically acceptable carrier. Another embodiment is directed to a pharmaceutical composition comprising an effective amount of a pharmaceutically acceptable ester of one or more (e.g., one) compounds of Group A or B, and a pharmaceutically acceptable carrier. Another embodiment is directed to a pharmaceutical composition comprising an effective amount of a solvate of one or more (e.g., one) compounds of Group A or B, and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g, one) compounds of Group A or B, and an effective amount of one or more (e.g,, one) other pharmaceutically active ingredients (e.g., drugs), and a pharmaceutically acceptable carrier. Examples of the other pharmaceutically active ingredients include, but are not limited to drugs selected form the group consisting of: (a) drugs useful for the treatment of Alzheimer's disease, (b) drugs useful for inhibiting the deposition of amyloid protein (e.g., amyloid beta protein) in, on or around neurological tissue (e.g., the brain), (c) drugs useful for treating neurodegenerative diseases, and (d) drugs useful for inhibiting gamma-secretase. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of Group A or B, and effective amount of one or more BACE inhibitors, and a pharmaceutically acceptable carrier. WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 9O Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of Group A or B, and an effective amount of one or more cholinesterase inhibitors (e.g., acetyland/or butyrylchloiinesterase inhibitors), and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of Group A or B, and effective amount of one or more muscarinic antagonists (e.g., ml agonists or m2 antagonists), and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of Group A or B, and effective amount of Exelon (rivastigmine), and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of Group A or B, and effective amount of Cognex (tacrine), and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of Group A or B, and effective amount of a Tau kinase inhibitor, and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of Group A or B, and effective amount of one or more Tau kinase inhibitor (eg., GSK3beta inhibitor, cdk5 inhibitor, £RK inhibitor), and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 compounds of Group A or B, and effective amount of one anti-Abeta vaccine (active immunization), and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of Group A or B, and effective amount of one or more APP ligands, and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of Group A or B, and effective amount of one or more agents that upregulate insulin degrading enzyme and/or neprilysin, and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of Group A or B, and effective amount of one or more cholesterol lowering agents (for example, statins such as Atorvastatin, Fluvastatin, Lovastatin, Mevastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin, and cholesterol absorption inhibitor such as Ezetimibe), and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of Group A or B, and effective amount of one or more fibrates (for example, clofibrate, Clofibride, Etofibrate, Aluminium Clofibrate), and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of Group A or B, and effective amount of one or more LXR agonists, and a pharmaceuticaiiy acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 compounds of Group A or B, and effective amount of one or more LRP mimics, and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of Group A or B, and effective amount of one or more 5-HT6 receptor antagonists, and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of Group A or B, and effective amount of one or more nicotinic receptor agonists, and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of Group A or B, and effective amount of one or more H3 receptor antagonists, and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of Group A or B, and effective amount of one or more historie deacetylase inhibitors, and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of Group A or B, and effective amount of one or more hsp90 inhibitors, and a pharmaceutically acceptable carrier. Another embodiment of this Inventíon is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of Group A or B, and effective amount of one or more ml muscarinic receptor agonists, and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of Group A or B, and effective amount of one or more 5-HT6 receptor WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 antagonists mGluRl or mGluR5 positive allosteric modulators or agonists, and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of Group A or B, and effective amount of one or more one mGtuR213 antagonists, and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of Group A or B, and effective amount of one or more antiinflammatory agents that can reduce neuroinflammation, and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of Group A or B, and effective amount of one or more Prostaglandin EP2 receptor antagonists, and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of Group A or B, and effective amount of one or more PAl-1 inhibitors, and a pharmaceutically acceptable carrier. Another embodiment of this invention is directed to a pharmaceutical composition comprising an effective amount of one or more (e.g., one) compounds of Group A or B, and effective amount of one or more agents that can induce Abeta efflux such as gelsolin, and a pharmaceutically acceptable carrier. The compounds of Group A or B can be useful as gamma secretase modulators and can be useful in the treatment and prevention of diseases such as, for example, central nervous system disorders (such as Afzheimers disease and Downs Syndrome), and treating mild cognitive impairment, glaucoma, cerebral amyloid angiopathy, stroke, dementia, microgliosis, brain inflammation, and olfactory function toss. WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Thus, another embodiment of this invention is directed to a method for modulating (including inhibiting, antagonizing and the like) gamma-secretase comprising administering an effectíve (i.e., therapeutically effective) amount of one or more (e.g., one) compounds of Group A or B to a patient in need of such treatment. Another embodiment of this invention is directed to a method for modulating (including inhibiting, antagonizing and the like) gamma-secretase, comprising administering an effective (i.e., therapeutically effective) amount of a compound of Group A or B to a patient in need of treatment. t0 Another embodiment of this invention is directed to a method of treating one or more neurodegenerative diseases, comprising administering an effective (i.e., therapeutically effective) amount of one or more (e.g., one) compounds of Group A or B to a patient in need of treatment. Another embodiment of this invention is directed to a method of treating one or more neurodegenerative diseases, comprising administering an effective (i.e., therapeutically effective) amount of a compound of of Group A or B to a patient in need of treatment. Another embodiment of this invention is directed to a method of inhibiting the deposition of amyloid protein (e.g., amyloid beta protein) in, on or around neurological tissue (e.g., the brain), comprising administering an effective (i.e., therapeutically effective) amount of one or more (e.g., one) compounds of Group A or B to a patient in need of treatment. Another embodiment of this invention is directed to a method of inhibiting the deposition of amytoid protein (e.g., amyloid beta protein) in, on or around neurological tissue (e.g., the brain), comprising administering an effective (i.e., therapeuticatIy effective) amount of a compound of Group A or B to a patient in need of treatment. Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective (i.e., therapeutically WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 effective) amount of one or more (e.g., one) compounds of Group A or B to a patient in need of treatment. Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective (i.e., therapeutically effective) amount of a compound of Group A or B to a patient in need of treatment. Another embodiment of this invention is directed to a method of treating mild cognitive {mpairmenL glaucoma, cerebral amyloid angiopathy, stroke, dementia, microgliosis, brain inflammation, or olfactory function loss, comprising administering an effective (i.e., therapeutically effective) amount of one or more (e.g., one) compounds of Group A or B to a patient in need of treatment. Another embodiment of this invention is directed to a method of treating mild cognitive impairment, glaucoma, cerebral amyloid angiopathy, stroke, dementia, microgliosis, brain inflammation, or olfactory function loss, comprising ! 5 administering an effective (i.e., therapeutically effective) amount of a compound of of Group A or B to a patient in need of treatment. This invention also provides combination therapies for (1) modulating gamma-secretase, or (2) treating one or more neurodegenerative diseases, or (3) inhibiting the deposition of amyloid protein (e.g., amyloid beta protein) in, on or around neurological tissue (e.g., the brain), or (4) treating Alzheimer's disease. The combination therapies are directed to methods comprising the administration of one or more (e.g. one) compounds of of Group A or B, and the administration of one or more (e.g., one) other pharmaceutical active ingredients (e.g., drugs). The compounds of Group A or B, and the other drugs can be administered separately (i.e each is in its own separate dosage form), or the compounds of formula (l) can be combined with the other drugs in the same dosage form+ Thus, other embodiments of this invention are directed to any one of the methods of treatment, or methods of inhibiting, described herein, wherein the compounds of Group A or B are used in combination with an effective amount of one or more other pharmaceutically active ingredients selected from the group WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 consisting of: BACE inhibitors (beta secretase inhibitors); muscarinic antagonists (e.g., ml agonists or m2 antagonists); choline sterase inhibitors (e.g, acetyland!or butyryichlolinesterase inhibitors); gamma secretase inhibitors: gamma secretase modulators; HMG-CoA reductase inhibitors; non-steroidal anti-inflammatory agents; N-methyl-D-aspartate receptor antagonists; anti-amyloid antibodies: vitamin E; nicotinic acetylcholine receptor agonists; CB1 receptor inverse agonists or CB1 receptor antagonists; an antibiotic; growth hormone secretagogues; histamine H3 antagonists; AMPA agonists; PDE4 inhibitors; GABAA inverse agonists; inhibitors of amyloid aggregation; glycogen synthase kinase beta inhibitors; promoters of alpha secretase activity; PDE-10 inhibitors; Ëxelon (rivastigmine); Cognex (tacrine); Tau kinase inhibitors (e.g., GSK3beta inhibitors, cdk5 inhibitors, or ERK inhibitors); anti-Abeta vaccine; APP ligands; agents that upregulate insulin cholesterol lowering agents (for example, statins such as Atorvastatin, Fluvastatin, Lovastatin, Mevastatin, Pitavastatin, Pravastatin, t5 Rosuvastatin, Simvastatin); cholesterol absorption inhibitors (such as Ezetimibe); flbrates (such as, for example, for example, clofibrate, Clofibride, Etofibrate, and Aluminium Clofibrate); LXR agonists; LRP mimics; nicotinic receptor agonists; H3 receptor antagonists; histone deacetylase inhibitors; hspg0 inhibitors; ml muscarinic receptor agonists; 5-HT6 receptor antagonists; mGluR1; mGluR5; positive altosteric modulators or agonists; mGtuR2/3 antagonists; antiinflammatory agents that can reduce neuroinflammation; Prostaglandin EP2 receptor antagonists; PAI-I inhibitors; and agents that can induce Abeta efflux such as gelsolin. This invention also provides combination therapies for (I) modulating gamma-secretase, or (2) treating one or more neurodegenerative diseases, or (3) inhibiting the deposïtion of amyfoid protein (eg, amyioid beta protein) in, on or around neurological tissue (e.g., the brain), or (4) treating Atzheimer's disease. The combination therapies are directed to methods comprising the administration of one or more (e.g. one) compounds of Group A or B, and the administration of one or more (e.g., one) other pharmaceutical active ingredients (e.g., drugs). The WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 compounds of Group A or B, and the other drugs can be administered separately (i.e., each is in its own separate dosage form), or the compounds of Group A or B can be combined with the other drugs in the same dosage form. Thus, other embodiments of this invention are directed to any one of the methods of treatment, or methods of inhibiting, described herein, wherein the compounds of Group A or B are used in combination with an effective amount of one or more other pharmaceutically active ingredients selected from the group consisting of: BACE inhibitors (beta secretase inhibitors), muscarinic antagonists (e.g., ml agonists or m2 antagonists), ch olinesterase inhibitors (e.g., acetyland/or butyrylchlolinesterase inhibitors); gamma secretase inhibitors; gamma secretase modulators; HMG-CoA reductase inhibitors; non-steroidal anti-inflammatory agents; N-methyl-D-aspartate receptor antagonists; anti-amytoid antibodies; vitamin E; nicotinic acetylcholine receptor a gonists; CB1 receptor inverse agonists or CB1 receptor antagonists; an antibiotic; growth hormone secretagogues; histamine H3 antagonists; AMPA agonists; PDE4 inhibitors; GABAA inverse agonists; inhibitors of amyloid aggregation; glycogen synthase kinase beta inhibitors; promoters of alpha secretase activity; PDE-t0 inhibitors; Exelon (rivastigmJne); Cognex (tacrine); Tau kinase inhibitors (e.g., GSK3beta inhibitors, cdk5 inhibitors, or ERK inhibitors); anti-Abeta vaccine; APP ligands; agents that upregulate insulin cholesterol !owering agents (for example, statins such as Atorvastatin, Fluvastatin, Lovastatin, Mevastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin); cholesterol absorption inhibitors (such as Ezetimibe); fibrates (such as, for example, for example, clofibrate, Clofibride, Etofibrate, and Aluminium Clofibrate); LXR agonists; LRP mimics; nicotinic receptor agonists; H3 receptor antagonists; historie deacetylase inhibitors; hsp90 inhibitors; ml muscarinic receptor agonists; 5-HT6 receptor antagonists; mGIuRl; mGluR5; positive atlosteric modulators or agonists; mGtuR2!3 antagonists; antiinflammatory agents that can reduce neuroinflammation; Prostaglandin EP2 receptor antagonists; PAl-1 inhibitors; and agents that can induce Abeta efflux such as gelsolin. WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Other embodiments of this invention are directed to any one of the methods of treatment, or methods of inhibiting, described herein, wherein the compounds of Group A or B are used in combination with an effective amount of one or more other pharmaceutically active ingredients selected from the group consisting of: BACE inhibitors (beta secretase inhibitors), muscarinic antagonists (e.g., ml agonists or m2 antagonists), cholinesterase inhibitors (e.g., acetyland/or butyryfchlolinesterase inhibitors); gamma secretase inhibitors; gamma secretase modulators; HMG-CoA reductase inhibitors; non-steroidal anti-inflammatory agents; N-methyI-D-aspartate receptor antagonists; anti-amyloid antibodies; vitamin E; nicotinic acetylcholine receptor agonists; CB1 receptor inverse agonists or CB1 receptor antagonists; an antibiotic; growth hormone secretagogues; histamine H3 antagonists; AMPA agonists; PDE4 inhibitors; GABAA inverse agonists; inhibitors of amyloid aggregation; glycogen synthase kinase beta inhibitors; promoters of alpha secretase activity; PDE-10 inhibitors; and cholesterol absorption inhibitors (e.g., ezetimibe). Other embodiments of this invention are directed to any one of the methods of treatment, or methods of inhibiting, described herein, wherein the compounds of Group A or B are used in combination with an effective amount of one or more other pharmaceutically active ingredients selected from the group consisting of: Exelon (rivastigmine); Cognex (tacrine); Tau kinase inhibitors (e.g., GSK3beta inhibitors, cdk5 inhibitors, or ERK inhibitors); anti-Abeta vaccine; APP ligands; agents that upregulate insulin cholesterol lowering agents (for example, stains such as Atorvastatin, Fluvastatin, Lovastatin, Mevastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin);chotesterol absorption inhibitors (such as Ezetimibe); fibrates (such as, for example, for example cfofibrate, CIofibride, Ëtofibrate, and Aluminium Cfofibrate); LXR agonists; LRP mimics; nicotinic receptor agonists', H3 receptor antagonists; historie deacetylase inhibitors; hsp90 inhibitors; ml muscarinic receptor agonists; 5-HT6 receptor antagonists; mGluR1; mGfuR5; positive allosteric modulators or agonists; mGfuR2/3 antagonists; antiinflammatory agents that can reduce neuroinflammation; Prostaglandin EP2 WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 receptor antagonists; PAl-1 inhibitors; and agents that can induce Abeta efflux such as ge{so in. Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective (i.e., therapeutically effective) amount of one or more (e.g., one) compounds of Group A or B, in combination with an effective (i.e., therapeutically effective) amount of one or more cholinesterase inhibitors (such as, for example, (±)-2,3-dihydro-5,6dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyi]methy!]-I H -inden1 -one hydrochtoride, i.e., donepezil hydrochloride, available as the Aricept® brand of lû donepezil hydrochloride), to a patient in need of treatment. Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective (i.e., therapeutically effective) amount of a compound of Group A or B, in combination with an effective (i.e., therapeutically effective) amount of one or more (e.g., one) cholinesterase inhibitors (such as, for example, (+)-2,3-dihydro-5,6-dimethoxy-2-[[l- (phenylmethyi)-4-piperidinyl]methyl]-I H-inden-l-one hydrochloride, i.e., donepezil hydrochloride, available as the Aricept® brand of donepezil hydrochlodde), to a patient in need of treatment. Another embodiment of this invention is directed to a method of treating Atzheimer's disease, comprising administering an effective (i.e., therapeutically effective) amount of one or more (e.g., one) compounds of Group A or B selected from the group consisting of: in combination with an effective (i.e., therapeutically effective) amount of one or more compounds selected from the group consisting of A antibody inhibitors, gamma secretase inhibitors and beta secretase inhibitors. Another embodiment of this invention is directed to a method of treating AizheimeCs disease, comprising administering an effective (i.e., therapeuticalty effective) amount of one or more (e.g., one) compounds of Group A or B, in combination with an effective (i.e., therapeutically effective) amount of one or more BACË inhibitors. WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Another embodiment of this invention is directed to a method of treating Alzheimer's disease, comprising administering an effective (i.e., therapeutically effective) amount of a compound of Group A or B, in combination with an effective (i.e., therapeutically effective) amount of one or more BACE inhibitors. Another embodiment of this invention is directed to a method of treating Downs syndrome, comprising administering an effective (i.e., therapeutically effective) amount of one or more (e.g., one) compounds of Group A or B to a patient in need of treatment. Another embodiment of this invention is directed to a method of treating Downs syndrome, comprising administering an effective (i.e., therapeutically effective) amount of a compound of of Group A or B, to a patient in need of treatment. Another embodiment of this invention is directed to a method of treating Downs syndrome, comprising administering an effective (i.e., therapeutically effective) amount of one or more (e.g., one) compounds of Group A or B, in combination with an effective (i.e., therapeutically effective) amount of one or more cholinesterase inhibitors (such as, for example, (+)-2,3-dihydro-5,6dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-I H-inden-l-one hydrochloride, i.e., donepezil hydrochloride, available as the Aricept® brand of donepezil hydroch!oride), to a patient in need of treatment. Another embodiment of this invention is directed to a method of treating Downs syndrome, comprising administering an effective (i.e., therapeutically effective) amount of a compound of Group A or B, in combination with an effective (i.e., therapeutically effective) amount of one or more (e.g., one) cholinesterase inhibitors (such as, for example, (+)-2,3-dihydro-5,6-dimethoxy-2-[[!- (phenytmethyl)-4-piperidiny methyl]-1 H-inden-t-one hydrochloride, i.e., donepezii hydrochloñde, available as the Aricept®r brand of donepeziJ hydrochloride), to a patient in need of treatment. Another embodiment of this invention is directed to combinations (i.e., pharmaceuticaF compositions) comprising an effective (i.e., therapeuticai y WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 10t effective) amount of one or more (e.g., one) compounds of Group A or B in combination with an éffective (i.e., therapeutically effective) amount of one or more compounds selected from the group consisting of cholinesterase inhibitors (such as, for example, (±)-2,3-dihydro-5,6-dimethoxy-2-[[ t-(phenylmethyl) 4piperidinyl]methyl]-I H-inden-t-one hydrochloride, i.e donepezil hydroch]oride, available as the Aricept® brand of donepezil hydrochloride), Ai3 antibody inhibitors, gamma secretase inhibitors and beta secretase inhibitors. The pharmaceutical compositions also comprise a pharmaceutically acceptable carrier. This invention also provides a kit comprising, in separate containers, in a t0 single package, pharmaceutical compositions for use in combination, wherein one container comprises an effective amount of one or more (e.g., one) compounds of Group A or B in a pharmaceutically acceptable carrier, and another container (i.e., a second container) comprises an effective amount of another pharmaceutically active ingredient (as described above), the combined quantities of the compounds of Group A or B and the other pharmaceutically active ingredient being effective to: (a) treat Aizheimer's disease, or (b) inhibit the deposition of amyloid protein (e.g., amyloid beta protein) in, on or around neurological tissue (e.g., the brain), or (c) treat neurodegenerative diseases, or (d) modulate the activity of gammasecretase. This invention also provides a kit comprising, in separate containers, in a single package, pharmaceutical compositions for use in combination, wherein one container comprises an effective amount of a compound selected from the group consisting of the compounds of Group A or B in a pharmaceutically acceptable carrier, and another container (i.e., a second container) comprises an effective amount of another pharmaceutically active ingredient (as described above), the combined quantities of the compound of Group A or B and the other pharmaceutically active ingredient being effective to: (a) treat AIzheimer's disease, or (b) inhibit the deposition of amyloid protein (e.g., amyloid beta protein) in, on or around neurological tissue (e.g., the brain), or (c) treat neurodegenerative diseases, or (d) modulate the activity of gamma-secretase, WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Examples of cholinesterase inhibitors are tacrine, donepezil, ñvastigmine, galantamine, pyridostigmine and neostigmine, with tacrine, donepezil, rivastigmine and galantamine being preferred. Examples of ml agonists are known iñ the art. Examples of m2 antagonists are also known in the art; in particular, m2 antagonists are disclosed in US patents 5,883,096; 6,037,352; 5,889,006; 6,043,255; 5,952,349; 5,935,958; 6,066,636; 5,977,138; 6,294,554; 6,043,255; and 6,458,812; and in WO 03t031412, ail of which are incorporated herein by reference. Examples of BACE inhibitors include those described in: US2005/0119227 published 06/02/2005 (see also WO2005/016876 published 02/24/2005), US2005/0043290 published 02t2412005 (see also WO20051014540 published 02/17/2005 ), WO2005/058311 published 06/30/2005 (see also US2007/0072852 published 03/29/2007), US2006/0111370 published 05/25/2006 (see also WO2006/065277 published 06/22t2006), US Application Serial No. 11/710582 filed 02/23/2007, US2006/0040994 published 02/23/2006 (see also WO2006/014762 published 02/09/2006), WO2006/014944 published 02/09/2006 (see also US2006/0040948 published 02/23/2006), WO2006/138266 published 12128t2006 (see also US200710010667 published 01/11t2007), WO2006/138265 published 12/28/2006, WO2006/138230 published 12/28/2006, WO2006/138195 published 12/28/2006 (see also US2006/0281729 published 12/14t2006), WO2006t138264 published 12128t2006 (see also US2007/0060575 published 03/15/2007), WO2006/138192 published !2/28/2006 (see also US2006/028t730 published 12/14/2006), WO2006/1382! 7 published 12/28/2006 (see also US2006/0287294 published 12/21/2006), US2007/0099898 published 05/03/200 (see also WO2007/05072t published 05/03t2007), WO2007/053506 published 05/I0/2007 (see also US2007/099875 published 05/03/2007), U.S. Application Serial No. 1 t/759336 filed 06/07/2007, U.S. Application Serial No. 60/874362 filed 12/12/2006, and U.S. Application Serial No. 60t874419 filed 12112/2006, the disclosures of each being incorporated incorporated herein by reference thereto. WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solfd dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington'sPharmaceuticat Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pennsylvania. Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration. Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen. Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions. The compounds of the invention may also be deliverable transdermaJly. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be íncFuded in a transdermai patch of the matrix or reservoir type as are conventional in the an for this purpose. The compounds of this invention may atso be delivered subcutaneously. Preferably the compound is admínistered orally. Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose. The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 100 mg, preferably from about 1 mg to about 50 mg, more preferably from about 1 mg to about 25 mg, according to the particular application. The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required. The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as weJl as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 1 mgtday to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two to four divided doses. Another aspect of this invention is a kit comprising a therapeutically effective amount of at least one compound of Group A or B, or a pharmaceutically acceptable sait, sotvate, ester or prodrug of said compound and a pharmaceutically acceptable carrier, vehicle or dituent. Yet another aspect of this invention is a kit comprising an amount of at least one compound of Group A or B, or a pharmaceutically acceptable salt, solvate, ester or prodrüg of said compound and an amount of at least one additional agent listed above wherein the amounts of the two or more ingredients result in desired therapeutic effect. The invention disclosed herein is exemplified by the following illustrative example which should not be construed to limit the scope of the disclosure. WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Alternative mechanistic pathways and analogous structures will be apparent to those skilled in the art. Where NMR data are presented, I H spectra were obtained on either a Varian VXR-200 (200 MHz, 1H), Varian Gemini-300 (300 MHz) or XL-400 (400 MHz) and are reported as ppm down field from Me4Si with number of protons, multiplicities, and coupling constants in Hertz indicated parenthetically. Where LClMS data are presented, analyses was performed using an Applied Biosystems API-100 mass spectrometer and Shimadzu SCL-10A LC column: Altech platinum C18, 3 micron, 33mm x 7mm tD; gradient flow: 0 min - 10% CH3 CN, 5 min - 95% CH3 CN, 7 rein - 95% CH3 CN, 7.5 rein - 10% CH3 CN, 9 min - stop. The observed parent ion is given. Method Q ç R3 R4 + Oæ10 ..I ----I.- R R -...O R3 ''' 43OH 4 O R7 R7 BocHN R7 Q1 Q5 Q2 Q3 Q4 Q7 WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 RR34/ OR7 N H " lO ti,,-. R Q8 RL RiO O R7 o Q9 O R7 R RI R3 QI0 R3 . ì1 O R4 R R i S N R 7 Q11 Method Q, Step 1 Q1 (R3 = R4 = Me) and Q2 (R7 = 4-F-Phenyl) will react in THF in the presence of KOtBu to give compound Q3 (R7 = 4-F-Phenyt, R3 = R4 = Me) after work up and purification. I0 Method Q, Step 2 Q3 (R7 = 4-Fi-Phenyl, R3 = R4 = Me) will be converted to Q4 (R7 = 4-FPhenyl, R3 = R« = Me) using a method similar to L. Barboni and C. Lambertucci; J, Med. Chem. 2001, 44, 1576; To a stirred solution of tert-butyl carbamate (2.32 g, 15.3 mmol) in 2propanol (20 mL), a solution of NaOH (604 mg) in water (37 mL), tert-butyl hypochlorite (1.73 mL) and (DHQ)2 PHAL (198 mg)in 2-propanol (17,3 mL) will be sequentially added. After stirring at room temperature for 10 min, 4.95 mmoI of compound Q3 will be added, followed by K2 OsO2 (OH)4 (73 mg). After stirring at room temperature for 7 h, the reaction will be worked up by cooling in a ice bath and addition of saturated Na2 SO3 (49.5 mL). After further stirring for 15 rein, the reaction mixture wilt be extracted with EtOAc, and the organic phase will be washed with brine, dried (Na2 SO4 ) and evaporated. The residue wiI! bé WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 chromatographed on silica gel (hexanes-EtOAc) to give Q4 (R7 = 4-F-Phenyl, R3 = R4 = Me). Method Q, Step 3 To a THF solution of Q4 (R7 = 4-F-Phenyl, R3 = R4 = Me) will be added Nhydroxylphthalimide, ADDP and triphenylphosphine. The reaction will be stirred overnight to give compound Q5 (R7 = 4-Fi-Phenyl, R3 = R4 = Me) after workup and purification. Method Q, Step 4 Compound Q5 (R7 = 4-F-Phenyl, R3 = R4 = Me) will be treated with TFA in DCM to give compound Q6 (R7 = 4-F-Phenyl, R3 = R4 = Me). Method Q, Step Compound Q6 will be coupled with Q7 (R7 = 4-Fi-Phenyl, R1° = 3-MeOPhenyt, R9 = 4-(4-Methyl-imidazol-t-yl), R3 = R« = Me) using EDCIfTEA/DMF conditions to give Q8 (R7 = 4-Fi-Phenyl, R1° = 3-MeO-Phenyl, R9 = 4-(4-Methylimidazol-l-yl), R3 = R« = Me) after workup and purification. Method Q, Step 6 Compound Q8 (R7 = 4-F-Phenyl, R ° = 3-MeO-Phenyl, R9 = 4-(4-Methylimidazol-l-yl), R3 = R4 = Me) will be treated with Nail in DMF to give Q9 (R7 = 4F-Phenyl, R ° = 3-MeO-Phenyl, Re = 4-(4-Methyl-imidazol-l-yl), R3 = R4 = Me) after workup and purification. Method Q, Step 7 Compound Q9 (R7 -- 4-F-Phenyl, R ° = 3-MeO-Phenyl, R9 = 4-(4-MethyiimidazoFl-yl), Rg = R4 = Me) will be treated with hydrazine in methanol to give compound Q10 (R7 = 4-Fi-Phenyl, R ° = 3-MeO-Phenyl, R9 = 4-(4-Methylimidazol-l-yI), R3 = R4 = Me) after workup and purification. WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 t08 Method Q, Step 8 Compound Q10 (R7 = 4-F-Phenyl, R1° = 3-MeO-PhenyL R9 = 4-(4-Methylimidazol-l-yl), R3 = R4 = Me) will be converted to QIl(R7 = 4-F-Phenyl, R1°= 3MeO-Phenyl, R9 = 4-(4-Methyl-imidazol-l-yl), R3 = R4 = Me) through refluxing with P205 in ethanol. The following compounds will be synthesized using method similar to method Q. Rî Method R oHOyR3 I I RgR o ?SR7 ......... R2 NH2 O R3 .-O ...R3 . II T_R7 . R7 N Rg R4 Method R, Step 1 To a stirring mixture of 2-amino-l-(3,4,5-trifluorophenyl)ethanol (t mmol), acid Rt(R ° = 3-MeO-Phenyl, R9 = 4-(4-MethyFimidazol-l-yl), ! .0 mmol), HOBT (t 5 mmoJ) and DIEA (6 mmoi) in anhydrous DMF (5 mL) was added EDCl (t .5 retool). The solution resuíted was then stirred overnight at rt. Upon evaporating DMF under high vacuum, the residue was taken up into EtOAc (t00 mL) and saturated NaHCO3 (30 mL). The EtOAc layer was collected and dried over Na2SO4. After remove EtOAc, the residue was dissolved in THF (I0 mL). To this THF solution was then added NaOMe (2 rnmoI, 4.2 M in MeOH). The mixture WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 resulted was stirred over night at ft. After which, the THF was removed and residue was partitioned between EtOAc and H2 0. The EtOAc layer was collected and dried over Na2 SO4 . After evaporating EtOAc, the residue was purìfied through flash chromatography to afford the desired iactam R2 (R6 = R7 = H, R3 = 3,4,5-triF-Phenyl, RI° = 3-MeO-Phenyt, R9 = 4-(4-Methyi-imidazoFl-yl)). 1HNMR: 5(ppm) 7.93 (1H, bs), 7.81 (1H, bs), 7.34-7.37 (2H, m), 7.19 (1H, d, J = 6.8 Hz), 7.11 (2H, m), 7.04 (bs, 1H), 5.t8 (1H, bs), 3.97 (3H, s), 3.94 (!h, m), 3.60-3.70 (1H, m), 3.50 (1H, m), 3.3-3.4 (1H, m), 2.89 (2H, m), 2.39 (3H, s), 2.14 (2H, m). Method R, Step 2 The lactam R2 (R6 = R7 = H, R3 = 3,4,5-tri-Fi-Phenyl, R1° = 3-MeO-Phenyl, R9 = 4-(4-Methyl-imidazot-l-yl)), 0.5 retool) was mixed with PPh3 (1 mmol) and Nhydroxylphthalimide (1 retool) in anhydrous THF (5 mL) under N2 . The mixture was then cooled to -10 C. DIAD (1 mmot) was then added dropwisely. The mixture was allowed to warm up to rt and stir was continued for overnight. After which, the THF was removed, and the residue was taken up in EtOAc (50 mL). The EtOAc layer was further washed with NaHCO3 (2X3û mL) and then dried over Na2 SO4 . After removal of the EtOAc, the residue was dissolved in EtOH (!0 mL). NH2 NH2 (i mmol) was then added to the solution. After further stirring for overnight, the EtOH was removed and residue was dissolved in CH2 CI2 (50 mL). The CH2 C 2 layer was washed consecutively with H2 0 and brine, then, dried over Na2 SO4 . The 0H2012 was then removed and the residue was purified through flash chromatography to afford the desired hydroxylamine R3 (R6 = R7 = H, R3 = 3,4,5tri-Fi-Phenyl, R ° = 3-MeO-Pheny Rg = 4-(4-Methy!-imidazoFl-yl)). HNMR, (ppm): 7.80 (1H, bs), 7.7t (1H, s), 7.23-7.25 (1H, m), 7.0tW.1 (3H, m), 6.92 (1H, s), 5.45 (2H, b), 4.90 (IH, m), 3.85 (3H, s), 3.80 (tri, m), 3.53.6 (tri, m), 3.26-3.38 (2 H, m), 2.80 (2H, m), 2.29 (3H, s), 1.80-1.90 (2H, m). WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Method R, Step 3 The hydroxylamine R3 (R6 = R7 = H, R3 = 3,4,5-tri-Fi-Phenyl, R1° = 3-MeOPhenyl, R9 = 4-(4-Methyl-imidazol-l-yl)), 10 mg) was dissolved in EtOH (! mL). This solution was then added to a premixed mixture of P2 05 (30 mg) and EtOH (1 mL). The resulted mixture was then stirred at 80°C overnight. After the reaction mixture was cooled down, it was diluted with CH2 C12 (50 mL) and H20. Excess K2003 was then added to adjust the pli to ~9-10. The organic layer was then collected and dried over Na2 SO4 . After evaporating the 0H2 0t2 , the residue was purified with flash chromatography to afford the desired final product R4 (R6 = R7 = H, R3 = 3,4,5-tri-Fi-Phenyl, R1° = 3-MeO-Phenyt, R9 = 4-(4-Methyl-imidazoF1yl)). LCMS, retention time: 2.67 min. MS observed, 469.3. 1HNMR, 6(ppm): 7.68 (1H, s), 7.47 (1H, bs), 7.23 (1H, d, J = 10 Hz), 7.03 (2H, m), 6.90-6.96 (3H, m), 4.70 (ill, dd, J = 8.4 and 3.2 Hz), 3.83 (3H, s), 3.193.47 (4H, m), 2.73 (2H, m), 2.28 (3H, s), 1.91 (2H, m). Method T H2 3 N..OyR3 O . Il I__R7 -R7 Re" R1 o , "Re R9.R10 / '''"" IN 6 R2 R2 T1 T2 Compound T1 (R2 = Me, R3 = R6 = H, R7 = p-F-phenyl, Rt° = 3-MeO-Phenyl, R9 = 4-(4-Methyt-imidazol-l-yt)), synthesized using a method similar to method R, wilI be converted to T2 (R2 = Me, R3 = R6 = H, R7 = p-F-phenyl, RI° = 3-Meq-PhenyI, R9 = 4-(4-Methyl-imidazoi-l-yt)), using a method similar to method R. The following compounds were synthesized using a method similar to that listed in the tast column: WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 11t ì Rt (min) Obs. i Synthetic # i Compound ! Massi Method : ...... ::: ...................OH L ::: := ;-=: ........ l ==== := 2O3 t 0., racemic N racemic t O. I N -- N enantiomer I f O. F (R) 2.3 2,4 2,8 2.6 463.25 431,24 469,26 451.25 R R i WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 i i t O. I O. I O. O. N enantiomer I enantiomer I (R> N N F 2.7 3.1 475.20 433.24 ! R R F F 2.5 447.25 3,2 625.34 R R i i racem c WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 21t 212 J i O. f O. enantiomer tl racemic racemic N F F F 2.7 2.7 2.4 2.5 475.26 475.26 449.25 J E 447,25 R R R R J i WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 N F N racemic racemic F racemic N ..Oì N 2,67 2,5 2,6 469.3 447.25 433.24 R R R i WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 I O. J O.. N "N Y N C! (s) F 2.6 racemic N enantiomer tt F 3.1 enantiomer Il 451.25 469,26 R R R R R 433.24 469.26 F WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 The following compounds will be synthesized using a method similar to that listed in the last column: # Compound iSynthetic ........... ............................ rMethod: l N O. F I O. N F t O. N F Q N F F Q Q Q i i f WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 t17 O. 249i N "N ,25! O. I O. F F OH F Q Q Q Q Method U BCI3 U2 WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 t0 A solution of U1 (20 mg, RI=R2=H), which was synthesized following similar procedure as described for Method R, En CH2 Ct2 was cooled to -t0 °C, To this solution was then added BCI3 (0.15 mL, !M in hexanes), The resulted mixture was then al!owed to warm up to room temperature, Stirring continued at room temperature for 2 hours before the reaction was quenched by addition of water. The organic layer was then separated and discarded. The water tayer was basified and extracted with CH2 CI2 (3X20 mL). The combined organic layer was dried over Na2 SO4 . After removal of the volatile, the residue was purified by flash chromatography to afford the desired target U2 (R =R2=H), LCMS: observed 369.2 (M÷+I). tri NMR (CDCl3 , 400 MHz, 6): 7.82 (1H, s), 7.54 (1H, s), 7.33 (1H, d, J = 7.4 Hz), 7.04-7.08 (3H, m), 4.44 (1H, d, J = 11.5 Hz), 3.954.08 (2H, m), 3.93 (3H, s), 3.84 (1H, d, J = 12 Hz), 3.55 (1H, m), 3.44 (1H, m), 3.28 (IH, m), 2.79-2.94 (2H, m), 2.42 (3H, s), 2.02 (2H, m). Method V /O R20 N " \ / 1 R -,--J" -, NH NH2 R2 N"O"Ç , H i R'H "" °w',, " " ">< "" ..... oyC° , V5 EDCL HOBT N/OR2 ii J R li { i Method V, Step t: A mixture of V1 (lg, 2.72 mmol, R =R2=H), which was synthesized following method U, V2 (9!9 mg, 625 mmol) and PPhs (l .64g, 6.26 mmof) was WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 !19 t5 dissolved in anhydrous THF (20 mL) and was cooled to -10 °C under N2 . DIAD (t.26g, 6.24 mmoi) was then added to the solution. The mixture resulted was allowed to warm up to room temperature and stir continued until analysis suggested full consumption of the starting alcohol, Reaction was then quenched by dilution with EtOAc (100 mL) and aqueous NaHCO3 (30 mL). The EtOAc layer was the further washed with H2 0 (30 mL) and brine (25 mL). After which the EtQAc layer was dried over Na2 SO4 , and removal of ail volatile then afforded the crude product. Purification of the crude by flash chromatography then afforded the desired product V3 (R!=R2=H) LCMS: observed 498 (M +I). H NMR (CDCI3 , 400 MHz, 6): 7.85-7.88 (2H, m), 7.69-7.75 (3H, m), 7.39 (1H, s), 7.20 (1H, d, J =7.7 Hz), 6.87-7.00 (3H, m), 7.25 91H, d, J = 1&7 Hz), 4.10-4.15 (1H, m), 3.89 (1H, dd, J = 10 and 4 Hz), 3.82 (3H, s), 3.66 (1H, dd, J = 11.3 and 2.5 Hz), 3.543.61 (IH, m), 3.49-3.52 (1H, m), 3.14-3.19 (2H, m), 2.66-2.81 (2H, m), 2.29 (3H, s), 1.85-1.93 (2H, m). Method V, Step 2: To a solution of V3 (lg, R =R2=H) in EtOH (30mL) was added hydrazine monohydrate (0.3 g). The mixture was stirred at room temperature for 48 h. After which, the solution was heated at 100 C with mW heating for 5 minutes. The reaction mixture was then allowed to cool to room temperature and filtered, The filtrate was concentrated in vaccum and crude product of V4 (RI=R2=H) was isolated. LCMS: observed 368 (M++I). Method V, Step 3: Amine V4 was dissolved in MeCNÆHF (10 mgit mL, 3/1). To this soiution was then added polymer bound EDC (3 equiv,) HOBT (1.5 equiv) and RCOzH (I.5 equiv, 1M solution in DMF) was then added. The suspension was then shaken at room temperature for 24 hours. After which polymer bound isocyanate (57 mg) and polymer bound trisamine (42 mg) and additional MeCN (0.5 mL) was added. The mixture was further shaken for 24 hours. The resin was then filtered. The WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 filtrate was concentrated under vaccum to produce a library of amides V5 (Rt=R2=H). Method W W3 W1 (50 mg, RI=R2=H), which was synthesized following similar procedure as described for Method V, in dry CH2 C12 was treated with Et3 N and W2 (1.5 equiv, n=l). Stir until no starting material left. Aqueous workup then afforded a crude mixture. This crude mixture was then dissolved in dry THF and NaOMe (2 equiv) was added. The resulted mixture was further stirred until analysis suggested no uncyclized intermediate left. The volatile was then removed and the residue was partition in 0H2 012 and water. The 0H2 012 was then removed and the residue was purified to afford the desired product W3 (RI=R2=H, n=l) as its formate. LCMS: observed 436.2 (M÷+I). 1H NMR (CDCI3 , 400 MHz, 6): 7.76 (1H, s), 7.42 (1H, bs), 7.21 (1H, d, J = 7.4 Hz), 6.91-6.99 (3H, m), 4.08 (1H, d, J = 11.7 Hz), 3.83 (3H, s), 3.37-3.69 (7 H, m), 3.16-3.22 (1H, m), 2.64-2.80 (2H, m), 2.40 (2H, t, J = 8.6 Hz), 2.30 (3H, s), 2.02-2.10 (2H, m), t.83-1.90 (2H, m). Method X WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Amine X1 (50 mg, RI=R2=H), which was synthesized following similar procedure as described for Method V, Aryl boronic acid (30 mg, Ar=Phenyl) and Cu(OAc)2 (15 mg) was mixed with CH2 C12 (1 mL). Et3 N (0.1 mL) was then added and the mixture was stirred overnight. The mixture was then filtered through celite and after removal of a!l volatile, the resulted residue was purified by HPLC to afford X2 (RI=R2=H, Ar=Phenyl) as the TFA sait. LCMS: observed 444 (M÷+I). H ÑMR (CD3 OD, 400 MHz, 6): 9.18 (1H, s), 7.62 (1H, d, J = 8.1 Hz), 7.60 (1H, s), 7.32 (2H, m), 7.22 (1H, d, J =8.4 Hz), 7.15 (2H, t, J =8.7 Hz), 6.71 (2H, d, J =7.6 Hz), 6.65 (1H, t, J = 7.6 Hz), 4.56 (1H, d, J = 11.0 Hz), 4.0-4.02 (1H, m), 3.96 (3H, s), 3.76-3.85 (2H, m), 3.47-3.64 (3H, m), 2.76-2.90 (2H, m), 2.43 (3H, s), !.852.05 (2H, m). Method Y R2 R2 .R1 .R1 /OH O.. Swem oxidation Ri li ' v R ,, Method Y, Step 1" Y3 OxaIyl chioride (6.79 mmoi) was dissolved in CH2 Ct2 (15 mL) and cooled to -78 C. DMSO (530 mg) was then added to the solution. After the mixture was stirred for another 30 minutes, a suspension of Y1 (lg, RI=R2=R3=H), which was synthesized following similar procedure as described for Method U, in 0H2 012 (10 mL) was then added, The resulted mixture was then allowed to stir at this temperature for half an hour before Et3 N (690 mg) was added, The mixture was WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 allowed to warm up to room temperature. Thîs aldehyde intermediate Y2 (RI=R2=R3=H) was not further purified. Method Y, Step 2: To the above obtained solution (2 mL) was added HNR4R5 (2 equiv. R4=RS=Et) and excess triacetylborohydride. The mixture was then stirred at room temperature overnight. After which, the mixture was diluted with CH2 Ct2 and the organic layer was then washed with aqueous NaHCO3 . The organic layer was collected and evaporated to dryness. Residue was then purified through reverse phase HPLC to afford the desired product Y3 (RI=R2=R3=H, R4=RS=Et) as its formate. LCMS: observed 424. 1H NMR (CDCt3 , 400 MHz, ô): 7.84 (1H, s), 7.41 (tri, s), 7.21 (IH, d, J = 7.6 Hz), 6.91-6.97 (3H, m), 4.32 (1H, d, J = 10.4 Hz), 3.83 (3H, s), 3.65 (1H, d, J = 11 Hz), 3.43-3.52 (2H, m), 3.14-3.20 (1H, m), 2.93-2.98 (1H, m), 2.63-2.86 (TH, m), 2.31 (3H, s), 1.88 (2H, m), 1.15 (6H, t, J = 6.8 Hz). Method Z R2 Rz ,R ,R .-,,---0 < íOH R4M ! R4 To a solution of aldehyde Z1 (20 mg, R =R2=R3=H), which was synthesized folIowing similar procedure as described for Method Y, in anhydrous THF was added R4M (R4M=4-CI-phenylmagnesium bromide) (0.3 mL; 1 M solution in THF) at -20 C. After warm up to room temperature, the mixture was quenched. EtOAc and H2 O were then added. The EtOAc layer was further washed and dried over Na2SO4. After removal of the EtOAc, the residue was purified by prep-TLC to afford Z2 (R =R2=R3=H, R4=4-CI-Phenyl) as two diasteromers. LCMS: observed 479.3 (M+I). WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Aal Method Aa NIO €/R2 toN R3 " Nj Aa2 To a mixture of Aal (20 mg, R =R2=H, R3=3,4,5-trifluorophenyl), which was obtained through method R, and N-iodosuccinimide (2 equiv) was added CF3SO3H (0.5 mL) at 0 C. The mixture was stirred at this temperature for minutes. The mixture was then poured into iced Na2 S2 03 solution. EtOAc was added to extract the product out. After purification, Aa2 (R =R2=H, R3=3,4,5trifluorophenyl) was obtained. LCMS: observed, 595. H NMR (CDCI3, 400 MHz, õ): 8.00 (1H, br), 7.74 (IH, s), 7.31 (1H, s), 6.92-7.01 (4H, m), 4.26 (IH, m), 4.08 (2H, m), 3.83 (3H, s), 3.07-3.16 (2H, m), 2.55 (2H, m), 2.39 (3H, s), 1.88 (2H, m). Abl Method Ab R2 N/O.....!R2 .R1 .R1 =3 "R3 N Ab2 To a solution of Ab1 (R =R2=H, R3=3,4,5-trifluorophenyl) (45mg, 0.096mmoi), which was synthesized following similar procedure as described for Method R, in lo5mL MeOH was added CiPd(OH)2 (10%, 50mg), 2 drops of water and stirred under H2 (1 atmosphere) for 30 minutes at room temperature. The reaction mixture was filtered through celite and the celite was washed with MeOH (5mL X3). Combine ail filtrate and remove solvent to yield Ab2 (RI=R2=H, R3=3,4,5-trifluorophenyL 25mg, 56% yield). WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 !24 MS (M+H) = 47t.5; H NMR (400 MHz, ODOr3 ) Õ 1,53 to 1.60 (m, 1H), 1.65 to 1#9 (m, 2H), 1.87 to 1.95 (m, t H)» 2.27 (s, 3H), 2.78 to 2.84 (m, tri), 2.87 to 2.94 (m, 2H), 2.98 to 3.03 (m, IH), 3.28 to 3.33 (m, 1H), 3.8t (s, 3H), 3.84 to 3.88 (m, 1H), 4.02 to 4.06 (m,lH), 4.15 to 4.t7 (m, 1H), 6.85 to 6.93 (m, 4H), 7.14 to 7.17(d, J=8.23Hz, 1H), 7.64 (s, 1H). Method Ac NHí Re í i Q °'Y °T DPs .... ! h ! [ r ...... N , p N ,p. N y ;: - çc N'P" N At1 /-- Ac2 \Y' / At3 R R3 Method Ac, Step 1" Ac2 (RI=R2=R =H) was prepared from Acl using analogous conditions described in Method R. Method Ac, Step 2: Trimethylsilyt trifluoromethane sulfonate (2.37 mL) was added slowly to a stirred solution of Ac2 (3.9 g, R =R2=R3=H ) and TEA (1.83 mL) in 9.5 mL anhydrous DCE at -30°C under nitrogen atmosphere. The reaction mixture was stirred for 30 rein after remûvai of dry ice bath, and at 60°C overnight. The reaction mixture was allowed to coo to r.t, quenched with mixture of ice and aqueous sodium bicarbonate, and extracted with DCM. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated+ Residue was WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 purified on a silica gel column with Hexane and EtOAc to give 2.5 g (66% yìeld) of Ac3 (RI=R2=R3=H). LCMS: observed 607.33 (M+í). t0 Method Ac, Step 3: Acetyt Chloride (28 mL) was added dropwise to methanol (400 mL) in an ice-bath at 0°C. Then, a solution of A¢3 (4,3 g, RI=R2=R3=H) in 100mL of MeOH was added slowly at 0°C. Upon completion of addition, ice-bath was removed and the reaction solütíon was stirred at r.t overnight. Reaction mixture was neutralized with aqueous sodium carbonate to pli 7 in an ice-bath, concentrated in vacüo. The resulting residue was then dissolved in DCM and worked up. Organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. Residue was purified on a silica gel column with DCM and MeOH containing 0.5% NH4OH to give 2.37 g (91% yield) of Ac4 (RI=RZ=R3=H). LCMS: observed 369.2 (M+I). Method Ac, Step 4: Anhydrous DMSO (0.3 mL) in 3 mL anhydrous DCM were added dropwise to a solution of oxalyl chloride (0,22 mL) in 16 mL anhydrous DCM at -78°C under nitrogen atmosphere. The reaction mixture was stirred for 10min at -78 °C, and a solution of Ac4 (4.7 g, R =R2=R3=H) in 3 mL anhydrous DCM was added dropwise. After stirring for 1.5 h, TEA (1.2mL) was added at -78°C. The reaction mixture was stirred 30 min at -78 QC, stirred for additional 30 mín after removal of the dry ice bath, quenched by diluting with 15mL of saturated aqueous sodium chloride, and extracted with DCM. The organic phase was dried over anhydrous sodium sulfate to give 765.3 mg of Ac5 (R =R2=R3=H) which was used in next step without further purification. Method Ac, Step 5: A 0.5M solution of R4M (R4M=3,5-difluorophenylmagnesium bromide) in THF was added dropwise to a vigorously stirred slurry of Ac5 (765.3 mg, WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 RI=R2=R3=H) in 2mL anhydrous THF at -40 °C. The reaction mixture was stirred at -40°C for 30 rein and rt for 2.5 h, quenched over saturated aqueous ammonium chloride, and extracted with DCM. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The resulting residue was purified on a flash silica gel column with DCM and MeQH containing 0.5% NH4 OH to give 210 mg (21%) of a mixture of 4 diastereomers ofAc6 (Rt=R2=R3=H, R4=3,5difluorophenyl). Pure diasteriomers were obtained by chiral separation using Phenomenex Lux Cellulose-1 chiral column with Hexanes and 2-Propanol to give 1.9 mg of Diasteriomer 1; 9.4 mg of Diasteriomer 2; 6,7 mg of Diasteriomer 3 and 1,3 mg of Diasteriomer 4. LCMS: observed 481 (M+t). Method Af R2 N.O. R2 R2 , r', 3 U o. -'<.ïR M,c Eth N" N 6H --6CM Ñi N Lv,J OMs ......... - SO2 Me F Afl Af2 Af3 At 0 °C, to alcohol Af1 (1.46 g, 3.96 retool, Rt=R2=R3=H), which was synthesized following similar procedure as described for Method U, in DCM (100 mL) was added Et3 N (0.803 g, 1.1 mL, 7.93 mmol, 2.0 Equiv.) and MsCI (0,817 g, 0.55 mL, 7.13 mmol, 1.8 Equiv.) respectively, the reaction mixture was stirred at this temperature for an hr., and MS showed completion of the reaction. It was quenched with water, the aqueous layer was separated and extracted with DCM, and the combined organic layers were washed with brine, dried over MgSO4 , filtered, and evaporated to generate Af2 (1.65g, 3.70 mmol, 93%, R =R2=R3=H). H NMR (CDCI3 ) 5:8.00 (s, I H); 7.42 (s, !H), 7.24 (d, J = 8.0 Hz, 1H), 6.99-6.95 (m, 3H), 4.40-4.32 (m, 2H), 4.28-4.25 (d, J = tl.6 Hz, 1H), 3.84 (s, 3H), 3.74-3.68 (m, 1H), 3.69-3.46 (m, 1H), 3.46-3,38 (m, 1H), 3.26-3.18 (m, 1H), 3.07 (s, 3H), 2.84-2.62 (m, IH), 2.36 (s, 3H), 1.98-t .82 (m, 2H). Eiectrospray MS: Obs. [M+ H]: 447.2. WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Af2 (0.226g, 0.50 mmol, R =R2=R3=H), KI (0.252 g, 1.52 mmol, 3.0 equiv.), and NaSO2 CH3 (0.155g, í .52 retool, 3.0 Equiv.) in DMF (5 mL) was heated at 120°C for 1.5 hr. The reaction mixture was cooled to rt, quenched with water, and extracted with DCM The combined organic layers were washed with brine, dried over MgSO4 , filtered, and evaporated. The crude reaction mixture was purified with column chromatography (Eluent: CH3 OHtEtOAc = 0% to 25%) to afford Af3 (0.060g, 0ç14 mmol, yield 29%, RI=R2=R3=H). 1H NMR (CDCl3 ) 5:7.70 (s, 1 H); 7.40 (s, 1H), 7.21 (d, J = 7.6 Hz, 1H), 6.98-6.90 (m, 3H), 4.35 (d, J = 11.6 Hz, 1H), 3.90-3.96 (m: 1H), 3.82 (s, 3H), 3.84-3.76 (m, 1H), 3.52-3.40 (m, 2H), 3.32 (dd, J =4.4, 11.6 Hz, 1H), 3.22-3.12 (m, 1H), 3.01 (s, 3H), 2.80-2.62 (m, 2H), 2.28 (s, 3H), 1.98-1.80 (m, 2H). Electrospray MS: Obs. [M+ H]: 431.2. Method A,q 2 R2 I NO"( I I NOì/ D A. tf !.1r 3 f'-. Il x ID-* N - -r' B,,4 NCN, toluene U N " LP . L.# C'N Y-J Agt Ag2 I. Con, HOt, refluoE 2. SOCl2, CH3 OH R2 R2 i N CO2Me CO2Me Ni N Ag4 N N Ag3 Agl (1.42 g, 3.18 mmol, RI=R2=R3=H), which was synthesized following similar procedure as described for Method Af, and Bu«NCN (t.280 g, 4.77 mmot, t .5 Equiv.) in toluene (t00 mL) was stirred at 80°C for 1 hr, then cooled to rt, and diluted with EtOAc washed with water and brine, dried over MgSO«, filtered, and evpoarated. The crude reaction mixture was purified by column chromatography (Etuent: CH3 OH/EtOAc = 0% to 20%), and Ag2 (0.832 g, 2.20mmot, yield 69%, RI=R2=R3=H) was obtained. H NMR (CDC!3 ) õ: 7.66 (s, 1 H): 7.38 (s, 1H), 7.18 WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 (d, J= 8.0 Hz, 1H), 6.98-686 (m, 3H), 4.14 (d, J= 11.2 Hz 1H), 3.79 (s, 3H), 3.72 (dd, J = 2.0, 12.0 Hz, 1H), 3.64-3.58 (m, 1H), &52-3.40 (m, 1H), 3.22-3.t 4 (m, 1H), 2.80-2 60 (m, 4H), 2.25 (s, 3H), 1.98-1.80 (m, 2H), Electrospray MS: Obs. [M+ H]: 378.2. Ag2 (&489g, 1.30 mmol, RI=R2=R3=H) was stirred in concentrated HCI (15 mL) under reflux overnight, and solvent was removed under vacuum. To the crude reaction mixture in CH3 OH (20 mL) was added SOCI2 (0.309 g, 0.19 mL, 2.60 mmol, 2.0 Equiv.) slowly, then stirred at 50°C for till completion of the reaction. Solvent was removed under vacuum to afford Ag3 (RI=R2=R3=H). H NMR (CDCl3 ) 6:7.74 (s, 1 H); 7.42 (s, 1H), 7.14-7.08 (m, 3H); 6.98-6.84 (m, 3H), 4.15 (d, J= 11.6 Hz, 1H), 3.82 (s, 3H), 3.80-3.60 (m, 2H), 3.71 (s, 3H), 3.40-3.30 (m, 1H), 3.18-3.04 (m, 1H), 2.84-2.60 (m, 4H), 2.30 (m, 3H), 1,92-1.80 (m! 2H). Electrospray MS: Obs. [M+ H]: 411.2. At -78°C to Ag3 (0.292 g, 0.71 mmol, 1.0 equiv., RI=R2=R3=H) in THF (10 t5 mL) was added LiHMDS (1.1 mL, 1.1 mmol, 1.5 Equiv.) slowly, it was stirred at this temperature for 30 mins, then R41(0.152 g, 67 uL, 1.07 mmol, 1.5 Equiv., R4=Me) in THF (1 mL) was added. The reaction was warmed to rt slowly, and stirred at rt overnight. The reaction was quenched with water, extracted with EtOAc, washed with brine, dried over MgSO4 , filtered, and evaporated. The crude reaction mixture was purified by column chromatography (Eluent: CH3 OH/EtOAc = 0% to 20%), and Ag4 (0.173 g, 0.41 mmoI, yield 57%, R =R2=R3=H, R4=Me) was obtained as a mixture of two diastereomers. The NMR data is represented by the major isomer. 1H NMR (CDCI3 ) 5:7.67 (s, 1H), 7.36 (s 1H), 7.19 (d, J = 8.0 Hz, 1H), 6.98-6.82 (m, 6H), 4,25 (dd, J= 1.2, tl.2 Hz, IH), 4.18-4.02 (m, IH), 3.81 (s, 3H), 3.70 (s, 3H), &64°3.52 (m, 1H), 3.48-3.38 (m, 1H), 3.32-3.20 (m, 1H), 3.163.00 (m, 1H), 2.98-2.82 (m, 1H), 2.80-2.60 (m, 2H), 2.27 (s, 3H), " 90-t.76 (m 2H), 1.22 (d, J = 8.0 Hz, 3H). Electrospray MS: Obs. [M+ H]: 425.2. WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 t29 Method Ah R2 CO2Me R4M, THF R2 N'O'I/ bi 0 ',t 1..r R3 N N LvJ R4 ROCHE Ah2 To Ah1 (0.268 g, 0.65 mmof, R!=R2=R3=H), which was synthesized following similar procedure as described for Method Ag, in THF (20 mL) was added R4M (R4M=MeMgBr, 3.0 M in Et2 0, 0.65 mL, 1.96 mmol, 3.0 Equiv.) dropwise at ri, once TLC showed the completion of the reaction, it's quenched with Sat. NH4 CJ, and extracted with EtOAc. The combined organic layers was washed with Sat. NaHCO3 , dried over MgSO4 , filtered, and evaporated. The crude reaction mixture was purified by column chromatography (Eluent: CH3 OH/EtOAc = 0% to 20%), and Ah2 (0.050 g, yield 19%, RI=R2=R3=H, R4=Me) was obtained. 1H NMR (CDCI3 ) 6:7.68 (s, 1H), 7.40 (s, 1H), 7.19 (d, J = 8.0 Hz, 1H), 6.98-6.88 (m, 3H), 4.27 (dd, J = ! .6, 1 t.2 Hz, 1H), 3.80 (s, 3H), 3.80-3.72 (m, tri), 3.44-3.36 (m, 2H), 3.14-3.02 (m, ill), 2.78-2.62 (m, 2H), 2.27 (s, 3H), 2.10-2.04 (m, 1H), 1.94-1.78 (m, 2H), 1.78-1.62 (m, 1H), 1.30 (s, 6H). Electrospray MS: Obs. [M+ H]: 411.2. Method Ai R2 , ì , O N t ,..t •. R3 LiBr. acetçne:_ . «- NS N.pN-' OMs N j l Ail t Ai2 R2 Br The reaction mixture was stirred under reflux for 4.5 hrs, Ait was synthesized following similar procedure as described for Method Af, solvent was removed, the residue was diluted with EtQAc, washed with water and brine, dried over MgSQ4 , filter, and evaporated. The crude reaction mixture was purified by column chromatography (Eluent: CH3 OHiEtOAc = 0% to 20%), and the bromide WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Ai2 (1.03 g, 2.39 mmol, yield 57%, R =R2=R3=H) was obtained. 1H NMR (CDCI3 ) 5:7.74 (s, IH), 7.43 (s, IH), 7.22 (d, J = 7.6 Hz, tri), 6,98-6.90 (m, 3H), 4.45 (d, J = 11.2 Hz, 1H), 3.83 (s, 3H), 3.70-3.64 (m, tri), 3.60 (t, J = t0.8 Hz, 1H), 3.503.42 (m, 3H), 3.22-3.16 (m, 1H), 2.84-2.64 (m, 2h), 2.31 (s, 3H), 1.92-1.84 (m, 2H). Electrospray MS: Obs. [M+ H]: 433.2. Method Ai I o çOH I 0 O. R1 Swem Oxidation», O R2M Ail N Ai2 •R2 1. Mitsunobu Reaction 2, hydrazine. DCMiCH OH = 3. H3 PO4 , t-BuQH. 110 C Ai3 CeCI3, THF N.O,h R2 N,tN I " 4/ v F Aj4 At -78°C, to (0001)2 (0.243 g, 0.17 mL, 1.91 mmol, 2.2 Equiv.) in DCM (5 mL) was added DMSO (0.150 g, 0.14 mL, 1.91 mmol, 2.2 Equiv.)) slowly, and stirred at this temperature for 30 mins. Followed by addition of alcohol Ail (0.332 g, 0,87 retool, Rl=cyclopropyl), which was synthesized following similar procedure as described for Method R, in DCM (10 mL), the reaction mixture was stirred at78°C for 2 hrs, and quenched with Et3 N. It was warmed to rt, diluted with DCM, washed with water and brine, dried over MgSO4 , filtered, and evaporated. The aldehyde Ai2 obtained was used for the next step without any purification. At -78°C, to the suspension of CeCl3 (0.643 g, 2 61 retool, 3.0 Equiv.) in THF (10 mL) was added the Grignard reagent (R2M=4-F-phenyt magnesium bromide, 2.0 M in Et2 0, ! .30 mL, 2.61 mmoL 3,0 Equiv.) slowly, it's stirred at this temperature for 45 tains, followed by addition of the aldehyde (0.87 retool, 1.0 Equiv.) in THF (10 mL). The reaction mixture was warmed to ri slowly, and stirred at rt overnight. It's cooled to 0°C, and quenched with Sat. NH«Cl, extracted with EtQAc, the combined organic phases was washed with brine, dried over MgSO4 , filtered, and evaporated. The crude reaction mixture was pudfied by column WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 13i chromatography (Etuent: CH3 OHtEtOAc = 0% to 25%), and the alcohol was obtained a mixture of diastereomers Ai3 (0.115g, 0.24 retool, yield 25% for two steps, R1= cyclopropyl, R2=4-F-phenyl). Ai4 was then obtained from Ai3 via method R. For Ai4: H NMR (CDCl3 ) õ: 8.18 (s, 1H), 7.69 (s, 1H), 7.65-7.60 (m, 2H), 7.54 (s, tri), 7.50 (d, J = 7.6 Hz, 1H), 7.38-7.20 (m, 4H), 518 (d, J = 4.4 Hz, 1H), 4.12 (s, 3H), 4.04-3.96 (m, 1H), 3.423.38 (m, 2H), 3.10-2.90 (m, 3H), 2.62 (s, 3H), 228-1.98 (m, 2H), !.34-1.20 (m, 1H), 1.08-0.98 (m, tri), 0.88-0.60 (m, 2H), 0.10--0.02 (m, 1H). Electrospray MS: Obs. [M+ HI: 473.3. Method Ak I j NO" R2 O. EDCl coupling O. 3 CO2H " O/ Akl R4 Ak2 A solution of Akl (519.0 mg, 1.20 mmo!, RI=R2=R3=H), which was synthesized following similar procedure as described for Method Ag, in DMF (20.0 mL) was treated with 2.0 M of HNR4R5 in methanol (0.720 mL, 1.44 retool, R4=H, R5=Et), N-(3-Dimethytaminopropyt)-N-ethylcarbodiimide hydrochloñde (460.1 mg, 2.40 mmol), and 1-Hydroxybenzotriazole (324.0 mg, 2.40 retool) followed by the addition of N,N-Diisopropylethylamine (0.836 mL, 4.80 mmol) dropwise. After 18 h, the reaction mixture was diluted with saturated aqeous NaHCO3 and extracted with EtOAc (3x). The combined organic layers were washed with water (tx), brine (lx), dried over MgSO4 , and concentrated in vacuo. The residue was purified by flash chromatography (0-25% MeOH/ËtOAc) and then by reverse phase chromatography to afford Ak2 as a TFA sait (43.7 mg, 0.130 mmol, 8.6%, R =R2=R3=R4=H, RS=Ët). H NMR (CD3 OD 400 MHz) 6 7.60 (m, 2H), 7.38 (d, J = t5.37 Hz, 2H), 7.23 (d, J = 7.32 Hz, 2H), 4.42 (d, J = 1!.71 Hz, 1H), 4.13 (m, 2H), 3.97 (s, 3H), 3.72 (m, 1H), 3.56 (m, 1H), 3.21 (m, 2H), 2.92 (m, 2H), 2.75(m, 2H), 2.40 (s, 3H), 2.02 (mr 2H), I.!4 (m, 3H). LCMS: found 424.2 (M+t). WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Method Al O. R4_OH = OH N/Z" N"J -# LvJ O-R4 A solution of AIl (300.0 mg, 0.814 mmol, RI=R2=R3=H), which was synthesized following similar procedure as described for Method U, in Toluene (30.0 mL) was treated with R4OH (136.9 mg, 1.22 mmol, R4=4-F-phenyl), triphenylphosphine (427. I mg, 1.62 retool) was cooled at 0.0° C then the addition of diisopropyl azodicarboxylate (0.320 mL, 1.62 retool) dropwise and was heated to 60.0° C for 3 h. The reaction mixture was diluted with EtOAc (150 mL) and washed with IN NaOH, water, and brine. The crude mixture was dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (0-50% EtQAc/Hex) and then by reverse phase chromatography to give Al2 as a TFA sait (300.0 mg, 0.648mmol, 79.6%, RI=R2=R3=H, R4=4-Fphenyl), tri NMR (CD3 OD 400 MHz) õ 7.59 (m, 2H), 7.35 (m, 2H), 7.22 (m, 2H), !5 7.09 (m, 4H), 4.62 (d, J = 10.98 Hz, 1H), 4.3! (m, 2H), 4.15 (m, 2H), 3.98 (s, 3H), 3.86 (m, 1H), 3.61 (m= 1H), 2.90 (m, 2H), 2.42 (s, 3H), 2.02 (m, 2H). (m+H), m/z = 462.5, found 463.3 WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Method Am Ara1 R2 i OMs R4.SH Am2 R2 T R2 I NO" /Rl N N00S-R4 y Ara3 Method AM, Step 1: A solution of Am1 (300.0 mg, 0.671 mmol, RI=R2=R3=H), which was synthesized following similar procedure as described for Method Af, in EtOH (50 mL) was treated with R«SH (172.2 mg, ! .34 mmol, R4=4-F-phenyl) and KOH (56.54 mg, 1.0û mmol) portionwise and was heated at 70.0° C for 5 h. The reaction mixture was concentrated in vacuo and diluted with EtOAc (150 mL) then washed with water and brine. The crude mixture was dried over MgSO4 and I0 concentrated in vacuo. The residue was purified by flash chromatography (1075% EtOAciHex) to afford Ara2 (256.3 mg, 0.53 mmol, 79.7%, R =R2=R3=H, R4=4-F-phenyl). 1H NMR (CDCI3 400 MHz) õ 7.70 (s, ! H), 7.4! (m, 2H), 7.20 (m, 2H), 7.03 (m, 2H), 6.93 (m, 3H), 4.38 (d, J = t 1.71 Hz, 1H), 3.85 (s, 3H), 3.63 (d, J = I0,98 Hz, 1H), 3.34 (m, IH), 3.19 (m, 3H), 3.0t (m, 1H), 2.69 (m, 2H), 2.30 (s, I5 3H), 1.84 (m, 2H). (re+H), míz = 478.5, found 479.3 Method AM, Step 2: A solution of Am2 (251.6 mg, 0.525 mmo!, RI=R2=R3=H, R4=4-F-phenyl) in CH2CI2 (60.0 mL) was treated with m-Chloroperbenzoic acid (353.4 mg, 1.57 WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 mmoi). After 1 h. the reaction mixture was quenched with a i :1 ratio of saturated aqeous NaHCO3 (75mL), saturated Na2 S2 03 (75mL) and stirred for lh. The reaction mixture was extracted with CH2 Ct2 (3x) then the combined organic extracts were washed with 1N NaOH and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (0-30% MeOHtEtOAc), afforded Am4 (4.3 mg, .0087 mmoJ, 1.6%, RI=R2=R3=H, R4=4-Fphenyl): H NMR (CDCl3 400 MHz) õ 7.70 (m, 3H), 7.26 (m, 4H), 6.94 (m, 3H), 4.59 (d, J = 10.98 Hz, 1H), 3.95 (m, 4H), 3.76 (m, 2H), 3.31 (m, 1H), 3.19 (m, 1H), 2.97 (m, 1H), 2.78 (m, 2H), 2.31 (s, 3H), 1.91 (m, 2H). (m+H), m/z = 494.5, found 495.5. The residue was furthered purified by reverse phase chromatography to afford Am3 as a TFA sait (15.8 mg, 0.03 mmol, 5.9%, RI=R2=R3=H, R4=4-Fphenyt), tri NMR (CD3 OD 400 MHz) õ 8.09 (m, 3H), 7.57 (m, 2H), 7.42 (m, 2H), 7.27 (m, 2H), 7.16 (d, J = 8.05 Hz, 1H), 4.49 (d, J = 10.98 Hz, !H), 4.09 (m, 1H), 3.99 (m, 5H), 3.72(m, 2H), 3.58 (m, 1H), 2.79 (m, 2H), 2.41 (s, 3H), 1.91 (m, 2H). (re+H), m/z = 510.5, found 511.3. An1 Method An Ni Ñ - v s/i'-ÑH2 An2 WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Method An, Step 1: A solution of An! (1. !2g, 2.97 mmot, RI=R2=R3=H), which was synthesized following similar procedure as described for Method Ag, in N,N-Dimethyl acetoamide (30mL) was treated with (Me3 Si)2 S (0.93 mL, 4.45 mmol ) dropwise. After 7 h, the reaction mixture was diluted with saturated aqueous NaHCOî and extracted with EtOAc (3x). The combined organic layers were washed with water (lx), brine (lx), dried over MgSO4 , and concentrated in vacuo. The residue was purified by flash chromatography (0-25% MeOH/EtOAc) to give An2 (41û mg, 0.99mmol, 33.6%, RI=R2=R3=H). 1H NMR (CDCI3 400 MHz) õ 7.65 (s, 1H), 7.12 (d, J = 9.52 Hz, 1H), 6.85 (m, 1H), 5.85 (m, 1H), 4.13 (d, J = 10.98 Hz, 1H), 3.99 (m, 1H), 3.80 (s, 3H), 3.68 (m, 1H), 3.59 (s, 1H), 3.47 (s, 2H), 3.33 (m, 2H), 2.35 (m, 1H), 2.27 (s, 3H), 1.81 (m, 2H). (m+H), m/z = 411.5, found 412.4. Method An, Step 2: A solution of An2 (170.0 mg, 0.4t3 mmol, Rt=R2=R3=H) in DMF (10.0 mL) was treated with An3 (229.0 mg, 1.24 mmol, R4=H, RS=t-Butyl, X=Br). After 1.5 h, the reaction mixture was diluted with EtOAc (100 mL) washed with water and brine. The residue was dried over MgSO4 and concentrated in vacuo. The residue was püñfied by reverse phase chromatography to afford An4 as a TFA sait (40.2 mg, 0.08 mmol, 19.7%, RI=R2=R3=R4=H, R =tBu). H NMR (CD3OD 400 MHz) õ 7.52 (m, 1H), 7.42 (d, J = 8.05 Hz, 1H), 7.19 (s, 1H), 7.05 (s, tri), 6.98 (m, 1H), 6.18 (m, 1H), 4.23 (d, J = 10.98 Hz, 1H), 3.90 (s, 4H), 3.71 (m, 3H), 3.35 (m, 6H), 3.16 (m, 1H), 2.41 (s, 3H), 2.32 (m, 2H), 1.38 (s, 9H). (re+H), m/z = 491.6, found 492.3. WO 2010/056849 CA 02742486 2011-05-03 PÇT/US2009/064190 Method Ao HO. Bn2N / ", , , Aol N.O. RI AoS j, Bn2N ",, Ao2 R1M HO ..... R1 - Bn2 N#.,,,, Ao3 J Method R HO ..... R1 H2N Ao4 Method A0, Steps 1-3: To a solution of R1M (3 equiv., 60 mmot, Rl=3,5-difluorophenyl) in THF was added a solution of aldehyde Ao2 (20 mmol) in THF at 0°C and the resulting solution was stirred for 30 min at 0°C and then warmed to room temperature and stirred for an additional 30 minutes. Upon completion of the reaction, the reaction mixture was quenched with saturated NH4 CI, extracted with ethyl acetate, the organic layer was dried with MgSO4 , filtered, concentrated and purified using ethyl acetate in hexanes to afford the amino alcohol Ao3 (Rl=3,5-difluorophenyl) in 80% yield, tri NMR (CDCI3 ) 6 7.31-7.19 (m, 10H), 6.71 (m, 3H), 4.69 (d, 1H, J= 6.3 Hz), 3.69 (d, 2H, J = 13 Hz), 3.47 (d, 2H, J = 13 Hz), 3.04 (m 1H), 2.67 (br1H), 1.3 (d, 3H, J = 7Hz). To a solution of amino alcohol Ao3 (R =3,5difluorophenyl) in 100 mL methanol was added PdtC (2 gin of 10% Pd/C ) and the resulting solution was stirred under hydrogen for 18 hr or until the reaction completed. The reaction mixture was filtered through a pad of celite and concentrated to afford Ao4 (R :3,5-difluorophenyi) which was taken directly to the next step without purification. Method Ao, Steps 4-6 Following a similar procedure as described in Method R, Ao4 was transformed into Ao5 (R =3,5-difluorophenyl). H NMR (CDC!3 ) 7.69 (s, t H), WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 7.51 (s, 1H), 7.21 (m, 2H), 6.92 (m, 4H), 6.8 (m, IH), 5.9 (br-s, 1H), 3.83 (s, 3H), 3.48 (m, 1H), 3.42 (m, 1H), 3.13 (m, 1H), 2.80 (m, 1H), 2.70 (m, 1H), 2.29 (s, 3H), 1.91 (m, 2H), 1.01 (d, 2H, 6.3 Hz). Method Ap © © o O2N jO-.. O2N H2 N Apl Ap2 Ap3 J O 1 I Ap4 Ap5 Ap6 (EtO} o o il Ap6 H o Ap8 Ap7 ci WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 O I Ap9 OH R1 Apl0 CI NH2 Apl I R3 O H R2R CI Ap12 Ap13 R3 R Apl 4 or R4-B(OH)2 R4 Ap15 Method Ap, Compound Ap2: To a t2 L 3mecked round bottomed flask equipped with an addition funnel, under nitrogen and containing a solution of Apl (302.7 9, í.õ5 moi) in DMF (2.5 L) WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 was added K2 003 (905.3 g, 6.55 moi) portionwise over 5 min. Methyl iodide was then added dropwise via addition funnel over 70 min. and then the mixture was stirred overnight. The reaction mixture was slowly poured into an XL extractor containing a stirring mixture of water (7 L) and ice (3 L). The resulting mixture was extracted with ethyl acetate (1 x 6 L, I x 4 L), washed with water (1 x 4 L), and brine (1 x 2 L). The combined organic layers were dried over MgSO4 , filtered, and concentrated in vacuo to afford Ap2 (344 g, 97%) as yellow needles. 1HNMR (CDCI3, 400 MHz) 5 7.80 (d, 1H), L73 (d, 1H), 7.66 (dd, tri), 3.99 (s, 3H), 3.94 (s, 3H). Method Ap, Compound Ap3: To a 2 L Parr bottle containing a mixture of Ap2 (95 g, 0.45 mol) in MeOH (anhydrous, 1.3 L) under nitrogen was added (Raney nickel slurry in water (15 ml) exchanged with methanol 3 times). The reaction mixture was hydrogenated in a Parr shaker at 45 psi overnight. The reaction sat for 30 min. The top layer of the reaction mixture was decanted and filtered. The residue was diluted with DCM (1 L), swirled for 5 rein., and filtered resulting in Ap3 (> quantitative) as an off-white solid. 1HNMR (CDCI3 , 400 MHz) 5 7.52 (dd, 1H), 7.43 (d, 1H), 6.63 (d, IH), 4.21 (s, 2H), 3.88 (s, 3H), 3.84 (s, 3H). Method Ap, Compound Ap4: To a 12 L 3-necked round bottomed flask equipped with a mechanical stirrer, thermometer, addition funnel, nitrogen inlet, and containing a suspension of Ap3 (252 g, 1.39 mol) in water (3.5 L) at 0°C was added H2 SO4 (20% vol., 700 mL). A solution of NaNO2 (105.6 g, 1.53 mot) in water (550 mL) was added slowly over t h at 0°C to 3°C and the reaction mixture was stirred further for 1 h. Next, urea (25 g, 0.417 mol) was added to the reaction mixture portionwise and stirred for 15 min. Then a solution of KI (242.3 g, t .46 mol) in water (600 mL) was added to the 0°C reaction mixture over 30 rein. The reaction mixture was then heated at 55°C for 1o5 h. Next, ethyl acetate (4 L) was used to dìssõlve the reaction mixture WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 and the resulting solution was poured slowly into a solution of Na2 S2 05 (650 g) in ice water (4 L) and the flask was rinsed with ethyl acetate (2 L) and stirred for min. The resulting layers were separated and the aqueous phase (pli ~ 3) was extracted with ethyl acetate (2 L). The combined organic layers were washed with water (2 L x 2), brine (t L), dried over Mg2 SO4 , filtered, and concentrated in vacuo+ The crude material was purified via silica gel plug (ethyl acetate]hexanes) to afford Ap4 (370 g, 91%) as a white solid. 1HNMR (CDCI3 , 400 MHz) 7.83 (d, 1H), 7.43 (d, 1H), 7.35 (dd, 1H), 3.93 (s, 3H), 390 (s, 3H). Method Ap, Compound ApS: To a !2 L 3-necked round bottomed flask equipped with a mechanical stirrer, thermometer, nitrogen inlet, and containing a solution of Ap4 (270 g, 0.925 moi) in THF (4 L) was added LiBH4 (60.4 g, 2.77 mol) portionwìse at room temperature. The reaction mixture was placed in an ice bath and methanol (135 mL) was added dropwise. After the addition was complete the ice bath was removed and the reaction was heated to 65°C for I h. The reaction was then cooled in an ice bath and poured into an ice coPd solution of saturated aq. NH4 CI (2 L) and ethyt acetate (4 L) followed by rinsing of the flask with ethyl acetate (2 L). The solution was stirred for 15 min., the layers were separated and the aqueous layer was extracted with ethyl acetate (4 L). The combined organic layers were washed with water (2L x 2), brine (1 L), dried over MgSO4 , filtered and concentrated in vacuo to afford Ap5 (> quantitative) as a light-yellow oi/o 1HNMR (CDCI3, 400 MHz) 57.70 (d, 1H), 6.86 (d, 1H), 6.67 (dd, 1H), 4.64 (d, 2H), 3.88 (s, 3H). Method Ap, Compound Ap6: To a t 2 L 3-necked round bottomed flask equipped with a mechanical stirrer, thermometer, addition funnel, nitrogen inlet, and containing a solution of (COCI)2 (123.7 g, 0.975 mol) in DCM (3.5 L) at -70°C was added a solution of DMSO ('f73 g, 2.215 mo!! in DCM (250 mL) over 30 rein. and was stirred an WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 !41 additional 30 min. at -72°C. Next, a solution of Ap5 (234 g, 0.886 mol) in DCM (1 L) was added over 1.5 h to the reaction solution keeping the reaction temperature between -65°C and -70°C and then the reaction solution was stirred for an additional 30 min. at -70°C. Next: triethytamine (363 g, 3.587 mol) was added over t5 rein. and then the reaction mixture was stirred for an additional 1 h at - 65°0 The cooling bath was removed and the reaction mixture was poured into an extractor filled with ice water (3 L) and stirred for 15 rein. The layers were separated and the aqueous layer was extracted with DCM (2 L). The combined organic layers were washed with HCI (1541, 1.5 L), water (2 L x 3), brine (1 L), dried over MgSO«, filtered, and dried in vacuo. The crude material was triturated with hexanes (300 mL), filtered, washed with hexanes (100 mL x 2), and dried under vacuum to afford Ap6 (212.7 g, 92%) as an off-white solid. 1HNMR (CDCI3 , 400 MHz) 69.93 (s, 1H), 7.96 (d, 1H), 7.27 (d, 1H), 7.17 (dd, 1H), 3.94 (s, 3H). Method Ap, Compound Ap8: To a room temperature solution of Ap7 (50.0 g, 0.152 mol) and Ãp6 (37.7 g, 0.144 mol) in THF/EtOH (350 mL t 105 mL) and under nitrogen was added LiOH*H20 (14.6 g, 0.349 mol). After 24 h, the reaction was diluted with ethyl acetate and water and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over MgSO4 , and concentrated in vacuo. The crude material was purified by silica gel chromatography with ethyl acetate/hexanes to afford a yellow oil. The yellow oil was then dissolved in hot hexanes and gradually cooled to room temperature and then placed in an icebath. The resulting solid was filtered and washed with cold hexanes to afford Ap8 (23.97 g, 38%) as a white solid. 1HNMR (CDC13 , 400 MHz) 6 7.76 (d 1H), 7.52 (s, IH), 6.75 (d, íH), 6.68 (dd, 1H), 3.88 (s, 3H), 355 (t, 2H), 2.6t (m, 2H), 2.00 (m, 2H) 1.53 (s, 9H). WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Method Ap, Compound Ap9: To a round bottomed flask equipped with an addition funnel and nitrogen iñJet and containing a 10°C solution of Ap8 (23.97g, 0.054 moo in DCM (96 mL) was added trifluoroacetic acid (48 mL) dropwise over 45 minutes. After addition was complete, the cold bath was removed. After 3 h, the reaction was concentrated in vacuo and dried under vacuum to afford Ap9 (20.94 g, > 100%) as an off-white solid, tHNMR (CDCI3 , 400 MHz) 6 7.79 (t, 2H), 6.81 (d, 1H), 6.76 (dd, 1H), 3.90 (s, 3H), 3.59 (t, 2H), 2.70 (m, 2H), 2.05 (m, 2H); MS (LCMS, M+I) 381.0. Method Ap, Compound Ap11: To a room temperature solution of Ap9 (20.94 g, 0.055 mol), Apl0 (1&52 g, 0.0.55 mol, RI=R3=H, R2=3,4-5-trifluorophenyl), and HOBT (11.16 g, 0.082 mol) in DMF (149 mL) and under nitrogen was added diisopropylethylamine (58 mL, &33 moo followed by EDCI*HCI (19.51 g, 0.10 mol). After 16 h, the reaction was diluted with ethyl acetate (1 L), washed with aq. sat. NaHCO3 (2 x 300 mL), water (2 x 200 mL), and brine, (1 x 100 mL). The organic layer was then dried over Na2 SO4 , concentrated in vacuo, and dried under vacuum to afford crude Apll (R1=R3=H, R2=3,4-5-trifluoropheny0 as an orange oir. MS (LCMS, M+I) 554.0. Method Ap, Compound Ap12: To a room temperature solution of crude Ap11 (35.58 g, RI=R3=H, R2=3,4-5-trifluorõpheny0 in DMF (225 mL) and under nitrogen was added t-BuOK (88 g) in two portions. After 2.5 h, the reaction mixture was poured over icedbrine and then extracted with ethyl acetate. The combined organic layers 'were dried over Na2 SO4 , and concentrated in vacuo. The crude material was purified by silica gel chromatography with ethyl acetateimethanoghexanes to afford compound Ap12 (R1=R3=H, R2=3,4-5-trifluoropheny!). 1HNMR (CDCI3 , 400 MHz) õ 7.78 (m, 2H), 6.97 (t, 2H), 6.79 (d, lH), 6.72 (dd, 1H), 5.68 (t, lH) 4.14 (m, 2H), WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 3.88 is, 3H), 3.35 (m, IH), 3.15 (m, 1H), 2.78 (m, 2H), t.81 (m, 2H); MS (LCMS, M+t) 518.2. t0 Method Ap, Compound Ap13: Compound Ap13 (RI=R3=H, R2=3,4-5-trifluorophenyl) was synthesized using a method similar to Method R, Step 2. 1HNMR (CDCI3 , 400 MHz) 8 7.82 (s, tri), 7.75 (d, 1H), 6.93 (t, 2H), 6.80 (d, tri), 6.75 (dd, IH), 6.29 it, 1H), 4.13 (d, 2H), 3.83 (s, 3H), 3.27 (m, 1H), 3.03 (m, 1H), 2.81 (m, 2H), 1.86 (m, 2H) MS (LCMS, M+I) 533.2. Method Ap, Compound Ap2:Ap14 Compound Ap14 was synthesized using a method similar to Method R, Step 3. Purified compound Ap14 (RI=R3=H, R2=3,4-5-trifluorophenyt ) was then resolved via SFC using an OD-H column, tHNMR (CDCI3 , 400 MHz) 6 7.73 (d, 1H), 7.47 (s, IH), 6.98 (t, 2H), 6.76 (s, 1H), 6.68 (d, tri), 4 26 (s, IH), 4.03 (s, 2H), 3.87 (s, 3H), 3.11 (m, 2H), 2.70 (m, 2H), 1.80 (m, 2H); MS (LCMS, M+I) 515.0. Method Ap, Compound Ap15: To a microwave vial under nitrogen was added compound Ap14 (R =R3=H, R2=3,4-5-trifluorophenyl, 0.250 g, 0.486 mmol), Pd(PPh3 )4 (0.056 g, 0.0486 mmol), R4Bpin (R4Bpin=l-methyl-lH-pyrazole-4-boronic acid pinacol ester, 0.303 g, 1.46 mmol), Na2 CO3 (0.155 g, 1.46 mmol)in water (1.5 mL), and acetonitrile (3.5 mL). This mixture was then heated in a microwave to 130°C for 30 min. on high absorption. The resulting mixture was then poured over iced-brine, and then extracted with ethyl acetate. The combined organic íayers were dried over Na2SO4, and concentrated in vacuo. The crude material was purified by silica gel chromatography with methanol/ammonium hydroxideiDCM and MeOH/CHCt3 to afford compound Ap15 (R =R3=H, R2=3,4-5-trifluoropheny!, R4=4-(t-methy[-tHpyrazole), 0.t09 g, 48%) as a yeJ!ow solid. HNMR (CDCB, 400 MHz) 5 7.86 (d, 2H), 7.5! (m, 2H), 6.99 (t, 3H), 6.9t (s, íH), 4.26 (t 1H), 4.03 (d. 2H), 3.95 (s, WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 3H), 3.90 (s, 3H), 3.11 (m, 2H), 286 (m, 1H), 2.76 (m, 1H), 186 (m, 2H); MS (LCMS, M+I) 469.3. Method Aq N R5 (RI=R3=R4=H, R2=3,4,5-trifluoropheny[, RS=Me) Method Aq, Step 1: H Aql F Aq2 F A mixture of compound Aql (7 g), propanepoxide (16 mL) and ZrC}4 (0.27 g) was stirred at room temperature over night before it was filtered through celite. Solvent was removed and the crude residue was purified by column chromatography eluting with EtOAc/hexanes to yield compound Aq2 (6 g). Method Aq, Step 2: ' O Ç_ OTBS TBSO_ F Aq3 NEt3 (5.2 mL) was added to Aq2 (6.77 g) in DCM (150 mL) followed with addition of 3,3-dimethyl propenoyl chloride (2.5 mL) at 0 oC. The reaction was WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 I45 quenched in 2 hours with addition of NaHCO3 solution. The aqueous layer was extracted with DCM The organic layer was washed with water, brine, dried over MgSO4, and concentrated to give the crude product which was purified by column chromatography eluting with EtOAc/hexanes to yield compound Aq3 (4.3 g). Method Aq, Step 2: OTBS F F Aq3 1. MeCHClCO2 Cl 2. Mitsunobu reaction HO,.. o F Aq4 F MeCHCICO2Cl (0.26 mL) was added to a solution of compound Aq3 (2.1 g) in MeOH (15 mL) at room temperature. The reaction was worked up in 3 hours by removing solvent. The crude residue was purified by column chromatography eluting with EtOAc/hexanes to yield diol (1.0 g). The diol (3.5 g) in THF (100 mL) was treated with N-hydroxyphthaJimide (2.6 g), 1,1'-(azodicarbonyl)dipiperidine (5.33 g) and PBu3 (5.1 mL) at room temperature. The mixture was heated at 80 °C overnight. The mixture was cooled to room temperature and solid was filtered through celite. The residue was taken up in EtOAc and treated with NaHCO3 solution The aqueous layer was extracted with EtOAc. The organic layer was washed with water, brine, dried over MgSO4 , and concentrated to give the crude product which was purified by column chromatography eluting with EtOAc/hexanes to yieid compound Aq4 (3.0 g). WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 Method Aq, Step 4: 1. NH2 NH2 2. P2 05 Aq5 Compound Aq4 (3.0 g) in MeOH/DCM (60 mL, 1/t) was treated with NH2NH2.xH20 (1.07 mL) at room temperature. The mixture was stirred for 2 hours before it was diluted with DCM and NaHCO3 solution. The aqueous layer was extracted with DCM. The organic layer was washed with water, brine, dried over MgSO4, and concentrated to give the crude product which was purified by column chromatography eluting with EtOAc/hexanes to yield oxyamine (1.6 g). The oxyamine was dissolved in EtOH (100 mL) and added to P2 05 (13.1 g). The resulting mixture was stirred at 80 °C over night before it was cooled and concentrated to 20 mL. The residue was diluted with EtOAc and NaOH solution (I0%). The aqueous layer was extracted with EtOAc. The organic layer was washed with water, brine, dried over MgSO«, and concentrated to give the crude product which was purified by column chromatography eluting with t5 EtOAclhexanes to yield compound Aq5 (1.5 g), WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 t5 Method Aq, Step 5: HO-.. 1o N F F Aq5 Aq6 Compound Aq5 (1.9 g) in MeOH/DCM (150 mL, 2/3) was ozonized at-78 °C for 1 hour. After purging away excess of 03 with 02 , Me2 S (3.3 mL) was added to quench the reaction. Solvent was removed. The residue was diluted with EtOAc and NaCI solution (10%), The aqueous layer was extracted with DCM The organic layer was washed with water, brine, dried over MgSO4 , and concentrated to give the crude product which was purified by column chromatography eluting with EtOAc/hexanes to yield compound Aq6 (0.9 g). Method Aq, Step 6: N''0 " O F 1) PPh3 .HBr "N 0 0 F Aq6 F F Aq7 Comopund Aq6 (0.46 g) in CICH2 CH2 CIiMeCN (20 mL, 1/t) was treated with PPh3 .HBr (0.73 g) and heated for 5 hours before solvent was removed. The residue was taken up in THFiDMF (27.5 mL, t0/1) and 3-methoxy-4-(1-(4methytinidazolyf))benzaldehyde (0.29 g) was added. The mixture was cooled to 0 °C and LHMDS (&5 mL, t.0 M in THF) was added dropwise. The mixture was stirred at 0 °C for 1 hour and then room temperature for I hour before NH4 CI was added to quench the reaction. The residue was dìtuted with EtOAc. The aqueous layer was extracted with EtOAc. The organic layer was washed with water, brine, dried over MgSO4 , and concentrated to give the crude product which was purified WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 by column chromatography eluting with EtOAc!hexanes to yield compound Åq7 (0.13 g). Method Ar Bn ,..Oy R3 TMS "- /f" OMe Y ./<$ oo J N? Arl N/ Af3 TFA (7.9 uL) was added at room temperature to a solution of compound Arl (40 mg, RI=R3=H, R2=3,4,54rífluorophenyi), which was synthesized following similar procedure as described for Method R, and compound Af2 (43.7 uL) in THF (I .2 mL). The mixture was stirred over night before solvent was removed. The residue was purified with Gilson reverse phase HPLC to give product Ar3 (38 mg, RI=R3=H, R2=3,4,5-trifluorophenyl ), LCMS (M + H) = 602.3. The compounds (253-394) in the table below were synthesized by the following procedures similar to those indicated in the "Method of Synthesis" column. WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 t49 Structure [ Observed J ] Method of i I Mass i t t / Synthesis i 9% ! ' !! j ! j 1,/ i i i \ J j q-,,.V/" Enantiomer l 607,33 i I il Y Enantiomer I \ J Ertantiolncr OH H X /" Di tstcr¢omc, r f F 369.2 481.2 R I ....... -- t.7 AC 2.2 Ac A¢ 1.6 WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 !50 I o,,,.., OH w I I! i F 481,2 481.26 423.23 423,23 1.6 2+7 Ac R R l I WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 N i \ H ! i "" i ii F I N/ i< iii t4 602.33 431.24 378,2I 2.5 2,1 Ar I f I Af Ag WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 t i í O.... /.o !i J i i fJ o 'J \ f 411.23 425.23 411.23 2.t 2.3 r 2.2 432.24 2.6 3.1 Ag Ag Ah Ai 473.26 Ai i WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 ŒEEf J Ji t i il I J F i I L-.wi 473.26 T 447,2 463,2 469.26 3.3 2,7 Ai Af A R ..... . .... d WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 I i i -- / ---.v/ ! N/° 381.21 491.27 339.19 429.24 i 2.2 i 3 i 1.7 2.5 R R R R WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 t55 \:J 459,25 3.1 R C 369.2 479,26 479.26 I 2.2 J WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 © hi i.w ',, .J---- .%/i .... .«/ \ J O i !i Nfi S%-/ F i N-i° ç I i[ i : I i 395.22 i .... i 459.25 1.9 369.2 2.3 469.26 3.4 R R R WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 F Ci i O o , F H !i ! ji .l i i t J y J -, ' i 469.2.6 492.3 506.3 3+4 H J 512.3 R V V V WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 if /,, O .,-,, A il B \ " i J l Y 29O 5t23 526.3 528,3 r il N "-s;:s" o " " V V V V WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 I i .J/ ï il W H /.,, «W / .I 540.3 540.3 V 554.3 --- t i 554,3 V V V V 478.3 ,.. 298 ...... i WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 t60 !l o 478,3 .... 486,3 V V 486.3 V 490.3 490.3 V V WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 ' if i, , , » - / z ! " O i N i i.i: i i i N i 'ì\ -çSY i / ""0 E 497.3 .... 487,3 .... 487.3 ..... 424.23 2.2 438.24 2 V V V Y Y WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 !62 O HN \ 436.24 436.24 465.26 368.2 i 2.2 Y 26 Y 2,4 Y 1.9 V 3 R WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 I I f o O ii y il I , N N" / f i il i í , , o i O F N / / £1 alltiom¢r lJ 3t8 450.25 436.24 i 395.22 407.22 2,4 i i i 2.2 2+8 3,2 W W R R 407.22 3.2 R WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 I I l E a ti¢,mcr [ t s I tl I 3t9 421.23 i 42t,23 ì 1,8 1,6 i R A R V WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 j =i . \ i H 571.31 I E 3,4 R X , R R WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 i i r o F H H I /0. y o Z S.. F --í l. r f i !i i í «s"-- fÇ F481.26 481.2 571.2 U U i ii J °--- S% =. i ! " j OH 481.2 i i U i WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 °--- «" w i Ji \ i 481.2 F i u I J J 571+2 465.2 Ao WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 \ I :.SJ F i li O, OH 465.2 493,2 475.2 ---1 Ao Ao Ao Ao WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 I69 o ] ii K"/ "" "' "" " """ F ! u : I L ! O ' , i if / i \ i Ra« i Nacemic 465.2 415.2 445,24 429.24 2.8 3.2 Ao R R R WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 t70 i .. I l , "ì S , i Rat€mie Rac miç \/ acelllic i Y \S" / Rac J¢ d 367.2 459.25 465.26 2,4 2.8 419,23 i 2.2 J R R R WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 anti0mcr [ ../0 il i i1 i i ii / i i S '/ i ./ Enami01 t r Il i / ......... 350 445.24 445,24 429.24 429,24 3,1 3.t R R R WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 o F F I 607.33 471,26 417.23 463.25 3.t 2,1 3.4 Ac Ab R AI WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 if j 438.24 Ak O i O, "\ j L i:SJ 466.26 2.5 Ak 479,26 Am 3.3 jO í 359 478.26 1.4 452.25 t .5 Ak l Ak WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 I j.o ° "-- <-" .,f- .,,,,,. il i i "ç i 490.27 424.23 E 511.28 i I i 495,27 464.26 2.7 1.9 2.3 2.4 Ak Ak Am Am Ak WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 o l,-j o,... f /..«<.. /A...4 ,, ,,9"--»i "-..Fy object i s/°'-... i J ° ""Y " i i i 450.25 2,2 J 487.27 1.7 i I I 464.26 2.6 Ak Ak An WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 i l! " = Il i N ! , /o 37O 484.27 »( ' i 433.24 433.24 433,24 484.27 i i 2.6 I 3 R i 2.6 2.6 I R 3 R WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 t77 ' i! .i i iJ 484.27 3 CI O i i i ii 451.25 2.7 467.26 2.7 2.7 2,7 447,25 I 451,25 R R R R WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 i ii i f E i G! O l iJ õ if y i I i s O i ! ii \ OESJ 467,26 467.26 451.25 483.27 2.9 2,9 2.6 3.6 3.6 R R R WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 f I I N// '-'-N , !J J !I : , i I "," i V" W "" I ....... I 483.27 1 3.6 467.26 3.4 467,26 485,27 485,27 j i t i .............. R R 2 R 3,2 Aq 4.2 Aq J WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 i .Q i i i i i i t: F / D a ¢ eçmer l !l 485.27 485.27 467.3 467.3 467.3 4.2 4.2 i Aq Aq Aq Aq Aq -4 WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 !81 i i i « i F ' Dia tcr¢omer IV 467.3 mr i i i ! Aq i Assay: S ecretase Reaction and AI3 Analysis in Whole Cells: HEK293 cells overexpressing APP with Swedish and London mutations were treated with the specified compounds for 5 hour at 37 °C in 100 ml of DMEM medium containing 10% fetal bovine serum. At the end of the incubation, total AI3, Ap40 and Ap42 were measured using etectrochemiluminescence (ECL) based sandwich immunoassays. Total Ap was determined using a pair of antibodies TAG-W02 and biotin-4G8, A 40 was identified with antibody pairs TAG-G2-10 and biotin4G8, while AI342 was identified with TAG-G2-11 and biotin-4G8. The ECL signal was measured using Sector tmager 2400 (Meso Scale Discovery). MS Analysis of AI3 Profile: At3 profile in conditioned media was determined using surface enhanced laser desorptiontionization (SELDI) mass spectrometry. Conditioned media was incubated with antibody W02 coated PS20 ProteinChip array. Mass spectra of At3 captured on the array were read on SELDI ProteinChip Reader (Bio-Rad) according to manufacture's instructions. CSF At3 Analysis: AI3 in rat CSF was determined using MSD technology as described above. A#40 was measured using antibody pair Tag-G2-10 and biotin4G8, while A#42 was measured using Tag-anti A1342 (Meso Scale Discovery) and biotim4G8. The ECL signal was measured using Sector Imager 2400 (Meso Scale Discovery). Matrix-assisted laser desorption/ionization mass spectrometric (MALD! MS) analysis of At] is performed on a Voyager-DE STR mass spectrometer (ABI, Framingham: MA). The instrument is equipped with a pulsed nitrogen laser (337 WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 rim). Mass spectra are acquired in the linear mode with an acceleration voltage of kV. Each spectrum presented in this work represents an average of 256 laser shots. To prepare the sample-matrix solution, 1 /,4_ of ímmunoprecipitated A,6 sample is mixed with 3 L of saturated ct-cyano-4-hydroxycinnamic acid solution in 0. I% TFA!acetonitriEe. The sample-matrix solution is then applied to the sample plate and dried at ambient temperature prior to mass spectrometric analysis. Ail the spectra are externally calibrated with a mixture of bovine insulin and ACTH (18-39 clip). Certain compounds of the invention had an Ab42 1C50 within the range of about 1 ! .4 riM to about 20,000 riM. Certain compounds of the invention had an Ab42 ICso within the range of about 11.4 riM to about 97 nM. Certain compounds of the invention had Abtotal/Ab42 ratio within the range of about 1 to 1222. Certain compounds of the invention had Abtotal/Ab42 ratio within the range of about 205 to 602. While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and other variations thereof will be apparent to those of ordinary skill in the art. A I such alternatives, modifications and variations are intended to lai1 within the spirit and scope of the present invention. WO 2010/056849 CA 02742486 2011-05-03 PCT/US2009/064190 !83 In its many embodiments, the present invention provides a novel class of heterocyclic compounds of Group A or Group, as defined herein, as modulators of gamma secretase, methods of preparing such compounds, pharmaceutical compositions containing one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition, or amelioration of one or more diseases associated with the central nervous system using such compounds or pharmaceutical compositions. 1. A compound selected from the group consisting of compounds of Q 11, R4, T2, U2, W3, X2, Y3, Z2, Aa2, Ab2, Ac6, Af3, Ag4, Ah2, Ai2, Aj4, Ak2, Al2, Am3, Am4, An4, Ao5, Ap15, Aq7, Ar3, 201-203, 206-215, 220-222, 226-227, 229, 231, 233, and 245-394, or a pharmaceutically acceptable salt thereof. 2. The compound of Claim I selected from the group consisting of compounds Q11, R4, T2, U2, W3, X2, Y3, Z2, Aa2, Ab2, Ac6, Af3, Ag4, Ah2, Ai2, Aj4, Ak2, Al2, Am3, Am4, An4, Ao5, Ap15, Aq7, Ar3, 201-203, 206-215, 220-222, 226-227, 229, 231, 233, and 245-394. 3. A pharmaceutically acceptable salt of a compound of Claim 1. 4. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Claim 1, and a pharmaceutically acceptable carrier. 5. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Claim 1, and a pharmaceutically acceptable carrier, and and an effective amount of one or more other pharmaceutically active drugs selected form the group consisting of: (a) drugs useful for the treatment of Alzheimer's disease, (b) drugs useful for inhibiting the deposition of amyloid protein (e.g., amyloid beta protein) in, on or around neurological tissue, (c) drugs useful for treating neurodegenerative diseases, and (d) drugs useful for inhibiting gamma-secretase. 6. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Claim 1, and a pharmaceutically acceptable carrier, and an effective amount of one or more BACE inhibitors. 7. A pharmaceutical composition: (1) comprising a therapeutically effective amount of at least one compound of Claim 1, or a pharmaceutically acceptable salt, solvate, or ester thereof, and at least one pharmaceutically acceptable carrier, or (2) comprising a therapeutically effective amount of at least one compound of Claim 1, or a pharmaceutically acceptable salt, solvate, or ester thereof, and at least one pharmaceutically acceptable carrier, and an effective amount of one or more other pharmaceutically active drugs selected form the group consisting of: (a) drugs useful for the treatment of Alzheimer's disease, (b) drugs useful for inhibiting the deposition of amyloid protein (e.g., amyloid beta protein) in, on or around neurological tissue, (c) drugs useful for treating neurodegenerative diseases, and (d) drugs useful for inhibiting gamma- secretase, or (3) comprising a therapeutically effective amount of at least one compound of Claim 1, or a pharmaceutically acceptable salt, solvate, or ester thereof, and at least one pharmaceutically acceptable carrier, and an effective amount of one or more BACE inhibitors, (4) comprising a therapeutically effective amount of at least one compound of Claim 1, or a pharmaceutically acceptable salt, solvate, or ester thereof, and at least one pharmaceutically acceptable carrier, and effective amount of one or more cholinesterase inhibitors, or (5) comprising a therapeutically effective amount of at least one compound of Claim 1, and at least one pharmaceutically acceptable carrier, and effective amount of one or more cholinesterase inhibitors, or (6) comprising a therapeutically effective amount of at least one compound of Claim 1, or a pharmaceutically acceptable salt, solvate, or ester thereof, and at least one pharmaceutically acceptable carrier, and effective amount of one or more BACE inhibitors, muscarinic antagonists, cholinesterase inhibitors; gamma secretase inhibitors; gamma secretase modulators; HMG-CoA reductase inhibitors: non-steroidal anti-inflammatory agents; N-methyl-D- aspartate receptor antagonists-, anti-amyloid antibodies; vitamin E; nicotinic acetylcholine receptor agonists; CB1 receptor inverse agonists or CB1 receptor antagonists; an antibiotic; growth hormone secretagogues; histamine H3 antagonists; AMPA agonists; PDE4 inhibitors-, GABA A inverse agonists; inhibitors of amyloid aggregation-, glycogen synthase kinase beta inhibitors; promoters of alpha secretase activity; PDE-10 inhibitors and cholesterol absorption inhibitors, or (7) comprising a therapeutically effective amount of at least one compound of Claim 1, and at least one pharmaceutically acceptable carrier, and effective amount of one or more BACE inhibitors, muscarinic antagonists, cholinesterase inhibitors; gamma secretase inhibitors; gamma secretase modulators-, HMG-CoA reductase inhibitors; non-steroidal anti -inflammatory agents; N-methyl-D-aspartate receptor antagonists; anti-amyloid antibodies; vitamin E; nicotinic acetylcholine receptor agonists; CB1 receptor inverse agonists or CB1 receptor antagonists; an antibiotic; growth hormone secretagogues; histamine H3 antagonists; AMPA agonists; PDE4 inhibitors; GABA A inverse agonists; inhibitors of amyloid aggregation; glycogen synthase kinase beta inhibitors; promoters of alpha secretase activity; PDE-10 inhibitors and cholesterol absorption inhibitors, or (8) comprising a therapeutically effective amount of at least one compound of Claim 1, or a pharmaceutically acceptable salt, solvate, or ester thereof, and at least one pharmaceutically acceptable carrier, and an effective amount of donepezil hydrochloride, or (9) comprising a therapeutically effective amount of at least one compound of Claim 1, and at least one pharmaceutically acceptable carrier, and an effective amount of donepezil hydrochloride. 8, A method of: (a) modulating gamma-secretase comprising administering an effective amount of one or more compounds of Claim 1 to a patient in need of such treatment; or (b) treating one or more neurodegenerative diseases, comprising administering an effective amount of one or more compounds of Claim 1 to a patient in need of treatment; or (c) inhibiting the deposition of amyloid protein in, on or around neurological tissue, comprising administering an effective amount of one or more compounds of Claim 1 to a patient in need of treatment. 9. A method of treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1 to a patient in need of treatment. 10. A method of (a) modulating gamma-secretase, (b) treating one or more neurodegenerative diseases, (c) inhibiting the deposition of amyloid protein in, on or around neurological tissue, or (d) treating Alzheimer's disease, comprising administering administering: (1) an effective amount of a compound of Claim 1, and (2) an effective amount of one or more other pharmaceutically active ingredients selected from the group consisting of: BACE inhibitors, muscarinic antagonists, cholinesterase inhibitors; gamma secretase inhibitors; gamma secretase modulators; HMG-CoA reductase inhibitors; non-steroidal anti- inflammatory agents; N-methyl-D-aspartate receptor antagonists; anti-amyloid antibodies-, vitamin E; nicotinic acetylcholine receptor agonists; CB1 receptor inverse agonists or CB1 receptor antagonists; an antibiotic; growth hormone secretagogues, histamine H3 antagonists; AMPA agonists; PDE4 inhibitors-, GABA A inverse agonists; inhibitors of amyloid aggregation; glycogen synthase kinase beta inhibitors; promoters of alpha secretase activity; PDE-10 inhibitors and cholesterol absorption inhibitors, to a patient in need of such treatment. 11. A method of treating Alzheimer's disease, comprising administering an effective amount of a compound of Claim 1, and an effective amount of one or more compounds selected from the group consisting of A.beta. antibody inhibitors, gamma secretase inhibitors and beta secretase inhibitors, to a patient in need of such treatment. 12. A method of treating Alzheimer's disease, comprising administering an effective amount of a compound of Claim 1, and an effective amount of one or more BACE inhibitors, to a patient in need of such treatment. 13. A method of: (1) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1, in combination with an effective amount of one or more cholinesterase, to a patient in need of treatment, or (2) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1, in combination with an effective amount of donepezil hydrochloride, to a patient in need of treatment, or (3) treating Alzheimer's disease, comprising administering an effective amount of a compound Claim 1, in combination with an effective amount of one or more cholinesterase, to a patient in need of treatment, or (4) treating Alzheimer's disease, comprising administering an effective amount of a compound of Claim 1, in combination with an effective amount of donepezil hydrochloride, to a patient in need of treatment, or (5) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1, in combination with an effective amount of (rivastigmine, to a patient in need of such treatment, or (6) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1, in combination with an effective amount of tacrine, to a patient in need of such treatment, or (7) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1, in combination with an effective amount of a Tau kinase inhibitor, to a patient in need of such treatment, or (8) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1, in combination with an effective amount of one or more Tau kinase inhibitors selected from the group consisting of: GSK3beta inhibitors, cdk5 inhibitors, ERK inhibitors, to a patient in need of such treatment, or (9) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1, in combination with an effective amount of one anti-Abeta vaccination, to a patient in need of such treatment, or (10) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1, in combination with an effective amount of one or more APP ligands, to a patient in need of such treatment, or (11) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1, in combination with an effective amount of one or more agents that upregulate insulin degrading enzyme and/or neprilysin, to a patient in need of such treatment, or (12) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1, in combination with an effective amount of one or more cholesterol lowering agents, to a patient in need of such treatment, or (13) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1, in combination with an effective amount of one or more cholesterol lowering agents selected from the group consisting of: Atorvastatin, Fluvastatin, Lovastatin, Mevastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin, and Ezetimibe, to a patient in need of such treatment, or (14) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1, in combination with an effective amount of one or more fibrates, to a patient in need of such treatment, or (15) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1, in combination with an effective amount of one or more fibrates selected from the group consisting of, clofibrate, Clofibride, Etofibrate, Aluminium Clofibrate, to a patient in need of such treatment, or (16) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1, in combination with an effective amount of one or more LXR agonists, to a patient in need of such treatment, or (17) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1, in combination with an effective amount of one or more LRP mimics, to a patient in need of such treatment, or (18) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1, in combination with an effective amount of one or more 5-HT6 receptor antagonists, to a patient in need of such treatment, or (19) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1, in combination with an effective amount of one or more nicotinic receptor agonists, to a patient in need of such treatment, or (20) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1, in combination with an effective amount of one or more H3 receptor antagonists, to a patient in need of such treatment, or (21) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1, in combination with an effective amount of one or more histone deacetylase inhibitors, to a patient in need of such treatment, or (22) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1, in combination with an effective amount of one or more hsp90 inhibitors, to a patient in need of such treatment, or (23) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1, in combination with an effective amount of one or more ml muscarinic receptor agonists, to a patient in need of such treatment, or (24) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1, in combination with an effective amount of one or more 5-HT6 receptor antagonists mGluR1 or mGluR5 positive allosteric modulators or agonists, to a patient in need of such treatment, or (25) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1, in combination with an effective amount of one or more mGluR2/3 antagonists, to a patient in need of such treatment, or (26) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1, in combination with an effective amount of one or more anti-inflammatory agents that can reduce neuroinflammation, to a patient in need of such treatment, or (27) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1, in combination with an effective amount of one or more Prostaglandin EP2 receptor antagonists, to a patient in need of such treatment, or (28) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1, in combination with an effective amount of one or more PAl-1 inhibitors, to a patient in need of such treatment, or (29) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1, in combination with an effective amount of one or more agents that can induce Abeta efflux, to a patient in need of such treatment, or (30) treating Alzheimer's disease, comprising administering an effective amount of one or more compounds of Claim 1, in combination with an effective amount of gelsolin, to a patient in need of such treatment,or (31) treating Downs syndrome, comprising administering an effective amount of one or more compounds of Claim 1 to a patient in need of treatment, or (32) treating Downs syndrome, comprising administering an effective amount of a compound of Claim 1 to a patient in need of treatment, or (33) treating Downs syndrome, comprising administering an effective amount of one or more compounds of Claim 1, in combination with an effective amount of one or more cholinesterase inhibitors, to a patient in need of treatment. (34) treating Downs syndrome, comprising administering an effective amount of one or more compounds of Claim 1, in combination with an effective amount of donepezil hydrochloride, to a patient in need of treatment, or (35) treating Downs syndrome, comprising administering an effective amount of acompound of Claim 1, in combination with an effective amount of one or more cholinesterase inhibitors, to a patient in need of treatment. (37) treating Downs syndrome, comprising administering an effective amount of a compound of Claim 1, in combination with an effective amount of donepezil hydrochloride, to a patient in need of treatment, or (38) treating mild cognitive impairment, comprising administering an effective amount of one or more compounds of Claim 1 to a patient in need of treatment, or (39) treating glaucoma, comprising administering an effective amount of one or more compounds of Claim 1 to a patient in need of treatment, or (40) treating cerebral amyloid angiopathy, comprising administering an effective amount of one or more compounds of Claim 1 to a patient in need of treatment, or (41) treating stroke, comprising administering an effective amount of one or more compounds of Claim 1 to a patient in need of treatment, or (42) This invention also provides a method of treating dementia, comprising administering an effective amount of one or more compounds of Claim 1 to a patient in need of treatment, or (43) treating microgliosis, comprising administering an effective amount of one or more compounds of Claim 1 to a patient in need of treatment, or (44) treating brain inflammation, comprising administering an effective amount of one or more compounds of Claim 1 to a patient in need of treatment, or (45) treating olfactory function loss, comprising administering an effective amount of one or more compounds of Claim 1 to a patient in need of treatment. 14. A kit comprising, in separate containers, in a single package, pharmaceutical compositions for use in combination, wherein one container comprises an effective amount of a compound of Claim 1 in a pharmaceutically acceptable carrier, and another container comprises an effective amount of another pharmaceutically active ingredient, the combined quantities of the compound of claim 1 and the other pharmaceutically active ingredient being effective to: (a) treat Alzheimer's disease, or (b) inhibit the deposition of amyloid protein in, on or around neurological tissue, or (c) treat neurodegenerative diseases, or (d) modulate the activity of gamma-secretase.