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Title:
TRIAZOLOPYRIDINES AND TRIAZOLOPYRIMIDINES THAT LOWER STRESS-INDUCED P-TAU
Document Type and Number:
WIPO Patent Application WO/2017/035528
Kind Code:
A1
Abstract:
Pharmaceutical compounds, compositions, methods, and uses therefor are presented using selected triazolopyridines and triazolopyrimidines to inhibit or reduce phosphorylation of tau proteins or that act as antagonists of corticotropin-releasing factor. Viewed from another perspective, compounds, compositions, and methods are presented for treating or preventing symptoms of Alzheimer's disease by inhibiting or reducing the phosphorylation of tau proteins.

Inventors:
JOHN VARGHESE (US)
BUZKO OLEKSANDR (US)
BREDESEN DALE (US)
SPILMAN PATRICIA (US)
JAGODZINSKA BARBARA (US)
Application Number:
PCT/US2016/049270
Publication Date:
March 02, 2017
Filing Date:
August 29, 2016
Export Citation:
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Assignee:
NANTNEURO LLC (US)
International Classes:
C07D487/04; A61K31/519; A61K45/06
Domestic Patent References:
WO1997035539A21997-10-02
WO2014202541A12014-12-24
Foreign References:
EP0778277A11997-06-11
Other References:
YE, Y. ET AL.: "3D-QSAR study of corticotropin-releasing factor 1 antagonists and pharmacophore-based drug design", NEUROCHEMISTRY INTERNATIONAL, vol. 56, no. 1, 1 January 2010 (2010-01-01), pages 107 - 117, XP026906722
GANNON, R. L. ET AL.: "The corticotropin-releasing factor (CRF)1 receptor antagonists CP154,526 and DMP695 inhibit light-induced phase advances of hamster circadian activity rhythms", BRAIN RESEARCH, vol. 1083, no. 1, 1 April 2006 (2006-04-01), pages 96 - 102, XP055365424
Attorney, Agent or Firm:
FESSENMAIER, Martin et al. (US)
Download PDF:
Claims:
CLAIM'S

Wliai is claimed mi

1. A compound having a structure according to Formula I

wherein:

X is N or CH;

Ri and R3 are independently aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkyi, substituted alkyL cycloalkyl, substituted cycioalkyl, heteroeyeloalkyl, substituted heteroeycloalkyl, heteroalkyl, substituted heteroalkyl, alkoxy, or substitiiied alkoxy; and

2 is hydrogen, deuterium, C¾, CF3, CHF2, or C¾F.

2. The compound of claim 1, wherein X is N.

3. The compound of claim 1. wherein Ri is , where , R5, and Re are independently selecied from the group consisting of hydrogen, deuterium, OH. halogen, methyl, CF3, CHF2, CH2F, or alkoxy.

4. The compoimd of claim 1. wherein ¾ is

1¼ Rs, and R¾ are independently selecte from the g oi^ consistin of hydrogen, deuterium, OH, halogen, methyl CF3j CHF2, CH2F, or alfcoxv.

5. The compound of claim 1. wherein Rj is . Tlie compound of claim 1, wherein ;< is

compound of claim 1. wherein R2 is I or hydrogen.

8. The compound of claim 1. wherein R2 is hydrogen.

9. The compound of claim 8, wherein ¾ is

10. The compound of claim §., wherein ¾ is

11. The compoimd of claim 8, wherem ¾ is

12. The compoimd of claim 8, wherem ¾ is

13. The ccm¾>oiiad according' to my one of cla ims 8-12, wherem R3 is

14. The compound accor in to any one of claims 8-12, ¾½*rein¾ i

15. The compound .acc.ordi.ag to any one of claims 8-12, wherein R3

16. The ccmipoiind accord ng to any one of claims 8- 12, wherem R3 is

17. The ccs33¾ ound of claim l , whei:ein R.?is CH3. 8. The ccmipoiind of claim 17. wherein Ri. is

19. The coaopoBfid of claim 17, wherein ¾ is 20. The■compound/of claim 17, wherein ¾ is

The cesnpoimd of elaiin 17. wherein "¾ is

The compound .according to -any one of claim s 17-21, wherein R3 is

23. The compound according to any one of claims 17-21, wherein ¾ is

24. The compound according to any one of claims 17-21 , wherein J¾ is

25. The compound accca dmg to any one of claims 17-21, wherein ¾ is

26. The eorapoiBid of claim 1, wherein the eorapeamd has a fonmila selected from the group consisting of Formula i-XIII:

27. A pharmaceutical composition, comprising a phamaeeutic ally acceptable carrier in combination with a compound according to any one of claims I -26, wherein tiie compound is optionally present as a pharmaceutically acceptable salt, a hydrate, a. solvate, or in crystalline form.

28. The pharmaceutical composition of claim 27. wlierein the compound is present in an amount effective to reduce eoriicotrophin-releasing factor (CRF-I) induced tau protein phosphorylation (p-tau) .

29. The pharmaceutical composition of claim 27, wherein the composition is fomiuiated for oral administration or injection.

30. The pharmaceutical composition of claim 27, further comprising a second pharmaceutical agent suitable for treatment of a neurological condition.

31. The pharmaceutical composition of claim 30, wherein the second pharmaceutical agent is selected from the group consisting of disuliiram, honokiol, nimeiazepam, a tropiiiol-ester, a TrkA kinase inhibitor, a hydantom, a D2 receptor agonist an alphal-adrenergic receptor antagonist, an APP-speeific BACE inhibitor, galangin, a galangin prodrug, rutin, a rutin prodrug, an acetylcholinesterase inhibitor, (-)phenserine, tacrine, ipidaeriiie, galantamme, donepezil, icopezil, zanapezil. rivastigmme, huperzine A, phenserine, physostigmine, neostigmine, pyridostigmine, ambenonium, demarcarium, edrophonium, iadostigii, ungeremine, a NMDA receptor antagonist, memantine, a muscarinic receptor agonist. talsaclidine, AF-1G2B, AF-267B (NGX-267), a nicotinic receptor agonist, isprcsnieline (AZD- 3480), a beta secretase inhibitor, a tbiazoiidiiiedkaie. rosiglitazone, pioglitazone, a gainraa- secreiase inhibitor, semagacestat (LY-450139), MK-Q752, E-2012, BMS-708163, PF- 3084014, begacesiat (GSI- 53), NK5-15, an inhibitor of Αβ aggregation, clioquinol (ΡΒΊΤ), PBT2, trarniprcssate (boBiotaiifise), scylla-inosliol. bapmeuzeiiiab, epigailoesiechm-3-g¾IIa†e, all ami-mflaminaiory agent a cyekxxxygenase II iiihibitor, an anii-oxidani vitamin E, or a gjnkolide.

32. Use of a compound according to any one of claims 1-26 in fire mami&etore of a pharmaceutical composition.

33. Use of a compound according to any one of claims 1-26 to reduce CKF-l¾ctivity.

34. Use of a compound according to any one of claims' 1-26 to prevent o delay onset of a pre-Alzheimer s condition or cognitive dysfunction.

35. Use of a compound according to any one of claims 1-26 to treat a Symptom of

Alzheimer's disease.

36. A memod for treating and or preventing a symptom of Alzheimer's disease, which comprises a step of administermg to a subject in need thereof an effective amount of a compound of any one of claims 1-26 or a pharmaceutical composition of claims 27-29.

37. A method of decreasing, inhibiting, or preventing an increase in p-tau in a mammal, which comprises adrninis ering to the mammal an effective amount of one or more

compounds of any one of claims 1-26 or a pharmaceutical composition of claims 27-29.

AMENDED CLAIMS

received by the International Bureau on 10 February 2017 (10-02-2017)

1. A compound having a stmcture according to Formula I

(I)

wherein:

is or CH

R2 is hydrogen, deuterium, C¾, CF3, CHF2, or CH2F.

2. The compound of claim 1, wherein X is N.

3. (currently amended) The compound of claim 1, wherein R4, R5> and ¾ are independently selected from the group consisting of hydrogen, methyl, or alkoxy.

4. (currently amended) The compound of claim 1, wherein R4, R5, and Rg are independently selected from the group consisting of hydrogen, OH, halogen, methyl, or alkoxy.

The compound of claim 1, wherein The compound of claim 1, wherein R3 is

7. The compound of claim 1„ wherein R2 is CH3 or hydrogen.

8. The compound of claim 1, wherein R2 is hydrogen.

9. The compound of claim 8, wherein i is

10 The compound of claim 8, wherein Ri is

11. The compound of claim 8, wherein Ri is

12. The compound of claim 8, wherein Ri is

13. The compound according to any one of clai ms 8-12, wherein R3 is 14. The compound according to any one of claims 8-12, wherein R3

15. The compound according to any one of claims 8-12, wherein R3

16. The compound according to any one of claims 8-12, wherein R3 is

17. The compound of claim I, wherein R2 is C¾.

18. The compound of claim 17, wherein

19. The compound of claim 17, wherein

20. The compound of claim 17, wherein i is

21. The compound of claim 17, wherein Ri 13

22. The compound according to any one of claim s 17-21, wherein R3 is

23, The compound according to any one of claims 17-21, wherein R3 is

24. The compound according to any one of claims 17-21, wherein R3 is

25. The compound according to any one of claims 17-21, wherein 3 is

52

27. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier in combination with a compound according to any one of claims 1-26, wherein the compound is optionally present as a pharmaceutically acceptable salt, a hydrate, a solvate, or in crystalline form.

28. The pharmaceutical composition of claim 27, wherein the compound is present in an amount effective to reduce corticotrophin-releasing factor (CRF-1) induced tau protein phosphorylation (p-tau).

29. The pharmaceutical composition of claim 27, wherein the composition is formulated for oral administration or injection.

30. The pharmaceutical composition of claim 27, further comprising a second pharmaceutical agent suitable for treatment of a neurological condition.

31. The pharmaceutical composition of claim 30, wherein the second pharmaceutical agent is selected from the group consisting of disulfuam, honoMol, nimetazepam. a tropinol-ester, a TrkA kinase inhibitor, a hydantoin, a D2 receptor agonist, an alphal-adrenergic receptor antagonist, an APP-specific BACE inhibitor, galangin, a galangin prodrug, rutm, a rutin prodrug, an acetylcholinesterase inhibitor, (-)phenserine, tacrine, ipidacrine, galantarnme, donepezil, icopezil, zanapezil, rivastigmine, huper2me A, phenserine, physostigmine, neostigmine, pyridostigmine, ambenonium, demarcar um, edrophonium, ladostigil, ungeremine, a NMD A receptor antagonist, memantine, a muscarinic receptor agonist, talsaclidine, AF-102B, AF-267B (NGX-267), a nicotmic receptor agonist, ispronicline (AZD- 3480), a beta secretase inhibitor, a thiazolidinedione, rosiglitazone, pioglitazone, a gamma- secretase inhibitor, semagacestat (LY-450139), MK-0752, E-2012, BMS-708163, PF- 3084014, begacestat (GSI-953), NIC5-15, an inhibitor of Αβ aggregation, clioquinol (PBTI), PBT2, tramiprosate (homotaurine), scylla-inositol, bapineuzemab, epigallocatechin-3-gallate, an anti-iriflammatory agent, a cyclooxygetiase II inhibitor, an anti-oxidant, vitamin E, or a ginkolide.

32. Use of a compound according to any one of claims 1-26 in the manufacture of a pharmaceutical composition.

33. Use of a compound according to any one of claims 1-26 to reduce CRF-1 activity.

34 Use of a compound according to any one of claims 1-26 to prevent or delay onset of a pre- Alzheimer's condition or cognitive dysfunction.

35. Use of a compound according to any one of claims 1-26 to treat a symptom of

Alzheimer's disease

36. A method for treating and/or preventing a symptom of Alzheimer's disease, which comprises a step of administering to a subject in need thereof an effective amount of a compound of any one of claims 1-26 or a pharmaceutical composition of claims 27-29,

37. A method of decreasing, inhibiting, or preventing an increase in p-tau in a mammal, which comprises administering to the mammal an effective amount of one or more compounds of any one of claims 1-26 or a pharmaceutical composition of claims 27-29.

Description:
JRIAZOLOPYRIDI ES AN TRiAZOLOPYMMIIMKES THAT LOWER STMESS-

IN JCEB P-TAII

P OI] This application claims the benefit of priority to U.S. provisional application having serial number 62/210947, filed pa 27- ug- 15.

Field of the Invent-oi

|0002] The field of the invention is pharmaceutically active compounds, compositions, and methods therefor, and particularly as it. relates to triazolopyridmes and triazolopyiiinidmes.

Background of the Invention f ΘΘ03] The background descripiion includes information that may be useful in. imderctanding the present invention. It is not an admission that any of the infomiatkai provided herein is prior ait or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior ait.

|0004] All publications or patent applications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorpor ated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.

[0005] Alzheimer's Disease (AD) is estimated to afflict more than 20 million people worldwide and is believed to be the most common cause of dementia. As the World population ages, the number of people with AD, currently approximately 5.4 million in the United States, will continue to rise. Alzheimer's is a neurodegenerative disease associated with progressive dementia and memory loss. Two key characteristics of AD ar e the accumulation of extracellular deposits containing aggregated Αβ peptide and neuronal synaptic loss in specific brain regions. Although AD pathogenesis is complex, compelhng genetic and biochemical evidence suggest that overproduction of Αβ, or failure to clear this peptide is the earliest event in the amyloid cascade that leads to AD primarily through amyloid deposition, which is presumed to be involved in neiirofibrillary tangle formation, neuronal dysfunction and microglia activation, that characterize AD-affected brain tissues. |0006] Neurofibrillary tangles, along with plaques comprised of A peptide, are a pathological hallmark of AD, Hyperphospharylstion of the B3ierotu «]e-sia.bitizin protein tau leads to tangle forma tion . In people diagnosed with. AD the level of tan phosphoiylafion has the closest correlation to cognitive impairment indeed, treatment regimes for AD including tan protein phosphorylation inhibitors are known (see e.g., US 2015/0017148, WO 2013/082045), . ' as .-are ' treatments to reduce tais protein phosphorylation by use of

tnazolopyrimidmes derivatives to .inhibit glycogen synthase kinase (see e.g., US 7560458).

{0007] However, all known trea ments fail to appreciate the benefits of particular

triazolopyrimidine derivatives when used as corticonopin-releasmg factor ("CRF-1") antagonists to reduce or prevent p-tau production. Therefore, there is still a need for new and alternative treatments for AD with via a CRF-1 antagonist pathway.

Summary of The Invention

[0008] The inventive subject matter is directed to pharmaceutical compoimds, compositions, and methods therefor, and particularly to selected triazoiopyridines and triazolopyrimidines that inhibit or reduce phosphorylation of tau protein (phospho-tau or p-tau) or that act as antagonists of corticotropin-releasing factor. Viewed from another perspective, the invents ve subject matter is drawn to compounds, compositions, and methods for treating or preventing symptoms of Alzheimer's disease by inhibiting or reducing the production of p-tau.

|0009] hi one aspect of the inventive subject matter, the inventors contemplate a compound having a structure according to Formula I

Form ula I wherein X is CH, or more preferably N. ¾ and R 3 independently from each other can be ary (substituted or non-substituted), a heteroaryl (substituted or non-substituted), an alkyl (substituted or uon-substituted}, a eycioaikyl (substituted or non-subst-fated). a

heteroeyeloaltiyl (substituted or Bon-substituted), a heteroalkyl (substituted orson- sebs ituted), or an alkoxyCsubstifnied or MOii-s¾bstiteied). It is foiiher coitteiiiplaied that ¾ can be, deiiteriiini, CJ¾, CH-¾ or.Q¾F, and is most preferably hydrogen or C¾.

[0018] Therefore, and viewed Sarni a different perspective, compounds are also eonteiBplated such thai RY an ¾ nidependeBtl ' have a structure selected frorn

where each of ¾, R¾, '.and ' ¾ can be one of -hydrogen, deuterium, OH, a halogen, a methyl, Q¾, CHFj, QEfeF, o m alkoxy. In preferred aspects, the compounds will have a structure such that Ri and R3 independently have a structure selected from

fOOi!] Most preferably, compounds of Hie inventive subject matter will have a structure aeeordiHg to any one of Formulae H-VSI:

[0012] In further contemplated aspects pharmaceutical compositions are contemplated that comprise a pharmaceutically acceptable earner in combination with one or more compound presented herein, wherein the compound may be present as a pharmaceutically acceptable salt, a hydrate, a solvate, or in crystalline form. Most preferably, the compound will be presen in the pharmaceutical composition in an amount effective to inhibit or reduce production of p-taii, or as an antagonist of CRF-1 in a patient when administered (e.g., orally or via injection) to the patient. As will be readily appreeiaied, such formulations have CRF-1 inhibitory activity and will be suitable (alone or in combination with another pharmaceutical agent) for treatment of a neurological condition, and particularly for treatment of Alzheimer's Disease. f0t)13] Therefore, the inventors also contemplate the use of one or more compounds presented herein in the manufacture of a pharmaceutical composition or medicament, especially where the composition is used in the treatment of a neurodegenerative disease, and/or where the composition is for the reduction of CRF-1 activity or p-t.au levels in a patient. Vsewed from another perspective, use of compositions of triazolopyrimidines and triazolopyridines to reduce or preven neurofibrillary tangling are contemplated.

Consequently, CRF-1 inhibitors, triazolopyridines, and triazoiopyrimidines, and uses thereof, are also specifically contemplated herein and particularly include treatment of neurological conditions (e.g., Alzheimer's Disease). The inventors also contemplate methods for treating and or preventing neurological conditions that typically comprise a step of administering to a patient an effec tive amount of one or more compounds presented herein. [0014] Various .objects, features, aspects and advantages of the inventive ..subject . matter will become more apparent from' the following detailed description of preferred em o iments, along with the accompanying drawing figures in which like-numerals represent : like components. Brief ' Description of The Drawing

[0015] Figure 1 illustrates design considerations for JOS analogs.

[0016] Figure 2 is a synthesis scheme for J19.

[0017] Figure 3 is the structure for J03.

[0018] Figure 4 is the structure for J04. [0019] Figure 5 is the structure for J 14.

[0020] Figure 6 is the structure for J 17.

[0021] Figure 7 is the structure for J19.

[0022] Figure 8 is the structure for J30.

[0023] Figure 9 is the structure for J32. [0024] Figures 10A-10I reflect experimental results for studies with J03.

[0025] Figures 1 lA-1 IC reflect experimental results for studies with 103 with respect to taw and p-tau.

[0026] Figures 12A-12B reflect experimental results ' for studies with 103 with, respect to memory. [0027] Figures 13A-13C reflect experimental results for studies with J03 with respect to sAPPa.

[0028] Figures 14A-14C reflect experimental results for studies with J03 with respect to Αβ. [0029] Figure 15 reflects experimental results for studies with J03 with respect to Αβ. [0030] Figure 16 reflects experimental results for studies with J03 with respect to p-tau. P 3i] Figures 17A-17F reflect experimental results for further studies with J03.

[0032] Figures 18A-1 SB reflect experimental results .for. further studies with J03 with respect to pliarmacofciBeties.

[0633] Figure 1 reflects experimental . resiifts for 303 analogs.

[0034] Figures 20A-20B reflect experimental results for 304

[0035] Figures 21A-21E : reflect experimental results for studies with 117.

[0036] Figures 22A-22C reflect further experimental results for studies with 117.

[0037] Figures 23A-23B reflect yet further experimental results for stadies with J 17.

[0038] Figures 24A-24D reflect still further experimental results for stadies with J17.

[0035] Figures 25A-25C reflect additional experimental results for stadies with J17.

[0040] Figures 26A-26C reflect more experimental results for studies with J17.

[0041] Figures 27A-27C reflect still more experimental results for studies with Jl 7.

[0042] Figures 28A-2SB reflect experimental results for studies with J14.

[0043] Figures 29A-29C reflect further experimental results for studies with J 14.

[0044] Figures 30A-3OB reflect yet fiirtlier experimental results for studies with J14.

[0045] Figures 31A-31F reflect stiii fiirtlier experimental results for studies with J14.

[0046] Figures 32A-32H reflect experimental results for studies with J 19.

[0047] Figures 32A-32H reflect experimental results for studies with J 19.

[0048] Figures 33A-33B reflect experimental res iiis for Studies with J30 and J32.

[0049] Figures 33C-33D reflect experimental results for studies with J32. Detailed Description

|065Q] The inventive subject matter is directed towards varioss pharmaceutical compounds, compositions, and methods therefor, and particularly to selected triazolopyridines and triazolopyiimidines that inhibit or reduce phosphoryla lion of tan protein {phospho-tau or p- ta i) or that act as antagonists of cortieotropin-reteashig factor, for exanipleia the treatmen or pr evention of AD symptoms, So prepared compounds, compositions and methods -are deemed to be useful in the manufacture of a medicament and the treatment of

neurodegenerative diseases responsive to such compounds and compositions. While not wishing to he bound by any particular theory or hypothesis, it is contemplated that the compounds will reduce or inhibit phosphorylation of tan proteins via a CRF-1 antagonist pathway, thus reducing or preventing neurofibrillary tangling. Consequently, such

compounds may be particularly beneficial for treatment of ongoing AD, in the delay or pr evention of the onset of AD. in the onset of mild cognitive impairment {"MCI"), in the delay of a transition from MCI to AD, and in the delay or prevention of MCI.

|0051] In especially preferred aspects of the inventive subject matter, several compounds were identified and further evaluated for reduction or prevention of tau protein

phosphorylation.

Contemplated Compounds

|0052] The present inventive subject matter is related to compounds .having general Formula (I) or a pharmaceutically acceptable salt thereof, wherein

Form ula I wherein X is a CH or heteroatom, preferably N. Ri and ¾ are independently an aryl, substituted aryl, heieroar l, substituted heteroaryl, alfcyl, substituted alkyl, cycloalkyl, -substituted cyeloalkyl, heterocycloalfcyi, substituted heteroeyeloalfcyl, aeteroajkyl, substituted heteroalkyl, alkoxy, or substituted alkoxy: and i is CjEfcj.CFj, CHEs, 0¾F- or a heteroatoni, preferably hydrogen or deuterium.

[0053] Another embodiment provides a eompeim of Formula. I or a pliaii¾ace«tieally acceptable salt thereof such that ¾ and I¾ mdependently hsye a structure selected from

where each of ¾ , ¾, aad ¾ can be one of a heteroatom, preferably hydrogen or deiuerium, a halogen, preferably CI, OH, aliyl (optionally substituted), preferably methyl, CFi, CHF2, C¾F S or a heteroalkyi (optionally substituted), preferably an aJkoxy.

10054] Still frBtber embodiments provide compounds of Formula I or a phamiaceiiticaily acceptable salt thereof such that i and ; < independently have a structure selected from

[0055] Yet further embodiments provide compounds according to Formula 1, or a pharmaceutically acceptable salt thereof such that R-> is hydrogen. In some embodiments having compounds of Formula I where R 2 is hydrogen, Ri is one of

and '.preferably

and most preferably

In such embodiments, ¾ can be

and preferably one of |8656] Ye! farther embedments provide corapaaads according to Formula or a pnai"inace¾iically acceptable salt thereof, s11dh.that.R2 -is <¾. in some erebodiiBents having eoiBpoiiiicfe of Formula . Γ where ¾ is C¾, ¾ is

and preferably

and most preferably one of

In such embodiments, R_¾ can be one of

and preferably md most preferably

[0057] In especially preferred embodiments having eompomids of Fornrala I where Ra is CH 3> R. is

[0058] In preferred embodiments, compounds of the inventive subject matter, or pharmaceutically suitable salts thereof, will have a structure according to any one of Formulae II- VIII:



[0059] In the most preferred embodiments, compounds of the inventive subject matter, or pharmaceutically suitable salts thereof, will have a structure according to any one of

Formulae IV or VII.

[0060] While the above structures are shown with specific aryl and heteroaryl groups, numerous suitable alternative aryl or heteroaryl groups include (optionally substituted) aromatic monocyclic or polycyclic groups, typically comprising between 5 and 18 carbon ring members, which may be unsubstituted or substituted by one or more suitable substituents as defined herein, and to which may he fused one or more cyeloalkyl groups,

heterocyeioalkyl groups, or heteroaryl groups, which themselves may be i substituted or substituted by one or more suitable substituents. Thus, the term "aryl group" includes a benzyl group (Bzl). Examples include phenyl, biplienyl, 1 ,2,3,4-teirahydrooaphthyl, naphfhyl, anthryl, and phenantfaryL Suitable heteroaryl groups will typically include aromatic

monocyclic or polycyclic groups comprising generally between 4 and 18 ring members, including 1 -5 heteroa oms selected from nitrogen, oxygen, and sulfur, which ma be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyi groups, heterocyeioalkyl groups, or aryl groups, wlisch themselves ma be unsubstituted or substituted by one or more suitable substituents. Examples include thienyl, furanyl, tliiazolyl, triazolyl. imidazolyL isoxazolyi oxadiazolyl, tetrazoiyl, pyridyL pyrrolyl, thiadiazolyl, oxadiazolyl, oxathiadiazolyl, thiatriazolyl,

pyrimidinyl, isoquinolinyl, quinolinyl, napthyridinyl, phthalimidyl, benzimidazolyl, and benzoxazolyl. [0061] The term "alkyl" Herein alone or as pari of another group refers to a monovalent alkape (hydrocarbon) de iv d radical containing from 1 to 12 carbo atoms unless, otherwise defined. ALfcyi groups -may be substituted at any available point of a tadiiaent. An alkyl group substituted with another alfcyl group is also referred to s a "branched. alky, group".

Exemplary alkyl groups includ methyl ethyl, propyl, isopropyl. -n-butyi, i-hisiyl, isobutyl, peiuyl, lexyl, isohexyl, heptyi, dimethylpeotyi oetyi, 2,2,4-trinieihyipefityl, norryl, deeyl, ndecyl, dodeeyl, and the life. Exemplar siibstit ents include one or more of the following groups: alkyl, aryl, halo (such as F, CI, Br, I), haloalkyl (such as CC¾ or CF 3 }, alkoxy, alkylthio, hydroxy, carboxy (-COOH), alkyloxycarbonyl (-C(O) ). alkylcarbonyloxy (- GCOR), amino (- ¾), carbamoyl (- HCOOR- or -OCG HR-), urea (- HCONHR-) or thiol (-SH). In some preferred embodiments of the present inventive subject matter, alkyl groups are substituted with, for example, amino, heterocycloalkyl. such as niorpholine, piperazine, piperidine, azetidine, hydroxy!, methoxy, or heteroaryl groups such as pyrrolidine, [0062] The term "cycloalkyl" herein alone or as part of another group refers to fully saturated and partially unsaturated hydrocarbon rings of 3 to 9, preferably 3 to 7 carbon atoms. The examples include cyclopropyl, cyclobutyL cyclopentyl and cyclohexyl, and like. Further, a cycloalkyl may be substituted. A substituted cycloalkyl refers to such rings having one, two, or three substifuenfs, selected from the group consistin of halo, alkyl, substituted alkyl, alkenyl, alkynyi, nitro, cyano, oxo (=0), hydroxy,, alkoxy, thioalkyl, -C02H, -C(=0}H, C02- alkyL - C(=Q)alkyl, keto, =N-OH, =N-0-alkyl, aryl heteroaiyl heterocyclo, -NR'R", - C(=0) R'R". -C02 R'R", -C(=0) R'R", - R , C02R". - NR C(=0)R", -SQZNKR", and - NR'S02R" 3 wherein each of R aadR" are independently hydrogen, alkyl, substituted alkyl, or cycloalkyl, or where R and R" together form a heteroeycio or heteroaiyl ring. [0063] The term "alkoxy" alone or as part of another group denotes an alkyl grou as described above bonded through an oxygen linkage (-Q-). Preferred alkoxy groups have from 1 to 8 carbon atoms. Examples of such groups include the methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobiitoxy, sec-butoxy, tert-butoxy, n-pentyioxy, isopentyloxy, n- hexyloxy, cyclohexyloxy, n-hepryloxy. n-octyloxy and 2-ethylhexyIoxy. [0064] The term "aryl", alone or as part of another group, refers to monocyclic or bicyclie aromatic rings, e.g., phenyl, substituted phenyl and the like, as well as aromatic ring systems where rings are fused, e.g., napthyl, phenanthrenyl and the like. An aryl group may thus contain at least one ring haying at least 6 atoms, with up t five such rings being present containin op to 20 atoms therein, with alternating (resonating) double bonds between adjacent carbo atoms or s«iiabie heteroatoma. Aryl groups may ' .optionally be aubstirufed with one or more groups iehiding. halogen, a&yl, such as methyl, ethyl, propyl, alkoxy, such as inethoxy or ethoxy, hydroxy, carboxy. carbamoyl, alkyloxycarboayl. nitxo.

alkenyloxy, trifluoromerhyi amino, eycloalkyl, aryl, heteroaiyi cyaiio, a&yl S(0) ¾ (m=0, 1, 2), or thi ol.

|0065] The term "aromatic" refers to a cyclically '.conjugated molecular entity with a stability, due to delocalization. significantly greater than that of a hypothetical localized structure, such aa the Kekule structure.

[0066] The term '¾eteroatom" refers to any atom other than carbon, for example, N, O, or S.

[0067] The term "heteroaryl" herein refers to an aromatic earhoeyeiic radical in which at least one ring atom is a heteroatom independently aelected tan nitrogen, oxygen, and sulrar, the remaining ring atoms being carbcai. Heteroaiyi groups may be optionally substituted with one or more sitbstititents described herein. In one example, the heteroaiyi group contains 1 to 9 carbon ring atoms (C1-C9). In other examples, the heteroaiyi group is Q-Cs, C3-C5 or <¾- C5. In one embodiment, exemplary heteroaiyi groups include 5-10-inembered rings or 5-6- meinbered rings, or monocyclic aromatic 5-, 6- and 7-membered rings containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur. I another embodiment, exemplary heteroaiyi groups include fused ring systems of up to 10, or in another example 9. carbon atoms wherein at least one aromatic ring contains one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur. "HeteroaryF' includes heteroaryl groups rased with an aryl, eycloalkyl, or other heterocyelyl group. Examples of heteroaryl groups include pyridinyi, imidazolyi, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyi, pyrazinyl, tetrazoiyl. furyl, thienyi, isoxazolyl, thiazolyl, oxazolyl, isotmazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyi, benzimidazolyl, benzofuranyl, cirmolinyl, indazolyl, indolizinyl, phthalazmyL pyridazm l, triazinyl, isoindolyl, pieridinyl, purinyl, oxadiazoiyl. triazolyi, thiadiazoiyl, furazanyi, benzofuiazanyl, benzothiophenyl,

benzothiazolyl, benzoxazolyi, quiiiazolinyl, qitinoxalinyl, naphthyridmy!. pyrroiopyrimidmyl. pyi¾zolopyriinidinyl and fiHopyiidinyi. |ΘΘ68]

to a eyclaaflsyl;. group (non-aromatic) in which one of the carbon atoms in the ring i replaced, by a heteraatom selected from O, S and N. The "heierocyele" may have loia 1 to 3 fused, pendant, or spiro rings, at least one of which is a heterocyclic ring (i.e. , one or more ring atoms is a heteroaf o n, with the remaining ring /atoms feeing carbon). The heterocyclic ring maybe optionally substituted at one or inore suhs ituiable ring positions b one or more g oins independentl selected from .alkyl (preferably lower alkyl), heteroeycIoalkyL heteroaryl, alkoxy (preferably lower alkoxy), nitro, monoalkylaniino (preferably a lower alkylamino), dialkylainino (preferably a aJk lamino), cyano. halo, haloalkyl (preferably trifluoromethyl), alkanoyl, amiiiocaiboiiyl, monoalkylannnocarbonyl, dialkylaminocaibonyl, alkyl arnido (preferably lower alkyl ainido), alkoxyalkyl (preferably a lower alkoxy; lower alkyl), alkoxycarboiryl (preferably a lower alkoxycarbonyl), alkylcarbonyloxy (preferably a lower alkylcarbonyloxy). and a d (preferably phenyl), the aryl being optionally substituted by halo, lower alkyl and lower alkoxy groups. A heterocyclic group may generally be linked via any ring or substituent atom, provided that a stable compound results.

J0069j Typically, a heterocyclic ring comprises 1-4 heteroatoms. Within certain

embodiments, each heterocyclic ring has 1 or 2 heteroatoms per ring. Each heterocyclic ring generally contains from 3 to 8 ring members, and heterocycles comprising fused, pendant or spiro rings typically contain from 9 to 14 ring members comprising carbon atoms and one, two, or tlnee heteroatoms selected from nitrogen, oxygen, and sulfur. Therefore, examples of "heterocycle" or "heterocycloalkyl" groups include piperaz ne, piperidine, morpholine, thiomoipholine, pyrrolidine, imidazolidine, and thiazolide. f 0070] In general, the various moieties or functional groups for variables in the formulae may be substituted by one or more suitable "substiraents". The term "snbstitiient" as used herein, refers to a molecular moiety that is covalently bonded to an atom within a molecule of interest. For example, a "ring substituent" may be a moiety such as a halogen, alkyl gr oup, haloalkyl group or other group discussed herein that is covalently bonded to an atom

(preferably a carbon or nitrogen atom) that is a ring member. Most typically, the substituent will replace a hydrogen.

[00711 The term "optionally substituted" means that a group ma be substituted at one or more substitutable positions with one or more substituent. For example, suitable optional substituents include alkyl (preferably lower alkyl), alkoxy (preferably lower alkoxy), nitro, inonoaI¾la iBo (preferably wil« to six carbons), dialkylarnino (preferably with one to six carbons), eyano, halo, haloalkyl (preferably uiiluoromefhyl), alkanoyi, arn ocarbonyl, moiioallgdMniiiocail m L u^alkylaiimioGarboiwl, .a&yl amido (preferabl lower alkyl

alkoxyear aayi). afiwlearbonyloxy (preferably a lower alk lcarbonyloxy), and aryi

(preferably phenyl), the aryl being optionally substituted by halo, lower alkyl and lower alkoxy groups. 0 >tioni¾I substituiioii is also indicated by the phrase "substituted with from 0 to X substifuents," where X is the maximum number of possible substituents. Certain optionally substituted groups ar e substituted with from 0 to 2, 3 or 4 independently selected substituents.

[0072] All subsiifuents may optionally be fmther substituted with a substituent selected from groups such as hydroxyl groups, halogens, oxo groups, alkyl groups, acyi groups, sulfonyl groups, mercapto groups, alkylthio groups, alkyloxyl groups, cycloalkyl groups,

heferoeyeloalkyl groups, aryl groups, heteroaryl groups, carboxyl groups, amino groups, alky!amino groups, dia!kylamhio groups, carbamoyl groups, aryloxyl groups, heteroaryloxyl groups, arylthio groups, heteroaiylthio groups, and the like. The term "optionally

substituted" is intended to expressl indicate that the specified group is unsubstituted or substituted by one or more suitable substituents, unless the optional substituents are expressly specified, in which case the term indicates that the group is unsubstituted or substituted with the specified substituents. As defined above, various groups may be unsubstituted or substituted (i.e., they are optionally substituted) unless indicated otherwise herein (e.g., by indicating that the specified group is unsubstituted). f ΘΘ73] The term "therapeutically effective amount" refers to the amount of the compound or pharmaceutical composition thai will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician, e.g., reduction of tumor cell growth, induction of apoptosis, reduction of metastasis, etc.

[0074] The terms "adnunistration of a compound" or "administering a eoinpoiffid'' refer to the act of providin a compound according to the inventive subject matter or pharmaceutical composition to the subject in need of treatment. |8075] acceptable" refers to the fact that the carrier, diluent or . exeipient must be compatible with tie otter ingredients of the formulation and not deleterious to the recipient, thereof.

[0076] The term, "pharmaceutically acceptable salt" of a compound recited herei is an acid or base sal that is. suitable for use- in contact with Are -tissues of hiiraan beings or aniraals without excessive toxicity or- -caiciaogeaicit , and preferably without irritation, allergic response, or other problem or eon¾ lication. Such salts include mineral and organic acid salts of basic residues such as amines, as well as alkali or organic salts of acidic residues such as carboxylic acids. Specific pharmaceutical salts include salts of acids such as hydrochloric,, phosphoric, hydrobromic, malic, glycolic, fiimaric, sulfuric, sulfamic, sulfanilic, formic, tohienesulfonic, methaiiesulfonic, benzene sulfonic, ethane disulfonic, 2- hydroxyethylsulfonic, nitric, benzoic, 2-acetoxybenzoic, citric, tartaric, lactic, stearic, salicylic, glutamic, ascorbic, panioic, succinic, fumaric, maleic, propionic, hydroxymaleie, ydroiodic, phenylacetic, alkanoic such as acetic, HOOC- (C¾) n -COOH where n is 0-4, and the like. Similarly, pharmaceutically acceptable cations include sodium, potassium, calcium, aliHisiium, lithium and annnonimn. Tliose of ordinary skill in the ait will recognize further pharmaceutically acceptable salts for the compounds provided herein, hi general, a

pharmaceutically acceptable acid or base salt can be synthesized from a parent, compound that contains a basic or acidic moiety by any conventional cheiiiical method. Briefly, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or hi a mixture of the two; generally, die use of non-aqueous media, such as ether, ethyl acetate, etlianol, isopropano! or aeetonitriie, is preferred. It will be apparent that each compound of Formula I may, but need not, be formulated as a hydrate, solvate or non- covalent complex. In addition, the various crystal forms and polymorphs are within die scope of the present inventive subject matter.

[0077] Also provided herein are prodrugs of the compounds of Formula I. The term

"prodrug" as used herein refers to a modifica tion of contemplated compounds, wherein the modified compound exhibits less pharmacological activity (as compared to the modified compound) and wherein the modified compound is converted within a target cell {e.g., B- cell) or target organ anatomic structure (e.g., joint) back into the modified form. For example, conversion of contemplated compounds into prodrugs may be useful where the active drug is too toxic for safe systemic .acfarmnstratton, or where the contemplated compound is poorly absorbed by the digestive . . tract, .ot ' Oilier compartment or cell or where the body breaks down the contemplated compoun before reaching its target Thus, it should be recognized that the compomids according to the inventive subject matter can be modified in numerous manners, and especially preferred odificatkms include those that improve one or mor

pharmacokinetic and or pharmacodynamic parameter: For example, one or mor suhstifuents maybe added or replaced- to achieve a higher AUG in serum.

J0078J On the other hand, and especially where increased sohsbiliry is desired, hydrophilie groups may be added. Still further, where contemplated. compounds contain one or more bonds that can be hydrolyzed (or otherwise cleaved), reaction products are also expressly contemplated. Exemplary suitable protocols for conversion of contemplated compounds into the correspondin prodrug form can be found in "Prodrugs (Drugs and the Pharmaceutical Sciences: a Series of Textbooks and Monographs)" by Kenneth B. Sloan (ISBN:

0824786297), and Tiydrolysis in Dnig and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology" by Bernard Testa, Joachim M. Mayer ' (ISBN: 39Q639025X), both .of which are incorporated by reference herein. Moreover, especially where contemplated compoiffios have a higher activit when the compound is metabolized (e.g. , hydrolyzed, hydroxylated, glucuronidated, etc.), it should be appreciated that metabolites of contemplated compounds are also expressly contemplated herein. [0079] Therefore, the compound described herein can be the compound of Formula I, a phannaceutieally-aeceptable salt thereof, a hydrate thereof, a solvate thereof, a tautorner thereof, an optical isomer thereof, E-isomer thereof, Z-isomer thereof, or a combination thereof.

[0080] It is contemplated by the inventive subj ect matter that a compound of Formula I can further comprise or be used in combination with other therapeutic agents or approaches used to treat or prevent AD symptoms. Such therapeutic agents or approaches include disulfirani, honokiol, nimetazepam, tropinol-esters, a TrkA kinase inhibitor, hydantoins, a D2 receptor agonist, an alphal-adrenergic receptor antagonist an APP-specific BACE Inhibitor, gaiangin, a gaiangin prodrug, rutin, a rutin prodrug, an acetylcholinesterase inhibitor, (-)pheriserine, enantiomer, tacrine, ipidacrine, galantamine, donepezil, ieopeziL zanapezil, rivastigmine, huperzine A, phenseiine, physostigrnine, neostigmine, pwidostigmine, ambenonium, demarcarhim, edrophonium, ladostigil, ungeremine. a NMDA receptor antagonist. Meniantine, .a muscarinic receptor agonist, Talsaelidine, .AF-102B, A -Z&lB (NGX-267), a nicotiiiie receptor agonist, Ispromelnie (AZD-3480). a betasecreiase inhibitor,

thiazolidmedioBeSj rosiglitazoee., pioglitazone, gamiBa-seeretase inhibitor, semagaeestai CLY¾G13¾ MK-0752, Β-20.Ϊ2, BMS-708M3 ? PF-308 014, begaeestai (GSI-953), MfC5- 15, an inhibitor of Αβ aggregation. Clioqaiael (ΡΒΊΊ), PBT2, traniiprosate (liomotaiEiae), SeyMa-isosiioI, an Αβ - fragment, Bapieeuzsmab. .EpigailocateGliin-3-gailate, an anii- iiiSaBiinatory agent, a cycloosygenase II mfB¾itor, an anti-oxidant, Vitami E, or a gjnkolide. f ΘΘ81] It should be appreciated that in some embodiments phamiaceiitical compositions of the inventive subject matter include a pharmaceutically acceptable earner in combination with a compound as described herein, optionally present as a pharmaceutically acceptable salt, a hydrate, a solvate, or in crystalline form,

|0082] In further embodiments, pharmaceutical compositions include compounds of the inventive subject matter in art amount effective to reduce corticotfophiii-releasing factor (CRF-1) induced tau protein phosphorylation (p-taii).

[0083] Further uses of a compound of the inventive subj ct matter include use in the

manufacture of a pharmaceutical composition, use to reduce CRF-1 activity, use to prevent or delay onset of a pre-Alzheimer's condition or cognitive dysfunction, or use to teat a symptom of Alzheimer ' s disease

[ΘΘ84] The inventive subject matter further contemplates a method for Heating and/or preventing a symptom of Alzheimer's disease by administering to a subject an effective amount of a compound or pharmaceutical composition as disclosed herein.

|0085] Yet further, a method of decreasing, inhibiting, or preventing an increase in p-tau in a mammal is contemplated including administering to the mammal an effective amount of one or more compounds or pharmaceutical compositions of die inventive subject matter'.

Experimental Data and Results

[ΘΘ86] Novel compounds that inhibit corticotiOpin-releasiiig factor CRF-1 associated phosphorylation of tau are identified herein. Without bein bound to a particular theory, it is believed these compounds show efficacy hi die treatment of ongoin Alzheimer's Disease, m the delay or prevention of the onset of Alzheimer's disease, in the onset of mild cognitive impairment (MCI) when mediated by an amylqidogenic process, in the delay of.a transition from MCI to AD, and in the delay or prevention of MCI.

|0087] fa pecsple diagnosed with Alzheimer's disease (AD), and in our hands using th 120 -.mouse inotiel of AD, the. level of iau phosphorylation provides the closest 5 correlation to degree of cognitive impairment. The reversal of tau pathology alone can improve memory , evm.'ia the presence of ' high Ap42 in J20 mice. Stress and the associated increase in coilicoti pm-releasing factor CRF-1 is known to increase fee phospiiorylatioii of tau. f ΘΘ88] To identify therapeutic candidates, a clinical library of CRF-1 inhibitors to was screened to deiemiine their effects on coriisol-iiiduced p-tan increases. One compound, designated " JO 3 " (N-(4-Meilioxy-2-inethylphenyi)- 1 -[ 1 -(inethoxyrneiliyl}propyi]-6-inethyl- lH-l,23-ti"iazolo[4,5-c]pyridiiie-4-aniine) acted as a CRF-1 antagonist (Ki~ 7.9n ) and showed no binding to CRFR2 (Ki> IQ.OOQnM). J03 was shown specifically to inhibit stress- induced p-tait increases by Cortisol in vitro. Notably, testing of another set of CRF-1 antagonists did not induce a similar inhibition of p-iau. [0089] Following the observations of J03 a number of analogs were developed. One design focus was to replace fee triazolopyridine ring of J03 with a iiiazolopyriniidine ring (see, e.g., Figure 1) and to explore the orientation of and vary the subsfituents around the

triazolopyridine and triazolopyiiniidine rings. It is noted that with respect to any

triazolopyridine and iriazolopwknidine described herein a compound with snbstitueiits A and B in reversed positions (see, e.g.. Figure 1) is also contemplated. Synthetic schemes have been developed and the analog synthesis lias been performed. Biological activity and pharmacokinetics has been evaluated (see. Example 2).

[0090] Table 1. Table 2, and Table 3 below list exemplary results for selected compounds presented herein.

Table 3

|ί 91] Compounds with effects highlighted (in green) were belter than those for JOS. f ΘΘ92] As illustrated, a number of these compounds are effective in lowering p-tau and or reducing or preventing a stress-induced increase in p-tau. Moreover, as indicated above, reduction in p-tau (or inlnbition of p-tau increase) is an important metric of efficacy in pathologies characterized by the accumulation of amyloid plaque (e.g., Alzheimer's disease, MCI, etc.). It is believed these compounds and analogs thereof, pharmaceutically acceptable salts and clathrates thereof, and the like are useful in the prophylaxis and/or treatment of pathologies characterized by the accumulation of amyloid plaque.

[0093] Accordingly it is believed that these agents ) (e.g., tiiazolopyriinidine and/or triazolopyridhie compounds described herein, or a tautomer(s) or stereoisomer(s) thereof, or pharmaceutically acceptable salts or solvates of said eompounds(s), said stereoisomers), or said tautonier(s), or analogues, derivatives, or prodrugs thereof) can be used to decrease p-tau in a mammal, and/or to inhibit or prevent an increase in p-tau, and or to prevent or delay the onset of a pre-Afzheimer's cognitive dysfunction, and or to ameliorate one or moresymptoms of a pre-Akheimer's cognitive dysfunction, and/or to prevent or delay the progression of a pre-Aizhemier's condition or cognitive dysfunction to Alzheimer's disease, and/or to promote the processing of amyloid precursor protein (APP) by the nonamyloidogenic pathway. In certain embodiments these agents can be used in the treatment of Alzheimer's disease (e.g.. to lessen the severity of the disease, and/or to ameliorate one or more symptoms of the disease, and/or to slo w the progression of the disease).

[0094] Synthetic firotoeols: [0Θ95] Contemplated eompormds can be prepared using various methods known in the art, and all of those are deemed suitable for use herein. Methods of preparing

iriazolopyrirrndme(s) and/or niazolopyridine(s) such as are described herein are known to those of skill in the ait. f ΘΘ96] Generally, in one approach, the relevant triazolopyrirnidine and/or triazolopyridine is illustrated in Example 1, below, describing the synthesis of J19 (depicted in Figure 7). As illustrated therein, the synthesis of J19 involves the preparation of 6-Chloro-N4- substituted pwuindiiie-4,5-dianmie followed by a cyclisaiioii to the triazolopwimidiiie and displacement of the chlorine on the pyrimidine ring to yield the desired analog. A similar synthetic pathway would be used for the other analogs described herein. Additionally, a similar synthetic pathway would be used for the triazoiopyridine series, the final product would involve separation of the pyridine isomers.

[ΘΘ97] One iilastrative, but non-liiiiiting, protocol for the synthesis of J1 is provided in Figure 2 and Example 1. Synthesis of additional compounds described, herein ar e

straightforward variations of the synthesis schemes provided herein. Contemplated Formulations

[0098} The inventive subject matter is also drawn fe therapeutic, compositions comprising one or more of contemplated compounds as active ingredient n ftiiiher combination with a pharrnaceutically-acceptable earner. Mos typically, such compositions re formulated for administratkai to a mammalian subjec using any suitable route. [0099] The amount of therapeutically active compound that is administered and the dosage regimen for tr eating a dis ease condition with the compounds and or compositions of this inventive subject matter depends on a variety of factors, including the age, weight, sex and medical condition of the subject, the severity of the disease, the route and frequency of administration, and the particular compound employed, and thus may vary widely. However, especially suitable quantities are provided above, and may therefore/allow, for a daily dose of about 0.001 (or even less) to 100 nig/kg body weight, preferably between about 0.01 and about 50. mg kg bod weight and most preferably from about 0. to 20 mg&g body weigh Typically, a daily dose can be administered in one. to. four doses per day. fOOiO©] Depending on the particular use aid structure, it is therefore contemplated that t e compounds according to the inventive siibject matter are present in th composition in. an amount between 1 microgram to 1000 milligram, more typically between 10 microgram to 500 milligram, and most typically between 50 microgram to 500 milligram per single dosage unit. Tims, preferred concentrations of contemplated compounds in vivo or m vitro will generally be between 0.1 nM and 500 microM, more typically between 50 nM and 400 microM, and most typically between 100 nM and 200 microM.

[00101] As alread noted above, contemplated compounds may be provided as

substantially pure compound or as a salt thereof, and pharmaceutically acceptable salts of the compounds include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, alginate, aspaitate, benzoate, benzenesulfonate, bisulfate, butyrate. citrate, camphorate, camphorsiilfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethaiiesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycoiate, hemisulfaie, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, maionate, methanesuifonate, 2-naphmalenesulfonate, lucotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate. Oilier acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the inventive subject matter and their phai iraeeiiticali acceptable acid addition salts.

[00102] Salts derived from appropriate bases include alkali metal (e.g., sodium and potassium), alkaline earth metal (e.g., magnesium), ammonium and +(Ci_4 alkyl}* salts. This inventive subject matter also envisions the quatemization of any basic nitrogen- containing groups of the compounds disclosed herein. Wa ter or oil-soluble or dispersible products may be obtained by such quatemization. |0Θ103 j Contemplated compositions may be administered orally, parenteraily. by inhalation spray, topically, rectaily, nasally, buecaliy, vaginally or via an. implanted reservoir. The temi "parenteral" as used tierein iiicliides subcutaneous, intravenous, miramuscular, intra-articiiiar, intia-synovial, intrasternal, intrathecal, intrahepatic, intealesioiial and intracranial injection or infusion techniques. Preferably, the compositions are administered, orally, iatraperiioriealiy or iiravenoiisl .

[00104] For example, contemplated pharmaceutically acceptable compositions may be orally administered in any orally acceptable dosage form including capsules, tablets, todies, elixirs, suspensions, syrups, wafers, chewing gums, aqueous suspensions or solotioiis. Oral compositions may contain additional ingredients such as: a binder such as rnicrocrystalline cellulose, gum iragacanth or gelatin: an excipient such as starch or lactose, a disintegrating agent such as alginic acid, com starch and the like; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; and a sweetening agent such as sucrose or saccharin or flavoring agent, such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it ma additionally contain a liquid carrier such as a fatty oil. Other dosage unit forms may contain other various materials which modify the physical form of the dosage unit, such as, for example, a coating. Thus, tablets or pills may be coated with sugar, shellac, or other enteric coating agents. A syrup may contain, in addition to the active ingredients, sucrose as a sweetening agent and certain preservatives,, dyes and colorings and flavors. Materials used in preparing these various compositions should be pharmaceutically or veterinarally pure and non-toxic in the amounts used.

[00105] For the purposes of parenteral therapeutic administration, the active ingredient may be incorporated into a solution or suspension. The solutions or suspensions may also include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as eihyienedianiinetetraaeetic acid: buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed i ampoules, disposable syringes or mul tiple dose vials made of glass or plastic.

[00106] The pharmaceutical forms suitable for injectable use include sterile solutions, dispersions, emulsions, and sterile powders. The final form should be stable under conditions of manufacture and storage. Furthermore, the fiaai pharmaceutical form slioold be protected -against contamination and should, therefore, be able to iubibit the growth of rmeroorganisms such as bacteria or fungi. A single intravenous or -intraperitoneal dose can be adtt«nistered. Alternatively, a slow long-term nifijsion or multiple short-term daily infusions may be utilized, typically lasting from 1 to 8 days. Alternate day dosin -or dosing once every several days may .also be utilized.

[00107] Sterile, injectable solutions may be prepared by incorporating a compound in tlie required amount into one or more appropriate solvents to which oilier ingredients, listed above or known to those skilled in the art, may be added as required. Sterile injectable solutions may be prepared by incorporating the compound in the required amount in the appropriate solvent with various other ingredients as required. Sterilizing procedures, such as filtration or irradiation (e.g. , gamma or e-bearn), may then follow. Typically, dispersions are made by incorporating the compound into a sterile vehicle which also contains the dispersion medium and the required other ingredients as indicated above. In the case of a sterile powder, the preferred methods include vacuum drying or freeze (hying to which any required ingredients are added.

[Θ0108] Suitable pharmaceutical carriers include sterile water; saline, dextrose; dextrose in water or saline; condensation products of castor oil and ethylene oxide combining about 30 to about 35 moles of ethylene oxide per mole of castor oil; liquid acid; lower alkanols; oils such as com oil; peanut oil, sesame oil and the like, with emulsifiers such as mono- or di-glyceride of a fatty acid, or a phosphatide, e.g., lecithin, and the like; glycols; polyalkylene glycols; aqueous media in the presence of a suspending agent, for example, sodium

carboxyniei ylceiliilose; sodium alginate; poIy(vinylpyrolidone) ; and the like, alone, or with suitable dispensing agents such as lecithin; polyoxyethyiene stearate: and the like. The carrier may also contain adjuvants such as preserving stabilizing, wetting, emirfsifying agents and the like together with the penetration enhancer, hi all cases, the final form, as noted, must be sterile and should also be able to pass readily through an injection device. The proper viscosity may be achieved and maintained by the proper choice of solvents or excipients. Moreover, the use of molecular or particulate coatings such as lecithin, the proper selection of particle size in dispersions, or the use of materials with surfactant properties may be utilized. OIW] Alternatively, the pha niaceutically acceptable composifesns of this inventive -subject matter may be administered in the form of suppositories errectal administration. "These can be prepared by mixing the agent with a suitable non-inilaSing excipient thai is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. ' Such materials include cocoa butter, beeswax and polyethylene .glycols.

[00110] The pharmaceutically acceptable compositions of this inventive subject matter may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically- transdemial patches may also be used.

[00111] For topical applications, the pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compomids of this inventive subject matter include mineral oil. liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable camers. Suitable carriers include mineral oil, sorbitan monostearate, polysorbate 60, eetyl esters wax, ceteaiyl alcohol, 2-octyldodecanoI, benzyl alcohol and water.

[00112] For ophthalmic use, the pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.

[00113] The pharmaceutically acceptable compositions of this inventive subject matter may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepar ed as solutions in saline, employing benzyl alcohol or other suitable preservatives. absorption promoters to enhanc bioavailability, Suorocarbom. . and/or other conventional soMnlizing or dispersin agents.

|001i4] Most preferably, the harmaceutically acceptable eoBipositions of this inventiv subject matter are formulated for o al adniiiBstraiioii. [00115] When oilier therapeutic agents are einployed in .combination with the compounds of the present inventive subject matter, they may be used for example in amounts as noted in the Physician Desk Reference (PDR) or as otherwise detennined by one having ordinary skill in the art.

Examples

{00116] The following examples are provided to further illustrate the present inventive subject matter but, of course, should not be construed as in any way limiting its scope.

[00117] Example 1 - Synthesis of Jl 9

[00118] An illustrative, but non-limiting synthesis scheme for Jl 9 is shown in Figure 2. Reagents and conditions for synthesis Scheme 1 were: (a) 2-methoxyethanol, 125°C; (b) NaN02 , DCM, acetic acid, r.t: (c) THF, 100 C C, sealed tube.

6- uoro-N4-(4- doro-2-nrethylp^ (3)

[00119] A 250 niL round bottom flask equipped with a reflux condenser was char ged with a mixture of 4,6-dichloiO-2-ineihylpyriiiiidin-5-8miiie (2.170 g, 12.2 mmol, 1.0 eqitiv.), 4- chloro-2-meihylaniline (1.726 g, 12.2 rnmol, i.O eqiiiv.) and 2-methoxyethanol ( 100 inL) and the mixture was heated to an oil bath temperature of i 25°C with stirring under nitrogen. After 48 hours, TLC (1 : 1 ethyl acetaterhexane) indicated completion of the reaction. The mixture was concentrated under reduced pressure to leave a viscous oil . This was dissolved in ethyl acetate (approximately 30 mL) and the desired product precipitated upon the addition of hexane with stirring (approximately 100 mL). The mixture was allowed to sit at 4 ' °

overnight and Hie solid .was. collected by- filtration,, washed with hexane and dried under vacuum tagive tfee product a ten api£ig2.4 g, 69%). lHKMR (CI)a 3 , 300 ΜΗζ):δ I ' M (d, J=9.3 Hz, 1H), 7.21-7.19 (m, 2H) 3 6.79 (hs, 1H), 3.29 (½, 2H), 2.49 & SH), 2.29 (s, 3¾ LC MS: 283.3(M+1).

f6&I2Q] Soa m .nitrite (0.289/ g, 4.2 mrnoL 1.1 equiv.) was added to e vigorously stirring mixture of 6-chioro-N4-( 4-di!oro-2-niei% (1.060 g. 3.7 rraiiol, 1.0 equiv:) in diehlo omethane (15 mL) and acetic acid (15mL) at room temperature. After 45 minutes, TLC indicated complete disappearance of the starting material (1 :3 ethyl acetate rliexaiie). The mixture was transferred to a separately funnel and 50 mL of water was added. The dic oromethaiie layer was removed and washed with water, brine and dried over magnesium sulfate. The organic layer was then concentrated to dryness to leave a tan solid whic was used directly without further purification (LlOg, 100%). 1H MR

(CDC1 3 , 300 MHz): 7.46-7.35 (m, 3H), 2.85 (s, 3H), 2.19 (s, 3H). LC/MS: 294.2 <M) + .

3-(4-Cyoro-2-methvIphem

d]pyiiiiiidin-7-amiae (6) P012i] A mixture of 7-ehloro-3-( 4-c k»ro-2-m†iiyiphmyi}-5-metliyl-3H- [1.2 ]a'i^olo 5-d p>Ttmidrii (1.0 g, 3,4 rnmoi, l.Q qiriv.) and l-methoxybutan-2-an3ine (0.89 g, S.9 minol, 2.5 eqiiiv.) i THF (15mL) was heated in a sealed reaction vessel to .an oil bat temperature of 100°C with Stirling. After 3 hours, TLC (20% ethyl acetate in hexaaes) indicated complete disappearance of startin material and formation of a single product. Hie mixture was allowed to cool to room tenipemiiire. The mixture was concentrated to ' dryness and ' purified by flash eIm>matograph over silica gel (0.to ' 100% ethyl acetate/ hexane gr adient) to give the title product as a white solid after drying. (0.470, 60.8%). ¾ N.MR ( CD30D, 300 MHz): S7.54-7.53(m, 1H), 7.46-7.38 (in, 2H), 4.69-4.59 (in, HT), 3.63- 3.50 (m, 2H), 3.40 (s, 3H), 2.49 (s, 3H), 2.12 (s, 3H), 1.90-1.62(m, 2H), L02(r, 7.5 Hz, 3H). "C-NMR (75 MHz, CD30D) δ 9.89, 16.87, 24.45, 24.99, 25.09, 51.60, 55.06, 58.17, 74.04, 74.53, 126.96, 128.98, 131.00, 132.83, 135.97, 137.80, 150.12, 10 155.01, 168.03. LC-MS (m/z): 360 [M ]+, 362 [M+ 2]+.

[00122] Example 2 - Evaluation of J03 and Analogs [00123] As described below, in vitro studies were performed using SHSY-5Y cells. These cells are a useful neurological model that differentiate into cells with morphological and biochemical char acteristics of mature neurons includin mature isoforms of tail.

[00124] Animal experiments were performed using J20 mice. The 120 mouse is a model of for Alzheimer's disease. This model overexpresses human APP with two mutations linked to familial Alzheimer's disease (the APP M670/6 1NL (Swedish) and 5 APP V717F (Indiana) mutations).

[00125] The effects of JO 3 (Figure 3) and analogs J04 (Figure 4), 114 (Figure 5), J17

(Figure 6), 119 (Figure 7), J30 (Figure 8), and J32 (Figure 9) on tau and -tau levels were studied.

[00126] As shown in Figures 10A and 10B, J03 reduces tau and phospho-tau (p-tau) increases induced by CRF. hi an initial study, SHSY-5Y ceils were cultured without serum to induce differentiation and increase tau expression, CRF was added to the cultures at increasing concentrations and, as shown in Figures 10A and 10B. both tau (Fig. 10A) and phospho-tau {Fig. 10B) increased with CRF in a dose-dependent maimer. The increases were proportional and both were abou 50%. 103 reduced the CRF-induced tau increases more than the p-tau increases. The increase in tau was unpredictable as CRF reduces neuronal differentiation (see Che et al. (2004) Proc, Natl. Acad. Set USA, 101(44); 15782-15787), however, it can inci ease tan acciimelation.

[00127] A standard pharmacokmefic smdy of J03 was performed in which. J03 (10 rnk delivered in a 5 tng/rol D SO stock, 50 nil} was injected suhcirianeously (SQ) into 120 mice. As shown in Figure IOC. J03 brain levels were low and the bi¾i'plasraa ratio was 1 :2, but levels stayed up for hows, resulting in good exposure of brain tissue, even fioni a single injection. After oral delivery by feeding (not gavage) also at 10 mg kg, brain levels were slightly higher at the peak (open grey box), and the braiir.plasma ratio was close to 1:1.

[00128] In pilot study #1 , 120 mice housed singl were treated by SQ injection of J03 in PEG/b-MCD at 10 ikd for 12 days. NOR analysis of object memory (N = 5/group) was performed. The results are illustrated in Figures 10D-10I. As shown there was a slight improvement, in behavior in single housed J03-treated J20 mice (Fig. 10D). There was no difference in Αβ1-40 (Fig. IGE), but a decrease in Apl-42 (Fig. I OF). The Αβ 1-40/ 1-42 ratio was significantly increased (Fig. 10G). SAPP was very slightly increased (Fig. 10H), as was the sAPP /Αβΐ -42 ratio (Fig. Ϊ 01).

[00129] Total tan was decreased by J03 (Figure 11 A), but largely due to one mouse. P-tau was significantly lower (Figure 11 A), and the ratio was slightly higher, but with great individual variation (Figure 11 A).

[ΘΘ13Θ] Based on these promising results, the study was repeated (pilot study #2) with oral delivery and a longer duration.

[00131] As illustrated in Figures 12 A and 12B, J03 treated mice performed well in both novel location (Fig. 12A) and novel object {Fig. 12 A) assays.

[00132] As shown in Figures 13A-13C, sAPPa increased slightly (Fig. 13 A), sAPPp was unchanged (Fig. 13B), and die sAPPa/sAPPP ratio (Fig. 13C) was slightly increased. Both ΑβΙ-40 (Figure 14A) and Αβ1-42 (Figure 14B) were unchanged with no significant trend to increase. The Αβ1-40/ Α 1-42 ratio (Figure 14C) was unchanged.

[00133] Figure 15 illustrates the effects of 103 on Αβϊ -42 in pilot studies #1 and #2. The curves here suggest there is some Αβΐ -decreasing effect if treatment is started hi younger mice, but it is lost if treatment is started after Αβ amplification is underway. f00134] Figure 16 snows the effect of J03 on p-tau in pilot study #2. Not only was p-tau decreased again here as it was in pilot, study # 1 , the decrease readied statistical significance. 00135 j Figures I 7A-17F shows the effect of J03 on p-tau and aiernery. There was good correlation to p-tau levels (Fig. 17B). Mice that scored above 8 had significantly lower p-tau levels (Fig. ί 7C). Novel location preference was even clearer tor JG3-treated J20 mice (Fig. I7D), and also stowed good correlation to p-tau levels (Fig. 1 ?E), and mice that scored over 0, therefore showing some novel location preference, had significantly lower p-tau (Fig. 17F).

[00136] To obtain an early look at plasma and brain J03 levels after oral dosing in

formulation, two additional mice were dosed on the first day of the study and euthanized two hours later. In these mice brain levels were higher than expected, at 170 ng/g, (Figure 18 A) but with great variation between the two mice. At the end of the study brain levels were in the expected range of about 35 ng/g (Figure iSB).

[00137J J04 was designed as an analog with replacement of the tiiazoiopyridine with the taazok^yrirmdine ring. In a primary screen in SH-Sy5Y cells, J04 did not lower tau in the primary screen, but did lower p-tau (see, Figure 1 ). J04 lowered p-tau to the same level as J03. Brain levels after SQ injection or oral delivery (Figure 20A) were similar at -55 ng/g, although clearance after injection was slower. Clearance after oral delivery is shown in Figure 20B.

[00138] 117 was observed to significantly lower tau (Figure 21 A), and p-tau (Figure 21B) in SH-Sy5Y cells and the effect was greater than that measured for JOS.

[00139J As shown in Figure 21C, after exposure to CRF, sAPPa was the same for control as for J! 7, but lower for J03 in this experiment. Tau was decreased for both J03 and J17

(Figure 21D). P-tau was decreased for both J03 and J17 (Figure 2iE).

[00140] Figures 22A-22B illustrate the effect of J03 and J l 7 on sAPPa, tau, and p-tau with increasing concentrations of CRF. The decrease in sAPPa with J17 was seen withou CRF and at 50 nM (Fig. 22 A), but not at other concentrations. The decrease in tau was seen without CRF and at 50 and 100 nM (Fig. 22B). The decrease in p-tau was seen at all

concentrations of CRF tested, excluding 0 (Fig, 22C). [00141] Figures 23A-23B illustrate in vivo phaniMeokmeties of Jl 7. After subcutaneous injection of 10 nig/kg, brain levels were low ( -400 ng/g) relative to plasma levels ( --4000 ng½i) (Fig. 2.3 A). After oral delivery at the same dose, brain levels were only -50 ng/g and plasma levels were once again almost I O-fold higher (Fig. 23B). [00142] In a 117 pilot study (#1 pilot study) male and female J20 mice were housed singly and treated with J 17 at 10 rnkd by oral delivery for 28 days. The results ibr raales and females showed some differences and are presented together and separately in Figures 24A- 24D. As shown therein, both J03 and Jl 7 lowered activity, but not significantly due to individual variation (Fig. 24A). Overall. J03 increased novel object preference more than 17, but only the increase with J17 was significant as there was less variation {Fig. 24B). Males (n=6 per group) showed a pattern similar" to all the mice (Fig. 24C), with the improvement i memory 7 being less and more similar between J03 and J17.

[00143] Figures 25A-25C shows the effect of J03 and 117 on sAPPot, sAPPP, and the ratio sAPPa/sAPPp. The sAPPa results were similar for both enders and showed an increase with J03 but not. 117 (Fig. 25A). sAPPp* results were also similar. There was a decrease with Jl 7 only (Fig. 25B). There was only a slight increase in the ratio for males with J03, and it. was greater with J17. but the two females showed an even greater increase in the ratio (Fig. 25C).

[Θ0144] When data from ail mice are presented (Figure 26A). there are no significant differences i Αβ1-42, but when the low outlier (10-fold lower) from one sibling pah was eliminated, there is a significant reduction in Apl-42 hi male mice (Figure 26B). There was no significant difference in the Αβ1-40/ Αβ1-42 ratio (Figure 26C).

[00145] Tau (Figure 27A) was increased in males, but an important readout for this series of compounds, p-tau, was slightly lower in male mice ((Figure 27B) and the p-tau/tau ratio ((Figure 27C) was lower' still. [00146] J14 is an analog of J03 and part of the triazolopyrinndme series described herein. Figures 28A-28B illustrate two screens for tau and p-tau levels. 114 decreased both total tau and p-tau levels more than J03 in Figure 28A, while neither J 14 nor J03 decreased total tau or p-tau in Figure 2SB.

[00147] As depicted hi Figure 29A, when screened with CRF-1 at. !OOnM for 3 days, both J03 and Jl 4 (at 20oM) decreased total tau and p-tau. P0148] Figures 29B-29C depicts screening with CRF- 1 at OBM, 50BM 5 and 1 OOnM, and shows, that total tan and p-tau increase with CRF-1 concentration, with J14 decreasing p-tau and tau more than 103,

[00149] After subcutaneous injection at 10 mg/kg, plasma (798 ng/mL) and brai (485 ng/g) levels peaked 2 hours after injection, with a brain:plasma ratio of 0.6, as seen in Figure 30A. After oral feeding at the same dose of lOnig/feg, brain levels also peaked at 2 hoins, but at a much lower level of 13.3 ng/g (Figure 30B). The braiir.plasma ratio was 1.33.

100150] Figures 3 IA-3 IF depict total sAPPa, Αβΐ -40, and Αβΐ -42, and tau, p-tau, and p- tau'tau ratio, respectively, after daily SQ injection at lOmkd does for 12 days. Figure 31 A shows a decrease in sAPPa for J14 treated mice compared to vehicle treated mice. There was a trend toward decrease in both ΑβΙ-40, and Αβ1-42 (Figs. 31B-31C). There was a fiend for lower levels of tau protein for both vehicle and J14 treated B254 mice having the Swedish and Indiana mutations, but also a D664A APP mutation that prevents caspase cleavage, as seen in Figures 31D-31F.

[00151] J19 is an analog of J03 similar to J17 and is part of the ti iazolopyrimidine series described herein. Figures 32A-32D illustrate the effect of J03 and JI9 on CRF-induced tau and p-tau alterations. J03 significantly decreased tau both in the absence of CRF and in the presence of IGOnM CRF (Fig, 32A). J19 also showed a tend to decrease tan. Both J03 and J 19 significantly reduced p-tau in the presence and absence of CRF (Fig. 32B). The p-iau/fau ratios were highly significantly decreased by J03 and 119 at both 50 and 100 oM CRF, and were decreased in the absence of CRF (Fig. 32C). There was a trend for sAPPa to be higher with 103 and J19 that reached significance for J03 at !OOnM CRF (Fig. 32D).

[00152] JI9 decreased tau and both J03 and JI9 decreased p-tau (Figure 39E). Therefore, while the p-tau tau ratio looks unchanged for J19 Figure 39F. This is due to the tau decrease and not due to a lack of effect.

|00153] Figure? 32G-32H illustrate the in vim pharmacokinetics of J19, After SQ injection of 119 at litakd, brain levels were ~T90ng/ g at the peak 4 hours after injection. Levels remained relatively high until 8 hours (left panel). With oral delivery- (right, panel), levels were much lower, hat again remained detectable from.1 to 6 - hours.. P0154j Figures 33A-33B depict the p-tm and tau-lowering effects of J30 ' and J32 com ared to a control J03. As depicted, J3i> lowered total tan levels, while J32 significantly lowered the p aii¾» ratio.

[00155] J32 was further studied for its effects o p-tau tau ratio. Figure 33 illustrates the sigrnSeant decrease is p-taa½« ratio by 132 compared to J03 and a control for Ι Μ of 132 in a SH-SY5Y cells. Further, Figure 33D illustrates f avofatt!e concentrations of J32 in the brain and blood serum after SQ injection, intraperitoneal injection (IP), and oral administration of 10mg kg doses. Plasma and brain levels peaked 1 hour after SQ injection, with, a

brain:piasma ratio of 0.75. After IP injection, brain levels peaked at 2 hours but cleared out slowly over 8 hours. Oral dosing at gave much lower levels in plasma and brain.

[00156] In some embodiments, the numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term "about.' " Accordingly, in some embodiments, the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment The recitation of ranges of values herein is merely intended to serve as a shorthand metiiod of referring mdividually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein.

[00157] As used in the description herein and throughout the claims that follow, die meaning of "a," "an," and "tire" includes plural reference unless the context clearly dictates otherwise. Ail methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearl contradicted by context lire use of any and all examples, or exemplary language (e.g. "such as") provided with respect to certain ernbodiments herein is intended merel to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention. [00158] It should be appar ent to those skilled in the ait that many more modifications besides those already described are possible without departing from the inventive concepts herein, Tbe inventive subject matter, therefore, .is. not to be restricted except in the scope of the appended elairas Moreover, m mteipretiag botli tlie speciireatioa and ibe elairas, all terms sfioald be mteipreted in the broadest possible manner consis tent m th the context, in p ttcular. tire terms "comprises" and "coiaprisiag*' should be interpreted as l eteiiing to elements, components,, or steps in a non-exclusive manner, indicating that tbe referenced elements, components, or steps may be present or utilized, or combined with other elements, components, or steps that are not expressly referenced. Wher !fc specification clainis refer s to at least one of something selected from the group consisting of A, B, C .... an , the text should be interpreted as requiring only one element from the group, not A plus N, or B plus N, etc.