TW201311680A - 5-substituted iminothiazines and their mono- and dioxides as BACE inhibitors, compositions, and their use - Google Patents

Abstract

In its many embodiments, the present invention provides provides certain iminothiazine compounds and mono- and dioxides thereof, including compounds Formula (I): and tautomers and stereoisomers thereof, and pharmaceutically acceptable salts of said compounds, said tautomeros and said stereoisomers, wherein each of the variables shown in the formula are as defined herein. The novel compounds of the invention may be useful as BACE inhibitors and/or for the treatment and prevention of various pathologies related thereto. Pharmaceutical compositions comprising one or more such compounds (alone and in combination with one or more other active agents), and methods for their preparation and use, including Alzheimer's disease, are also disclosed.

Description

5-substituted imidothiophenes as BACE inhibitors and their mono- and di-oxides, compositions and uses thereof

The present invention provides certain 5-substituted imidothiophenes Compounds and single and dioxide thereof and compositions comprising the same, which are useful as inhibitors of BACE and for the treatment or prevention of conditions associated therewith.

The starch-like beta peptide ("Aβ") is a major component of beta-starch fibrils and plaques, and it is believed that these beta-type starch fibrils and plaques play a role in an increasing number of conditions. Examples of such conditions include, but are not limited to, Alzheimer's Disease, Down's syndrome, Parkinson's disease, memory loss (including with Alzheimer's) Disease and memory loss associated with Parkinson's disease), attention deficit symptoms (including symptoms of attention deficit associated with Alzheimer's disease ("AD"), Parkinson's disease and Down's syndrome), dementia (including Pregnancy dementia, Alzheimer's disease, dementia associated with Alzheimer's disease, Parkinson's disease and Down's syndrome, progressive supranuclear palsy, cortical basal ganglia degeneration, neurodegeneration, olfactory disorders (including Zermochrome, Parkinson's disease and Down's syndrome associated olfactory disorders), beta-type amylovascular disease (including brain amylovascular disease), hereditary cerebral hemorrhage, mild cognitive impairment ("MCI"), Glaucoma, amyloidosis, type 2 diabetes, hemodialysis (β ₂ microglobulin and complications caused by it), nerves such as scrapie, bovine spongiform encephalitis and Creutzfeld-Jakob disease Degenerative diseases and the like.

Aβ peptide short peptide, which is produced by proteolytic decomposition of a transmembrane protein called an amyloid precursor protein ("APP"). Aβ peptide system from APP by β-minute The secretase activity is produced at a position corresponding to the N-terminus of Aβ and is cleaved by the γ-secretase activity at a position corresponding to the C-terminus of Aβ. (APP is also cleaved by α-secretase activity, resulting in a non-starch-derived secretory fragment called soluble APPα.) β-APP lyase (“BACE-1”) is considered to be produced by β-secretase activity The major aspartame thiol protease responsible for abnormal Aβ. Inhibition of BACE-1 has been shown to inhibit the production of A[beta].

It is estimated that more than 200 million people worldwide suffer from Alzheimer's disease and are believed to be the most common cause of dementia. AD is a disease characterized by neuronal degeneration and loss and also characterized by the formation of senile plaques and neurofibrillary tangles. Currently, the treatment of Alzheimer's disease is limited to the treatment of its symptoms rather than the underlying causes. Symptom modifiers approved for this purpose include, for example, N-methyl-D-aspartate receptor antagonists, such as memantine (Namenda®, Forrest Pharmaceuticals); cholinesterase Inhibitors such as donepezil (Aricept®, Pfizer), rivastigmine (Exelon®, Novartis), galantamine (Razadyne Reminyl®) and tacrine (tacrine) ) (Cognex®).

In AD, Aβ peptides formed by β-secretase and γ-secretase activity can form a tertiary structure that can aggregate to form starch-like fibrils. Aβ peptides have also been shown to form Aβ oligomers (sometimes referred to as "Aβ aggregates" or "Aβ oligomers"). The Aβ oligomer is composed of 2 to 12 Aβ peptides which are structurally different from the small multimeric structure of Aβ fibrils. Amylopectin-like fibrils can be deposited as dense plaques in areas of the brain that are important for memory and cognition outside of neurons, known as senile plaques, neuritic plaques or diffuse plaques. Aβ oligomers are cytotoxic when injected into rat brain or cell culture. This Aβ plaque is formed and deposited and/or The formation of Aβ oligomers and the resulting neuronal death and cognitive impairment are all characteristic of the pathophysiology of AD. Other features of AD pathophysiology include intracellular neurofibrillary tangles and neuroinflammation consisting of aberrantly phosphorylated tau protein.

There is evidence that Aβ and Aβ fibrils and plaques play a causal role in the pathophysiology of AD. (See Ohno et al., Neurobiology of Disease, 26 (2007), 134-145.) Mutations in APP and presenilin 1/2 (PS1/2) genes are known to cause familial AD, and 42-amino groups are considered The increase in the production of acid form of Aβ is the cause. Aβ has been shown to be neurotoxic in culture and in vivo. For example, when injected into the brain of an aged primate, fibrillar A[beta] causes neuronal cell death around the injection site. Other direct and contextual evidence for the role of Aβ in Alzheimer's etiology has also been published.

BACE-1 has become an acceptable therapeutic target for the treatment of Alzheimer's disease. For example, McConlogue et al, J. Bio. Chem. , Vol. 282, No. 36 (September 2007) have shown that a decrease in the locality of BACE-1 enzyme activity and a concomitant decrease in Aβ concentration significantly inhibits Aβ-driven AD-like conditions (while minimizing the side effects of complete inhibition), making β-secretase a target for therapeutic intervention in AD. Ohno et al, Neurobiology of Disease, 26 (2007), 134-145 report that deletion of BACE-1 gene in 5XFAD mice terminates Aβ production, blocks starch-like deposition, and prevents cerebral cortex and lower feet (5XFAD mice) It shows neuronal loss found in the brain region of the most severe amyloidosis, and rescues memory deficits in 5XFAD mice. The group also reported the ultimate cause of neuronal death in Aβ-based AD and concluded that BACE-1 inhibition has been demonstrated as a method for the treatment of AD. Roberds et al, Human Mol. Genetics , 2001, Vol. 10, No. 12, 1317-1324, determined that inhibition or loss of β-secretase activity does not produce significant phenotypic defects, accompanied by a decrease in β-amyloid peptides . Luo et al., Nature Neuroscience , Vol. 4, No. 3, March 2001 reported that mice lacking BACE-1 have normal phenotype and abolished beta-type starch production.

BACE-1 has also been identified or demonstrated to be a therapeutic target for several other different conditions in which A[beta] or A[beta] fragments have been identified to function. Other examples are for the treatment of symptoms of AD type in patients with Down syndrome. The gene encoding APP was found to be located on chromosome 21, which is also the chromosome found in the Down syndrome as an additional copy. Patients with Down syndrome often develop AD at an early stage, and almost all of these patients develop Alzheimer's type symptoms over 40 years. It is believed that this is due to the extra copy of the APP gene found in such patients, resulting in APP overexpression and thus increased A[beta] concentration, making AD more prevalent in this population. Furthermore, Down's patients with replication of a small region of chromosome 21 that does not include the APP gene do not develop AD symptoms. Therefore, BACE-1 inhibitors are believed to be useful in reducing Alzheimer's type conditions in patients with Down's syndrome.

Another example relates to the treatment of glaucoma (Guo et al, PNAS , Vol. 104, No. 33, August 14, 2007). Glaucoma is a retinal disease of the eye and is the leading cause of irreversible blindness worldwide. Guo et al. reported that Aβ coexists with apoptotic retinal ganglion cells (RGC) in experimental glaucoma and induces significant RGC cell loss in vivo in a dose- and time-dependent manner. Reports from this group have confirmed that targeting different components of the A[beta] formation and aggregation pathway (including inhibition of [beta]-secretase alone and with other methods) is effective in reducing glaucomatous RGC apoptosis in vivo. Thus, reduction of A[beta] production by inhibition of BACE-1 can be used alone or in combination with other methods for the treatment of glaucoma.

Another example relates to the treatment of olfactory disorders. Getchell et al, Neurobiology of Aging, 24 (2003), 663-673 have observed that the olfactory epithelium (the neuroepithelial lining the dorsal region of the nasal cavity) presents many of the same pathological changes found in the brains of AD patients, including in particular Aβ. Deposition, hyperphosphorylation of the presence of tau protein and dystrophic axons. Additional evidence in this regard has been obtained by Bacon AW et al, Ann NY Acad Sci 2002; 855: 723-31; Crino PB, Martin JA, Hill WD et al, Ann Otol Rhinol Laryngol, 1995; 104: 655-61; Davies DC Et al, Neurobiol Aging, 1993; 14: 353-7; Devanand DP et al, Am J Psychiatr, 2000; 157: 1399-405; and Doty RL et al, Brain Res Bull, 1987; 18: 597-600. It is reasonable to show that addressing these changes by inhibiting BACE-1 to reduce A[beta] can help restore olfactory sensitivity in patients with AD.

Other different conditions characterized by inappropriate formation of Aβ or fragments thereof and deposition of and/or starch-like fibrils include neurodegenerative diseases (eg, scrapie, bovine spongiform encephalitis, Cuija disease, and the like), Type II diabetes (characterized by local accumulation of cytotoxic amyloid fibrils in insulin-producing cells of the pancreas) and amyloplasty. In this regard, reference is made to the patent literature. For example, Kong et al., US 2008/0015180 discloses methods and compositions for treating amyloidosis using agents that inhibit the formation of A[beta] peptides. Another example is the treatment of traumatic brain injury. As another example, Loane et al. report targeted amyloid precursor protein secretase as a therapeutic target for traumatic brain injury. (Loane et al., "Amyloid precursor protein secretases as therapeutic targets for traumatic brain injury", Nature Medicine, Advance Online Publication , published online March 15, 2009.) Inappropriate formation and deposition of Aβ or fragments thereof and/or Still other different modalities characterized by the presence of starch-like fibrils and/or expected therapeutic agents of BACE-1 are discussed further below.

The therapeutic potential to inhibit A[beta] deposition has spurred many groups to characterize BACE-1 and recognize inhibitors of BACE-1 and other secretase inhibitors. Examples from the patent literature are increasing and include US2005/0282826, WO2006009653, WO2007005404, WO2007005366, WO2007038271, WO2007016012, US2007072925, WO2007149033, WO2007145568, WO2007145569, WO2007145570, WO2007145571, WO2007114771, US20070299087, US2007/0287692, WO2005/016876, WO2005 / 014540, WO2005/058311, WO2006/065277, WO2006/014762, WO2006/014944, WO2006/138195, WO2006/138264, WO2006/138192, WO2006/138217, WO2007/050721, WO2007/053506, WO2007/146225, WO2006/138230 WO2006/138265, WO2006/138266, WO2007/053506, WO2007/146225, WO2008/073365, WO2008/073370, WO2008/103351, US2009/041201, US 2009/041202, WO 2009/131975, WO 2009091016 and WO 2010/047372.

BACE inhibitors, in particular BACE-2 inhibitors, are an industry-recognized target for the treatment of diabetes. Type 2 diabetes mellitus (T2D) is caused by insulin resistance and insufficient insulin secretion from pancreatic β-cells, resulting in poor glycemic control and hyperglycemia (M Prentki and CJ Nolan, "Islet beta-cell failure in type 2 diabetes. J. Clin. Investig ., 2006 , 116(7), 1802-1812). Patients with T2D have an increased risk of microvascular and macrovascular disease and a range of related complications including diabetic neuropathy, retinopathy and cardiovascular disease.

Β-cell failure and consequent decrease in insulin secretion and the onset of hyperglycemia marker T2D (M Prentki and CJ Nolan, "Islet β-cell failure in type 2 diabetes." J. Clin. Investig ., 2006 , 116 (7) ), 1802-1812). Most current treatments do not prevent the loss of β-cell populations that characterize significant T2D. However, recent developments in GLP-1 analogs, gastrin and other agents have shown that beta-cell prevention and proliferation can be achieved, resulting in improved glucose tolerance and slow progression to significant T2D. (LL. Baggio and DJ. Drucker, "Therapeutic approaches to preserve islet mass in type 2 diabetes", Annu. Rev. Med. 2006, 57, 265-281.)

Tmem27 has been identified as promoting β-cell proliferation (P. Akpinar, S. Juqajima, J. Krutzfeldt, M. Stoffel, "Tmem 27: A cleaved and shed plasma membrane protein that stimulates pancreatic beta-cell proliferation", Cell. Metab. 2005 , 2, 385-397) and insulin secretion (K. Fukui, Q. Yang, Y. Cao, N. Takahashi et al., "The HNF-1 target Collectrin controls insulin exocytosis by SNARE complex formation", Cell. Metab . 2005, 2, 373 -384) protein. Tmem27 is a 42 kDa membrane glycoprotein that effluxes from the surface of β-cells due to degradation of the full-length cell Tmem27. Tmem27 overexpresses glucose tolerance in a DIO model that increases beta-cell population and improves diabetes in transgenic mice. (P. Akpina, S. Juqajima, J. Krutzfeldt, M. Stoffel, "Tmem 27: A cleaved and shed plasma membrane protein that stimulates pancreatic beta-cell proliferation", Cell. Metab . 2005, 2, 385-397; (K. Fukui Q.Yang, Y. Cao, N. Takahashi et al., "The HNF-1 target Collectrin controls insulin exocytosis by SNARE complex formation", Cell. Metab. 2005, 2, 373-384.) In addition, rodent β-cells The siRNA gene knockdown of Tmem27 in proliferation assays (eg, using INS1e cells) reduced the rate of proliferation, indicating the role of Tmem27 in controlling the beta-cell population.

In vitro, BACE-2 (but reportedly not BACE-1) cleaves peptides based on the sequence of Tmem27. The BACE-2 membrane binds to aspartame chymotrypsin and coexists with Tmem27 in rodent pancreatic β-cells (G. Finzi, F. Franzi, C. Placidi, F. Acquati et al., "BACE-2 is stored In secretory granules of mouse and rat pancreatic beta cells", Ultrastruct. Pathol. 2008, 32(6), 246-251). It is also known to be able to degrade APP (I. Hussain, D. Powell, D. Howlett, G. Chapman et al., "ASP1 (BACE2) cleaves the amyloid precursor protein at the beta-secretase site", Mol. Cell. Neurosci . 2000, 16, 609-619), IL-1 R2 (P. Kuhn, E. Marjaux, A. Imhof, B. De Strooper et al., "Regulated intramembrane proteolysis of the interleukin-1 receitpro II by alpha-, beta-, and Gamma-secretase", J. Biol. Chem., 2007 , 282 (16), 11982-11995). Therefore, inhibition of BACE-2 is proposed to treat T2D, which may maintain and restore the β-cell population and stimulate insulin secretion in pre-diabetic and diabetic patients. See, for example, WO2010128058.

The present invention provides certain imidothiophenes Compounds and their oxides and dioxides, which are collectively or individually referred to herein as "compounds of the invention", are as described herein. The compounds of the invention are expected to be useful as inhibitors of BACE-1. In some embodiments, a compound of the invention is contemplated to be an inhibitor of BACE-2.

In one embodiment, the compound of the invention has the structural formula (I):

Or a tautomer thereof having the formula (I'):

Or a pharmaceutically acceptable salt thereof, wherein: W is selected from the group consisting of S, S(O) and S(O) ₂ ; and R ^1A and R ^1B are each independently selected from the group consisting of H, halogen, Alkyl, alkoxy, haloalkyl, heteroalkyl, alkenyl, alkynyl, aryl, -alkyl-aryl, monocyclic heteroaryl, -alkyl-(monocyclic heteroaryl), monocyclic Cycloalkyl, -alkyl-(monocyclic cycloalkyl), monocyclic heterocycloalkyl, -alkyl-(monocyclic heterocycloalkyl), polycyclic group, and -alkyl-(polycyclic group) Wherein the alkyl group, alkoxy group, haloalkyl group, heteroalkyl group, alkenyl group, alkynyl group, aryl group, -alkyl-aryl group, monocyclic heteroaryl group, -alkyl group of R ^1A and R ^1B (monocyclic heteroaryl), monocyclic cycloalkyl, -alkyl-(monocyclic cycloalkyl), monocyclic heterocycloalkyl, -alkyl-(monocyclic heterocycloalkyl), polycyclic group And -alkyl-(polycyclic groups) are each optionally unsubstituted or substituted with one or more groups independently selected from R ⁸ ; ring A is selected from aryl, monocyclic heteroaryl a monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocycloalkyl, monocyclic heterocycloalkenyl, and polycyclic group; ring B (when present) is independently Consisting of aryl, monocyclic heteroaryl, monocyclic cycloalkyl, a monocyclic cycloalkenyl group, a monocyclic heterocyclic group, alkenyl group and monocyclic heterocyclic group consisting of a polycyclic group; -L ₁ - (when When present, independently represents a bond or a divalent moiety group selected from the group consisting of: -alkyl-, -haloalkyl-, -heteroalkyl-, -alkenyl-, -alkynyl-, -N ( R ⁶ )-, -NHC(O)-, -C(O)NH-, -CH ₂ NHC(O)-, -CH ₂ C(O)NH-, -NHS(O) ₂ -, -CH ₂ NHS(O) ₂ -, -CH ₂ SO ₂ NH-, -S(O) ₂ NH-, -O-CH ₂ -, -CH ₂ -O-, -NHCH ₂ -, -CH ₂ NH- and - CH(CF ₃ )NH-, -NHCH(CF ₃ )-; m, n and p are each independently selected integers, wherein: m is 0 or greater.

n is 0 or 1; and p is 0 or greater, wherein the maximum value of m is the maximum number of hydrogen atoms that can be substituted on ring A, and wherein the maximum value of p is the maximum number of hydrogen atoms that can be substituted on ring B. Each R ² (when present) is independently selected from the group consisting of: halogen, -OH, -CN, -SF ₅ , -OSF ₅ , -NO ₂ , -Si(R ⁵ ) ₃ , -P (O)(OR ⁵ ) ₂ , -P(O)(OR ⁵ )(R ⁵ ), -N(R ⁶ ) ₂ , -NR ⁷ C(O)R ⁶ , -NR ⁷ S(O) ₂ R ⁶ , -NR ⁷ S(O) ₂ N(R ⁶ ) ₂ , -NR ⁷ C(O)N(R ⁶ ) ₂ , -NR ⁷ C(O)OR ⁶ , -C(O)R ⁶ ,- C(O) ₂ R ⁶ , -C(O)N(R ⁶ ) ₂ , -S(O)R ⁶ , -S(O) ₂ R ⁶ , -S(O) ₂ N(R ⁶ ) ₂ , -OR ⁶ , -SR ⁶ , alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, -alkyl-cycloalkyl, aryl, -alkyl-aryl, heteroaryl, - alkyl - heteroaryl, heterocycloalkyl and - alkyl - heterocycloalkyl, wherein R ² of the alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, - alkyl - cycloalkyl, aryl, -alkyl-aryl, heteroaryl, -alkyl-heteroaryl, heterocycloalkyl and -alkyl-heterocycloalkyl, each unsubstituted or via one or Multiple independent Substituted from a group selected from R ⁸ ; each R ³ (when present) is independently selected from the group consisting of halogen, -OH, -CN, -SF ₅ , -OSF ₅ , -NO ₂ , -Si (R ⁵ ) ₃ , -P(O)(OR ⁵ ) ₂ , -P(O)(OR ⁵ )(R ⁵ ), -N(R ⁶ ) ₂ , -NR ⁷ C(O)R ⁶ ,- NR ⁷ S(O) ₂ R ⁶ , -NR ⁷ S(O) ₂ N(R ⁶ ) ₂ , -NR ⁷ C(O)N(R ⁶ ) ₂ , -NR ⁷ C(O)OR ⁶ ,- C(O)R ⁶ , -C(O) ₂ R ⁶ , -C(O)N(R ⁶ ) ₂ , -S(O)R ⁶ , -S(O) ₂ R ⁶ , -S(O) ₂ N(R ⁶ ) ₂ , -OR ⁶ , -SR ⁶ , alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, -alkyl-cycloalkyl, aryl, -alkyl An aryl group, a heteroaryl group, an -alkyl-heteroaryl group, a heterocycloalkyl group, and an -alkyl-heterocycloalkyl group, wherein the alkyl group, haloalkyl group, heteroalkyl group, alkenyl group, alkynyl group of R ³ , cycloalkyl, -alkyl-cycloalkyl, aryl, -alkyl-aryl, heteroaryl, -alkyl-heteroaryl and heterocycloalkyl are each unsubstituted or one or more Substituents independently selected from R ⁸ ; R ⁴ is selected from the group consisting of alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, aryl, -alkyl-aryl, heteroaryl Base, -alkyl-hetero , cycloalkyl, -alkyl-cycloalkyl, cycloalkenyl, -alkyl-cycloalkenyl, heterocycloalkyl, -alkyl-heterocycloalkyl, heterocycloalkenyl and -alkyl-hetero cycloalkenyl, wherein the alkyl group R ⁴ of, haloalkyl, heteroalkyl, aryl, - alkyl - aryl group, a heteroaryl group, - alkyl - aryl, heteroaryl, cycloalkyl, - alkyl - ring Each of an alkyl group, a cycloalkenyl group, an -alkyl-cycloalkenyl group, a heterocycloalkyl group, an -alkyl-heterocycloalkyl group, a heterocycloalkenyl group, and an -alkyl-heterocycloalkenyl group is not Substituted or substituted with one or more independently selected R ¹¹ groups; each R ⁵ (when present) is independently selected from the group consisting of alkyl, heteroalkyl, haloalkyl, cycloalkyl, - An alkyl-cycloalkyl group, an aryl group, an -alkyl-aryl group, a heteroaryl group, and an -alkyl-heteroaryl group, wherein each of the R ⁵ is an aryl group, an -alkyl-aryl group, a heteroaryl group, and An alkyl-heteroaryl group which is unsubstituted or one or more independently selected from the group consisting of halogen, alkyl, cycloalkyl, heteroalkyl, haloalkyl, alkoxy, heteroalkoxy and haloalkoxy groups; each R ⁶ (when present) is independently selected from the system consisting of the group consisting of: H, alkyl, - alkyl -OH Alkenyl, alkynyl, heteroalkyl, -heteroalkyl-OH, haloalkyl, -haloalkyl-OH, cycloalkyl, lower alkyl substituted cycloalkyl, lower alkyl substituted alkane a base-cycloalkyl group, a heterocycloalkyl group, an -alkyl-heterocycloalkyl group, an aryl group, an -alkyl-aryl group, a heteroaryl group, and an -alkyl-heteroaryl group, wherein each of R ⁶ is heterozygous Cycloalkyl, -alkyl-heterocycloalkyl, aryl, -alkyl-aryl, heteroaryl and the -alkyl-heteroaryl are unsubstituted or one or more independently selected from halo a group substituted with an alkyl group, a cycloalkyl group, a heteroalkyl group, a halogenated alkyl group, an alkoxy group, a heteroalkoxy group, and a halogenated alkoxy group; each R ⁷ (when present) is independently selected from the group consisting of : H, alkyl, heteroalkyl, haloalkyl, cycloalkyl, -alkyl-cycloalkyl, aryl, -alkyl-aryl, heteroaryl and -alkyl-heteroaryl, wherein R ⁷ Each of the aryl, -alkyl-aryl, heteroaryl and -alkyl-heteroaryl groups is unsubstituted or one or more independently selected from the group consisting of halogen, alkyl, cycloalkyl, heterocycloalkyl , haloalkyl, alkoxy, heteroaryl, alkoxy and haloalkoxy groups the substituent group; each of R ⁸ ( When present) is independently selected from the Department of the group consisting of: _{halo, -OH, -CN, -SF 5,} -OSF 5, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, - alkyl -cycloalkyl, -O-cycloalkyl, -O-alkyl-cycloalkyl, -O-benzyl, heteroalkyl, -O-heteroalkyl and -alkyl-OH; R ⁹ and R ¹⁰ Each is independently selected from the group consisting of H, halogen, -OH, -CN, -P(O)(OR ⁵ ) ₂ , -P(O)(OR ⁵ )(R ⁵ ), -N(R ⁶ ₂ , -NR ⁷ C(O)R ⁶ , -NR ⁷ S(O) ₂ R ⁶ , -NR ⁷ C(O)N(R ⁶ ) ₂ , -NR ⁷ C(O)OR ⁶ , -C (O)R ⁶ , -C(O) ₂ R ⁶ , -C(O)N(R ⁶ ) ₂ , -S(O)R ⁶ , -S(O) ₂ R ⁶ , -S(O) ₂ N(R ⁶ ) ₂ , —OR ⁶ , —SR ⁶ , alkyl, haloalkyl, heteroalkyl, alkenyl and alkynyl, wherein the alkyl, haloalkyl, heteroalkyl, alkene of R ⁹ and R ¹⁰ Each of the yl and alkynyl groups is unsubstituted or substituted with one or more independently selected R ¹² groups; each R ¹¹ (when present) is independently selected from the group consisting of: halogen, - OH, -CN, -SF ₅ , -OSF ₅ , -P(O)(OR ⁵ ) ₂ , -P(O)(OR ⁵ )(R ⁵ ), -N(R ⁶ ) ₂ , -NR ⁷ C (O)R ⁶ , -NR ⁷ S(O) ₂ R ⁶ , -N R ⁷ S(O) ₂ N(R ⁶ ) ₂ , -NR ⁷ C(O)N(R ⁶ ) ₂ , -NR ⁷ C(O)OR ⁶ , -C(O)R ⁶ , -C(O ₂ R ⁶ , -C(O)N(R ⁶ ) ₂ , -S(O)R ⁶ , -S(O) ₂ R ⁶ , -S(O) ₂ N(R ⁶ ) ₂ , -OR ⁶ , -SR ⁶ , alkyl, haloalkyl, haloalkoxy, heteroalkyl, -alkyl-OH, cycloalkyl, -alkyl-cycloalkyl; each R ¹² (when present) is independently selected Free group consisting of: halogen, -OH, -CN, -SF ₅ , -OSF ₅ , -P(O)(OR ¹³ ) ₂ , -P(O)(OR ¹³ )(R ¹³ ), -N( R ¹⁴ ) ₂ , -NR ¹⁴ C(O)R ¹⁴ , -NR ¹⁴ S(O) ₂ R ¹⁴ , -NR ¹⁴ S(O) ₂ N(R ¹⁴ ) ₂ , -NR ¹⁴ C(O)N( R ¹⁴ ) ₂ , -NR ¹⁴ C(O)OR ¹⁴ , -C(O)R ¹⁴ , -C(O) ₂ R ¹⁴ , -C(O)N(R ¹⁴ ) ₂ , -S(O)R ¹⁴ , -S(O) ₂ R ¹⁴ , -S(O) ₂ N(R ¹⁴ ) ₂ , -OR ¹⁴ , -SR ¹⁴ , alkyl, haloalkyl, haloalkoxy, heteroalkyl, -alkyl- OH; each R ¹³ (when present) is independently selected from the group consisting of alkyl, -alkyl-OH, alkenyl, alkynyl, heteroalkyl, -heteroalkyl-OH, haloalkyl, haloalkyl-OH the group composition; and each R ¹⁴ (when present) is independently selected from the lines consisting of H, alkyl, - alkyl -OH, alkenyl, alkynyl, heteroalkyl - -OH heteroalkyl, haloalkyl, - consisting of -OH haloalkyl group.

In other embodiments, the invention provides compositions comprising a pharmaceutical composition comprising one or more compounds of the invention (eg, a compound of the invention) or a tautomer thereof or the compound or compounds and/or the or The pharmaceutically acceptable salts or solvates of such tautomers, optionally with one or more other therapeutic agents, are optionally present in an acceptable (e.g., pharmaceutically acceptable) carrier or diluent.

In other embodiments, the invention provides methods of treating, preventing, ameliorating, and/or delaying the onset of A[beta] conditions and/or delaying the onset thereof, comprising administering to a patient in need thereof an effective amount of one or more compounds of the invention. Or a tautomer thereof or a combination of the compound or compounds and/or a pharmaceutically acceptable salt or solvate of the tautomer. Such methods additionally comprise, as the case may be, administering one or more of the other therapeutic agents suitable for treating the patient being treated.

These and other embodiments of the invention, which are described in detail below, or which are well known to those skilled in the art, are included within the scope of the invention.

For each of the following examples, any variable not explicitly defined in the examples is as defined in formula (I) or (IA).

In one embodiment, in each of Formulas (I) and (IA): -L ₁ - (when present) independently represents a bond or a divalent moiety group selected from the group consisting of: - alkyl -, - haloalkyl -, - heteroalkyl -, - alkenyl -, - alkynyl ^{-, - N (R 6)} -, - NHC (O) -, - C (O) NH -, - NHS (O) ₂ -, -S(O) ₂ NH-, -O-CH ₂ -, -CH ₂ -O-, -NHCH ₂ -, -CH ₂ NH- and -CH(CF ₃ )NH-, - NHCH(CF ₃ )-; each R ⁸ (when present) is independently selected from the group consisting of halogen, -OH, -CN, -SF ₅ , -OSF ₅ , alkyl, alkoxy, haloalkane , haloalkoxy, cycloalkyl, -alkyl-cycloalkyl, -O-cycloalkyl, -O-alkyl-cycloalkyl, heteroalkyl, -O-heteroalkyl and -alkyl- OH; and R ⁹ and R ¹⁰ are each independently selected from the group consisting of halogen, -OH, -CN, -P(O)(OR ⁵ ) ₂ , -P(O)(OR ⁵ )(R ⁵ ) , -N(R ⁶ ) ₂ , -NR ⁷ C(O)R ⁶ , -NR ⁷ S(O) ₂ R ⁶ , -NR ⁷ C(O)N(R ⁶ ) ₂ , -NR ⁷ C(O )OR ⁶ , -C(O)R ⁶ , -C(O) ₂ R ⁶ , -C(O)N(R ⁶ ) ₂ , -S(O)R ⁶ , -S(O) ₂ R ⁶ , _{-S (O) 2 N (R} 6) 2, -OR 6, -SR 6, alkyl, haloalkyl, heteroalkyl, alkenyl and alkynyl groups Wherein each of R ⁹ and R ¹⁰ of the alkyl group, haloalkyl, heteroalkyl, alkenyl and alkynyl groups in the system or unsubstituted with one or more of the substituents independently selected R ¹² groups.

In one embodiment, the compounds of the invention have the structural formula (I) described above.

In one embodiment, the compound of the invention has the structural formula (IA):

Or a tautomer thereof having the formula (IA'):

Or a pharmaceutically acceptable salt thereof, wherein each variable is as defined in formula (I).

In one embodiment, the compound of the invention has the structural formula (IB):

Or a tautomer thereof having the formula (IB'):

Or a pharmaceutically acceptable salt thereof, wherein each variable is as defined in formula (I).

In one embodiment, in each of formulas (I), (IA), (IA'), (IB), and (IB'), R ⁹ is H.

In one embodiment, in Formula (I), (IA), (IA '), (IB) and (IB') of each of the, R ¹⁰ H. Department

In one embodiment, in each of Formulas (I), (IA), (IA'), (IB), and (IB'), R ¹⁰ is H and R ⁹ is H.

In one embodiment, in each of Formulas (I), (IA), (IA'), (IB), and (IB'), R ⁹ is selected from the group consisting of H, halo, alkyl, haloalkyl And a group of heteroalkyl groups.

In one embodiment, in each of formulas (I), (IA), (IA'), (IB), and (IB'), R ⁹ is selected from the group consisting of H, halo, and lower alkyl. a group consisting of halogenated lower alkyl and lower alkyl ethers.

In one embodiment, in each of Formulas (I), (IA), (IA'), (IB), and (IB'), R ¹⁰ is selected from the group consisting of H, halo, alkyl, haloalkyl And a group of heteroalkyl groups.

In one embodiment, in each of Formulas (I), (IA), (IA'), (IB), and (IB'), R ¹⁰ is selected from the group consisting of H, halo, and lower alkyl. a group consisting of halogenated lower alkyl and lower alkyl ethers.

In one embodiment, in each of Formulas (I), (IA), (IA'), (IB), and (IB'), R ⁹ is selected from the group consisting of H, halo, alkyl, haloalkyl And a group of heteroalkyl groups; and R ¹⁰ is H.

In one embodiment, in each of Formulas (I), (IA), (IA'), (IB), and (IB'), R ⁹ is selected from the group consisting of H, halo, and lower alkyl. a group consisting of a halogenated lower alkyl group and a lower alkyl ether; and R ¹⁰ is H.

In one embodiment, in each of Formulas (I), (IA), (IA'), (IB), and (IB'), R ⁹ is H and R ¹⁰ is selected from H, halo, a group consisting of an alkyl group, a halogenated alkyl group, and a heteroalkyl group.

In one embodiment, in Formula (I), (IA), (IA '), (IB) and (IB') of each of the, R ⁹ and R ¹⁰ H line selected from the group consisting of H, halo, A group consisting of a lower alkyl group, a halogenated lower alkyl group, and a lower alkyl ether.

In one embodiment, in each of Formulas (I), (IA), (IA'), (IB), and (IB'), R ⁴ is selected from the group consisting of a lower alkyl group and a lower carbon number alkyl halide. Group of bases.

In one embodiment, in each of Formulas (I), (IA), (IA'), (IB), and (IB'), R ⁴ is selected from the group consisting of -CH ₃ , -CH ₂ F, - A group consisting of CHF ₂ and -CF ₃ .

In one embodiment, in each of Formulas (I), (IA), (IA'), (IB), and (IB'), R ⁴ is selected from the group consisting of -CH ₃ and -CHF ₂ .

In one embodiment, in each of formulas (I), (IA), (IA'), (IB), and (IB'): R ⁴ is -CH ₃ and -CHF ₂ ; R ⁹ is H And R ¹⁰ is H.

In one embodiment, in each of formulas (I), (IA), (IA'), (IB), and (IB'): R ⁴ is -CH ₃ and -CHF ₂ ; R ⁹ and R One of ¹⁰ is H and the other is selected from the group consisting of H, halogen, alkyl, haloalkyl, and heteroalkyl.

In one embodiment, in each of formulas (I), (IA), (IA'), (IB), and (IB'): R ⁴ is -CH ₃ and -CHF ₂ ; and R ⁹ and One of R ¹⁰ is H and the other is selected from the group consisting of H, a lower alkyl group, a lower carbon haloalkyl group, and a lower alkyl ether.

In one embodiment, the compound of the invention has the structural formula (II):

Or a tautomer thereof having the formula (II'):

Or a pharmaceutically acceptable salt thereof, wherein each variable is as defined in formula (I).

In one embodiment, the compound of the invention has the structural formula (IIA):

Or a tautomer thereof having the formula (IIA'):

Or a pharmaceutically acceptable salt thereof, wherein each variable is as defined in formula (I).

In one embodiment, the compound of the invention has the structural formula (IIB):

Or a tautomer thereof having the formula (IIB'):

Or a pharmaceutically acceptable salt thereof, wherein each variable is as defined in formula (I).

In an embodiment, in formula (I), (IA), (IA'), (IB), (IB'), In each of (II), (II'), (IIA), (IIA'), (IIB), and (IIB'): W system S.

In one embodiment, in Formulas (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), (IIB) In each of (IIB'): W is S(O).

In one embodiment, in Formulas (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), (IIB) In each of (IIB'): W is S(O) ₂ .

In one embodiment, in Formulas (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), (IIB) And each of (IIB'): R ^1A and R ^1B are each independently selected from the group consisting of H, fluorine, methyl, ethyl, vinyl, propyl, propenyl, low carbon halogenated alkane , cyclopropyl, -CH ₂ -cyclopropyl, cyclobutyl, -CH ₂ -cyclobutyl, -OCH ₃ , -CH ₂ OH, -CH ₂ OCH ₃ , -CH ₂ OCH ₂ CH ₃ , three Fluoromethyl, -CH ₂ F, -CHF ₂ , -CH ₂ CF ₃ , phenyl, pyridyl, pyrimidinyl, pyrazinyl, benzyl, benzotriazolyl, -CH ₂ -benzotriazolyl , benzoxazolyl, -CH ₂ -benzoxazolyl, tetrahydropyranyl, -CH ₂ -tetrahydropyranyl, -CH ₂ -pyridyl, -CH ₂ -pyrimidinyl and -CH ₂ a pyrazinyl group; wherein each of R ^1A and R ^1B is phenyl, pyridyl, pyrimidinyl, pyrazinyl, benzyl, -CH ₂ -pyridyl, -CH ₂ -pyrimidinyl, -CH ₂ -pyridyl The alkyl group is unsubstituted or one or more independently selected from halo, alkyl, cycloalkyl, heteroalkyl, alkoxy, -O-benzyl, -O-cycloalkyl, -O-CH ₂ - group and the cycloalkyl group of an alkyl halide Generations.

In one embodiment, in Formulas (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), (IIB) And (IIB') each: R ^1A and R ^1B are each independently selected from the group consisting of H, fluorine, methyl, ethyl, propyl, cyclopropyl, -CH ₂ -cyclopropane , -OCH ₃ , -CH ₂ OH, -CH ₂ OCH ₃ , -CH ₂ OCH ₂ CH ₃ , trifluoromethyl, -CH ₂ F, -CHF ₂ , phenyl, pyridyl, pyrimidinyl, pyrazine a benzyl group, a benzyl group, a -CH ₂ -pyridyl group, a -CH ₂ -pyrimidinyl group, and a -CH ₂ -pyrazinyl group; wherein each of R ^1A and R ^1B is a phenyl group, a pyridyl group, a pyrimidinyl group, a pyrazinyl group, Benzyl, -CH ₂ -pyridyl, -CH ₂ -pyrimidinyl, -CH ₂ -pyrazinyl are unsubstituted or one or more independently selected from halo, alkyl, cycloalkyl, heteroalkyl Substituted by a group consisting of an alkoxy group, an -O-cycloalkyl group, and a halogenated alkyl group.

In one embodiment, in Formulas (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), (IIB) And (IIB'): R ^1A is selected from the group consisting of methyl, ethyl and -CH ₂ OCH ₃ ; and R ^1B is selected from the group consisting of H, fluorine, methyl, Ethyl, vinyl, propyl, propenyl, lower carbon haloalkyl, cyclopropyl, -CH ₂ -cyclopropyl, cyclobutyl, -CH ₂ -cyclobutyl, -OCH ₃ , -CH ₂ OH , -CH ₂ OCH ₃ , -CH ₂ OCH ₂ CH ₃ , trifluoromethyl, -CH ₂ F, -CHF ₂ , -CH ₂ CF ₃ , phenyl, pyridyl, pyrimidinyl, pyrazinyl, benzyl , benzotriazolyl, -CH ₂ -benzotriazolyl, benzoxazolyl, -CH ₂ -benzoxazolyl, tetrahydropyranyl, -CH ₂ -tetrahydropyranyl, - CH ₂ -pyridyl, -CH ₂ -pyrimidinyl and -CH ₂ -pyrazinyl; wherein each of R ^1A and R ^1B is phenyl, pyridyl, pyrimidinyl, pyrazinyl, benzyl, -CH ₂ a pyridyl group, a -CH ₂ -pyrimidinyl group, a -CH ₂ -pyrazinyl group which is unsubstituted or one or more independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, alkoxy, - O-benzyl, -O-cycloalkyl, -O-CH ₂ - ring Substituted by a group of alkyl and haloalkyl groups.

In one embodiment, in Formulas (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), (IIB) And each of (IIB'): R ^1A and R ^1B are each independently selected from the group consisting of H, methyl, ethyl, propyl, cyclopropyl, -CH ₂ -cyclopropyl, -CH ₂ OH, -CH ₂ OCH ₃ , -CH ₂ OCH ₂ CH ₃ , trifluoromethyl, -CH ₂ CF ₃ , -CH ₂ F and -CHF ₂ .

In one embodiment, in Formulas (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), (IIB) And each of (IIB'): R ^1A and R ^1B are each independently selected from the group consisting of H, methyl, ethyl, propyl, cyclopropyl, -CH ₂ -cyclopropyl, -CH ₂ OH, a group consisting of -CH ₂ OCH ₃ , -CH ₂ OCH ₂ CH ₃ , trifluoromethyl, -CH ₂ F and -CHF ₂ .

In one embodiment, in Formulas (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), (IIB) And (IIB') each of: R ^1A is selected from the group consisting of H and methyl; and R ^1B is selected from the group consisting of H, methyl, ethyl, vinyl, propyl, Isopropyl, propenyl, butyl, butenyl, cyclopropyl, -CH ₂ -cyclopropyl, cyclobutyl, -CH ₂ -cyclobutyl, -CH ₂ OH, -CH ₂ OCH ₃ ,- CH ₂ OCH ₂ CH ₃ , trifluoromethyl, -CH ₂ F, -CHF ₂ , -CH ₂ CF ₃ , phenyl, phenyl substituted with 1 to 3 R ⁸ groups, benzyl, 1 substitution of one to three groups R ⁸ a benzyl group, a pyridyl group, substituted by 1 to 3 R ⁸ groups of pyridinyl, tetrahydropyranyl group and a -CH ₂ - tetrahydropyranyl.

In one embodiment, in Formulas (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), (IIB) And (IIB') each of: R ^1A is selected from the group consisting of H and methyl; and R ^1B is selected from the group consisting of H, methyl, ethyl, vinyl, propyl, Isopropyl, propenyl, butyl, butenyl, cyclopropyl, -CH ₂ -cyclopropyl, cyclobutyl, -CH ₂ -cyclobutyl, -CH ₂ OH, -CH ₂ OCH ₃ ,- CH ₂ OCH ₂ CH ₃ , trifluoromethyl, -CH ₂ F, -CHF ₂ , -CH ₂ CF ₃ , phenyl, benzyl, pyridyl, tetrahydropyranyl and -CH ₂ -tetrahydropyran a group wherein each of the phenyl, benzyl and pyridyl groups is optionally composed of 1 to 3 selected from the group consisting of F, Cl, Br, -OCH ₃ , -CH ₂ F, -CHF ₂ and -CF ₃ The group of the group is replaced.

In one embodiment, in Formulas (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), (IIB) In each of (IIB'): R ^1A and R ^1B are each independently selected from the group consisting of H and methyl.

In one embodiment, in Formulas (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), (IIB) In each of (IIB'): R ^1A and R ^1B are each a methyl group.

In some embodiments, in Formulas (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), (IIB) In each of (IIB'): n is 1. In these embodiments, part: , with form: .

In another embodiment, in formula (I), (IA), (IA'), (IB), (IB'), In each of (II), (II'), (IIA), (IIA'), (IIB), and (IIB'): n is 1; m is 0 or greater; and ring A is selected from the following Group consisting of: phenyl, pyridyl, pyrazinyl, furyl, thienyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, quinazolinyl, benzofuranyl Benzimidazolyl, benzoxazolyl, benzotriazolyl, benzothienyl, naphthyl, quinolyl, isoquinolyl, oxazolyl, indolyl and thienopyrazolyl.

In another embodiment, in Formula (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), In each of IIB) and (IIB'): n is 1; m is 0 or greater; and ring A is selected from the group consisting of phenyl, pyridyl, thienyl, thiazolyl, naphthyl, isoquinolyl, A group consisting of a benzothienyl group, a benzimidazolyl group, a carbazolyl group, a fluorenyl group, and a thienopyrazolyl group.

In another embodiment, in Formula (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), In each of IIB) and (IIB'): n is 1; m is 0 or greater; and ring A is selected from the group consisting of phenyl, thienyl and pyridyl.

In another embodiment, in Formula (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), In each of IIB) and (IIB'): n is 1; m is 0 or greater; and each R ² (when present) is independently selected from the group consisting of: halogen, -CN, - _{SF 5, -OSF 5, -NO 2} , -NH 2, -N ( alkyl) _2, -NH (alkyl), - NHC (O) R 6, -NHS (O) 2 R 6, -NHC ( O)N(R ⁶ ) ₂ , -NHC(O)OR ⁶ , -C(O)R ⁶ , -C(O) ₂ R ⁶ , -C(O)N(R ⁶ ) ₂ , -S(O R ⁶ , -S(O) ₂ R ⁶ , -S(O) ₂ N(R ⁶ ) ₂ , -OR ⁶ , -SR ⁶ , lower alkyl group, lower carbon haloalkyl group, lower carbon number Alkyl, lower alkenyl, lower alkynyl, phenyl, benzyl, lower cycloalkyl, -CH ₂ - (lower cycloalkyl), monocyclic heteroaryl, and -CH ₂ - (monocyclic heteroaryl), wherein R ² of the phenyl, benzyl, lower cycloalkyl, -CH ₂ - (lower cycloalkyl group), a monocyclic aryl group and heteroaryl -CH ₂ - (monocyclic heteroaryl) is unsubstituted or one or more independently selected from halo, alkyl, heteroalkyl, haloalkyl, alkoxy, -O-cyclopropyl, heteroalkoxy, haloalkane group, -CN, -SF ₅ and -OSF ₅ The substituent group into the group.

In an alternative to the examples just set forth above, m is 0, 1, 2 or 3, and each R ⁶ (when present) is independently selected from H, lower alkyl, lower carbon rings a group consisting of an alkyl group, a lower carbon haloalkyl group, and a lower carbon heteroalkyl group.

In another embodiment, in Formula (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), In each of IIB) and (IIB'): each R ³ group (when present) is independently selected from the group consisting of halogen, -CN, -SF ₅ , -NH ₂ , -NH ( Alkyl), -N(alkyl) ₂ , -OH, -O-alkyl, -SH, -S(alkyl), methyl, ethyl, propyl, haloalkyl, -C≡C-CH ₃ , cyclopropyl, -CH ₂ -cyclopropyl, -C(O)OH, -C(O)O-alkyl, -O-haloalkyl, optionally substituted phenyl and optionally substituted Cycloheteroaryl, wherein each of the optional substituents is independently as defined in formula (I).

In another embodiment, in Formula (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), In each of IIB) and (IIB'): n is 1; m is 0 or greater; and each R ² group (when present) is independently selected from the group consisting of: halogen, -CN , -SF ₅ , -NHCH ₃ , -N(CH ₃ ) ₂ , -OCH ₃ , -OCH ₂ CH ₃ , -O-cyclopropyl, -S(CH ₃ ), methyl, ethyl, propyl, Cyclopropyl, -CH ₂ -cyclopropyl, -C≡C-CH ₃ , -CF ₃ , -CHF ₂ , -C(O)OH, -C(O)OCH ₃ , -C(O)OCH ₂ CH ₃ , -OCF ₃ and -OCHF ₂ .

In an alternative to the embodiment just described above, m is 0, 1, 2 or 3.

In another embodiment, in Formula (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), In each of IIB) and (IIB'): n is 1; m is 0 or greater; and each R ² group (when present) is independently selected from the group consisting of: halogen, -CN , -SF ₅ , -NHCH ₃ , -N(CH ₃ ) ₂ , -OCH ₃ , -OCH ₂ CH ₃ , -O-cyclopropyl, -S(CH ₃ ), methyl, ethyl, propyl, Cyclopropyl, -CH ₂ -cyclopropyl, -C≡C-CH ₃ , -CF ₃ , -CHF ₂ , -C(O)OH, -C(O)OCH ₃ , -C(O)OCH ₂ CH ₃ , —OCF ₃ , —OCHF ₂ and —NHC(O)R ⁶ , wherein R ⁶ is selected from the group consisting of —CH ₂ CF ₃ , —CF ₂ CH ₃ , —CH ₃ , —CH ₂ CH ₃ , —CH ₂ A group consisting of OCH ₃ , CHF ₂ and -CH ₂ N(CH ₃ ) ₂ .

In an alternative to the embodiment just described above, m is 0, 1, 2 or 3.

In another embodiment, in Formula (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), In each of IIB) and (IIB'): n is 1; m is 0, 1 or 2; and each R ² group (when present) is independently selected from F, Cl, Br, -CN , -CF ₃ , -CHF ₂ , cyclopropyl, -OCF ₃ and -OCHF ₂ .

In another embodiment, in Formula (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), In each of IIB) and (IIB'): n is 1; ring A is selected from the group consisting of phenyl, thienyl and pyridyl; m is 0, 1 or 2; and each R ² group ( when present) is independently selected from the group consisting of line F, Cl, Br, -CN, -CF 3, -CHF 2, cyclopropyl, -OCF ₃ and -OCHF ₂ group of the composition.

In another embodiment, in Formula (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), In each of IIB) and (IIB'): n is 1; and -L ₁ - represents a bond or a divalent moiety selected from the group consisting of: -NHC(O), -C(O)NH -, -CH ₂ NHC(O)-, -CH ₂ C(O)NH-, -CH ₂ NHSO ₂ -, -CH ₂ SO ₂ NH-, -C≡C-, -NHS(O) ₂ -, -S(O) ₂ NH-, -O-CH ₂ -, -CH ₂ -O-, -NHCH ₂ -, -CH ₂ NH- and -CH(CF ₃ )NH-.

In another embodiment, in Formula (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), In each of IIB) and (IIB'): n is 1; and -L ₁ - represents a bond or is selected from -NHC(O), -C(O)NH-, -NHS(O) ₂ -, - a divalent moiety group of the group consisting of S(O) ₂ NH-, -O-CH ₂ -, -CH ₂ -O-, -NHCH ₂ -, -CH ₂ NH-, and -CH(CF ₃ )NH- .

In another embodiment, in Formula (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), In each of IIB) and (IIB'): n is 1; and -L ₁ - represents a bond or a divalent moiety selected from the group consisting of -NHC(O), -CH ₂ NHC(O )-, -CH ₂ C(O)NH-, -C≡C-, -C(O)NH-, -NHS(O) ₂ -, -S(O) ₂ NH-, -O-CH ₂ - , -CH ₂ -O-, -NHCH ₂ -, -CH ₂ NH-, and -CH(CF ₃ )NH-.

In another embodiment, in Formula (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), In each of IIB) and (IIB'): n is 1; and -L ₁ - represents a bond or is selected from -NHC(O), -CH ₂ NHC(O)-, -CH ₂ C(O)NH a divalent moiety group of a group consisting of -, -C≡C- and -C(O)NH-.

In another embodiment, in Formula (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), In each of IIB) and (IIB'): n is 1; and -L ₁ - represents a bond or is selected from -NHC(O), -CH ₂ NHC(O)-, -CH ₂ C(O)NH - and -C(O)NH- group of divalent moieties of the group.

In another embodiment, in Formula (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), In each of IIB) and (IIB'): n is 1; and -L ₁ - represents a bond or a divalent moiety selected from the group consisting of -NHC(O)- and -C(O)NH- .

In another embodiment, in Formula (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), In each of IIB) and (IIB'): n is 1; and -L ₁ - represents a bond.

In another embodiment, in Formula (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), In each of IIB) and (IIB'): n is 1; p is 0 or greater; and ring B is selected from the group consisting of phenyl, monocyclic heterocycloalkyl, monocyclic heteroaryl, and polycyclic groups. a group of people.

In an alternative to the embodiment just described above, m and p are each independently 0, 1, 2 or 3.

In another embodiment, in Formula (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), In each of IIB) and (IIB'): n is 1; p is 0 or greater; and ring B is selected from the group consisting of phenyl, monocyclic heterocycloalkyl and monocyclic heteroaryl.

In an alternative to the embodiment just described above, m and p are each independent Site number 0, 1, 2 or 3.

In another embodiment, in Formula (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), In each of IIB) and (IIB'): n is 1; p is 0 or greater; and ring B is selected from phenyl, pyridyl, pyrimidinyl, pyrrolyl, oxazolyl, isoxazolyl , pyrazinyl, thienyl, pyrazolyl, furyl, thiazolyl, pyridazinyl, isothiazolyl, isoxazolyl, isothiazolyl, indolyl, pyrrolopyridinyl, pyrrolopyrimidinyl and A group consisting of oxadiazole groups.

In an alternative to the embodiment just described above, m and p are each independently 0, 1, 2 or 3.

In another alternative of the examples just set forth above, Ring B is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl, oxazolyl, pyrrolyl, decyl, oxa Diazolyl, cyclopropyl, cyclobutyl, oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, dihydroisoxazolyl, isoquinolinyl, thienyl, 5,6-dihydro- 4H -pyrroline group, triazolopyridyl group, imidazolinyl group, imidazothiazolyl group, imidazopyridyl group, benzotriazolyl group and benzoxazolyl group.

In another embodiment, in Formula (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), In each of IIB) and (IIB'): n is 1; p is 0 or greater; and ring B is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyrrolyl, oxazolyl , isoxazolyl, pyrazinyl, thienyl, pyrazolyl, Furanyl, thiazolyl, pyridazinyl, isothiazolyl, isoxazolyl, isothiazolyl, indolyl, pyrrolopyridinyl and pyrrolopyrimidinyl.

In another embodiment, in Formula (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), In each of IIB) and (IIB'): n is 1; p is 0 or greater; and ring B is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl, oxazolyl, pyrrolyl, a group consisting of sulfhydryl and oxadiazolyl.

In an alternative to the embodiment just described above, m and p are each independently 0, 1, 2 or 3.

In another embodiment, in Formula (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), In each of IIB) and (IIB'): n is 1; p is 0 or greater; and ring B is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl, oxazolyl, pyrrolyl and The group consisting of 吲哚.

In another embodiment, in Formula (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), In each of IIB) and (IIB'): n is 1; p is 0 or greater; and each R ³ (when present) is independently selected from the group consisting of: halogen, -CN, - _{SF 5, -OSF 5, -NO 2} , -NH 2, -N ( alkyl) _2, -NH (alkyl), - NHC (O) R 6, -NHS (O) 2 R 6, -NHC ( O) N(R ⁶ ) ₂ , -NHC(O)OR ⁶ , -C(O)R ⁶ , -C(O) ₂ R ⁶ , -C(O)N(R ⁶ ) ₂ , -S(O R ⁶ , -S(O) ₂ R ⁶ , -S(O) ₂ N(R ⁶ ) ₂ , -OR ⁶ , -SR ⁶ , lower alkyl group, lower carbon haloalkyl group, lower carbon number Alkyl, lower alkenyl, lower alkynyl, phenyl, benzyl, lower cycloalkyl, -CH ₂ - (lower cycloalkyl), monocyclic heteroaryl, and -CH ₂ - (monocyclic heteroaryl), wherein R ³ of the phenyl, benzyl, lower cycloalkyl, -CH ₂ - (lower cycloalkyl group), a monocyclic aryl group and heteroaryl -CH ₂ - (monocyclic heteroaryl) is unsubstituted or one or more independently selected from halo, alkyl, heteroalkyl, haloalkyl, alkoxy, -O-cyclopropyl, heteroalkoxy, haloalkane group, -CN, -SF ₅ and -OSF ₅ The substituent group into the group.

In an alternative to the examples just described above, m and p are each independently 0, 1, 2 or 3, and each R ⁶ (when present) is independently selected from H, lower alkyl a group consisting of a low carbon number cycloalkyl group, a low carbon number halogenated alkyl group, and a low carbon number heteroalkyl group.

In another alternative of the examples just set forth above, Ring B is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl, oxazolyl, pyrrolyl, decyl, oxa Diazolyl, cyclopropyl, cyclobutyl, oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, dihydroisoxazolyl, isoquinolinyl, thienyl, 5,6-dihydro- 4H -pyrroline group, triazolopyridyl group, imidazolinyl group, imidazothiazolyl group, imidazopyridyl group, benzotriazolyl group and benzoxazolyl group.

In another embodiment, in Formula (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), In each of IIB) and (IIB'): n is 1; p is 0 or greater; and each R ³ group (when present) is independently selected from the group consisting of: halogen, -OH , -CN, -SF ₅ , -NH ₂ , -NH(CH ₃ ), -N(CH ₃ ) ₂ , -OCH ₃ , -OCH ₂ CH ₃ , -O-cyclopropyl, -S(CH ₃ ) , methyl, ethyl, propyl, cyclopropyl, -CH ₂ -cyclopropyl, -C≡C-CH ₃ , -CF ₃ , -CHF ₂ , -C(O)OH, -C(O) OCH ₃ , -C(O)OCH ₂ CH ₃ , -OCF ₃ , -OCH ₂ CF ₃ and -OCHF ₂ .

In an alternative to the embodiment just described above, m and p are each independently 0, 1, 2 or 3.

In another alternative of the examples just set forth above, Ring B is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl, oxazolyl, pyrrolyl, decyl, oxa Diazolyl, cyclopropyl, cyclobutyl, oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, dihydroisoxazolyl, isoquinolinyl, thienyl, 5,6-dihydro- 4H -pyrroline group, triazolopyridyl group, imidazolinyl group, imidazothiazolyl group, imidazopyridyl group, benzotriazolyl group and benzoxazolyl group.

In another embodiment, in Formula (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), In each of IIB) and (IIB'): n is 1; p is 0 or greater; and each R ³ group (when present) is independently selected from the group consisting of: halogen, -OH , -CN, -SF ₅ , -NH ₂ , -NH(CH ₃ ), -N(CH ₃ ) ₂ , -OCH ₃ , -OCH ₂ CH ₃ , -O-cyclopropyl, -S(CH ₃ ) , methyl, ethyl, propyl, cyclopropyl, -CH ₂ -cyclopropyl, -C≡C-CH ₃ , -CF ₃ , -CHF ₂ , -C(O)OH, -C(O) OCH ₃ , -C(O)OCH ₂ CH ₃ , -OCF ₃ , -OCH ₂ CF ₃ , -OCHF ₂ , optionally substituted oxadiazolyl, optionally substituted isoxazolyl, optionally Substituted oxazolyl, optionally substituted triazolyl and optionally substituted phenyl, wherein each of the optional substituents is independently selected from the group consisting of F, Cl, CN, -CH ₃ a substituent of a group consisting of -OCH ₃ and -CF ₃ .

In an alternative to the embodiment just described above, m and p are each independently 0, 1, 2 or 3.

In another embodiment, in Formula (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), In each of IIB) and (IIB'): n is 1; ring A is selected from the group consisting of phenyl, thienyl and pyridyl; m is 0 or 1; each R ² group (when present ) is independently selected from the group consisting of: halogen, -CN, -SF ₅ , -NHCH ₃ , -N(CH ₃ ) ₂ , -OCH ₃ , -OCH ₂ CH ₃ , -O-cyclopropyl, - S(CH ₃ ), methyl, ethyl, propyl, cyclopropyl, -CH ₂ -cyclopropyl, -C≡C-CH ₃ , -CF ₃ , -CHF ₂ , -C(O)OH, -C(O)OCH ₃ , -C(O)OCH ₂ CH ₃ , -OCF ₃ and -OCHF ₂ ; -L ₁ - linkage or selected from -NHC(O)-, -CH ₂ NHC(O)- a divalent moiety group of a group consisting of -CH ₂ C(O)NH- and -C(O)NH-; the ring B is selected from the group consisting of phenyl, monocyclic heterocycloalkyl, monocyclic heteroaryl and a group of cyclic groups; p is 0 or greater; and each R ³ group (when present) is independently selected from the group consisting of: halogen, -OH, -CN, -SF ₅ , -NH ₂ , -NH(CH ₃ ), -N(CH ₃ ) ₂ , -OCH ₃ , -OCH ₂ CH ₃ , -O-cyclopropyl, -S(CH ₃ ), methyl, ethyl, propyl, cyclopropyl, -CH ₂ - _{Propyl, -C≡C-CH 3, -CF 3} , -CHF 2, -C (O) OH, -C (O) OCH 3, -C (O) OCH 2 CH 3, -OCF 3, -OCH ₂ CF ₃ and -OCHF ₂ .

In another alternative of the examples just set forth above, Ring B is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl, oxazolyl, pyrrolyl, decyl, oxa Diazolyl, cyclopropyl, cyclobutyl, oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, dihydroisoxazolyl, isoquinolinyl, thienyl, 5,6-dihydro- 4H -pyrroline group, triazolopyridyl group, imidazolinyl group, imidazothiazolyl group, imidazopyridyl group, benzotriazolyl group and benzoxazolyl group.

In an alternative to the examples just set forth above, each R ³ group, when present, is independently selected from the group consisting of halogen, -OH, -CN, -SF ₅ , -NH ₂ , -NH(CH ₃ ), -N(CH ₃ ) ₂ , -OCH ₃ , -OCH ₂ CH ₃ , -O-cyclopropyl, -S(CH ₃ ), methyl, ethyl, propyl, cyclopropyl , -CH ₂ -cyclopropyl, -C≡C-CH ₃ , -CF ₃ , -CHF ₂ , -C(O)OH, -C(O)OCH ₃ , -C(O)OCH ₂ CH ₃ , -OCF ₃ , -OCH ₂ CF ₃ , -OCHF ₂ , optionally substituted oxadiazolyl, optionally substituted triazolyl, optionally substituted isoxazolyl, optionally substituted An azolyl group and optionally a substituted phenyl group, wherein each of the optional substituents is one to three independently selected from the group consisting of F, Cl, CN, -CH ₃ , -OCH ₃ and -CF ₃ Substituent.

In another embodiment, in Formula (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), In each of IIB) and (IIB'): n is 1; ring A is selected from the group consisting of phenyl, thienyl and pyridyl; m is 0 or 1; each R ² group (when present ) is independently selected from the group consisting of: halogen, -CN, -SF ₅ , -NHCH ₃ , -N(CH ₃ ) ₂ , -OCH ₃ , -OCH ₂ CH ₃ , -O-cyclopropyl, - S(CH ₃ ), methyl, ethyl, propyl, cyclopropyl, -CH ₂ -cyclopropyl, -C≡C-CH ₃ , -CF ₃ , -CHF ₂ , -C(O)OH, -C(O)OCH ₃ , -C(O)OCH ₂ CH ₃ , -OCF ₃ and -OCHF ₂ .

a -L ₁ - linkage or a divalent moiety selected from the group consisting of -NHC(O)-, -CH ₂ NHC(O)-, -CH ₂ C(O)NH-, and -C(O)NH- Ring B is selected from the group consisting of phenyl, monocyclic heterocycloalkyl and monocyclic heteroaryl; p is 0 or greater; and each R ³ group (when present) is independently selected from Groups of the following: halogen, -OH, -CN, -SF ₅ , -NH ₂ , -NH(CH ₃ ), -N(CH ₃ ) ₂ , -OCH ₃ , -OCH ₂ CH ₃ , -O-ring Propyl, -S(CH ₃ ), methyl, ethyl, propyl, cyclopropyl, -CH ₂ -cyclopropyl, -C≡C-CH ₃ , -CF ₃ , -CHF ₂ , -C( O) OH, -C(O)OCH ₃ , -C(O)OCH ₂ CH ₃ , -OCF ₃ , -OCH ₂ CF ₃ and -OCHF ₂ .

In an alternative to the embodiment just described above, p is 0, 1, 2 or 3.

In another alternative of the examples just set forth above, Ring B is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl, oxazolyl, pyrrolyl, decyl, oxa Diazolyl, cyclopropyl, cyclobutyl, oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, dihydroisoxazolyl, isoquinolinyl, thienyl, 5,6-dihydro- 4H -pyrroline group, triazolopyridyl group, imidazolinyl group, imidazothiazolyl group, imidazopyridyl group, benzotriazolyl group and benzoxazolyl group.

In an alternative to the examples just set forth above, each R ³ group, when present, is independently selected from the group consisting of halogen, -OH, -CN, -SF ₅ , -NH ₂ , -NH(CH ₃ ), -N(CH ₃ ) ₂ , -OCH ₃ , -OCH ₂ CH ₃ , -O-cyclopropyl, -S(CH ₃ ), methyl, ethyl, propyl, cyclopropyl , -CH ₂ -cyclopropyl, -C≡C-CH ₃ , -CF ₃ , -CHF ₂ , -C(O)OH, -C(O)OCH ₃ , -C(O)OCH ₂ CH ₃ , -OCF ₃ , -OCH ₂ CF ₃ , -OCHF ₂ , optionally substituted oxadiazolyl, optionally substituted triazolyl, optionally substituted isoxazolyl, optionally substituted An azolyl group and optionally a substituted phenyl group, wherein each of the optional substituents is one to three independently selected from the group consisting of F, Cl, CN, -CH ₃ , -OCH ₃ and -CF ₃ Substituent.

In another embodiment, in Formula (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), In each of IIB) and (IIB'): n is 1; ring A is selected from the group consisting of phenyl, thienyl and pyridyl; m is 0 or 1; each R ² group (when present ) is independently selected from the group consisting of: halogen, -CN, -SF ₅ , -NHCH ₃ , -N(CH ₃ ) ₂ , -OCH ₃ , -OCH ₂ CH ₃ , -O-cyclopropyl, - S(CH ₃ ), methyl, ethyl, propyl, cyclopropyl, -CH ₂ -cyclopropyl, -C≡C-CH ₃ , -CF ₃ , -CHF ₂ , -C(O)OH, -C(O)OCH ₃ , -C(O)OCH ₂ CH ₃ , -OCF ₃ and -OCHF ₂ .

a -L ₁ - linkage or a divalent moiety selected from the group consisting of -NHC(O)-, -CH ₂ NHC(O)-, -CH ₂ C(O)NH-, and -C(O)NH- Ring B is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyrrolyl, oxazolyl, isoxazolyl, pyrazinyl, thienyl, pyrazolyl, furyl, thiazolyl, pyridazinyl, iso a group consisting of thiazolyl, isoxazolyl, isothiazolyl, indolyl, pyrrolopyridyl, pyrrolopyrimidinyl and oxadiazolyl; p-line 0 or greater; and each R ³ group (when When present) are independently selected from the group consisting of: halogen, -OH, -CN, -SF ₅ , -NH ₂ , -NH(CH ₃ ), -N(CH ₃ ) ₂ , -OCH ₃ , -OCH ₂ CH ₃ , -O-cyclopropyl, -S(CH ₃ ), methyl, ethyl, propyl, cyclopropyl, -CH ₂ -cyclopropyl, -C≡C-CH ₃ , -CF ₃ , -CHF ₂ , -C(O)OH, -C(O)OCH ₃ , -C(O)OCH ₂ CH ₃ , -OCF ₃ , -OCH ₂ CF ₃ and -OCHF ₂ .

In another alternative of the examples just set forth above, Ring B is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl, oxazolyl, pyrrolyl, decyl, oxa Diazolyl, cyclopropyl, cyclobutyl, oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, dihydroisoxazolyl, isoquinolinyl, thienyl, 5,6-dihydro- 4H -pyrroline group, triazolopyridyl group, imidazolinyl group, imidazothiazolyl group, imidazopyridyl group, benzotriazolyl group and benzoxazolyl group.

In another alternative of the examples just set forth above, each R ³ group, when present, is independently selected from the group consisting of: halogen, -OH, -CN, -SF ₅ , -NH ₂ , -NH(CH ₃ ), -N(CH ₃ ) ₂ , -OCH ₃ , -OCH ₂ CH ₃ , -O-cyclopropyl, -S(CH ₃ ), methyl, ethyl, propyl, Cyclopropyl, -CH ₂ -cyclopropyl, -C≡C-CH ₃ , -CF ₃ , -CHF ₂ , -C(O)OH, -C(O)OCH ₃ , -C(O)OCH ₂ CH ₃ , -OCF ₃ , -OCH ₂ CF ₃ , -OCHF ₂ , optionally substituted oxadiazolyl, optionally substituted triazolyl, optionally substituted isoxazolyl, optionally substituted An oxazolyl group and optionally a substituted phenyl group, wherein each of the optional substituents is one to three independently selected from the group consisting of F, Cl, CN, -CH ₃ , -OCH ₃ and -CF ₃ Substituents of the group.

In another alternative of the examples just set forth above, Ring B is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl, oxazolyl, pyrrolyl, indolyl and oxadiazolyl. group.

In another alternative of the examples just set forth above, Ring B is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl, oxazolyl, pyrrolyl, decyl, oxa Diazolyl, cyclopropyl, cyclobutyl, oxetanyl, tetrahydropyranyl, tetrahydrofuranyl and dihydroisoxazolyl.

In an alternative to the embodiment just described above, m and p are each independently 0, 1, 2 or 3.

In another embodiment, in Formula (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), In each of IIB) and (IIB'): n is 1; ring A is selected from the group consisting of phenyl, thienyl and pyridyl; m is 0 or 1; each R ² group (when present The lines are independently selected from the group consisting of halogen, -CN, -SF ₅ , -NHCH ₃ , -N(CH ₃ ) ₂ , -OCH ₃ , -OCH ₂ CH ₃ , -O-cyclopropyl, - S(CH ₃ ), methyl, ethyl, propyl, cyclopropyl, -CH ₂ -cyclopropyl, -C≡C-CH ₃ , -CF ₃ , -CHF ₂ , -C(O)OH, -C(O)OCH ₃ , -C(O)OCH ₂ CH ₃ , -OCF ₃ and -OCHF ₂ .

a -L ₁ - linkage or a divalent moiety selected from the group consisting of -NHC(O)-, -CH ₂ NHC(O)-, -CH ₂ C(O)NH-, and -C(O)NH- Ring B is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyrrolyl, oxazolyl, isoxazolyl, pyrazinyl, thienyl, pyrazolyl, furyl, thiazolyl, Pyridazinyl, isothiazolyl, isoxazolyl, isothiazolyl, indolyl, pyrrolopyridyl and pyrrolopyrimidinyl; p-system 0 or greater; and each R ³ group (when present) The group is independently selected from the group consisting of halogen, -OH, -CN, -SF ₅ , -NH ₂ , -NH(CH ₃ ), -N(CH ₃ ) ₂ , -OCH ₃ , -OCH ₂ CH ₃ , -O-cyclopropyl, -S(CH ₃ ), methyl, ethyl, propyl, cyclopropyl, -CH ₂ -cyclopropyl, -C≡C-CH ₃ , -CF ₃ , -CHF ₂ , -C(O)OH, -C(O)OCH ₃ , -C(O)OCH ₂ CH ₃ , -OCF ₃ , -OCH ₂ CF ₃ and -OCHF ₂ .

In an alternative to the examples just set forth above, Ring B is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl, oxazolyl, pyrrolyl and fluorenyl.

In another alternative of the examples just set forth above, Ring B is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl, oxazolyl, pyrrolyl, decyl, oxa Diazolyl, cyclopropyl, cyclobutyl, oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, dihydroisoxazolyl, isoquinolinyl, thienyl, 5,6-dihydro- 4H -pyrroline group, triazolopyridyl group, imidazolinyl group, imidazothiazolyl group, imidazopyridyl group, benzotriazolyl group and benzoxazolyl group.

In an alternative to the embodiment just described above, m and p are each independently 0, 1, 2 or 3.

In another embodiment, in Formula (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), In each of IIB) and (IIB'): n is 1; ring A is phenyl or pyridyl; and part Has the form: or Wherein: m is 0 or 1; each R ² group (when present) is independently selected from the group consisting of: halogen, -CN, -SF ₅ , -NHCH ₃ , -N(CH ₃ ) ₂ , -OCH ₃ , -OCH ₂ CH ₃ , -O-cyclopropyl, -S(CH ₃ ), methyl, ethyl, propyl, cyclopropyl, -CH ₂ -cyclopropyl, -C≡C -CH ₃ , -CF ₃ , -CHF ₂ , -C(O)OH, -C(O)OCH ₃ , -C(O)OCH ₂ CH ₃ , -OCF ₃ and -OCHF ₂ ;-L ₁ - a bond or a divalent moiety selected from the group consisting of -NHC(O)-, -CH ₂ NHC(O)-, -CH ₂ C(O)NH-, and -C(O)NH-; ring B system Selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyrrolyl, oxazolyl, isoxazolyl, pyrazinyl, thienyl, pyrazolyl, furyl, thiazolyl, pyridazinyl, iso Thiazolyl, isoxazolyl and isothiazolyl; p is 0 or greater; and each R ³ group, when present, is independently selected from the group consisting of halogen, -OH, -CN, - SF ₅ , -NH ₂ , -NH(CH ₃ ), -N(CH ₃ ) ₂ , -OCH ₃ , -OCH ₂ CH ₃ , O-cyclopropyl, -S(CH ₃ ), methyl, ethyl , propyl, cyclopropyl, -CH ₂ - _{cyclopropyl, -C≡C-CH 3, -CF 3} , -CHF 2, -C (O) OH _{-C (O) OCH 3, -C} (O) OCH 2 CH 3, -OCF 3, -OCH 2 CF 3 and -OCHF _2.

In an alternative to the examples just set forth above, each R ³ group, when present, is independently selected from the group consisting of halogen, -OH, -CN, -SF ₅ , -NH ₂ , -NH(CH ₃ ), -N(CH ₃ ) ₂ , -OCH ₃ , -OCH ₂ CH ₃ , -O-cyclopropyl, -S(CH ₃ ), methyl, ethyl, propyl, cyclopropyl , -CH ₂ -cyclopropyl, -C≡C-CH ₃ , -CF ₃ , -CHF ₂ , -C(O)OH, -C(O)OCH ₃ , -C(O)OCH ₂ CH ₃ , -OCF ₃ , -OCH ₂ CF ₃ , -OCHF ₂ , optionally substituted oxadiazolyl, optionally substituted triazolyl, optionally substituted isoxazolyl, optionally substituted An azolyl group and optionally a substituted phenyl group, wherein each of the optional substituents is one to three independently selected from the group consisting of F, Cl, CN, -CH ₃ , -OCH ₃ and -CF ₃ Substituent.

In an alternative to the examples just set forth above, Ring B is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyrrolyl, oxazolyl, isoxazolyl, pyrazinyl, thienyl , pyrazolyl, furyl, thiazolyl, pyridazinyl, isothiazolyl, isoxazolyl, isothiazolyl, indolyl, pyrrolopyridinyl, pyrrolopyrimidinyl and oxadiazolyl; In another alternative of the examples just described, Ring B is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl, oxazolyl, pyrrolyl, indolyl, oxadiazolyl , cyclopropyl, cyclobutyl, oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, dihydroisoxazolyl, isoquinolyl, thienyl, 5,6-dihydro- 4H -pyrrole Polinyl, triazolopyridyl, imidazolinyl, imidazothiazolyl, imidazopyridyl, benzotriazolyl and benzoxazolyl.

In another alternative of the examples just set forth above, Ring B is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl, oxazolyl, pyrrolyl, decyl, oxa Diazolyl, cyclopropyl, cyclobutyl, oxetanyl, tetrahydropyranyl, tetrahydrofuranyl and dihydroisoxazolyl.

In an alternative to the embodiment just described above, m and p are each independently 0, 1, 2 or 3.

In another embodiment, in Formula (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), In each of IIB) and (IIB'): n is 1; ring A is thienyl; and part Has the form: or Wherein: m is 0 or 1; each R ² group (when present) is independently selected from the group consisting of: halogen, -CN, -SF ₅ , -NHCH ₃ , -N(CH ₃ ) ₂ , -OCH ₃ , -OCH ₂ CH ₃ , -O-cyclopropyl, -S(CH ₃ ), methyl, ethyl, propyl, cyclopropyl, -CH ₂ -cyclopropyl, -C≡C -CH ₃ , -CF ₃ , -CHF ₂ , -C(O)OH, -C(O)OCH ₃ , -C(O)OCH ₂ CH ₃ , -OCF ₃ and -OCHF ₂ .

a -L ₁ - linkage or a divalent moiety selected from the group consisting of -NHC(O)-, -CH ₂ NHC(O)-, and -C(O)NH-; the ring B is selected from the group consisting of Group: phenyl, pyridyl, pyrimidinyl, pyrrolyl, oxazolyl, isoxazolyl, pyrazinyl, thienyl, pyrazolyl, furyl, thiazolyl, pyridazinyl, isothiazolyl, isomerism And oxazolyl and isothiazolyl; p is 0 or greater; and each R ³ group, when present, is independently selected from the group consisting of halogen, -OH, -CN, -SF ₃ , -NH ₂ , -NH(CH ₃ ), -N(CH ₃ ) ₂ , -OCH ₃ , -OCH ₂ CH ₃ , O-cyclopropyl, -S(CH ₃ ), methyl, ethyl, propyl, ring Propyl, -CH ₂ -cyclopropyl, -C≡C-CH ₃ , -CF ₃ , -CHF ₂ , -C(O)OH, -C(O)OCH ₃ , -C(O)OCH ₂ CH ₃ , -OCF ₃ , -OCH ₂ CF ₃ and -OCHF ₂ .

In an alternative to the embodiment just described above, m and p are each independently 0, 1, 2 or 3.

In an alternative to the examples just set forth above, Ring B is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyrrolyl, oxazolyl, isoxazolyl, pyrazinyl, thienyl , pyrazolyl, furyl, thiazolyl, pyridazinyl, isothiazolyl, isoxazolyl, isothiazolyl, fluorenyl, Pyrrolopyridinyl, pyrrolopyrimidinyl and oxadiazolyl.

In another alternative of the examples just set forth above, Ring B is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl, oxazolyl, pyrrolyl, decyl, oxa Diazolyl, cyclopropyl, cyclobutyl, oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, dihydroisoxazolyl, isoquinolinyl, thienyl, 5,6-dihydro- 4H -pyrroline group, triazolopyridyl group, imidazolinyl group, imidazothiazolyl group, imidazopyridyl group, benzotriazolyl group and benzoxazolyl group.

In another alternative of the examples just set forth above, Ring B is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl, oxazolyl, pyrrolyl, decyl, oxa Diazolyl, cyclopropyl, cyclobutyl, oxetanyl, tetrahydropyranyl, tetrahydrofuranyl and dihydroisoxazolyl.

In another alternative of the examples just set forth above, each R ³ group, when present, is independently selected from the group consisting of: halogen, -OH, -CN, -SF ₅ , -NH ₂ , -NH(CH ₃ ), -N(CH ₃ ) ₂ , -OCH ₃ , -OCH ₂ CH ₃ , -O-cyclopropyl, -S(CH ₃ ), methyl, ethyl, propyl, Cyclopropyl, -CH ₂ -cyclopropyl, -C≡C-CH ₃ , -CF ₃ , -CHF ₂ , -C(O)OH, -C(O)OCH ₃ , -C(O)OCH ₂ CH ₃ , -OCF ₃ , -OCH ₂ CF ₃ , -OCHF ₂ , optionally substituted oxadiazolyl, optionally substituted triazolyl, optionally substituted isoxazolyl, optionally substituted An oxazolyl group and optionally a substituted phenyl group, wherein each of the optional substituents is one to three independently selected from the group consisting of F, Cl, CN, -CH ₃ , -OCH ₃ and -CF ₃ Substituents of the group.

In formula (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), (IIB) and (IIB') Part of each Non-limiting examples are shown in the examples depicted in the table below.

When -L ₁ - represents a bond, formulas (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), Part of each of (IIB) and (IIB') Non-limiting examples are shown in Table 3-1 and the examples depicted in the table of example compounds following method WW8.

In some embodiments, in Formulas (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), (IIB) In each of (IIB'), n is 0. In these embodiments, part: With form .

In another embodiment, in Formula (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), In each of IIB) and (IIB'): n is 0; ring A is selected from the group consisting of phenyl, pyridyl, pyrazinyl, furyl, thienyl, pyrimidinyl, pyridazinyl, thiazolyl and oxazole a group consisting of bases; and R ² and m are each as defined in formula (I).

In another embodiment, in Formula (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), In each of IIB) and (IIB'): n is 0; ring A is selected from the group consisting of phenyl, pyridyl, pyrazinyl, furyl, thienyl, pyrimidinyl, pyridazinyl, thiazolyl and oxazole a group of base groups; m is 0 to 5; and each R ² (when present) is independently selected from the group consisting of halogen, -OH, -CN, -SF ₅ , -OSF ₅ , -NO ₂ , -N(R ⁶ ) ₂ , -NR ⁷ C(O)R ⁶ , -NR ⁷ S(O) ₂ R ⁶ , -NR ⁷ C(O)N(R ⁶ ) ₂ , -NR ⁷ C(O )OR ⁶ , -C(O)R ⁶ , -C(O) ₂ R ⁶ , -C(O)N(R ⁶ ) ₂ , -S(O)R ⁶ , -S(O) ₂ R ⁶ , -S(O) ₂ N(R ⁶ ) ₂ , -OR ⁶ , -SR ⁶ , lower alkyl, -(lower alkyl)-OH, lower carbon haloalkyl, lower carbon heteroalkyl , lower alkyl alkenyl, lower alkynyl, phenyl, benzyl, lower cycloalkyl, -CH ₂ - (lower cycloalkyl), monocyclic heteroaryl and -CH ₂ - ( monocyclic heteroaryl), wherein R ² of the phenyl, benzyl, lower cycloalkyl, -CH ₂ - (lower cycloalkyl group), a monocyclic heteroaryl group and -CH ₂ - (single Ring heteroaryl) unsubstituted or one or more Independently selected from the group consisting of halogen, alkyl, heteroalkyl, haloalkyl, alkoxy, -O-cyclopropyl, heteroalkoxy, haloalkoxy, -CN, -SF ₅ and -OSF ₅ Replacement of the group.

In one such embodiment, each R ⁶ (when present) is independently selected from the group consisting of H, lower alkyl, lower haloalkyl, and lower carbon heteroalkyl, and R ⁷ ( When present, is selected from the group consisting of H, lower alkyl.

In another embodiment, in Formula (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), In each of IIB) and (IIB'): n is 0; ring A is selected from the group consisting of phenyl, pyridyl and thienyl; and R ² and m are each as defined in formula (I).

In another embodiment, in Formula (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), In each of IIB) and (IIB'): n is 0; ring A is phenyl; and R ² and m are each as defined in formula (I).

In another embodiment, in Formula (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), In each of IIB) and (IIB'): n is 0; ring A is phenyl; m is 0 to 5; and each R ² (when present) is independently selected from the group consisting of: halogen , -CN, -SF ₅ , -OSF ₅ , -NO ₂ , -NH ₂ , -N(alkyl) ₂ , -NH(alkyl), -NHC(O)R ⁶ , -NHS(O) ₂ R ⁶ , -NHC(O)N(R ⁶ ) ₂ , -NHC(O)OR ⁶ , -C(O)R ⁶ , -C(O) ₂ R ⁶ , -C(O)N(R ⁶ ) ₂ , -S(O)R ⁶ , -S(O) ₂ R ⁶ , -S(O) ₂ N(R ⁶ ) ₂ , -OR ⁶ , -SR ⁶ , lower alkyl, lower carbon haloalkyl , lower carbon heteroalkyl, lower alkenyl, lower alkynyl, phenyl, benzyl, lower cycloalkyl, -CH ₂ - (lower cycloalkyl), monocyclic heteroaryl And -CH ₂ -(monocyclic heteroaryl), wherein the phenyl, benzyl, lower cycloalkyl, -CH ₂ - (lower cycloalkyl), monocyclic heteroaryl of R ² And -CH ₂ -(monocyclic heteroaryl) are unsubstituted or one or more independently selected from halo, alkyl, heteroalkyl, haloalkyl, alkoxy, -O-cyclopropyl, hetero Alkoxy, haloalkoxy, -CN, -SF ₅ And the group consisting of -OSF ₅ is replaced by a group.

In an alternative to the examples just set forth above, each R ⁶ (when present) is independently selected from the group consisting of H, lower alkyl, lower haloalkyl, lower cycloalkyl and lower carbon A group of heteroalkyl groups.

In another embodiment, in Formula (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), In each of IIB) and (IIB'): n is 0; ring A is phenyl; m is 0 to 4; and each R ² group (when present) is independently selected from the group consisting of : halogen, -CN, -SF ₅ , -NHCH ₃ , -N(CH ₃ ) ₂ , -OCH ₃ , -OCH ₂ CH ₃ , -O-cyclopropyl, -S(CH ₃ ), methyl, B Base, propyl, cyclopropyl, -CH ₂ -cyclopropyl, -C≡C-CH ₃ , -CF ₃ , -CHF ₂ , -C(O)OH, -C(O)OCH ₃ , -C (O) OCH ₂ CH ₃ , -OCF ₃ , -OCHF ₂ and -NHC(O)R ⁶ , wherein R ⁶ is selected from -CH ₂ CF ₃ , -CF ₂ CH ₃ , -CH ₃ , -CH ₂ CH _a group consisting of ₃ , -CH ₂ OCH ₃ , CHF ₂ and -CH ₂ N(CH ₃ ) ₂ .

In another embodiment, in Formula (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), In each of IIB) and (IIB'): n is 0; ring A is phenyl; m is 0 to 4; and each R ² group (when present) is independently selected from the group consisting of : halogen, -CN, -SF ₅ , -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -OCH ₃ , -OCH ₂ CH ₃ , -O-cyclopropyl, -S(CH ₃ ), Methyl, ethyl, propyl, cyclopropyl, -CH ₂ -cyclopropyl, -C≡C-CH ₃ , -CF ₃ , -CHF ₂ , -C(O)OH, -C(O)OCH ₃ , -C(O)OCH ₂ CH ₃ , -OCF ₃ and -OCHF ₂ .

In another embodiment, in Formula (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), In each of IIB) and (IIB'): n is 0; ring A is phenyl; m is 0 to 4; and each R ² group (when present) is independently selected from halo, haloalkyl a group consisting of cyclopropyl and -CN.

In an alternative to the examples just set forth above, each R ² group, when present, is independently selected from the group consisting of halogen, -NH ₂ , -NO ₂ , haloalkyl, cyclopropyl and -CN. group.

In another embodiment, in Formula (I), (IA), (IA'), (IB), (IB'), (II), (II'), (IIA), (IIA'), In each of IIB) and (IIB'): n is 0; ring A is phenyl; m is 0 to 4; and each R ² group (when present) is independently selected from fluorine, chlorine, a group consisting of bromine, cyclopropyl, -CF ₃ and -CN.

In an alternative to the examples just set forth above, each R ² group, when present, is independently selected from the group consisting of fluorine, chlorine, bromine, -NH ₂ , -NO ₂ , cyclopropyl, -CF ₃ And the group consisting of -CN.

In an alternative to the embodiment just described above, m is 0, 1, 2 or 3.

Specific non-limiting examples of the compounds of the invention are shown in the tables of the examples below. Although only one tautomeric form of each compound is shown in the tables, it is to be understood that all tautomeric forms of the compounds are intended to be within the scope of the non-limiting examples.

In another embodiment, one to three carbon atoms of the compound of the invention may be substituted with one to three germanium atoms as long as all atomic price requirements are met.

In another embodiment, a composition comprising a compound of the invention and a pharmaceutically acceptable carrier or diluent is provided.

Another embodiment provides a composition comprising a compound of the invention and a pharmaceutically acceptable carrier or diluent as the sole active agent or, optionally, in combination with one or more other therapeutic agents. Non-limiting examples of other therapeutic agents for use in combination with a compound of the invention include those selected from the group consisting of: (a) a medicament for the treatment of Alzheimer's disease and/or for the treatment of Alzheimer's disease a drug for one or more symptoms of the disease, (b) a drug for inhibiting Aβ synthesis, (c) a drug for treating a neurodegenerative disease, and (d) for treating type 2 diabetes and/or one or more thereof A symptom or related condition.

Other non-limiting examples of other therapeutic agents for use in combination with the compounds of the present invention include those useful in the treatment, prevention, or delay of any condition associated with A[beta] and/or its symptoms. Non-limiting examples of conditions associated with Aβ include: Alzheimer's disease, Down's syndrome, Parkinson's disease, memory loss, memory loss associated with Alzheimer's disease, and Parkinson's disease Memory loss, attention deficit symptoms, attention deficit symptoms associated with Alzheimer's disease ("AD"), Parkinson's disease and/or Down's syndrome, dementia, stroke, microgliosis (microgliosis) And brain inflammation, senile dementia, senile dementia, dementia associated with Alzheimer's disease, Parkinson's disease and/or Down's syndrome, progressive supranuclear palsy, cortical basal ganglia degeneration, neurodegeneration, Olfactory disorders, olfactory disorders associated with Alzheimer's disease, Parkinson's disease and/or Down's syndrome, beta-type amylovascular disease, brain amylovascular disease, hereditary cerebral hemorrhage, mild cognitive impairment ("MCI"), glaucoma, amyloidosis, type II diabetes, hemodialysis complications (beta ₂ microglobulin derived from hemodialysis patients and complications caused by it), scrapie, bovine spongiform encephalitis And CJ's disease, package The administration of at least one compound of the present invention or a tautomer or isomer thereof or a pharmaceutically acceptable salt of the compound or the tautomer to the patient in an amount effective to inhibit or treat the condition or the condition Or a solvate.

Other non-limiting examples of other therapeutic agents for use in combination with the compounds of the invention include: a scopolamine antagonist (eg, an m ₁ agonist (eg, acetylcholine, oxotremode, cyancholine, or McNa343) or m ₂ antagonists (such as belladonna, dicycloverine, tolterodine, oxybutynin, ipratropium, methoctramine, piren Tripitramine or gallamine); cholinesterase inhibitors (eg, ethionyl- and/or butyl cholinesterase inhibitors such as Aricept® (±) -2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-hexahydropyridyl]methyl]-1H-indol-1-one hydrochloride Salt), garlandyne (Razadyne®) and rivastigmine (Exelon®); N-methyl-D-aspartate receptor antagonists (eg, Namenda® (Memantine HCl, Available from Forrest Pharmaceuticals; cholinesterase inhibitor in combination with N-methyl-D-aspartate receptor antagonist; gamma secretase modulator; gamma secretase inhibitor; non-steroidal anti-inflammatory Agent; anti-inflammatory that can reduce nerve inflammation Anti-amyloid antibodies (eg, bapineuzemab, Wyeth/Elan); vitamin E; nicotinic acetylcholine receptor agonists; CB1 receptor inverse agonists or CB1 receptor antagonists; antibiotics; growth hormone secretagogue Histamine H3 antagonist; AMPA agonist; PDE4 inhibitor; GABA _A inverse agonist; inhibitor of starch-like aggregation; hepatic synthase kinase beta inhibitor; promoter of alpha secretase activity; PDE-10 inhibitor a tau kinase inhibitor (eg, a GSK3β inhibitor, a cdk5 inhibitor or an ERK inhibitor); a tau aggregation inhibitor (eg, Rember®); a RAGE inhibitor (eg, TTP 488 (PF-4494700)); an anti-Aβ vaccine APP ligand; a cholesterol lowering agent that upregulates insulin, such as an HMG-CoA reductase inhibitor (eg, statins such as atorvastatin (atorvastatin), fluvastatin, lovastatin) Lavastatin, mevastatin, pitavastatin, Pravastatin, rosuvastatin, simvastatin, and/or cholesterol absorption inhibitors ( For example, Ezetimibe or HMG-CoA reductase Formulation of a cholesterol absorption inhibitor in combination (e.g., Vytorin®); fibrates (fibrates) (e.g., clofibrate (the clofibrate), moclobemide (Clofibride), relying on Bethe (etofibrate) and clofibric acid, aluminum (Aluminium Clofibrate)); a combination of a fibrate with a cholesterol lowering agent and/or a cholesterol absorption inhibitor; a nicotinic receptor agonist; nicotinic acid; a nicotinic acid and cholesterol absorption inhibitor and/or a cholesterol lowering agent Combination (eg, Simcor® (nicotinic acid/simvastatin, available from Abbott Laboratories); LXR agonist; LRP mimetic; H3 receptor antagonist; histone deacetylase inhibitor; hsp90 inhibitor; 5-HT4 agonist (eg, PRX-03140 (Epix Pharmaceuticals)); 5-HT6 receptor antagonist; mGluR1 receptor modulator or antagonist; mGluR5 receptor modulator or antagonist; mGluR2/3 antagonist; prostate An EP2 receptor antagonist; a PAI-1 inhibitor; an agent that induces Aβ efflux, such as gelsolin; a metalloprotein attenuating compound (eg, PBT2); and a GPR3 modulator; and an antihistamine, for example Dimebolin (eg, Dimebon®, Pfizer)

Another embodiment provides a method of preparing a pharmaceutical composition comprising the steps of: at least one compound of the invention or a tautomer or stereoisomer thereof or the compound, the stereoisomer or the tautomer A pharmaceutically acceptable salt or solvate is admixed with a pharmaceutically acceptable carrier or diluent.

Another embodiment provides a method of inhibiting β-secretase (BACE-1 and/or BACE-2) comprising exposing a population of cells exhibiting β-secretase to at least one of the present invention for inhibiting the amount of β-secretase a compound or a tautomer or a stereoisomer thereof or a pharmaceutically acceptable salt or solvate of the compound, the stereoisomer or the tautomer. In one such embodiment, the population of cells is in vivo. In another such embodiment, the population of cells is ex vivo. In another such embodiment, the population of cells is in vitro. Expected to use these methods Research and/or therapeutic use as discussed herein.

Thus, another embodiment provides a method of inhibiting beta-secretase in a patient in need thereof. Another embodiment provides a method of inhibiting the formation of A[beta] from APP in a patient in need thereof. In another embodiment, the present invention provides for inhibiting the formation of A[beta] plaques and/or A[beta] fibrils and/or A[beta] oligomers and/or A[beta] oligomers in, on or around nerve tissue (eg, brain) in a patient in need thereof. A method of senile plaque and/or neurofibrillary tangles and/or inhibition of deposition of amyloid (eg, amyloid-like protein). Each of the embodiments comprises administering at least one compound of the invention, or a tautomer or stereoisomer thereof, or the compound, the stereoisomer or the mutual, in a therapeutically effective amount to inhibit the condition or condition of the patient. A pharmaceutically acceptable salt or solvate of an isomer.

In another embodiment, the invention provides methods of treating, preventing one or more conditions associated with Aβ and/or one or more symptoms associated with Aβ and/or delaying the onset thereof . Non-limiting examples of conditions associated with Aβ include: Alzheimer's disease, Down's syndrome, Parkinson's disease, memory loss, memory loss associated with Alzheimer's disease, and Parkinson's disease Memory loss, attention deficit symptoms, attention deficit symptoms associated with Alzheimer's disease ("AD"), Parkinson's disease and/or Down's syndrome, dementia, stroke, microglial hyperplasia and brain Inflammation, senile dementia, senile dementia, dementia associated with Alzheimer's disease, Parkinson's disease and/or Down's syndrome, progressive supranuclear palsy, cortical basal ganglia degeneration, neurodegeneration, olfactory disturbance, Olfactory disorders associated with Alzheimer's disease, Parkinson's disease and/or Down's syndrome, beta-type amylovascular disease, brain amylovascular disease, hereditary cerebral hemorrhage, mild cognitive impairment ("MCI") , glaucoma, amyloidosis, type 2 diabetes, hemodialysis complications (beta ₂ microglobulin from hemodialysis patients and complications from it), scrapie, bovine spongiform encephalitis and Cuija Disease, included to be effective Making or administering to the patient at least one compound of the invention or a tautomer or stereoisomer thereof or the compound, the stereoisomer or the tautomer thereof is pharmaceutically acceptable a salt or solvate.

In one embodiment, the invention provides a method of treating Alzheimer's disease, comprising administering to a patient in need of treatment an effective (ie, therapeutically effective) amount of one or more compounds of the invention (or tautomers thereof) Or a stereoisomer or the compound, the stereoisomer or a pharmaceutically acceptable salt or solvate of the tautomer, optionally in association with one or more effective treatments for Alzheimer's disease Further therapeutic combinations of other therapeutic agents. In embodiments in which one or more additional therapeutic agents are administered, the agents can be administered sequentially or together. Non-limiting examples of related diseases or conditions and non-limiting examples of suitable other therapeutically active agents are as described above.

In one embodiment, the invention provides a method of treating Down's syndrome comprising administering to a patient in need of treatment an effective (ie, therapeutically effective) amount of one or more compounds of the invention (or tautomers or stereoisomers thereof) A construct or a compound, the stereoisomer or a pharmaceutically acceptable salt or solvate of the tautomer).

In one embodiment, the invention provides a kit comprising a combination of pharmaceutical compositions in a single container, in a single container, wherein a container comprises an effective amount of a compound of the invention in a pharmaceutically acceptable carrier. (or a tautomer or a stereoisomer or the compound, the stereoisomer or a pharmaceutically acceptable salt or solvate of the tautomer, and the other container (ie, the second container) comprises an effective Another pharmaceutically active ingredient, a combined amount of a compound of the invention and another pharmaceutically active ingredient, is effective to: (a) treat Alzheimer's disease, or (b) inhibit in neural tissue (eg, brain), Amylopectin is deposited thereon or around it, or (c) treats a neurodegenerative disease, or (d) inhibits the activity of BACE-1.

In various embodiments, in the compositions and methods disclosed above and below, wherein the compound of the invention is selected from the group consisting of the compounds of the invention described below.

In another embodiment, the invention provides a compound of the invention, or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of the compound, the stereoisomer or the tautomer Use for the manufacture of one or more A[beta] conditions, delaying its onset and/or preventing it and/or for treating one or more symptoms of one or more A[beta] conditions, delaying its onset and / or prevent its medicine.

definition

The terms used herein have their ordinary meaning, and the meaning of such terms is independent each time they appear. Nevertheless, and unless otherwise stated, the following definitions apply throughout the specification and claims. Chemical names, common names, and chemical structures that describe the same structure are used interchangeably. Unless otherwise indicated, the terms apply regardless of whether the terms are used alone or in combination with other terms. Therefore, the definition of "alkyl" applies to "alkyl" and "hydroxyalkyl", "haloalkyl", arylalkyl-, alkylaryl-, The "alkyl" portion of "alkoxy" or the like.

It should be understood that in various embodiments of the invention described herein, any variable not explicitly defined in the context of the embodiments is as defined in formula (I). It is assumed that all atomic valences that are not explicitly filled are filled with hydrogen.

In the various embodiments described herein, each variable is selected independently of the other variables unless otherwise indicated.

As described herein, the variables of the formulae presented herein (eg, Ring A and Ring B) can be unsubstituted or substituted with "one or more" groups. For example, Ring A can be unsubstituted or substituted with one or more R ² groups; Ring B can be unsubstituted or substituted with one or more R ³ groups. It should be understood that the upper limit of the number of substituents (mentioned in the phrase "one or more substituents") may be used in the relevant part (for example, ring A or ring B) to be substituted by a substituent and will be chemically produced. The number of available hydrogen atoms in a stable and chemically neutral portion. Thus, for example, in the various formulae of the compounds of the invention (for example, in formula (I)), m, n and p are each independently selected integers, wherein: m is 0 or greater, n is 0 or 1; And p is 0 or greater, wherein the maximum value of m is the maximum number of hydrogen atoms which can be substituted on ring A, and wherein the maximum value of p is the maximum number of hydrogen atoms which can be substituted on ring B. As a non-limiting illustration, when the ring A is In the case of a group, the maximum value of m is 5. Ring A In the case of a group, the maximum value of m is 3. Ring A In the case of a group, the maximum value of m is 4.

"Patient" includes both human and non-human animals. Non-human animals include their research animals and companion animals such as mice, rats, primates, monkeys, chimpanzees, adult baboons, dogs (eg, dogs), and felines (eg, domestic cats).

"Pharmaceutical composition" (or "pharmaceutically acceptable composition") means a composition suitable for administration to a patient. Such compositions may contain the neat compounds (or compounds) of the invention or mixtures thereof or salts, solvates, prodrugs, isomers or tautomers thereof, or they may contain one or more pharmaceutically acceptable Carrier or diluent. The term "pharmaceutical composition" is also intended to encompass both the total composition and the individual dosage unit, which consists of more than one (eg, two) pharmaceutically active agents (eg, a compound of the invention and other agents selected from the list of other agents described herein). And any pharmaceutically inactive excipient composition. The total composition and each individual dosage unit may contain a fixed amount of the above "one or more pharmaceutically active agents". The overall composition is a material that has not yet formed individual dosage units. Illustrative dosage units are oral dosage units such as troches, pills, and the like. Similarly, the methods described herein for treating a patient by administering a pharmaceutical composition of the invention are also intended to encompass administration of the above-described overall compositions and individual dosage units.

"Halogen" means fluorine, chlorine, bromine or iodine. Preferred are fluorine, chlorine and bromine.

"Alkyl" means an aliphatic hydrocarbon group which may be straight or branched and which contains from about 1 to about 20 carbon atoms in the chain. Preferred alkyl chains contain from about 1 to about 12 carbon atoms. More preferably, the alkyl chain contains from about 1 to about 6 carbon atoms. Branched means that one or more lower alkyl groups are attached to the linear alkyl chain, such as methyl, ethyl or propyl. "Lower alkyl" means a group having from about 1 to about 6 carbon atoms in a chain which may be straight or branched. "Alkyl" may be unsubstituted or optionally substituted with one or more substituents which may be the same or different, each substituent being as described herein or independently selected from the group consisting of halo, alkyl, Haloalkyl, spirocycloalkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amine, -NH(alkyl), -NH(cycloalkyl), -N( Alkyl) ₂ , -OC(O)-alkyl, -OC(O)-aryl, -OC(O)-cycloalkyl, carboxy and -C(O)O-alkyl. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and tert-butyl.

"Haloalkyl" means an alkyl group as defined above wherein one or more hydrogen atoms on the alkyl group are replaced by a halo group as defined above.

"Heteroalkyl" means an alkyl moiety as defined above having one or more carbon atoms (eg, one, two or three carbon atoms) substituted with one or more heteroatoms which may be the same or different, wherein The point of attachment to the remainder of the molecule is achieved by the carbon atom of the heteroalkyl group. Suitable such heteroatoms include O, S, S(O), S(O) ₂ and -NH-, -N(alkyl)-. Non-limiting examples include ethers, thioethers, amines, and the like.

"Alkenyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and comprising from about 2 to about 15 carbon atoms in the chain. Preferably, the alkenyl chain has from about 2 to about 12 carbon atoms; and more preferably from about 2 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups are attached to the linear alkenyl chain, such as methyl, ethyl or propyl. "Lower carbon number alkenyl" means about 2 to about 6 carbon atoms in a chain which may be straight or branched. "Alkenyl" may be unsubstituted or, as the case may be, one or more These substituents may be 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-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.

"Alkyl" means a difunctional group obtained by removing a hydrogen atom from an alkyl group as defined above. Non-limiting examples of alkylene groups include methylene, ethyl and propyl. More generally, the suffix "ene" of an alkyl group, an aryl group, a heterocycloalkyl group or the like indicates a divalent moiety group, for example, -CH ₂ CH ₂ - is an ethyl group, and It is a pair of phenyl groups.

"Alkynyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and comprising from about 2 to about 15 carbon atoms in the chain. Preferably, the alkynyl chain has from about 2 to about 12 carbon atoms; and more preferably from about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to the linear alkynyl chain. By "lower alkynyl" is meant having from about 2 to about 6 carbon atoms in a chain which may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl. "Alkynyl" may be unsubstituted or optionally substituted with one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and cycloalkyl.

"En stretched alkenyl" means a difunctional group obtained by removing a hydrogen atom from an alkenyl group as defined above. Non-limiting examples of alkenylene groups include -CH = CH -, - C ( CH 3) = CH- and -CH = CHCH ₂ -.

"Aryl" means about 6 to about 14 carbon atoms, preferably about 6 to An aromatic monocyclic or polycyclic ring system of about 10 carbon atoms. The aryl group may be optionally substituted by one or more "ring system substituents" which may be the same or different and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl. "Monocyclic aryl" means phenyl.

"Heteroaryl" means an aromatic monocyclic or polycyclic ring system comprising from about 5 to about 14 ring atoms, preferably from about 5 to about 10 ring atoms, wherein one or more ring atom systems An element other than carbon, such as only nitrogen, oxygen or sulfur or a combination thereof. Preferred heteroaryl groups contain from about 5 to about 6 ring atoms. "Heteroaryl" may be optionally substituted by one or more 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. The nitrogen atom of the heteroaryl group can be oxidized to the corresponding N-oxide, as the case may be. "Heteroaryl" may also include a heteroaryl group as defined above fused to an aryl group as defined above. Non-limiting examples of suitable heteroaryl groups include pyridinyl, pyrazinyl, furyl, thienyl (which may alternatively be referred to as thiophenyl), pyrimidinyl, pyridone (including N substituted pyridone) , isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, pyrazolyl, furazyl, pyrrolyl, pyrazolyl, triazolyl, 1,2, 4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, pyridazinyl, hydroxydecyl, imidazo[1,2-a]pyridyl, imidazo[2,1-b] Thiazolyl, benzofurazinyl, fluorenyl, azaindole, benzimidazolyl, benzothienyl, quinolyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidinyl And pyrrolopyridyl, imidazopyridyl, isoquinolyl, benzazepine, 1,2,4-triazinyl, benzothiazolyl and the like. The term "heteroaryl" also refers to a moiety. Saturated heteroaryl moieties such as tetrahydroisoquinolinyl, tetrahydroquinolyl and the like. The term "monocyclic heteroaryl" refers to the monocyclic form of the heteroaryl group described above and includes 4 to 7 membered monocyclic heteroaryl groups containing from 1 to 4 ring heteroatoms, such ring heteroatoms. Independently selected from the group consisting of N, O and S and their oxides. The point attached to the parent moiety is attached to any available ring carbon or ring heteroatom. Non-limiting examples of monocyclic heteroaryl moieties include pyridyl, pyrazinyl, furyl, thienyl, pyrimidinyl, pyridazinyl, pyridinyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazole , isoxazolyl, pyrazolyl, furazolyl, pyrrolyl, pyrazolyl, triazolyl, thiadiazolyl (eg, 1,2,4-thiadiazolyl), imidazolyl, and triazine a group (for example, 1,2,4-triazinyl) and an oxide thereof.

"Cycloalkyl" means a non-aromatic monocyclic or polycyclic ring system comprising from about 3 to about 10 carbon atoms, preferably from about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain from about 5 to about 7 ring atoms. The cycloalkyl group may be optionally substituted with one or more substituents which may be the same or different as described above. Monocyclic cycloalkyl refers to the monocyclic form of the cycloalkyl moiety described herein. Non-limiting examples of suitable monocyclic cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Non-limiting examples of suitable polycyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl, and the like. Other non-limiting examples of cycloalkyl groups include the following:

"Cycloalkenyl" means a non-aromatic monocyclic or polycyclic ring comprising from about 3 to about 10 carbon atoms, preferably from about 5 to about 10 carbon atoms, containing at least one carbon-carbon double bond. system. Preferred cycloalkenyl rings contain from about 5 to about 7 ring atoms. The cycloalkenyl group may be optionally substituted with one or more substituents which may be the same or different as described above. The term "monocyclic cycloalkenyl" refers to the monocyclic form of the cycloalkenyl described herein and includes non-aromatic 3 to 7 membered monocyclic cycloalkyl groups containing one or more carbon-carbon double bonds. Non-limiting examples of suitable monocyclic cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohepta-1,3-dienyl, and the like. A non-limiting example of a suitable polycyclic cycloalkenyl group is a norbornenyl group.

"Heterocycloalkyl" (or "heterocyclyl") means a non-aromatic saturated monocyclic or polycyclic ring containing from about 3 to about 10 ring atoms, preferably from about 5 to about 10 ring atoms. A ring system in which one or more atomic systems in the ring system are other than carbon, such as only nitrogen, oxygen or sulfur or a combination thereof. There are no adjacent oxygen and/or sulfur atoms in the ring system. Preferred heterocyclic groups contain from 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 of the heterocyclyl rings may be present in a protected form, for example, in the form of -N(Boc), -N(CBz), -N(Tos), and the like; such protection may also be considered to be the invention Part of it. The heterocyclyl can be substituted, as described herein, with one or more substituents which may be the same or different. The nitrogen or sulfur atom of the heterocyclic group may optionally be oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Thus, the term "oxide" when used in the definition of a variable in the general structure described herein refers to the corresponding N-oxide, S-oxide or S,S-dioxide. "Heterocyclyl" also includes rings wherein =O replaces two available hydrogens on the same carbon atom (i.e., a heterocyclic group includes a ring having a carbonyl group in the ring). These =O groups may be referred to herein as "sideoxy groups." An example of this part is pyrrolidinone (or pyrrolidone): . The term "monocyclic heterocycloalkyl" as used herein, refers to the monocyclic form of the heterocycloalkyl moiety described herein and includes 4 to 7 membered monocyclic heterocycloalkyl groups containing from 1 to 4 ring heteroatoms, The isobaric hetero atom is independently selected from the group consisting of N,N-oxide, O, S, S-oxide, S(O), and S(O) ₂ . The point attached to the parent moiety is attached to any available ring carbon or ring heteroatom. Non-limiting examples of monocyclic heterocycloalkyl groups include hexahydropyridyl, oxetane, pyrrolyl, hexahydropyrazinyl, morpholinyl, thiomorpholinyl, tetrahydrothiazolyl, 1,4 - Dioxoalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, beta-actamamine, gamma lactam, delta-decalamine, beta lactone, gamma lactone, delta lactone and pyrrolidone and their oxides. Non-limiting examples of lower alkyl substituted oxetanyl groups include: .

"Heterocyclenyl" means an element comprising from about 3 to about 10 ring atoms, preferably from about 5 to about 10 ring atoms (wherein one or more atomic systems in the ring system are other than carbon, for example only A non-aromatic monocyclic or polycyclic ring system comprising at least one carbon-carbon double bond or a carbon-nitrogen double bond of nitrogen, oxygen or sulfur atoms or a combination thereof. There are no adjacent oxygen and/or sulfur atoms in the ring system. Preferred heterocyclenyl rings contain from about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclenyl 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 with one or more substituents which may be the same or different as described above. The nitrogen or sulfur atom of the heterocyclenyl group can optionally be oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable heterocycloalkenyl groups include 1,2,3,4-tetrahydropyridyl, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6- Tetrahydropyridyl, 1,4,5,6-tetrahydropyrimidinyl, 2-pyrroline, 3-pyrroline, 2-imidazolinyl, 2-pyrazolyl, dihydroimidazolyl, dihydrogen Oxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl, fluorodihydrofuranyl, 7-oxabicyclo[2.2.1] Heptenyl, dihydrothienyl, dihydrothiopyranyl and the like. "Heterocyclenyl" also includes rings wherein =O replaces two available hydrogens on the same carbon atom (ie, a heterocyclic group includes a ring having a carbonyl group in the ring). Examples of such parts are pyrrolidinone or pyrrolone: . The term "monocyclic heterocycloalkenyl" as used herein, refers to a monocyclic form of a heterocycloalkenyl moiety as described herein and includes a 4- to 7-membered monocyclic heterocycloalkenyl group containing from 1 to 4 ring heteroatoms. The isobaric hetero atom is independently selected from the group consisting of N,N-oxide, O, S, S-oxide, S(O), and S(O) ₂ . The point attached to the parent moiety is attached to any available ring carbon or ring heteroatom. Non-limiting examples of suitable heterocycloalkenyl groups include 1,2,3,4-tetrahydropyridyl, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6- Tetrahydropyridyl, 1,4,5,6-tetrahydropyrimidinyl, 2-pyrroline, 3-pyrroline, 2-imidazolinyl, 2-pyrazolyl, dihydroimidazolyl, dihydrogen Oxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl, fluorodihydrofuranyl, dihydrothienyl, dihydrothiopyranyl And its oxides.

It should be noted that in the hetero atom-containing ring system of the present invention, no hydroxyl group is present on a carbon atom adjacent to N, O or S, and no N or S group is present on the carbon adjacent to the other hetero atom. No -OH is attached directly to the carbons labeled 2 and 5.

The term "polycyclic group" as used herein refers to a fused ring system comprising two (two rings), three (three rings) or more fused rings, wherein each ring system of the fused ring system is independently A group consisting of a phenyl group, a monocyclic heteroaryl group, a monocyclic cycloalkyl group, a monocyclic cycloalkenyl group, a monocyclic heterocycloalkyl group, and a monocyclic heterocycloalkenyl group is selected. The point attached to the parent moiety is attached to any of the available ring carbons or, if present, ring heteroatoms on any of the fused rings. It will be appreciated that each of the following polycyclic groups depicted may be unsubstituted or substituted as described herein. Only the points attached to the parent portion are displayed by wavy lines.

The term polycyclic group includes a bicyclic aromatic group. Non-limiting examples of polycyclic groups that are bicyclic aromatic groups include: .

The term polycyclic group includes a bicyclic heteroaromatic group containing from 1 to 3 ring heteroatoms, each of which is independently selected from the group consisting of N, O and S, S(O) , S(O) ₂ , and oxides of N, O and S, and oxides thereof. Non-limiting examples of polycyclic groups which are bicyclic heteroaromatic groups contain from 1 to 3 ring heteroatoms, and the compounds of the present invention shown in the following table are independently selected from the group consisting of N, O and S. Each of the ring heteroatoms.

The term polycyclic group includes saturated bicyclic cycloalkyl. Non-limiting examples of polycyclic groups that are saturated bicyclic cycloalkyl groups include the following:

The term polycyclic group includes partially unsaturated bicyclic cycloalkyl. Non-limiting examples of polycyclic groups comprising a partially unsaturated bicyclic cycloalkyl group include the following:

The term polycyclic group includes partially or fully saturated bicyclic groups containing from 1 to 3 ring heteroatoms, each of which is independently selected from the group consisting of N, O and S, S(O). ), S(O) ₂ , and oxides of N, O and S. Non-limiting examples of such polycyclic groups are shown in the compounds of the invention and their oxides as shown in the table below.

The term polycyclic group includes aromatic tricyclic groups, cycloalkyl tricyclic groups, and heteroaromatic and partially and fully saturated tricyclic groups. For a tricyclic group comprising a ring heteroatom, the tricyclic group comprises one or more (eg, 1 to 5) ring heteroatoms, wherein each of the ring heteroatoms is independently selected from N, O And S, S (O), S (O) ₂ , and oxides of N, O and S. Non-limiting examples of such polycyclic groups are shown in the compounds of the invention and their oxides as shown in the table below.

"Arylalkyl" (or "aralkyl") means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyl groups contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthylmethyl. The bond to the parent moiety is achieved by means of an alkyl group. The term (and like terms) can be written as "arylalkyl-" to indicate the point of attachment to the parent moiety. Similarly, "heteroarylalkyl", "cycloalkylalkyl", "cycloalkenylalkyl", "heterocycloalkylalkyl", "heterocycloalkenylalkyl" and the like means as described above A heteroaryl group, a cycloalkyl group, a cycloalkenyl group, a heterocycloalkyl group, a heterocycloalkenyl group or the like bonded to the parent moiety through an alkyl group. Preferred groups contain a lower alkyl group. The alkyl groups can be straight or branched, unsubstituted and/or substituted as described above.

"Alkylaryl" means an alkyl-aryl- group in which the alkyl and aryl are as previously described. Preferred alkylaryl groups contain a lower alkyl group. A non-limiting example of a suitable alkylaryl group is a tolyl group. The bond to the parent moiety is achieved by means of an aryl group.

"Cycloalkyl ether" means a non-aromatic ring of 3 to 7 members containing an oxygen atom and 2 to 7 carbon atoms. The ring carbon atom may be substituted, with the restriction that the substituent adjacent to the epoxy does not include a halogen group or a substituent bonded to the ring via an oxygen, nitrogen or sulfur atom.

"Cycloalkylalkyl" means a cycloalkyl moiety attached to the parent core via an alkyl moiety (defined above) as defined above. Non-limiting examples of suitable cycloalkylalkyl groups include cyclohexylmethyl, gold alkyl alkyl, adamantyl, and the like.

"Cycloalkenylalkyl" means a cycloalkenyl moiety attached to the parent core via an alkyl moiety (defined above) as defined above. Non-limiting examples of suitable cycloalkenylalkyl groups include cyclopentenylmethyl, cyclohexenylmethyl, and the like.

"Heteroarylalkyl" means a heteroaryl moiety attached to the parent core via an alkyl moiety (defined above) as defined above. Non-limiting examples of suitable heteroarylalkyl groups include 2-pyridylmethyl, quinolinylmethyl, and the like.

"Heterocyclylalkyl" (or "heterocycloalkylalkyl") means a heterocyclyl moiety attached to the parent core via an alkyl moiety (defined above) as defined above. Non-limiting examples of suitable heterocyclylalkyl groups include hexahydropyridylmethyl, hexahydropyrazinylmethyl, and the like.

"Heterocyclenylalkyl" means a heterocycloalkenyl moiety attached to the parent core via an alkyl moiety (defined above) as defined above.

"Alkynylalkyl" means an alkynyl-alkyl- group in which both alkynyl and alkyl are as previously described. Preferred alkynylalkyl groups contain a lower alkynyl group and a lower alkyl group. The bond to the parent moiety is achieved by means of an alkyl group. Non-limiting examples of suitable alkynylalkyl groups include propargylmethyl.

"Heteroaralkyl" means a heteroaryl-alkyl- group in which both a heteroaryl group and an alkyl group are as previously described. Preferred heteroaralkyl groups contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl and quinolin-3-ylmethyl. The bond to the parent moiety is achieved by means of an alkyl group.

"Hydroxyalkyl" means an alkyl-alkyl group wherein the alkyl group is as previously defined. Preferred hydroxyalkyl groups contain a lower alkyl group. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.

"Cyanoalkyl" means an alkyl-alkyl group wherein the alkyl group is as previously defined. Preferred cyanoalkyl groups contain a lower alkyl group. Non-limiting examples of suitable cyanoalkyl groups include cyanomethyl and 2-cyanoethyl.

"Alkoxy" means an alkyl-O- group wherein 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 achieved by ether oxygen.

"Alkoxyalkyl" means a radical derived from an alkoxy group and an alkyl group, as defined herein. The bond to the parent moiety is achieved by means of an alkyl group.

"Spirocycloalkyl" means a cycloalkyl group attached to the parent moiety at a single carbon atom. Non-limiting examples of a spirocycloalkyl group in which the parent moiety is a cycloalkyl group Including snail [2.5] octane, snail [2.4] heptane and the like. A non-limiting example of a spirocycloalkyl group in which the parent moiety is attached. The alkyl moiety attached to the fused ring system (e.g., the alkyl moiety of the heteroaryl fused heteroarylalkyl group) can be optionally substituted with a spirocycloalkyl group or other groups described herein. Non-limiting spirocycloalkyl groups include spirocyclopropyl, spirobutyl, spiroheptyl and spirocyclohexyl.

"Spirocycloalkyl" means a heterocycloalkyl group attached to the parent moiety at a single carbon atom as defined herein.

The term "substituted" means that one or more hydrogens on a given atom are replaced by a group selected from a specified group, the limitation being no more than the normal valence of the specified atom in the prior case and the substitution resulting 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 robust enough to withstand separation from the reaction mixture to a useful purity and formulated into an effective therapeutic.

The term "optionally substituted" means an optional substitution using a specified group (groups or radicals) or a partial implementation.

a cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, aryl fused cycloalkylalkyl- moiety or the like includes a ring portion of the group and / or a substitution on an alkyl alkyl group.

When a variable appears more than once in a group (e.g., -N (R ⁶⁾ in the ₂ R ⁸⁾ or a variable appears more than once in the structure presented herein, may be the same or different variables.

solid line As a bond, a mixture or a mixture of possible isomers (for example, containing (R)- and (S)-stereochemistry) is usually indicated. E.g: Means contain and One or both.

A wavy line that is crossed with a line representing a chemical bond as used herein. Indicates the point of attachment to the rest of the compound. Draw a line into the ring system (for example ) indicates that the indicated line (bond) can be attached to any substitutable ring atom.

"Sideoxy" is defined as a double bond to a cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl or other ring as described herein (eg, The oxygen atom of the ring carbon.

In the present specification, if a plurality of oxygen and/or sulfur atoms are present in the ring system, then no adjacent oxygen and/or sulfur may be present in the ring system.

As is well known in the art, unless otherwise stated, a bond drawn from a particular atom in which no portion is drawn at the end of the bond indicates the methyl group bonded to the atom by the bond. E.g:

In another embodiment, the compounds of the invention and/or compositions comprising the same are present in isolated and/or purified form. The terms "purified," "in purified form," or "in isolated and purified form" refer to the physical state of the compound after separation from a synthetic process (eg, from a reaction mixture) or a natural source, or a combination thereof. Thus, the terms "purified," "in purified form," or "in isolated and purified form" with respect to a compound mean a process known from the purification process or as described herein or familiar to those skilled in the art (eg, chromatography, Recrystallization and the like) after obtaining the compound (or its tautomer) Or a physical state of the stereoisomer or the compound, the stereoisomer or a pharmaceutically acceptable salt or solvate of the tautomer, which is sufficiently pure for in vivo or medical use and/or Characterized by standard analytical techniques well known or familiar to those skilled in the art.

It should be understood that any carbon and heteroatoms in the text, schemes, examples, and tables that have unsatisfied valences have a sufficient number of hydrogen atoms to satisfy the valence.

When a functional group in a compound is referred to as "protected," it is meant that the group is in a modified form to avoid undesired side reactions at the protected site when the compound is reacted. Suitable protecting groups can be recognized by those skilled in the art and can be found in reference to standard textbooks (e.g., TW Greene et al, Protective Groups in organic Synthesis (1991), Wiley, New York).

Another embodiment provides prodrugs and/or solvates of the compounds of the invention. The discussion on prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 , ACSSymposium Series, and Bioreversible Carriers in Drug Design, (1987) edited by Edward B. Roche, American Pharmaceutical Association And Pergamon Press. The term "prodrug" means a compound (eg, a prodrug) that is converted in vivo to form a compound of the invention or a pharmaceutically acceptable salt, hydrate or solvate of the compound. Transformation can be achieved by a variety of mechanisms (e.g., by metabolic or chemical processes), for example, by hydrolysis in blood. Discussions on the use of prodrugs are provided in T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems", Volume 14 of the ACS Symposium Series, and Bioreversible Carriers in Drug Design, edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

For example, if the compound of the present invention or a pharmaceutically acceptable salt thereof contains a carboxylic acid functional group, the prodrug may comprise an ester formed by substituting a hydrogen atom of the acid group with a group such as: (C ₁ -C) ₈ ) an alkyl group, a (C ₂ -C ₁₂ ) alkanoyloxymethyl group, a 1-(alkylindenyloxy)ethyl group having 4 to 9 carbon atoms, having 5 to 10 carbon atoms 1-methyl-1-(alkylindolyloxy)-ethyl, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1-(alkoxy) having 4 to 7 carbon atoms Alkylcarbonyloxy)ethyl, 1-methyl-1-(alkoxycarbonyloxy)ethyl having 5 to 8 carbon atoms, N-(alkoxy) having 3 to 9 carbon atoms Carbonyl)aminomethyl, 1-(N-(alkoxycarbonyl)amino)ethyl, 4-mercapto, 4-crotonolide, γ-butyrolactone having 4 to 10 carbon atoms 4-yl, di-N,N-(C ₁ -C ₂ )alkylamino (C ₂ -C ₃ )alkyl (eg β-dimethylaminoethyl), amine methyl ketone-( C ₁ -C ₂ )alkyl, N,N-di(C ₁ -C ₂ )alkylaminemethanyl-(C ₁ -C ₂ )alkyl and hexahydropyrido(C ₂ -C ₃ ) alkane , pyrrolidino(C ₂ -C ₃ )alkyl or morpholine (C ₂ -C ₃ Alkenyl and the like.

Similarly, if the compound of the present invention contains an alcohol functional group, the prodrug can be formed by replacing a hydrogen atom of an alcohol group with a group such as: (C ₁ -C ₆ ) alkanoyloxymethyl, 1- ((C ₁ -C ₆ ) alkenyloxy)ethyl, 1-methyl-1-((C ₁ -C ₆ )alkyl fluorenyloxy)ethyl, (C ₁ -C ₆ ) alkoxy Carbocarbonyloxymethyl, N-(C ₁ -C ₆ ) alkoxycarbonylaminomethyl, amber fluorenyl, (C ₁ -C ₆ )alkyl fluorenyl, α-amino group (C ₁ -C ₄ An alkyl group, an aryl fluorenyl group and an α-amino fluorenyl group or an α-amino fluorenyl-α-amino fluorenyl group, wherein each α-amino fluorenyl group is independently selected from a naturally occurring L- Amino acid, P(O)(OH) ₂ , -P(O)(O(C ₁ -C ₆ )alkyl) ₂ or a glycosyl group (this group is derived from a carbohydrate in the form of a hemiacetal to remove a hydroxyl group Obtained), and so on.

If a compound of the invention incorporates an amine functional group, the prodrug can be formed by substituting a hydrogen atom in the amine group with a group such as: R-carbonyl, RO-carbonyl, NRR'-carbonyl (wherein R and R' Each independently is a (C ₁ -C ₁₀ )alkyl group, a (C ₃ -C ₇ )cycloalkyl group, a benzyl group, or an R-carbonyl natural α-amino fluorenyl group or a natural α-amino fluorenyl group, -C(OH)C(O)OY ¹ (wherein Y ¹ is H, (C ₁ -C ₆ )alkyl or benzyl), -C(OY ² )Y ³ (wherein Y ² is (C ₁ -C) ₄ ) alkyl, and Y ³ (C ₁ -C ₆ ) alkyl, carboxy (C ₁ -C ₆ ) alkyl, amine (C ₁ -C ₄ ) alkyl or mono-N- or di-N , N-(C ₁ -C ₆ )alkylaminoalkyl), -C(Y ⁴ )Y ⁵ (wherein Y ⁴ is H or methyl, and Y ⁵ is mono-N- or di-N,N -(C ₁ -C ₆ )alkylamino, morpholinyl, hexahydropyridin-1-yl or pyrrolidin-1-yl) and the like.

One or more compounds of the invention may exist as unsolvated as well as solvates with pharmaceutically acceptable solvents such as water, ethanol, and the like, and the invention is intended to encompass both solvates and unsolvated forms By. "Solvate" means a physical association of a compound of the invention with one or more solvent molecules. This physical association involves varying degrees of ionic bonding and covalent bonding (including hydrogen bonding). In some cases, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" encompasses both the solution phase and the solvable solvate. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. The "hydrate" is a solvate in which the solvent molecule is H ₂ O.

One or more compounds of the invention may optionally be converted to a solvate. The preparation of solvates is well known. Thus, for example, M. Caira et al., J. Pharmaceutical Sci ., 93(3), 601-611 (2004) describe the preparation of a solvate of the antifungal fluconazole in ethyl acetate and from water. . Solvates, hemisolvates, hydrates, and the like are prepared by ECvan Tonder et al, AAPS Pharm SciTech ., 5(1) , 12 (2004); and ALBingham et al, Chem . Commun ., 603 -604 (2001). A typical non-limiting process involves dissolving a compound of the invention in a desired amount of a desired solvent (organic solvent or water or mixture thereof) above ambient temperature and cooling the solution at a rate sufficient to form crystals, which are then separated by standard methods. The crystals. Analytical techniques such as IR spectroscopy show the presence of a solvent (or water) in the crystals as a solvate (or hydrate).

"Effective amount" or "therapeutically effective amount" is intended to describe the amount of a compound or composition of the invention that is effective to inhibit the above mentioned conditions and thereby produce a desired therapeutic, ameliorating, inhibiting or prophylactic effect.

Another embodiment provides a pharmaceutically acceptable salt of a compound of the invention. Therefore, unless otherwise indicated, a compound of the invention referred to herein is to be understood to include the salts thereof. The term "salt" as used herein denotes an acidic salt formed using an inorganic acid and/or an organic acid and an alkaline salt formed using an inorganic base and/or an organic base. In addition, when the compound of the present invention contains a basic moiety such as, but not limited to, pyridine or imidazole, and an acidic moiety such as, but not limited to, a carboxylic acid, a zwitterion ("internal salt") can be formed and is included in the term " Within the salt. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts may also be employed. For example, by making the invention The compound is reacted with a quantity of an acid or base (e.g., an equivalent amount) in a medium such as a medium in which the salt can be precipitated or in an aqueous medium, followed by lyophilization to form a salt of the compound of the present invention.

Exemplary acid addition salts include acetates, ascorbates, benzoates, besylate, hydrogen sulfate, borates, butyrates, citrates, camphorates, camphorsulfonates, fumaric acid Salt, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, salicylate Acid salts, succinates, sulfates, tartrates, thiocyanates, toluenesulfonates (also known as tosylate) and the like. Further, an acid which is generally considered to be suitable for forming a pharmaceutically useful salt from an alkaline pharmaceutical compound is described, for example, in P. Stahl et al., Camille G. (ed.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. 2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al . The Practice of Medicinal Chemistry (1996), Academic Press, New York; and The Orange Book (Food & Drug Administration, Washington, DC, on its website). The disclosures are hereby incorporated by reference.

Exemplary basic salts include ammonium salts, alkali metal salts (e.g., sodium, lithium, and potassium salts), alkaline earth metal salts (e.g., calcium and magnesium salts), and organic bases (e.g., organic amines such as dicyclohexylamine, third butyl). The salt formed by the base amine and a salt formed with an amino acid (for example, arginine, lysine, and the like). Can be used The following reagents quaternize basic nitrogen-containing groups: lower alkyl halides (eg, chlorides, bromides, and iodides of methyl, ethyl, and butyl), dialkyl sulfates (eg, , dimethyl sulfate, diethyl sulfate and dibutyl sulfate), long-chain halides (for example, sulfhydryl, lauryl and stearyl chlorides, bromides and iodides), aralkyl halides (for example, bromide of benzyl and phenethyl) and others.

For the purposes of the present invention, all such acidic and basic salts are intended to be pharmaceutically acceptable salts within the scope of the invention, and all acidic and basic salts are considered equivalent to the free form of the corresponding compound.

Another embodiment provides a pharmaceutically acceptable ester of a compound of the invention. The esters include the following groups: (1) a carboxylic acid ester obtained by esterification of a hydroxy group, wherein the non-carbonyl moiety of the carboxylic acid moiety of the ester group is selected from a linear or branched alkyl group (for example, Ethyl, n-propyl, tert-butyl or n-butyl), alkoxyalkyl (eg methoxymethyl), aralkyl (eg benzyl), aryloxyalkyl (eg , phenoxymethyl), aryl (for example, phenyl substituted by, for example, halogen, C _1-4 alkyl or C _1-4 alkoxy or amine); (2) sulfonate , for example, an alkyl- or aralkylsulfonyl group (for example, methylsulfonyl); (3) an amino acid ester (for example, L-guanidinium or L-isoleucine); (4) Phosphonates and (5) mono-, di- or triphosphates. The phosphate ester can be further esterified with, for example, a C _1-20 alcohol or a reactive derivative thereof or via 2,3-di(C _6-24 )mercaptoglycerol.

As mentioned herein, another embodiment provides tautomers of the compounds of the invention and salts, solvates, esters and prodrugs thereof. It will be understood that all tautomeric forms of such compounds are within the scope of the compounds of the invention. For example, all keto-enol and imine-enamine forms of such compounds, when present, are included in the present invention. As another non-limiting example, in the embodiments described above wherein one or both of R ^1A and R ^1B are hydrogen, specifically when the W system is S(O) or S(O) ₂ , a compound of the formula: And compounds of the formula: Also a compound of the formula: It is encompassed within the scope of the compounds of the invention.

The compounds of the invention may contain asymmetric or palmar centers and thus exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the invention, as well as mixtures thereof including racemic mixtures, are intended to form part of the invention. Additionally, the invention encompasses all geometric and positional isomers. For example, if a compound of the invention incorporates a double bond or a fused ring, both cis- and trans-forms as well as mixtures are encompassed within the scope of the invention.

Another embodiment provides a mixture of non-Spiegelmers and individual mirror image isomers of the compounds of the invention. By the difference in physicochemical properties of the non-image isomers The mixture of diastereomers can be separated into individual non-image isomers by methods well known to those skilled in the art (e.g., by chromatography and/or fractional crystallization). The Spiegelmer can be isolated by converting the Spiegelmer mixture to a non-mirrored by reaction with a suitable optically active compound (for example, a palmitic adjuvant such as palmitic alcohol or Mosher® chlorine). The mixture of the constructs separates the non-Spiegelmers and converts (e.g., hydrolyzes) the individual non-Spiegelmers to the corresponding pure mirror image isomers. Likewise, certain compounds of the invention may be atropisomers (e.g., substituted diaryls) and are considered as part of this invention. Mirror isomers can also be separated by using a pair of HPLC HPLC columns.

All stereoisomers (eg, geometric isomers, optics) of the compounds of the invention, including the salts, solvates, esters and prodrugs thereof, and salts, solvates and esters of such prodrugs Isomers and the like, for example, which exist as a result of asymmetric carbons on each substituent, including the mirror image isomer form (which may be present even in the absence of asymmetric carbon), rotamer form, hindered Trans Isomer Forms and Non-Spiegelmer Forms, which are included within the scope of the invention, positional isomers (e.g., 4-pyridyl and 3-pyridyl) are also encompassed within the scope of the invention Example. (For example, if a compound of the invention incorporates a double bond or a fused ring, both cis- and trans-forms, as well as mixtures, are encompassed within the scope of the invention. Likewise, for example, all keto-enols of such compounds And imine-enamine forms are included in the present invention.)

Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may, for example, be a mixture of racemates or be combined with all other or other selected stereoisomers. The palm center of the present invention may have an S or R configuration as defined by the IUPAC 1974 Recommendations. The terms "salt", "solvate", "ester", "prodrug" and the like are intended to be equally applicable to the mirror image isomers, stereoisomers, rotamers, tautomers of the compounds of the invention. Salts, solvates, esters and prodrugs of a conformation, positional isomer, racemate or prodrug.

In the compounds of the present invention, each atom may exhibit its natural isotopic abundance, or one or more atoms may be artificially enriched with the same atomic number but the atomic mass or mass number is different from the atomic mass or mass number found in nature. Specific isotope. The invention is intended to include all suitable isotopic variations of the compounds of the invention. These compounds are identical to those described herein except that the atomic mass or mass of one or more atoms differs from the atomic mass or mass number normally found in nature. For example, different isotopic forms of hydrogen (H) include deuterium ( ¹ H) and deuterium ( ² H). It is the main hydrogen isotope found in nature. Other examples of isotopes that may be included in the compounds of the invention include, when present, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, respectively. , ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl.

Certain isotopically-labeled compounds of the invention (e.g., those labeled with ³ H and ¹⁴ C) can be used for compound and/or matrix tissue distribution analysis. The ruthenium (i.e., ³ H) and carbon-14 (i.e., ¹⁴ C) isotopes are particularly preferred for their ease of preparation and detectability. In addition, substitution with isotopes such as deuterium (ie, ² H) may provide certain therapeutic advantages derived from higher metabolic stability (eg, increased in vivo half-life or reduced dosage requirements), and thus may be good. Isotopically labeled compounds of the invention can generally be prepared by substituting an isotopically labeled reagent with an appropriately isotopically labeled reagent by procedures similar to those disclosed in the schemes and/or examples hereinafter.

In another embodiment, the compounds of the invention are used as research or diagnostic reagents by isotopic labeling. For example, the compounds of the invention can be labeled for compound and/or matrix tissue distribution analysis. The ruthenium (i.e., ³ H) and carbon-14 (i.e., ¹⁴ C) isotopes are preferred for their ease of preparation and detectability. In another embodiment, the compounds of the invention may be labeled with isotopes such as deuterium (ie, ² H). Enrichment of the compounds of the present invention may provide certain therapeutic advantages derived from higher metabolic stability (eg, increased in vivo half-life or reduced dosage requirements), or may provide compounds for use as a standard for characterizing biological samples, and Therefore, it may be preferred in some cases. The isotopically-labeled compounds of the present invention can generally be replaced by appropriate isotopically labeled reagents by procedures similar to those disclosed in the Schemes and/or the Examples below, without undue experimentation. Isotope-labeled reagents are prepared. Markers suitable for such research or diagnostic reagents include, but are not limited to, nuclear spin labels (eg, ¹⁹ F magnetic resonance imaging (MRI) probes), radioactive labels (eg, ¹⁸ F, ¹¹ C, ¹⁵ N, ¹²⁵ I and ³ H (also known as "氚") isotopic labels) and complexes of metal atoms or metal ions with chelating agents. The labeled compounds can be used for in vitro or in vivo imaging (especially) BACE in tissues such as brain, heart, liver, kidney, and lung to quantitatively measure BACE and determine the distribution and region of such receptors in the tissue. Combining characteristics. Such analytical probes can be used, inter alia, in conjunction with such diagnostic techniques (eg, MRI and positron emission tomography (PET) and single photon emission computed tomography (SPECT)).

Thus, for example, some of the compounds of the invention contain one or more methyl ether groups. Those skilled in the art will recognize that the carbon-11 isotope analog of the methyl ether group can be readily prepared by methods well known in the art. Some of the compounds of the invention include fluoro groups. Those skilled in the art will also recognize that ¹⁸ F can be used as an isotopic substitute for the fluorine group present in the compounds of the present invention, and that the ¹⁸ F analog of the compound of the present invention containing a fluorine group can be used in a variety of industries. It is known by known methods. Non-limiting examples of compounds of the invention that can be prepared as isotopic analogs and which encompass other embodiments of the compounds of the invention, including methyl ether groups, include Examples 9a, 9d, 9p, 9m, 9o, 9u, 9y, 9ac, 9ce, 9cm-a, 9cm-b, 9cx-a, 9cx-b, 9dc-a, 9dc-b, 9dj-a, 9dj-b, 9do-a, 9do-b, 9dq-a, 9dq-b, 9dt-a, 9dx-a, 9dx-b, 9eb-a, 9eb-b, 3, 9n, 9w, 9z, 9ae, 9by, 9cg, 9cn-a, 9cn-b, 9cq-a, 9cq-b, 9ct-a, 9cy-a, 9cy-b, 9dd-a, 9dd-b, 9dg-a, 9dg-b, 9dk-a, 9dk-b, 9dm-a, 9dm-b, 9dr-a, 9dr- b, 9du-a, 9dy-a, 9dy-b, 9ec-a, 9ec-b, 9ee-a and 9ee-b. Non-limiting examples of compounds of the invention that can be prepared as ¹⁸ F isotope analogs and which encompass other embodiments of the compounds of the invention, including fluoro groups, include those examples 1, 2, 7, 9c, 9d, 9f, 9k, 9o, 9s, 9x, 9aa, 9ba, 9ca, 9cd, 9cl-a, 9cl-b, 9co-a, 9cr-a, 9cv-a, 9cv-b, 9da-a, 9da-b, 9db-a, 9db-b, 9dc-a, 9dc-b, 9dd-a, 9dd-b, 9de-a, 9de-b, 9df-a, 9df-b, 9dg-a, 9dg-b, 9dh-a, 9dh- b, 9dn-a, 9dp-a, 9dp-b, 9ds-a, 9dv-a, 9dv-b, 9ea-a, 9ea-b, 9ed-a, 9ed-b and 9ef.

It is known that carbon-11 instead of carbon-12 or ¹⁸ F instead of ¹⁹ F has little or no adverse effect on the affinity of the compounds of the invention for BACE, as it is well known in the art that isotopic compositions have no effect on receptor affinity. Thus, another embodiment provides a carbon-11-rich analog of the compound of the invention wherein the carbon-12 group of the methyl ether group present on the compound is replaced by carbon-11 or a pharmaceutically acceptable Preparation and use of salts, pharmaceutical compositions comprising the same, and their use in a variety of well known imaging techniques, including positron emission tomography (PET tracers). A further embodiment provides the preparation and use of an ¹⁸ F-rich analog or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the same, and various well-known imaging techniques (including positrons) Use in emission tomography (PET tracer)). The preparation of this non-limiting example of a carbon-11 analog is set forth in Example 9 dc-a-11C from the preparation of Example 9 dc-a below.

[ ¹¹ C] Iodomethane was captured at room temperature in Example 9eg (0.45 mg, 0.899 μmol) and cesium carbonate (2.2 mg, 6.75 μmol) in dimethylformamide (300 μL). In a 0.9 mL vial. The resulting reaction mixture was heated at 70 ° C for 5 minutes. The solution was transferred to a 0.9 mL vial containing water (700 μL) at room temperature, mixed and injected into a semi-preparative HPLC column. The product was purified using a Zorbax Eclipse XDB C-18 (5 μm, 9.4 x 250 mm (Agilent)) at a flow rate of 5 mL/min. The mobile phase was 50% to 80% acetonitrile/NaH ₂ P _{4 in} water (10 mM) in 10 min. The radioactive fraction eluted between 6.7 minutes and 7.0 minutes was collected, evaporated under negative pressure, diluted with 0.9% saline solution (3 mL) and transferred to a sterile container.

The chemical and radiochemical purity of the final product was tested by means of an analytical HPLC system (Waters) using Xbridge C18, 5 μm, 4.6 x 150 mm column (Waters) at a flow rate of 1.5 mL/min. The mobile phase consisted of a mixture of 45% acetonitrile and 55% 0.1 trifluoroacetic acid in water. The concentration of Example 9dc-a-11C was determined by means of a UV detector (260 nm). The product was confirmed by co-injection of a sample of Example 9dc-a, and the radiochemical purity was determined using a sodium iodide detector (Bioscan). The retention time of Example 9dc-a-11C was 3.03 min and the chemical and radiochemical purity was 100%.

The invention is intended to include polymorphic forms of the compounds of the invention and polymorphic forms of the salts, solvates, esters and prodrugs of the compounds of the invention.

Another embodiment provides suitable dosages and dosage forms of the compounds of the invention. Suitable dosages for administering a compound of the invention to a patient can be readily determined by those skilled in the art (e.g., by the attending physician, pharmacist, or other skilled artisan), and can be based on the patient's condition, age, weight The frequency of administration, the use of other active ingredients, and/or the indications for which the compound is administered varies. The dosage may range from about 0.001 mg/kg body weight/day to 500 mg/kg body weight/day of the compound of the invention. In one embodiment, the dosage is from about 0.01 mg/kg body weight/day to about 25 mg/kg body weight/day of a compound of the invention or a pharmaceutically acceptable salt or solvate of the compound. In another embodiment, the amount of active compound in a unit dosage formulation may be between 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, depending on the particular application. Change or adjust. In another embodiment, a typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about It is administered in two to four doses in the range of about 500 mg/day, preferably from 1 mg/day to 200 mg/day.

As discussed above, the clinical attending physician can modulate the administration of the compound of the present invention and/or its pharmaceutically acceptable salt, taking into account factors such as the age, condition and shape of the patient and the severity of the condition being treated. Quantity and frequency.

When used in combination with one or more other therapeutic agents, the compounds of the invention may be administered together or sequentially. When administered sequentially, the compounds of the invention may be administered before or after one or more other therapeutic agents, as determined by those skilled in the art or patient preferences.

If formulated at a fixed dose, such combination products employ a compound of the invention within the dosage range described herein and another pharmaceutically active agent or treatment within the dosage range thereof.

Accordingly, another embodiment provides a combination comprising an amount of at least one compound of the invention, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and an effective amount of one or more of the other agents described above.

The pharmacological properties of the compounds of the invention can be confirmed by a number of pharmacological analyses. Some analyses are exemplified elsewhere in this document.

Another embodiment provides a pharmaceutically acceptable composition comprising a compound of the invention as a neat chemical or, as the case may be, further comprising other ingredients. For the preparation of a pharmaceutical composition from a compound of the invention, the pharmaceutically acceptable inert carrier can be either solid or liquid. Solid form preparations include powders, lozenges, dispersible granules, capsules, cachets, and suppositories. Powders and lozenges may comprise from about 5% to about 95% of the active ingredient. Suitable solid carriers are known in the art, for example, magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of preparing various compositions can be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences , 18th Ed., (1990), Mack Publishing, Inc., Easton, Pennsylvania.

Liquid form preparations include solutions, suspensions and emulsions. Examples which may be mentioned are water or water-propylene glycol solutions for parenteral injection, or sweeteners and opacifiers which can be added to oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.

Aerosol formulations suitable for inhalation may include solutions and solids in powder form in admixture with pharmaceutically acceptable carriers (for example, inert compressed gases (e.g., nitrogen).

Also included are solid form preparations which are intended to be converted into liquid form preparations for oral or parenteral administration just prior to use. Such liquid forms include solutions, suspensions and emulsions.

Another embodiment provides a composition comprising a compound of the invention formulated for transdermal delivery. Compositions for transdermal delivery may be in the form of creams, lotions, aerosols and/or emulsions and may be included in the matrix or storage type transdermal patches conventionally employed in the art for this purpose.

Another embodiment provides a composition comprising a compound of the invention formulated for subcutaneous delivery. Another embodiment provides a composition suitable for oral delivery. In some embodiments, a pharmaceutical formulation comprising one or more compounds of the invention may advantageously be prepared in unit dosage form. When using these forms, the formulation can be subdivided into A unit dose containing a suitable amount of the active ingredient, for example, an effective amount to achieve the desired purpose. Each of the foregoing alternatives and their corresponding methods of use are considered to be included in various embodiments of the invention.

Preparation example

The compounds of the invention can be prepared using procedures known in the art. The following reaction schemes show typical procedures, but those skilled in the art will recognize that other procedures are also applicable. The reaction may involve monitoring the consumption of the starting materials, and there are many methods for this monitoring, including but not limited to, thin layer chromatography (TLC) and liquid chromatography mass spectrometry (LCMS), and those skilled in the art. It will be appreciated that if a method is specified, other non-limiting methods can be substituted.

Techniques, solvents and reagents can be mentioned as follows:

method 1

Step 1: slowly add NaH (8.0 g, 60%, stored in a stirred solution of commercially available 2-(methylsulfonyl)-acetonitrile (11.9 g, 100 mmol) in 300 mL of THF at 0 °C. In mineral oil, 200 mmol). After 20 min, MeI (28.4 g, 200 mmol) was added dropwise over a period of 1.5 h. The mixture was allowed to warm from 0 °C to room temperature overnight (20 h). (250 mL) it was quenched with H ₂ O, and evaporated THF. The aqueous solution was extracted with three 250 mL portions of ethyl acetate. The combined organic extracts were washed with brine (200 mL) The residue was triturated with hexane/ether to give 2-methyl-2-(methylsulfonyl)propanenitrile (13.6 g, 93%). ¹ H NMR (CDCl ₃ 400 MHz) δ 3.15 (s, 3 H), 1.76 (s, 6H).

Step 2: Add 3.0 mL (2.5 M) to a stirred solution of 1.05 g (7.13 mmol) of 2-methyl-2-(methylsulfonyl)-propanonitrile in 20 mL of tetrahydrofuran at -78 °C. , 7.5 mmol) of butyllithium in hexane. After 30 minutes, a solution of sulfinamide 5-1 (1.30 g, 4.54 mmol) in 5 mL of THF was added. The mixture was stirred at -78 ℃ 2h, 60 mL of a saturated aqueous NH ₄ Cl was quenched and extracted with two 100 mL parts of ethyl acetate. The combined organic extracts were concentrated. And two non-purified by flash chromatography (40 g of SiO _2, the in hexanes 0% to 70% EtOAc) The residue was purified twice to give the pure compound 1-1a (876 mg) enantiomer A mixture of compound compounds (398 mg, 1-1a/1-1b 7:3). LCMS 1-1a for the (Condition _{A): t R = 2.27 min} , m / e = 456 (M + Na). LCMS 1-1b for the (Condition _{A): t R = 2.23 min} , m / e = 456 (M + Na).

Step 3: A solution of 0.700 g (1.62 mmol) of compound 1-1a in 10 mL of MeOH and 4 mL of 4 M HCl solution in dioxane was stirred at room temperature for 1.5 h. This was concentrated; the residue was triturated with ether and a small volume of dichloromethane to afford compound 1-2 (0.585 g, 99%) as HCl salt. LCMS 1-2 for the (Condition _{A): t R = 1.36 min} , m / e = 330 (M + H).

Step 4: containing 0.58 g (1.59 mmol) compound 1-2 (HCl salt) and 60 mg 10% Pd / C with H ₂ present in the balloon on the flask in 15 mL MeOH was stirred suspension. The mixture was stirred at room temperature for 4 h under H ₂ atmosphere and then filtered. The filtrate was concentrated; by flash chromatography (12 g of SiO _2: stored 0% to 6% MeOH CH ₂ Cl ₂ plus 1% NH ₄ OH in of) the residue was purified to give compound 1-3 (0.37 g , 78%). LCMS 1-3 for the (Condition _{A): t R = 0.73 min} , m / e = 300 (M + H).

Step 5: Add 0.289 g (1.14) to a suspension of aniline compound 1-3 (0.17 g, 0.57 mmol) and 0.104 g (0.74 mmol) of 5-fluoropyridine-2-carboxylic acid in 5 mL of dichloromethane. Methyl bromide and 0.22 g (1.7 mmol) of diisopropylethylamine. The solution was stirred at room temperature for 40 min and quenched with water (10 mL). The mixture was extracted with two 30 mL portions of dichloromethane. The organic extracts were combined and concentrated; by flash chromatography (12 g of SiO _2: stored in CH ₂ Cl ₂ plus 1% NH ₄ OH in the 0% to 4% MeOH) The residue was purified to give the free base, The free base was treated with HCl in ether to afford salt 1-4a (0.192 g, 74%). LCMS 1-4a for the (Condition _{A): t R = 1.94 min} , m / e = 423 (M + H).

The following compounds were prepared in a similar manner:

Step 6: A suspension of 0.15 g (0.33 mmol) of compound 1-4a (HCl salt) and 0.05 g (0.51 mmol) of CuCI in 5 mL of EtOH was heated under reflux for 4 h. It was diluted with saturated aqueous NaHCO 40 mL of _3, and extracted with two parts of 50 mL of dichloromethane. The organic extracts were combined and concentrated; by flash chromatography (12 g of SiO _2: stored in CH ₂ Cl ₂ plus 1% NH ₄ OH in the 0% to 4% MeOH) The residue was purified to give the free base, The free base was treated with HCl in ether to afford Example 1 (0.122 g, 81%) as HCl salt. LCMS (Condition A) for Example 1 : t _R = 1.95 min, m/e = 423 (M + H).

The following examples were prepared in a similar manner (Example 2 from 1-4b and Example 3 from 1-4c):

Method 2

Step 1: A suspension of 1.41 g (3.85 mmol) of compound 1-2 and 0.40 g (4.04 mmol) of Cu(I)Cl in 50 mL of ethanol was stirred under reflux for 5 h. The mixture was concentrated, and the residue was diluted with 30 mL of 1 N NaOH solution and extracted with three 80 mL portions of dichloromethane. The combined organic extracts were concentrated. By flash chromatography (40 g of SiO _2: gradient stored in CH ₂ Cl ₂ plus 1% NH ₄ OH in the 0% to 5% MeOH) The residue was purified to give compound 2-1 (1.75 g, 95%). LCMS 2-1 for the (Condition _{A): t R = 1.75 min} , m / e = 330 (M + H).

Step 2: To a solution containing 1.20 g (3.64 mmol) compound 2-1 and 0.11 g 10% Pd / C in the flask was stored in 70 mL MeOH was charged with a suspension of H ₂ balloon. The mixture was stirred at room temperature for 6 h and filtered. The filtrate was concentrated. The residue was dissolved in 100 mL of dichloromethane and filtered thru a pad. The filtrate was concentrated, and the residue was triturated with diethyl ether and filtered to give <RTIgt; The filtrate was concentrated and purified by flash chromatography (24 g SiO _2: gradient stored in CH ₂ Cl ₂ plus 1% NH ₄ OH in the 0% to 4% MeOH) The residue was purified to give additional 0.27 g of Compound 2 -2. LCMS 2-2 for the (Condition _{A): t R = 0.69 min} , m / e = 300 (M + H).

Step 3: Add T3P to a suspension of compound 2-2 (0.300 g, 1.00 mmol) and 0.205 g (1.30 mmol) of 5-chloropyridine-2-carboxylic acid in 10 mL of dichloromethane at 0 °C. (0.957 g, 50% solution in ethyl acetate, 1.50 mmol). The solution was stirred at 0<0>C for 1 h and at rt for 2 h then quenched with 30 mL EtOAc. The mixture was extracted with two 50 mL portions of dichloromethane. The combined organic extracts were concentrated. By flash chromatography (24 g of SiO _2: gradient stored in CH ₂ Cl ₂ plus 1% NH ₄ OH in the 0% to 4% MeOH) The residue was purified to give Example 5 (0.417 g, 95% ). For example LCMS (Conditions A) 5 _{of: t R = 2.00 min, m} / e = 439 (M + H).

Use the procedure outlined in Step 2 of Method 2, by using the necessary Formic acid was prepared from compound 2-2 as an example in Table 2-1. Example 4 and Example 8 can be prepared in a similar manner. Alternatively, Example 4 and Example 8 were prepared according to Method 2B.

Method 2A

Step 1: Add 13.6 mL (2.5 M) to a stirred solution of 4.71 g (32.0 mmol) of 2-methyl-2-(methylsulfonyl)-propanonitrile in 100 mL of tetrahydrofuran at -78 °C. , in hexane, 34 mmol) of butyl lithium. After 30 minutes, a solution of sulfinimide 5-4 (5.19 g, 20 mmol) in 20 mL of THF was added. The solution was stirred for 3 h at -78 ℃, and diluted with NH ₄ Cl solution was quenched with 120 mL of warp. The mixture was extracted with two 200 mL portions of dichloromethane. The combined organic extracts were concentrated. The residue was purified by flash chromatography (120 g of EtOAc, EtOAc (EtOAc:EtOAc) , 50 × 250 mm Chiralcel OJ-H column, particle size 5 μm, 25% isopropanol / CO ₂ , 150 bar, 250 g / min, 40 ° C) The mixture was isolated to give compound 2A-1a (3.4 g) and compound 2A-1b (0.24 g). LCMS 2A-1a for the (Condition _{A): t R = 2.26 min} , m / e = 407 (M + H). 2A-1b for the LCMS (Conditions _{A): t R = 2.22 min} , m / e = 407 (M + H).

Step 2: A solution of 3.3 g (8.12 mmol) of compound 2A-1a in 100 mL of MeOH and 20 mL of 4 M HCl solution in dioxane was stirred at room temperature for 18 h. The mixture was concentrated, and the residue was crystalljjjjjjjjjj LCMS 2A-2 for the (Condition _{A): t R = 1.81 min} , m / e = 303 (M + H).

Step 3: A suspension of 2.7 g (7.97 mmol) of compound 2A-2 and 0.828 g (8.37 mmol) of Cu(I)Cl in 80 mL of ethanol was stirred under reflux for 5 h. The mixture was concentrated. The residue was diluted with 50 mL of 1N NaOH solution and extracted with two 120 mL portions of dichloromethane. The combined organic extracts were concentrated. By flash chromatography (40 g of SiO _2: gradient stored in CH ₂ Cl ₂ plus 1% NH ₄ 0% to 5% MeOH OH in the) the residue was purified to give Compound 2A-3 (1.99 g, 83%). LCMS 2A-3 against the (Condition _{A): t R = 1.81 min} , m / e = 303 (M + H).

Step 4: Compound at 0 ℃ 2A-3 (1.98 g, 6.55 mmol) was dissolved in 16 g of concentrated H ₂ SO ₄ in. 4.13 g (65.5 mmol) of fuming HNO ₃ was slowly added to the stirred solution. The mixture was stirred at 0 ° C to 5 ° C for 1 h and then poured into 100 mL of ice water. The mixture to about pH 9 was basified with NH ₄ OH, and extracted with three 100 mL of parts of dichloromethane. The combined organic extracts were concentrated. By flash chromatography (40 g of SiO _2: gradient stored in CH ₂ Cl ₂ plus 1% NH ₄ 0% to 4% MeOH OH in the) the residue was purified to give Compound 2A-4 (2.18 g, 96%). For LCMS (Conditions A) 2A-4 _{of: t R = 1.82 min, m} / e = 348 (M + H).

Step 5: To 2.15 g (6.19 mmol) of the compound containing 10% Pd 2A-4 and 0.2 g of / C stored in a flask of 80 mL of MeOH was stirred suspension was charged with H ₂ balloon. The mixture was stirred at room temperature for 6 h and filtered. The filtrate was concentrated, and the residue was evaporated mjjjjjjjjjjj For LCMS (Conditions A) 2A-5 _{of: t R = 1.44 min, m} / e = 318 (M + H).

Step 6: Add T3P to a suspension of compound 2A-5 (0.286 g, 0.90 mmol) and 0.165 g (1.17 mmol) of 5-fluoropyridine-2-carboxylic acid in 10 mL of dichloromethane at 0 °C. (0.859 g, 50% in ethyl acetate, 1.35 mmol). The solution was stirred at 0<0>C for 1 h and stirred at rt for 2 h and then quenched with saturated aqueous sodium hydrogen sulfate (30 mL). The mixture was extracted with two 50 mL portions of dichloromethane. The combined organic extracts were concentrated and purified by flash chromatography (24 g of SiO _2, gradient stored in CH ₂ Cl ₂ plus 1% NH ₄ OH in the 0% to 4% MeOH) The residue was purified to give Example 9k (0.255 g, 65%). For example 9k of LCMS (Conditions _{A): t R = 1.99 min} , m / e = 441 (M + H).

The examples in Table 2A-1 were prepared from the compound 2A-5 using the necessary formic acid using procedures similar to those outlined in Step 2 of Method 2A.

The examples in Table 2A-2 were prepared using procedures similar to those outlined in Method 2A, with the following exceptions: (i) Substituting the specified ketimine for the ketimine 5-4, (ii) SFC chromatography is not carried out as part of step 1, (iii) using the appropriate formic acid in step 6, and (iv) any other modification specified by the notes following the table.

Note to Table 2A-2 above:

1. For Example 9x-9z, SFC chromatography was performed on the product isolated from Step 4 according to the following conditions: Thar 80 instrument, Chiralpak AD-H, 30 x 250 mm column, particle size 5 μm, stored in CO in the ₂ 20% MeOH (with 0.05% NH ₄ OH), 100 bar, 60 mL / min, column temperature 38 ℃.

2. For Example 9ab-9ad, the following coupling conditions were used in step 6: 1.0 equivalents of formic acid, 1.5 equivalents of HATU, 3.0 equivalents of DIEA, DMF as solvent, room temperature (see, for example, 2A-8 to Example 9t below) Conversion).

3. For Examples 9s-9w, the nitro intermediate formed in Step 4 was converted to each example as described below for Example 9t. For Example 9s, T3P was used instead of HATU.

Step 1: at 25 deg.] C solution of compound 2A-6 (7 g, 20 mmol) stored in (70 mL) in the solution of DCM was added _{Boc 2 O (13 g, 60} mmol) and DMAP (2.4 g, 20 mmol) . The mixture was then stirred at 25 ° C for 3 h. The mixture was quenched with water and extracted with DCM. The combined extracts were washed with brine, dried over Na ₂ SO _4, and concentrated to provide the compound 2A-7 (8 g, 71 %). ¹ H NMR (CDCl ₃ ): 8.40 (s, 1H), 8.29 (s, 1H), 3.53 to 3.71 (m, 2H), 1.88 (s, 3H), 1.67 (s, 3H), 1.59 (s, 3H) ), 1.56 (s, 18H).

Step 2: at 0 ℃ 2A-7 (5.6 g , 10 mmol) of the compound present in the _{THF / EtOH / H 2 O (} 3: 1: 0.3,100 mL) was added in the NH ₄ Cl (2.65 g, 50 mmol). Zinc powder (6.5 g, 100 mmol) was then added at 0 ° C and stirred at 80 ° C for 16 h. The mixture was filtered. The filtrate was concentrated to provide compound 2A-8 (2.5 g, 50%). It was used directly in the next step without further purification.

Step 3: Add 5-chloropicolinic acid (236 mg, 1.5 mmol), HATU (1.14 g, 3.00) to a solution of compound 2A-8 (800 mg, 1.5 mmol) in DMF (26 mL). Methyl) and DIEA (387 mg, 3.00 mmol) were then stirred at 25 ° C for 16 h. The mixture was quenched with water and extracted with EtOAc. The combined extracts were washed with brine, dried over Na ₂ SO _4, and concentrated. The residue was dissolved in TFA / DCM (10%EtOAc) elute

Method 2B

Parallel preparation of Example 9af-9ay (Table 2B-1): The necessary formic acid (0.072 mmol) was added to a 1-dram vial containing a stir bar. Compound 2-2 is then added to each vial (18 mg, 0.060 mmol) and diisopropylethyl amine (0.016 mL, 0.090 mmol) stored in CH ₂ Cl ₂ (1.0 mL) in the solution, followed by addition of T3P (50% wt/wt in EtOAc, 0.050 mL, 0.084 mmol). The vial was capped and the mixture was stirred overnight at room temperature. Water (50 μL) was then added to each vial. The mixture was stirred for 30 min at room temperature. The stir bar was removed and the solvent was removed under vacuum (at a maximum temperature of 40 ° C). Each crude product was redissolved in 1 mL of DMSO and filtered. Mass-triggered HPLC [Waters XBridge C18 column, 5 μm, 30 × 100 mm, gradient range from 5%-10% MeCN (initial) to 35%-45% in water (0.1% NH ₄ OH) _{MeCN (0.1% NH 4 OH)} , 25 mL / min, 8 min run time] The crude product was purified to provide example 9af-9ay.

Using the procedure similar to those outlined in Method 2B and substituting Compound 2A-5 for 2-2 as the starting material, the examples in Table 2B-2 were prepared by using the necessary formic acid with the following modifications: i) by mass-triggered HPLC [Waters Sunfire C18 column, 5 μm, 19 × 100 mm, gradient range from 5%-15% (initial) to 20%-45% in water (0.1% formic acid) (final MeCN (0.1% formic acid), 50 mL/min, 8 min run time] The crude product was purified to afford Example 9az-9bx. (ii) Gradient elution by mass-triggered HPLC [Waters Sunfire C18 column, 5 μm, 19 × 100 mm, 15% to 40% MeCN (0.1% TFA) in water (0.1% TFA), 50 Example 9bx was repurified by purification of mL/min, 8 min run time] to provide Example 9bx.

Method 2C

Step 1: 0.364 g (2.0 mmol) of NBS was added to a stirred solution of 0.51 g (1.7 mmol) of aniline 2-2 in 12 mL of DMF at 0 °C. The mixture was stirred at 0 °C for 2 h and concentrated. The residue was subjected to flash chromatography (24 g of SiO _2: stored in CH ₂ Cl ₂ plus 1% NH ₄ OH in the 0% to 4% MeOH), to give 2C-1 (0.402 g, 62 %). LCMS (Condition A): t _R = 2.18 min, m/e = 380 (M+H).

Step 2: Compound 2C-1 was treated according to Step 6 of Method 2A to provide Example 9by. LCMS (Condition A): t _R = 2.21. min, m/e = 516 (M+H).

Method 2D

To a stirred solution of 0.20 g (0.42 mmol) of compound Example 9p in 4 mL of dichloromethane was added 2 mL of TFA. The mixture was stirred at room temperature for 30 min and concentrated. By flash chromatography (24 g of SiO _2: stored in CH ₂ Cl ₂ plus 1% NH ₄ 0% to 5% MeOH OH in the) the residue was purified to give Example 9bz (0.135 g, 70%) . LCMS (Conditions _{A): t R = 1.80 min} , m / e = 422.0 (M + H).

Method 2E

Using the procedure described in steps 1, 2 and 3 of Method 2A, substituting 碸14-1 for 2-methyl-2-(methylsulfonyl)propanenitrile in step 1 and using the following SFC purification conditions after step 2 in a similar manner to the preparation of compound 2E-1: Chiralpak 250 × 21 mm AD-H column, at 40 ℃, 20% isopropanol / 120 bar CO _2, on Thar SFC Prep 80 system 50 g / min. LCMS (Condition A): t _R = 1.70 min, m / e = 328 (M+H).

Step 1: To a 0.033 g (0.10 mmol) and the compound 2E-1 0.025 g (0.023 mmol) 10% Pd / C suspension was stored in 3 mL MeOH loading of H ₂ in a balloon. The mixture was stirred at room temperature for 4 h and filtered through celite. The filtrate was concentrated; by flash chromatography (22 g of SiO _2: stored 0% to 10% MeOH CH ₂ Cl ₂ plus 0.1% NH ₄ OH in of) the residue was purified to give 0.023 g (77%) of Compound 2E-2. LCMS (Conditions _{A): t R = 0.65 min} , m / e = 300 (M + H).

Step 2: Add T3P to a suspension of compound 2E-2 (0.023 g, 0.077 mmol) and 0.014 g (0.1 mmol) of 5-fluoropyridine-2-carboxylic acid in 1.5 mL of dichloromethane at room temperature. (50% solution in EtOAc, 0.069 mL, 0.115 mmol). The solution was stirred at room temperature for 1 h and then quenched with saturated aqueous sodium bicarbonate. Extract with dichloromethane (3X). The combined organic layers were dried over Na ₂ SO _4, filtered and concentrated. By flash chromatography (23 g of SiO _2: stored in CH ₂ Cl ₂ in the 0% to 7.5% MeOH and 0.1% NH ₄ OH) residue was purified to give Example 9ca (0.0016 g). LCMS (Condition A): t _R = 1.94 min, m / e = 423 (M+H).

Method 2F

Step 1: To a solution of 2-methyl-2-(methylsulfonyl)propanenitrile (3.67 g, 25 mmol) in THF (120 mL) at -78 ° C under argon over a period of 35 min. 10.0 mL (2.5 M in hexane, 25 mmol) of n-BuLi solution was added dropwise with stirring. After the addition was completed, stirring was continued for another 40 minutes at -78 °C. A solution of compound 5-8 (4.00 g, 12.45 mmol) in THF (40 mL) was added dropwise to the mixture over 40 min. The reaction was stirred at -78 °C for 4 hr. Then at -78 deg.] C by the addition of saturated NH 80 mL of it was quenched ₄ Cl solution and extracted with three 200 mL portion of EtOAc. The combined organic extracts were concentrated; the residue was purified by flash chromatography eluting eluting eluting Separation by SFC (Thar SFC system, IC column, 25% isopropanol / supercritical CO ₂ ) gave Compound 2F-1 (4.60 g, 78.9%). LCMS (Conditions _{A): t R = 2.40 min} , m / e = 468 (M + H).

Step 2: To a stirred solution of compound 2F-1 (7.49 g, 16 mmol) in 100 mL MeOH was added 50 mL of 4N HCl in dioxane. Stirring was continued for 4 hr at room temperature. The mixture was concentrated, and the~~~~~~~~~~~~~~~~~~ A suspension of 4.33 g (3.85 mmol) of this crude material and 1.24 g (12.48 mmol) of Cu(I)Cl in 100 mL of EtOH was stirred under reflux for 5 h. It was then concentrated; the residue was diluted with 30 mL of 1 N NaOH solution and extracted with three 80 mL portions of dichloromethane. The combined organic extracts were concentrated; by flash chromatography (120 g of SiO _2: stored 0% to 5% MeOH CH ₂ Cl ₂ plus 1% NH ₄ OH in of) the residue was purified to give compound 2F- 2 (3.07 g, 70.9%). LCMS (Condition A): t _R = 2.11 min, m/e = 364 (M+H).

Step 3: Compound 2F-2 (1.50 g, 4.12 mmol), Cu(I) ₂ O (59 mg, 0.412 mmol), K ₂ in ethylene glycol (8 mL) at 60 ° C - 65 ° C _{CO 3 (114 mg, 0.824 mmol} ), N, N'- dimethylethylenediamine (36 mg, 0.412 mmol) and the mixture _{NH 4 OH (22.1 mL, 165} mmol) of was stirred in a sealed tube for 12 hr. The mixture was then cooled to room temperature, diluted with 150 mL H ₂ O, and extracted with three 200 mL parts of EtOAc. The combined EtOAc extracts were concentrated; by flash chromatography (120 g of SiO _2: stored 0% to 5% MeOH CH ₂ Cl ₂ plus 1% NH ₄ OH in of) the residue was purified to give compound 2F- 3 (689 mg, 55.7%). LCMS (Condition A): t _R = 1.57 min, m / e = 301 (M+H).

Step 4: at 0 ℃ 2F-3 (422 mg , 1.40 mmol) and a solution of compound 5-cyano - 2-carboxylic acid (257 mg, 1.69 mmol) in 25 mL of the stored CH ₂ Cl ₂ in a suspension of T3P (50% in EtOAc, 1.34 g, 2.11 mmol). The reaction was stirred at 0 ℃ 1 h, and then stirred at room temperature for 20 h, and then with a saturated _aqueous solution of NaHCO 10 mL quenched. Extract with three 20 mL portions of dichloromethane. The combined organic extracts were concentrated. By flash chromatography (24 g of SiO _2: stored in CH ₂ Cl ₂ plus 1% NH ₄ 0% to 4% MeOH OH in the) the residue was purified to give Example 9cb (507 mg, 77%) . LCMS (Condition A): t _R = 1.93 min, m/e = 431 (M+H).

The examples in Table 2F-1 were prepared from the compound 2F-3 using the necessary formic acid using the procedure outlined in Step 2 of Method 2F.

Method 2G

Treatment of 碸14C-2 according to Method 2A, Steps 1-3, followed by SFC chromatography (Berger MultiGramTM SFC, Mettler Toledo, Inc., Chiralpak AD column, 250 mm x 30 mm, 5 μm, 70% supercritical CO ₂ , 30% MeOH (0.05% NH ₄ OH), 50 mL/min, column temperature: 38 ° C, nozzle pressure: 100 bar, 220 nm) Separation of the non-Spiegelmers to give compounds 2G-3a and 2G-3b. The compounds were treated individually according to steps 2 and 6 of Method 2A to provide Examples 9cl-a and 9cl-b.

The examples in Table 2G-1 were prepared using procedures similar to those outlined in Method 2G with the following exceptions: (i) by substituting 碸14C-2 with the specified 碸 in step 1, (ii) From the use of appropriate formic acid in step 5, and (iii) any other modification specified by the annotation.

Note to Table 2G-1 above:

1. For the following examples, LHMDS was used in step 1: 9cr-a, 9cs-a, 9ct-a, 9cu-a.

2. For the following examples, Zn/HOAc: 9ds-a, 9dt-a, 9du-a were used in the nitro reduction.

3. For the following examples, the above two modifications are used: 9dm-a, 9dm-b.

Method 2H

0.053 g (0.14 mmol) of aniline 2-2 and 0.022 g (0.16 mmol) of 3,5-difluoropyridyl nitrile and 0.20 g (0.20) in 4 mL of EtOH under reflux. A mixture of mmol of CuCl was heated for 70 h. The mixture was concentrated and by preparative TLC (in stored in CH ₂ Cl ₂ plus 1% NH ₄ OH 5% MeOH in the elution) to give the residue, to give examples 9ef (0.009 g, 15%) .

Method 2I.

Compound 2I-1 was prepared from hydrazine 14A-6 using procedures similar to those used in Method 2G for the conversion of hydrazine 14C-2 to compound 2G-4a.

Add T3P (0.33 g, 0.55) to a solution of 2I-1 (150 mg, 0.39 mmol) and compound 18-4 (80 mg, 0.43 mmol) in THF (5 mL). Methyl, 50%, in EtOAc. The resulting solution was stirred at 0 ° C for 30 min and then at room temperature for a further 16 h. Water was added to the solution and the mixture was stirred for 10 min at room temperature. The aqueous layer was extracted with EtOAc. The combined extracts were washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by preparative EtOAc (EtOAc: EtOAc) 32%). ¹ H NMR (400 MHz, CD ₃ OD): 8.09 to 8.48 (m, 3H), 7.62 to 7.85 (m, 1H), 7.56 to 7.59 (m, 1H), 7.41 to 7.45 (m, 2H), 7.24~ 7.35 (m, 3H), 4.19 (d, J = 16 Hz, 1H), 3.97 (d, J = 16.0 Hz, 1H), 2.29 (s, 3H), 2.15 (s, 3H). LCMS (Conditions _{F3): t R = 2.12 min} , m / e = 501 (M + H).

Method 3

Step 1: Add 5.6 mL (2.5 M) to a stirred solution of 2.07 g (14.1 mmol) of 2-methyl-2-(methylsulfonyl)-propanonitrile in 30 mL of tetrahydrofuran at -78 °C. , 14.0 mmol) of butyllithium in hexane. After 30 minutes, a solution of sulfinamide 5-2 (2.25 g, 7.03 mmol) in 10 mL of THF was added. The mixture was stirred at -78 ℃ 3 h, and quenched with saturated aqueous NH ₄ Cl and 20 mL of 80 mL of water. Extract with two 150 mL portions of ethyl acetate. The combined organic extracts were concentrated. By flash chromatography (80 g of SiO _2, the in hexanes 0% to 70% EtOAc) The residue was purified twice, to obtain 1.53 g of as a mixture of two diastereomeric isomers, by Further purification by SFC (TharSFC80, Chiralcel OJ-H column 21 × 250 mm, particle size 5 μm, 150 bar CO ₂ , 50 g / min, 10% 2-propanol as cosolvent, 40 ° C) Isomers gave compound 3-1a (1.17 g, 36%) and 3-1b (0.07 g, imp., 2%). LCMS 3-1a for the (Condition _{A): t R = 2.38 min} , m / e = 467 (M + H). LCMS 3-1b for the (Condition _{A): t R = 2.31 min} , m / e = 467 (M + H).

Step 2: A solution of 1.1 g (1.62 mmol) of compound 3-1a in 5 mL of MeOH and 5 mL of 4 M HCl solution in dioxane was stirred overnight (18 h). It was concentrated; the residue was diluted with 50 mL of saturated NaHCO ₃ solution and extracted with three 60 mL portion of dichloromethane. The combined organic extracts were concentrated; by flash chromatography (24 g of SiO _2: stored 0% to 4% MeOH CH ₂ Cl ₂ plus 1% NH ₄ OH in of) the residue was purified to give compound 3- 2 (0.72 g, 84%). LCMS 3-2 for the (Condition _{A): t R = 1.88 min} , m / e = 365 (M + H).

Step 3: A suspension of 0.55 g (1.51 mmol) of compound 3-2 and 0.20 g (2.0 mmol) of CuCI in 10 mL of EtOH was stirred for 4 h under reflux. It was diluted with 80 mL of dichloromethane and filtered through a pad of Celite. The filtrate was concentrated; by flash chromatography (24 g of SiO _2: stored 0% to 4% MeOH CH ₂ Cl ₂ plus 1% NH ₄ OH in of) the residue was purified to give compound 3-3 (0.214 g , 39%). LCMS 3-3 for the (Condition _{A): t R = 1.87 min} , m / e = 365 (M + H).

Step 4: 0.073 g (0.20 mmol) of compound 3-3, 0.044 g (1.49 mmol) of 3-cyanophenylboronic acid, 0.023 g (0.02 mmol) of Pd(PPh ₃ ) ₄ and 0.15 mL under reflux. (0.3 mmol) of ₂ M Na 2 CO ₃ aq stored in 2 mL of EtOH and 2 mL of toluene was heated 2 h. It was concentrated; by flash chromatography (12 g of SiO _2, 0% to deposit 4% MeOH CH ₂ Cl ₂ plus 1% NH ₄ OH in of) the residue was purified to give Example 10 (0.074 g, 97%). For LCMS (Conditions A) of Example _{10: t R = 1.99 min, m} / e = 386 (M + H).

Step 5: Prepared by a procedure similar to the procedure in Step 4, substituting 1-(t-butoxycarbonyl)-7-methoxy-1H-indol-2-ylboronic acid for 3-cyanophenylboronic acid Compound 3-4. LCMS 3-4 for the (Condition _{A): t R = 1.87 min} , m / e = 530 (M + H). A solution of 0.08 g (0.15 mmol) of crude compound 3-4 and 1 mL (13.3 mmol) of TFA in 2 mL CH ₂ Cl ₂ was stirred at room temperature for 2 h. Concentration of the residue by flash chromatography (12 g of SiO ₂ : 0% to 4% MeOH in CH ₂ Cl ₂ plus 1% NH ₄ OH) TLC (in CH 5% MeOH present in the elution of the OH ₂ Cl ₂ plus 1% NH ₄₎ the product was purified further, to obtain the compound of example 11 (0.03 g, two steps from the compound in a yield of 3-3 47%). For LCMS (Conditions A) of Example _{11: t R = 2.08 min, m} / e = 430 (M + H).

Using the procedure described in Step 4 of Method 3, Examples 12-15 of Table 3-1 can be prepared by coupling Compound 3-3 with the necessary boronic acid. Compound 3-3 can be coupled with 1-(t-butoxycarbonyl)-5-(methoxycarbonyl)-1H-pyrrol-2-ylboronic acid according to Method 3, Step 4, and then according to Method 3, Step 5. The product was processed to prepare Example 16. Example 16a was prepared from Intermediate 3-3 using boronate 16-1 in Step 4.

Method 3A

0.070 g (0.192 mmol) of compound 2F-3, 0.040 g (0.269 mmol) of 3-cyanophenylboronic acid, 0.044 g (0.038 mmol) of Pd(PPh ₃ ) ₄ and 0.192 by microwave at 110 ° C. A mixture of mL 2 (0.384 mmol) of 2 M Na ₂ CO ₃ in 2 mL of EtOH and 2 mL of toluene was heated in a sealed vial for 1 hr and then cooled and concentrated. By preparative TLC (at present in the 5% 7 M NH ₃ / MeOH elution of CH ₂ Cl ₂ in) the residue was purified to give Example 16b. (72 mg, 97%). LCMS 16b for the example of (Conditions _{A): t R = 1.97 min} , m / e = 387 (M + H).

The examples in Table 3A-1 were prepared according to Method 3A using the appropriate boronic acid or borate ester as the coupling partner. Example 16e was prepared using (1-(t-butoxycarbonyl)-7-methoxy-1H-indol-2-yl)boronic acid.

Method 4

Compound 4-1 was prepared in a similar manner using the procedure described in steps 1, 2 and 3 of Method 3, in which the ketimine 5-2 was replaced with ketimine 5-3 in Step 1. LCMS 4-1 for the (Condition _{A): t R = 1.95 min} , m / e = 387 (M + H).

Step 1: To a solution of Compound 4-1 in dichloromethane, (Boc) ₂ O was added. The solution was stirred at room temperature for 3 h and concentrated. The residue was purified by flash chromatography to provide compound 4-2.

Step 2: To a solution of the compound 4-2 in THF was added methylmagnesium bromide at 0 °C. The reaction was stirred at 0 °C for 30 minutes and then cooled to -78 °C. A solution of n-butyllithium in hexane was added over 10 minutes and the reaction was stirred at -78 °C for an additional 1 hour. The CO ₂ gas was then bubbled through the reaction for 5 minutes, at which time the cold bath was removed. After warming to room temperature, 1 N HCl and ethyl acetate were added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, the dried (MgSO _4), filtered, and concentrated in vacuo. The residue was purified by gel chromatography to provide 4-3.

Step 3: Compound 4-3 is coupled with 2-amino-6-methylpyridine using the procedure in Step 5 of Method 1, to provide 4-4.

Step 4: Store compound 4-4 in TFA: dichloromethane (1:1) at room temperature The solution was stirred for 3 h and concentrated. The residue was purified by flash chromatography to give Example 17.

Following the procedure described in Methods 4, Steps 3 and 4, the examples shown in Table 4-1 can be prepared by substituting the appropriate aniline in Step 3 from Compound 4-3. Alternatively, Examples 18-23 were prepared according to the procedure described in Method 4A by employing the appropriate phenylamine from compound 4-1 in step 7. Example 17 can be prepared in a similar manner.

Method 4A

Step 1: Add 11.7 mL (2.5 M) to a stirred solution of 4.30 g (29.2 mmol) of 2-methyl-2-(methylsulfonyl)-propanonitrile in 110 mL of tetrahydrofuran at -78 °C. , 29.2 mmol) of butyllithium in ethane. After 30 minutes, a solution of sulfinamide 5-3 (5.0 g, 14.6 mmol) in 40 mL of THF was added. The solution was stirred at -78 ℃ 3 h, and diluted with NH ₄ Cl solution was quenched with 150 mL of warp. Extract with two 200 mL portions of dichloromethane. The combined organic extracts were concentrated; the residue was purified by silica gel chromatography and then SFC (4.6×250 mm OJ-H column, 10% isopropanol/CO ₂ , 250 g/min) to give compound 4A- 1 (3.8 g, 53%). LCMS (Condition A): t _R = 2.45 min, m / e = 491 (M+H).

Step 2: A solution of 4.0 g (8.16 mmol) of 4A-1 in 130 mL of MeOH and 20 mL of 4 M HCl solution in dioxane was stirred at room temperature for 18 h. This was concentrated; the residue was triturated with ether and a small volume of dichloromethane to afford compound 4A-2 (3.3 g, 96%) as HCl salt. LCMS (Condition A): t _R = 2.0 min, m / e = 387 (M+H).

Step 3: A suspension of 3.28 g (7.77 mmol) of compound 4A-2 and 0.81 g (8.16 mmol) of Cu(I)Cl in 80 mL of ethanol was heated under reflux for 5 h. It was concentrated; the residue was diluted with 70 mL of 1N NaOH solution and extracted with three 100 mL portions of dichloromethane. The combined organic extracts were concentrated; by flash chromatography (80 g of SiO _2: stored 0% to 4% MeOH CH ₂ Cl ₂ plus 1% NH ₄ OH in of) the residue was purified to give compound 4- 1 (2.82 g, 94%). LCMS (Conditions _{A): t R = 1.95 min} , m / e = 387 (M + H).

Step 4: Add Pd(dppf)Cl ₂ (0.87 g, 1.0 mmol) and sodium acetate (1.31 g, 15.9 mmol) to bromide 4-1 (4.1 g, 10.6 mmol) in MeOH (41 mL) . The vessel was purged with nitrogen (3X) and then purged with CO (3X). The reaction was heated to 80 ° C at 200 psi CO for 18 h while stirring at 1000 RPM. The reaction was cooled and concentrated under vacuum to afford 4A-4 which was taken directly to next.

Step 5: To the ester 4A-4 from Step 4 in DCM (37 mL) was added di-t-butyl dicarbonate (4.8 g, 22 mmol). The reaction was stirred at room temperature for 16 h. The reaction mixture was then filtered and concentrated in vacuo to give a crystallite crystals crystals The yield from 4A-3 was 84%).

Step 6: To a solution of 4A-5 (4.1 g, 8.8 mmol) EtOAc (EtOAc) The reaction was stirred at room temperature for 18 h. The reaction was neutralized with 0.1 N HCl and then extracted with EtOAc. The combined organics were washed with water and brine, dried (MgSO _4), filtered and concentrated in vacuo to provide 4A-6 (3.5 g, 88 %) acid.

Step 7: Parallel preparation of Examples 18-22, 22a-22v: Add the necessary amine monomer and stir bar to the 1-bara vial. A solution of compound 4A-6 (33 mg, 0.073 mmol), T3P (61.0 μl, 0.102 mmol) and DIEA (38.3 μl, 0.220 mmol) in DCM (1.0 mL) was then added to each vial. The vial was capped and the reaction was stirred at room temperature overnight. Thereafter, water (50 μL) was added to each vial, followed by addition of TFA (500 μl, 6.49 mmol), and the vial was stirred at room temperature for 2 hours. Remove the stir bar from the vial. The solvent was removed under vacuum (at a maximum temperature of 40 ° C). Each product was redissolved in 1 mL of DMSO and filtered. Mass-triggered HPLC [Waters Sunfire C18, 5 μm, 19 x 100 mm, using 8-10% (initial) in water (0.1% formic acid) to 22-42% (final) MeCN (0.1% formic acid) The gradient range, 50 mL/min, 8 min run time] was used to purify the crude product to provide Examples 18-22, 22a-22v.

Note: Mass-triggered HPLC [Waters XBridge C18 column, 5 μm, 30 x 100 mm, gradient range from 8-15% (initial) to 42-60% MeCN (0.1%) in water (0.1% NH ₄ OH) NH ₄ OH), 25 mL/min, 8 min run] Examples 22 and 22v were repurified to provide Examples 22 and 22v.

Method 5

Step 1: 1-(2-Fluorophenyl)ethanone (90.0 g, 652 mmol) was added dropwise to a mechanically stirred slurry of concentrated H ₂ SO ₄ (93-98%, 360 mL) at -42 °C. A solution of fuming nitric acid (53.1 mL) in concentrated H ₂ SO ₄ (129 mL). The slurry was stirred at -42 ° C for 30 min. The mixture was slowly poured onto 1.3 kg of ice. Water (1 L) was added to the mixture. The product precipitated from the solution. After all the ice has melted, the product is collected via filtration. The solid was dissolved in EtOAc. The organic layer was washed with 5% Na ₂ CO ₃ solution (2 × 300 mL), water (1 × 300 mL) and brine (1 × 300 mL), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated to give 1-(2-fluoro-5-nitrophenyl)ethanone (115 g, 97%).

Step 2: Add (R)-(+)-2-A to a solution of 1-(2-fluoro-5-nitrophenyl)ethanone (115 g, 628 mmol) in THF (900 mL) Benz-2-propanesulfonamide (87.7 g, 691 mmol) and Ti(OEt) ₄ (315 g, 1.38 mol). The solution was heated under reflux for 20 h, cooled to room temperature and poured onto ice (3 kg). The mixture was stirred for 20 min and then filtered. The organic layer of the filtrate was washed with brine, dried over Na ₂ CH ₄ By flash chromatography (SiO _2, 15% EtOAc in hexanes stored in the medium) the residue was purified to give compound 5-1 (154 g, 86%) . LCMS 5-1 for the (Condition _{A): t R = 2.26 min} , m / e = 287 (M + H).

The ketimine of Table 5-1 was prepared from the necessary ketone according to the procedure outlined in Step 2 of Method 5. These ketones are commercially available unless otherwise stated. For ketimine 5-6 and 5-7, ( S )-(-)-2-methyl-2-propanesulfonamide is used in step 2 instead of its ( R )-(+) isomerism body.

Method 5A

From 5-bromine by methods known to those skilled in the art, for example by first reacting with N-methyl-N-methoxyamine hydrochloride and EDCI, followed by reaction with methylmagnesium bromide after separation. 3-Chlorothiophene-2-carboxylic acid (available, for example, from S. Nomura et al., WO2005012326, page 163) to prepare 1-(5-bromo-3-chlorothien-2-yl)ethanone 5A-1.

Additional preparation details for both 1-(5-bromo-3-chlorothiophen-2-yl)ethanone and 5-bromo-3-chlorothiophene-2-carboxylic acid are provided below: at 0 ° C to 3- A solution of methyl chlorothiophene-2-carboxylate (50 g, 0.28 mol) in MeOH (100 mL). The resulting mixture was stirred at room temperature for 2 h. After removal of MeOH, the aqueous was washed with ether and acidified with 2 N HCI. The solid formed was collected by filtration and dried to give 45 g of 3-chlorothiophene-2-carboxylic acid in a yield of 98%. MS (M+H ⁺ ): 163.

Add a solution of n- BuLi (104 mL, 0.26 mol, 2.5 M in n-hexane) to a solution of DIPA (26.3 g, 0.26 mol) in 400 mL of dry THF under nitrogen at -78 °C. . After the addition was completed, the mixture was stirred for 1 h, and then warmed to 0 ° C and stirred for 30 min. A solution of 3-chlorothiophene-2-carboxylic acid (21 g, 0.13 mol) in THF (50 mL) was added to the above LDA solution at -78 °C. After stirring for 1 h, a solution of 1,2-dibromo-ethane (48.9 g, 0.26 mmol) in THF (50 mL) was added at -78. The mixture was stirred at -78 °C for 1.5 h and slowly warmed to room temperature. The mixture was poured into aqueous HCl and then extracted with EtOAc. The combined extract was dried over Na ₂ SO ₄ and concentrated to give 25 g of 5-bromo-3-chlorothiophene-2-carboxylic acid in a yield of 80%. MS (M+H ⁺ ): 241, 243. ¹ H NMR (400 MHz, DMSO-d6): δ 7.50 (s, 1 H).

Add N,O-dimethylhydroxylamine hydrochloride (40.4 g, 0.42 mol) and EDCI (87 g) to a solution of compound 3 (50 g, 0.21 mol) in pyridine (500 mL). , 0.42 mol). The mixture was stirred overnight at room temperature, concentrated and purified by silica gel chromatography to afford 35 g of compound 4 in yield 60%. MS (M+H ⁺ ): 284, 286. ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.98 (s, 1 H), 3.70 (s, 3 H), 3.31 (s, 3 H).

At room temperature under N _2, of 5-bromo-3 -N- methoxy -N- methyl-thiophene-2-acyl-amine (1 g, 3.5 mmol) kept in THF (10 mL) in MeMgBr (1.1 mL, 3.5 mmol) was added to the stirred solution. The mixture was stirred for 0.5 h at room temperature and by ₄ Cl NH quenched with aq. The resulting solution was extracted with EtOAc. The organic layer was dried over Na ₂ SO _4, concentrated and purified by silica gel chromatography to obtain 0.6 g of 1- (3-chloro-5-bromo-thiophen-2-yl) ethanone, 75% yield. MS (M+H ⁺ ): 239, 241. ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.95 (s, 1 H), 2.57 (s, 3 H).

Method 5B

Step 1: Add 18.0 dropwise to the stirred solution of 6-bromo-3-fluoro-2-pyridinecarboxaldehyde (10.0 g, 49 mmol) in 200 mL of THF at -78 °C over a period of 35 min. mL of MeMgBr (3.0 M in ether, 54 mmol). The reaction was stirred at -78 °C for 3 hr then warmed to 0 ° C and stirred at 0 ° C for further 1 hr. At 0 ℃ The mixture was treated with saturated NH 150 mL of ₄ Cl solution was quenched and extracted with 200 mL three parts of EtOAc. The combined organic extracts were concentrated; by flash chromatography (220 g of SiO _2: stored in hexanes 0% to 30% EtOAc) the residue was purified to give compound 5B-1 (9.41 g, 87 %) . LCMS (Condition A): t _R = 1.91 min, m/e = 220 (M+H).

Step 2: To a solution of 8.74 g (39.7 mmol) of compound 5B-1 in 175 mL of CH ₂ Cl ₂ at room temperature, 21.4 g (99.0 mmol) of pyridinium chlorochromate and 7.50 g of hydrazine were added. Algae soil. The reaction mixture was stirred for 25 h at room temperature and then filtered through diatomaceous earth and washed with CH ₂ Cl _2. CH ₂ Cl ₂ and the filtrate was concentrated; by flash chromatography (220 g of SiO _2: stored in hexanes 0% to 10% EtOAc) the residue was purified to give compound 5B-2 (6.82 g, 79 %) . LCMS (Condition A): t _R = 2.11 min, m / e = 218 (M+H).

Method 5C

n-Butyllithium (2.5 M, 1.7 mL, 4.2 mmol) was added to 6-bromobenzo[d]thiazole (0.85 g, 3.9 mmol) in THF (16 mL). The reaction was stirred at -78 °C for 1 h, then N -methoxy- N -methylacetamide (0.41 g, 3.9 mmol). The reaction was stirred for 30 minutes at -78 ℃, and then quenched with saturated aqueous NH ₄ Cl quenched. The reaction was warmed to rt and extracted with EtOAc. The organic layer was washed with water and brine, the dried (MgSO _4), filtered, and concentrated in vacuo. The residue was purified by EtOAc (EtOAc:EtOAc)

Method 5D

Step 1: To a cooled to -78 deg.] C of compound 5D-1 (17 g, 133 mmol) stored in THF (300 mL) was added in the n -BuLi (120 mL, 293 mmol , 2.5 M, in hexanes Medium), and the mixture was stirred at -78 ° C for 30 min. A solution of N-fluorobenzenesulfonimide (50 g, 159 mmol) in THF (300 mL) was added and the mixture was stirred at -78 °C for 4 h and warmed to ambient temperature overnight. The reaction was quenched with 1N EtOAc (150 mL)EtOAc. The combined extracts were dried over Na ₂ SO _4, and concentrated by silica gel chromatography (PE: EtOAc = 3: 1 ) and purified to provide compound 5D-2 (18 g). ¹ H NMR (CDCl ₃ ): 10.7 (s, 1 H), 7.53 (dd, J = 5.4, 3.6 Hz, 1 H), 6.89 (d, J = 5.4 Hz, 1 H).

Step 2: Add EDCI (53.1 g, 277 mmol) and O,N-dimethylhydroxylamine hydrochloride to a solution of compound 5D-2 (18 g) in pyridine (150 mL). 27 g, 277 mmol), and then the mixture was stirred at room temperature overnight. The mixture was concentrated. The residue was dissolved in EtOAc and washed with water, dried over Na ₂ SO _4, and concentrated by silica gel chromatography (PE: EtOAc = 20: 1 ) and purified to provide compound 5D-3 (18 g).

Step 3: Br ₂ (45 g, 281 mmol) was added to a solution of compound 5D-3 (18 g) in AcOH / H ₂ O (1:1, 150 mL). The mixture was slowly warmed to ambient temperature and stirred overnight. The mixture was quenched with water and extracted with EtOAc. The combined extracts were washed with EtOAc EtOAc (EtOAc)EtOAc. ¹ H NMR (CDCl ₃ ): 6.85 (s, 1 H), 3.71 (s, 3 H), 3.27 (s, 3 H).

Step 4: To a solution under N ₂ was cooled to 0 ℃ of compound 5D-4 (16 g) is stored in (150 mL) in of THF was added MeMgBr (60 mL, 3 M, stored in ether) solution. The mixture was stirred for 1 h and by an aqueous solution of NH ₄ Cl and water quenched. The resulting solution was extracted with EtOAc. The organic layer was dried over Na ₂ SO _4, and concentrated by silica gel chromatography (PE: EA = 50: 1 ) and purified to provide compound 5D-5 (4 g). ¹ H NMR (CDCl ₃ ): 6.90 (s, 1 H), 2.53 (s, 3 H).

Conversion of thiophene-2-carboxylic acid to 1-(5-bromo-3-fluorothiophen-2-yl)ethanone 5D-6 by a method similar to that described in Method 5D, but omitting step 3. .

Method 6

Following the procedure described in Step 4 of Method 3, Compound 4-1 was converted to Example 23 and Example 27a by using the appropriate boronic acid. Examples 24-27 can be prepared in a similar manner.

Alternatively, Examples 24-27 were prepared according to Method 6A, additionally applying Method 3, Step 5, to produce Example 27. Examples 27a-27d were formed in a similar manner using a suitable boronic acid or boronic ester using procedures similar to methods 6 and 6A.

Other details of the preparation of Example 23: at reflux 0.10 g (0.259 mmol) of the compound 4-1,0.089 g (0.389 mmol) of 3-cyano-pyridyl boronic acid, 0.03 g (0.026 mmol) of Pd (PPh _{3) 4} and 0.20 mL (0.40 mmol) of a 2M aqueous solution of Na ₂ CO ₃ in a mixture of 2 mL of EtOH and 2 mL of toluene were heated for 7 hrs and then concentrated. By flash chromatography (12 g of SiO _2: stored in CH ₂ Cl ₂ plus 1% NH ₄ 0% to 6% MeOH OH in the) the residue was purified to give Example 23. (94 mg, 73%). LCMS (Condition A): t _R = 1.92 min, m / e = 409 (M+H).

Notes to Table 6-1: (1) For Example 27b, borate ester 16-2 was used. (2) For Example 27c, borate ester 16-4 was used. (3) For Example 27d, boric acid ester 16-6 was used.

Method 6A.

Parallel preparation of Examples 27e-27z: to a reaction 4-1 (20 mg, 0.052 mmol), boric acid or in 1,4-dioxane (2 mL) A mixture of ester (1.3 eq.) and [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (7.59 mg, 10.4 μmol) was added to water (0.16 mL). Potassium carbonate (21.50 mg, 0.156 mmol). The reaction was carried out at 120 ° C for 20 minutes under microwave reaction conditions. Water (2 mL) and EtOAc (2 mL) were added and the mixture was stirred for 10 min. The organic layer was separated and concentrated. Each crude product was redissolved in 1 mL of DMSO and filtered. Mass-triggered HPLC (Waters XBridge C18 column, 5 μm, 30 x 100 mm, using 10-30% (initial) in water (0.1% NH ₄ OH) to 30-80% (final) MeCN (0.1) The crude product was purified by gradient range of % NH ₄ OH) to provide Examples 27e-27z in Table 6A-1.

Method 6B

Step 1: To a solution of bromide 4-1 (0.15 g, 0.39 mmol) in t- BuOH (1.3 mL), boronic acid ester 16-7 (0.17 g, 0.58 mmol), Pd(dppf)Cl ₂ ( 0.057 g, 0.078 mmol) and 2 MK ₂ CO ₃ (0.029 mL, 0.58 mmol). Nitrogen gas was bubbled through the reaction mixture for 5 minutes. The reaction was warmed to 65 ° C and stirred for 3 h. The cooled reaction was added to water and EtOAc. The mixture was extracted with EtOAc. The organic layer was washed with water and brine, the dried (MgSO _4), filtered, and concentrated in vacuo. The residue was used directly by absorption in DCM (1.3 mL) and di-t-butyl dicarbonate (0.10 g, 0.47 mmol). The reaction was stirred for 12 h and then purified directly by EtOAc (EtOAc:EtOAc)

Step 2: To a solution of 6B-1 (0.19 g, 0.33 mmol) in DCM (l. The reaction was stirred at room temperature for 30 minutes and then concentrated under vacuum to provide an example of a TFA salt. (0.19 g, 99%).

The examples in Table 6B-1 were prepared according to Method 6B (Examples 27aa-27ad) or Method 6 (Examples 27ae-27ag) using the indicated boronic acid or boron ester from 4-1.

Method 6C

Preparation of bromide 6C-1 by substituting ketimine 5-11 for ketimine 5-4 by a method similar to that described in Methods 2A, Steps 1-3, for the 6C-1 LCMS (Condition G) t _R = 1.56 min, m/e = 352.9 (M+H). Di-tert-butyl dicarbonate (0.43 g, 2.0 mmol) was added to bromide 6C-1 (0.46 g, 1.3 mmol) in DCM (4.4 mL). The reaction was stirred at room temperature for 12 h. The reaction was concentrated in vacuo and EtOAc EtOAc m.

The compound of Table 6C-1 was prepared by a method similar to that described in Method 6B by using the designated bromide and boric acid or boron ester.

Method 6D

Step 1: Add n-butyllithium to a stirred solution of 2-methyl-2-(methylsulfonyl)propanenitrile (10.71 g, 72.8 mmol) in THF (331 mL) at -78 °C 2.5 M in ethane, 29.1 mL, 72.8 mmol). After 30 minutes, a solution of sulfinamide 5-14 (9.0 g, 36.4 mmol) in THF (33.1 mL) was added. The reaction mixture was stirred for 4h at -78 ℃, and washed with saturated aqueous NH ₄ Cl quenched. The organic layer was extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried with MgSO4, filtered and evaporated. The residue was purified by column chromatography eluting with EtOAc EtOAc EtOAc LCMS (Condition A): t _R = 2.23 min, m/e = 395 (M+H).

Step 2: To a stirred solution of EtOAc (4 mL, EtOAc (EtOAc) The solution was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and ether (25 mL). The precipitate was filtered and washed with ether (2×10 mL) to afford 6D-2 (6.82 g, 20. LCMS (Condition A): t _R = 1.71 min, m / e = 291 (M+H).

Step 3: Cu(I)Cl (2.17 g, 21.9 mmol) was added to a stirred solution of compound 6D-2 (6.82 g, 20.9 mmol) in EtOH (104 mL). The solution was stirred at 80 ° C for 5 h. The reaction was concentrated and diluted with 50 mL of 1N NaOH. The aqueous layer was extracted with dichloromethane (3×100 mL). The combined organic layers were dried with MgSO4, filtered and evaporated. By column chromatography (in DCM and 0.1% NH ₄ OH in the 0% to 5% MeOH) (the in DCM to 3% MeOH elution) to give a residue. The combined fractions were concentrated under reduced pressure to afford 6D-3 (5.03, 17.3 mmol). LCMS (Condition A): t _R = 1.62 min, m / e = 291 (M+H).

Step 4: To a stirred solution of compound 6D-3 (5.56 g, 19.2 mmol. The solution was stirred at 50 ° C for 16 h. Another portion of NBS (3.75 g, 21.1 mmol) was added to the reaction mixture and stirred at 50 ° C for further 16 h. The reaction mixture was cooled to room temperature and diluted with EtOAc (250 mL). The organic layer was washed with water (3×100 mL). The organic layer was dried with MgSO4, filtered and evaporated. The residue was purified by column chromatography eluting with 40%EtOAcEtOAcEtOAc The combined fractions were concentrated to give compound 6D-4 (5.89 g, 16.0 mmol). LCMS (Conditions _{A): t R = 1.95 min} , m / e = 371 (M + H).

Step 5: To 7-methoxyindole-2-boronic acid Ester (111 mg, 0.41 mmol), compound 6D-4 (100 mg, 0.27 mmol), PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (22 mg, 0.03 mmol) and potassium carbonate (2 M, stored in Dioxane (2.7 mL) was added to a mixture of water, 0.34 mL, 0.68 mmol. The reaction mixture was sealed and purged with nitrogen by subsurface bubbling for 5 min. The reaction mixture was heated to 100 ° C for 16 h. The reaction was cooled to room temperature and diluted with a saturated aqueous solution of sodium bicarbonate. The aqueous layer was extracted with dichloromethane (3×25 mL). The combined organic layers were dried with MgSO4, filtered and evaporated. The residue was purified by column chromatography eluting with 35% ethyl acetate in dichloromethane. The combined fractions were concentrated under reduced pressure to give mp. LCMS (Condition A): t _R = 2.15 min, m/e = 436 (M+H).

The examples in Table 6D-1 were prepared using a procedure similar to that of Method 6D Step 5 and using bromide or boronic ester from bromide 6D-4. If the entry in the column of boric acid or borate is blank, the reagent is commercially available.

Method 6E

Step 1: Add benzopyrene (0.050 g, 0.37 mmol), TEA (0.14 mL, 1.0 mmol) and T3P (exist) to acid 4A-6 (0.15 g, 0.33 mmol) in EtOAc (1.1 mL) 50% solution in EtOAc, 0.50 mL, 0.83 mmol). The mixture was stirred at room temperature for 18 h. Water was added and the mixture was stirred vigorously for 15 minutes. The mixture was then extracted with EtOAc. The organic layer was washed with water and brine, the dried (MgSO _4), filtered and concentrated in vacuo to provide 6E-4, which was used directly in the next step.

Step 2: 6E-4 (0.19 g, 0.33) in THF (1.7 mL) Mmol) Add Burgess reagent (0.20 g, 0.83 mmol). The mixture was heated to 65 ° C and stirred for 1 h. The reaction was concentrated under vacuum. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc)

Step 3: To a solution of 6E-5 (0.080 g, 0.15 mmol) in DCM (0.8 mL). The reaction was stirred at room temperature for 30 minutes and then concentrated under vacuum. Use SFC (MeOH / CO ₂₎ the residue was purified to provide Example 27ba (0.040 g, 59%) .

The examples in Table 6E-1 were prepared using procedures similar to those in Steps 6-6 of Method 6E and using the appropriately substituted benzopyrene from Acid 6E-3 in Step 4. Purification of these examples by reverse phase chromatography (Waters Sunfire C18, 5 μm, 19 x 100 mm, 50 mL/min, 12 min run time, mobile phase A = water + 0.1% formic acid, mobile phase B = MeCN+ 0.1% formic acid, 10 to 50% B).

The examples in Table 6E-2 were prepared using procedures similar to those in Method 6E and using the appropriately substituted benzopyrene from bromide 6D-4 in Step 4.

Method 6F.

Compounds 6F-3a and 6F-3b were prepared using procedures similar to those described in Methods 4A, Steps 1-3, with the following modifications: (i) using 碸14C-5 and ketimine 5 in step 1. -13 instead of 2-methyl-2-(methylsulfonyl)propionitrile and ketimine 5-3; (ii) subjecting the product of step 3 to SFC chromatography (Berger MultiGramTM SFC, Mettler Toledo, Inc., Chiralpak AD column, 250 mm × 30 mm, 5 μm, 70% supercritical CO ₂ , 30% MeOH (0.05% NH ₄ OH), 60 mL/min, column temperature: 38 ° C, nozzle pressure: 100 bar, 220 nm) to give compounds 6F-3a and 6F-3b. Each of the two compounds is then treated individually according to Method 6 or Method 6D Step 5 using 3-cyanophenylboronic acid as the coupling partner to provide Examples 27bj-a and 27bj-b.

Prepare Table 6F-1 using a procedure similar to that described above for Examples 27bj-a and 27bj-b, substituting the specified hydrazine reagent in Step 1 and using the appropriate boronic acid or borate ester in Step 4. Example. For the examples 27bk-a, 27bk-b, 27bp-a, 27bp-b, the borate ester 16-2 was used.

The examples in Table 6F-2 were prepared using the methods similar to those described in Method 6F, from the specified hydrazines and using the appropriate boronic acid or boronic esters in Step 4 with the following exceptions: In Step 1 The ketimine 5-3 was used instead of the ketimine 5-13. For Example 27bu, borate 16-2 was used in step 4. For the example 27bv, (1-(t-butoxycarbonyl)-7-methoxy-1H-indol-2-yl)boronic acid was used.

Method 6G

Step 1: 6F-3 (Non-Spiethy isomer mixture in dioxane (10 mL) at 25 ° C under N ₂ , Method 6F Step 3 before SFC Chromatography, 1 Pd(PPh ₃ ) ₄ (133 mg, 0.12 mmol) was added to a mixture of g, 2.3 mmol) and hexamethylditin (835 mg, 2.5 mmol). The mixture was stirred at 110 ° C for 2 h, quenched with water andEtOAc. The combined extracts were washed with water, the dried over Na ₂ SO _4, concentrated and purified by column chromatography on silica gel to provide a compound of 6G-1 (640 mg, 53 %).

Step 2: compound at 25 deg.] C under N _2, to in toluene (40 mL) of the 6G-1 (640 mg, 1.2 mmol) and 2-bromo-5- (4-chlorophenyl) -1, Pd(PPh ₃ ) ₄ (284 mg, 0.25 mmol) was added to a mixture of 3,4-oxadiazole (321 mg, 1.2 mmol). The mixture was stirred at 110 ° C for 2 h, quenched with water and EtOAc. The combined extracts were washed with water, the dried over Na ₂ SO _4, concentrated and purified by column chromatography on silica gel to provide 450 mg (68%) of product as a mixture, by SFC (Thar 80, Chiralpak The product was isolated by AD 250 mm × 20 mm, 10 μm, column temperature 38 ° C, 40% MeOH (0.05% NH ₄ OH), 100 bar, 80 mL/min, 220 nm in supercritical CO ₂ . Thus, examples 27by-a and 27by-b are obtained.

The examples in Table 6G-1 were prepared by methods analogous to those described in Method 6G, using the intermediate from Method 6F Step 3 and prepared from the specified hydrazine.

Method 6H

Step 1 : Add N,O -dimethylhydroxylamine hydrochloride (0.29 g, 2.9 mmol), N, N - 2 to 4A-6 (1.1 g, 2.5 mmol) in THF (4.0 mL) Isopropylethylamine (1.3 mL, 7.4 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphine-2,4, 6-Oxide (2.0 mL, 3.4 mmol). The reaction was stirred at room temperature for 18 h. Water was added to the reaction and the mixture was stirred vigorously for 10 minutes. The mixture was extracted with EtOAc. The combined organic layer with 1N HCl, saturated aqueous NaHCO _3, water and brine, dried (MgSO _4), filtered and concentrated in vacuo to provide 6H-1 (1.1 g, 90 %).

Step 2: Methylmagnesium chloride (3.0 M in THF, 1.8 mL, 5.6 mmol) was taken from EtOAc (EtOAc) The ice bath was removed and the mixture was stirred at room temperature for 5 h. 0.2 N HCl _{(aq) was} added to the mixture and the mixture was stirred for 10 minutes. The mixture was then extracted with EtOAc. The organics were washed with water and brine, the dried (MgSO _4), filtered and concentrated in vacuo. The residue was purified by EtOAc (EtOAc:EtOAc)

Step 3: A solution of 33% HBr in acetic acid (0.8 mL, 0.67 mmol) and bromo (0.05 mL, 1.0 mmol). The reaction was stirred at rt for 1 h and then concentrated in vacuo. To the residue was added EtOAc (2 mL) and saturated aqueous NaHCO ₃ (2 mL), followed by addition of di - tert-butyl ester (0.44 g, 2.0 mmol). The reaction was stirred at room temperature for 18 h and water was added. The reaction was extracted with EtOAc. The organic layer was washed with water and brine, the dried (MgSO _4), filtered and concentrated in vacuo. The residue was purified by EtOAc (EtOAc:EtOAc)

Step 4: To a solution of 6H-3 (0.12 g, 0.23 mmol) in EtOH (1.1 mL), 2-aminopyridine (0.023 g, 0.25 mmol). The reaction was warmed to 85 ° C and stirred for 30 minutes. The reaction was concentrated under vacuum. The residue was taken up in DCM, and the mixture was washed with saturated aqueous NaHCO _3, washed with water and brine, dried (MgSO _4), filtered and concentrated in vacuo. The residue was purified by EtOAc EtOAc (EtOAc) elute

Step 5: To a solution of 6H-4 (0.03 g, 0.05 mmol) in DCM (1 mL). The reaction was stirred at room temperature for 30 min and concentrated in vacuo to afford <RTI ID=0.0>

Example 28a was prepared in the same manner as Example 28 in Method 6H except that 2-amino-3-methoxypyridine was used instead of 2-aminopyridine in Step 4 and third butanol was used instead of EtOH.

Example 28b was prepared in the same manner as Example 28 in Method 6H except that 2-aminothiazole was used instead of 2-aminopyridine in Step 4 and third butanol was used instead of EtOH. Alternatively, the product mixture after step 4 was subjected to another Boc protection step and then purified using the procedure described in Scheme EG1. In addition, by reverse phase HPLC (Waters Sunfire C18 column; 5 μm, 30 × 250 mm; mobile phase A = water + 0.1% TFA, mobile phase B = acetonitrile + 0.1% TFA; 50 mL / min; 5% - The final product was purified by 35% B over 8 minutes.

Example 28c was prepared in the same manner as Example 28b except that 2-amino-6-methoxypyridine was used instead of 2-aminopyridine in Step 4.

Method 6I

The bromide 6I-1 was prepared by substituting the ketimine 5-12 with the ketimine 5-4 in a similar manner to those described in Steps 1-3 of Method 2A. Add PdCl ₂ (dppf) (0.020 mg, 0.025 mmol), 2 MK ₂ CO ₃ (0.31 mL, 0.62) to bromide 6I-1 (0.10 g, 0.25 mmol) in dioxane (2 mL). Methyl) and phenylboronic acid (0.045 mg, 0.37 mmol). The reaction was flushed with nitrogen and discharged three times, and then heated to 75 ° C and stirred for 4 h. The cooled reaction was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by reverse phase chromatography (yield I) to afford Example 29 (0.012 g, 9.4%).

The examples in Table 6I-1 were prepared using procedures similar to those described in Method 6I and using the appropriate boric acid.

Method 7

0.050 g (0.137 mmol) of compound 2F-3, 0.028 g (0.192 mmol) of 3-chloro-2-fluoroaniline, 0.014 g (0.021 mmol) in 3 mL of toluene at 110 ° C under nitrogen. A mixture of BINAP, 0.006 g (0.010 mmol) of Pd(dba) ₂ and 0.019 g (0.19 mmol) of t-BuONa was heated for 4 hr and then concentrated. By preparative TLC plate (as stored in 5% CH ₂ Cl ₂ eluted in the MeOH) to give the residue to give Example 30 (5.8 mg, 9.8%) . LCMS (Condition A): t _R = 2.09 min, m / e = 429 (M+H).

The compounds in Table 7-1 were prepared using methods analogous to those described in Method 7 and using the appropriate aniline as the coupling partner.

Method 7A

Step 1: 0.26 g (0.59 mmol) of Example 2 and 0.48 g (1.18 mmol) of Lawesson's reagent in 5 mL of toluene and 0.5 mL of pyridine were stirred for 4 h and cooled to room temperature. . The mixture was diluted with saturated aqueous NaHCO 20 mL of _3, and extracted with two parts of 30 mL of ethyl acetate. The combined organic extracts were concentrated; by flash chromatography (24 g of SiO _2: stored in CH ₂ Cl ₂ plus 1% NH ₄ OH in the 0% to 5% MeOH) The residue was purified to give 7A-1 (0.026 g, 10%). LCMS (Condition A): t _R = 1.81 min, m/e = 457.2 (M+H).

Step 2: A solution of 0.023 g (0.05 mmol) of 7A-1 and 0.016 g (0.15 mmol) of TMSONH ₂ in 3 mL of EtOH was stirred for 3 h under reflux and concentrated to give 7A-2. Used in the next step.

Step 3: Add 3 mL of DMF and 0.21 g (0.15 mmol) of K ₂ CO ₃ to 7A-2. The mixture was stirred at 70 ° C for 18 h and cooled to room temperature. It was diluted with 10 mL of brine and extracted with two 20 mL portions of ethyl acetate. The combined organic extracts were concentrated; by preparative TLC (to add in dichloromethane 1% NH ₄ OH in the 8% MeOH elution) to give the residue, to thereby obtain 2 mg of Example 30b.

Method 8

0.068 g (0.187 mmol) of compound 2F-3, 0.029 g (0.243 mmol) of 4-alkynylanisole 12, 0.006 g in 5 mL of DME stirred at 80 ° C under nitrogen. 0.0056 mmol) of _{Pd (PPh 3) 4, 0.002} g (0.011 mmol) of Cu (I) I and 0.052 g (0.373 mmol) of triethylamine the mixture was heated 11 hr, and then concentrated. By preparative TLC plate (as stored in CH ₂ Cl ₂ in the 5% 7M NH ₃ / MeOH elution) to give the residue, to give Example 31 (19 mg, 25.2%) . LCMS (Condition A): t _R = 2.11 min, m/e = 416 (M+H).

The compounds in Table 8-1 were prepared using methods analogous to those described in Method 8 and using the appropriate acetylene as the coupling partner.

Method 9.

Examples 32-a and 32-b were prepared using procedures similar to those described in Methods 2A, Steps 1-3, with the following modifications: (i) using hydrazine 14H-4 and ketimine 5 in step 1. -9 instead of using 2-methyl-2-(methylsulfonyl)propionitrile and ketimine 5-4 in step 1; (ii) subjecting the product of step 3 to SFC chromatography (Berger MultiGramTM SFC, Mettler Toledo Co., Ltd., Chiralcel OJ column, 250 mm × 30 mm, 5 μm, 75% supercritical CO ₂ , 25% MeOH (0.05% NH ₄ OH), 60 mL/min, column temperature: 38 ° C, nozzle Pressure: 100 bar, 220 nm), giving examples 32-a and 32-b.

The examples in Table 9-1 were prepared by substituting the indicated hydrazine reagents in step 1 using procedures similar to those described above for Examples 32-a and 32-b.

The examples in Table 9-2 were prepared using procedures similar to those described in Method 9, wherein Step 1 was modified as follows: (i) using 5-10 instead of 5-9 as the ketimine and (ii) using The designated hydrazine reagent replaces 14H-4.

Method 10

Add bis(pentamidine) diboron (0.089 g, 0.35 mmol), 1,3-bis(2,6-) chloride to Example 32g-a (0.10 g, 0.23 mmol) in THF (4 mL) Diisopropylphenyl)imidazolium (0.020 g, 0.047 mmol) and potassium acetate (0.069 mg, 0.70 mmol). Nitrogen gas was bubbled through the reaction for several minutes. Palladium acetate was added and the nitrogen was bubbled through the reaction for another 2 minutes. The reaction was warmed to 70 ° C and stirred for 18 h. The cooled reaction was filtered through a pad of Celite, and filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (10 to 75% EtOAc /hexane) to afford Example 33 as the main product.

Method 11

Step 1: To a solution of Example 32f-a (0.29 g, 0.75 mmol) in DCM (10 mL). It was allowed to warm to room temperature while stirring for 4 hours. Methanol (0.5 mL), followed by the addition of saturated aqueous K ₂ CO ₃ (5 mL). The reaction was extracted with DCM. The organic layers were washed with water and brine, the dried (MgSO _4), filtered and concentrated in vacuo. By silica gel chromatography (35% to 75% EtOAc / hexanes) the residue was purified to provide Example 34 (0.21 g, 74%) .

Step 2: Add TEA (0.30 mL, 2.1 mmol), 4-dimethylaminopyridine (0.013 g, 0.11 mmol) and two to Example 34 (0.20 g, 0.53 mmol) in DCM (20 mL) Di-tert-butyl carbonate (0.41 g, 1.9 mmol). The reaction was stirred at room temperature for 18 h. The reaction was diluted with DCM, washed with water and brine, dried (MgSO _4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (10% to 50% EtOAc / hexanes) to provide 11-1 (0.18 g, 51%) .

Step 3: Sodium methoxide (25% w/w, 0.15 mL, 0.65 mmol) was added to 11-1 (0.18 g, 0.27 mmol) in DCM (6 mL). The reaction was stirred at room temperature for 2 h. 1N aq. HCl (10 mL) was added and the mixture was extracted with DCM. The organic layer was washed with water and brine, the dried (MgSO _4), filtered and concentrated in vacuo to provide 11-2 (0.12 g, 90%) .

Step 4: Potassium carbonate (0.020 g, 0.15 mmol) was added to 11-2 (0.065 g, 0.14 mmol) in DMF (2 mL). The reaction was stirred at 0 °C for 20 min at which time bromobenzyl bromide (0.018 mL, 0.15 mmol). The reaction was allowed to warm to room temperature while stirring for 18 h. The reaction was then diluted with EtOAc and washed with water and brine. The organic layer was dried (MgSO _4), filtered and concentrated in vacuo to provide 11-3 (0.068 g), which was used directly in the next step.

Step 5: To a solution of 11-3 (0.068 g, 0.12 mmol) in DCM (4 mL). The reaction was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was purified by reverse phase EtOAc (EtOAc) (EtOAc)

Method 11A

Potassium tert-butoxide (0.015 g, 0.14 mmol) was added to 11-2 (0.061 g, 0.13 mmol) in DMF (2 mL). The reaction was stirred at 0 °C for 20 minutes and then warmed to room temperature. (Bromomethyl)cyclopropane (0.014 mL, 0.15 mmol) was added. The reaction was warmed to 45 ° C and stirred for 5 h. The cooled reaction was washed with diluted with EtOAc and washed with water and brine, dried (MgSO _4), filtered and concentrated in vacuo. The crude residue was used directly by absorption in DCM (4 mL) and TFA (2 mL). The reaction was stirred at room temperature for 2 h and then concentrated under vacuum. The residue was purified by reverse phase HPLC (M.) to afford mp.

Examples of Table 11A-2 are prepared starting with Example 32e-a or Example 32e-b and using procedures similar to those described in Method 11.

Method 12

0.15 g (0.50 mmol) of aniline 2-2 and 0.185 g (0.60 mmol) of 5-bromoisobenzofuran-1(3H)-one were stored in 5 mL of 1,4-dioxane under reflux. The solution was stirred for 20 h and concentrated. By flash chromatography (12 g of SiO _2: stored in CH ₂ Cl ₂ plus 1% NH ₄ OH in the 0% to 4% MeOH) The residue was purified to give Example 35 (0.116 g, 50%) . LCMS (Condition A): t _R = 2.06 min, m / e = 495 (M+H).

Method 12A

0.10 g (0.259 mmol) of bromide 4-1, 0.012 g (0.013 mmol) of Pd ₂ (dba) ₃ , 0.023 g (0.04) in 2 mL of 1,4-dioxane at 120 °C A mixture of Xphos and 0.057 g (0.31 mmol) of fluorine, 0.118 g (0.36 mmol) of Cs ₂ CO ₃ was stirred for 3 h and cooled to room temperature. It was concentrated; by flash chromatography (24 g of SiO _2: stored 0% to 4% MeOH CH ₂ Cl ₂ plus 1% NH ₄ OH in of) the residue was purified to give the crude material, prepared by -TLC (in stored in CH ₂ Cl ₂ plus 1% NH ₄ OH 5% MeOH in the elution) to afford the crude material to give example 35a (0.005 g, 5%) . LCMS (Conditions _{A): t R = 1.76 min} , m / e = 456 (M + H).

Method 13

Step 1: Add N,N -dicyclohexylmethylamine (0.84 mL, 3.9 mmol) to 4-1 (0.50 g, 1.3 mmol) in toluene (5.2 mL) Glycol monovinyl ether (0.24 mL, 2.6 mmol). Nitrogen gas was then bubbled through the reaction mixture for 5 minutes. Compound 17-3 (0.066 g, 0.13 mmol) was added and gas nitrogen was bubbled through the mixture for 1 min. The reaction vessel was capped and warmed to 80 ° C and then stirred for 12 h. The cooled reaction mixture was filtered through a bed of celite. The filtrate was concentrated under vacuum to afford crude enol ether 13-1 which was taken directly to next.

Step 2: 1 N HCl (2 mL) was added to the enol ether obtained in Step 1 in THF (5 mL), followed by 4N HCl in dioxane (2 mL). The reaction mixture was stirred at room temperature for 30 minutes, followed with saturated aqueous NaHCO ₃ solution basified to about pH 9. The mixture was then extracted with EtOAc. The organics were washed with water and brine, the dried (MgSO _4), filtered and concentrated in vacuo. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc) Further purification (Waters Sunfire C18, 5 μm, 19 × 100 mm, 50 mL/min, 20 min run time, mobile phase A = water + 0.1% formic acid, mobile phase B = MeCN + 0.1% formic acid, 5-40% B ) to provide an example 36 of the formate.

Method 14

Room temperature mixture of methanesulfonyl acetonitrile (1.00 g, 8.39 mmol) and benzyltriethylammonium bromide (0.228 g, 0.839 mmol) in 50% aqueous hydroxide (14 mL, 175 mmol) 1,2-Dibromoethane (0.72 mL, 8.32 mmol) was added. After 2 h, the reaction mixture was diluted with H.sub.2 (25 mL). The combined organic layers were washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to afford compound 14-1 (0.85 g, 5.56 mmol, 66% yield). ¹ H NMR (CDCl ₃ , 500 MHz) δ 3.18 (s, 3H), 1.88-1.86 (m, 2H), 1.76-1.73 (m, 2H).

Method 14A

Step 1: Toluene (7.8 mL, 100 mmol) was added to benzotriazole (10 g, 84 mmol) and pyridine (11 mL, 130 mmol) in toluene (100 mL). . The reaction was allowed to warm to room temperature while stirring for 18 h. Add EtOAc and water. The organic phase was separated and dried (MgSO _4), filtered and the concentrated in vacuo. The residue was recrystallized from toluene to afford 14A-1 (13.4 g, 81%).

Step 2: To a solution of potassium 2-butoxide (1.4 g, 2-(3-(trifluoromethyl)phenyl)acetonitrile (1.0 mL, 6.4 mmol) in DMSO (30 mL) 13 mmol). The reaction was stirred at this temperature for 10 min, then 14A-1 (1.2 g, 6.4 mmol). The reaction was allowed to warm to room temperature and stirred for 16 h. The reaction was poured into water ₄ Cl and diluted with saturated aqueous NH. The mixture was extracted with EtOAc. The organic layer was washed with water and brine, the dried (MgSO _4), filtered and concentrated. The residue was purified by silica gel chromatography (20% to 50%EtOAc) to afford 14A-2 (1.0 g, 60%).

Step 3: To a solution of 14A-2 (4.0 g, 16 mmol) in THF (150 mL). The reaction was stirred at 0 °C for 20 min and then iodomethane (1.8 mL, 29 mmol). The reaction was allowed to warm to room temperature and stirred for 18 h. A saturated aqueous solution of NH ₄ Cl was added to the reaction. The mixture was then extracted with EtOAc. The organic layer was washed with water and brine, the dried (MgSO _4), filtered and concentrated in vacuo. The residue was purified by EtOAc (EtOAc:EtOAc)

The methyl hydrazine in Table 14A-1 was prepared using the procedure described in Method 14A and using the appropriately substituted acetonitrile in Step 2.

Method 14B

Step 1: Slowly add 47.9 mL (2.5 M, to a solution of 7.5 g (59.9 mmol) of 2-(tetrahydro-2H-pyran-4-yl)acetonitrile in 120 mL of THF at -78 °C. Stored in ethane, 120 mmol) of n-BuLi. The mixture was stirred for a further 1 h at -78 °C. A solution of 11.82 g (59.9 mmol) of 14A-1 in 70 mL of THF was added via cannula. The mixture was slowly warmed to room temperature and stirred overnight. By ₄ Cl solution and water, it was quenched with saturated NH. The mixture was extracted with EtOAc (2×). The organic extracts were combined, dried and concentrated. By flash chromatography (SiO _2: 40% to 75% EtOAc / hexanes) the residue to give 14B-1 (1.7 g, 13.96 %). ¹ H NMR (CDCl ₃ ): 1.75 (m, 3H), 2.05 (m, 1H), 2.65 (m, 1H), 3.2 (s, 3H), 3.5 (m, 2H), 3.9 (m, 1H), 4.05 (m, 2H).

Step 2: To a solution of 2.14 g (10.53 mmol) of 14B-1 in 100 mL of THF, 4.12 g (12.63 mmol) of Cs ₂ CO ₃ and 0.79 mL (12.63 mmol) of CH ₃ I were added. The mixture was stirred overnight at room temperature. It was quenched with water and extracted with EtOAc EtOAc. The combined organic extracts were dried and concentrated. The residue was purified to give 14B-2 (2 g, 87 %): by flash chromatography (50% to 100% EtOAc / hexane to 40 g of SiO _2). ¹ H NMR (CDCl ₃ ): 1.55 (m, 2H), 1.78 (S, 3H), 1.9-2.1 (m, 2H), 2.6 (m, 1H), 3.2 (s, 3H), 3.4-3.6 (m) , 2H), 4.1 (m, 2H).

Method 14C

Methanesulfonyl acetonitrile (5.0 g, 42.0 mmol) was added portionwise to a suspension of 60% NaH (1.68 g, 42.0 mmol) in THF (100 mL). The reaction was stirred at 0 °C for 20 minutes. A solution of iodomethane (5.96 g, 42.0 mmol) in THF (5 mL) was then evaporated and evaporated. Water was added and extracted with DCM (2×200 mL). The combined organic layers were dried and the solvent was removed in vacuo. The crude sample was dissolved in THF (100 mL) and cooled to 0 °C. 60% NaH (1.2 g, 30.0 mmol) in mineral oil was added portionwise and stirred at 0 °C for 20 min. A solution of allylic bromopropyl bromide (4.5 g, 37.2 mmol) in THF (5 mL) was evaporated. The reaction was slowly warmed to room temperature and stirred overnight. Water was added and extracted with DCM (2×200 mL). The combined organic layers were washed with brine and dried over sodium sulfate. The solvent was removed under vacuum. The residue was purified by EtOAc (EtOAc EtOAcEtOAcEtOAcEtOAc g, 27.7 mmol).

The methyl hydrazine in Table 14C-1 was prepared using the procedure described in Method 14C and using the appropriate electrophile in the second alkylation instead of the allyl bromide.

Method 14D

60% NaH (3.52 g, 88.0 mmol) in mineral oil was added portionwise to a solution of methanesulfonyl acetonitrile (5.0 g, 42.0 mmol) at 0 °C. The reaction was stirred at 0 ° C for 30 minutes. A solution of chloromethyl methyl ether (7.86 g, 88.0 mmol) in THF (10 mL) was added dropwise, and the mixture was stirred at 0 ° C for 1 h. A saturated aqueous solution of ammonium chloride was added and extracted with EtOAc (2×200 mL). The combined organic layers were washed with brine, dried over magnesium sulfate and evaporated <~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ -1 (8.0 g, 38.6 mmol).

Method 14E.

Step 1: To a solution of tetrahydro- 2H -pyran-4-carbaldehyde (5.0 g, 43.8 mmol) and (methylsulfanyl)acetonitrile (4.35 g, 49.9 mmol) in THF (100 mL) Benzyltrimethylammonium hydroxide (40% solution, 22.7 mL, 49.9 mmol) was added dropwise to the stirred solution. The reaction was stirred at 0 °C for 3 h. Water was added and the aqueous layer was extracted with ether (2×200 mL). The combined organic layers were washed with brine and dried over sodium sulfate. The solvent was removed under vacuum and the residue was passed through a short pad to afford 14E-1 (5.6 g, 30.6 mmol). LCMS 14E-1 for the (Conditions _{A): t R = 2.14 min} , m / e = 184 (M + H).

Step 2: To a stirred solution of compound 14E-1 (5.6 g, 30.6 mmol The solution was stirred at 0 ° C for 30 minutes and then warmed to room temperature for 1 h. Water was added and extracted with ether (3 x 100 mL). The solvent was dried and removed under vacuum to afford 14E-2 (5.5 g, 29.7 mmol). LCMS 14E-2 for the (Condition _{A): t R = 2.06 min} , m / e = 186 (M + H).

Step 3: To a stirred solution of EtOAc (2. The reaction mixture was stirred for 1 minute. Methyl iodide (1.62 mL, 25.9 mmol) was added dropwise and stirred at room temperature for 15 h. Water was added and extracted with ether (2 x 200 mL). The solvent was dried and removed in vacuo to give 14E-3 (2.8 g, 14.0 mmol). For the LCMS 3 (Conditions _{A): t R = 2.15 min} , m / e = 200 (M + H).

Step 4: mCPBA (70%, 6.93 g, 28.1 mmol) was added to a stirred solution of 14E-3 (2.8 g, 14.05 mmol) in DCM (100 mL). The reaction mixture was stirred at 0 °C for 3 h. The reaction was washed with a 5% aqueous sodium hydrogencarbonate solution and water. The organic layer was dried and concentrated in vacuo to give &lt;RTI ID=0.0&gt;&gt; For LCMS (Conditions A) 14E-4 _{of: t R = 1.80 min, m} / e = 233 (M + H).

The methyl oxime in Table 14E-1 was prepared by using the aldehydes necessary from Step 1 similar to those described in Method 14E.

Method 14F.

Step 1: Add cyclobutanone (12 g, 100 mmol) and DL-proline (2.4 g) to a solution of methanesulfonyl acetonitrile (16.8 g, 240 mmol) in 200 mL of THF at room temperature. , 20 mmol). The reaction mixture was refluxed for 6 h and cooled to 0 °C. NaBH ₄ (8 g, 200 mmol) was added to the above mixture in portions. The mixture was stirred at rt EtOAc (EtOAc) The organic extract was washed with brine, dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography to afford 14F-1 (4 g, 24%). ¹ H NMR (CDCl ₃ ): 1.98 to 2.32 (m, 6H), 3.09 (s, 3H), 3.16 to 3.22 (m, 1H), 3.92 (d, J = 6.8 Hz, 1H).

Step 2: A solution of 14F-1 (2.5 g, 14.5 mmol) in THF (20 mL) was added to a suspension of NaH (580 mg, 14.5 mmol) in 20 mL of THF. After stirring for 30 min at 0 ℃, the _{CH 3 I (4.8 g, 33.8} mmol) was added oriented text mixture. The mixture was stirred at room temperature overnight, quenched with saturated aqueous NH ₄ Cl and extracted with EtOAc (2X). The combined organic extracts were washed with brine w... The residue was purified by silica gel chromatography to afford 14F-2 (1.9 g, 70%). ¹ H NMR (CDCl ₃ ): 1.61 (s, 3H), 1.90 to 2.29 (m, 6H), 2.87 to 2.93 (m, 1H), 3.05 (s, 3H).

Method 14G

Step 1: methanesulfonyl acetonitrile (10.0 g, 84 mmol), 2-iodopropane (28.6 g, 168 mmol) and DBU (14 g, 92.4 mmol) in toluene (140 mL). The mixture was stirred for 4 h and then filtered. The filtrate was washed with dilute EtOAc (10%) brine brine The residue was purified by silica gel chromatography (PE: EA = 10:1) to afford 14G-1 (5.5 g, 40%). ¹ H NMR (CDCl ₃ ): 3.82 (d, J = 4 Hz, 1H), 3.15 (s, 3H), 2.70 to 2.74 (m, 1H), 1.29 (d, J = 8 Hz, 3H), 1.22 ( d, J = 8 Hz, 3H).

Step 2: 14G-1 (2.5 g, 14.5 mmol) was added to a suspension of NaH (1.2 g, 30.5 mmol) in EtOAc. After stirring for 30 min at 0 ℃, the _{CH 3 I (4.4 g, 30.5} mmol) was added oriented text mixture. The mixture was stirred at room temperature overnight, quenched with saturated aqueous NH ₄ Cl and extracted with EtOAc (2X). The combined organic extracts were washed with brine w... The residue was purified by silica gel chromatography (PE: EA = 20:1) to afford 14G-2 (2.8 g, 59%). ¹ H NMR (CDCl ₃ ): 3.15 (s, 3H), 2.59 to 2.65 (m, 1H), 1.71 (s, 3H), 1.29 (d, J = 8 Hz, 3H), 1.17 (d, J = 8) Hz, 3H).

Method 14H

Step 1: To a suspension of LiAlH ₄ (8.72 g, 218 mmol) in THF (100 mL), a solution of 2-methylbenzo[d]thiazole-5-carboxylic acid (21 g, 109 mmol) solution in THF. The mixture was stirred at room temperature for 2 h then quenched with water and 1 M EtOAc and filtered. The filtrate was extracted with EtOAc (EtOAc)EtOAc. The residue was purified by silica gel chromatography (PE: EA = 3:1) to afford 14H-1 (12 g, 57%). ¹ H NMR (MeOD): 7.83 (d, J = 8.4 Hz, 2 H), 7.36 (d, J = 8.4 Hz, 1 H), 4.71 (s, 2 H), 2.79 (s, 3 H).

Step 2: Stir a mixture of 14H-1 (12 g, 67 mmol), PPh ₃ (26.3 g, 100.5 mmol) and CBr ₄ (33.4 g, 100.5 mmol) in DCM (250 mL). 6 h. The solution was concentrated and purified by silica gel chromatography (PE: EA = 5:1) to afford 14H-2 (10 g, 62%). ¹ H NMR (CDCl ₃ ): 7.93 (d, J = 1.2 Hz, 1 H), 7.79 (t, J = 8.0 Hz, 1 H), 7.37~7.39 (m, 1 H), 4.71 (s, 1 H) ), 4.62 (s, 1 H ), 2.82 (d, J = 2.0 Hz, 3 H).

Step 3: Add methanesulfonyl acetonitrile (5.43 g, 45.6 mmol) dropwise to a suspension of NaH (1.8 g, 45.6 mmol) in THF (25 mL) and stirring at 0 ° C. 1 h. To this mixture was added dropwise a solution of 14H-2 (10 g, 41.5 mmol) in THF (30 mL). The resulting mixture was stirred at 0 ℃ 2 h, and quenched with H ₂ O and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, evaporated, and evaporated. ¹ H NMR (CDCl ₃ ): 7.85 (s, 1 H), 6.78 (d, J = 8.0 Hz, 1 H), 7.25 to 7.28 (m, 1 H), 4.05 to 4.09 (m, 1 H), 3.59 ~3.64 (m, 1 H), 3.28~3.43 (m, 1 H), 3.10 (s, 3 H), 2.79 (s, 3 H).

Step 4: 14H-3 (7.8 g, 27.8 mmol) in THF (50 mL) was added dropwise EtOAc (EtOAc) And stirred at 0 ° C for 1 h. To this mixture was added MeI (7.9 g, 55.6 mmol) dropwise. The resulting mixture was stirred at 0 ℃ 4 h, and quenched with H ₂ O and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, evaporated, and evaporated. ¹ H NMR (CDCl ₃ ): 7.95 (d, J = 0.8 Hz, 1 H), 7.86 (d, J = 8.0 Hz, 1 H), 7.40 to 7.42 (m, 1 H), 3.62 (d, J = 13.6 Hz, 1 H), 3.23 (d, J = 13.6 Hz, 1 H), 3.14 (s, 3 H), 2.89 (s, 3 H), 1.67 (s, 3 H).

The methylhydrazine in Table 14H-1 was prepared by the procedure described in Method 14H and using the appropriate formic acid instead of 2-methylbenzo[d]thiazole-5-carboxylic acid in Step 1.

Method 14I

Step 1: methanesulfonyl acetonitrile (292 mg, 2.5 mmol), 2-bromo-4-(trifluoromethyl)pyridine (500 mg, 2.2 mmol) in 10 mL of DMSO at 120 °C and A mixture of Cs ₂ CO ₃ (2.2 g, 6.7 mmol) was heated overnight and then cooled to room temperature. The mixture was diluted with water and extracted with EtOAc (EtOAc). The organic extract was washed with brine, dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography to give 14I-1 (500 mg, 85%). ¹ H NMR (CD3OD): 3.33 (s, 3H), 4.86 (s, 1H), 6.93 (d, J = 6.8 Hz, 1H), 7.93 (s, 1H), 8.97 (d, J = 5.2 Hz, 1H) .

Step 2: 14I-1 (300 mg, 1.2 mmol), K ₂ CO ₃ (315 mg, 2.3 mmol) and CH ₃ I (324 mg, 2.3 mmol) in 10 mL of THF at room temperature The mixture was stirred overnight. Which was treated with saturated aqueous NH ₄ Cl was quenched and extracted with EtOAc (2X). The combined organic extracts were washed with brine, dried over sodium sulfate The residue was purified by silica gel chromatography to afford 14I-2 (154 mg, 49%). ¹ H NMR (CDCl ₃ ): 2.28 (s, 3H), 3.11 (s, 3H), 7.68 (d, J = 4.8 Hz, 1H), 7.78 (s, 1H), 8.92 (d, J = 4.8 Hz, 1H).

Method 15

To a solution of 3-bromo-5-fluorobenzoic acid (4.0 g, 18.3 mol) in EtOAc (45 mL), EtOAc (1,1 g, 18.3 mmol), TEA (7.6 mL, 54.8 mmol) Propanephosphonic acid cyclic anhydride (50% solution in EtOAc, 27.2 mL, 45.7 mmol). The mixture was warmed to 80 ° C and stirred for 12 h. The cooled mixture was added to water and then EtOAc was extracted. The organic layers were washed with water and brine, the dried (MgSO _4), filtered and concentrated in vacuo. The residue was purified by EtOAc (EtOAc:EtOAc)

Bromide 15-2 was prepared in the same manner as 15-1 except that 3-bromobenzoic acid was used instead of 3-bromo-5-fluorobenzoic acid.

Method 15A

Add potassium carbonate (6.6 g, 48 mmol) and isocyanatotoluene methyl (5.1 g) to 3-bromo-5-fluorobenzaldehyde (4.8 g, 24 mmol) in MeOH (79 mL) , 26 mmol). The reaction was allowed to warm to reflux and stirred for 4 h. The cooled reaction was concentrated under vacuum and water was added to the residue. The precipitate was filtered, washed with water and air dried. The solid was taken up in DCM and dried (MgSO _4), filtered and concentrated in vacuo to provide 15A-1 (5.5 g, 95 %).

Bromide 15A-2 was prepared in the same manner as 15A-1 except that 5-bromonicotinic aldehyde was used instead of 3-bromo-5-fluorobenzaldehyde in step 1.

Method 15B

Step 1: To a solution of 5-bromonicotinaldehyde (1.5 g, 8.1 mmol) in toluene (80 mL) was added 2,2-dimethoxyethylamine (1.1 mL, 10 mmol). The mixture was allowed to warm to reflux and water was removed using a Dean-Stark apparatus. After 2.5 h, the reaction was cooled and poured into EtOAc. The mixture was washed with water and brine, dried (MgSO _4), filtered and concentrated in vacuo to provide 15B-1 (2.1 g, 95 %).

Step 2: Add concentrated sulfuric acid (40 mL, 750 mmol) to the imine 15B-1 (5.5 g, 20 mmol) obtained in Step 1 after cooling to 0 ° C, followed by the addition of phosphorus pentoxide (3.7 g) , 26 mmol). The mixture was then warmed to 100 ° C and stirred for 30 minutes. The cooled reaction mixture was poured onto ice, a concentrated NH ₄ OH and the pH was adjusted to about pH 8. The resulting mixture was extracted with DCM. The organic layers were washed with water and brine, the dried (MgSO _4), filtered and concentrated in vacuo. The residue was purified by EtOAc EtOAc (EtOAc) elute

Method 15C

Was added to N stored in EtOAc (34 mL) of the 3-bromo-benzoic acid (2.0 g, 9.9 mmol) in - hydroxy as acetamide (0.74 g, 9.9 mmol) and TEA (4.2 mL, 30 mmol) . T3P (50% solution in EtOAc, 15 mL, 25 mmol) was slowly added to the mixture. The reaction was warmed to 80 ° C and stirred for 3 h. The cooled reaction was poured into water and the mixture was extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO ₃ and brine, dried (MgSO _4), filtered and concentrated in vacuo. The residue was purified by EtOAc (EtOAc:EtOAc)

Method 15D

Add methyl hydrazine (0.62 g, 10 mmol), TEA (4.3 mL, 31 mmol) and T3P (50% solution) to 5-bromonicotinic acid (2.1 g, 10 mmol) in EtOAc (52 mL) , stored in EtOAc, 15 mL, 26 mmol). The reaction was warmed to 80 ° C and stirred for 12 h. Water was added to the cooled reaction and the mixture was extracted with EtOAc. The organic layer was washed with water and brine, the dried (MgSO _4), filtered and concentrated in vacuo to provide bromide 15D-1 (1.9 g, 84 %).

Method 15E

Step 1: To a solution of 3-bromo-4-fluorobenzoic acid (148 g, 0.855 mol) in CH ₂ Cl ₂ (750 mL, 15 vol), EtOAc (66.4 g) , 0.898 mol), HOBt (34.6 g, 0.256 mol), NMM (281 mL, 2.56 mol) and EDC ̇HCl (245 g, 1.28 mol). The reaction mixture was stirred at the same temperature for 16 h. The reaction mixture was concentrated to dryness, water (2. The solid obtained was filtered, washed with EtOAc (EtOAc EtOAc) ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 10.43 (s, 1H), 9.95 (s, 1H), 8.21-8.18 (m, 1H), 7.96-7.91 (m, 1H), 7.52 (t, J = 8.4 Hz, 1H), 1.93 (s, 3H).

Step 2: A 5 L three-necked round bottom flask equipped with a reflux condenser was charged with 15E-1 (168 g, 0.610 mol) and POCl ₃ (1.68 L) at room temperature. The reaction mixture was heated to reflux for 1 h. The reaction mixture was concentrated to dryness. EtOAc (EtOAc) The combined organics were washed with brine (800 mL), dried over anhydrous Na ₂ SO _4, and concentrated under reduced pressure, to provide 15E-2 (135 g, 86 %). ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.23 - 8.20 (m, 1H), 8.03 - 7.98 (m, 1H), 7.60 (t, J = 8.7 Hz, 1H), 2.59 (s, 3H) .

Method 16

Add bis(pentamidine) diboron (2.1 g, 8.3 mmol), 1,3-bis- (diiso) to bromide 15-1 (1.7 g, 7.1 mmol) in THF (8.9 mL) Propylphenyl)-imidazolium (0.18 g, 0.43 mmol), palladium acetate (0.05 g, 0.2 mmol) and potassium acetate (1.7 g, 17.8 mmol). Nitrogen gas was bubbled through the reaction mixture for 5 minutes. The reaction was then allowed to warm to reflux and stirred for 2 h. The cooled mixture is passed through a silicone pad. The filtrate was concentrated in vacuo and the residue was purified eluting eluting eluting eluting

The bromide in Table 16-1 was converted to its boronate using conditions similar to those described in Method 16.

Method 16A

To 15D-1 (1.1 g, 4.7 mmol) in DMSO (19 mL) was added bis(pentamidine) diboron (1.3 g, 5.2 mmol) and potassium acetate (1.4 g, 14 mmol). Nitrogen gas was bubbled through the reaction for 5 minutes. PdCl ₂ (dppf) (0.17 g, 0.23 mmol) was added and nitrogen was bubbled through the reaction for 1 min. The reaction was warmed to 80 ° C and stirred for 24 h. Water was added to the cooled reaction and the mixture was extracted with EtOAc. The organic layers were washed with water and brine, the dried (MgSO _4), filtered and concentrated in vacuo. The residue was purified by reverse phase chromatography (C18 column; solvent A: 0.1% formic acid/water; solvent B: 0.1% formic acid/acetonitrile; 5%-100% B over 10 column volumes) to afford 16A -1 (0.20 g, 15%).

Method 16B

The 15E-2 (110 g, 0.429 mol) stored in THF (1.10 L) in the stirred solution was cooled to -78 ℃, stored over 45 min with n-hexane (268 mL, 0.429 mol, 1.60 M) in the n -BuLi was filled dropwise and stirred at -78 °C for 30 min. Triisopropyl borate (198.6 mL, 0.858 mol) was charged dropwise to the reaction mixture over 30 min. The reaction mixture was stirred at -78 °C for 30 min, warmed to room temperature and stirred for 2 h. At this time, 2 N HCl (800 mL) was added and the mixture was extracted with EtOAc / MeOH (9:1, 4 x 1.00 L). The combined organics were washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated. The crude compound was washed with EtOAc / EtOAc (EtOAc (EtOAc:EtOAc) ¹ H NMR (300 MHz, DMSO- d ₆ ): δ 8.48 (bs, 2H), 8.18-8.16 (m, 1H), 8.05-8.00 (m, 1H), 7.32 (t, J = 8.7 Hz, 1H) , 2.58 (s, 3H). MS (MM) m/z 223 [M+H] ⁺ .

Method 17

Step 1: Trimethylchloromethane (85 mL, 665 mmol) was added to isopropyl acetate (600 mL) and MeOH (36 mL, 886 mmol). The mixture was stirred for 30 minutes and [1,1'-biphenyl]-2-amine (75 g, 440 mmol) was added. The reaction was aged for 18 h, and the solid was collected by filtration and washed with isopropyl acetate to afford 17-1 (90 g, 99%).

Step 2: Palladium acetate (4.4 g, 19.5 mmol) was added to a slurry of 17-1 (4.0 g, 19.5 mmol) in THF (120 mL). The reaction was warmed to 60 ° C and stirred for 75 minutes. A portion of the solvent (50-60 mL) was removed in vacuo. Heptane (50 mL) was added to the stirred solution over 20 min at room temperature, at which time the slurry was aged for 30 min. The solid was filtered and washed with 25% heptane / THF (2 x 50 mL) to afford 17-2 (5.8 g, 93%).

Step 3: To a solution of 17-2 (4.1 g, 6.5 mmol) in EtOAc (20 mL). The reaction was stirred at room temperature for 30 min and then a solid was filtered and washed with hexane to afford 17-3 (5.8 g, 87%).

Method 18

Step 1: a solution of compound 18-1 (0.6 g, 4.3 mmol) in memory (10 mL) in a solution of MeOH was added _{SOCl 2 (1.1 g, 8.6 mmol} ). The mixture was stirred at 70 ° C for 8 h and concentrated to give compound 18-2 (0.66 g, 100%).

Step 2: To a solution of the compound 18-2 (0.5 g, 3.2 mmol) . The solution was stirred at rt for 4 h then quenched with EtOAc EtOAc. The combined extracts were washed with brine, dried over Na ₂ SO _4, concentrated and by column (PE: 1: EA = 3 ) purified to provide compound 18-3 (0.4 g, 67%) . ¹ H NMR (400 MHz, CDCl ₃ ): 8.46 (d, J = 2.4 Hz, 1H), 8.09 (d, J = 4.8 Hz, 1H), 7.43 to 7.46 (m, 1H), 5.26 (s, 2H) , 3.97 (s, 3H), 3.48 (s, 3H).

Step 3: A solution of compound 18-3 (0.4 g, 2 mmol) elute The solution was neutralized with AcOH and extracted with EtOAc. The combined extracts were washed with brine, dried over Na ₂ SO _4, and concentrated to afford compound 18-4 (0.2 g, 57%) . ¹ H NMR (400 MHz, CD ₃ OD): 8.41 (d, J = 2.4 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.63 to 7.65 (m, 1H), 5.36 (s, 2H) ), 3.51 (s, 3H).

In addition to the examples shown above, the compounds of the invention include those compounds in Table A below:

LC/MS conditions

Condition A: Column: Agilent Zorbax SB-C18 (3.0 x 50 mm) 1.8 μm; mobile phase: A: 0.05% trifluoroacetic acid in water, B: 0.05% trifluoroacetic acid in acetonitrile; gradient: 90:10 (A:B) for 0.3 min, 1.2 min 90:10 to 5:95 (A:B), 5:95 (A:B) for 1.2 min, flow rate: 1.0 mL/min; UV detection: 254 nm and 220 nm; mass spectrometer: Agilent 6140 quadrupole.

Condition B: Column: Agilent Zorbax SB-C18 (3.0 x 50 mm) 1.8 μm; column temperature 50 ° C; mobile phase: A: 0.1% trifluoroacetic acid in water, B: 0.1% in acetonitrile Trifluoroacetic acid; gradient: 1.5 min 90:10 to 5:95 (A:B), 5:95 (A:B) for 1.2 min; flow rate: 1.0 mL/min; UV detection: 254 nm and 220 nm; Mass spectrometer: Agilent 6140 quadrupole.

Condition C: Column: Agilent SB-C18 (3.0 x 50 mm) 1.8 μm; column temperature 50 ° C; mobile phase: A: 0.1% trifluoroacetic acid in water, B: 0.1% in acetonitrile Fluoroacetic acid, gradient: 90:10 (A:B) for 0.3 min, 5 min 90:10 to 5:95 (A:B), 5:95 (A:B) for 1.2 min; flow rate: 1.0 mL/ Min; UV detection: 254 nm and 220 nm; mass spectrometer: Agilent 6140 quadrupole.

Condition D: Acquity UPLC BEH-C18, 1.7 μm, 2.1×50 mm; 5%-100% MeCN/water and 0.1% NH ₃ , 1.4 min, 1 mL/min flow.

Condition E: Agilent 1100 LC/MS, column: Waters Xterra C18 (2.1 x 20 mm) 3.5 μm; mobile phase: 0.1% trifluoroacetic acid in water, B: 0.1% trifluoroacetic acid in acetonitrile; Gradient: 3.25 min 90:10 (A:B) to 2:98 (A:B), 2:98 (A:B) for 0.75 min; flow rate: 1.5 mL/min; UV detection: 254 nm and 220 nm Mass spectrometer: Agilent ESI+.

Condition F1: Column: Agilent TC-C18 (2.1 x 50 mm) 5 μm; mobile phase: A: 0.0375% trifluoroacetic acid in water, B: 0.01875% trifluoroacetic acid in acetonitrile; gradient: 100: 0 (A: B) for 0.4 min, 3 min 100:0 to 20:80 (A:B), 0.6 min 20:80 to 0:100 (A:B); flow rate: 0.6 mL/min; UV Detection: 254 nm and 220 nm; mass spectrometer: Agilent 6110 quadrupole.

Condition F2: Column: Agilent TC-C18 (2.1 x 50 mm) 5 μm; mobile phase: A: 0.0375% trifluoroacetic acid in water, B: 0.01875% trifluoroacetic acid in acetonitrile; gradient: 99: 1 (A:B) for 0.4 min, 3 min 99:1 to 10:90 (A:B), 0.6 min 10:90 to 0:100 (A:B); flow rate: 0.8 mL/min; UV Detection: 254 nm and 220 nm; mass spectrometer: Agilent 6110 quadrupole.

Condition F3: Column: Agilent TC-C18 (2.1 x 50 mm) 5 μm; mobile phase: A: 0.0375% trifluoroacetic acid in water, B: 0.01875% trifluoroacetic acid in acetonitrile; gradient: 90: 10 (A:B) for 0.4 min, 3 min 90:10 to 0:100 (A:B), 0:100 (A:B) for 0.6 min; flow rate: 0.8 mL/min; UV detection: 254 nm And 220 nm; mass spectrometer: Agilent 6110 quadrupole.

Condition F4: Column: Xbridge RP 18 (2.1 x 50 mm) 5 μm; mobile phase: A: 0.05% NH3 in water, B: 100% acetonitrile; gradient: 95:5 (A: B) for 0.4 min, After 3 min 95:5 to 10:90 (A:B), 0.6 min 10:90 to 0:100 (A:B); flow rate: 0.8 mL/min; UV detection: 254 nm and 220 nm; mass spectrometer : Agilent 6110 quadrupole.

Condition F5: Column: Agilent TC-C18 (2.1 x 50 mm) 5 μm; mobile phase: A: 0.0375% trifluoroacetic acid in water, B: 0.01875% trifluoroacetic acid in acetonitrile; Gradient: 75: 25 (A:B) for 0.4 min, 3 min 75:25 to 0:100 (A:B), 0:100 (A:B) for 0.6 min; flow rate: 0.8 mL/min; UV detection: 254 nm And 220 nm; mass spectrometer: Agilent 6110 quadrupole.

Condition F6: Column: Shimadzu ODS 2.1 × 30 mm 3 μm column; mobile phase: A: 0.0375% trifluoroacetic acid in water, B: 0.01875% trifluoroacetic acid in acetonitrile; gradient: 2 min 90:10 to 20:80 (A:B); flow rate: 1.2 mL/min.

Condition G: Column: Agilent Zorbax SB-C18 (3.0 x 50 mm) 1.8 μm; column temperature 50 ° C; mobile phase: A: 0.05% trifluoroacetic acid / 0.5% acetic acid in water; B: in acetonitrile 0.05% trifluoroacetic acid/0.5% acetic acid; gradient: 1.5 min 90:10 to 5:95 (A:B), 5:95 (A:B) for 1.2 min; flow rate: 1.0 mL/min; UV Detection: 254 nm and 220 nm; mass spectrometer: Agilent 6140 quadrupole.

Condition H: System: Waters Acquity UPLC/MS, electrospray positive ion mode; column: Waters Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7 μm; mobile phase: A: H2O/0.05% TFA, B: ACN/0.05 % TFA; Gradient: 0 min-1.8 min, 5%-99% B; flow rate: 0.8 mL/min; UV: 254 nm.

Condition I: HPLC: Column: Novapak HR-C18 (25 x 100 mm) 6 μm in a Waters PrepLC 25 mm module; mobile phase: A: 0.1% TFA in water, B: 0.1 in acetonitrile % TFA; Gradient: 90:10 (A:B) for 1 min, 10 min 90:10 to 5:95 (A:B), 5:95 (A:B) for 5 min; flow rate: 30 mL/ Min; UV detection: 254 or 220 nm.

Condition J: System: Agilent 1100/Waters ZQ LC/MS. Column: Waters XTerra MS C18, 3.5 μm, 3.0×50 mm; mobile phase: A: H2O/0.05% TFA, B: ACN/0.05% TFA; flow rate: 1.5 mL/min. Gradient: 0-1.28 min, 5-98% B; UV detection: 190-400 nm.

analysis

Schemes for determining the potency values of the compounds of the invention are set forth below.

BACE1 HTRF FRET analysis Reagent

Acetic acid Na ⁺ pH 5.0; 1% Brij-35; glycerol; dimethyl hydrazine (DMSO); recombinant human soluble BACE1 catalytic domain (>95% pure); APP Swedish mutant peptide substrate (QSY7-APP ^swe- Eu) :QSY7-EISEVNLDAEFC-铕-amine.

Using a homogeneous time-resolved FRET assay measured IC ₅₀ values of inhibitors of the catalytic domain of the soluble human BACE1. This assay monitored the 620 nm fluorescence increase caused by BACE1 cleavage by the APPswedish APP ^swe mutant peptide FRET receptor (QSY7-EISEVNLDAEFC-铕-decylamine). This acceptor contains an N-terminal QSY7 moiety that acts as a quencher for the C-terminal fluorene fluorophore (620 nm Em). In the absence of enzymatic activity, 620 nm fluorescence was lower in this assay and linearly increased in 3 hours in the presence of uninhibited BACE1 enzyme. Inhibitors of QSY7-APP ^swe -Eu-induced BACE1 cleavage showed inhibition of 620 nm fluorescence.

10 μl volume of inhibitor at different concentrations from 3 × final desired concentration at 30 ° C in reaction buffer containing pH 5.0 20 mM Na, 10% glycerol, 0.1% Brij-35 and 7.5% DSMO The cells were pre-incubated with the purified human BACE1 catalytic domain (3 nM in 10 μl) for 30 minutes. The reaction was initiated by adding 10 μl of 600 nM QSY7-APP ^swe- Eu substrate (200 nM, final) to obtain a final reaction volume of 30 μl in a 384-well Nunc HTRF plate. The reaction was incubated at 30 ° C for 1.5 hours. The 620 nm fluorescence was then read on a Rubystar HTRF plate reader (BMG Labtechnologies) using a 50 millisecond delay followed by a 400 millisecond acquisition time window. Inhibitors IC ₅₀ values of the non-linear regression analysis of concentration-response curves were obtained from. Then using the Cheng-Prusoff equation using a previously determined QSY7-APP ^swe -Eu the receiving quality at the BACE1 μm to 8 μM IC ₅₀ value calculated from the value of K _i values. Method measuring Compound Examples 1, 2 and 3 of each in this assay and exhibits less than about 5 nM of K _i values. The K _i values of other compounds of the present invention measured using this assay are reported in the above table.

BACE-2 analysis

In the measurement QSY7-EISEV NL DAEFC-Eu- Amides FRET peptide by proteolytic endpoint assay (BACE-HTRF assay) was measured under the inhibitor purified human IC-2 autoBACE ₅₀ hydrolysates of time-resolved. BACE-mediated hydrolysis of this peptide resulted in an increase in relative fluorescence (RFU) at 620 nm after excitation with 320 nm light. The inhibitor compound (in a 1 x BACE assay buffer (pH 5.0 20 mM sodium acetate, 10% glycerol, 0.1% Brij-35) supplemented with 7.5% DMSO in a black 384-well NUNC plate at 30 °C Prepare 3× desired final concentration) pre-incubated with an equal volume of autoBACE-2 enzyme diluted in 1×BACE assay buffer (final enzyme concentration 1 nM) for 30 minutes by adding an equal volume at 7.5% supplement QSY7-EISEV NL DAEFC-Eu-melamine receptor prepared in DMSO 1×BACE assay buffer and incubated at 30 °C for 90 minutes (200 nM final concentration, for autoBACE-2, K _m = 8 μM or 4 μM) to start the analysis. The DMSO line was present at a final concentration of 5% in the analysis. After excitation of the sample with 320 nm laser, the 620 nm fluorescence signal was collected on a RUBYstar HTRF plate reader (BMG Labtechnologies) for 400 ms after a delay of 50 μs. Raw RFU data were corrected to maximum (1.0 nM BACE/DMSO) and minimum (no enzyme/DMSO) RFU values. % By nonlinear regression analysis of the inhibition data (S-shaped dose response, variable slope) determining the IC ₅₀ values, where the minimum and maximum values are set to 0% and 100%. A similar IC _{50 is} obtained when using raw RFU data. Using the Cheng-Prusoff equation, K _i from the IC ₅₀ values calculated. Examples 1 to 3, 5 to 7, 9 to 9o, 10, 11, 23, and 27a have BACE2 K _i values of less than 200 nM. Table A Compound of 2-2,2A-5,3-3,4-1 having between about 0.5 μM BACE2 K _i value of between and 10 μM.

Unless otherwise indicated below, above or BACE1 inhibitory data are recorded in the table and examples of a compound having BACE2 K _i values within <0.2 nM to 9.0 μM range.

The examples in Table 2-1 have BACE2 K _i values 10 nM with the following exceptions: Example 9i (49 nM), 9p (16 nM).

The example in Table 2A-1 has a BACE2 K _i value 10 nM with the following exceptions: Example 9n (12 nM).

The examples in Table 2A-2 have BACE2 K _i values 10 nM with the following exceptions: Example 9v (13 nM), 9y (11 nM), 9z (59 nM), 9ac (13 nM), 9ad (41 nM), 9ae (69 nM).

The examples in Table 2B-1 have BACE2 K _i values between 50 nM and 4.0 μM with the following exceptions: Examples 9ai (18 nM), 9ak (13 nM), 9al (44 nM), 9ap (4) nM), 9at (14 nM), 9aw (47 nM), 9ax (22 nM).

The examples in Table 2B-2 have BACE2 K _i values between 50 nM and 5.0 μM with the following exceptions: Examples 9ba (1 nM), 9bd (40 nM), 9bf (11 nM), 9bg (3) nM), 9bh (4 nM), 9bi (9 nM), 9bk (12 nM), 9bl (40 nM), 9bo (22 nM), 9bu (5 nM).

The examples in Table 2E-1 have the following BACE2 K _i values: Example 9by (2.9 μM), 9bz (13 nM), 9ca (9 nM).

The example in Table 2F-1 has a BACE2 K _i value 20 nM with the following exceptions: Examples 9cf (40 nM), 9cg (85 nM), 9ci (44), 9cj (21 nM). In addition, both instances 9cc and 9ck have BACE2 K _i values 10 nM.

Table of examples 2G-1 have BACE2 K _i value in the range of 0.3 nM to 700 nM of. Further, examples of Table 2G-1 have BACE2 K _i value 10 nM with the following exceptions: (i) The following examples have BACE2 K _i values from 11 nM to 100 nM: Examples 9cm-b, 9cn-b, 9cq-b, 9cu-a, 9cv-b, 9cw-b, 9cy-a, 9cz-a, 9da-b, 9db-b, 9dc-a, 9df-b, 9dk-b, 9dl-b, 9dm-b, 9dp-b, 9dq-b, 9dv-b, 9dw- b, 9ea-b, 9ec-a, 9ee-b; (ii) BACE2 K _i values from 101 nM to 700 nM: Examples 9cx-b, 9cy-b, 9cz-b, 9dd-b, 9de-b , 9dg-b, 9dr-b, 9dx-b, 9dy-b, 9dz-b, 9eb-b, 9ec-b.

In Table 2H-1, Example 9ef has a BACE2 K _i value of 218 nM.

In Table 3-1, each example has the following BACE2 K _i values: Example 10 (176 nM), 11 (13 nM), 16a (445 nM).

The examples in Table 3A-1 have BACE2 K _i values in the range of 1.0 μM to 8.0 μM.

The examples in Table 4-1 have BACE2 K _i values 50 nM. In particular, Example 20 having BACE2 K _i value of 8 nM.

The examples in Table 4A-1 have BACE2 K _i values in the range of 100 nM to 1.0 μM with the following exceptions: Example 22g (51 nM), 22u (77 nM), 22f (1.8 μm).

The examples in Table 6-1 have BACE2 K _i values 50 nM with the following exceptions: Example 24 (314 nM). In addition, Examples 25 and 27 have BACE2 K _i values. 10 nM.

The examples in Table 6A-1 have BACE2 K _i values in the range of 3 nM to 1.2 μM. In addition, the following example has a BACE2 K _i value 10 nM: Examples 27e, 27l, 27s, 27u and 27v.

The example in Table 6B-1 has a BACE2 K _i value 20 nM with the following exceptions: Example 27ae (21 nM).

The examples in Table 6C-1 have BACE2 K _i values in the range of 15 nM to 160 nM.

The example in Table 6D-1 has a BACE2 K _i value 100 nM. In addition, examples 27an, 27ao, 27aq, 27as, and 27at have BACE2 K _i values. 20 nM.

The example in Table 6E-1 has a BACE2 K _i value 100 nM. In addition, examples 27bb, 27bc, 27bf, 27bg, and 27bh have BACE2 K _i values 20 nM.

The examples in Table 6F-1 have BACE2 K _i values in the range of 30 nM to 2.0 μM with the following exceptions: Example 27bj-a (7 nM), 27bk-a (9 nM), 27bl-a (9) nM), 27bm-a (7 nM), 27br-a (10 nM), 27bs-a (9 nM).

The examples in Table 6F-2 have BACE2 K _i values in the range of 1 nM to 240 nM. In addition, the following example has a BACE2 K _i value 10 nM: Examples 27bv and 27bx.

The examples in Table 6G-1 have BACE2 K _i values in the range of 9 nM to 320 nM.

The examples in Table 6H-1 have BACE2 K _i values in the range of 4 nM to 120 nM.

The examples in Table 6I-1 have BACE2 Ki values in the range of 100 nM to 500 nM.

In Table 7-1, each example has the following BACE2 K _i values: Example 30 (862 nM), 30a (517 nM).

In Table 7A-1, Example 30b has a BACE2 K _i value of 5 nM.

Examples 8-1 in the table having value BACE2 K _i of 5 μM.

The examples in Table 9-1 have BACE2 Ki values in the range of 400 nM to 2.5 μM with the following exceptions: Examples 32-a, 32-b, 32e-b, and a mixture of 32b-a and 32b-b Inhibition in the range of 1% to 24% of BACE2 was shown at 10 μM.

The examples in Table 9-2 have BACE2 Ki values in the range of 100 nM to 4.5 μM. In particular, examples and 32g-a 32h-a BACE2 K _i values each having 145 nM and 126 nM of.

Table 11A-1 Example of having BACE2 K _i value in the range of 200 nM to 750 nM of.

The examples in Table 11A-2 have BACE2 K _i values in the range of 800 nM to 7.5 μM with the following exceptions: Example 34d-b shows 10% inhibition of BACE2 at 10 μM.

In Table 12A-1, each example has the following BACE2 K _i values: Example 35 (779 nM), 35a (1.4 μM).

In Table 13-1, Example 36 has a BACE2 K _i value of 1.2 μM.

In Table A, compounds that provide BACE1 inhibition have BACE2 K _i values in the range of 100 nM to 9 μM with the following exceptions: entries 30, 40, 61, 69, 77, and 88 show BACE2 at 10 μM Inhibition in the range of 29% to 47%.

Use HEK293-APP ^Swe/lon Cell assay for BACE inhibitor intact cell IC ₅₀

The HEK293 cell line was obtained from the American Type Culture Collection (ATCC) and stabilized by human amyloid precursor protein cDNA containing FAD Swedish (promoting β-secretase processing) and London (promoting Aβ42 cleavage) mutations. Transfection. The HEK293 stable pure line (HEK293-APP ^swe/lon ) with Aβ expression was identified and maintained at 37 ° C, 5% CO ₂ and in ATCC recommended growth medium supplemented with hygromycin. Assay HEK293-APP ^{swe / lon} cells inhibiting APP processing (reduced Aβ1-40, sAPPβ concentration and [beta] 1-42) IC ₅₀ value of the compound is diluted by lines 37 ℃, 5% CO ₂ at various concentrations of the in fresh Compounds in complete growth medium were treated with cells for 4 hours to achieve. Mesoscale-based ELISA analysis was used to measure Aβ40 or Aβ42 in 15 μl of medium. Full-length Aβ40 and Aβ42 peptides were captured by N-terminal specific biotinylated WO2 monoclonal antibody, and ruthenylated Aβ40 C-terminal specific monoclonal antibody G2-10 or 钌-labeled Aβ42 C-terminal specific monoclonal antibody G2 was used, respectively. -11 to detect. Raw electrochemiluminescence values were measured using a Mesoscale Sector Imager plate reader and plotted against compound concentration. The nonlinear regression analysis using the data (S-shape of the dose-response with variable slope fit) using the GraphPad Prism software interpolation IC ₅₀ values from the data.

Claims (16)

A compound, or a stereoisomer of the compound, or a pharmaceutically acceptable salt of the compound or the stereoisomer, which has the structural formula (I): Or a tautomer thereof having the formula (I'): Or a pharmaceutically acceptable salt thereof, wherein: W is selected from the group consisting of S, S(O) and S(O) ₂ ; and R ^1A and R ^1B are each independently selected from the group consisting of H, halogen, Alkyl, alkoxy, haloalkyl, heteroalkyl, alkenyl, alkynyl, aryl, -alkyl-aryl, monocyclic heteroaryl, -alkyl-(monocyclic heteroaryl), monocyclic Cycloalkyl, -alkyl-(monocyclic cycloalkyl), monocyclic heterocycloalkyl, -alkyl-(monocyclic heterocycloalkyl), polycyclic group, and -alkyl-(polycyclic group) Wherein the alkyl group, alkoxy group, haloalkyl group, heteroalkyl group, alkenyl group, alkynyl group, aryl group, -alkyl-aryl group, monocyclic heteroaryl group, -alkyl group of R ^1A and R ^1B (monocyclic heteroaryl), monocyclic cycloalkyl, -alkyl-(monocyclic cycloalkyl), monocyclic heterocycloalkyl, -alkyl-(monocyclic heterocycloalkyl), polycyclic group And -alkyl-(polycyclic groups) are each optionally unsubstituted or substituted with one or more groups independently selected from R ⁸ ; ring A is selected from aryl, monocyclic heteroaryl a monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocycloalkyl, monocyclic heterocycloalkenyl, and polycyclic group; ring B (when present) is independently Consisting of aryl, monocyclic heteroaryl, monocyclic cycloalkyl, a monocyclic cycloalkenyl group, a monocyclic heterocyclic group, alkenyl group and monocyclic heterocyclic group consisting of a polycyclic group; -L ₁ - (when When present, independently represents a bond or a divalent moiety group selected from the group consisting of: -alkyl-, -haloalkyl-, -heteroalkyl-, -alkenyl-, -alkynyl-, -N ( R ⁶ )-, -NHC(O)-, -C(O)NH-, -CH ₂ NHC(O)-, -CH ₂ C(O)NH-, -NHS(O) ₂ -, -CH _{2 NHS (O) 2 -, -} CH 2 SO 2 NH -, - S (O) 2 NH -, - O-CH 2 -, - CH 2 -O -, - NHCH 2 -, - CH 2 NH- and - CH(CF ₃ )NH-, -NHCH(CF ₃ )-; m, n and p are each independently selected integers, wherein: m is 0 or greater; n is 0 or 1; and p is 0 or greater Wherein the maximum value of m is the maximum number of hydrogen atoms that can be substituted on ring A, and wherein the maximum value of p is the maximum number of hydrogen atoms that can be substituted on ring B; each R ² (when present) is independently Select from the following group: halogen, -OH, -CN, -SF ₅ , -OSF ₅ , -NO ₂ , -Si(R ⁵ ) ₃ , -P(O)(OR ⁵ ) ₂ , -P(O (OR ⁵ )(R ⁵ ), -N(R ⁶ ) ₂ , -NR ⁷ C(O)R ⁶ , -NR ⁷ S(O) ₂ R ⁶ , -NR ⁷ S(O) ₂ N(R ⁶ ) ₂ , -NR ⁷ C(O N(R ⁶ ) ₂ , -NR ⁷ C(O)OR ⁶ , -C(O)R ⁶ , -C(O) ₂ R ⁶ , -C(O)N(R ⁶ ) ₂ , -S( O) R ⁶ , -S(O) ₂ R ⁶ , -S(O) ₂ N(R ⁶ ) ₂ , -OR ⁶ , -SR ⁶ , alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl , cycloalkyl, -alkyl-cycloalkyl, aryl, -alkyl-aryl, heteroaryl, -alkyl-heteroaryl, heterocycloalkyl and -alkyl-heterocycloalkyl, wherein the alkyl group of R ^2, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, - alkyl - cycloalkyl, aryl, - alkyl - aryl group, a heteroaryl group, - alkyl - Heteroaryl, heterocycloalkyl and -alkyl-heterocycloalkyl are each unsubstituted or substituted with one or more groups independently selected from R ⁸ ; each R ³ (when present) is independently selected from the group consisting of: _{halo, -OH, -CN, -SF 5,} -OSF 5, -NO 2, -Si (R 5) 3, -P (O) (OR 5) 2, -P (O)(OR ⁵ )(R ⁵ ), -N(R ⁶ ) ₂ , -NR ⁷ C(O)R ⁶ , -NR ⁷ S(O) ₂ R ⁶ , -NR ⁷ S(O) ₂ N (R ⁶ ) ₂ , -NR ⁷ C(O)N(R ⁶ ) ₂ , -NR ⁷ C(O)OR ⁶ , -C(O)R ⁶ , -C(O) ₂ R ⁶ , -C( _{^{O) N (R 6) 2}} , -S (O) R 6, -S (O) 2 R 6, -S (O) 2 N (R 6) 2, -OR 6, -SR 6, , haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, -alkyl-cycloalkyl, aryl, -alkyl-aryl, heteroaryl, -alkyl-heteroaryl, hetero cycloalkyl, and - alkyl - heterocycloalkyl, wherein the R ³ alkyl group, the haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, - alkyl - cycloalkyl, aryl, - Alkyl-aryl, heteroaryl, -alkyl-heteroaryl and heterocycloalkyl are each unsubstituted or substituted by one or more groups independently selected from R ⁸ ; R ⁴ is selected from Groups of the following: alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, aryl, -alkyl-aryl, heteroaryl, -alkyl-heteroaryl, cycloalkyl, -alkyl a cycloalkyl, cycloalkenyl, -alkyl-cycloalkenyl, heterocycloalkyl, -alkyl-heterocycloalkyl, heterocycloalkenyl and -alkyl-heterocycloalkenyl group, wherein R ⁴ Alkyl, haloalkyl, heteroalkyl, aryl, -alkyl-aryl, heteroaryl, -alkyl-heteroaryl, cycloalkyl, -alkyl-cycloalkyl, cycloalkenyl, -alkane Each of the cyclo-cycloalkenyl, heterocycloalkyl, -alkyl-heterocycloalkyl, heterocycloalkenyl and -alkyl-heterocycloalkenyl groups is unsubstituted or The one or more independently selected R ¹¹ groups; each R ⁵ (when present) is independently selected from the system consisting of the group consisting of: alkyl, heteroalkyl, haloalkyl, cycloalkyl, - alkyl - a cycloalkyl, aryl, -alkyl-aryl, heteroaryl and -alkyl-heteroaryl group, wherein each of said R ⁵ , -alkyl-aryl, heteroaryl and -alkyl a heteroaryl group which is unsubstituted or substituted by one or more groups independently selected from the group consisting of halogen, alkyl, cycloalkyl, heteroalkyl, haloalkyl, alkoxy, heteroalkoxy and haloalkoxy Each R ⁶ (when present) is independently selected from the group consisting of H, alkyl, -alkyl-OH, alkenyl, alkynyl, heteroalkyl, -heteroalkyl-OH, haloalkyl , -haloalkyl-OH, cycloalkyl, lower alkyl substituted cycloalkyl, lower alkyl substituted -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl , an aryl group, - alkyl - aryl group, a heteroaryl group and - alkyl - heteroaryl, wherein R ⁶ of each of the heterocycloalkyl, - alkyl - heterocycloalkyl, aryl, - alkyl - aryl, heteroaryl and the -alkyl-heteroaryl are unsubstituted or independently or one or more independently Substituted with a group selected from the group consisting of halogen, alkyl, cycloalkyl, heteroalkyl, haloalkyl, alkoxy, heteroalkoxy and haloalkoxy; each R ⁷ (when present) is independently selected from the group consisting of a group consisting of H, alkyl, heteroalkyl, haloalkyl, cycloalkyl, -alkyl-cycloalkyl, aryl, -alkyl-aryl, heteroaryl and -alkyl-heteroaryl, wherein each of the R ⁷ aryl group, - alkyl - aryl group, a heteroaryl group and - alkyl - heteroaryl based unsubstituted or substituted with one or more groups independently selected from halogen, alkyl, cycloalkyl, Substituted by a heteroalkyl, haloalkyl, alkoxy, heteroalkoxy and haloalkoxy group; each R ⁸ (when present) is independently selected from the group consisting of halogen, -OH, - CN, -SF _5, -OSF _5, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, - alkyl - cycloalkyl, -O- cycloalkyl, -O- alkyl - ring Alkyl, -O-benzyl, heteroalkyl, -O-heteroalkyl and -alkyl-OH; R ⁹ and R ¹⁰ are each independently selected from the group consisting of H, halogen, -OH, -CN , -P(O)(OR ⁵ ) ₂ , -P(O)(OR ⁵ )(R ⁵ ), -N(R ⁶ ) ₂ , -NR ⁷ C(O)R ⁶ , -NR ⁷ S(O ₂ R ⁶ , -NR ⁷ C(O)N(R ⁶ ) ₂ , -NR ⁷ C(O)OR ⁶ , -C(O)R ⁶ , -C(O) ₂ R ⁶ , -C(O N(R ⁶ ) ₂ , -S(O)R ⁶ , -S(O) ₂ R ⁶ , -S(O) ₂ N(R ⁶ ) ₂ , -OR ⁶ , -SR ⁶ , alkyl, haloalkane a heteroalkyl, alkenyl or alkynyl group, wherein each of the alkyl, haloalkyl, heteroalkyl, alkenyl and alkynyl groups of R ⁹ and R ¹⁰ is unsubstituted or one or more Individually selected R ¹² groups are substituted; each R ¹¹ (when present) is independently selected from the group consisting of: halogen, -OH, -CN, -SF ₅ , -OSF ₅ , -P(O) ( OR ⁵ ) ₂ , -P(O)(OR ⁵ )(R ⁵ ), -N(R ⁶ ) ₂ , -NR ⁷ C(O)R ⁶ , -NR ⁷ S(O) ₂ R ⁶ , -NR ⁷ S(O) ₂ N(R ⁶ ) ₂ , -NR ⁷ C(O)N(R ⁶ ) ₂ , -NR ⁷ C(O)OR ⁶ , -C(O)R ⁶ , -C(O) ₂ R ⁶ , -C(O)N(R ⁶ ) ₂ , -S(O)R ⁶ , -S(O) ₂ R ⁶ , -S(O) ₂ N(R ⁶ ) ₂ , -OR ⁶ , -SR ⁶ , alkyl, haloalkyl, haloalkoxy, heteroalkyl, -alkyl-OH, cycloalkyl, -alkyl-cycloalkyl; each R ¹² (when present) is independently selected from Groups of the following: halogen, -OH, -CN, -SF ₅ , -OSF ₅ , -P(O)(OR ¹³ ) ₂ , -P(O)(OR ¹³ )(R ¹³ ), -N(R ¹⁴ ) ₂ , -NR ¹⁴ C(O)R ¹⁴ , -NR ¹⁴ S(O) ₂ R ¹⁴ , -NR ¹⁴ S(O) ₂ N(R ¹⁴ ) ₂ , -NR ¹⁴ C(O)N(R ^{_{14) 2, -NR 14 C (}} O) OR 14, -C (O) R 14, -C (O) 2 R 14, -C (O) N (R 14) 2, -S (O) R 14 , -S(O) ₂ R ¹⁴ , -S(O) ₂ N(R ¹⁴ ) ₂ , -OR ¹⁴ , -SR ¹⁴ , alkyl, haloalkyl, haloalkoxy, heteroalkyl, -alkyl-OH Each R ¹³ (when present) is independently selected from the group consisting of alkyl, -alkyl-OH, alkenyl, alkynyl, heteroalkyl, -heteroalkyl-OH, haloalkyl, haloalkyl-OH And R ¹⁴ (when present) are independently selected from the group consisting of H, alkyl, -alkyl-OH, alkenyl, alkynyl, heteroalkyl, -heteroalkyl-OH, haloalkyl, - a group consisting of haloalkyl-OH. A compound according to claim 1, or a tautomer thereof, or a stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable compound, the tautomer or the stereoisomer Salt, wherein: W is S(O) ₂ . A compound according to claim 2, or a tautomer thereof, or a stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable compound, the tautomer or the stereoisomer a salt, wherein: R ⁴ is selected from the group consisting of a lower alkyl group and a lower carbon haloalkyl group. A compound according to claim 3, or a tautomer thereof, or a stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable compound, the tautomer or the stereoisomer a salt, wherein: one of R ⁹ and R ¹⁰ is H and the other is selected from the group consisting of H, a lower alkyl group, a lower carbon haloalkyl group, and a lower alkyl ether. A compound according to claim 3, or a tautomer thereof, or a stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable compound, the tautomer or the stereoisomer salt thereof, wherein: R ^1A selected from the group consisting of the group consisting of H and methyl; and the group consisting of R ^1B is selected from the Department of: H, methyl, ethyl, vinyl, propyl, isopropyl, propenyl, butyryl Base, butenyl, cyclopropyl, -CH ₂ -cyclopropyl, cyclobutyl, -CH ₂ -cyclobutyl, -CH ₂ OH, -CH ₂ OCH ₃ , -CH ₂ OCH ₂ CH ₃ , three Fluoromethyl, -CH ₂ F, -CHF ₂ , -CH ₂ CF ₃ , phenyl, benzyl, pyridyl, tetrahydropyranyl and -CH ₂ -tetrahydropyranyl, wherein the phenyl, benzyl Each of the group and the pyridyl group is optionally substituted with one to three groups selected from the group consisting of F, Cl, Br, -OCH ₃ , -CH ₂ F, -CHF ₂ and -CF ₃ . A compound according to claim 5, or a tautomer thereof, or a stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable compound, the tautomer or the stereoisomer a salt, wherein: n is 1; ring A is selected from the group consisting of phenyl, thienyl and pyridyl; m is 0 or 1; each R ² group, when present, is independently selected from the group consisting of Group: halogen, -CN, -SF ₅ , -NHCH ₃ , -N(CH ₃ ) ₂ , -OCH ₃ , -OCH ₂ CH ₃ , -O-cyclopropyl, -S(CH ₃ ), methyl, Ethyl, propyl, cyclopropyl, -CH ₂ -cyclopropyl, -C≡C-CH ₃ , -CF ₃ , -CHF ₂ , -C(O)OH, -C(O)OCH ₃ ,- C(O)OCH ₂ CH ₃ , -OCF ₃ and -OCHF ₂ ; -L ₁ - linkage or selected from -NHC(O)-, -CH ₂ NHC(O)-, -CH ₂ C(O)NH - and -C(O)NH- group of divalent moiety groups; ring B is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl, oxazolyl, pyrrolyl, anthracene Mercapto, oxadiazolyl, cyclopropyl, cyclobutyl, oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, dihydroisoxazolyl, isoquinolinyl, thienyl, 5,6 -dihydro- 4 H -pyrroline, triazolopyridyl, imidazolinyl, imidazothiazolyl, imidazopyridyl, benzotriazolyl and benzoxazolyl; p-based 0 or greater; and each R ³ The group, when present, is independently selected from the group consisting of: halogen, -OH, -CN, -SF ₅ , -NH ₂ , -NH(CH ₃ ), -N(CH ₃ ) ₂ , -OCH ₃ , -OCH ₂ CH ₃ , -O-cyclopropyl, -S(CH ₃ ), methyl, ethyl, propyl, cyclopropyl, -CH ₂ -cyclopropyl, -C≡C-CH ₃ , -CF ₃ , -CHF ₂ , -C(O)OH, -C(O)OCH ₃ , -C(O)OCH ₂ CH ₃ , -OCF ₃ , -OCH ₂ CF ₃ and -OCHF ₂ . A compound according to claim 5, or a tautomer thereof, or a stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable compound, the tautomer or the stereoisomer a salt, wherein: n is 0; ring A is selected from the group consisting of phenyl, pyridyl, pyrazinyl, furyl, thienyl, pyrimidinyl, pyridazinyl, thiazolyl and oxazolyl; m is 0 to 5; and each R ² (when present) is independently selected from the group consisting of: halogen, -OH, -CN, -SF ₅ , -OSF ₅ , -NO ₂ , -N(R ⁶ ) ₂ , ^{-NR 7 C (O) R 6} , -NR 7 S (O) 2 R 6, -NR 7 C (O) N (R 6) 2, -NR 7 C (O) OR 6, -C (O) R ⁶ , -C(O) ₂ R ⁶ , -C(O)N(R ⁶ ) ₂ , -S(O)R ⁶ , -S(O) ₂ R ⁶ , -S(O) ₂ N(R ⁶ ) ₂ , -OR ⁶ , -SR ⁶ , lower alkyl, -(lower alkyl)-OH, lower carbon haloalkyl, lower carbon heteroalkyl, lower alkenyl, low carbon Alkynyl, phenyl, benzyl, lower cycloalkyl, -CH ₂ - (lower cycloalkyl), monocyclic heteroaryl and -CH ₂ -(monocyclic heteroaryl), wherein R ^a phenyl group, a benzyl group, a lower carbon cycloalkyl group, a -CH ₂ - (lower carbon cycloalkyl group), Monocyclic heteroaryl and -CH ₂ -(monocyclic heteroaryl) are unsubstituted or one or more independently selected from halo, alkyl, heteroalkyl, haloalkyl, alkoxy, -O- Substituents of the group consisting of cyclopropyl, heteroalkoxy, haloalkoxy, -CN, -SF ₅ and -OSF _{5 are} substituted. A compound according to claim 5, or a tautomer thereof, or a stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable compound, the tautomer or the stereoisomer a salt, wherein: n is 0; ring A is selected from the group consisting of phenyl, thienyl and pyridyl; m is 0 to 4; and each R ² group, when present, is independently selected from the group consisting of Groups: halogen, -CN, -SF ₅ , -NHCH ₃ , -N(CH ₃ ) ₂ , -OCH ₃ , -OCH ₂ CH ₃ , -O-cyclopropyl, -S(CH ₃ ), methyl , ethyl, propyl, cyclopropyl, -CH ₂ -cyclopropyl, -C≡C-CH ₃ , -CF ₃ , -CHF ₂ , -C(O)OH, -C(O)OCH ₃ , -C(O)OCH ₂ CH ₃ , -OCF ₃ , -OCHF ₂ and -NHC(O)R ⁶ , wherein R ⁶ is selected from -CH ₂ CF ₃ , -CF ₂ CH ₃ , -CH ₃ , -CH _a group consisting of ₂ CH ₃ , -CH ₂ OCH ₃ , CHF ₂ and -CH ₂ N(CH ₃ ) ₂ . A compound according to any one of claims 1 to 5, or a tautomer thereof, or a stereoisomer of the compound or the tautomer, or the compound, the tautomer or the stereoisomer a pharmaceutically acceptable salt, wherein: each R ⁶ (when present) is independently selected from the group consisting of H, lower alkyl, lower haloalkyl and lower alkyl, and R ⁷ (when present) is selected from the group consisting of H, lower alkyl. A compound according to claim 1, or a tautomer thereof, or a stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable compound, the tautomer or the stereoisomer Salt, where: A compound according to claim 1, or a tautomer thereof, or a stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable compound, the tautomer or the stereoisomer a salt, the compound being selected from the group consisting of: A compound according to claim 1, or a tautomer thereof, or a stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable compound, the tautomer or the stereoisomer a salt, the compound being selected from the group consisting of: A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 12, or a tautomer thereof, or the compound or the tautomer A stereoisomer of the isomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. The pharmaceutical composition of claim 13, wherein the at least one other therapeutic agent is at least one agent selected from the group consisting of: an m ₁ agonist; an m ₂ antagonist; a cholinesterase inhibitor; galantamine; Rivastigmine; N-methyl-D-aspartate receptor antagonist; combination of cholinesterase inhibitor and N-methyl-D-aspartate receptor antagonist Γ-secretase modulator; γ-secretase inhibitor; non-steroidal anti-inflammatory agent; anti-inflammatory agent that can reduce neuroinflammation; anti-amyloid antibody; vitamin E; nicotinic acetylcholine receptor agonist; CB1 Inverse agonist; CB1 receptor antagonist; antibiotic; growth hormone secretagogue; histamine H3 antagonist; AMPA agonist; PDE4 inhibitor; GABA _A inverse agonist; inhibitor of starch-like aggregation; glycogen synthase Kinase beta inhibitor; promoter of alpha secretase activity; PDE-10 inhibitor; tau kinase inhibitor; tau aggregation inhibitor; RAGE inhibitor; anti-Aβ vaccine; APP ligand; up-regulated insulin; cholesterol lowering agent; Cholesterol absorption inhibitor; HMG-CoA reductase inhibitor and cholesterol absorption inhibitor Combination; fibrates; combination of fibrates with cholesterol lowering agents and/or cholesterol absorption inhibitors; nicotinic receptor agonists; nicotinic acid; nicotinic acid and cholesterol absorption inhibitors and/or Combination of cholesterol lowering agents; LXR agonist; LRP mimetic; H3 receptor antagonist; histone deacetylase inhibitor; hsp90 inhibitor; 5-HT4 agonist; 5-HT6 receptor antagonist; mGluR1 receptor Modulators or antagonists; mGluR5 receptor modulators or antagonists; mGluR2/3 antagonists; prostaglandin EP2 receptor antagonists; PAI-1 inhibitors; agents that induce Aβ efflux; metalloprotein attenuating compounds; GPR3 regulation Agent; and antihistamine. Use of a compound of claim 1 or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment, prevention, or/or delay of the onset of a disease or condition The disease or condition is selected from the group consisting of Alzheimer's disease, Down's syndrome, Parkinson's disease, memory loss, and Alzheimer's disease. Memory loss, memory loss associated with Parkinson's disease, attention deficit symptoms, attention deficit symptoms associated with Alzheimer's disease, Parkinson's disease and/or Down's syndrome, dementia, stroke, microglia Microgliosis and brain inflammation, senile dementia, senile dementia, dementia associated with Alzheimer's disease, Parkinson's disease and/or Down's syndrome, progressive supranuclear palsy, cortical basal ganglia degeneration , neurodegenerative, olfactory disorders, olfactory disorders associated with Alzheimer's disease, Parkinson's disease and/or Down's syndrome, beta-type amylovascular disease, brain amylovascular disease, hereditary cerebral hemorrhage, mild recognize Amyloid disorder ( "MCI"), glaucoma, amyloid degeneration, type II diabetes, the diabetes-related generation, complications of hemodialysis (and complications from arising therefrom in hemodialysis patients of β ₂ microglobulin ), scrapie, bovine spongiform encephalitis, traumatic brain injury ("TBI"), Creutzfeld-Jakob disease, and traumatic brain injury. The use of claim 15, wherein the A[beta] condition is Alzheimer's disease.