SA07280338B1 - Novel Isoindole Derivatives - Google Patents

Abstract

This invention relates to novel compounds having the structural formula I and to their pharmaceutically acceptable salt, compositions and methods of use. These novel compounds provide a treatment or prophylaxis of cognitive impairment, Alzheimer Disease, neurodegeneration and dementia.(I)

Description

B- Novel isoindole derivatives Full description Background of the invention The present invention relates to new compounds; and pharmaceutical formulations. In addition, the present invention relates to therapeutic methods for the treatment and/or prevention of pathological features associated with AP such as “8” syndrome and B-amyloid angiopathy, including but not limited to cerebral amyloid angiopathy. ; hereditary cerebral hemorrhage; Disorders associated with Shay! loss and symptoms of lack of concentration and attention associated with Alzheimer's disease; attention deficit symptoms; dementia of mixed vascula 1 degenerative origin pre-senile dementia ¢ dementia associated with + or progressive supranuclear palsy Or cortical basal degeneration 0 There are many groups that have aspartate proteinase enzymes that are identified and separated

Hussain et al., (1999); Lin et. al, (2000); Yan et. [ secretase = p, which has the activity of an enzyme

Creamy - ‎Sinha et. al., (1999) and Vassar et. al., (1999). et. al, 1999) or memapsin-2 (Lin et al., 2000) (805)]. BACE has been identified using a number of experimental methods such as database analysis (Hussain et al., "EST"). © (1999; cloning expressed by genetic trait (1999) Vassar et al. Identification of human homologues through public databases of predicted (C. elegans) proteins (1999 ¢) (Yan et al.) Finally; The use of an inhibitor of protein purification from the human brain (1999) (Sinha et al.) Thus, there are five groups that use three different experimental methods that lead to the identification of the same enzyme, which makes the strong case in which the (BACE) is an enzyme 8- secret.

0 We have found that BACE is an aspartic proteinase similar to pepsin in which the mature enzyme is composed of a (N-terminal) nitrogen seed-terminated catalytic domain, a Jil transmembrane domain and a small cytoplasmic. BACE has optimal activity at hydrogenad, (pH) ranging from (4.0) to (2.0) (Vassar et al 1999), and is weakly inhibited by standard pepstatin' inhibitors or standard such as 'pepstatin'". It has been shown that the catalytic domain or

0 notch minus the aie transmembrane domain and the cytoplasmic domain is effective against enzymatic substrate peptides Jad (2000 et al, 1a). BACE is a type 1 membrane-associated protein that is synthesized in the form of a partially active proenzyme; it is genetically expressed abundantly or abundantly in brain tissue. It is believed to be Ji activity. The main enzyme of secretase - ¢ and it is taken into account as the rate-limiting step in the production of protein -]-

0 Amyloid (AD) It is thus of particular interest in the pathology of Alzheimer's disease; In the development of drugs such as the development of therapeutic drugs for the treatment of Alzheimer's disease.

a

The (AB) or -8- epigenetic protein is the major constituent of brain lamellae that are characteristic of patient (AB) (De 500006: et al., 1999) Alzheimer ala) is a residual peptide (39- 42) It is formed by specific cleavage of a class I transmembrane transporter protein (APP) or amyloid-producing protein. The activity of the ~AB secretase enzyme cleaves this protein among residues (Asp672) (Met671) (numbered aa isoform of sail 770 (APP) to form the terminal ends of the (N-terminus) nitrogen seed of (AB) the second fission of the peptide is bound to the enzyme (-secretase Alzheimer's disease (AD) has been assessed to afflict more than 10 million people worldwide and is thought to be the most common generalized form of dementia. Alzheimer's disease 10 is a progressive dementia in which large mass deposits of lumpy protein degradation products, amyloid plaques, and tangles of nerve fibers accumulate in the brain. Alzheimer's disease patients. The probability of developing Alzheimer's disease increases with increasing age and with the increasing age of the developing world's YO population; This disease becomes a huge problem even more massive. Furthermore it; There is a genetic link with Alzheimer's disease; Thus, any individuals who possess the double mutation of (APP) known as the Swedish mutation [in which the mutated (APP) forms an enzyme-acting substance significantly improved have value and consideration for (BACE) and have a much, much higher chance to develop and develop Alzheimer’s disease “(AD) Alzheimer’s disease at an early age [See also Ye US Patents Nos. 17489974 and 28797799_ concerning mutated rodents containing –APP]

M - Swedish]. And therefore; There is also a strong and urgent need to develop a compound that could be used in a prophylactic or prophylactic manner in these individuals. The genetic coder found the trait (APP) ihe on the (71) chromosome, which is the chromosome that was also found as an extra or extra copy of Downs syndrome. © Patients with Downs syndrome tend to acquire a disease Alzheimer's disease at an early age, as most of these patients over the age of (0) years show a pathology of Alzheimer's type (Oyama et al, 1994) This is believed to be due to the extra copy of the gene (APP) present in these patients; which leads to overexpression of the (APP) genotype and then to increased levels of (APPR) causing the high dominance of Alzheimer's disease seen in this segment of the population. Thus, BACE inhibitors can be useful in reducing the pathology of Alzheimer's disease present in patients with Downs' syndrome. Hence, drugs that reduce the effectiveness of BACE should By reducing levels of AB and levels of AB fragments present in the brain, where A is or where A fragments are deposited, thus slowing the formation of amyloid plaques and the progression of AD or Jabal other inclusive 01 Deposition of (A) its fragments [(1999) [Yanker, 1996; De Strooper and Konig, 35. (BACE) is considered an important candidate for drug development in the form of drugs for the treatment and prevention of diseases associated with - (AB) Ss Jie Downs syndrome and B- amyloid vascular disease. amyloid angiopathy including, but not limited to, cerebral amyloid angiopathy ¢, hereditary cerebral hemorrhage ¢ and disorders associated with cognitive impairment 0; to name but not limited to "MCI" YoYY

(Sha) mild cognitive impairment and Alzheimer's disease; memory loss; deficit symptoms associated with Alzheimer's disease; neurodegeneration associated with Alzheimer's disease or dementia, including dementia of mixed vascular and atrophic origin; his pre-aging degenerative origin; pre-senile dementia; Dementia associated with Parkinson's disease | dementia associated with Parkinson's or still progressive progressive supranuclear palsy or cortical basal degeneration. Hence, it would be advantageous to inhibit the deposition of AB and its fragments. of it by inhibition of (BACE) 0 through inhibitors such as the compounds presented herein The therapeutic potential of inhibition of (AB) precipitation has many driving groups to isolate and characterize the 6 enzymes and to identify and identify their potential inhibitors (see For example, international patent applications: pass [IVETE 5 Lammat, Cato Talart, and SN TIO And NAKA and SPEER ARR EE: Amat and Mahktnaart and YA NL and 17717 and ¢ La and 3 0 and 195779 YIAYY Ye Rla and 11801 L 0 and American numbers 246476400 and Fah contain Hot UYNIYTO 5 EVAT Yo for Hala A and 1 No “Hala and European 880144 .

_No_ compounds of the present invention exhibit improved properties compared to potential inhibitors known in this field of the art; For example, improved selectivity (RERG). The general description of the invention is hereafter providing new compounds with the following structural formula 0): (R3)m Y 2 L J=N H,N 5 I C are selected from: - Q-Ca.calkenyl, -Q-Cy.6alkynyl, -Q-Cscycloalkyl, -rapolaC90-0- hydrogen, nitro, cyano, Q-Cs.seycloalkenyl, -Q-C;.galkylC;.cycloalkyl, -Q -aryl, -Q-heteroaryl, -Q-C,.salkylaryl, -Q-C,.¢alkylheteroaryl, -Q-heterocyclyl and -Q-C, salkylheterocyclyl, wherein said -Q- Ye ‎Cyealkyl, -Q-Cy.galkenyl, -Q-C,.alkynyl, -Q-Cj.cycloalkyl, -Q-Cs.cycloalkenyl, -Q-Ci. salkylCa.cycloalkyl, -Q-aryl, -Q-heteroaryl, -Q-C.calkylaryl, -Q-C,_galkylheteroaryl , -Q- heterocyclyl, or -Q-C.salkylheterocyclyl mentioned by one, two, or three of R7 NO 88 is: YoYY

_ A — if (CRHR*)RS, C,.salkenylR®, Ca.4alkynyIR®, Cs.cycloalkenyIR®, nitro or cyano are independent of the other groups; CRHRY) then every 1 < n was : independently of R? Then select hydrogen, halogen, 1 alkyl, Cs.salkenyl, Ci.salkynyl, Cs.scycloalkyl, Cs.icycloalkenyl, aryl, heteroaryl, heterocyclyl, CsalkylCs.¢cycloalkyl, ben salkylaryl, Cj.¢alkylheteroaryl © and C .salkylheterocyclyl, wherein said Cy.ealkyl, Cs.galkenyl, Cs.alkynyl, Cs. cycloalkyl, Cs.scycloalkenyl, aryl, heteroaryl, heterocyclyl, Ci.salkylCs.scycloalkyl, © salkylaryl, C;.6alkylheteroaryl or C; salkylheterocyclyl (A) mentioned with one; two; or three groups : be direct bond or -0- 0 -CONH-, -CO-, -CON(C;.¢alkyl)-, -CON(Cs.cycloalkyl) )-, -SO-, -SO;-, -SO,NH-, -

SO,N(Cy.galkyl)-, -SO2N(Cs.cycloalkyl)-, -NHSO;-, -N(C, alkyDSO;-, -NHCO-, -

N(C.6alky)CO-, -N(Cs.cycloalkyl)CO- or ~N(Cs.cycloalkyl)SO,-;

R* or that hydrogen, cialkyl, cyano, halo or nitro; are picked independently from the RS SR? ¢ 0x0, Caecycloalkyl or heterocyclyl and together they form 0 where “methyl, Cacycloalkyl, heterocyclyl, aryl and heteroaryl” from RS are selected with a number ranging from methyl, Cs.geycloalkyl, heterocyclyl, aryl or heteroaryl an optional substitution other than aryl or aryl between one and four of the 87 groups; And where any of the groups can merge

- and or cycloalkenyl group or “cycloalkyl atoms” VY Sat 5; or Set homologous optionally by the number of a bicyclic ring system and where there is an optionally substitution in the SE heterocyclyl (A bicyclic) ring system optionally by a number of between one and four groups halogen, nitro, CHO, Co.salkylCN, OC, salkylCN, independently of RT is then selected

Co.calkylOR®, OC,.alkylOR®, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, © fluoromethoxy, difluoromethoxy, trifluoromethoxy, Co.salkyINR®R', OC.alkyINR*R', 0C,.6alkylOC,.calkyINR®R® , NRPOR®, Cg 6alkylCO:R®, 00 .calkylCO:R',

Co.alkylCONR®R®, OC, 6alkylCONR®R®, OC,.calkyINRY(CO)R’, Co.calkyINR® (COR’,

O(CO)NRR', NR CO)OR®, NR¥(CO)NR®R', O(CO)OR®, O(CO)R?, CoalkylCOR®, 0C, .¢alkylCOR®, NR¥) CO)(CO)R®, NR¥(CO)(COINR®R', Co.alkylSR®, 01

Coalkyl(SO2)NRER®, OC.salkyINR¥(SO2)R’, OCs.6alkyl(SO)NR’R’,

Coalkyl(SOINR®R, 00 galkyl(SO)NR®R’, 05057 50:87

CosalkyINRE(SO)NR®R', Co.6alkyINR}(SO)R', OC2.calkyINR*(SO)R®, 00 alkylSO.R®, 0 85, 50 Aboldum. CosalkylSOR®, Ci.salkyl, Cagalkenyl, Co. salkynyl,

Co-salkylCs.ecycloalkyl, Co.salkylaryl, Cosalkylheteroaryl, Coealkylheterocyclyl and \o

OC,.salkylheterocyclyl, : where is an optional substitution in Cosalkenyl, Cealkynyl, Co.salkylCs.cycloalkyl, Co.calkylaryl,

Cosalkylheteroaryl, Co.salkylheterocyclyl or OCyealkylheterocyclyl

YoVY

1. aryl or aryl mentioned with one or more of group *8 and where any of the cycloalkenyl groups or cycloalkyl atoms of YSto optionally odd odd heteroatoms can be combined with 4; or, to form a bicyclic ring system where there is an optional substitution in the heterocyclyl de sane, provided that the A ring system is a bicyclic ring system with a number between one and four groups: the ring is not Sse indane, benzo[ 1,3]dioxole or 2,3-dihydrobenzo[1,4]-dioxine ring system; : extensively selected from RY halogen, nitro, CHO, Co.salkylCN, OC _alkylCN, Co.salkylOR?, OC, alkylOR®, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, Co.salkyINR ®R®, OCa.calkyINR'R', OC;.6alkylOCs.calkyINR'R', 01

NRPOR?? ',

NR¥CO)NRPR?, O(CO)OR®, O(CO)R®, Co salkylCOR®, 00 .salkylCOR’,

NR¥(CO)(CO)R®, NR¥(CO)COINR®R®, Cy.alkyISR®, Co.salkyl(SONR'R', 0C,.salkyINR¥(SO2)R', OCy.salkyl( SO2)NR®R', Co.6alkyl (SO)NRR', Vo

OC, 4alkyl(SO)NR®R?, OSO:R?, SOsR®, Co.salkyINR* (SO:)NR'R’,

CocalkyINRESO)R®, OC.salkyINR}(SO)R®, 00 6alkylSO;R®, Cy.ealkylSOR®,

Co.salkylSOR®, C,.salkyl, Caealkenyl, Cosalkynyl, Co.calkylCs.cycloalkyl, Cocalkylaryl,

Cogalkylheteroaryl, Co.¢alkylheterocyclyl and OCy.ealkylheterocyclyl: where an optional substitution is in Ye lia aya mer aba

— \ \ _ Ci.alkyl, Capealkenyl, Cealkynyl, Co-salkylCs_¢cycloalkyl, Coalkylaryl, Co.salkylheteroaryl, Co_ealkylheterocyclyl or OC, salkylheterocyclyl with a number between one and four of the groups (A) selected. R' R® independently from : hydrogen and C;-salkyl, Co-salkenyl, Ca-salkynyl, fluoromethyl, difluoromethyl, © trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, Co-ealkylCs- cycloalkyl, Co -salkylaryl, Co-calkylheteroaryl, Co.salkylheterocyclyl and C;- salkyINR'R", where there is an optional substitution in: -galkyl, Vo 0 Cy-salkenyl, Co-salkynyl, Co-galkylCs- cycloalkyl, Co-salkylaryl, Co-salkylheteroaryl or Co-salkylheteroaryl is optionally substituted by A; homologs picked from FN©; or 5 in which there is optionally a substitution of group 8; and when two 1' groups occur in the structural formula then together they optionally form a heterocyclic system having number of © or 6 atoms containing one or more of unexamined atoms picked from oN or ©0; or 5; which has an optional substitution of group M; ag picking R' and :R ! as adapted from : YoYY

_ 1 Y —_ hydrogen, C;

Co-salkylheterocyclyl and Co-alkylheteroaryl, : where there is an optional substitution in

Ci-salkyl, Cs-alkenyl, Cs-salkynyl, Co-galkylCs-scycloalkyl, Co-salkylaryl, C or A with group qalkylheteroaryl or Cosalkylheteroaryl © together a heterocyclic system with a number ranging from ; to 3 atoms contains RTS RY and can form ©; or 5 for which the SN is on one or more heteroatoms picked from optionally substituted by group m; led 1 or Y is yellow or 3 or m

FvSySa be pure or © A : from A and oxo, halogen, nitro, CN, OR", C 1salkyl, Caealkenyl, Casalkynyl, Cosalkylaryl, Co. salkylheteroaryl, Co salkylCs.¢cycloalkyl, Co are selected .salkylheterocyclyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, NR?R"?, CONR'?R", NR'((CO)R"?, O(CO)C.6alkyl, (CO)OC;.Vo salkyl, COR', (SO)NR'IR'3, NSO;R'?, SO;R'2, SOR? (CO)C.6alkyINR'R', (SO)CyalkyINR' ?R'?, 0SO,R'? and SOsR "2 : where there is an optional substitution in

YoYY

60 050: 87 halo, trifluoromethyl, fluoromethoxy, difluoromethoxy or trifluoromethoxy 2 and RY and 85 are selected independently from: hydrogen, Cigalkyl, Csgcycloalkyl, aryl, heteroaryl and heterocyclyl, wherein there is an optional substitution in: Crealkyl, Csecycloalkyl, aryl, heteroaryl or heterocyclyl with one, two or three of the 0 cyano hydroxy groups or halo ¢ or alkyloxy Ci. ¢ or RP RP together can form a heterocyclic system with A number from − to 3 atoms containing one or more heteroatoms picked from SN 0; or 5 and in which an optionally substituted with a hydroxy − or alkyloxy Cis© or cyano groups is halo ¢ in the form of a pharmaceutically acceptable free base or salt or a solute or solute of a salt thereof.Ve In another aspect of the invention, a compound of the formula [:

— \ $ _ (R3)m ba . — R2

N

L I : Ig is obtained from gen, nitro, cyano, -0-0 alkyl, with the addition of 0-0- -Q-Cy.galkynyl, -Q-Cs.¢cycloalkyl, -Q-Cs . cycloalkenyl, -Q-Cy.ealkylCs.cycloalkyl, -Q-aryl, -Q-heteroaryl, -Q-C,.¢alkylaryl, -Q-°

C,.salkylheteroaryl, -Q-heterocyclyl, and -Q-C,_salkylheterocyclyl, : where there is an optional substitution in -Q-C, alkyl, -Q-Cy.ealkenyl, -Q-Cpealkynyl, -Q-Cs.cycloalkyl, - Q-Cs_cycloalkenyl, -Q-

C,.salkylCs_¢cycloalkyl, -Q-aryl, -Q-heteroaryl, -Q-C

R7 mentioned by one, two, or three of : be RY (CRHR NIRS, CyalkenylR®, Ca.salkynylR®, Cs.cycloalkenylR®, nitro or cyano are independent of the other groups; CRYRY) so each 1 > « If it is

YoYY

mg 1 _ and 83 is selected independently from: hydrogen, halogen, © alkyl, Cs.salkenyl, Cs.salkynyl, Cs.scycloalkyl, Cs.scycloalkenyl, aryl, heteroaryl, heterocyclyl, Ci.salkylCs cycloalkyl, C,. alkylaryl, C.salkylheteroaryl and C,_alkylheteroaryl, 2 where there is an optional substitution in: © ,Ans?alkmin ,Anwaaq Cyealkynyl, Cs.scycloalkyl, Csscycloalkenyl, aryl, heteroaryl, heterocyclyl, Ci.¢alkylCs.scycloalkyl, Ci. salkylaryl, C ealkylheteroaryl meaning calkylheterocyclyl mentioned with one; or two; or three groups (A 0 -0- that are directly bonding; or: -CONH-, -CO-, -CON(C;.salkyl)-, -CON(Cs.¢cycloalkyl)-, -SO- , -8§O2~, -SO;NH-, -

SO,N(C.salkyl)-, -SO:N(Cs.cycloalkyl)-, -NHSO,-, -N(C,.salky)SO»-, -NHCO-, -

N(C1.¢alky)CO-, -N(Cs.4cycloalkyl)CO- or -N(Cscycloalkyl)SO,-; ;CO-R is independently selected from hydrogen, C;.galkyl, cyano, halo or nitro ¢ or ¢ heterocyclyl si cycloalkyl Cs that 4 and 85 together form H; or 0 R® is selected from methyl “¢ cycloalkyl asthma” or aryl g ¢ aryl s “heterocyclyl heterocyclic”; where is an optional substitution of methyl ; or and from the cycloalkyl + or heterocyclyl « aryly » aryl heterocycle mentioned in a number between one and four of the 187 groups; and where

- 11 -

Vv or optionally heterogeneous 6 geo by 4; or aryl can fuse any of the heterocyclyl groups (JSS) or the bicyclic ring system (cycloalkenyl group); Or, cycloalkyl atoms, and where there is an optionally substitution in the bicyclic ring system optionally with a number ranging from one (A) to four of the groups: 187 are selected independently from © logen, nitro, CHO, Abu Alqiu 0, OC, salkylCN, Co.calkylOR®, 0C,.alkylOR®, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, Co.calkyINR*R', OCs salkyINR'R', 0C1.6alkylOC, salkyINR* R',

NRPOR®, CosalkylCO,R®, 00.6alkyl COR, Co.salkyl CONR’R’, OC; alkyl CONR®R', 0C,.6alkyINRE(CO)R', Co.salkyINR® (CO)R', O(COINR'R', NRS(CO)OR', 01 1) for Saroo O(CO) OR?, O(CO)R®, Abu Lamqim 08 OC, salkylCOR®,

NRY(CO)(CO)R®, NR} (CO)(CO)NR®R’, Co.calkyISR’, Co.calkyl(SO.)NR®R’,

OC 6alkyINR}(SO2)R’, OCq.alkyl(SO2)NRR’, Co.calkyl(SO)NR*R’,

OC salkyl(SO)NR®R®, OSO;R®, Betty Co.calkyINR¥(SO2)NR°R,

CosalkyINR}(SO)R®, OC.salkyINR¥(SO)R®, OCy.salkylSO:R’, © alkylSOR?, Yo

CocalkylSOR®, Cyalkyl, Cagalkenyl, Cosalkynyl, CosalkylCs. ecycloalkyl, Cosalkylaryl,

Co.salkylheteroaryl, Co.calkylheterocyclyl, and OC,.alkylheterocyclyl,

Co. salkylheteroaryl, Co. calkylheterocyclyl or OC;. salkylheterocyclyl Y.

- 1 aryl or aryl and where any of the said RY groups may be combined with one or more group or cycloalkenyl or cycloalkyl atoms Vv or optionally 0 odd heterocyclic b4; or © or to form a bicyclic ring system where there is an optional substitution in the heterocyclyl group of the bicyclic ring system with a number of between one and four m groups, provided that the ring system: the ring is not Ae indane, benzo [1,3]dioxole or 2,3-dihydrobenzo[1,4]-dioxine ring system; : Independently from RY halogen, nitro, CHO, Co alkylCN, 00 C is selected to meet CoalkylOR®, OC) calkylOR®, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, 01 trifluoromethoxy, L. 0 Abul Qom00 17 Abul Alef 002 3 1 Abul Laqiu 7 1112015 Cy.calkylCO:R®, 00 3and0 null Co.calkylCONR'R?, OC 1.6alkyl CONR®R', 0C,.6alkyINRE(CO)R', Cy.calkyINR ® (CO)R', O(CO)NR'R', NR} (CO)OR',

NR} (CO)NR®R?, O(CO)OR®, O(CO)R®, Co.salkylCOR®, OC.alkylCOR®,

NRY(CO)(CO)R®, NR¥CO)CO)NRR?, Cocalky!SR®, Co.salkyl(SO)NR'R', Vo 0C,.calkyINR¥(SO2)R®, OCo.6alkyl (SO)NR®R', Co.6alkyl(SO)NR*R', 06 6alkyl(SO)NR®R', OSO:R®, SO3R®, Co.calkyINR}(SO)NR®R',

CosalkyINRA SOIR’, OCa.calkyINRE(SO)R®, OC .salkylSOR’, © alkylSO;R®,

Co.calkylSOR?, C.alkyl, C.ealkenyl, Coealkynyl, Co.calkylCs.ecycloalkyl, Co.salkylaryl,

Co¢alkylheteroaryl, Co. salkylheterocyclyl and OC, salkylheterocyclyl Ye

Where is an optional substitution in: CosalkylCs.scycloalkyl, Cosalkylaryl, Csalkyl, Ca.galkenyl, Cosalkylheteroaryl, Co.calkylheterocyclyl or OCyealkylheterocyclyl mentioned with a number between one and four groups (A ©) is selected. rR' RS independently of : : hydrogen, C,-salkyl, Co-salkenyl, C,-salkynyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, Co-salkylCs-free cycloalkyl, Co-galkylaryl, Co-ealkylheteroaryl, Cosalkylheterocyclyl and calkyINR'R", Yo where is an optional substitution in: C,-salkyl,Co-salkenyl, Cy-salkynyl, Co-salkylCs-cycloalkyl, Co- alkylaryl, Co- salkylheteroaryl or Co.galkylheteroaryl and Crs with group tA and together 85 R75 can form a heterocyclic system with a number ranging from ; to 6 atoms containing VO containing one or more Heteroatoms picked from SN©0;or 5 in which there is optionally a substitution of an A group and when two RY groups occur in the structural formula then together they optionally form a heterocyclic system with a number of © or 6 atoms Contains one Yovy

or more unexamined atoms selected Noe or 0; or 5; which has an optional substitution of group M; Then select R'® and ! JET form of: C3-salkenyl, Cs-salkynyl, Co-salkylCs-scycloalkyl, Co-salkylaryl, Cosalkylheterocyclyl and Co-galkylheteroaryl, © where there is an optional substitution In : Cs-salkenyl, Cs-salkynyl, Co-salkylCs-cycloalkyl, Co-salkylaryl, Co-, anolago- salkylheteroaryl or Co.galkylheteroaryl with group SHA 0 and RY and 8 together can form a system heterocyclic having a number ranging from ; to + atoms contains one or more heteroatoms picked from aN or © ; or 8 in which the group is optionally substituted (A 111 be Jia or 3 or 7 or 1 1 be yellow or 0 or Y or 1 pg Yo pick A from: oxo, halogen, nitro, CN, OR!

a - difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, NR} (CO)R", O(CO)Cyalkyl, )00(00, L extraction 0Ca.alkyNR'ZR"?, NR2R', salkyl, COR'2, (SO2)NR'?R'?, NSO,R'?, SOR", SOR'%, (CO)C.salkyINR''R", (SO2)C,. calkyINR'2R'?, 0502 and SOR", © where there is an optional substitution in: Cogalkenyl, Co.ealkynyl, Coealkylaryl, Co.salkylheteroaryl, Co. Panolq© salkylheterocyclyl or Co.galkylCs.cycloalkyl mentioned: halo, 050 2 SO;R'?, nitro, cyano, OR'?, C.salkyl, fluoromethyl ‎difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromcthoxy or trifluoromethoxy; hydrogen, Cisalkyl, Cs.cycloalkyl, aryl, heteroaryl and heterocyclyl, wherein there is an optional substitution in: Csgcycloalkyl, aryl, heteroaryl or heterocyclyl , terald..0 with one, two, or three of 05 hydroxy groups ¢ or cyano¢ or halo¢ or da-alkyloxy; or RZ 5 RZ together can form a heterocyclic system having a number of − to + atoms containing one or more heteroatoms selected from 8; or 0; or 5 in which the “hydroxy” groups are optionally substituted by “hydroxy” or “halo sl” cyano ¢ groups.

— Y \ —_ provided that the following compounds are excluded: 3-amino-1-cyano-N-phenyl-1H-isoindole-1-carboxamide; 3-amino-1-(1H-benzimidazol-2-yl) -1H-isoindole-1-carbonitrile;4 4'-(3-amino-1H-isoindole-1,1-diyl)diphenol; 1-phenyl-1H-isoindol-3-amine; ° 1-methyl-1H-isoindol-3-amine; 1,1-dimethyl-1H-isoindol-3-amine; 2-[3-amino-1-(4-hydroxyphenyl)-1H-isoindol-1-yl]phenol; In the form of a pharmaceutically acceptable free base, salt, solubility or solubility of a salt thereof. 1: For the invention another compound of formula J is provided from cla in Yo (R3)m

Gs — R2

N

HN

[ : Which is picked up from hydrogen, nitro, cyano, bangta?

Q-Cs.cycloalkenyl, -Q-Ci.6alkylCs cycloalkyl, -Q-aryl, -Q-heteroaryl, -Q-Cj.¢alkylaryl, \o

Yavyy

_ Y Y _ -Q-C.galkylheteroaryl, -Q-heterocyclyl and -Q-C,.salkylheterocyclyl, wherein said -Q- © Bolgo -Q-C.galkenyl, -Q-Ca alkynyl, -Q-Cs.cycloalkyl, -Q-Cs .cycloalkenyl, -Q-Ci. salkylCs.cycloalkyl, -Q-aryl, -Q-heteroaryl, -Q-Cy.ealkylaryl, -Q-C;.ealkylheteroaryl, -Q- heterocyclyl or -Q-C_salkylheterocyclyl

Re mentioned by one, two or three ©: about le are and if (CRH(R))aR®, Ca.4alkenylR®, by the combination of blood and nitro or cyano substances are independent of the other groups; CRHRY) select each 1 < n was : and then independently select 3 from hydrogen, halogen, Cs.¢alkenyl, Cs.salkynyl, Cs.cycloalkyl, Cs.cycloalkenyl, Ve aryl, heteroaryl, heterocyclyl, C.¢alkylCs cycloalkyl, Cyalkylaryl, C;.¢alkylheteroaryl and Cy.salkylheterocyclyl, wherein said C,.salkyl, Cs.salkenyl, Cs salkynyl, Cs. cycloalkyl, Csscycloalkenyl, aryl, heteroaryl, heterocyclyl, Cy salkylCs.ecycloalkyl, C,. salkylaryl, Cy alkylheteroaryl or Cj¢alkylheteroaryl (A) mentioned with one, two, or three Vo groups being direct bonding; or -©-

— Sc -CON(Cs cycloalkyl)-, -SO-, -50- -SO,NH-, - amohalation”.0011)6- -CO-, -01111©- SO,N(C ,.salkyl)-, -SO,N(Csecycloalkyl)-, -NHSO,-, -N(Cy.6alky)SO,-, -NHCO-, - N(C,.salkyl)CO-, -N (Cs.cycloalky)CO- or —N(Cs.cycloalkyl)SO,-; 4R* are independently selected from ¢hydrogen, Calkyl, cyano, halo and nitro; or © 84 and 85 together two forms oxo from cycloalkyl see heterocyclyl ; methyl (—e RS) is selected from cycloalkyl » or aryls » aryl s » heterocyclyl heterocyclyl; where an optional substitution is by methyl « or cycloalkyl Cae. » i.e. heterocyclyl « aryl and the said heterocyclic analyte with a number of between one and four RT groups; and where any of the aryl or aryl heterocyclic groups can be optionally combined with 4; or ©; or 6 or 7 0 cycloalkenyl sl “atoms” cycloalkyl or heterocyclyl group (JS) a dicyclic ring system and where there is an optional substitution in the bicyclic ring system optionally with a number of between one and four groups (A) RY is selected independently from : Co.calkylOR ®, OCa.salkylOR®, 106 Boulaki 00 halogen, nitro, CHO, Co.calkylCN, hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, \o difluoromethoxy, trifluoromethoxy, CosalkyINR®R®, OCa. 6alkyINR*R®, 0C,.4alkylOC,.alkyINR®R®, NR*OR', Cq.6alkylCO;R?, OC;.6alkylCO:R®, CosalkylCONR®R?, OC; 5alkyl CONR® R®, OC; alkyINR*(CO)R', Co.calkyINR® (CO)R', O(COINR®R', NR¥(CO)OR®, NR (CO)NR®R', O (CO)OR®, O(CO)R?, Co.alkylCOR®, OC alkyl COR?, NR¥(CO)(CO)R®, NR¥(CO)(CONR®R', Co.ealkylSR ®, Ye Yovy

77 500118) Cocalkyl(SO)NR®R®, OC.6alkyINR}(SO2)R', cash. .calkyINRY (SO)NR®R®, Co. salkyINR¥ SOIR', OC; salkyINR}(SO)R®, OC16alkylSO:R?, C.alkylSO;R®, CoalkylSOR®, Cgalkyl, Casalkenyl, Co.ealkynyl, Co-salkylCs.gcycloalkyl, Coalkylaryl, Cosalkylheteroaryl, Cosalkylheterocyclyl and © OC; ¢alkylheterocyclyl, where is an optional substitution in: Ciealkyl, Cyalkenyl, Cagalkynyl, CosalkylCs.scycloalkyl, Cosalkylaryl, Co.salkylheteroaryl, Co.¢alkylheterocyclyl or OCy.salkylheterocyclyl Ve with one or more of group 4c and where possible The fusion of any aryl Ole gana or aryl heterocyclic optionally with ef, Seo 6, or V atoms of a cycloalkyl, cycloalkenyl, or heterocyclyl group to form a dicyclic ring system where There is an optional substitution in the dicyclic ring system by between one and four m groups provided that the dicyclic ring system is not: indane, benzo[1,3]dioxole or 2,3-dihydrobenzo[1,4]-dioxine ring system; \o The RM is selected independently from: CosalkylOR®, OC;.alkylOR?, Ran Apollo M 011 , 0040 Abul-Qayyim 0 halogen, nitro, CHO, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, Co.calkyINR®R®, OC, 6alkyINR®R®, OC. 6alkylOC; salkyINR®R’,

_ Y SA M 1101, RTO Abu Al-Qabou 00 6alkylCO,R®, Paulelm. 06 , 01157 CONR®R’, Term (LOL 0 Co.salkyINR® (CO)R’, 60 (07 AD) 1182, to communicate with it

NR¥CO)NR®R®, O(CO)OR®, O(CO)R®, Boulaf 0013 0013 Abul Qimam 085 11) Tarq) Rum NR¥(CO)(COINR®R?, Co .alkylSR®, 502(118)POLLHMM 757 0C, ¢alkyINR¥(SO2)R?, Abu Dhabi 06) 5 03157, Co.calkyl(SO)NR'R', 0 0C6alkyl(SOINRPR', refueling 18) 60118 7

CocalkyINRE(SO)R’, 0 Abu Al-Faman 1145 0(16 7, OC) B 0 5 Abula. Rad 6 Abu Luqm.

Co.alkylSOR®, © Banoualqi Ca.salkenyl, Co.calkynyl, and 0 cycloalkyl, Co.calkylaryl,

Cosalkylheteroaryl, Co.salkylheterocyclyl and OCa.ealkylheterocyclyl, where is an optional substitution in 0

Cisalkyl, Caealkenyl, Cosalkynyl, Co.salkylC;.¢cycloalkyl, Coalkylaryl,

Cosalkylheteroaryl, Co.alkylheterocyclyl or OCyealkylheterocyclyl (A) mentioned in a number ranging from one to four of the groups: Independently from R75 RY hydrogen, C,-salkyl, , is selected for the 0 collection of fluoromethyl, difluoromethyl, Vo trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, Co-salkylCs- cycloalkyl, Co-salkylaryl, Co-salkylheteroaryl, Cosalkylheterocyclyl and 0 salkyINR''R"", wherein said C,-galkyl,

Cy-salkenyl, Cy-salkynyl, Co-alkylCs-cycloalkyl, Co-salkylaryl, Co-salkylheteroaryl or ¢A dc ganalli Crs 5 Cosalkylheterocyclyl together a heterocyclic system with a number ranging from ; to 6 atoms containing R75 RY and may form or ©; Or 5 which is ON on one or more of the heterocyclic atoms that are picked from in the structural formula then RY and when two groups $A occur in it optionally replaced by the group © optionally a heterocyclic ring system with a number ranges from © or 6 atoms containing one Lee forming an or ©; or 5; Which has a substitution of ON or more of the non-selective atoms that are selected from: and then the selection of mag and | independently of hydrogen, C-salkyl, Cs-salkenyl, Cs-alkynyl, Co-salkylCs-cycloalkyl, Co-calkylaryl, Ve

Co.salkylheterocyclyl and Co-galkylheteroaryl, where there is an optional substitution in Cs-salkenyl, Cs-salkynyl, Co-salkylCs-scycloalkyl, Co-galkylaryl, Co- salkylheteroaryl or Co.alkylheteroaryl in the group. M; or VO together a heterogeneous ring system with a number ranging from ; to 6 atoms contains RY GRY and can form ©; or 5 for which the SN is on one or more heteroatoms picked from in which optionally substituted by the m group;

Yovy ey or Y or oy or dja be 111 3 or be 1 4 or Jia be n : from A select alg oxo, halogen, nitro, CN, OR". '2R'?, CONR'?R", NR'}(CO)R", O(CO)C alkyl, (CO)OC;. ,Olaq COR'2, (SO,)NR''R'>, NSO;R'2, SO;R'2, SOR'?, (CO)C.alkyINR “R”, (SO,)CsalkyINR '2R>, OSO,R'? : halo, 050:87 SO3R!2 nitro, cyano, OR"2, C.salkyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy or trifluoromethoxy; 1 : and crown independently of rR"? selection alg hydrogen, Cy.salkyl, Cs.cycloalkyl, aryl, heteroaryl and heterocyclyl,

where there is an optional substitution in: Crealkyl, Csgcycloalkyl, aryl, heteroaryl or heterocyclyl by one or both; or three of the hydroxy ¢ or cyano ¢ or halo ¢ or alkyloxy groups; OR RY and 83 together may form a heterocyclic system having a number of ; to 6 atoms © contains one or more heteroatoms picked from N©0; or 5 in which the hydroxy groups are optionally substituted ; or cyano sl “alkyloxy Ci.” i.e. halo ¢, provided that the following compounds are excluded: 3-amino-1-cyano-N-phenyl-1H-isoindole-1-carboxamide; 3-amino-1 -(1H-benzimidazol-2-yl)-1H-isoindole-1-carbonitrile;4,4'-(3-amino-1H-isoindole-1,1-diyl)diphenol; 01 1-phenyl-1H-isoindol-3-amine; 1-methyl-1H-isoindol-3-amine; 1,1-dimethyl-1H-isoindol-3-amine;2-[3- amino-1-(4-hydroxyphenyl)-1H-isoindol-1- yl]phenol; VO provided that the following compounds are excluded: 3-methy!-3-phenylisoindolin-1-imine; 3 '-(3-methyl-2,3-dihydro-1H-isoindol-1-yl)biphenyl-3-carbonitrile;

_Y q —_ 3-(3’methoxybiphenyl-3-yl)-3methylisoindolin-1-imine; 3-(3’chlorobiphenyl-3-yl)-3-methylisoindolin-1-imine; and 3-methyl-3-(3-pyridin-3-ylphenyl)isoindolin-1-imine;

In the form of a free base, a salt, a soluble form, or a soluble form of a salt thereof, which is pharmaceutically acceptable. © In another aspect of the invention; A compound of the formula is provided [; Cun ize is picked from -0- aryl ; or -9- Jal aryl is homogeneous; and where there is an optionally substituted in aryl -Q- ; or aryl -Q- heterozygous mentioned by one, two, or three RT R? is 6087087(,85) or if « > 1 then all 008908 are independent of other groups; als Ye picking 3c separately from . hydrogen, halogen, C;.salkyl, Cssalkenyl, Csalkynyl, Cs.¢cycloalkyl, Csscycloalkenyl, aryl, heteroaryl, heterocyclyl, CysalkylCs cycloalkyl, Cyalkylaryl, Cy salkylheteroaryl or Cy.¢alkylheterocyclyl, where there is an optional substitution In: Cs.ealkenyl, Csealkynyl, Csscycloalkyl, Cs.scycloalkenyl, aryl, heteroaryl, 1, Abu al-Laqqi: © or Ci. ; or two; or three sets tA Yavy

Yr. = - -0- is a direct bond; R’ sR’ is independently selected from hydrogen, Cyalkyl, cyano, halo or nitro;185 is selected from an aryl or aryl heterocyclic; where there is a heterogeneous optional substitution caryle or aryl mentioned in between one and four of the 87 groups; and where © any of the odd aryl or aryl heterologous groups can be optionally combined by the number 4 ; or 0 or a or 7 cycloalkyl atoms » ie cycloalkenyl heterocyclyl group to form a double ring system; ak select R' independently from: Cogalkylaryl and Co.galkylOR®, hydroxy, Co.galkylheteroaryl, Calkyl, Coealkylaryl and Co.galkylheteroaryl mentioned by one. or more from group (R' R' is independently selected from halogen, 05028 and Co.calkylOR®, 8 is independently selected from hydrogen, C;-salkyl and trifluoromethyl « in Pharmaceutically acceptable free base form or salt or solubility or solubility of a salt thereof.In another aspect of the invention, the present invention provides pharmaceutical compositions comprising an effective amount of a compound of Formula 1 as an active ingredient in association with excipients; or acceptable carriers or diluents ua Lanya 0 Ha

1h In another aspect of the invention; The present invention provides a compound described in the application or a pharmaceutically acceptable salt thereof; For use as a medicine. In another aspect as well of the invention; The present invention provides a compound described in the application or a pharmaceutically acceptable salt thereof; for use as a drug in the treatment or prevention of a disease related to © AB in another aspect also of the invention; The present invention provides a compound described in the application or a pharmaceutically acceptable salt thereof for use as a drug in the treatment or prevention of a disease related to AB where the disease related to AB is Downs' syndrome and Bramyloid amyloid vascular disease 808107 -8, for example, but not limited to cerebral amyloid angiopathy, hereditary cerebral hemorrhage, and disorders associated with cognitive impairment, to name a few. MCI (mild cognitive impairment (“Alzheimer’s disease”; “memory loss”), attention deficit symptoms associated with Alzheimer’s ¢ and neurodegeneration Jie (ally) Alzheimer's disease or dementia 0 including dementia of mixed vascula ¢ degenerative origin “pre-senile dementia” dementia Dementia associated with Parkinson's disease, progressive supranuclear palsy, or cortical basal degeneration. YoYY

the name _

In another aspect as well of the invention; The present invention provides a compound described herein for use in

Manufacture of a drug to treat or prevent a disease related to AB

In another aspect as well of the invention; The present invention provides a compound described herein for use in

Manufacture of a drug for the treatment or prevention of an AB-related disease (AB) where the AB-related disease is

© is “W0005” syndrome and B-amyloid angiopathy 8 for example

For example, but not limited to cerebral amyloid angiopathy, and bleeding

Gaal hereditary cerebral hemorrhage » and disorders associated with cognitive impairment

“MCI” to name a few ¢ disorders associated with cognitive impairment

Mild cognitive impairment ¢ Alzheimer's disease “memory loss” and symptoms of lack of focus and attention associated with Alzheimer's disease Attention

neurodegeneration and neurological atrophy « deficit symptoms associated with Alzheimer's

Diseases associated with Alzheimer's disease, Alzheimer's disease, or dementia, including dementia of origin

Dementia of mixed vascula

0 + pre-senile dementia ¢ dementia associated with Parkinson's 0 or progressive supranuclear palsy

Or cortical basal degeneration.

In another aspect as well of the invention; The present invention also provides methods for inactivating the enzyme L

J with a compound having the formula (BACE) comprising a contacting action of (BACE)

‎YoYY

srs _

In another aspect as well of the invention; The present invention also provides methods for the treatment or prevention of

disease related to AAP Mammal; It includes giving the patient a therapeutically effective amount of a compound

It has the formula J

These methods could be Ble about ways to treat or prevent disease related to 48 in AS

© Mammal; It includes giving the patient a therapeutically effective amount of a compound that has the formula! and one factor on

least cognitively enhancing; a memory-enhancing agent; or an anti-inflammatory agent; or a choline enzyme inhibitor

. esterase

Mentioned could be a method for treating or preventing a disease related to AB in

mammal It includes giving the patient a therapeutically effective amount of a compound of formula 1 in combination 0 with an atypical antipsychotic agent.

The aforementioned methods refer to a predatory organism, and the mammalian organism may be Ble from a human.

Disease related to AP can be selected from Downs’ syndrome and B-amyloid cerebral vascular disease, to name but not limited to cerebral amyloid 8- angiopathy

¢ hereditary cerebral hemorrhage and hereditary cerebral hemorrhage » amyloid angiopathy disorders associated with cognitive impairment Vo

but not limited to “MCI” (Sha) mild cognitive impairment (“

Alzheimer's disease and memory loss; Symptoms of lack of focus and attention

Attention deficit symptoms associated with Alzheimer's; and atrophy

Neurodegeneration associated with Jie disease Alzheimer's disease or dementia 0 including dementia of mixed vascula origin

da

_ P Y _ degenerative origin “pre-senile dementia ¢ dementia associated with Parkinson's” or progressive supranuclear palsy or cortical basal atrophy cortical basal degeneration. © Cognitive enhancers, memory enhancers, and choline esterase inhibitors » include, but are not limited to: onepezil (Aricept), galantamine (Reminy! or Razadyne), rivastigmine (Exelon), tacrine (Cognex) and memantine ( Namenda, Axura or Ebixa) and atypical antipsychotic agents include; But not exclusively; olanzapine (marketed as Zyprexa), aripiprazole (marketed as Abilify), risperidone Vo (marketed as Risperdal), quetiapine (marketed as Seroquel), clozapine (marketed as Clozaril), ziprasidone (marketed as Geodon) and olanzapine/fluoxetine (marketed as Symbyax). on the AT side of the invention; The compounds of the present invention are represented by a method for the prevention of diseases related to VO of 08m comprising administration to humans of a therapeutically effective amount of a compound of Formula 1 or a salt thereof acceptable in another aspect of the invention; The present invention provides that the mammal or human being being treated with a compound of the invention has been diagnosed with a particular disease or disorder; like that one

Yo —_ — described in the request. In such cases; The mammal or human being being treated is in need of such treatment. However; It does not require that the diagnosis has been made previously. c is -0- aryl ; and where there is an optional substitution in -©- aryl mentioned © by one; or two; or three of ;?; R® is le for (CRHRNMR® - © - is a direct link; RE is an aryl where said aryl has an optional substitution between one and four of 87 and where can The single aryl group is optionally combined with a heterocyclyl group of 0 number 1 feo Seg or 7 atoms to form a dicyclic ring system; R' is selected independently from : halogen, Co.alkylOR® , hydroxy, 050:7 Ciealkyl, Cogalkylaryl and Cosalkylheteroaryl, where there is an optional substitution in: Co.alkylaryl and Co.calkytheteroaryl | 0, removing the mentioned.© by one or more of the group (R' R' is selected independently from ,10157 and for values of halogen, 05011 and * is selected independently from hydrogen, C,-salkyl and trifluoromethyl ed

name m is an array; 8 be pure; In the form of a free base, a salt, a soluble form, or a soluble form of a salt thereof, which is pharmaceutically acceptable. In another aspect of the invention; A compound of the formula ] is presented; where © !1 is selected from a -0- aryl and -0- aryl heterocyclic; and where there is an optional substitution in aryl —Q- aryl -- heterozygous mentioned by one; or two; or three of RT p be {(CRHYRMR® R? be halogen ¢ Q - be direct bond; 0 RO is picked from non-aryl aryl a congener where the said aryl or aryl hetero-aryl has an optional substitution between one and four RT 17 are selected independently from : halogen, Cop.salkylCN, CosalkylOR?, trifluoromethyl, trifluoromethoxy, Co .salkylaryl and Co.salkylheteroaryl, Ve, where there is an optional substitution in: the deafness of the coalkylaryl or 0 peaks mentioned with one or more of the group (R' YoYY

RY is not independently selected from: halogen, CHO, Co.alkylCN, Co.calkylOR®, CosalkylCONR®R', (CO)R' and Ci alkyl; R® and 1873 are independently selected from hydrogen, C-galkyl; . be dia or 1; and Jia asin ©

On the AT side of the invention; A compound of the formula ] is presented; where a is a nodal:.,0-0 p1 is CRHRMR® - © - is a direct link;

0 187 is aryl where said aryl has an optional substitution between one or two of 87; RY is selected independently from halogen » or 4m06 calkyl CN or 06mm 08 alpha; or “alkyl aryl Cos alkyl aryl Cos heterocyclic” and wherein in said Cos alkyl aryl Cogs alkyl aryl heterocycles there is an optional substitution with one or more of the R'™

0 R™ is independently selected from halogen « 3 mm06 having i calkyl mm06 OR® abola; RE is an alkyl Cis ;

YoVy

—_YA —

© is ple of zero; And

Sin is zero.

On the other side of | to invent; Then a compound of formula 1 Cua is introduced

Li is selected from -90- aryl and -9- aryl heterocyclic; and where is -0- aryl and -0- aryl

The mentioned heterogeneous © has an optional replacement by one; or two; or three of RT

It is CRHRNR®

¢ halogen is RY

- © - is a direct link;

R® is selected from an aryl aryl heterocyclic where the said aryl aryl heterocyclic has 0 optional substituents between one and four of 87

187 are selected independently from:

halogen “or mm0”alkyl CN or hydro “alkyl OR? or trifluoromethyl ¢ or

trifluoromethoxy + or alkyl aryl Cos and mo-alkyl aryl heterocyclic; where there is

Optional substitution in said alkyl aryl Cos and heterocyclic alkyl aryl Cos with one or more 0 of the group RM

R'™ is independently selected from the halogen ¢ R «CHO R alkyl CN OCos that alkyl OCo

¢ alkyl rum (COR® R “alkyl CONR®R® RV” OR?

RR? is selected independently from the alkyl rum hydrogen ¢ “” be zero or 1; and “ be row. In another aspect of the invention; A compound of the formula ] is presented; where is 3,3-Diphenyl-3H-isoindol-1-ylamine; 5 3-(3'-Methoxy-biphenyl-3-yl)-3-(4-methoxy-phenyl)-3H-isoindol-1-ylamine trifluoroacetate; Trifluoro-methanesulfonic acid 5-[3- amino-1-(4-methoxy-phenyl)-1H-isoindol-1-yl]-3'- methoxy-biphenyl-2-yl ester trifluoroacetate; 5-[3-Amino-1-(4- methoxy-phenyl)-1H-isoindol-1-yl]-3'-methoxy-biphenyl-2-ol Vo trifluoroacetate; 4,4'-(3-amino-isoindole-1,1-diyl)- bis-phenol;4-[3-Amino-1-(4-methoxy-phenyl)-1H-isoindol-1-yl]-2-pyridin-3-yl-phenol trifluoroacetate;4-[ 3-Amino-1-(4-methoxy-phenyl)-1H-isoindol-1-yl}-2-pyrimidin-5-yl-phenol Vo trifluoroacetate; 3-(4-Methoxy-phenyl)-3 -(3-pyridin-3-yl-phenyl)-3H-isoindol-1-ylamine trifluoroacetate;

and 3-[3-(2-Fluoro-pyridin-3-yl)-phenyl]-3-(4-methoxy-phenyl)-3H-isoindol-1-ylamine trifluoroacetate; 3-(3- Bromo-phenyl)-3-(4-methoxy-phenyl)-3H-isoindol-1-ylamine; 3-(4-Methoxy-phenyl)-3-[3-(5-methoxy-pyridin-3-yl) )-phenyl]-3H-isoindol-1-ylamine trifluoroacetate; 2 3-(4-Methoxy-phenyl)-3-(3-pyrimidin-5-yl-phenyl)-3H-isoindol-1-ylamine trifluoroacetate;

Methanesulfonic acid 3'-[3-amino-1-(4-methoxy-phenyl)-1H-isoindol-1-yl]-5-methoxy- biphenyl-3-yl ester trifluoroacetate; 3-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-3-(3-(2-fluoropyridin-3-yl)phenyl)-3H-01 isoindol-1-amine trifluoroacetate; 3-(2,3-Dihydrobenzo[b][1,4]dioxin-6-y!)-3-(3-(5-methoxypyridin-3-yl)phenyl)-3H-isoindol-1-amine trifluoroacetate; 3-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-3-(3-(pyridin-3-yl)phenyl)-3H-isoindol-1- amine trifluoroacetate; Yo 3-(2,3-Dihydrobenzo[b][ ,4]dioxin-6-yl)-3-(3-(pyrimidin-5-yl)phenyl)-3H-isoindol-1- amine trifluoroacetate; As for

_1 _ 3-(3-Bromo-phenyl)-3-(4-methoxy-3-methyl-phenyl)-3H-isoindol-1-ylamine trifluoroacetate; 3-(3'-Methoxy-biphenyl-3-yl)-3-(4-methoxy-3-methyl-phenyl)-3H-isoindol-1 -ylamine trifluoroacetate; 3-(4-Methoxy-3-methyl-phenyl)-3-[3-(5-methoxy-pyridin-3-yl)-phenyl]-3H-isoindol-1-© ylamine trifluoroacetate; 3-(4-Methoxy-3-methyl-pheny!)-3-(3-pyridin-3-yl-phenyl)-3H-isoindol-1-ylamine trifluoroacetate; 3-(4-Methoxy-3-methyl-phenyl)-3-(3-pyrimidin-5-yl-phenyl)-3H-isoindol-1-ylamine trifluoroacetate; 01 3-[3-(2-Fluoro-pyridin-3 -yl)-phenyl}-3-(4-methoxy-3-methyl-phenyl)-3H-isoindol-1- ylamine trifluoroacetate;

Methanesulfonic acid 3'-[3-amino-1-(4-methoxy-3-methyl-phenyl)-1H-isoindol-1-yl}-5- methoxy-biphenyl-3-yl ester trifluoroacetate; 5'-(3-Amino-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-isoindol-1-y1)-5- Yo methoxybiphenyl-3-yl methanesulfonate trifluoroacetate ; 3-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-3-(3'-methoxybiphenyl-3-yl)-3H-isoindo I-1- amine trifluoroacetate;

YaaYyY

— $ Y —_ 3-Benzo[1,3]dioxol-5-yl-3-(3-pyridin-3-yl)-3H-isoindol-1-ylamine trifluoroacetate; 3-Benzo[1,3]dioxol-5-yl-3-(3-bromophenyl)-3H-isoindol-1-ylamine; 3-Benzo[1,3]dioxol-5-yl-3-(3-pyrimidin-5-ylphenyl)-3H-isoindol-1-ylamine trifluoroacetate; 3-Benzo[1,3]dioxol-5-yl-3-[3-(2-fluoropyridin-3-yl)-phenyl]-3H-isoindol-1-ylamine © trifluoroacetate; 3-Benzo[1,3]dioxol-5-yl-3-[3-(5-methoxypyridin-3-yl)-phenyl]3H isoindol-1-ylamine trifluoroacetate;

In the form of a free base, a salt, a soluble form, or a soluble form of a salt thereof, which is pharmaceutically acceptable.

0 The AT side of the present invention provides compounds of the formula ]; where 3-Benzo[1,3]dioxol-5-yl-3-(3'-methoxy-biphenyl-3-yl)-3H-isoindol-1-ylamine is trifluoroacetate; (3-amino-1-benzo[1,3]dioxol-5-yl-1H-isoindol-1-yl)-5- methoxy-biphenyl-3-yl ester trifluoroacetate; -amino-1-(3-pyridin-3-yl-phenyl)-1H-isoindol-1-yl]-phenyl Vo ester trifluoroacetate;

Methanesulfonic acid 4-[3-amino-1-(3-bromo-phenyl)-1H-isoindol-1-yl]-phenyl ester trifluoroacetate;

Methanesulfonic acid 4-{3-amino-1-[3-(2-fluoro-pyridin-3-yl)-phenyl]-1H-isoindol-1- yl}-phenyl ester trifluoroacetate;

Methanesulfonic acid 4-[3-amino-1-(3-pyrimidin-5-yl-phenyl)-1H-isoindol-1-yl]-phenyl 2 ester trifluoroacetate;

Methanesulfonic acid 4-{3-amino-1-[3-(5-methoxy-pyridin-3-yl)-phenyl]-1H-isoindol-1- yl}-phenyl ester trifluoroacetate;

Methanesulfonic acid 4-[3-amino-1-(3'-methoxy-biphenyl-3-yl)-1H-isoindol-1-yl]- phenyl ester trifluoroacetate; 01

Methanesulfonic acid 4-[3-amino-1-(5'-methanesulfonyloxy-3'-methoxy-biphenyl-3-yl)- 1H-isoindol-1-yl]-phenyl ester trifluoroacetate; 3-[3-(2-Fluoro-pyridin-3-yl)-phenyl}-3-pyridin-4-yl-3H-isoindol-1-ylam ine trifluoroacetate, 3-(3-Bromo-phenyl)-3- pyridin-4-yl-3H-isoindol-1-ylamine trifluoroacetate; Vo 3-Pyridin-4-yl-3-(3-pyridin-3-yl-phenyl)-3H-isoindol-1-ylamine trifluoroacetate; 3-Pyridin-4-yl-3-(3-pyrimidin-5-yl-phenyl)-3H-isoindol-1-ylamine trifluoroacetate; Abi Aya Mr

_ $ —

3-[3-(5-Methoxy-pyridin-3-yl)-phenyl]-3-pyridin-4-yl-3H-isoindol-1-ylamine trifluoroacetate ; 3-(3'-Methoxy-biphenyl-3-yl)-3-pyridin-4-yl-3H-isoindol- 1-ylamine trifluoroacetate; 3-{3-[3-Amino-1-(4-methoxyphenyl)-1H-isoindol-1-yl]phenyl} thiophene-2- carbaldehyde 1,5 acetate; 2 4-[3-Amino-1-(3-bromophenyl)-1H-isoindol-1-yl}benzonitrile; 1-(3-Bromophenyl)-1-[4~(trifluoromethyl)phenyl]-1H-isoindol-3-amine; 1-(3-Bromophenyl)-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-isoindol-3-amine acetate; 1-[3-(1-Isobutyl-1H-pyrazol-4-yl)phenyl]-1-(4-methoxyphenyl)-1H-isoindol-3-amine 0.5 acetate; 01 1-(4-Methoxyphenyl)-1-[3-(5-methyl-2-furyl)phenyl]- | H-isoindol-3-amine 0.5 acetate; 3'-[3-Amino-1-(4-methoxyphenyl)- 1H-isoindol-1-yl]biphenyl-2-carboxamide 0.5 acetate; 1-[3-(5-Fluoropyridin-3-yl)phenyl]-1-[4-(trifluoromethoxy)phenyl]-1H-isoindol-3-amine 0.75 acetate; Vo 1-(3-Pyrimidin-5-ylphenyl)-1-[4-(trifluoromethoxy)phenyl]-1H-isoindol-3-amine 0.25 acetate;

slept

D-4-[3-Amino-1-(3-pyrimidin-5-ylphenyl)-1H-isoindol-1-yl]benzonitrile 0.25 acetate; 1-[3-(5-Fluoropyridin-3-yl)phenyl]-1-[4-(trifluoromethyl)phenyl]- 1 H-isoindol-3-amine 0.25 acetate; 1-(3-Pyrimidin-5-ylphenyl)-1-[4-(trifluoromethyl)phenyl]-1H-isoindol-3-amine 0.25 acetate; 0 3-[3-(3-Amino-1-pyridin-4-yl-1H-isoindol-1-yl)phenyljthiophene-2-carbaldehyde; 1-[3-(1-Isobutyl-1H-pyrazol-4-yl)phenyl]-1-pyridin-4-yl-1H-isoindol-3-amine 0.25 acetate; 1-[3-(5-Methyl-2-furyl)phenyl]-1-pyridin-4-yl-1H-isoindol-3-amine acetate; 3'-(3-Amino-1-pyridin-4-yl-1H-isoindol-1-yl)biphenyl-2-carboxamide 0.25 acetate; Ve 4-{3-Amino-1-[3-(2-fluoropyridin-3-yl)phenyl]-1H-isoindol-1-yl} benzonitrile; 1-[3-(2-Fluoropyridin-3-yl)phenyl]-1-[4-(trifluoromethyl)phenyl]-1H-isoindol-3-amine; 1-[3-(5-Fluoropyridin-3-yl)phenyl]-1-pyridin-4-yl-1H-isoindol-3-amine 0.75 acetate; 1-(4-Fluoro-3-pyrimidin-5-ylphenyl)-1-pyridin-4-yl-1H-isoindol-3-amine 0.5 acetate; 1-[4-Fluoro-3-(5-fluoropyridin-3-yl)phenyl]-1-pyridin-4-yl-1H-isoindol-3-amine 0.75 Vo acetate;

YAYY

— A" 4 _—

1-(3-Fluoropyridin-4-yl)-1-[3-(5-fluoropyridin-3-yl)phenyl]-1H-isoindol-3-amine 0.5 acetate; 1-(3-Fluoropyridin-4-yl)-1-(3-pyrimidin-5-ylphenyl)-1H-isoindol-3-amine 1.25 acetate; 1-(3-Fluoropyridin-4-yl)-1-[3-(2-fluoropyridin-3-yl)phenyl]-1H-isoindol-3-amine 1.25 acetate; 0 1-(3-Fluoropyridin-4-yl)-1-(4-fluoro-3-pyrimidin-5-ylphenyl)- 1 MNSA-1-15010001-3] 5 acetate; 1-[4-Fluoro-3-(5-fluoropyridin-3-yl)phenyl]-1-(3-fluoropyridin-4-yl)-1H-isoindol-3- amine 1,5 acetate; 1-[4-Fluoro-3-(2-fluoropyridin-3-yl)phenyl]-1-(3-fluoropyridin-4-yl)-1H-isoindol-3- 01 amine 1,5 acetate; 5-[3-(3-Amino-1-pyridin-4-yl-1H-isoindol-1-yl)phenyl]nicotinotrile acetate; 6-Fluoro-1-(4-methoxyphenyl)-1-(3-pyrimidin-5-ylphenyl)- 1H-isoindol-3-amine; 6-Fluoro-1-(4-methoxypheny!)-1-(3-pyridin-3-ylphenyl)-1H-isoindol-3-amine; 6-Fluoro-1-(3'-methoxybiphenyl-3-yl)-1-(4-methoxyphenyl)-1H-isoindol-3-amine; Vo 6-Fluoro-1-(4-methoxyphenyl)-1-[3-(5-methoxypyridin-3-yl)phenyl}-1 H-isoindol-3- amine;

- Al 6-Fluoro-1-pyridin-4-yl-1-(3-pyridin-3-ylphenyl)-1H-isoindol-3-amine; 6-Fluoro-1-pyridin-4-yl-1-(3-pyrimidin-5-ylphenyl)-1H-isoindol-3-amine; 6-Fluoro-1-[3-(5-methoxypyridin-3-yl)phenyl]-1-pyridin-4-yl-1H-isoindol-3-amine; 6-Fluoro-1-[3-(2-fluoropyridin-3-yl)phenyl]-1-pyridin-4-yl-1H-isoindol-3-amine; 1-(3',5'-Dichlorobiphenyl-3-yl)-1-(4-methoxyphenyl)-1H-isoindol-3-amine acetate; 5 1-(3-Bromophenyl)-1-isopropyl-1H-isoindol-3-amine hydrochloride; 3'-(3-Amino-1-cyclopropyl-1H-isoindol-1-yl)-5-methoxybiphenyl-2-carbonitrile acetate; 1-Cyclopropyl-1-(3-pyrimidin-5-ylphenyl)- | H-isoindol-3-amine acetate; 3'-(3-Amino-1-methyl-1H-isoindol-1-yl)-5-methoxybiphenyl-2-carbonitrile acetate; 1-(3',5"-Dichlorobiphenyl-3-yl)-1-methyl-1H-isoindol-3-amine hydrochloride; Yo 1-Methyl-1-(3-pyrimidin-5-ylphenyl)-1H-isoindol- 3-amine acetate; 1-[3-(2-Fluoropyridin-3-yl)phenyl]-1-methyl-1H-isoindol-3-amine acetate; 1-Isopropyl-1-(3-pyrimidin-5-ylphenyl) and 1-[3-(5-Fluoropyridin-3-yl)phenyl]-1-methyl-1H-isoindol-3-amine acetate;

0 in the form of a free base, a salt, or a soluble or a soluble of a salt thereof, which is pharmaceutically acceptable. YoYY

M - Some compounds of the formula present in the invention may be characterized by stereoisomers and/or She is geometric isomers (Br and -2 isomers); It will be understood that the invention involves all such optical isomers; enantiomers; binary stereoisomers; recessive isomers and engineering isomers. © The present invention relates to the use of compounds of the formula ] as defined above as well as

salts thereof. The salts for use in pharmaceutical compositions will be pharmaceutically acceptable salts but other salts may be useful in the production of compounds of formula I. It will be understood that the present invention relates to any and all isoforms of compounds of formula I

0 The compounds of the invention can be used as medicines. in some models. The present invention provides compounds of any formulations described herein; or pharmaceutically acceptable salts or synthetic forms or substances thereof that are hydrolyzable in living organisms; For use as medicines. in some embodiments; The present invention provides compounds described herein for use as drugs to treat or prevent diseases related to AB in some other embodiment; Diseases related to 8M are Downs Syndrome; and vascular disease

0 Amyloid Ap « and cerebral amyloid angiopathy; hereditary cerebral hemorrhage” and the disorder associated with cognitive impairment; MCLs (“mild cognitive impairment”) and Alzheimer’s disease; memory loss; symptoms of impaired attention associated with Alzheimer's disease; neurological disorder associated with Alzheimer's disease and dementia caused by mixed vascular Jal; dementia of disordered origin; His degenerative pre-aging condition

Parkinson's disease associated with dementia; and pre-senile dementia ¢ origin V+

‎YoYY

sq — -; Or progressive supranuclear palsy or (Pla) cortical basal degeneration. in some embodiments; The present invention provides compounds of any formulations described herein; or pharmaceutically acceptable salts or synthetic forms or substances thereof that are hydrolyzable in living organisms; In © the manufacture of a drug for the treatment or prevention of diseases related to 88. In some other embodiments; Diseases related to AB include Downs syndrome; amyloid angiopathy, AB; cerebral amyloid angiopathy; hereditary cerebral hemorrhage; disorder associated with cognitive impairment; MCI ("mild cognitive impairment"); Alzheimer's disease; memory loss; the symptoms of impaired attention associated with Alzheimer’s disease “the neurological disorder associated with Alzheimer’s disease 0; dementia of mixed vascular origin” and dementia of autistic origin; his pre-aging degenerative origin; pre-senile dementia; dementia associated with Parkinson's disease, progressive supranuclear palsy, or cortical basal degeneration. VO in some embodiments; The present invention provides a method for the inactivation of BACE comprising contact of the BACE with a compound of the present invention. It is believed that BACE represents the main activity of the 8-releasing enzyme and is the rate-limiting step in the production of amyloid-8 protein (AB) and thus; It inhibits BACE through some inhibitors such as the compounds that are presented in the application, which is useful in inhibiting the precipitation of AB and parts of it. And since the deposition of AB and parts of it is associated with diseases such as Alzheimer's disease 0; BACE is an important candidate for drug development such as the treatment and/or prevention of 7 major diseases

HH - associated with AP”_as amyloid angiopathy AB but not limited to; cerebral amyloid angiopathy; hereditary cerebral hemorrhage” and disorders associated with cognitive impairment; For example, but not limited to MCT ("mild cognitive impairment"); Alzheimer's disease; memory loss; symptoms of lack of concentration associated with Alzheimer’s disease © and neurodegeneration associated with diseases Jie Alzheimer’s disease or Ley dementia, including mixed vascular dementia and degenerative origin; degenerative origin ¢ pre-senile dementia dementia associated with Parkinson's disease or mast progressive supranuclear palsy cortical basal degeneration. 0 In some embodiments, the invention provides a method for treating diseases related to 8m Jie Downs syndrome; and amyloid angiopathy 8m » cerebral amyloid angiopathy, hereditary cerebral hemorrhage; disorder associated with cognitive impairment; and 1401 (“mild cognitive impairment”); Alzheimer's disease; memory loss” and symptoms of impaired attention associated with Alzheimer’s disease” and neurological disorder associated with Alzheimer’s disease “dementia 0 of mixed vascular origin” and dementia of a disorder origin; degenerative origin “pre-senile dementia” “dementia associated with Parkinson’s disease” or “progressive supranuclear palsy” or “cortical basal degeneration” 358 ¢ It comprises the administration of a therapeutically effective amount of a compound of any formulations described in the application; pharmaceutically acceptable salts; synthetic forms or 0 _ products thereof that are hydrolyzable in a living organism; to a mammal (including a human). YAYY

- H1

In some embodiments, the invention provides a way to prevent diseases related to 8M such as Downs syndrome; amyloid angiopathy 88 » cerebral amyloid angiopathy; hereditary cerebral hemorrhage; Cognitive Impairment Associated Disorder and 1401 (“mild cognitive impairment”); Alzheimer's disease; memory loss; symptoms of attention deficits associated with Alzheimer's disease ©; neurological disorder associated with Alzheimer's disease (dementia) of mixed vascular origin; dementia of disordered origin; degenerative origin “pre-senile dementia ¢ dementia associated with Parkinson's disease” or progressive supranuclear palsy or cortical basal degeneration ¢ It includes the administration of a therapeutically effective amount of a compound of any formulations described in the application; or pharmaceutically acceptable salts or synthetic forms or

Substances produced therefrom are hydrolyzable in living organisms; to a mammal (including a human). In some embodiments, the invention provides a method for treating or preventing diseases related to AB such as Downs syndrome; amyloid angiopathy (AP); cerebral amyloid angiopathy; hereditary cerebral hemorrhage; disorder associated with cognitive impairment; MCLs ("Vo-moderate cognitive impairment")"; Alzheimer's disease and memory loss. symptoms of impaired attention associated with Alzheimer's disease; a neurological disorder associated with Alzheimer's disease and axlll dementia of mixed vascular origin; dementia of disordered origin; his pre-aging degenerative origin; pre-senile dementia ¢ Dementia 538 associated with Parkinson's disease or progressive supranuclear palsy 00 or cortical basal degeneration; It includes administration of a therapeutically effective amount of a compound from any formulations described in the application; or acceptable salts

1 are

oy — - pharmaceuticals, synthetics or substances produced therefrom that are hydrolysable in the organism; to a mammal (including a human) and an agent to enhance cognition and/or memory. In some embodiments, the invention provides a method for treating or preventing diseases related to AP such as Downs syndrome; amyloid angiopathy, AB; cerebral amyloid angiopathy; © and hereditary cerebral hemorrhage; disorder associated with cognitive impairment; MCLs (‘mild cognitive impairment’); Alzheimer’s disease; memory loss; symptoms of attention impairment associated with Alzheimer’s disease » and Alzheimer’s-associated neurological disorder; dementia of mixed vascular origin; dementia dementia of a disordered origin; degenerative origin ¢ pre-senile dementia “dementia 0 associated with Parkinson's disease” or progressive supranuclear palsy or Cortical basal degeneration; comprising the administration of a therapeutically effective amount of a compound of any formulations described in the application; or pharmaceutically acceptable salts or synthetic forms or products thereof that are hydrolysable in vivo; to a mammalian Ly) In that human); where the constituents are presented in the application; or a cholinesterase inhibitor 0 or an anti-inflammatory agent. In some embodiments the invention provides a method for the treatment of or prevention of diseases related to “Jie AB Downs syndrome” and “Downs syndrome” AP amyloid angiopathy; cerebral amyloid angiopathy; hereditary cerebral hemorrhage; disorder associated with cognitive impairment; MCL (“mild cognitive impairment”) and Alzheimer’s disease; memory loss; symptoms of attention deficits associated with Alzheimer's disease; a nerve disorder associated with Alzheimer's disease; And I cursed him, YAYY

— ov —

dementia of mixed vascular origin; dementia of disordered origin; his consciousness

pre-aging degenerative origin; Pre-senile dementia ¢ dementia

progressive or progressive supranuclear palsy » Parkinsons disease associated with dementia

supranuclear palsy or cortical basal degeneration; or any disease; or © disturbance; or a condition described in the application; By giving a mammal (including a human) a compound

of the present invention; and an atypical antipsychotic agent. Atypical factors included

anti-psychiatric disorder; But not exclusively; on Olanzapine (marketed

Aripiprazole 5” (Zyprexa aul (marketed as Qazakam)); and Risperidone (marketed as

(Marketed as “Risperdal” and Quetiapine (marketed as 5800061); and JClozapine (Marketed as Ziprasidone 0) (Clozaril (Marketed as Fluoxetine / Olanzapine 5 (Geodon)

It is marketed as Symbyax

in some models; The mammal or human being treated with a compound of the invention

the current claim that he is suffering from a particular disease or disorder; such as those described in the application. And in this

cases; The mammal or human being being treated is in need of such treatment. However Vo; It is not necessary to make a diagnosis in advance.

The present invention also includes pharmaceutical formulations that contain; as an active ingredient; on one or more

The compounds of the invention in the application together with a carrier; or a diluent; or at least one excipient

Pharmaceutical acceptable.

The definitions provided in this application are intended to clarify the terms used throughout this Yo specification. Where “in order” means the entire order.

one -

A variety of compounds in the present invention can exist in geometric or stereoscopic forms

specific. The present invention takes into account all of these compounds; Including the Si and isomers

trans; the homologues of Fig. 18 and 5; isomers (0); isomers (1); and racemic terminator mixtures and mixtures

other terminators to be covered within the scope of this invention. Non-carbon atoms can exist

© is an additional homolog in a substituting group such as an alkyl group . All Jie are these isomers; Furthermore

Terminated mixtures are intended to be included in this invention. It can contain compounds

that are described in demand for asymmetric centers. The compounds of the present invention can be isolated

They contain an atom that is dissimilarly substituted in either photoactive or racemic forms. and it is known

Well in the art how to prepare photoactive images, for example, by analyzing racemic images from

0 Optically active materials. and when necessary; Racemic matter separation can be achieved by two methods

known in art. Many engineering isomers can also be olefins; And

double bond groups 14 = © ; and the like are present in the compounds that are described in

demand; All Jie these stable isomers are predicted in the present invention. The isomers are described

Cis and trans are compounds of the present invention and can be isolated as mixtures of isomers or in

0 separate isomeric images. And all chiral forms are; dichotomous » and racemic; and isomerism

engineering concerned; Unless a form of stereochemistry or a particular isomerism is specifically indicated.

When it turns out that a linker in a substitution group aad is a linker connecting two atoms in the cle loop then

This de sane Jie substitution can be attached to any atom of the ring. And when a substitution group of what

0 is listed without indicating the atom by which such a substitution group is related in a remainder

the compound of a given formula; ia Jie This substitution group can be associated with

No but m except

Any atom in such a substitution group. They are not combinations of substitution groups and/or

Variants are allowed unless Jie results in these combinations of stable compounds.

according to its use in the application”; The term alkyl "" meaning "alkylenyl" or 'alkylene' used

alone or as a suffix or prefix; It is intended to contain both hydrocarbon groups

0 Aliphatic with both branched and straight chain containing a number ranging from 1 to 11 carbon atoms

Or if a specific number of carbon atoms, Jia, is provided, this specific number is what is meant. include

: but not limited to ¢ alkyl for examples 1 methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl.

according to its use in the application; It is understood that “alkyl C1-3” is either a terminal substituent or an alkylene 0 ) or an alkylenyl ) bonding group of two substituents; It includes specifically

on both methyl; ethyl s and propyl of de jie chain and straight.

according to its use in the application”; The term "abolite" refers to an alkyl group containing a bond

One or more carbon-carbon pairs. Examples of alkylenyl groups include ethynyl ; And

cyclohexenyl s « propynyl ; and the like. The term “alkenylenyl” refers to the valence bond als 0-alkylenyl group.

according to its use in the application; The term * alkylenyl " denotes an alkyl group containing one or more

More than one carbon-carbon triple bond. Examples of alkylenyl groups include ethynyl ;

propynyl; and the like. The term "alkynylenyl" refers to an alkylenyl bonding group

bivalent.

1e - as used in the application; The term "aromatic" refers to hydrocarbyl groups containing one or more polyunsaturated carbon rings containing aromatic letters; Oi); 0 +? repositionable electron) and contain up to about VE carbon atoms. according to its use in the application; The term aryl ' ' denotes an aromatic ring structure of © to VE © carbon atoms. Ring structures with Vo 8 carbons can be monocyclic aromatic groups; for example » phenyl Ring structures with a number of OY OY 01 AA 13 or VE can be a polycyclic moiety in which at least one carbon atom is a co-atom of any two of its bonding rings (eg The rings are 'fused rings', eg naphthyl. There can be substitution of the aromatic ring at one or more of the ring positions with such substitution groups as described above. The term may also include "aryl" on polycyclic ring systems containing two or more cyclic groups and in which two or more carbon atoms are shared with two of the bonding rings (the rings are "combined rings") where at least one of the rings is aromatic; eg dial 0 other acyclic groups can be cycloalkyl compounds , cycloalkenyls , or cycloalkenyls . The terms ortho, meta and para apply to components 1 285 ?- f *- and 1- = f have no substitution; respectively. For example; 1,2-dimethylbenzenee lan! and dimethylbenzene are synonyms. according to its use in the application; The term "cycloalkyl" refers to non-aromatic Te cyclic hydrocarbons including cycloalkyl; the alkylenyl ¢ alkenyl groups; containing a specified number of YoYY

mother carbon atoms. The cycloalkyl groups may include monocyclic or polycyclic groups (Ola) containing 7 oF or ; fused or bridged rings). Examples of cycloalkyl groups include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, ° adamantyl, and the like. Also included in this definition of cycloalkyl moieties are moieties that contain one or more aromatic rings fused (i.e. contain a co-bond with) a cycloalkyl ring, for example; Benzo derivatives of: cyclopentane (i.e., indanyl), cyclopentene, cyclohexane 0 and the like. The term "cycloalkyl" also includes saturated ring groups; It contains a definite number of carbon atoms. These combinations may include integrated or bridged multiloop systems. Preferred cycloalkyl compounds contain a number of ? to 10 carbon atoms in its ring structure; It contains more preferably an oF of 4; ©; and 1 carbon atoms in the ring structure. For example \o the term alkyl C3-6" () refers to Je such groups as: cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Lad, for its use in callall the term "cycloalkenyl" to ring-containing hydrocarbyl groups containing at least one carbon-carbon double bond in the ring; and containing from * to 11 carbon atoms.

g - according to its use in the application; "halogen" I "halo" stands for fluoro and chloro; And bromo, and iodo. The term “antiion” is used to represent small, negatively or positively charged species such as: chloride (CI), bromide (3«), hydroxide (OH), acetate (01]11:000), sulfate ( S04%), © tosylate (CH;-phenyl-SO5"), benezensulfonate (phenyl-SOs'), sodium ion (Na), ammonium (NH,"), per potassium and the like According to its use in the application, the term 'heterocyclyl', 'heterocyclic group' or 0 'heterocyclic' refers to monovalent and divalent ring-containing structures containing one or more heterocyclic atoms; which are picked independently from ON, 0, and 5; as part of the ring structure and have from * to Ye atoms in rings; Jog more preferably has − to 7 atoms in the ring. The number of ring constituent atoms in the heterocyclic ring is given in values between the ranges in the order.For example, 0 indicates the expression 0-9 and heterocyclyl denotes a ring structure comprising ne ranging from © to 01 constituent atoms for a ring where at least one of the atoms is SN ©0”; or 5. Heterocyclic groups can be partially saturated, saturated, or unsaturated and contain one or more double bonds; Heterocyclic groups may contain more than one ring as in the case of polycyclic systems. The non-homogeneous 0-cyclic groups described in the application may have a substitution on the carbon or on the heterocyclic atom if it is important

-uh - the resulting compound was stable. If this is specifically noted; The nitrogen in the heterocyclic ring can be tetramer. It should be understood that when the total number of 5 and 0 atoms in the heterocyclic ring exceeds 1; Mina These heterogeneous atoms are not adjacent to each other. Examples include heterocyclic groups; but not limited to © 111-11022016, 2-pyrrolidonyl, 2H, 6H-1, 5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1 , 2,5-thiadiazinyl, acridinyl, azabicyclo, azetidine, azepane, aziridine, azocinyl, benzimidazolyl, benzodioxol, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzis othiazolyl, benzimidazalonyl, yo-carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, diazepane, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dioxolane, furyl, 2,3-dihydrofuran, 2,5-dihydrofuran, dihydrofuro[2,3-b] tetrahydrofuran, furanyl, furazanyl, homopiperidinyl, imidazolidine, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, Yo isoindolinyl, isoindolyl, isoquinolinyl , isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl , oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxirane, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl , phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, Ye

YoYY pteridinyl, piperidonyl, 4-piperidonyl, purinyl, pyranyl, pyrrolidinyl, pyrroline, pyrrolidine, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoxazole, pyridoimidazole, pyridothiazole, pyridinyl, N-oxide-pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidinyl dione, pyrrolinyl, pyrrolyl, pyridine, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, © tetramethylpiperidinyl, tetrahydroquinoline, tetrahydroisoquinolinyl, thiophane, thiotetrahydroquinolinyl, 6H-1,2, 5-thiadiazinyl, 1,2,3 -thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiopheneyl, thiirane, triazinyl, 1,2,3 -triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl. 01 heterocyclic" to heterocyclic aromatic ring; aryl" as used in the application; The term nitrogen sl ¢ oxygen sl sulfur denotes a sulfur Jie containing at least heterocyclic ring 53

Sie) heterocycles contain monocyclic and polycyclic aryl systems and include heterocyclic groups; and without aryl containing ?; or © or; united rings). Examples of groups include: Restriction on 0 pyridyl (I.E., pyridinyl), pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, frylyl (I.E. Furanyt), quinolyl, ISOQUINLYL, Thienyl, IMIDAZALYL, Thiazol yl, indolel, pyryl, oxzolyl, benzofuryl, benzothienyl , benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, Ye.

YAYY

and the like. in ax forms; The aryl group heterocyclic contains from 1 to 1 carbon atom; And in additional models of about? to about Ye carbon atom. In some oz Sad the heterogeneous aryl group contains a number ranging from about ? to about VE and from; to about VE and who? To about So of © to + atoms form a ring. in some embodiments; © The aryl heterocycle contains 1 to about ef and 1 to about ©; or from 1 to ? BY is not homogeneous. in ax forms; The non-homonym aryl group contains 353 non-homonyms, according to his use in the application; Jia the term 'alkoxy' or 'alkyloxy' an alkyl group as defined above with the indicated number of carbon atoms attached through an OXygen bridge. 01 examples include alkoxy 'but not exclusively ¢ to:

methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, n-pentoxy, isopentoxy, cyclopropylmethoxy, allyloxy and propargyloxy. According to the alkyl group 'thioalkoxy' or similarly 'alkylthio'; the term represents

Its definition, Lad, is preceded by the indicated number of carbon atoms attached through a sulfur bridge, 501802. YO as defined in the application; The term 'carbonyl' is known in the art and includes such

cracks according to what can be represented by the following general formula: 0 0 or xg , mal where 36 is a bond or represents an oxygen or sulfur atom » and R represents hydrogen ; or alkyl “alkenyl sl” or “-(CHp)m-R” a pharmaceutically acceptable salt; It stands for hydrogen or alkyl or

a

alkylenyl or (CH)RY where ““ is an integer less than or equal to ten; and RY is

alkyl; or aryl Se alkylenyl Se cycloalkyl ¢ or aryl heterocyclic. where X is an atom

Rs ; oxygen is X ; The formula represents "ester". where hydrogen is not R's Rs oxygen

shall be in accordance with what has been defined above; The section referred to in the application is:

© ccarboxyl group Specifically when you are 18 1700880 ; The formula represents "acid."

cscarboxyl where X is oxygen ¢ and R' is hydrogen ' and the formula is 'image'. As

public Where the oxygen atom of the aforementioned formula, Le, is replaced by a sulfur atom; represent

The formula is a 'thiocarbonyl group'. Where X is a sulfur and R's is not

hydrogen and 8 is sulfur forming sulfur X where “thiolester” the formula represents ¢ hydrogen; hydrogen and 1 being sulfur forming sulfur X and where “carboxylic acid”; The formula is Ve

hydrogen not be Ry be bonding; X on the other hand; where “thiolformate” is the formula Jus

0, the aforementioned formula represents the “ketone” group. where X is bond; and be

“aldehyde” and the aforementioned formula represents the group “hydrogen.”

according to its use in the application”; The term sulfonyl” denotes a moiety that can be represented by the following general formula Vo:

1 8 0 R Cus is represented by; but not exclusively “cycloalkyl s” alkyl s “hydrogen; 5 aryl «aryl ¢ alkylenyl heterocyclic» and null: ; or aralkyl heterocyclic.

Y — 3 _ as used in the application; Some substitution groups are described in combination of two or more groups. For example; The expression “cycloalkyl C(=0)C.o 8 is intended to denote the following structure: 0 © m p ) r where m is Vo YY) or not (ie; mon cycloalkyl ; is Cig cycloalkyl has a substitution by (RY) and the conjugation point of " cycloalkyl C(=0)Ciu "IR is through the carbon atom of the carbonyl group ; which is to the left of the expression. According to its usage In the application, “dels group” means temporary substituting groups that protect a potentially reactive functional group from unwanted chemical conversions. Jie Yo examples of such protecting groups include: esters of carboxylic acids, silyl ethers of alcohols , and acetals and ketals of aldehydes and ketones, respectively.The field chemistry of protective groups was reviewed in (Greene, T.W.; Wuts, P.G.M.

Protective Groups in Organic Synthesis, 3" ed.; Wiley: New York, 1999). Vo As used in the application, the term "pharmaceutically acceptable" is used to refer to such compounds, substances, compositions, and/or dosage forms; which are within the scope of medical good judgment; suitable for use in contact with human tissues and organisms without toxicity; or irritation; or

Excessive allergic response or any problem or complication pal equal to a reasonable benefit/risk ratio. according to its use in the application; The terms "pharmaceutically acceptable salts" refer to derivatives of disclosed compounds where the parent compound is modified by the action of an acid or a Lege© base salt (ie, also includes counterions). Examples of pharmaceutically acceptable salts include; But not exclusively; contain mineral or organic acid salts from the basic building units such as amines; or alkaline or organic salts from acid building units such as carboxylic acids; and the like. Pharmacologically acceptable salts include non-toxic conventional salts or quaternary ammonium elements of the principal compound formed; For example; of 0 non-toxic inorganic or organic acids. For example; Such conventional non-toxic salts include those derived from inorganic acids hydrochloric acid (ie ¢ phosphoric ; and the like); and salts prepared from organic acids lactic, Jie , maleic, citric, benzoic, methanesulfonic » and the like. The pharmaceutically acceptable salts of the present invention may be synthesized from the principal compound containing 05 acid or base moieties by conventional chemical methods. In general, such salts may be prepared by reaction of 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 in a mixture of the two; or non-aqueous media may be used such as: ether, ethyl acetate, ethanol, isopropanol, YoYXY

A “_ as used in the application”; the term “biogenic hydrolysable precursors” means an in vivo hydrolyzable (or fissionable) ester of a compound of any of the formulas described in the application and which contains a group carboxy or hydroxy . For example, amino esters s «acid esters» mal © Jie : methoxymethyl; Cy alkanoyloxymethyl esters 8 such as: Jie pivaloyloxymethyl; Cs.gcycloalkoxycarbonyloxy C,.ealkyl esters : 1-cyclohexylcarbonyloxyethyl, acetoxymethoxy, or phosphoramidic cyclic esters as used in the application; The term "isomer" means other structural isomers that exist in equilibrium resulting from the transfer of a hydrogen atom. For example; Jil is a form of keto enol where the resulting compound Ye has the properties of both a ketone and an unsaturated alcohol. according to its use in the application; The terms 'stable compound' and 'stable structure' are intended to refer to a compound which is sufficiently strong to resist sequestration to a useful degree of purity from a mixture (Jolin) and formulation into an active therapeutic agent. The present invention also comprises equally numbered compounds Surface Tension of the Invention The “isotonic” or “radioactive” compound is a compound of the invention in which one or more atoms are replaced or replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number Which is typically found in nature (i.e., naturally occurring).

abbreviation of the word deuterium); and PH (also written as 7 as an abbreviation for the word tritium); Cs

M3 PNG MC Ratha Ramota Run 05617 Thul 5 5S 5 PF Roth Br “2 Bry”

Br 2315« 12415 12515« and 11'. It is the radionuclide that is inserted

In immediate radioactive numbered compounds depending on the specific application of that radioactive numbered compound.

© for example; For future digitization and in vitro digitization experiments; Which vehicles are

Me, Br, BT, BL BS contain or will contain the most useful. with regards

For radiographic applications it will be M 778 f Tgp Too (131 nm) 123 [125 18 Nig, most

utility in general.

It is understood that a “radio-labelled compound” is a compound that contains at least one radioactive nucleotide 0. In some embodiments a radionuclide is selected from the pool

CH, BEN" PLL, PS and 8+ which consist of

The anti-dementia treatment specified in the application may be applied alone or may include; Bonus

on the compound of the invention; on conventional chemotherapy. This may include chemotherapy

contain one or more of the following classes of agents: acetyl cholinesterase inhibitors or anti-inflammatory agents » or cognitive enhancing agents and

Or memory enhancing agents or anti-psychological or atypical disorders

Atypical antipsychotic agents

Jie can achieve this combined treatment by instantaneous doses; or sequential or discrete components

individual treatment. Such combination products use the compounds of this invention.

TV —_ _ compounds of the present invention may be administered orally; or through the alimentary canal; or temples; or vagina; or rectal; or inhalation; or andl or under the tongue; or in muscles; or under the skin; or superficial, in the nose, or in the peritoneum; or inside the chest; or into a vein; or in the epidural; or in the sheath; or inside the brain and inside the neck; And by injections into the joints.

5 The dose will depend on the route 'ec acy', disease severity ¢, age and weight of the patient, and other factors considered by the attending physician in | to be considered gle and when determining the individual treatment regimen and dose level as the most appropriate for a particular patient. The effective amount of a compound of the present invention for use in the treatment of dementia is an amount sufficient to relieve symptoms in GIS blood Specifically hot

0 person for dementia; olay the development of dementia; or reduce the risk of the condition becoming worse in patients with symptoms of dementia. For the preparation of pharmaceutical compositions from the compounds of this invention, the pharmaceutically acceptable inert carriers can be either solid or liquid. Solid formulations include powders; or “al il” or dispersible granules; capsules; rivet; and suppositories.

VO can be the solid carrier ple for the sale one or ST which can function as diluents; or flavoring agents; solvents, lubricants, suspension agents, dials or tablet disintegrating agents; It can also be a laminated material. in powders; The carrier is a solid that has been broken down to a fine size; Ally is in a mixture with the active ingredient, dissolving into a stream. in discs; The active ingredient is mixed with the substance

‎YoYY

A — 3 _ Wanted. for the preparation of suppositories; A low melting point wax such as a mixture of glycerides of fatty acids and cocoa butter is first melted and the active ingredient dispersed in it by; For example JE © flipping. The melted homogeneous mixture is then poured into appropriately sized molds and left to cool and solidify. Suitable carriers include: magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, Ve, etc. like. in some embodiments; The present invention provides a compound having any of the formulations described in the application or a compound thereof that is pharmaceutically acceptable for therapeutic use (including prophylactic treatment) in mammals including humans 'Ae Lia ally' normally in accordance with standard pharmaceutical practice in the form of a hunting formulation Because 0 in addition to the compounds of the present invention”; The pharmaceutical composition of this invention may also contain or be administered in combination (simultaneously or sequentially) with; One or more pharmacological agents of value in the treatment of one or more of the pathological conditions referred to in the application. 71 d

(a) The term composition is intended to include the formula of the active ingredient or pharmaceutically acceptable salt with a pharmaceutically acceptable carrier. For example Ji this invention can be formulated by means known in the art into a form of; For example; pall or aqueous or oily solutions; or suspensions; or emulsifiers; or creams; or ointments; or glat; or nasal spray; or suppositories; or finely divided powders, aerosols or aerosols for inhalation and non-gastrointestinal use (including intravenous, intramuscular, or infusion) as sterile aqueous or oily solutions, suspensions, or sterile emulsions. Liquid forms of formulations contain solutions, suspensions and emulsions. Sterile water or aqueous solutions with propylene glycol of the active compounds may be used as examples of liquid preparations suitable for non-gastrointestinal administration. Liquid formulations may also be formulated in an aqueous propylene glycol solution. Aqueous solutions for oral administration may be prepared by dissolving the active ingredient in water and adding appropriate colorants, flavoring agents, stabilizers and thickening agents as desired. Aqueous suspensions for oral use can be made by dispersing the active ingredient finely atomized in water with a viscous material such as natural and synthetic asma & resins, methyl cellulose, sodium carboxymethyl cellulose 0 and other suspension agents known in the pharmaceutical formulation field. Pharmaceutical formulations can be in the form of a dose unit. And in that picture; The formulation is broken down into dosage units that contain appropriate amounts of the active ingredient. The dosage form may be an encapsulated preparation; As the packaged preparation contains separate quantities of 01 preparations; For example tablets, capsules and powders packed in vials or ampoules. Can ba no m only

— that the form of the dose unit is also the same as the capsule, mini-tablet or tablet; Or it could be the appropriate number of any of these packaged images. Compositions may be formulated for any appropriate route and medium of administration. Appropriate, pharmaceutically acceptable carriers or diluents include those used in formulations suitable for oral, rectal, rectal administration, topically (including temporally and sublingually), vaginally, or externally (ie subcutaneous, transdermal, intravenous, transdermal, or intravenous). sheath or leather). It is also possible to give these formulas in the form of images and units of doses, or they can be prepared by any of the methods known in the field of pharmacy. For solid installations; Conventional non-toxic solid carriers for example Ye include pharmaceutical grades of mint and : lactose, cellulose, cellulose derivatives, starch, magnesium stearate, sodium saccharin, talcum, glucose, sucrose, magnesium carbonate, and the like that and that can be used. and liquid compounds which may be administered from allll pharmaceuticals may be prepared for example by dissolving, dispersing, etc. active compound as yo specified above and optionally pharmaceutical auxiliaries in the carrier; such as saline water aqueous dextrose, glycerol, ethanol, and the like; to form a solution or suspension. And if desired, the pharmaceutical composition that is given to Lad can contain ALE quantities of additional non-toxic substances, Jie wetting or emulsifying agents; pH factors and the like, for example:

sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, sorbitan Actual Methods of Preparation Dosage Images LA. monolaurate, triethanolamine oleate, : is known or will be pronounced; for the experienced in this field; See for example

Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton,

Pennsylvania, 15th Edition, 1975. 2 The compounds of the present invention can be derived in a number of ways. According to the components used here, it includes salts (i.e. pharmaceutically acceptable salts) and any complexes (i.e. “guid” or coordination complexes with ions, cyclodextrins Jie with clathrates, input complexes, or interchangeable esters For in vivo degradation, bases Jie &70; 10 Je metal esters or drugs (hydrates (sf) and free acids; polymeric forms of compounds and solutes 0" prodrugs or lipids, coupling agents and protecting groups By “prodrugs” means, for example, any compound that is transformed in the body of a living organism into a bioactive compound. The salts of the compounds of this invention are preferred to be physiologically good and non-toxic. There are many examples of salts known to the experienced. In this field, all of these salts fall within the scope of the present invention, and the references for the compounds include the images of the VO salts of the compounds. Alkylation agent according to the known methods JB for example ammonium © within the scope of the present invention. quaternary ammonium for those skilled in this field. These vehicles are located bah la

Compounds that have an amine function can form N-oxides. The reference may include:

The compound containing an amine function on the N-oxide.

When the compound contains several amine functions; One or more atoms can be oxidized

1008. To form N-oxide. Specific examples of N-oxides are the N-oxides of amine

© triplet or nitrogen atom of heterocycle containing 100860 .

N-oxides can be formed by treating the corresponding amine with hydrogen peroxide Jie

or a primary acid (Je) e.g. peroxycarboxylic acid ); See, for example, Advanced Jad).

Organic Chemistry, by Jerry March, 40 Edition, Wiley Interscience, pages, and more

482 N-oxides can be made by the procedure for L,1977,7.

W.

Deady (Syn.

Comm

: using the amine in which compound 509-5 14) Ve

Jie eg + in an inert solvent + m-chloroperoxybenzoic acid (MCPBA)

,. dichloromethane

When compounds contain AHS She all phototypes are located like isomers

enantiomers and epimers; 5 diastereoisomers; In addition to mixtures

The official VO of the vehicles within the scope of this invention.

Compounds can exist in a number of different geometric isomeric ¢ and isoforms as well

Reference Jia vehicles include these pictures. And so that suspicion can be avoided; where it is

A compound may be present in one of the many isomeric or geometric forms

Describe one of them specifically and all other images are not included within the scope of this invention. Bad a

The amount of compound for the compound that can be administered will vary from the patient being treated and will vary from 100 ng/kg body weight to 100 mg; / kg of body weight per day, preferably from 01 pg / kg to 01 mg per day. For example, doses can be easily verified by those skilled in this field with this disclosure© and their knowledge in this field. Hence an experienced person can easily quantify the compound and other optional additives and/or carrier compounds; and/or carrier in the fittings and is given by the methods mentioned in the present invention. Compounds of the present invention have been shown to inhibit Gu secretase activity (including BACE) in vitro. β-secretase inhibitors have been shown to be useful in inhibiting the formation or aggregation of the ABVe peptide and for this reason have such beneficial effects In the treatment of Alzheimer's disease, Alzheimer's disease and other Dail nerve diseases associated with elevated levels and / or deposition of peptide AB. For this reason, it is believed that the compounds of the present invention can be used in the treatment of Alzheimer's disease, Alzheimer's disease, and dementia-related disease. Hence, it is expected that the compounds of the present invention and their salts will be effective against age-related diseases, Jie Alzheimer's, as well as diseases related to AB, Jia 05 Downs syndrome, and amyloid neuropathy related to 5. The compounds of the present invention can most likely be used in combination with a wide range of cognitive impairment enhancing agents but may also be used as a single agent.Methods of PreparationThe present invention further relates to processes for preparing a compound having the formula !in the form of a free base or a pharmaceutically acceptable salt of _0. The length of the following description of such operations shall be understood; that wherever it is ada

Appropriate protecting groups will be added to and then removed from the various reactants and intermediates in a manner that will be readily understood by a person skilled in the field of organic synthesis. Conventional procedures for using such protective groups as well as examples of suitable protective groups are described for example in: “Protective Groups in Organic Synthesis”, T.W.

Greene, P.G.M. Wutz, Wiley- 8 Interscience, New York, 1999. It will be understood that microwaves can be used to heat reaction mixtures. Examples 0 General methods The general procedures for the operation of the compounds of the invention are as follows: The invention will now be described also with reference to the following illustrative examples and in them unless otherwise indicated: Temperatures are given in degrees Celsius (C) and operations are performed at a temperature room or 0 air temperature, i.e. between 18 and 75 2 m; The organic solutions were dried with anhydrous magnesium sulfate; Evaporation of the organic solvent was performed using a rotary evaporator under reduced pressure (0.£ = To mm Hg) with a Bl bath up to Te m.

Yo — _ means flash chromatography on silica gel ¢ and thin layer chromatography (TLC) was performed on silica gel plates ¢ Reaction pathways were generally tracked by TLC or liquid chromatography/spectrum analysis (MS/LC) AES) Reaction times are given for illustration only; © Melting points were uncorrected and (06) indicates dissociation; End products have satisfactory proton nuclear magnetic resonance (NMR) and/or AS data. when given to them Uae & NMR data as Delga values for key diagnostic protons in parts per million (ppm) for tetramethylsilane (TMS) as an internal standard; Measured at Yoo Ve MHz at 01150 - 6L using: chloroform (CDCI;), dimethylsulphoxide (ds-DMSO) or dimethylsulphoxide/TFA (ds-DMSO/TFA) as solvent; Conventional abbreviations are used for the form of the sign; For AB spectra the observed displacements are directly reported; Conjugation constants (1) are given in Hz; Ar Yo defines an aromatic proton When such a mapping is made low pressure values are given as absolute pressure off in Pascals ¢(Pa) and high pressure values are given as pressure values In bar scale; non-aqueous reactions were performed under nitrogen atmosphere; 7e

Mass spectra (MS) were performed using an automated system with atmospheric pressure chemical (APCI), electrospray (HES), or ionization. in general; Only spectra for which a major JIS has been observed have been reported. The principal ion is reported for the lowest mass of molecules for which the ©_isotonic separation produces multiple mass spectral peaks (eg when chlorine is present). Mass spectra were recorded using any of the 59888 MICROMASS si HEWLETT PACKARD QUATTRO-1 MASS SPECTROMETER and reported as ©/2 for the major molecular ion along with its relative intensities. 0 CONDITIONS: LC-MS HPLC COLUMN 58-08 01 X 10 ae AGILENT ZORBAX mm. Flow: 014 ml/min Graduation: de ol to 90 7 over a range of ? minutes; Hold 1 min ramp down to mA over 1 min hold time 1 min. where acetonitrile / 1 = A in water using acid. + 7 711 8 jformic water in acetonitrile using .+ 7 formic .UV-DAD 50-701 . acid Ve LC-MS HPLC conditions for micromass data: AGILENT ZORBAX SB-C8 column mm X ID 0 mm. Flow: [de 140 min. Scale: 7 90 a to 7 0 b over dro min; 1 minute hold Ramp down to 55 7a over 1 minute and 1 minute hold time. where A - ? acetonitrile 7 in water using .+ / formic acid and 8 1#7 water in acetonitrile using 7 100 formic acid. LUV-DAD 400-701

For no - mass spectra were otherwise recorded using the following systems: LC-MS analyzes were performed on an LC-MS system consisting of a Waters Alliance 2795 HPLC 0 and a Waters PDA 2996 li lens valve detector. A Sedex 75 ELS detector and a single quadrupole 2340 AES spectrometer. The mass spectrometer was equipped with a 0 electrophoresis ion source (BS) operated in positive or negative ion mode. And the capillary voltage was set to 7.? kV and the cone voltage is set to 0 volts; respectively. The mass spectrometer was checked between -100 mz-001 with a scan time of 17 seconds. The J-valve system detector was scanned from -7010 4060 nm. The detector temperature was set at 8 to 1 m and the pressure was set at 0.4 bar. For a linear gradient separation was applied starting from 0 0 7 001 a to 0: mM of ammonium acetate in lo of acetonitrile ( ) and ending at 001 / ( acetonitrile ( ) and the column that used was X-Terra MS C8 mm X 00 mm; operated at 7.5 µM Waters at a flow rate of 1 mL/min. The shaft furnace temperature was set to 560 °C or LC-MS analyzes were performed on an LC-MS system consisting of a Waters Alliance 2795 HPLC “V0”, a 2996 “Waters PDA diode array detector, a Sedex 75 ELS detector, and a quadruple mass spectrometer. Single electrode 2240. The mass spectrometer was fitted with an electrophoresis ion source (ES) operated in positive or negative ion mode.The capillary voltage was set to FLY kV and the cone voltage was set to VO volts, respectively The mass spectrometer was scanned between Veo -001 mz with a scan time of 17 Al and the To system detector was scanned with a fer -701 nm diode.The detector temperature was set to 81.5 to 40 M

VI

mm; And was O00 X? X-Terra MS C8 mm bar. Separation was performed at 0.9 and pressure was set at ml/min. A linear gradient 1 was applied at the operating Waters flow rate of 7.8 μM.

A or acetonitrile in © / from ammonium acetate mM from 01: a to 001 starting at (b: 7 0001) and ending at (acetonitrile from 1 oe in) formic acid and column furnace temperature was set at 1 C or © acetonitrile and LC-MS analysis was performed on Water Acquity system using 2996 PDA (Waters) and Waters mass spectrometer ZQ Column: 0117 Acquity UPLC™ BEH Cy 7.1 μM 5007 mm Column temperature set to 15 C. Linear gradient ?min of 17 000 (: 40 7 M) applied. From ammonium acetate in MilliQ water and 75 acetonitrile (to 001 / Jo Jo 00) + + . molar ammonium acetate in MilliQ water and 58 / (acetonitrile) for the LC separation At a flow rate of 017 mL [min. The PDA was scanned from 701 - 0©?nanmolar and 794 nmolar was extracted to determine the purity. A 20-nm mass spectrometer was operated with ES in conversion mode from Positive/Negative The capillary voltage was −kV and the cone voltage was ©0 V, or V0 Then LC-MS analyzes were performed on Su LC-MS from Waters due 27770 manager; a dual 1525 Waters m pump, a 1500 “Waters column furnace and a single Waters ZQ four-pole spectrophotometer; Leas Waters PDA2996 diode detection device, detection 515 85, Sedex. The mass spectrometer was configured with an atmospheric chemical ionization ion source (4001) which was also equipped with an atmospheric pressure photoionization device (APP) and the mass spectrometer was scanned in 0 positive position; Switched between APPL APIC mode. The mass range was set to “VY mz 7e

- no -

0 using a scan time of 1.7 seconds. APPL and 7001m peak were set to VAT kV pA A » respectively. Moreover, the melting temperature (a Too), the melting gas (4060 l/h), and the cone gas (0 l/h) were constant for both the APCI method and the 1 method.. cha ) Separation using a C18 Gemini column (¥ mm X 00 mm; 3 μmol © Phenomenex) and run at a flow rate of 1 mL/min. A linear gradient starting at 100 ol was used. (a: 01 mM NH40Ac in © 7 (MeOH) ending in 001 rb (MeOH)

The shaft furnace temperature was to te C or LC-MS analyzes were performed on an LC-MS consisting of Waters due 27770 principal; Dual 1525 Waters blood pump, 1500 Waters column furnace, 0 720 Waters single quadrupole spectrometer; 0082996 Waters diode system detector and 85 21.5 Sedex detector. The mass spectrometer is supplied with a source. Ion electrophoresis (ES) which operates between wave and negative ion mode The mass spectrometer was scanned between 701 - 001 mz using a scan time of LT sec. The capillary voltage was set to 3.4 kV and the cone voltage was set to 0 V, respectively. The Ee SY diode system detector was scanned at 0 nm, the BLS detector temperature was set to 40 °C and the pressure was set at 0.4 Bar.To perform the separation a linear gradient was applied starting from 7001a to 0 mM of 11114086 in ©7 of CH3CN or A mM of HCOOH in ©#7 of CH3CN and ending at 0001 7 (B: 01130©7)._The column used was (Gemini C18© mm Ts cas Or X μmol (Phenomenex) operated at a flow rate of 1 ml/min. The column furnace temperature

0 on 46 m.

B Lamla

M. - GC-MS: Compound discrimination was performed on a GC-MS system (6890, 60 GC-MS) (5973N MSD)_ supplied by Agilent Technologies. The column used was a column of 115.10 77-5 0.78 X 10 m; 175 microns (Varian Ine) i.e. a linear temperature gradient was applied starting from 4000°C (1 minute detention) and ending at 705°C (1 minute detention); and 75 m/min. The © mass spectrometer was equipped with an ion source for chemical ionization (CI) and the reactant gas was methane . The mass spectrometer was fitted with an electron impact ion (EI) source and the electron voltage was set to 71 V. : The mass spectrometer scanned between ial 75 m/z 800 - 800 bits Scanning speed on © 7.7 scans/sec. The preparative chromatograph was run as follows: 0 F preparative reverse-phase HPLC (AGILENT) compounds were purified using a YY X You ) PHENOMENEX LUNA C18 mm reverse-phase column; and 01 micron particle size). For an experienced person in the field; It is understood that raw samples can be dissolved in methanol, DMF, or a wide range of acetonitrile LBA | Water with or without TFA, methanol or DMF in concentrations ranging from a diluent to a concentrate. All purifications were performed using 778 nano VO molar wavelength to collect the fragments. The detention time was (08) minutes. The gradient of 1 AGILENT (1 6m) was: acetonitrile 7 ia using TFA©+7 minutes; slope of zero - .5 / TFA 7 +) xe elo / acetonitrile on VY ae min; And a holding time at 50 7 acetonitrile / water for ? acetonitrile minutes / 001-ov / water with ).+ 7 TFA on V minutes; Then the flow rate was 50 [de min. Scale 001 = 02:01 (1 Agilent 1 acetonitrile 0 / water w/) + 7 TFA over 10 minutes; at a flow rate of 50 [de min. scale b lam b

81 - - Agilent ¥ (03d): acetonitrile / 0 with .+ 7 TFA over ¥ minutes; with a gradient of 0 - acetonitrile / 0 / water b).+ 7 TFA over YO min; At a flow rate of tv ml/min, the preparative chromatograph was run on an automated HPLC water purification system using a diode detector ©. Column used: 08 001 » 14 (XTerra MS) mm 01 μM. The gradient was using acetonitrile / .+ molar of acetate 20110010 in 5 7 661001011 in water 1!:0. Flow rate: 01 ml/min. jeg toward alternative; Protection was achieved on a semipreparative Shimadzu LC-8A HPLC using a Shimadzu SPD-10A UV-vis detection lea. Waters Symmetry® column supply (018); © 001 mm µm (VX 0 gradient was using trifluoroacetic acid + .) / acetonitrile in MilliQ Water . Flow rate: 01 ml/min. alternatively; another column was used; 618,001 14 Atlantis mm; Column © µm. Gradient using acetonitrile / ).+ M ammonium acetate in #5 acetonitrile in MilliQ Water Flow Rate: Yo ml/min; OR preparative HPLC was run on a Waters FractionLynx system using an Autosampler “combined Automated Fraction Collector (Waters 2767) 0 5 ¢ Step Pump (Waters Regeneration Pump (Waters 600), Make Up Pump (Waters 515), Waters Active 2525), “Splitter, Column Switch (Waters CFO), PDA (Waters 2996) and Waters ZQ. column mass spectrometer used; 001L14 XBridge™ Prep C8 Sum OBD™ mm; Using a 01 XTerra © Prep MS C8 01 µm XV mm protective shaft for the cartridge. A graded application of 0.1 000 ol (do 1) + molar of ammonium acetate in MilliQ water and 70 acetonitrile was applied.

AY - - ) to 7 001b ( 7 001 acetonitrile for LC separation at yo flow rate mL/min; PDA scanned from -7” 701 1©?nano Molar. The mass spectrometer 20 was operated with 185 in positive mode. The capillary voltage was −kV and the cone voltage was −0.01 V. Mixed start was performed, UV and MS signal were determined for part assembly. © and analyzes were performed. HPLC on the 1101100 Agilent System consisting of a Micro 0613798 'Vacuum Degasser', a G1312A Binary Pump', a 061367 Well-Plate Autosampler', a GI316A Thermostatted Column Compartment, and a diode system detector. 8e The detector operating with an AU valve system was scanned from 10? to 300 nanomolar, and the degree and apex widths were set to 1 nanometer and 1.05 minutes, respectively. The used column was 0. 001 XV X-Terra MS C8 mm; 7.5 μm (Waters) was run at flow rate [de 1 min. Column furnace temperature was set to ∼C. A linear gradient was projected. ; starting from 01: (17 0010 mM NHsOAc in CH3CN © 7) and ending with 7001b (b: (CH3CN) Usual Phase Chromatograph Conditions: Flash chromatograph used as a method for purifying Vo compounds The argument that is chosen. Equipment: Isco CombiFlash Sq 16x pre-prepared disposable still-phase RediSep SiO columns (4 volumes; 1 01 40 VY g) with step-down filtering at 0 - YYO mL/min of the binary mixture selected solubility; UV detection (range 71 - 160 nM) or time-cycle collection; The path length of the flow cell is (vl) mm or silica gel (Merck 00 ten-act 00 mm) was used. B did not

AY — — TH NMR spectra were recorded in the indicated solvent processed at 50860 MHz unless otherwise indicated Wh using a Bruker DPX400 NMR spectrometer operating at 500 MHz and equipped with a ;- head Nuclear probe in 2 steps or Bruker avd00 NMR spectrometer with 111-130 581 probe tip for ¥ mm flow injection in steps of 7; Using a © Fluids 215 BEST fluid injection vehicle. Resonance multiples are denoted by the abbreviations os and 0; and and 0; br my for single and double '; , triple , quadruple , multiple ¢ , and wide , respectively. Microwave Heating Equipment: A Personal Chemistry Smith Synthesizer (Single Model 7.40G 7006 pm Watt Max.) or Creator, an Initiaror or a Smith Synthesizer Single Method microwave cavity continuous radiation at Yio. 01 mega An, and that is in microwave heating on all stoves. Commercial reagents were used without further purification. Room temperature denotes a degree between YO Yn C. Terms and Abbreviations: Solvent mixture compositions are given as volumetric ratios or proportional quantities by volume. In cases where the NMR spectrum is complex; Only diagnostic signals are transmitted. VO “00 p: atmospheric pressure; and Boc: t-butoxycarbonyl; Cbz: benzyloxycarbonyl; DCM: dichloromethane; DIPEA: diiso-propylethylamine; DMF: N;N-dimethylformamide; DMSO: dimethyl sulfoxide; Et, O: diethyl ether; EtoAc: ethyl acetate; h: hour(s); HPLC: high pressure liquid chroma-lamella

— Ag — topography; minute(s): min.; NMR: nuclear magnetic resonance; psi: pounds per square inch; TFA: trifluoroacetic acid; THF: tetrahydrofuran; ACN: acetonitrile. Or Model 3, which is “A aA Model” ACD/Name, and the vehicles have been named using the program

Advanced Chemistry Development, Inc. (ACD/Labs), Toronto ON, on software from Beilstein AutoNom Model 4.01 or ¢Canada, www.acdlabs.com, 2004 and 2005 © ¢4 Model 4 ChemDraw Ultra or MDL Information Systems GmbH, Frankfurt Germany

CambridgeSoft Corporation, Cambridge, MA, USA, which is software from www.cambridgesoft.com - Chart No. 1 od PhLi OC) CY

CN=N

HN

A Yo 3,3-Diphenyl-3H-isoindol-1-ylamine (Scheme #1, A) : 1 Example # =N

HN

mmol) in 0.97 cane 001 (1,2-dicyanobenzene M of VA- to a solution cooled to di-n-butylether in phenyllithium Molar of 180 mL) was added 01 ( tetrahydrofuran min. The reaction mixture was warmed to room temperature Ve and after 0. mmol YOY filling 0 vy) \o A L M A A

— A o —

The reaction was quenched by adding (Jo 1.0) ele and the solvent was removed under reduced pressure. The ull color ball was purified by reverse phase using ele / acetonitrile in mobile phase on a 018 column using the following gradient:

© It took a second purification with preparative SFC using a Berger pyridyl column with a gradient of yo 0 / of MeOH.CO, for A minutes (holding time 5.776 minutes) to give us the compound mentioned in the title in Picture of a white solid (vv mg A%).

No, no, only

I H NMR (300 MHz, DMSO-dg) 6 717.77 - 7.73 (m, 1 H), , 7.64 (t, 4.3 Hz, 1 H), 7.41 (dt, J = 8.8, 4.9 Hz, 2 H), 7.30 - 7.14 (m, 10H); MS (TOF ES+) m/z 285 [M+1]"; tz = 6.65 min. Exact Mass: Calculated 285.1392, Found 285.1315.

Scheme 2

OH OH m CL, == = —

CN = 9 = N = 9

HN " ® oh Xo ® OH Xo 1 ® OH

Cc D

B o o | NBS 06 CL$ BOM), a Night 10 © to Night =N ©. © ® B o A 3 U C oH N and 2 a F 2 No O) oH

Br

G ? F ? 1 2:

H

> 7 1 © Example 3-(3'-Methoxy-biphenyl-3-yl)-3-(4-methoxy-phenyl)-3 H-isoindol-1-ylamine trifluoroacetate (Scheme #2, H) Oh Leah, Mr. Abba

0n A : HN 0 to : 5-[3-tert-butoxycarbonylamino-1-(4-methoxy-phenyl)-1H-isoindol-1-yl]-3'-methoxy- biphenyl-2-yl ester © (scheme no. ?; (G ( 560 mg 0.0975 mmol) added potassium phosphate YY) 10 mg + 11 mmol (dichlorobis(triphenylphosphine)palladium) Il mg YY .. mL (Use 7-1 dimethoxyethane : water: oY :7 :7 (ethanol ¥ ml). The reaction mixture was heated in a microwave at 175 °C for 15 min; more dichlorobis(triphenylphosphine)palladium(II) ) mg; tr YY mmol) was added and the reaction mixture was reheated at 175 °C for 15 min. The solvent was removed under reduced pressure and the raw material was dissolved in acetonitrile/water with :Yo : Vo) trifluoroacetic acid 1:00 mL); The insoluble material was filtered out and 480 leachates were filtered using RP-YV.Y = fz (HPLC AGI min). Freeze-dried purified joint fractions 8.33 MHz, DMSO-d¢/TFA-d (4, 1277 Hz, 1 H) 7.87 (m, 2 H), 7.22 11218 (300 Hz) (m, 4H) , 7.76 - 7.64 (m, 2 H), 7.59 - 7.47 (m, 2 H), 7.40 - 7.29 (m, 2 H), 6.97 7.13 = YAYY

AA _ — (d, /=8.8 Hz, 3H), 3.81 (s, 3 H), 3.76 (s, 3 H); MS (ES+) m/z 421 [M+1]"; tr 8 min. 5-[3-tert-butoxycarbonylamino- 1-(4-methoxy-phenyl)-1H-isoindol-1-yl] -3'-methoxy- biphenyl-2-yl ester (Scheme No. ¥ ¢ (G _ 0 O F — 0 LTS N oH oi Pe 0 0 E to : [ 3-(6-hydroxy-3'-methoxy-biphenyl-3-yl)-3-(4-methoxy-phenyl)-3 H-isoindol-1-yl]- carbamic acid tert-butyl este ) No. 9 VAT (F mg tT mmol) In an ice-cooled solution of dichloromethane pyridine (0 μl 1.7710 mmol) was added, followed by the addition of μl AY) trifluoromethanesulfonic anhydride l EVA + mmol).After stirring for 0?min, the reaction mixture was removed from the solvent under reduced pressure and the crude mixture was purified on 10 g of silica eluate elution using 5 7 of 7e

acetone/dichloromethane to give us the compounds mentioned in the title as a white solid

.)7 97 cana YY) 'H NMR (300 MHz, DMSO-ds) 6 [17.86 (d, J=7.5 Hz, 1 H), 7.72 - 7.64 (m, 2 H), 7.58 -7.36 (m, 5H), 7.28 - 7.20 (m, 2H), 7.02 - 6.84 (m, 5H), 3.77 (s, 3H), 3.72 (m, 3H), 1.49(m, 9H); MS (APCI+) m/z 669 [M+1]"; tr = 2.94 min.

Example number? Trifluoro-methanesulfonic acid 5-[3-amino-1-(4-methoxy-phenyl)-1H-isoindol-1-yl}-3'- methoxy-biphenyl-2-yl ester trifluoroacetate — 0 F — N 9 F 5 0 L I F 0 0 0 to : trifluoro-methanesulfonic acid 5-[3-tert-butoxycarbonylamino-1-(4-methoxy-phenyl)- 1H-isoindol-1-yl]-3"-methoxy-biphenyl-2-yl ester

- 9. = trifluoroacetic acid mg; 77.2 µmol) YY.0 (GY) was added (scheme No. 01 min.) removed and the reaction mixture was stirred for (Je? 1-7 01) dichloromethane overnight 50 m. The solvent is under low pressure and the resulting gum is placed under a high vacuum at (You give us the compound mentioned in the title in the form of a waxy solid of 7.3 mg).

TH RMR (300 MHz, DMSO-ds) 6 8.30 (d, /= 7.7 Hz, 1 H), 7.88 (q, J= 8.2 Hz, 2 H), 7.77- 7.71 (m, 1 H), 7.62 - 7.59 (m, 1 H), 7.49 - 7.38 (m, 3 H), 7.20 - 7.16 (m, 2 H), 7.05 - 6.96 (m, 5 H), 3.78 (s, 3 H), 3.74 (5, 3 H); MS (APCI+) m/z 569 [M+1]"; tg = 2.64 min. 6 Example #5-[3-Amino-1-(4-methoxy-phenyl)-1 H-isoindol-1-yl ]-3'-methoxy-biphenyl-2-ol 01 trifluoroacetate 0 — 7 OH HN 2 OH 0 : to [3-(6-hydroxy-3'-methoxy-biphenyl-3-yl) -3-(4-methoxy-phenyl)-3 H-isoindol-1-yl}- carbamic acid tert-butyl ester Yo Ba La Mala

— 8 1 — in trifluoroacetic acid μmol) was added 1806 mg; solvents under low pressure and the resulting resin was placed in a high vacuum at 0 m overnight (pe 0 + 6) to give us the compound mentioned in the title in the form of a waxy solid 1 (300 MHz, 101150-06 08.26 (d, 727.8) MS (APCI+) m/z 437 [M+1]"; tr = 2.14 min. [3-(6-hydroxy-3'-methoxy-biphenyl-3-yl)-3-(4-methoxy-phenyl)-3 H-isoindol-1-yl]- carbamic acid tert-butyl este ) 7 b" ( Chart 0 0 —

So N

N Oc

Xo H ; 0 : to [3-(3-bromo-4-hydroxy-phenyl)-3-(4-methoxy-phenyl)-3H-isoindol-1-yl]-carbamic acid tert-butyl ester either 7

ay — - (Chart No. (E «V ( 714 mg; VY + mM (Use YY) potassium phosphate added 0.47 cana mmol); 5 V1Y) 3 -methoxyphenylboronic acid mg; 0.11 mmol); 0 ) dichlorobis(triphenylphosphine)palladium(Il) mg; rr VY mM “YO sds dimethoxyethane and water (V) ethanol: : ?: 01 oY mL). The reaction mixture was placed in a hot bath and heated to reflux. After 10 minutes, additional 3-methoxyphenylboronic acid (61 mg) 5 YO) dichlorobis(triphenylphosphine)palladium (Il) mg) was added and the reaction mixture was heated to reflux for ASE Tr and ethyl was added acetate 1 was filtered out for salts; The filtered material was removed from the solvent under reduced pressure. The mixture was purified three times; using 01 grams of silica from the product of elution using © 7 of acetone 0 dichloromethane; secondly using silica aha 01 with dichloromethane and then using dichloromethane / acetone Lo » and thirdly using 500 grams of silica eluting using a gradient from hexanes to +© 7 hexanes [ethyl acetate . The product was removed from the solvent under reduced pressure to give the compounds mentioned in the title as a white solid which was placed under high vacuum overnight ( 708 cane 54 7 ). LH N®IR (300 MHz, DMSO-d¢/TFA-d) 6 8.62 (d, /- 7.9 Hz, 1 H), 7.88 (1, J = 7.6 Hz, 1 H), 7.78 - 7.69 (m, 2 H), 7.34 - 7.29 (m, 4 H), 7.10 - 7.02 (m, 3 H), 6.95 - 6.86 (m, 4 1), (d, 722.1 Hz, 6 H), 1.62 (s, 9 H); MS (APCI+) m/z 537 [M+1]"; fg = 2.50 min 3.76 Example #0 4-[3-Amino-1-(4-methoxy-phenyl)-1H-isoindol-1-yl] -2-bromo-phenol trifluoroacetate AEMA

_ q 7 _ 0 b - ra HN 2 OH

Br : to [3-(3-bromo-4-hydroxy-phenyl)-3-(4-methoxy-phenyl)-3H-isoindol-1-yl]-carbamic acid tert-butyl ester in trifluoroacetic acid micromol) added VAT (Chart No. ?; 8) (4.0 mg; © min. Ye was removed and the reaction mixture was stirred for (Ju? 0-00) dichloromethane 80 m solvent overnight under low pressure and the resulting gum was placed under high vacuum at . mg) 1.01 to give us the compound mentioned in the title in the form of a waxy solid

IH NMR (300 MHz, DMSO-dg) 6 28.26 (d, J=7.7 Hz, 1 H), 7.83 (t, J = 7.2 Hz, 1 H), 7.761-7.68 (m, 2 H), 7.30 (d , J=2.3 Hz, 1 H), 7.16 (d, J = 8.8 Hz, 2 H), 7.04 (dd, J = 8.5, 2.3 Hz, 1 H), 6.97 - 6.93 (m, 3 H), 3.75 ( 5, 3H); MS (APCI+) m/z 409 [M+1]"; tg = 1.95 min. [3-(3-bromo-4-hydroxy-phenyl)-3-(4-methoxy-phenyl)-3H-isoindol-1 -yl}-carbamic acid tert-butyl ester (E oY) (Chart 1).

q 4 _ _ — 0 — 0 A 3 N Xo H OH Br to a cooled gill solution of: [3-(3-bromo-4-hydroxy-phenyl)- 3-(4-methoxy-phenyl)-3H-isoindol- 1-yl]-carbamic acid tert-butyl este ° (Chart No. ?; (D 7 mg; 0.556 mmol) in chloroform daf N-YY)bromosuccinimide added mg; 0.946 mM (Use in parts over 0 ? min) and the reaction mixture was stirred for YO min. The solvent was removed under reduced pressure and the mixture was subjected to chromatography on Avg silica for an eluting Using © 7 of acetone in dichloromethane .0 the purified cofactors were removed from the solvents under reduced pressure and placed under high vacuum to give us the compound mentioned in the title as a copper-colored solid (Ya. mg; Oa 7( Hz, 1 H), 7.88 (t, /J= 7.3 Hz, 1 8.0 resolving (d, 8.63 h) TH NMR (300 MHz, DMSO-d¢/TFA-d) H), 7.75 - 7.70 (m, 2 H), 7.48 (d, J=2.3 Hz, 1 H), 7.29 (d, /= 8.9 Hz, 2 H), 7.07 (dd, J Hz, 1 H), 6.94 (dd, J = 8.8, 2.4 Hz, 3 H), 3.77 (5, 3 H), 1.62 (s, 9 H); MS = 8.692.3 (APCI+) m/z 509 [M +1]"; tr = 2.27 min ‎YAYY

_ H95 — [3-(4-Hydroxy-phenyl)-3-(4-methoxy-phenyl)-3H-isoindol-1-yl]-carbamic acid tert-butyl ester :)0 7 (Chart No. 0 — 0 — x 2 5

N

Xo H OH : to a solution of © [3,3-bis-(4-hydroxy-phenyl)-3H-isoindol-1-yl]-carbamic acid tert-butyl ester (scheme no. VY aba ©) (C ¢Y m 11 "Ja 7.4 ( cesium carbonate sy (Use mmol) in NoN- 001 ( dimethyl formamide mL) iodomethane added). + mL; 1114 mM ) Uso in (Je 7 ) N,N-dimethyl formamide and the mixture was stirred at ambient temperature for YA 0 h.N-dimethyl formamide was removed under low pressure to produce a yellow-brown syrup. To this mixture (Je YOu ( ethyl acetate) was added and the reaction mixture was stirred vigorously for ½ hour. The insoluble materials were filtered and the filtrate was concentrated under reduced pressure to produce a copper-colored solid. The crude compound was purified using flash chromatography ( ethyl acetate : dichloromethane V+ : 0 ¢ silica ) to give us the compound mentioned in the heading (% Ye g 0.1) in the form of a white solid 0

LH NMR (300 MHz, DMSO-dg) 5 07.83 (d, J=7.5 Hz, 1 H), 7.64 (t, J= 7.3 Hz, 1 H), 7.55-7.49 (m, 2 H), 7.16 (d , J = 8.8 Hz, 2 H), 7.04 (d, J = 8.6 Hz, 2 H), 6.89 (d, J = 8.8 solid

Hz, 2 H), 6.71 (d, J = 8.7 Hz, 2 H), 3.71 (d, J = 8.3 Hz, 3 H), 1.46 (s, 9 H); MS (APCI+) m/z 430 [M+1]7; tg = 2.20 min. [3,3-Bis-(4-hydroxy-phenyl)-3H-isoindol-1-yl]-carbamic acid tert-butyl ester (6) Scheme No. (

Oh

0 — 3 a

N

Xo H OH o Jad) (B ¢Y Scheme No. ( 4,4'-(3-amino-isoindole-1,1-diyl)-bis-phenol to a mL solution; and 7. 4 mmol) in 1.3 (triethylamine) added (Use 09.8 mM aha 0) (1 mM 17.6 g; YA) di-tert-butyl-dicarbonate mL) 001 ( N,N-dimethyl formamide

NN- hour. VA sad (mol) was removed and the reaction mixture was stirred at ambient temperature under reduced pressure to give an orange syrup. To this mixture, dimethyl formamide (V ml) was added, and the resulting precipitate was filtered to give us compound 001 (dichloromethane, adding . (7 SY mentioned in the title in the form of a light pink solid) .6 grams;

TH NMR (300 MHz, DMSO-dg/TFA-d) 5 718.59 (d, J = 7.8 Hz, 1 H), 7.86 ) J = 7.2 Hz, 1 H), 7.68 (m, 2 H), 7.14 (d , J= 8.7 Hz, 4 H), 6.75 (d, J= 8.7 Hz, 4 H), 1.61 (s, 9 H);

MS YAPCI+) m/z 417 [M+1]"; tg = 1.48 min. 4,4'-(3-Amino-isoindole-1,1-diyl)-bis-phenol (Scheme #2, B) : 1 Example No

YAYY

_ 9 unless —

Oh

—=N

HN

Oh

A mixture of phenol (YE) g was heated; 7.01 mol) 5 V1 aha 01 ( 1,2-dicyanobenzene + mol) to reflux at 188 m for a duration of ? hours. The reaction mixture was cooled to room temperature and diluted with 0.* (hexane : ether 1 : 1 L). © The resulting precipitate was stirred for one hour and filtered. The isolated leachate was pulverized with dichloromethane (+L); It was stirred for 0.5 hours and filtered. The pure crude compound was purified using flash chromatography (Ye: 168 silica ov:ov; and see NH;OH 7 +.) using methanol : acetone : dichloromethane © methanol : dichloromethane using 6.1 7 of NH OH ¢ ; to reflux 5 methanol using 1.9 00 01.0117 ; 1 L) to give the compound mentioned in the title as a yellow solid (7 Y 0 pale 5 g; H NMR (300 MHz, DMSO-d¢/TFA-d) 608.47) 4 777.8 Hz, 1 H), 7.91 (t, /J=7.2 Hz, 1 H), 7.87 (m, 2 H), 7.25 (d, solution 8.7 Hz, 4 H), 6.98 (d, J = 8.7 Hz, 4H); MS (ES+) m/z 317 [M+1]%; tr = 1.24 min No Examples from 1 -? Then prepare the following compounds using the procedure described above:

—_ q A —_ (1) Table m/z mra | NMR structural formula Su eg (min) | (Ioniza : tion) YRA NMR (300 MHz ,

DMSO0-d6) & 8.72 (s,

H), 8.54 (s, 1 H), 8.27 m os 1 4-[3-Amino-1- (d,J=7.7 Hz, 1 H), en (4-methoxy- 408 |8.00(d, J=7.9 Hz, |OL)|phenyl)-18-011| Lotm | H), 7.86 - 7.80 (m, 2 oH isoindol-1-yl]-2- |1 +) | H), 7.73 - 7.68 (m, 1H), pyridin-3-yl- 7.53 - 7.49 (m, 1H), phenol 7.21 -7.10 (m, 3H), trifluoroacetate 7.01 -6.92 (m, 4H) , 3.74 (s, 3 H), NMR (300 MHz,

DMSO0-d6) § 9.11 (s, 1

H), 8.92 (s, 2H), 8.26 . (d, J=7.6 Hz, 1 H), Se pA 1- 0 . . 409 a year i. Man R phenyl)-1H- except | (APCI '7 04 isoindol-1-yl]-2- A 7.28(d,J=2.4 Hz, 1 Co 00 10,719 -7.14 (m, 2 1D) pyrimidin-3-yl-n' ' ' phenol 7.03 - 6.99 (m, 2 H), trifluoroacetate 6.94 (d, J=8.8 Hz, 2

H), 6.75 (d, J = 8.7 Hz, 1 H), 3.74 (s, 3 H). [Z NMR (500 MHz,

DMSO) 6 8.85 (s, 1H), 8.60 (s, 1H), 8.29 (d, J - 7.9 112, 1H), 8.05 (d,

J=80Hz, 1 H)7.90(d, | “or (I 3-(4-Methoxy- 392 | J=7.7Hz, 1H), 7.85, sd 0.011 | (ES+) | J=7.6 Hz 14(, 7.76 - =x pyrdin-3-y q phenyl)-3H- 7.71 (m, 2H), 7.61 (s, 1 isoindol-1-ylamine

H), 7.56 - 7.50 (m, 2 H), trifluoroacetate 7.37 (d,J=7.9 Hz, 1

H), 7.17 (d, J=8.7 Hz, 2H), 6.96 (d, J=8.8

Hz, 2 H), 3.74 (s, 3 H).

Scheme 3 0 0n = af

Li rest ow © © yo oC EGE = BT

CN u Br —N HN 2 ma L = F : or 2 lrga 01 No. Jud 3-[3-(2-Fluoro-pyridin-3-yl)-phenyl]-3-(4 -methoxy-phenyl)-3H-isoindol-1-ylamine triflouroacetate (JF) (Chart No. © 0 —_— =N llama no to 3-(3-bromo-phenyl)-3-(4 -methoxy-phenyl)-3H-isoindol-1-ylamine ( Scheme no

AY) potassium phosphate (ge m + VV came 00) was added (Ex. 11 “I oF VA cane . + mmol); 717 ( fluoropyridyl-3-boronic acids mg; +1 mmol); -1 mmol); and ro mg; 4 ( (dichlorobis(triphenylphosphine)palladium(II 5 Vo dimethoxyethane) : water : 1 7 : 7 : 7 ( ethanol mL). The reaction mixture was heated in a gm reactor

Yes. — - agg Saas at 1 ve ° C for 1 2 minutes. ADs Filtration of the Caddy Je tall mixture The removal of the leachate from the solvent under reduced pressure. The resulting residue was dissolved in acetonitrile/water using “trifluoroacetic acid ( 20a: er.) 2 YO ? Ml); and purified with RP-HPLC 2 (; = 10.Y min). The purified combined fractions were lyophilized to give 0 compound mentioned in the title (£100 mg; (FY TH NMR (500 MHz, DMSO) 5 8.29 (d, J=7.8 Hz, 1 H), 8.25 (d, J= 4.6 248 (m, 1H), 7.84 (d,J=4.0 Hz, 2 H), 7.75 - 7.71 (m, 1 H), 7.64 (d, J= 7.6 Hz, 1 H), 8.04 - (t,J=7.8 Hz, 2 H), 7.51 (s, 1 H), 7.48 - 7.45 (m, 2 H), 7.38 (d, J = 8.0 Hz, 1 H), 7.55 (d, J= 8.9 Hz, 111), 6.96 (d, J= 8.9 Hz, 1 H), 3.75 ( 3H); MS (ES+) m/z 537 7.17 MAI; tr = 2.50 min. Example 11 to 3-(3-bromo-phenyl)-3-(4-methoxy-phenyl)-3H-isoindol-1-ylamine (Scheme No. ?; ] ( b0 —N Br 0 To a solution cooled to — VA M of 4-bromoanisol 4 μl .90 mmol) in 01 (tetrahydrofuran mL) 016 M of 4-bromoanisol was added n-butyllithium in 0.1 (4) hexanes (da) 7.50 mM (ge) and the solution was stirred for 10 minutes. This mixture was placed in a vial at Yavy -

0 \ —_ \ _ Lea YA solution of 0 ) 1,2-dicyanobenzene mg; 50. mmol) in (Ja Y 0 ) tetrahydrofuran. And to a separate Lal & round flask add 1 bromo gh benzenes (17 μl Vode 0 mL) tetrahydrofuran (Js ml) and the solution is cooled in a VA-bath . To this mixture was added 0.6 M of nrbullithium in hexanes © ;. ml Vode mmol) and the solution was stirred for 10 minutes. This anion was placed in a vial in a reaction mixture of 2-dicyanobenzene 1 and the reaction mixture was stirred at -VA a for 2 hours. The reaction mixture was poured into saturated ammonium chloride (100 ml) and ethyl acetate was extracted. The joint organic layers were washed with saturated sodium chloride; It was dried over magnesium sulfate and removed from the solvent under 0 low pressure to give a pink oil. The pink oil was placed on 0 5 grams of silica gel column and rinsed with (10:9) methanol / dichloromethane, and the common parts were removed, which were then purified from the solvent under low pressure to give us the compound mentioned in the title in the form A copper-colored solid (170 mg; 11 7). 'H NMR (300 MHz, DMSO-dg/TFA-d) 5 £8.33 (d,J=7.7 Hz, 1 H), 7.89 - 7.71 (m, 3 H), 3:50 (d,J =7.7 Hz, 1 H), 7.48 (5, 1 H), 741 - 7.29 (m, 2 H), 7.17 (d, J = 8.8 Hz, 2 H), 6.97 )4, 1 8.8 Hz, 2 H), 3.77 (s, 3H); MS (ES+) m/z 393 [M+1]"; 1g = 1.89 min. Examples from YO -11 Then prepare the following compounds using the method described above: Table (Y) Yovy

1 0 Y —_m m/z M+] - Example No. Combine Structural Formula (Ionizatio NMR (min) n) “HNMR (500 MHz, DMSO) (m, 1 H) , 8.74 - 58.83-8.78 (m, 1 H), 8.38 - 8.33 H,N " 0 3-(4-Methoxy- 8.68 (m, 2H), 7.97 - 7.84 (mm, 3 = 0) o — |phenyl)-3-[3-(5- H), 7.77 - 7.72 (m, 2 H), methoxy-pyridin-3- i.3 lm0 b rz 08 1 vvy | 422 (ES+) (LJ=79 (d,J=7.4Hz, | H), isoindol-1-ylamine 7.53 (d, J=8.7 Hz, 2H), trifluoroacetate 7.16 (d, J =8.9 Hz, 2 H), 6.96 (s,3 H), 3.76 (s, 3 H). 4.07 'H NMR (500 MHz, DMSO) (s, 1 H), 9.11 (s) , 2 H), 89.21 J=177 Hz, 1 H), HN 2 ou 3-(4-Methoxy- , 8.33 (d,J=7.9 Hz, | H), =N phenyl)-3- (3: 7.94 -7.82(m, 2 H), 7.73 (t, ©. N pyrimidin-5-yl- 7.88 \ } phenyl)-3H-isoindol- 1" bin Wen = VIBES Sh H ), 7.59 (t, J Hz, 1 H), 7.46 )1, 7-0 1-ylamine 7.9 Hz, 1 H), 7.18 (d, J=8.8 Hz, trifluoroacetate 2H), 6.96 (d,/J=9.0 Hz, 2 H), 3.76 (s, 3 H). '"H NMR (500 MHz, DMSO) (t.J=7.6 Hz, 1 H), o~ Methanesulfonic acid 88.34 3"-[3-amino-1-(4-9 ( O - 7.75 (m, 2 H), 7.93-7.84 (m, 2 H), 7.67 - 7.62 0) methoxy -phenyl)- 111 7.71 isoindol-1-yl]-5- Ve 9 © rh 3 11 SIS (ES#) | (m, 1 H), 7.59 - 7.51 (m, H), 7.44 - 7.30 (m, 2H), 955:6 methoxy-biphenyl-3- (m, 2H), 6.98 - ylester 7.15- 7.20 (m, 2H), 3.86 (s, 3H), trifluoroacetate 6.96 (s, 3 H), 3.41 (s, 3 H). 3.76 "HNMR (500 MHz, DMSO) (s, 1 H), 10.01 (s, 1 811.67 H), 9.45(s, 1 H), 8.28 (d,J = Hz, 1 H), 8.26 - 8.24 (im, 7.5 1H), 8.07 (t,J=8.8 Hz, 1 32.3 H), 7.88 - 7.82 (m, 2H), ro Dihydrobenzo[b][1,4 ‎Mioxin6-yD)-3-(3-(2- | n © © (t,J=7.1 Hz, 1 H), 7.73 (ES+) | 7.63 (d,J=7.5Hz, 1 H), _J fluoropyridin-3- Vo 438 yDphenyl)-3H- l ) (1,J="7.8 Hz, 1 H), 7.55 ( s, 1 H), 7.47 (1, J = 6.1 r Ego 1-amine 7.51 Hz, 1 H), 7.39 (d,J= 8.2 Hz, riiuoroacetate H), 6.91 - 6.87 (m, 1 H ), 1 (m, 2 H), 4.27 - 6.68 - 6.73 (m, 4 H). 4.20 "HNMR (500 MHz, DMSO) (s, 1 H), 10.01 (s, 1 311.66 ne, |3-)2,3- 0 H), 9.47 (s, 1 H), 8.43 (s, 1 ( ©. N= 3 Dihydrobenzo[b][1,4 H] ),8.32(d,J=27Hz 1 H), | =, Idioxin-6-y1)-3-(3-(5-

0 | 450 (ES+) | 8.28 (d,/J= 8.2 Hz, | H), 4 f 0 © methoxypyridin-3- V1 7.93 (d,J=8.2 Hz, 1 H), N yDphenyl)-3H- 7.85(t,J= 7.8 Hz, |H), isoindol-1-amine 7.76 (d, J = 8.2 Hz, 1H), trifluoroacetate 7.73 (t,J=7.8 Hz, |H),

— 1 0 A -— ' = miz M+1 (Ionizatio NMR Example Complex Number Structural Formula (min) n) 7.62 -7.60 (m, 1 H), 7.59 - 7.57 (m, 1 H), 7.54 (1 , J = 8.0 Hz, 2 H), 7.38 (d, J = 7.8

Hz, I H), 6.88 (d, J=8.9 Hz, 1 H), 6.71 - 6.67 (in, 2 H), 4.25 - 4.19 (m, 4 H), 3.90 (s, 3 H). 'H NMR (500 MHz, DMSO) 811.67 (s, 1 H), 10.00 (s, 1

H), 9.46 (s, 1 H), 8.86 - 8.84 (m, 1 H), 8.60 (d, J=5.4 Hz, 1H), 829(d,/=7.5Hz 1 m 3-2.3 -

H), 8.05 (d,/=8.2 Hz, |H), ! " Dihydrobenzo[b][1,4 7.93 (d,J=82 Hz, | H), 0 Zn1 Jdioxin-6-y1)-3-(3- YMA 420 (ES+) - (pyridin- 3- Vy 7.83 oh)7/2 7.8 Hz, 1 H), _ 0 yl)phenyl)-3H- 7.76 - 7.72 (m, 2 H), 7.61 (s, 0 0 isoindol-1-amine

IH), 7.57 - 7.50 (m, 2 H), trifluoroacetate 7.37 (d, J=8.2 Hz, | H), 6.90 - 6.87 (m, 1 H), 6.72 - 6.68 (m, 2 H), 4.25 - 9 (m, 4H). 'H NMR (500 MHz, DMSO) 811.68 (s, 1 H), 10.02 (s, 1

H), 9.48 (s, | H), 9.20 (s,

H), 9.08 (s, 2 H), 8.29 (d, J = m-3)2.3- 7.2 Hz, | H), 7.95 d,J=1.2 1 we that | 421 riyals | [1% FH), 7.87-7.80 (m, 2 H N= (pyrimidin-5- | m H), 7.73 (t,J=7.5 Hz, 1 H), N= 0 yhphenyl)- 3H- 770-769 (m 1H). 7586, | §_p—¢) isoindol-]amine

J=75Hz 1H),744 (d,J= trifluoroacetate 8.8 Hz, 1 H), 6.90 - 6.86 (m, 1H), 6.70 - 6.67 (m, 2 H), 4.25 - 4.18 (m, 4 H). '"H NMR (500 MHz, DMSO) 88.32(d,/=8.7Hz, | H), 7.87 - 7.81 (m, 2H), 7.75 Pa) J=7.5Hz, 1H), 7.60 (d, J = 7.5Hz, 1H), 7.45 (s, 1H), Br 0 3-(3-Bromo-phenyl)- 7.38(1,J=7.6 Hz, 1H), 3-(4~-methoxy- 3- 7 M 7.28 (0.7 7.4 Hz, | H), ul 0 Va 7.16 (m, 2 H), 6.96 (d, J = Ny isoindol-1-ylamine 8.7 Hz, 2 H), 3.79 (s, 3 H), N trifluoroacetate 2.11 (s, 3 H).'H NMR (500 MHz, DMSO) o 8832(d,J=8.7 Hz, 1 H), 0 = _, 3+3"- Methoxy- 7.85(m,2H),7.77-7.63 | aaa alloys" Nd | 435(ES+) | (m, 210,754 7.45 (m, 2 0 0 ® phenyl SS) Y.

H), 7.38 (t,J=17.6 Hz, 1H), ? I-ylamine 7.28(d,J=7.4 He, 1 H), trifluoroacetate 7.15 (m, 2 H), 7.05 (m, 2 H),

— \ 0 _

Le m/z M+1 (Ionizatio NMR) Example Complex Number Structural Formula (min) of 6.96 (in, 2 H), 3.86 (s, 3 H), 3.79(s,3 H), 2.11 ( s, 3 H). -Methoxy-3-

J=8.7 Hz, LH) 791-784 fun ( N methyl-phenyl)-3.[3. (m, 2H), 7.77 - 7.72 (m, 2 b (5-methoxy-pyridin-

OES 63 (= 7.9 Fz 1 JO a o | Lad Lm30 | © 7.51(d, J=7.4 Hz, | H), / isoindol- 1-ylamine 7.09 (m, 2 H), 6.96 (d, J = trifluoroacetate 8.9 Hz, 2 H), 4.06 (s, 3 H), 3.78 (s, 3 H), 2.10 (s, 3 H).'H NMR (500 MHz, DMSO) 89.20 (s, 1 H) , 8.95 (im, 1 11), 8.32 (d, J = 8.8 Hz, 2 H), 8.15 (m, 1H), 7.95(d.J= | pn N 3-(4-Methoxy-3- 8.7 Hz, 1 H) ), 7.91 - 7.84 (mn, =N 2 3 th | 406 (ES+) | 2H), 7.77-7.72 (m, 2 H), 2 m | 7 ny ; vy 7.63 (t.J=7.9 Hz, 1 H), N — ylamine 751(d,J=7.4Hz, | H), trifluoroacetate 7.02 (m, 2 H), 6.96 (d, J = 8.9 Hz, 2 H), 3.78 (s, 3 H) ), 2.10 (s, 3 H).'H NMR (500 MHz, DMSO) 89.21 (s, 1 H), 9.10 (s, 2 H), 835(d,/=8.7 Hz, 1 H), m ‎ 9 3-(4-Methoxy-3- 7.94 (d,J=8.9 Hz, | I), Men [0 methyl-phenyl)-3-(3- 7.88 - 7.82 (m, 2H), 7.78 - rimidin -5-yl- voor | 407 (ES+) 7.73 (m, 2 3 Ab J= 2 P / " phenyl 3tLisomdal. 7.9 Hz, 1 H), 7.46 (d. J=7.8 -N - I- ylamine

Hz, 1 H), 7.18 (im, 2 H), 6.96 trifluoroacetate (d,J=9.0 Hz, 2 H), 3.78 (s, 3H), 2.10 (s, 3 H). 'H NMR (500 MHz, DMSO) 88.34 (d,J=8.0 Hz, 1 H), 3-[3-(2-Fluoro- 8.27 (m, 1 H), 7.84 (m, 2 H), ou pyridin -3-yl)- 7.75 (m, 1 H), 7.65 (m, LH), | HN (J) phenyl]-3-(4- "01 1 424 (ES+) | 7.63 (m, 1 H), 7.58 - 7.51 A methoxy-3-methyl- ve (m, 2H), 7.37 (d, J = 8.0 Hz, phenyl)-3H-isoindol- 111), 7.05 (in, 2H), 6.96 (d, ¢ _ I-ylamine

J=9.5He, 2H), 3.79 (s.3 trifluoroacetate).

H), 2.11 (s, 3H). HNMR (500 MHz, DMSO) 88.34(t,J=7.6 Hz, |H), 7.93 - 7.84 (m, 2H), 7.75 - 0 Methanesulfonic acid 7.71 (m, 2H), 7.59 (s, 1H) , CS o” 3-[3-amino-1-(4- 7.55(d,J=8.0 Hz, 1 H), NN ® methoxy-3-methyl-vas | 529 (ES+) | 7.33 (d, J= 2H, 8.0 Hz, 1 528 phenyl)-1H-isoindol-Yo

H), 7.17 (s, 1H), 7.15 (s, 1 FoI-yl]-5-methoxy-

H), 7.05 (m, 2H), 6.96 (s, 1 biphenyl-3-yl ester

H), 6.92 (d, J=8.0 Hz, 1 trifluoroacetate).

H), 3.86 (s, 3 H), 3.79 (s, 3

H), 3.41 (s, 3H), 2.11 (s, 3

- Y.0 — 7 m/z M+1 (Ionizatio NMR Example No. Compound Structural Formula (min) 9 'H NMR (500 MHz, DMSO) $11.61 (s, 1 H), 9.99 (s, I

H), 9.44 (s, 1 H), 8.28 (d, J = 8.2 Hz, 1 H), 7.91 (d, 7-232 E: mm

Hz, 1 H), 7.85 (t, /= 7.7 Hz, © 0) LN 5'«(3-Amino-1-(2,3- 1 H), 7.76 - 7.69 (m, 2 H), = Al 00 | SBE 735 Waddanm Akt Sam | Ogre (A L | flowin Tons 5 — 0 “Amro”

Hz, 1H), 7.34 (d,/=7.7 He, © methoxybiphenyl-3-

IH), 7.14(d, J=153 Hz, |yl methanesulfonate

H), 6.97 (s, 1H), 6.88 (d, J = 0 trifluoroacetate 9.3 Hz, 1H), 6.71 - 6.67 (in, 2H), 4.25- 4.21 (m, 4H), 3.84 (s, 3H) , 3.41 (5.3 H). 'H NMR (500 MHz, DMSO) 511.63 (s, 1H), 9.98 (s, 1H), 9.43 (s, 1H), 8.28 (d, J =8.2Hz, 1H), 8.28 (5, | H ), 7.93 -7.82 (m, 2 H), 7.73 (1, f « 3-03 17.4 Hz, 1H), 7.68(d, 1 = a+" | Dibydrobenvofblii a 7.7 Hz, 1 H), 7.52 (s , IH), Idioxin-6-yl)-3-(3'-

ESD and s=79 1a, 1 1), ) J methoxybiphenyl-3- | * 7.38 (t,J=8.5Hz, | H), -311-15010001-1-(excl. 729)1, 127.7 Hz, 1 H) for amine trifluoroacetate 7.12(s, 1 H), 6.96 (d/=88 | 7

Hz, 1 H), 6.90 - 6.87 (m, 1

H), 6.73 - 6.68 (m, 2 H), 4.22 (s, 4 H), 3.80 (s, 3 H). According to what was clarified in 04, the necessary required for example No. boronic ester was prepared.

Scheme 4 cl cl 0 o m / 001500 > o digit 9 — —_— 1 yah ~ 5 f od So oH 0 07 0 0 uh and

KL"

Methanesulfonic acid 3-methoxy-5-(4,4,5,5-tetramethyl- 1,3,2]dioxaborolan-2-yl)- phenyl ester©

VT - Scheme 4 (M qri 0 Jo! - ~ 0-11 0 0 to Gla -VA) tricyclohexylphosphine 1.74 mmol) and: vd 9) tris(dibenzylideneacetone )dipalladium(0) grams; 7.11 mmol) in a round-bottomed flask under nitrogen atmosphere was added (Ja 0 ( 1,2-dimethoxyethane) and the reaction mixture was stirred for 10 minutes. To this mixture was added: methanesulfonic acid 3-chloro-5-methoxy-pheny! ester ) chart (Le ( 900 mg; 10” mmol); and Avo) 4,4,4'4'55,5',5 "-octamethyl-2,2"-bi-1,3,2-dioxaborolane g; 4 mmol); ‎aha £00 ) potassium acetate 5 0 0 mmol) and the resulting mixture was heated in reflux for 0 hours. after cooling; The mixture was filtered through a cellite and the solvent was removed under reduced pressure to give a brown gum. The mixture was subjected to chromatography first on pha 010 of silica sequentially rinsed with = dichloromethane / hexanes 7 0.0 using a final wash of acetone » and then subjected to chromatography on 6 grams of silica Rinse sequentially vo with from hexane | ethyl acetate to give us the compound mentioned in the title in the form of semi-purified gum (VY) which was used as a mixture in the Suzuki reactions

- Vay

MS (ES+) m/z 329 [M+1]:: 1g = 2.35 min. (L 4 chart) Methanesulfonic acid 3-chloro-5-methoxy-phenyl ester

Cl oY

H

So empty 0 Scheme No. 4; ( 3-chloro-5-methoxy-phenol Ula) into solution at a temperature of; m mt mg (07 g; 01.850 mmol) 1 5 A) pyridine fill 157.70 mmol) in 051 ( dichloromethane mL) to 19.78 (Ja A (methanesulfonyl chloride mmol) The reaction mixture was warmed to room temperature and stirred for YE h.The dichloromethane was removed under reduced pressure and the raw material was fractionated between ethyl acetate and 1p hydrochloric acid. The organic layer was washed with 1 p of hydrochloric acid (£ “(XY) saturated potassium carbonate 5 ¢(X 1) saturated aqueous 0 chloride “(X V+”) magnesium sulfate was removed and It was dried over (XV) 000?-saturated aqueous chloride dichloromethane solvent under reduced pressure.The raw solid was crystallized overnight from (50 ml) and the crystals were filtered and washed with dichloromethane and placed under high vacuum to give us The compound mentioned in lial (4.70 g) 78 (7 MHz, DMSO-de) 8 177.09 (t, J = 2.0 Hz, 1 H),07.05 (1, J = 1.9 Hy, | 300) (11114r] H), 693 (tJ=2.1 Hz, 1 H), 3.82 (5, 3 H), 3.42 (s, 3 H); MS (APC) m/z 237 [M+1]: fr = 2.28 min. YovYy

1 0 A —_ _ 3-Chloro-5-methoxy-phenol ) Scheme #4 » (KCl ~N 0 OH 0 to 177.06 ha 0.7 ) sodium methanethiolate mmol) was added: (Ja Vo ) 1-methyl-2-pyrrolidine followed by the addition of 01 ( I-chloro-3,5-dimethoxy-benzene 115.87 aa© mmol) The reaction mixture was heated in a 0060°C bath for 1 hour and then stirred at room temperature overnight. The [-methyl-2-pyrrolidine] was removed under low pressure and the material was fragmented between ethyl acetate / water 1]p hydrochloric acid. The organic layer was washed twice with 1p of hydrochloric acid and once with saturated aqueous sodium chloride; It was dried over magnesium sulfate and the solvent was removed under reduced pressure 0 to give a yellowish solid. The solid matter was subjected to chromatography on 400 ml of a silica gel stopper, to a sequential rinse with dichloromethane. The purified common fractions were removed from the solvent to give us the compound mentioned in the title in the form of a yellow solid 116.67 (grams » 460 7). J = 1.9 Hz, | H), b 6.40 “HNMR (300 MHz, DMSO-de) 5 06.43 (t, = 2.0 Hz, 1 H), J=2.1 Hz, 1 H), 3.71 (5, 3 H); MS (APCI) m/z 159 [M+1]: 1g = 2.04 min 6.286

- 101. = © Scheme no

Li 0 0

SRS 2 To "

cn 0

Br reflux I 2) HCI, MeOH, rt 0 -

N 0 Rn Ar-B(OH), Pd(PPh,), DME 1M NaHCO, reflux

NH,

N

2 Ar 0°

P

YA Example #3-Benzo(1,3]dioxol-5-y1-3-(3-pyridin-3-yl)-3H-isoindol- 1 -ylamine trifluoroacetate (Pood; (scheme) oo

NH,

Cy

CL

0_0 : both are merged

YoYY

‎VY. = - ‎3-Benzofl ,3]dioxol-5-yl-3-(3-bromophenyl)-3H-isoindol- I-ylamine ) 0 »; graram; A ¢ 1 0 mmol) Scheme 0’ 0 Example (Y q 5 01 ( tetrakis(triphenylphosphine)palladium (0) mg) in ethylene glycol dimethyl ether V.¢ ) ml ). © and added (on Y ©) Pyridine 3-boronic acid g; 1707 mmol) and 1 M of a solution of 1 ( LY sodium bicarbonate mL); respectively. The mixture was refluxed for one hour.” e cooled to ambient temperature; And he was nominated. The leachate was fractionated in water 0 ethyl acetate 4 and the organic fraction was washed (with water/brine); It was dried over (magnesium sulfate) and 0 was filtered and evaporated. The raw material was subjected to chromatography on a silica gel flash column using 0 / of? molar ammonia in dichloromethane / methanol. The purified material was then partially fractionated in acetonitrile/water and purified by RP-HPLC (2e = 01117 fy (min). The purified common fractions were freeze-dried to give us the compound mentioned in the title (0.0 17 grams). NRIR (500 MHz, DMSO-ds) 8 11.71 (s, 1 H), 10.02 (s, 1 H), 9.50 (s, 1 H), 8.86 (s, |z H). 8.61 - 8.60 (m, 1 H), 8.29 (d, J=7.8 Hz, | H), 8.06 (d, /- 8.0 Hz, 1 H), 7.94 d,J= Hz, 1 H), 7.87 - 7.84 (m, 1 H), 7.76 - 7.72 (m, 2 H), 7.61 (s, 1 H), 7.56 - 7.52 (m, 2 73 H), 7.36 (d, J=8.0 Hz, 1 H), 6.92 (d,./= 8.1 Hz, 1 H), 6.79 (5, 1 H), 6.74 - 6.72 (m, 1 H), 6.03 (s, 2 H); MS (APCI+) m/z 406 [M+1]"; t=1.67 min. YoYY

11010 = = Example #79 3-Benzof1,3]dioxol-5-yl-3-(3-bromophenyl)-3H-isoindol- 1-ylamine (scheme #0« 0) NH, N Ly PL 0 solution 0 (n-butyllithium mol VO fill 0109 mmol) was added dropwise to © solution at -VA mm of 0 (©) 4-bromo- 1,2-methylenedioxybenzene g” 01 mmol) in £.A) tetrahydrofuran ml) and stirred for “0 min. A solution of:

‎N-[(3-bromophenyl)(2 -cyanophenyl)methylene] -2-methylpropane-2-sulfinamide

Ea ) g + .mL (Use) Chart No. 0 (N) in (Je v ) tetrahydrofuran drip

over a period of 0 minutes and the stirring continued at -VA m for 2 hours. The reaction mixture was slowly warmed

ey the mixture between water and Aa m and the reaction was quenched by the addition of water (© ml). Yo- was reduced to 0 magnesium) and then the organic fraction was washed (with water; brine) » dried over 58 0 and concentrated to crude oil. The oil was subjected to a sulfate flash chromatogram

silica gel using ¥ ethyl acetate / hexane 0: to give us the intermediate compound in the form of gum

white. The glue was dissolved in 0 (methanol ml); It was treated with 1 M of hydrogen chloride 0 in (Ja 1 ( diethyl ether) and stirred at ambient temperature for YY h. The reaction mixture was concentrated and the residue was partitioned between a solution of dichloromethane 5 sodium bicarbonate

‎Yovy

117 - The organic part was washed (with saline solution); It was dried (over sodium sulfate); And it was fumigated. The raw material was subjected to chromatography on a silica gel flash column using © 7 of 1 M of ammonia in dichloromethane / methanol » and was then triturated with hexane to give us the compound mentioned in the title in the form of a substance yellowish solid (Ten) grams; (Evy oo TH NMR (300 Mz, DMSO-dg) § 7.78 - 7.67 (m, 2H), 7.47 - 7.37 (m, 4 H), 7.31 - 7.19 (m.2H), 6.78 - 6.72 (m, 5 H), 5.95 (s, 2 H); MS (APCI4+) m/z 407 [M+1]"; 1z=2.12 min. N-[(3-bromophenyl)(2-cyanophenyl) m ethylene]-2-methylpropane-2-sulfinamide (Scheme No. 0” (N B 11 aL Br 01) to a solution of 19.7 mM (aha vot A) titanium (IV) ethoxide mol) in tetrahydrofuran (Jo 14 (Y)3-bromo-2'-cyanobenzophenone mmol was added). After stirring for 2 minutes, 2-methyl-2-'aba +.4Y was added. propanesulfinamide 7-4 mmol).The mixture was refluxed for 11 hours and heated at 56 °C for 71 hours. After cooling to ambient temperature, the mixture was diluted with (0 ml methanol) and It was treated with a saturated aqueous sodium bicarbonate solution (Vo) to form a gelatinous precipitate.Then the material was further diluted with ethyl acetate and vacuum filtered through a sodium gasket.

to remove the sediment. The leachate was concentrated into crude oil that was purified by bicarbonate dichloromethane / acetonitrile from 7 0 using silica gel flash chromatography to give us the compound mentioned in the title in the form of ethyl acetate | hexane and triturated with (7 47 g; VAY) yellow solid '" H RMR (300 MHz, DMSO-ds) 8 7.98 (d, J= 7.7 Hz, 1 H), 7.87 - 7.79 ( m, 2 H), 7.72 - 7.66 (m, 2 H), 7.64 - 7.43 (m, 3 H), 1.27 (5, 9 H).

YY - 31 EXAMPLES FROM Additional compounds in Table No. were prepared according to Scheme No. © using the appropriate starting material. boronic acid (V) Table No. 01

m/z 1.017 * | Rather NMR Example compound Structural formula: (loniza 1 7 digit (min) tion 'H NMR (500 MHz, DMSO-d,) 811.68 (s, 1 H), 10.03 (s, 1 H) , 3- 9.49 (s, 1 H), 9.20 (s, 1 H), Benzo[1,3]diox 9.09 (s, 2H), 8.29 (d, 7-8 0 um | olSyl33 407 | Hz, 1H),7.96(d,/=78Hz1 | © 0) C8) | pyrimidin.s-

VA | (APCI | H), 7.75 - 7.66 (m, 2H), 7.87 - ylpheny!)-3H- +) | 7.82(m, 2H), 7.60 - 7.57 (m, 1 all" isoindol-1-

H), 7.44 - 7.42 (m, |H), 6.92 HN ylamine (d,J=83Hz 1 H), 6.77 (s, 1 trifluoroacetate

H), 6.72 - 6.70 (m, 1 H), 6.03 (5,2 H). 'H NMR (500 MHz, DMSO- 3 d6) 3 11.72 (s, 1 H), 10.03 (s, | © J

H), 9.50 (s, 1 H), 8.30 - 8.24 o s dio 424 (m, 2H), 8.09 - 8.05 (m, 1 H), | J OO 0 yh ot 4 van | Zouk | 789-783(m, 2H), 775-772 2 a Nh py v ( (m, 1 H), 7.65 - 7.63 (m, 1 H), exponential 1-311 1 +) 7.57-7.45 (m , 3 H), 7.37 (d, J spindol-1-

HN lamin =8.0 Hz, 1 H), 6.92 (d, J=82 L 0

Hz, 1 H), 6.80 (s, 1 H), 6.73 (d, ritluoroacetate

J=8.1 Hz, 1 H), 6.04 (s, 2 H).

- 116 —

M/z

LC2

M1 NMR Structural formula SM Example: (loniza 1 rm (min) tion 3- 'H NMR (500 MHz, DMSO-dq) Benzo[l1,3 ]diox 311.70 (s, 1 H) , 10.02 (s, 1H), 0l-5-y1-3-[3(5- 9.51 (s, I H), 8.43 (s, 1H), 8.33 mo -8.28(m, 2H), 7.94 (d, 7-8 0 -3-yl)-

Cs APC Hz, 1 H), 7.87 - 7.84 (m, 1 H), q]l phenyl]3H ry 7.78-7.72(m, 2H), 7.60 - 7.53 | ,,, Or oe isoindol-1- "(m3 H),737(d, J = 8.1 He, | ylamine 1

H), 6.92 (d, /= 8.2 Hz, 1 H), trifluoroacetate 6.73 - 6.71 (m, 2 H), 6.03 (s, 2

H), 3.90 (s, 3H). 'H NMR (500 MHz, DMSO-d) 11.71 (s, 1 H), 10.01 (s, 117 3- 9.50 (s, 1 H), 8.29 (d, J = 7.9 ). Benzo[1,3]diox

Hz, 1 H), 7.91 - 7.84 (m, 2 H), 0 m 0l-5-yl-3-(3"- 435 7.75-7.72 (m, 1 H), 7.68 (d, J 8 0 methoxy- 11 (APCL | =7.8 Hz, 1 H),7.51- 747 (m, |" TJ lmk | biphenyl3-yl)}- |TV +) | 2H),7.39- 7.36 (m, 1 H) , 7.28 3H-isoindol-1- (d,/=7.8Hz 1H), 7.15-7.11 ylamine (m, 2H), 6.97 - 6.91 (m, 2H), trifluoroacetate 6.79 (s, 1H), 6.75 - 6.73 (m,

H), 6.03 (s, 2 H), 3.80 (s, 3 H). '"H NMR (500 MHz, DMSO- .d6) 3 11.70 (s, 1 H), 10.02 (s, | Methanesulfoni

H), 9.51 (s, 1 H), 8.29 (d, J = ¢ acid 3 3- 7.8 Hz, 1 H), 7.92 )4, 1-8 le benzo 3 Jdiox 559 | Hz, 1H),7.87-7.83 (m, 1 H), Q (Ld; OLS IIL 10x vxe | (aber | 773:770(m 2H). 755-749 | 0 35 the | orn, .ara |ve (m, 2H),7.33(d,J=8.0 Hz 1 |" 0 "HY, 717-7102 (m, 2H), 6.98 - 5-methoxy- 6.96 (m, 1H), 6.92 (d , J = 8.2 biphenyl-3-yl

Hz, 1 H), 6.79 (s, 1 H), 6.74 - Ee oroacetate 6.71 (m, 1 H), 6.03 (s, 2 H), 3.84 (5, 3H), 3.41 (s. 3 H).

Yovy

— 1 1 o — 1 Chart No. > BR A B 7 A 2 © ) , 53 A > CRA Boc,0 CD) > - 2 Cr H,N - ] Sood - CRA a Br 8 | Br og” oy OH 3 2 o CD > CH,50,Ct . w= Ra Seay Ra Axo (OH 0 ’ T ) ° © og

O.L

Ra that v the Vo No. Jud

Methanesulfonic acid 4-[3-amino-1 -(3-pyridin-3-yl-phenyl)-1H-isoindol-1 -yl]-phenyl ester trifluoroacatete 2 (v Vad) schema ) 0

I

0-5

Il

O52 =~

H,N©

N.A

YoYY

- 1117 - : to methanesulfonic acid 4-[3-amino-1 -(3-bromo-phenyl)-1H-isoindol-1 -yl]-phenyl ester potassium phosphate mmol) tA was added mg 00 (Chart No. 1 «Na)) (mmol); +. YT cana "1 ( 3-pyridyl boronic acid mmol); 107 cana 11" (mmol), vA mg; Sustained ° als, and the reaction mixture was heated in (Je? oY iY av (ethanol, water: 1, 2-dimethoxyethane, Vo. min. for 100 aluminum at 10 m), and the reaction mixture was filtered. through a syringe filter and the filtrate was removed from the solvent under trifluoroacetic water with acetonitrile/water at low pressure The resulting residue was dissolved in RP-HPLC = (1100 ml) and purified with 62 M0: Yo: VO (for 0 minutes). The purified common fractions were freeze-dried to give us the compound mentioned in the title (7 89 ana oY.Y).

TH NMR (500 MHz, DMSO-de/TFA-d) 8 9.23 (d, /= 1.6 Hz, 1 H), 8.96 (d, J= 5.6 Hz,

LH) 8.87 (d, /=8.2 Hz, 1 H), 8.37 (d, J=7.8 Hz, 1 H), 8.17 (dd, J = 8.2,5.7 Hz, | H), 8.02(d,J=7.9 Hz, 1 H), 7.90 (dd, J=18.6,7.8 Hz, 2 H), 7.82 (s, 1 H), 7.77 tJ=176

Hz, I H), 7.67 (t, J=7.8 Hz, 1 H), 7.56 (d, J=8.2 Hz, 1 H), 7.41 (s, 4 H), 3.39 (s, 3 H);

MS (ES+) m/z 456 [M+1]"; x = 1.42 min.

Yovy

- 1117 -

VR Example No

Methanesulfonic acid 4-[3-amino-1 -(3-bromo-phenyl)-1H-isoindol-1 -yl]-phenyl ester trifluoroacetate (Ue Chart No. ( OL 0-5 NO) Yen( to order Br ° to: methanesulfonic acid 4-]1 -(3-bromo-phenyl)-3-tert-butoxycarbonylamino- 1H-isoindol- 1-yl]-phenyl ester trifluoroacetic acid from 701 mmol) 0.71 cana 0 (1 6) was added to the chart No. ? min. The solvent 0 was removed and the reaction mixture was stirred for (Je 01 (dichloromethane) at 00 under low pressure and was The resulting oil was placed under a high vacuum, 10 ml ether was added to the gum and the solvent was removed under reduced pressure to give us the compound mentioned in the heading (7 960 mg IVY: H NMR (500 MHz, DMSO-d) & 8.32 (d, J=7.9 Hz, 1 H), 7.90 - 7.86 (m, 2 H), 7.76 (ddd, 9=17.9,6.1,2.0 Hz, H), 7.63 (d, J=8.0Hz, 1 H) , 746 (t, J=1.8 Hz, 1 H), 741 -

110 - = (m, 5 H), 7.31 (d, J= 8.5 Hz, 1 H), 3.40 (d, /=4.0 Hz, 3 H); MS (ES+) m/z 457 7.35 [M+1T"; tg = 1.84 min. Methanesulfonic acid 4-[1 -(3-bromo-phenyl)-3-tert-butoxycarbonylamino- 1H-isoindol- 1-yl]-phenyl ester © ) Scheme 1 (T Qs 0-5 W\li — 0 t) = N eo H Br to: [3-(3-bromo-phenyi)-3 -(4-hydroxy-phenyl)-3H-isoindol-1 -yl]-carbamic acid tert-butyl ester 0 ) Chart 1 0 ) (S mg VAAN mM (Use in 0 ) tetrahydrofuran mL) was added on pyridine μl 7.716 mmol (YA) methanesulfonyl chloride μl YAY mmol) and after stirring Over night additional pyridine (Yael μL 7.776 mmol) was added and 718 (718 μL methanesulfonyl chloride; 7 mM) was added and the reaction mixture was left to stir for A hours. A was done ) the solvent was under low pressure Vo and the resulting oil was put under agitation in Je gl.Then the raw material was subjected to chromatography on Ye g silica gel by sequentially rinsing with 0.5 / of methanol / Yovy ‏

- 11 - from the solvent to give us the compound Lends, and the common parts that were dichloromethane (7 Ve mg YE) mentioned in the title were removed in the form of a white solid

Ty NMR (500 MHz, DMSO-d¢/TFA-d) 08.67 (d, J = 8.0 Hz, 1H), 7.92 (t, J=7.6 Hz, 1H), 7.84 (d, J=7.8 Hz , 1 H), 7.78 (t, J= 7.7 Hz, 1 H), 7.62 (d, J = 7.6 Hz, 2 H), 7.49 (d, P= 8.7 Hz, 2 H), 7.39 - 7.33 (m, 4H), 3.40 (s, 3H), 1.63 (s, 9H); MS (ES+) m/z 557 [M+1]%; x = 2.29 min. [3 -(3-Bromo-phenyl)-3-(4-hydroxy-phenyl)-3H-isoindol- I-yl]-carbamic acid tert-butyl ester (S 1 Chart No. )

Oh

0 —

I | 1 a

No H

Br 1 : to {3-(3 -bromo-phenyl)-3-[4-(tert-butyl-d imethyl-silanyloxy)-phenyl]-3H-isoindol-1 -yl}- carbamic acid tert- butyl ester (Jw 01 (tetrahydrofuran mmol) in 0 g; VV) 8) » Scheme No. (Multiplication V.9A) tetrahydrofuran in tetrabutylammonium fluoride molar of 1 After adding 10 minutes, the reaction was quenched with water (960 ml) and extracted twice using 01 mmol). And after

Yovy

_ 1 Y. — saturated mati; It was dried over sodium chloride and the organic layer was washed. ethyl acetate 0 was exposed and the solvent was removed under reduced pressure to give a yellow oil magnesium sulfate 7 56 gel for eluting with silica 010 g of this oil to the chromatograph on The solvent is under hexanes ethyl acetate from low pressure to give us the compound mentioned in the title in the form of a yellow solid (00 mg; © quantitative yield).

Tn NMR (300 MHz, DMSO-d¢/TFA-d) § 8.64 (d, J=7.7 Hz, 1 H), 7.89 (t, J= 7.7 Hz,

LH), 7.74 (t, J=7.5 Hz, 2 H), 7.61 - 7.57 (m, 2 H), 7.33 (dd, J= 4.7, 1.2 Hz, 2 H), 7.14 (dd, J=6.8, 1.9 Hz, 2H), 6.78 (d, /= 8.9 Hz, 2H), 1.62 (s, 9H); MS (APCI+) m/z 479 [MAT : =2.23 min. {3-(3-Bromo-phenyl)-3 -[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-3H-isoindol- 1 -yl}- carbamic acid tert-butyl ester (R 1) Scheme no. ( 0-5 3"

LC

N

XoH

Br : to 0

Yovy

171 - = 3-(3-bromo-phenyl)-3-[4-(tert-butyl-d imethyl-silanyloxy)-phenyl]-3H-isoindol-1- ylamine ) Scheme #1 9) (64 grams” 7.717 mmol) in dichloromethane added 04 di-tbutyl dicarbonate (£.9A mmol) . After 1 min an additional di-tbutyl dicarbonate© (0.75 g; 64 mM) was added (Use) and the reaction mixture was stirred for 1 h. The mixture was poured directly onto a silica gel column) Yu g) and the sequential ala lf chal was done using dichloromethane and the common fractions were removed from the solvent under reduced pressure to give us the product in the form of a semi-purified substance. This substance was then purified on a 0 g silica gel column by eluting with J Yo from a gradual gradient of hexanes to dichloromethane + ; 100 ml of each was washed. The purified conjugates were removed from the solvent under reduced pressure to give the compound mentioned in the title as a yellow solid (1 ot v (g 4 ¢ o%). NMR (300 MHz, DMSO-d) 56 7.86 ( d, J= 7.4 Hz, 1 H), 7.69 - 7.42 (m, 5 H), 7.29 1 (quintet, 72 7.9 Hz, 2 H), 7.16 (d, J= 8.7 Hz, 2 H), 6.84 - 6.75 (m,2 H), 1.50 (d, J = H), 0.93 (5, 9 H), 0.17 (d, 7 6.7 Hz, 6 H); MS (APCI+) m/z 593 IM+ 1]7; ylamine ) Chart No. 1 (Q Yovy

vy - - L -N \/ 0© m L L Br to a cooled solution of (Ja 7.87 ( (4-bromo-phenoxy)-tert-butyl-dimethyl-silanc )10.7 mmol) in 50 (tetrahydrofuran ml) 0.0 M Y of n-butyllithium in hexanes (7 fill 195.11 mmol) was added and the anion was stirred for 10 minutes. At the same time; In a separate round-bottom flask containing (YT) (Jay, AY) 1,3-dibromobenzene mmol) and (Je©) tetrahydrofuran cooled in a VA-bath 0.8 m was added. molar of n-butyllithium in “Ju 4.77 (hexanes 77.41 mmol)) and the anion was stirred for 10 minutes. The first anion was introduced into a vial in a solution at -VA m of 1,2-dicyanobenzene XY g; Vo) mmol) in (Je" 0 ) tetrahydrofuran and this mixture was stirred for 0 1 0 min. The second anion was introduced into a vial into the reaction mixture and the mixture was stirred for 0 0 min. The reaction mixture was poured out In saturated ammonium chloride (Je 001) it was extracted twice using ethyl acetate. Then the organic joint layers were washed with saturated sodium methyl chloride, dried over magnesium sulfate and removed from the solvent under low pressure to give us foam. amber, and the raw material was placed on a silica gel YAY column, gram, and the sequence was rinsed with a grade of 0 from dichloromethane to (1 9) methanol | dichloromethane for 71 minutes at fo ml / min. The purified fractions were removed from the solvent under reduced YoVy pressure

- 177 - 0114) to give us the compound mentioned in the title in the form of a white-yellowish solid. 0 y \ ala

HNMR (300 MHz, DMSO-ds) 8 7.69 (d,J=7.4Hz, 1 H), 7.60 - 7.47 (m, 3H), 7.42 (s,2H),7.28(d,J=7.5Hz, ?2 H), 7.14 (d, J= 8.6 Hz, 2 H), 6.76 (d,/J=8.6 Hz, 2 H), 0.92%(s, 9 H), 0.16 (s, 6 H); MS (APCI+) m/z 493 [IM+1]%; fr = 2.79 min. £) to 317 Examples Figures from using precursor 1 and the additional compounds in Table 1 were prepared; According to the appropriate chart No. boronic acid (4) Table No. mz

A mrp | LER Structural formula of the compound Example No. NMR (lonis 7726 1 (min) tion) "HNMR (500 MHz,

DMSO-d6/TFA-d) § 8.36 (d, J= 7.8 Hz, 1 H), 8.25(d, J=

Methanesulfonic acid No! 1 308 4-{3-amino-1-[3-(2- =o OD ( 8 Ho 1H).7.03 fluoro-pyridin-3-yl)- CO =N : 2 3 474 rv | phenyl]-1H-isoindol-1- N 0 ° 0.7.3 112 moq | 7° v1) -phenyl ester > 7.88 (t,J=7.5 Hz, 1 trifluoroacetate 0 H), 7.76 (t, 7-6

Hz, | H), 7.67 (d, J =7.8Hz 1 H), 7.61 - 7.55 (m, 2 H), 7.47 - 7.40 (m, 6 H), 3.39 (s, 3 H). 'H NMR (500MHz,

DMSO-d6/TFA-d) §

Methanesulfonic acid o 9.23 - 9.22 (m, 1 H), 4-[3-amino-1-(3- pi I 9.12(s, 2 H), 8.35 pyrimidin-5-yl- oe C aS (d,/= 79Hz 1 H), 457 +1 ra |phenyl)-1H-isoindol-1- LJ 8.01(d,/=79Hz, | starvation 1 yl]-phenyl ester HN 1 H), 7.90 - 7.84 (m, trifluoroacetate 2H), 7.78 - 7.75 (m, 2H),7.61(,J=179

Hz, 1H), 7.48(d, J

YoYy

- 1165 - oe LC tg Composite Dative Example No. NMR (loniza : tion) (min) =8.0Hz, 1 H), 7.40 (s,4 H), 339s, 3

H). HNMR (500MHz,

DMSO-d6/TFA-d) 8 8.82 (s, 1 H), 8.72 (d,/J=2.4Hz, |H),

Methanesulfonic acid o 8.37 (d,J=7.7Hz, 4-{3-amino-1-[3-(5- 05 2H),8.02(d,J=methoxy-pyridin-3-yl)- 7.8 Hz, 1 H), 7.94 - 486 | | Lo va | phenyl]-1H-isoindol-1- “I 7.87(m,2H),7.80- | (ES+) ' yl}-phenyl ester rah s | 775 (m2 H), 7.65 trifluoroacetate (t,J=7.8Hz, 1H), 7.55(d,J=7.7 Hz, 1H), 7.42 - 7.37 (m, 4H), 4.07 (s, 3H), 3.39 (s, 3H). 'H NMR (500MHz,

DMSO-d6/TFA-d) 8 7.95 (d, J=7.8 Hz, 1 H),7.89(t, J=17.5)

Hz, | H), 7.76 (t,J =

Methanesulfonic acid 7.6 Hz, FH), 7.71 : o_ (d,J=7.7Hz, 1 ID), 4-[3-amino-1-(3"- 0% 7.56 (s, 1 H), 7.52 methoxy-bipheny !-3- Ql J RAE 485 yb)-1H-isoindol-1-yl]- 9 0 J=78Hz, 1H), 1 py 1 00" phenyl ester HNN CO) o- 7.45 - 7.36 (m, 6 H) , trifluoroaceate 7.32(d,J=78 He, 1H), 7.17(d, J = 7.8 Hz, |H), 7.14 (s, |H), 6.96 (dd, J =8.2,2.2 Hz, |H), 3.81 (s, 3 H), 3.39 (s, 3 H). HNMR (500MHz,

DMSO-d6/TFA-d) 8 8.35 (0, / 7.8 117, . 1 H), 7.96 (d, J =

Methanesulfonic acid oss 7.8 Hz, 1 H), 7.89 (4, 4-[3-amino-1-(5'- Cl 9 9 solv 7.6 112, 2 H), methanesulfonyloxy- Ly 7.76 (t, J=9.6 Hz, |579 0 3'-methoxy-biphenyl- HN J H), 7.59 (s, 1 H), (ESH) YoY 3-yl)-1H-isoindol-1- 7.54 (t, J=7.8Hz 1 yl]-pheny! ester 0 0 if o- H), 7.45-7.38(m, 4 trifluoroacetate So H), 7.16 )0, 7-6

Hz, 2H), 6.98 (5, 1

H), 3.85 (s, 3 H), 3.40 (d, J=9.2 Hz, 6 H).

_ 1 Y o — 7 Scheme No. 0 N B(OH), 7 \ oN NN in horsepower 0 Cl — nC© = ho li aye _ —_— oo. Lt N 2) HCl HN OD HN ®

Br Br = F (Scheme 5, Example N) X 7 B 1 67 Example 3-[3-(2-Fluoro-pyridin-3-yl)-phenyl]-3-pyrid in-4-yl -3H-isoindol-1-ylamine trifluoroacetate 5 (Y 7 chart no. )

N

bl = N Ww LR) = F NO : to 001 (XY Scheme No. 3-(3-bromo-phenyl)-3-pyridin-4-yl- 3H-isoindol-1-ylamine (mmol) and 175 mg; 0 ) potassium phosphate mg; 0.75 mmol) (0 mmol added); and 177 mg; 0 ¥) 2-fluoropyridyl-3-boronic acid and (Use 1.175 mg ) dichlorobis(triphenylphosphine)palladium(1l)

Yovy

- AY - (77a: 7: 7+? ml). The reaction mixture was heated in blood ethanol mass: 1,2-dimethoxyethane min. The reaction mixture was filtered through a syringe filter and Ty sad 100 M aluminum was removed when the filtrate was removed from the solvent under reduced pressure. The resulting residue was dissolved in ; Ml); Purified 1: Yo 0 ( « trifluoroacetic acid using ela / acetonitrile ] and the combined fractions purified (Aida) en = rr) RP-HPLC 1 using © were freeze-dried and placed under high vacuum overnight. At 4 pm to give us the boat mentioned in the address (7 75 to £7).

TH NMR (500 MHz, DMSO-dg/TFA-d) 5 9.01 (d, J= 6.9 Hz, 2 H), 8.41 (d, J= 7.8 Hz,

IH), 8.26 (d, J=4.6 Hz, |H), 8.14 (d, J=6.8 Hz, 2 11), 8.12 - 8.08 (in, |H), 8.04 (d, J - 7.9 Hz, 1H) , 7.95 (t,J=7.6 Hz, 1 H), 7.84 (t, J=7.6 Hz, 1 H), 7.75 (d, J= 7.1 Hz, 1

H), 7.61 (t, J=79Hz, 1 H), 7.51(s, 1 H), 7.46 (t,J=7.0 Hz, | H), 7.34 (d, J=8.9 Hz, 1 H); MS (ES+) m/z 381 [M+1]"; tr = 1.37 min. 7 Example #3-(3-Bromo-phenyl)-3-pyridin-4-yl-3H-isoindol-1 -ylamine trifluoroacetate (XV) Chart No. ( Vo

N

0 7/7 1 —N

HN

Br

- 179 -

To a solution stirred 55% of 4-bromopyridine hydrochloride in 10ml water was added

Sodium bicarbonate is solid until gas formation stops. The mixture was Jue twice with Yo ( ether ml

(J) The combined organics were washed with saturated Sle sodium chloride; and placed in

amber flask and dried over sodium sulfate overnight while in a freezer at

© - L. The drying agent was filtered and washed with a minimal amount of ether; +016 has been removed from the article

Filtration product under a stream of nitrogen. pyridine bromo - 4 <u) was placed under high vacuum

for 10 minutes and then stored in a freezer under nitrogen atmosphere (1.4 g 6 VS 7).

NMR (500 MHz, DMSO-ds) 8 8.48 (dd, J=4.6, 1.4 Hz, 2 H), 7.68 (dd, J=4.6, 1.5 A

Hz, 2H).

0 to kiln dried; It was flushed with nitrogen. You ml capacity? Round bed holes were added 11101 de 0101 (NNN N'-tetramethyl-cthane-1,2-diamine mmol) followed by the addition of anhydrous tetrahydrofuran (50 (Je) and the solution was cooled in pentane/nitrogen please

to an internal temperature of - 0156 C. To this mixture was added 017 mol t-butyllithium in 0 ¥) pentane mL; 77.04 mmol) and the yellow solution was kept at 0°C

An internal temperature of 7.6 C. in a separate dry single hole of 0 8 mL; swept with nitrogen ¢ rounded bed ¢—pyridine bromo added prepared again (V.VA) g; FS mmol) and the solution was cooled in a bath = VA 0 and the 4-bromo pyridine solution was introduced into a vial dropwise into the t-butyllithium reaction mixture over y min carefully keeping the temperature internal is less than = VA . After addition, the reaction mixture was cooled to -

AYA - - 4 m. In a separate, dry, 0©-mL single well swept with nitrogen with a round coat was added: N-[(3-bromophenyl)(2-cyanophenyl)methylene]-2-methylpropane-2-sulfinamide) was added. Prepared according to Scheme No. 0<Example 0050 (N) g; 71077 mM tetrahydrofuran s (Use ) (Ja Yoo ©) and the solution was cooled in a VA-m bath. This mixture was introduced into a vial in 4-lithiopyridine anion was reacted over 2 minutes.The reaction mixture was stirred for 10 minutes;quenched with water;warmed to room temperature;extracted with ethyl acetate.Jue the organic layer Sle sodium chloride was saturated It was dried over sodium sulfate and removed from the solvent under reduced pressure to give a yellowish solid.The elution was carried out 0 on the chromatographic solid on 0 ¾ g silica gel using 100 mL shal of dichloromethane 5 dichloromethane using methanol: a and JV gl and the product was isolated in the form of a protected substance and an unprotected substance in the ratio of 0.£ : 1 and these mixtures were combined with Lee and transferred in a form Proceed to the next step, 0.87 (g). To this mixture of the protected and unprotected substance (0.87 grams) in ¾ mL of methanol VO was added V.Y0 M of hydrochloric acid in (Je "1 (methanol) and stirred reaction mixture for 10 min.The solvent was removed under reduced pressure to give a solid of coppery yellow color.The solids were pulverized with YO (ether mL) and filtered and transferred to a flask by dissolving it in methanol and the solvent was removed under reduced pressure The material was placed under a high vacuum at 90 m to give us the compound mentioned in the title in the form of a coppery-yellow solid, which was transported 0.0 to a raw form in the next reaction as it is 0.51 (gram). AED Small portion Yovy

- 179 — min) to give us the compound mentioned in title 1111 = rg) RP-HPLC AGI by (pe 001) purified and not mg. H NMR (500 MHz, DMSO-d¢/TFA- d) 9.02 (d, J= 6.9 Hz, 2 H), 8.40 ) 71 7.8 Hz, 1H),8.11(d, 72 6.8 Hz, 2 H), 8.00 ) J=7.8 Hz, | H), 7.94 (t, /=7.6 Hz, 1 H), 7.84 ) Jo 7.6 Hz, 1 H), 7.70 (d, J=9.1 Hz, 1 H), 7.48 (s, 1 H), 7.43 (t , J= 8.0 Hz, 1 H), 7.26 (d, J= 8.0 Hz, 1 H); MS (ES+) m/z 364 [M+1]*; tr = 1.34 min. 497 Ae Examples No. No. 7 using the substance Jaded dll and the additional compounds in Table No. 0 were prepared according to an appropriate prefix boronic acid (°) Table No. 01 m/z

LC

Example SH Structural formula NMR oa b ation) (min) 'H NMR (500 MHz, DM SO- d6/TFA-d) 9.26 (4, 71-7)

Hz, 1 H), 9.03 (d,J = 6.8 Hz, 2 H), 9.00 (d,J=5.6 Hz, 1 3-Pyridin-4-yl-3- H), 8.90 (d, /= 8.8 Hz , 1 H), (3-pyridin-3-yl- p &) 3 8.43(d,J=79 Hz, 1 H), pheny!)-3H- J 8.20 (dd, /=8.2,58 Hz , 1 363 Cy ¢ |isoindol-1- 0 © H),8.11(d,J=7.0 Hz, 2H), | (ES+) ylamine HN 8.08 (0, 717 7.9 112, 1 H), trifluoroacetate ? 8.00(d,J=8.1 Hz, 1 H), 7.95(t, J=7.6 Hz, 1 H), 7.84 (t,J=7.7Hz, 1 H), 7.77 (s, 1

H), 7.70 (t, J = 7.9 Hz, 1 H), 7.48 (d, J = 8.9 Hz, 1 H). 'H NMR (500 MHz, DMSO- 3-Pyridin-4-yl-3- N d6/TFA-d) 8 9.23 (s, 1 H), (-pyrimidin-s-yl-1b 0 um 9.14 (s,2 H),9.01 (d, J = 6.8 phenyl)-3H- to Hz,2H),841(d,J=78Hz, | 364 to | isoindol-1- N 2) 1H),8.11 (d,J=68Hz2 | (ES+) ylamine Wn H), 8.07 (d,/=79Hz 1 H), trifluoroacetate ? 7.95(q,/=7.1Hz 2H), 7.84 (1, J=77Hz 1H),7.72

— \ su c 72 jd LC tg Structural formula superimpose NMR . (loniz ation) (min) l em 11), 7.38 (d, J = 7.9 Hz, 1 H). 'H NMR (500 MHz, DM SO- d6/TFA-d) 89.02 (d, 1-8

Hz, 2 H), 8.85 (s, 1 H), 8.76 3-[3-(5-Methoxy- - (d.J=2.6 Hz, 1 H), 8.42 (d, pyridin-3-y-1) |J=72Hz, 2H), 8.08 (d, J = phenyl]-3-pyridin- | 0 y 393 2 | 4-yl-3H-isoindol- > N 0 6.3 112,3 118.01 (0.1 0 ) ES+) tr ylamine ; Hz, 1 H), 7.95(t, J=17.7 Hz, trifluoroacetate alma 1 11), 7.84 (t,/=77 Hz,

H), 7.75 (s, 1 H), 7.68 (a) 7.9 Hz, 1 H), 7.47 (d,J=7.9

Hz, 1 H), 4.07 (s, 3 H). H NMR (500 MHz, DM SO- d6/TFA-d) 89.00 (d, J=6.7

Hz,2 H), 8.41 (d, J= 7.8 Hz, 1 H), 8.14 (d,J=6.8 Hz, 2 3-(3'-Methoxy- H), 8.06 (d, 177.9 Hz, 1 H) , biphenyl 3-yD-3- 1 (=) Ng 7.95 (t,J=7.6 Hz, |H), 7.84 pyridin-4-yl-3H-Rn °C | (LJ=76Hz, I H) −7.79(d,J | 392 | | _, ¢v | isoindol-1- N© = 8.0 Hz, 1 H), 7.57 - 7.53 (ESH) ylamine Hn (m, 2 H), 7.38 (t, J = 8.0 Hz, trifluoroacetate 3 1 H),7.25(d,J=9.0Hz, 1

H), 7.19 (d, J= 7.8 Hz, 1 H), 7.16 (s, 1 H), 6.98 (dd, J = 8.3,2.4 Hz, 1 H), 3.81 (s, 3

H).

A Scheme No

Br 9 5 9 1) TL NH, P NH, 0 oN mkk 9 / A nBuLi a C N 10-8 © Ny 5

OC Sun -* 3 NBL 0 (50

Br ~o and A B (Scheme 5, Exampie N)

YoYY

- 171 -

EA Example #3-{3-[3-Amino-1-(4-methoxyphenyl)-1H-isoindol-1-yl]phenyl} thiophene-2- carbaldehyde 1,5 acetate (B A) Scheme # (

NH 0 ? /

Cr and of ~~ 0 ° v0 VR) 1-(3-Bromophenyl)-1-(4-methoxyphenyl)-1H-isoindol-3-amine g; 1.1 mmol) (Chart No. (2-formyl-3-thienyl)boronic acid «(A «A ( 497 ..” g; 1 mM [1,1'-bis(diphenylphosphino) )ferrocene]palladium(II) (Js chloride flux Y cabs v.11) dichloromethane .+ mmol) AY) potassium carbonate y + .g; 00 + 1 mmol) and solvent ( 1 ml of a mixture of dimethoxyethane and water 5 ethanol in a ratio of 1: ?: 1) was irradiated under an argon microwave atmosphere at 1716 m for 1 min. When cooled to ambient temperature the mixture was filtered and 1 dimethyl sulfoxide (ml) was added. The solution was concentrated in vacuo and purified by preparative HPLC to give us 0.2507 grams (; 7 yield) of the compound mentioned in the title. (s, 1 H), 8.15 (d, J= 5.02 Hz, 1 H), 7.79 (dd, J = 5.52, 3.01 9.68 E (DMSO-d) 11191 yZ Hz, 1 H), 7.73 (dd, J=5.52,2.76 Hz, 1 H), 7.68 - 7.53 (m, 1 H), 7.50 - 7.38 (m, 5 H), YAYY

- ary - 7.33 (d,J=5.02 Hz, 1 H), 7.26 (d, J= 8.78 Hz, 2 H), 6.83 (d, /= 8.78 Hz, 2 H), 3.71 (s, 3H), 1.91 (s, 3H); MS (AP) m/z 425 [M+1]".

NH,

N

Br 0 mmol) in TJs +. £0) 4-bromoanisole m from VA - to a solution cooled to © «Je 011 ¢ hexane M in n-butyllithium (0.0 mL) VO added (tetrahydrofuran :h added solution of 0.5 mmol); And yet YLT

N-[(3-bromophenyl)(2-cyanophenyl)methylene]-2-methylpropane-2-sulfinamide mL). © ( tetrahydrofuran g; ? mmol) was stirred in 10 ( (N «© Scheme no. The reaction mixture was magnesium sulfate with water and brine; it was dried over Jue 66 hydrochloric acid and treated with Jo YO ( methanol) to concentrate. The residue was dissolved in overnight. The mixture was concentrated The reaction was carried out after (Je Vode; magnesium sulfate over 0 (09 7 g” 0.70) of the compound mentioned in the title dichloromethane in methanol graded from

YAYY

- YY - 111121 (YL00) 8 7.57 - 7.48 (m, 3 H), 7.47 - 7.41 (m, 1 H), 7.39 - 7.32 (m, 2 H), 2 -7.28 (m, 1 H), 7.26 - 7.20 (m, 2 H), 7.10 (t, /=7.83 Hz, 1 H), 6.83 - 6.77 (m, 2 H), 5.86 (brs, 2 H), 3.75 (s, 3 H); MS (AP) m/z 393, 395 [M+1]". £9 Example No.

I-(3-Bromophenyl)-1-[4-(trifluoromethoxy)phenyl]-1H-isoindol-3-amine©

NH,

CC

N

Br = 0 starting with compound A oA The compound mentioned in the title was synthesized as described in Scheme No. 1/production yield. 1-bromo-4-(trifluoromethoxy)benzene 'H NMR (DMSO-ds) ) 5 7.86 - 778 (m, 1 H), 7.78 - 7.71 (m, 1 H), 7.55 - 7.36 (m, 6 H), 7.36'-7.21 (m, 4 H), 6.89 (brs, 2 H) ; MS (AP) m/z 447, 449 [M+1]" : © 0 Example 4-[3-Amino-1-(3-bromophenyl)-1H-isoindol-1-yl]benzonitrile

NH, Sir C Br

NZ

YoVYY

- 1174 - CE Starting from compound A The compound mentioned in the title was synthesized according to what was described in Scheme No. 14 7 production yield. 4-bromobenzonitrile 'H NMR (150/01-4) 5 7.84 - 7.79 (m, 1 H), 7.77 - 7.70 (m, 3 H), 7.51 - 7.40 (m, 6 H), 7.33 - 7.28 (m, 1 H), 7.28 - 7.21 (m, 1 H), 6.95 (br s, 2 H); MS (AP) m/z 387, 389

MA] 51 Example #1-(3-Bromophenyl)-1-[4-(trifluoromethyl)phenyl]-1H-isoindol-3-amine

NH,

CC

N

CBr. ! L F F Starting from compound A A The compound mentioned in the title was synthesized according to what was described in Scheme No. Production yield. 7 AY in 1-bromo-4-trifluoromethylbenzene Ve 'H NMR ( DMSO-ds) 5 7.85 - 7.78 (m, 1 H), 7.77 - 7.71 (m, 1 H), 7.63 (d, J = 8.34 Hz, 2 H), 7.53 - 7.39 (m, 6 H), 7.35 - 7.29 (m, 1 H), 7.29 - 7.20 (m, 1 H), 6.92 (br s, 2 H);

MS (AP) m/z 430, 432 [M+1]

Yeo - - Example No. 57 1-(3-Bromophenyl)-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-isoindol-3-amine acetate NH, N Br by A \ F F F ad Prepare the compound mentioned in the title according to what was then described in Scheme No. A « A starting from: Likely . 5-bromo-2-(trifluoromethyl)pyridine© Purification by column chromatography using a gradient elution from dichloromethane to dichloromethane : 0.¥ M ammonia in methanol 40 : © Preparative HPLC 11 7 Yield: H NMR (DMSO-dg) 5 8.67 (d, J= 2.01 Hz, 1 H), 7.94 (dd, J= 8.03, 1.76 Hz, 1 H), 7.89 - 7.79 (m, 3 H), 7.56 - 7.42 (m, 4 H), 7.39- 7.32 (m, 1 H), 7.32 - 7.23 (m, 1 H), 7.00 (br 5,2 HY, 1.89 (s, 3 H); MS (ES) m/z 432, 434 [M+1]" Scheme no. 1 Li 0 a NH,

S 1 ) Zn

CN Ki tBu } 2 tBuli N 1 Arami — 0 A \ 2) HCl No Br C (Scheme 5, Example N)

YAYY

1-(3-Bromophenyl)-1-pyridin-4-yl-1H-isoindol-3-amine (Chart No. 4; (C NH, Br 70 !) into a solution of 0117 (molar tert-butyllithium in Yeo “pentane ml; + mmol) in 01 (tetrahydrofuran ml) at -Nao M a solution of 4-iodopyridine VV aha ..18 0 was added mmol) in 10 (tetrahydrofuran ml) by drip, after which a solution of: 1 N-[(3-bromophenyl)(2-cyanophenyl)methylene]-2-methylpropane-2-sulfinamide g? mol) in 01 (tetrahydrofuran ml). After 1 hour at -151 the reaction mixture was quenched by adding water. The remaining mixture was partitioned between ethyl acetate and water; The organic phase 0 was dried over magnesium sulfate and evaporated. And the residue (Jw Yo) was dissolved and treated with hydrochloric acid) ? Molar in diethyl ether + ? Veda mmol) overnight. The reaction mixture was concentrated and then partitioned between saturated SL sodium bicarbonate and chloroform ¢ and the organic phase was dried over magnesium sulfate and concentrated. It was obtained through purification by column chromatography using a step-by-step gradient of methanol at 1°C (01 = (o) ethyl 7) using triethylamine 7 1 of the compound mentioned in the title (13.” g 11 7). . bam

- 197 - '" H NMR (CDCls) 5 8.56 - 8.48 (m, 2 H), 7.60 - 7.38 (m, 6 H), 7.27 - 7.21 (m, 3 H), 7.21 - 7.14 (m, 1 H) , 5.16 (br s, 2 H); MS (AP) m/z 364, 366 [M+1]" +4 to oF (example figures from ald) Additional compounds were prepared in Table ; According to the scheme No. + using the appropriate material. Boronic acid © (1) Table No. Example The structural formula of the compound NMR Miz No. 'H NMR (DMSO-d) § 8.00 (s, 1 H), 7.81 -7.76 (m, 1H), 1-[3-(1-Isobutyl-1H- NH, ~ 7.74 - 7.68 (m, 2H), 7.53 - pyrazol-4-ylphenyl}- ® Ny N 7.34 (m,4 H), 7.27 - 7.12 (m, 437 ov | 1-(4-methoxyphenyl)- Ln 4H), 681 (d,J=9.03 Hz, 2 APH

H-isoindol-3-amine 0 - H).3.91 (d,/= 7.28 Hz, 2H), 11 0.5 acetate b 3.70 (s, 3H), 2.20-2.02 (m,

H), 0.84 (d, 6 H), 1.91 (s, 1.5

H). NMR (DM SO-d,) 5 7.78 BS (dd, J =5.65,2.38 Hz, 1 H), = 7.66 (dd, J =5.77,2.26 Hz, 1 1-(4-Methoxyphenyl)- 2 H), 7.61 (s, 1 H), 7.49 - 7.40 1-[3-(5-methyl-2- OC “Wooo | wooo | No 6-7465 30,726s)furyl)pheny!])-1H - ~ 1H), 7.22 - 7.14 (m, 3 H), Arey isoindol-3-amine 0.5 ( ©. 6.81 (d, J = 8.78 Hz, 2 H), acetate -0 6.67 (d,J=3.26 Hz, 1 H), 6.20 - 6.13 (m, 1 H), 3.71 (s, 3 H), 2.31 (s, 3 H), 1.91 (s, 1.5 H).a 'H NMR (DMSO-d ;) 5 7.76 > Amito-l on b NH (d.J=7.28 Hz, 1 H), 7.71 (d, dol. 1 - bl 0 J=728 112,111, 7.64 (s, 1 434 ) H) , 7.49 - 7.34 (m, 5 H), 7.34 - yllbiphenyl-2- (5 O 7.18 (m, 6 H), 6.80 (d, J = 8.78 | APP) carboxamide 0.5 07 NH, 5 5 ora m Hz , 2 H), 3.70 (s, 3 H), 1.91 (s, 1.5 H).

- 1 m mt 0 digit' H NMR (400 MHz, DMSO- " dg) 58.64 (s, 1 H), 8.57 (d, J = 1 A Fluoropyridin A I" 276 hz, | 756 [70] (m. 3-yl)phenyl]-1-[4- N [ , 1. ,J=6.z, 464 o1 | (trifluoromethoxy)phe OC x" | H),7.82(d,J=6.02Hz, I H), (APH) nyl]-1H-isoindol-3- Fr ( 7.70 -7.57 (m,2 H), 7.53 - amine 0.75 acetate Ho 7.37 (m, 6 H), 7.26 (d, J = 8.53

Hz, 2 H), 6.86 (br s, 2 H), 1.91 (s, 2.3 H). 0 'H NMR (01150-2) 59.18 (s, 1-(3-Pyrimidin-5- { b 1 H), 9.00 (s, 2H), 7.91 - 7.87 ylphenyl)-1-[4-@ N ZN |(m, 1H), 7.83-7.78 (m, 1 H), 447 ov | (trifluoromethoxy)phe 0 bark1 7.69 7.62 (m, 2H).7.53 - 0 nyl]-1H-isoindol-3 - FF ( 7.41 (m, 6 H), 7.26 (d, J = 8.28 amine 0.25 acetate Xo Hz, 2 H), 6.82 (brs, 2 H), 1.91

F8 (s, 0.5H). 1

HNMR (DMSO-d) 5 9.18 (s 2 77 NH, , 4-[3-Amino-1-(3 0 1 H), 9.01 (s, 2 H), 7.93 - 7.88 pyrimidin-5-b button 2 3 1H). 7.85 - 7.80 111 phenyl)-1H- 0h l 1.745 7.80 (m, LH), | Mio oa | VP! ol] 02 7.73 (d, J=8.53 Hz, 2 H), (APH) bemonisile 0.25 ( 7.69 - 7.64 (m, 2 H), 7.55 - yl oon rev. of 7.44 (m, 6 H), 6.89 (brs , 2 H), acetate N 1.91 s, 0.5 H).

NH, 'H NMR (DMSO-d) 8 8.65 (5) with PY Lee one -yl)phenyl]-1-{4- f 1.754, J = 10. Z SQL 04 | (trifluoromethyi)phen OC Ne H), 7.88 (d, resolving 6.53 Hz, 1 H), (ES-) yl]-1H-isoindol-3- b 9 7.84 (d, 1 H), 7.69 - 7.60 (m, 4 amine 0.25 acetate H), 7.57 - 7.40 (m, 6 H), 6.87

F (brs, 2H), 1.91 (s, 1.0H).

NH. i m : H NMR (DM SO-dy) 8 9.18 (5, dm l 02 wa lacy | 110,901 (2H), 7.92-7.87 b ) - u 0 SON | (m, 1H), 7.85-7.80(m, 1H), | 429 "| L 1.91 (s, 0.5 H).

YAYY

- 18 - ref. - 1 CC) 2-carbaldehyde da TH NMR (DMSO-d) 3 8.44 (dd, 724.52, 1.51 Hz, 2 H), 8.03 (s, 1 H), 7.81 (dd, J = 1-[3] -(1-Isobutyl-1H- NH, ~ 5.14,3.14 Hz, 2 H), 7.72 (s, 1 pyrazol-4-yl)phenyl]- 2 N N H), 7.52 - 7.46 (m, 3 H), 7.43 408 7 | l-pyridin-4-yl-1H-| FN (d,J=7.78 Hz, 1 H), 7.31 - (ES) isoindol-3-amine 0.25 1 = OC 7.23 (m,3 H),7.21-7.13 (m, acetate Ca 1 H), 6.84 (brs, 2 H), 3.91 (d,

J=728Hz, 2H), 2.18 - 2.05 (m, 1H), 0.85 (d, J =6.78 Hz, 6H), 1.91 (s, 1.0H). 'H NMR (DMSO-d) & 8.45 (dd, J =4.52, 1.51 Hz, 2 H), 7.87 - 7.80 (m, 1 H), 7.79 - 1-[3-(5-Methyl-2- NH, 7.73 (m, 1 H), 7.61 (5, 1 H), furylyphenyl]-1- Cl Sy oy | 7.55-7.45(m, 311), 7.34- 366 27 |pyridin-4-yl-1H- = 7.25 ( m, 3H), 7.20(d, J = 53 (AP4) isoindol-3-amine © for Hz, 1 H), 6.88 (brs, 2 H), 0 acetate no) 4,7 3.26 Hz, 1 H), 6.21 - 6.12 (m, 1 H), 2.31 (s, 3 H), 1.91 (s, 3.0 H). 3'-(3-Amino-1- 0 "HNMR (W/01/50-4) 5 8.49 - pyridin-4-yl-1H- { 8.41 (m, 2H), 7.79 (t, J = 6.90 + |isoindol-1- OC N 0) Hz, 2 H), 7.67 (s, 1 H), 7.53 - 405 yl)biphenyl-2- = 0 7.25 (m, 11 H), 6.84 (brs, 2 (ES+) carboxamide 0.25 1 J 07 NH, H), 1.91 (s, 1.0 H).

Su p \ —_ Jha No. To 4-{3-Amino-1-[3-(2-fluoropyridin-3-yl)phenyl]-1H-isoindol-1-yl} benzonitrile NH, F N > Cr oO 7 N 1.77 aha » . . 1 mM (4-[3-Amino-1-(3-bromophenyl)-1H-isoindol-1-yl]benzonitrile mM (Use © (Example No. YY aba 0.0 47) (2-fluoropyridin-3) -yl)boronic acids + (#0 mmol) « and [1,1'-bis(diphenylphosphino)ferrocene]palladium(Il) chloride flux product of 0.77 m cab oie) A) dichloromethane mol) 0. 11 (potassium carbonates g; 17 mmol) and a solvent (1 mL of a mixture of dimethoxyethene + water and 5 ethanol in ratio:0) were irradiated under an atmosphere of 88800 in a microwave at 1756 °C for + minutes. 0 and when it was cooled to ambient temperature, the mixture was fractionated between ethyl acetate and water, the organic phase was dried over magnesium sulfate and evaporated. of the compound mentioned in the title. (dd, J = 3.28, 1.52 Hz, 1 H), 8.05 - 7.94 (m, 1 H), 7.84 - 8.22 E'H NMR (DMSO-ds) (m, 2 H), 7.75 - 7.69 (m, 2 H), 7.56 - 7.34 (m, 9 H), 6.90 (br s, 2 H); MS (AP) m/z 7.75 *[181+1 405] is important

- 141 - +” Example No. 1-[3-(2-Fluoropyridin-3-yl)phenyl]-1-[4-(trifluoromethyl)phenyl]-1 H-isoindol-3-amine

NH,

F N

CO7

Oo4)

F

F

Then, the compound mentioned in the title was synthesized according to what was then described in Example No. 10 starting from compound #1 (Example No. 1-(3-bromophenyl)-1-[4-(trifluoromethyl)phenyl]-1H-isoindol © -3-amine yield. 7 7 0 in 'H NMR (DMSO-ds) & 8.25 - 8.18 (m, 1 H), 8.05 - 7.95 (m, 1 H), 7.85 - 7.73 ( m, 2 H), 7.63 (d, J = 8.34 Hz, 2 H), 7.57 - 7.37 (m, 9 H), 6.89 (br s, 2 H); MS (AP) m/z 448 [M+1 ]". 01 Chart No. 0

NH,

F 8 ground UT m c

Br N 70 Fo / No 02 (Scheme #9, C) D

YoYY

- 157 -

TV Example #1-[3-(5-Fluoropyridin-3-yl)phenyl]-1-pyridin-4-yl-1H-isoindol-3-amine 0.75 acetate (D 0 for chart 1)

NH,

Cr 210 2 1-(3-bromophenyl)-1-pyridin-4-yl-1H-isoindol-3-amine A mixture of © and “(dss mm LY g; RAY) was irradiated. (C 3 Chart No. ) 01 gr; VY) 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine mmol); 460 cab ».00( potassium carbonate 5 mmol ); + YO g; The organic phase was concentrated and the substance, ethyl acetates, was documented, and its fractionation was carried out between water. Cady reaction: 0.0 41 grams (preparatory; this gave us the compound mentioned in the title, the remaining HPLC by (7 ot "H NMIR) DMSO-ds) 8 8.67 - 8.63 (m, 1 H), 8.57 (d, J=2.78 Hz, 1 H), 8.49 - 8.42 (m, 2

H), 7.99 - 7.90 (im, 2 H), 7.85 - 7.79 (m, 1 H), 7.67 - 7.62 (m, 2 H), 7.55 - 7.41 (m, 4 H), 7.37 - 7.28 (m, 2 H), 6.95 (brs, 2H), 1.91 (s, 2.2H); MS (ESI) m/z 381 [M+1]". 7e

- VEY - 11 Chart No. 9 1 ( CuCN the RS ) 0

LiBr no 0 Ti(OEt) 8 “or : CN N < L OC THF 2) “0 F reflux

Br F cl E F Br

T | 2) Hel 1) _N tBulli : HO 4 -OH ws NN 2

Nz

Cox O_o x AN Br 1 7 F 3 4 OC F

HG

SUA Example 1-(4-Fluoro-3-pyrimidin-5-ylphenyl)-1-pyridin-4-yl-1H-isoindol-3-amine 0.5 acetate (H:(Chart No. FA 2)

NH,

N

> 2 x 0 << N ~~ \

N 7 F: The compound mentioned in the title was synthesized from

- Vet -

LS (6 eV) (Chart No. 1-(3-bromo-4-fluorophenyl)- 1-pyridin-4-yl-1H-isoindol-3-amine : using 7 41 with a yield (D;01) (Chart No. TV is described in example. pyrimidin-5-ylboronic acid 'H NMR (DMSO-d) 8 9.02 (s, 1 H), 8.78 - 8.72 (m, 2 H), 8.30 - 8.23 ( m, 2 H), 7.78 - 7.70 (m, 1 H), 7.66 - 7.58 (m, 1 H), 7.41 - 7.26 (m, 4 H), 7.20 - 7.08 (m, 3 H), 6.76 (brs, © 2H), 1.72 (s, 1.9 H); MS (EST) m/z 382 [M+1]". (G VY (Chart #1-(3-Bromo-4-fluorophenyl)-1-pyridin) -4-yl-1H-isoindol-3-amine

NH, \ (Ly

Br ~~ \

N yb F beginning 7 01 The compound mentioned in the title was synthesized as described in Scheme No. 9; © With a score of: 0

N-[(3-bromo-4-fluorophenyl)(2-cyanophenyl)methylene]-2-methylpropane-2- sulfinamide .) 001 (Chart No.

MS (AP) m/z 382, 384 [M+1].” Pagam

Vio - - N-[(3-Bromo-4-fluoropheny!)(2-cyanophenyl)methylene] -2-methylpropane-2- sulfinamide (Chart No. (FO) 0 ll 5 CN N < J CL Br© “a mixture of 2-(3-bromo-4-fluorobenzoyl)benzonitrile (scheme) ¢ (E 5 ethyl) was stirred ortho titanate (1 M solution in 18 ¢ tetrahydrofuran ml; YAY mmol) for 0 min; then CAN 0111 (2-methyl-2-propanesulfinamide 5.17 mmol) was added and the resulting mixture was heated until reflux overnight. When the reaction was cooled to room temperature saturated (Sle sodium bicarbonate “methanol) and ethyl acetate were added. After filtration the reaction mixture was passed through a bed of sodium sulfate; and a resulting concentrate Filtration Purification of the remainder by column chromatography using chloroform as an eluent filter gave the compound mentioned in heading 0111 (g; 70 / in two steps). , 7.68 - 7.39 (m, 3 H), 7.18 (t, J = 8.21 Hz, 1 H), (brs, 9 H); MS (AP) m/z 407, 409 [M+17]. 1.38 2-(3-Bromo-4-fluorobenzoyl)benzonitrile Vo (Chart No. 11 8): A None Mar Ba

-1]1-

C.N.O

E

Br 01 « tetrahydrofuran M (.+0 molar in 7.2-cyanophenylzinc bromide to a mmol solution) and 001 can +94) copper cyanide mmol) a solution of 01 mL was added; ml); Slowly allowed tetrahydrofuran (V0 mmol) in 11 g; lithium bromide (VAY)

Yo -- min The reaction mixture was re-cooled to chamber 11; After Hh for the reaction to reach a degree (millimol) in 001 can 0.49 (3-bromo-4-fluorobenzoy! chloride M. M solution was added for an hour and at a temperature of Yo - The reaction mixture was stirred when (Ja 0 ) tetrahydrofuran “aqueous diethyl ether and ammonium chloride” were dried in the room overnight. After partitioning and concentrating to give the crude product mentioned in the heading above which magnesium sulfate is the organic phase Additional . AAT is used without 0

MS (ESI) m/z 304, 306 [M+1]". a Example 1-[4-Fluoro-3-(5-fluoropyridin-3-yl)phenyl]-1-pyridin-4-yl -1H-isoindol-3-amine 0.75 acetate

NH,

N

Or 0 > = F 7 F

N vo

YaYY

The compound mentioned in the title was synthesized from as 6) “VY (Chart No. 1-(3-bromo-4-fluorophenyl)-1-pyridin-4-yl-1H-isoindol-3-amine : Using 7 31 in net D Ve (TV number chart) is described in example 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine "H NMR (DMSO-dg) & 8.63 (d, J =2.78 Hz, 1 H), 8.57 - 8.51 (m, 1 H), 8.50 - 8.42 (m,2©

H), 7.95 - 7.86 (m, 2H), 7.85 - 7.78 (m, 1H), 7.56 - 7.46 (m, 4H), 7.36 - 7.27 (m, 3H), 6.96 (brs, 2H) , 1.91 (s, 2.5 H); MS (ESI) m/z 399 [M+1]".

VY Chart No

F

0 a ZN NH 1) 2 on Neu nBulli 4 diisopropylamine OC N

O00 — XO" 2) HCI on Br (N eg co) (Chart No. 01): 1 AY (Chart No. 1-(3-Bromophenyl)-1-(3-fluoropyridin-4) -yl)-1H-isoindol-3-amine

NH, > (Cy

Br

I

\_/

N F

YaavYY

To a solution of YA ~ m-diisopropylamine (l..ml 0.0 mmol) in tetrahydrofuran (Je 01(Y.0)m n-butyllithium at “Ja 7.7 ¢) was added hexane 9.5 mmol); The mixture was stirred for 0.8 h and then a solution of (£V) 3-fluoropyridine + .ml was added; 0.0 mmol) in (Ja XY) tetrahydrofuran after another 1.5 hours was added: N-{(3-bromophenyl)(2-cyanophenyl)methylene]-2-methylpropane-2-sulfinamide © ( Scheme “©” (N (0 4 g; © mmol) in tetrahydrofuran (© ml). After 0.5 hours at p VA - water was added; The mixture was extracted using ethyl acetate; And the drying of the organic phase over magnesium sulfate and its concentration. The remainder was dissolved in methanol (+£ mL) and treated with M (Y) hydrochloric acid at 01 cde©¢ diethyl ether mmol) 0 at A after evaporation; The remainder was divided between sodium bicarbonate saturated Ale and chloroform ; The organic phase was dried over magnesium sulfate and evaporated. Purification of the remainder by column chromatography using a gradient of methanol in 1-01 (chloroform 7) in steps as an eluent filter gave the compound mentioned in heading 0177 (gm 164 7). (d,J=2.78 Hz, 1 H), 8.35(d, J =5.05Hz, 1H), 7.76 (d, J = Vo 8.43 6 (ng0) 1 Hz, 1 H), 7.60 - 7.50 (m, 3 H), 7.45 - 7.37 (m, 2 H), 7.37 - 7.33 (m, 1 H), 7.20 - 8.08 (m, 2 H), 5.37 (br 5, 2 H); MS (AP) m/z 382, 384 [M+1 I]. 7.13 AVY

- 1)?-: V. Example 1-(3-Bromo-4-fluorophenyl)-1-(3-fluoropyridin-4-yl)-1 H-isoindol-3-amine

NH, (2

Br ~~ \_/

N F F

The compound mentioned in the title was synthesized from:

N-[(3-bromo-4-fluorophenyl)(2-cyanophenyl)methylene]-2-methylpropane-2- 5 sulfinamide 7 .16 in TOY as described in Scheme No. (Fe) (Chart No. "H NMR (DMSO-d) & 8.46 (d, 12 2.78 Hz, 1 H), 8.38 (d, J = 5.05 Hz, 1 H), 7.89 - 7.71 (m, 2 H), 7.66 - 7.53 (m , 2 H), 7.44 - 7.35 (m, 2 H), 7.19 - 7.13 (m, 1 H), 7.05 (t,] = 8.34 Hz, 1 H); MS (ESI) m/z 400, 402 [M +1]".

VY Example 1-(3-Fluoropyridin-4-yl)-1-[3-(5-fluoropyridin-3-yl)phenyl]-1H-isoindol-3-amine 0.5 acetate

NH,

N

Cr0)

N.S

ST

A JF either

- 14. The compound mentioned in the title was synthesized from As IVY (Chart No. 1-(3-bromophenyl)-1-(3-fluoropyridin-4-yl)- 1H-isoindol-3-amine: 7 517 is described in Scheme 10;0 with yield 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 'H NMR (DMSO- ds) 5 8.58 - 8.52 (m, 1 H), 8.49 (d, J = 2.78 Hz, 1 H), 8.37 (d, J = 2.78 °

Hz, 1 H), 8.27 (d, J = 4.80 Hz, 1 H), 7.88 - 7.82 (m, 1 H), 7.81 - 7.72 (m, 2 H), 7.60 - 7.53 (m, 1 H), 7.51 - 7.40 (m, 3 H), 7.35 (t, J = 7.71 Hz, 1 H), 7.30 - 7.25 (m, 1 H), 7.21 (dd, J = 6.82, 5.05 Hz, 1, not 6.95 ( brs, 2 H), 1.84 (5, 1.4 H); MS (ESI) m/z 399 [M+1 I].

VY Example, 1-(3-Fluoropyridin-4-y1)-1-(3-pyrimidin-5-ylphenyl)-1H-isoindol-3-amine 1.25 acetate

NH,

N

7

CY x NN ~~ \

NZ °F: The compound mentioned in the title was synthesized from As (I VY) (Chart No. 1-(3-bromophenyl)-1 -(3-fluoropyridin-4-yl)-1H-isoindol-3- amine .pyrimidin-5-ylboronic acid using 7 51 with a yield of 1 01 was described in chart no but money

_ 1 o 1 _ 'H NMR (DMSO-dg) 5 9.10 (s, 1 H), 8.91 (s, 2 H), 8.37 (d, 12 2.78 Hz, 1 H), 8.27 (d, J = 5.05 Hz , 1 H), 7.81 - 7.74 (m, 2 H), 7.62 - 7.56 (m, 1 H), 7.52 - 7.48 (m, 1 H), 7.46 - 734 (m, 3 H), 7.33 - 7.27 (m , 1 H), 7.21 (dd, J = 6.82, 5.05 Hz, 1 H), 6.95 (br s, 2 H), 1.84 (s, 3.6 H); MS (ESI) m/z 382 [M+1]".

VY Example © 1-(3-Fluoropyridin-4-yl)-1-[3-(2-fluoropyridin-3-yl)phenyl]-1 H-isoindol-3-amine 1.25 acetate

NH, \ F N

Cr 1) > ~~ \ J

N F

The compound mentioned in the title was synthesized from As I VY (Chart No. 1-(3-bromophenyl)-1-(3-fluoropyridin-4-yl)-1H-isoindol-3-amine 01 . (2-fluoropyridin-3-yl)boronic acid with /617 with a yield of 0 Vv was described in plot No. 'H NMR (DMSO-dg) 6 8.38 (d, J = 2.78 Hz, 1 H), 8.27 (d, J = 5.05 Hz, 1 H), 8.17 - 8.12 (m, 1 H), 7.96 - 7.88 (m, 1 H), 7.80 - 7.74 (m, 1 H), 7.71 - 7.65 (m, 1 H), 7.48 - 7.31 (m, 6 H), 7.27 - 7.20 (m, 2 H), 6.93 (brs, 2 H), 1.89 (s, 3.9 H); MS (ESI) m/z 397 [M- 17.

Vo:76 An example of either

- 1,7 — 1-(3-Fluoropyridin-4-yl)-1-(4-fluoro-3-pyrimidin-5-ylphenyl)-1H-isoindol-3-amine 1.25 acetate

NH, 8 N > N ~~ \

N JF F

: The compound mentioned in the title was synthesized from (V+ (ex. 1-(3-bromo-4-fluorophenyl)-1 -(3-fluoropyridin-4-yl)-1H-isoindol-3-amine © pyrimidin-5-ylboronic acid using / 61 described in Scheme 10;0 with a yield of '" H NMR (DMSO-dg) 5 9.00 (s, 1 H), 8.70 (d, J = 1.26 Hz). , 2 H), 8.24 (d,J = 3.03 Hz, 1

H), 8.13 (d, J = 5.05 Hz, 1 H), 7.68 - 7.60 (m, 2 H), 7.35 - 7.24 (m, 3 H), 7.24 - 7.18 (im, 1 H), 7.11 (dd, J = 10.11, 8.84 Hz, 1 H), 7.05 (dd, J = 6.82, 5.05 Hz, 1 H), 6.82 (brs, 2

H), 1.88 (s, 3.8 H); MS (ESI) m/z 400 M+17". Ye vo Jl 1-[4-Fluoro-3-(5-fluoropyridin-3-yl)phenyl]-1-(3-fluoropyridin-4-yl)-1 H-isoindol-3- amine 1.5 acetate Oh, oh, oh, oh, oh, oh, oh, oh

- 1 pm -

NH,

N

Cy (0) > = F \

N JF F

The compound mentioned in the title was synthesized from Ve (eg 1-(3-bromo-4-fluorophenyl)-1-(3-fluoropyridin-4-yl)-1H-isoindol-3-amine 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine ° 'H NMR (DMSO) -dg) 8 8.41 (d, J=2.78 Hz, 1 H), 8.30 (d, J = 1.52 Hz, 1 H), 8.25 (d, J = 2.78 Hz, 1 H), 8.13 (d, J = 4.80 Hz, 1 H), 7.59 - 7.70 (m, 3 H), 7.35 - 7.27 (m, 2 H), 7.25 -7.15 (m, 2 H), 7.13 - 7.03 (m, 2 H), 6.83 (brs, 2 H), 1.89 (s, 4.3 H); MS (ESI) m/z 415 [M-17". v1 Example Ve 1-[4-Fluoro-3-(2-fluoropyridin-3-yl)phenyl }-1-(3-fluoropyridin-4-yl)-1H-isoindol-3- amine 1,5 acetate

NH,

F N

>

Co 1) > -_- \ A ®

N F F

The compound mentioned in the title was synthesized from

— \ 3 4 — As (Ve Jb) 1-(3-bromo-4-fluorophenyl)-1-(3-fluoropyridin-4-yl)-1H-isoindol-3-amine : using 7 71 Described in Scheme No. 10; 0 with a score. (2-fluoropyridin-3-yl)boronic acid 'H NMR (DMSO-de) 5 8.25 (d, J = 2.78 Hz, 1 H), 8.16 - 8.06 (m, 2 H), 7.79 - 7.69 (m, 1

H), 7.67 - 7.60 (m, 1 H), 7.60 - 7.54 (m, 1 H), 7.36 - 7.22 (m, 3 H), 7.21 - 7.11 (m, 2H), 8 7.11 -7.03 (m, 2 H), 6.82 (br s, 2 H), 1.87 (s, 4.3 H); MS (ESI) m/z 415 [M-1]".

Scheme 13

NH, TL NH, oF 2 of

OC 7 H thylditi = OC he exame 11 \_/ amet yay (Scheme #9, C) J

VV Example, 5-[3-(3-Amino-1-pyridin-4-yl-1H-isoindol-1-yl)phenyl]nicotinotrile acetate (Scheme #13, 7)

NH,

N

Cr 0) 57) 7 p. 40 can +.1¥) hexamethylditin by irradiating argon ml) under an atmosphere of ¥ ( dimethoxyethane 5 mmol) 101 aa "d: in a microwave at 11°C for 1 hour. 05 was added

Yavyv

- \oo — (ax + VT) )0 (Chart No. 3; 1-(3-Bromophenyl)-1-pyridin-4-yl-1H-isoindol-3-amine mmol) 00 "a .. g; (tetrakis(triphenylphosphine)palladium mmol) and 10 M. The reaction mixture was filtered and divided for 100 hours at Saad into the reaction mixture and the preparatory heating was completed by HPLC; phase concentration and purification of the remainder by ethyl acetate 5 ¢ between (YY Cm v1) gave the compound mentioned in the title © 'H NMR 014150-40 5 8.97 (d, 122.27 Hz, 1 H), 8.93 (d, J = 1.77 Hz, 1 H), 8.48 (t, J = 2.02 Hz, 1 H), 8.43 - 8.34 (m, 2 H), 7.91 - 7.85 (m, 1 H), 7.78 - 7.73 (m, 1 H ), 7.66 - 7.57 (m, 2 H), 7.48 - 7.35 (m, 4 H), 7.23 (d, J = 6.06 Hz, 2 H), 6.91 (brs, 2 H), 1.83 Gs, 2.9 H); MS (ESI) m/z 388 [M+1]".

VE Scheme No. 0

N nz 1 0 8 N LNT Bu N 4 i 2) CuCNxaLisr lo 8 on, {ll A 8 = Br 1 JC oC

THF

Cl Or Br reflux

F F F Br

K L

1 en 2) Hal

So_nBulLi

Ul" HO. OH NH,

N A

ao nc

IE Gr 0 = 1 nm Br

Na oN

N M

Yo — - Example YA 6-Fluoro-1-(4-methoxyphenyl)-1-(3-pyrimidin-5-ylphenyl)-1H-isoindol-3-amine (Chart No. (N AR) NH, Cr OC NaN A mixture of: 1-(3-bromophenyl)-6-fluoro-1-(4-methoxyphenyl)-1H-isoindol-3-amine © ( Chart No. 14 (VY) 4 mg; VAY + mmol); YET Lana Yo) pyrimidin-5-ylboronic acid + mmol); and an excess effluent of: Vo.o) [1, 1'-bis(diphenylphosphino)ferrocene]palladium(ll) dichloride dichloromethan (cana 5018 mmol) and VAY) cesium carbonate combined; 10011 mmol) in a mixture of dimethoxyethane Ve ¢, water, and 1 7 (9 mL ethanol) by microwave irradiation at mC; under an argon atmosphere for V0 minutes. After cooling at ambient temperature, then the mixture was filtered, concentrated in vacuo, and purified by preparative HPLC to give 001 mg (yield 4) '" H NMR (CDCls) 8 9.17 (s, 1 H), 8.87 ) 2 H), 7.53 (m, 1 H), 7.48 - 7.37 (m, 4 H), 7.24 (m, 3 H), 7.12 (m, 1 H), 6.82 (m, 2 H), 3.78 (s , 3 H); MS (ESI) m/z 411 [M+1]". Vo a pass a pass

— \oV — 1-(3-Bromophenyl)-6-fluoro-1-(4-methoxyphenyl)- | H-isoindol-3-am ine:(M Ye) (Chart No

NH, >

Cy

CSC

—0 Br : Using O © the compound mentioned in the title was prepared as described in Scheme no

N-[(3-bromophenyl) (2-cyano-5-fluorophenyl)methylene]-2-methylpropane-2- 5 sulfinamide)7 7.5 as starting material (yield (Lo)£) (Chart No. "HNMR") CDCl3) 58 7.45 121.77 Hz, |H), 7.41 (dd, J = 8.21,4.67 Hz, 1 H), 7.37 (m, 1 H), 7.25 - 7.17 (m, 4 H), 7.19 - 7.09 (m, 2 H), 6.81 (m, 2 H), 3.78 (s, 3 H).

N-[(3-bromophenyl)(2-cyano-5-fluorophenyl)methylene]-2-methylpropane-2- 0 sulfinamide (L AR): (Chart No. 0

N 1 i NS oC

F Br Leah Aya Maraba

o A — \ _ Then prepare the compound mentioned in the title as described in Scheme No. M, N, using: 2-(3-bromobenzoyl)-4-fluorobenzonitrile (Chart No. (K VE) as a starting material (yield) 00 7( 'H NMR (CDCl5) 8 7.82 - 7.72 (m, 2 H), 7.67 (m, 1 H), 7.45 (m, 1 H), 7.30 (m, 2 H), (m, 1 H), 1.39 (brs, 9 H).0 7.12 2-(3-Bromobenzoyl)-4-fluorobenzonitrile (plot no. 06): N 1 F 0 transferred 1. Ghee g/ml of active zinc powder (YY) tetrahydrofuran ml .5 mmol) via a cannula to a solution of YO (pn 0 ) 2-bromo-4-fluorobenzonitrile mmol) in tetrahydrofuran Ve Non-Mathe 001 (ml) at room temperature under an argon atmosphere. The mixture was stirred at room temperature for © hours and then treated with sonic waves (358) for 0 ? min. Excess zinc was allowed to To settle overnight at = oa Yo, the upper solution was transferred via a cannula to another flask under an argon atmosphere and cooled at - 0 + m. To that a complex solution was added: 0002118 1 molar in tetrahydrofuran (Y1.Y). ml). Then 1 stir the resulting solution at -76°C for 10 minutes and at 0°C for YO minutes; Then it was cooled to Yo — M and chloride 1 O3-00001056020 was added. The mixture was stirred for 1 hour while the temperature was held between — Yo C and - VO C; Then it was stored in an incinerator at 0°C for two and a half days. YaavYY

1009 - - The reaction was quenched by adding a saturated ammonium chloride solution. The mixture was diluted with ethyl acetate ¢ and the organic phase Jus separated using 1 M hydrochloric acid and 1 M sodium carbonate solution; dried over magnesium sulfate and evaporated. Purification by column chromatography using a gradient of gradually increasing concentration of ethyl acetate in (VY) heptane (0 - 56 7) gave 0.04 g of the product mentioned in the heading (yield © "HNMR (CDCl) 8 7.96 (t, J = 1.64 Hz, 1 H), 7.88 (dd, J = 8.46, 4.93 Hz, 1 H), 7.80 (m, 1 H), 7.72 (m, 1 H), 7.44 - 7.37 (m, 2 H), 7.35 ( dd, J=8.08, 2.53 Hz, 1 H); MS (EI) m/z 304, 306 [M+1]". va Example 6-Fluoro-1-(4-methoxyphenyl)-1-( 3-pyridin-3-ylphenyl)-1H-isoindol-3-amine (NH, Cy - 4) t) NN Then prepare the compound mentioned in the title as described in the example VA (scheme no. k (N .7) 11 (yield of pyridin-3-ylboronic acid using “HNMR (J020) 8 8.76 (dd, J = 2.40, 0.88 Hz, 1 H), 8.56 (dd, J = 4.80, 1.52 Hz, 1 H), Ve 7.80 (m, 1 H), 7.53 (m, 1 H), 7.46 (m, 1 H), 7.42 - 7.36 (m, 2 H), 7.36 - 7.30 (m , 2H),

YoYY

- 11. 7.27 -7.23 (m, 3 H), 7.12 (m, 1 H), 6.82 (m, 2 H), 3.79 (s, 3 H); MS (ESI) m/z 410

M+1]". tA Example 6-Fluoro-1-(3'-methoxybiphenyl-3-yl)-1-(4-methoxyphenyl)- 1H-isoindol-3-amine

NH, \

N

© © J ~ 0 o (N Ve) (Chart No. YA) The compound mentioned in the title was prepared as described in Example 7 (YY (yield) (3-methoxyphenyl)boronic acid) using “HNMR (CDCls) ) 8 7.53 (m, 1 H), 7.46 (m, 1 H), 7.39 (dd, J = 8.34, 4.55 Hz, 1 H), 7.28 (m, 6 H), 7.09 (m, 2 H), 7.04 (m, 1 H), 6.87 (m, 1 H), 6.81 (m, 2 H), 3.83 (s, 3 H), 3.78 (s, 3 H); MS (ESI) m/z 439 [M+ 1]".

AY Example B Laumla

- 1110 - 6-Fluoro-1-(4-methoxyphenyl)-1-[3-(5-methoxypyridi n-3-yl)phenyl]-1H-isoindol-3- amine

NH,

N

(CL) - RA 0 2)

YONA, (NAR) (Chart No. YA). The compound in the title was prepared as described in the example 7£Y (yield (5-methoxypyridin-3-yl)boronic acid) using © 'H NMR (CDCl) 8 8.36 (d,J=1.77 Hz, 1 H), 8.26 (d, J = 2.78 Hz, 1 H), 7.53 (m, 1 H), 7.44 (m, 2 H), 7.38 (m , 1 H), 7.34 (m, 1 H), 7.30 (dd, J = 2.78, 1.77 Hz, 1 H), 7.24 (m, 3

H), 7.12 (m, 1 H), 6.82 (m, 2 H), 3.89 (s, 3 H), 3.78 (s, 3 H); MS (ESI) m/z 440 [M+17].

AY Example 1-(3-Bromophenyl)-6-fluoro-1-pyridin-4-yl-1H-isoindol-3-amine Vo

NH,

CC

- 3 Ra / km Br The compound mentioned in the title was prepared as described in Scheme No. 9; © using:

- 177 -

N-[(3-bromophenyl)(2-cyano-5 -fluorophenyl)methylene]-2-methylpropane-2- sulfinamide . 1a. as starting material (toll (LAR) (Chart No. 'H NMR (YL02)) 8 8.46 (m, 2 H), 7.83 (dd, J = 8.46, 4.93 Hz, 1 H), 7.75 (dd, J = 8.97, 2.15 Hz, 1 H), 7.47 - 7.43 (m, 2 H), 7.37 - 7.31 (m, 2 H), 7.30 - 7.23 (m, 3 H), 6.98 (brs, 2° H).

AY Jl 6-Fluoro-1-pyridin-4-yl-1-(3-pyridin-3-ylphenyl)-1H-isoindol-3-amine

NH,

Co) - ra) m \

N 7 ا Y _© No (N NV ¢) (scheme number VA) Then prepare the compound mentioned in the title as then described in Example 01: using pyridin-3-ylboronic acid and -1 3-bromophenyl)-6-fluoro-1 -pyridin-4-yl-1H-isoindol-3- amine (7) 18.5 (yield (AY) (ex. PAM)

- 117 - 'H NMR (DMSO-dg) 5 8.77 (m, 1 H), 8.55 (dd, J = 4.80, 1.52 Hz, 1 H), 8.46 (m, 2 H). 7.95 (m, 1 H), 7.87 - 7.81 (m, 2 H), 7.59 (m, 2 H), 7.47 (m, 1 H), 7.39 - 7.44 (m, 2 H), 737-731 (m, 3 H), 6.96 (br s, 2 H); MS (ESI) m/z 381 [M+1]".

AE Example 6-Fluoro-1-pyridin-4-yl-1-(3-pyrimidin-5-ylphenyl)-1H-iso indol-3-amine 5

NH,

Co - + Ra \ N—7 © NaN ) 8 004 (Chart No. VA) The compound mentioned in the title was prepared as described in the example and pyrimidin-5-ylboronic acid using al aa) (AY JL) 1-(3-bromophenyl)-6-fluoro-1 -pyridin-4-yl-1H-isoindol-3-amine (LX 0 "HNMR (CDCl3) 8 9.19 (s, 1 H), 8.87 (s, 2 H), 8.55 (m, 2 H), 7.53 - 7.45 (m, 4 H), 7.36 (m, 1 H), 7.29 - 7.25 (m, 3 H), 7.20 (m , 1 H); MS (ESI) m/z 382 [M+1]". Example blood:

- 174 2- 6-Fluoro-1-[3-(5-methoxypyridin-3-yl)phenyl]-1-pyridin-4-yl-1H-isoindol-3-amine

NH, \

Cp

CSO

\ \ 7 ©

Na 0 (N 04) (Chart No. VA) The compound mentioned in the title was prepared as described in the example: using (5-methoxypyridin-3-yl)boronic acid and 1 -(3-bromophenyl)-6 (-fluoro-1-pyridin-4-yl-1H-©isoindol-3-amine) 7 16 (yield (AY) (ex. '" H NMR (CDCl;) 8.54 (m, 2 H), 8.36 (d, J = 1.77 Hz, 1 H), 8.28 (111-2.73 Hz, 1 H), 7.52 - 7.45 (m, 3 H), 7.42 (m, 1 H), 7.32 - 7.25 (m, 5 H ), 7.18 (m, 1H), 3.90 (s, 3H);

MS (ESD) m/z 411 [M+1]". Vo

A Example 6-Fluoro-1-[3-(2-fluoropyridin-3-yl)phenyl]-1-pyridin-4-yl-1H-isoindol-3-amine in exchange

NH, \

Oo;

CSC

\ km = F No : using (2-fluoropyridin-3-yl)boronic acid and | -(3-bromopheny!)-6-fluoro-1-pyridin-4-yl-111- isoindol-3-amine 7 7.8) . (yield (AY) (ex. 'H NMR (CDCls) 5) 8.54 (m, 2 H), 8.18 (m, 1 H), 7.79 (m, 1 H), 7.50 (m, 1 H), 7.48 - 7.39 (m, 3 H), 7.32 (m, 1 H), 7.29 - 7.23 (m, 4 H), 7.18 (m, 1 H); MS (EST) m/z 399

M+1]".

AY Example > 0 1-(3-Bromophenyl)- 1-(4-methoxyphenyl)-1 H-isoindole-3-amine acetate

NH,

CL

N

’ 0 \ Ya ya Marah

3 [“Y), then prepare the compound mentioned in the title with a yield of L / as described in Scheme No. followed by dichloromethane in methanol Lye 8 purified by a chromatographic column using

JY aceticacid + 101 4 methanol : ethyl by column chromatography using H NMR (400 MHZ) 3 7.82 - 7.58 (m, 3 H), 7.58 - 7.49 (m, 1 H), 7.45 - 7.41 (m, 1 H). ), 7.36 - 7.24 (m, 3H), 7.19 - 7.12 (m, 2H), 6.96 - 6.86 (m, 2H), 3.73 (s, 3H), 1.91 (s, 3©

H); MS (ES) m/z 393, 395 [M+1]".

AA Example 1-(3",5-Dichlorobiphenyl-3-yl)-1-(4-methoxyphenyl)-1 H-isoindol-3-amine acetate

NH,

Cl\

So 0 \ beginning (NV ELE) (VA diagram) The compound mentioned in the title was prepared as described in Example 0 : from 5 (AY (Example 1-(3-bromopheny!)- 1-(4-methoxyphenyl)-1H-isoindole-3-amine acetate ./ 78 with a yield of (3,5-dichlorophenyl)boronic acid NAAAM ALA

- No H), 7.23 - 7.18 ) 2 H), 6.82 - 6.77 (m, 2 H), 3.69 (s, 3 H), 1.88 (s, 3

H); MS (ES) m/z 459, 461, 463 [M+1]". Vo diagram: Q MgBr 1 Is A NH,

SC — Maha R).

Br

Br > ng Scheme #5, N 0 o 0); Vo (scheme 1-(3-Bromophenyl)-1-cyclopropyl-1H-isoindol-3-amine acetate

NH, \ O WV, L Br molar in 18 mmol; N-[(3-bromophenyl)(2-cyanophenyl)methylene]-2-methylpropane-2-sulfinamide Ve at dry (Je01) tetrahydrofuran in (se g; 7.07 mV) ( ) «© No. h; then cooled to 7.6 sad C and stirred Fo The reaction was heated to argon in the room under an atmosphere of

- 18 - ethyl (ml) and extracted it twice using (©) methanol zero.m. The reaction was quenched with (saturated aqueous se and 0 chloride). The organic phases were collected; And wash it.. 6 and concentrate it. A solution of magnesium sulfate was given on a column chromatographic gradient and dried over

Y : h 0 molar methanol in 0.9 ammonia : dichloromethane dichloromethane in acetonitrile 7 Yo Mobile phase: Gemini C8 : preparative (HPLC column followed by © from (FV) g ( yield (0A) (0 ml/min) 1 mo; Flow: 100 water | ammonium acetate is the compound mentioned in the title. t, J = 7.78 Hz, 1 H), 1.89 ( 3 H), 1.86 - 1.81 (m, 1 H), 0.46 - 0.35 (m, 2 H), 0.21 - 0.13 (m, 1 H), -0.09 -0.02 (m, 1H); MS (ES) m/z 327, 329 [M+1]". Ye 11 Scheme 0 MgCl 1 N 7 1 ( J NH, vy - Ba oC 0 Br Scheme #5, N Pp

AS Example (Chart No. 1-(3-Bromophenyl)-1 -isopropyl-1H-isoindol-3-amine hydrochloride : 0 L Yo

- 118 -

NH, 02 Br slowly and drop by drop added V.01) isopropylmagnesium chloride filling Yor A milli-mol? Molar in tetrahydrofuran ) to : N-[(3-bromophenyl)(2-cyanophenyl)methylene]-2-methylpropane-2-sulfinamide (Chart © No. 1) (N g; Y.0V mmol) in dry tetrahydrofuran (10 (Je) at room temperature under an argon atmosphere. The reaction was heated to 70°C, stirred for ? hours, then cooled to 0°C. The reaction was quenched using (Ja©) slo and extracted twice using ethyl acetate, the organic phases were collected and washed with saturated Sle ammonium chloride The product was extracted five times using Y hydrochloric acid and once using 1 01 M hydrochloric acid. Water using sodium hydroxide and extracted twice using ethyl acetate The organic phase was concentrated Concentrated column chromatography using 70000-71 0 saturated with ammonia in chloroform and chloroform 7001-1 saturated with ammonia In chloroform any yield of the pure product Further purification was done by preparative HPLC using 0 — acetonitrile / 001 in ammonium acetate / water + molar followed by 0 1101.0 preparative (Column: (Gemini C8) using acetonitrile: water 7: 17 + 1 trifluoroacetic acid / . The remainder was divided between ethyl acetate and sodium bicarbonate. The organic phase (water) was washed; And dried over magnesium sulfate and concentrated. The remainder was dissolved in hydrochloric acid at 1 “Jw 07( mol diethyl ether); and stirred for 1 hour at YoYY degrees

- VY. — mg (7.7 yield (of the said compound in To) at ambient temperature and then concentrate it to give the title. 'H NMR (DMSO-de) 8.27 (d, J = 8.03 Hz, 1 H ), 7.92 (4 J = 7.78 Hz, 1 H), 7.84 - 7.76 (m.2 H), 7.70 (d, J = 8.03 Hz, 1 H), 7.64 (t, ] = 7.53 Hz, | H), 7.57 - 7.52 (m, 1 H), 9 (t.7=7.91 Hz, 1 H), 3.17 - 3.07 (m, 1 H), 0.88 (d, J = 7.03 Hz, 3 H), 0.51 (d, J = 6.78°

Hz, 3H); MS (ES) m/z 329, 331 [M+1]".

VV Scheme No. 0 Li 0 RA RH Solution Z — 4 RR) : 2) Hel

Br

Scheme #5, NQ

HQ VY (Chart No. 1-(3-Bromophenyl)-1-isopropyl-1H-isoindol-3-amine acetate

NH, > > © Br 1 molar at 1-7 edge ml 6 mm +. AA) isopropyllithium was added drop by drop to: B) pentane to fill

1711 - - N-[(3-bromophenyl)(2-cyanophenyl)methylene]-2-methylpropane-2-sulfinamide (Chart No. (N ( 7 g OVE mmol) in ( J ©) tetrahydrofuran at VA- , the temperature was allowed to increase to - YO C after 2 hours of stirring. The reaction was quenched with water (Je Y) and extracted with ethyl acetate. The organic phase (water) was washed and brine); Room temperature VA for 1 hour and then concentrated. The remainder was divided between dichloromethane and sodium aside bicarbonate The organic phase (ake solution) was washed and dried over magnesium sulfate to concentrate it. Purification by column chromatography Using stepwise eluting of ammonia: dichloromethane dichloromethane 0 #.?molar in 01:56 methanol and preparative HPLC gave 4 mg (yield 4.6 7) of the compound mentioned in the title. “HNMR (CDCl3) 67.97 ( d, 127.83 Hz, 1 H), 7.69 (t, J = 1.89 Hz, 1 H), 7.67 - 7.63 (m, 1H), 7.61 - 7.55 (m, 1 H), 7.55 - 7.45 (m, 2 H), 7.43 - 7.35 (m, 1 H), 7.22 (t, = 7.96 Hz, 1 H), 2.92 - 2.77 (m, 1 H), 2.11 (s, 3 H), 1.02 (d, J = 6.82 Hz, 3 H), 0.63 (d, J= 6.57 Hz, 3 H); MS (ES) m/z 329, 331 [M+1]". Yo +4 example: 1-(3-Bromophenyl)- 1-methyl-1H-isoindol-3-amine NH, Br .©

177 - - Added drop by drop: N-[(3-Bromophenyl)(2-cyanophenyl)methylene]-2-methylpropane-2-sulfinamide (scheme number M) (can) 7.27 mmol) in tetrahydrofuran dry (Je 01(refrigerated to — VA mm to For A cde 1.87) mmol methyl lithium; 016 mol in diethyl ether in tetrahydrofuran© dry (Je V+ ) at m m under an argon atmosphere. The reaction was stirred for 2 hours, then the temperature was allowed to increase to -75 C. The reaction was quenched with water () + (do) and extracted with ethyl acetate. The phases were collected organic matter; washed (brine; “ela” and dried over magnesium sulfate and concentrated. Chromatographic column using a stepwise solution of chloroform to anda chloroform: chloroform using ammonia zero: 0 001 gave the compound The medium, which was dissolved in methanol (0?mL) and hydrochloric acid (© 0M mL in diethyl ether) was added. The reaction mixture was stirred for YY h, and then concentrated. The remainder was divided between dichloromethane and sodium bicarbonate _ aqueous The organic phases were collected, washed (brine solution), dried over magnesium sulfate and concentrated. Column chromatography using a stepwise solution of dichloromethane to dichloromethane: ammonia 0 0 ¥ M in methanol 45 01 gave 14 g (yield 55 4) of the compound mentioned in the title. 'H NMR (DMSO-dg) ) 3 7.73 - 7.68 (m, 1 H), 7.59 - 7.52 (m, 3 H), 7.39 - 7.33 (m, 3 H), (t, J = 8.03 Hz, 1 H), 6.59 (brs, 2 H), 1.66 (s, 3 H); MS (ES) m/z 301, 303 (M+1 1". 7.24 either

- 177 - :51 Example 3'-(3-Amino-1-cyclopropyl-1 H-isoindol-1-yl)-5-methoxybiphenyl-2-carbonitrile acetate

NH, and CC' per Ii N (scheme no. VA). The compound mentioned in the title was prepared with yield 0 7 as described in example. Starting from (N p© 4- 0), Vo (Chart No. 1 -(3-bromophenyl)-1-cyclopropyl-1H-isoindol-3-amine acetate methoxy-2-(4, 4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)benzonitrile 'H NMR (DMSO-d) 7.89 - 7.84 (m, 2H), 7.75 - 7.68 (m, 1H), 7.68 - 7.63 (m, 1 H), 7.56 -7.51 (m, 1 H), 7.43 - 7.35 (m, 4 H), 7.12 (dd, J = 8.66, 2.64 Hz, 1 H), 7.06 (d, 1 < 2.51 Hz, 1 H), 3.89 (s, 3 H), 1.92 - 1.83 (m, 4 H), 0.49 - 0.38 (m, 2 H), 0.25 - 0.16 (m, 1 Ye

H), -0.04 - 0.03 (m, 1 H): MS (ES) m/z 380 [M+1]".: 97 Example: 1-Cyclopropyl-1-(3-pyrimidin-5-ylphenyl) -1H-isoindol-3-amine acetate

NHN

2 7 1] Tune R

- 1/6 - (Chart No. YA) The compound mentioned in the title was prepared with a yield of 85 7 as described in the example (Chart 1 -(3-bromophenyl)-1-cyclopropyl-1H-isoindol-3-amine 2661216 starting from ( 04 . pyrimidin-5-ylboronic acid No. 6 0 ) and ' H NMR (DMSO-d) 59.19 (s, 1 H), 9.10 (s, 2 H), 2 (t,J =176 Hz, LH), 7.77 (8, J = 8.03 Hz, 2 H), 7.64 (dd, J = 7.78, 1.25 Hz, 1 H), 7.60 - 7.55 (m, 1 H), 7.47-7.37 (m , 3 °

H), 2.05 - 1.94 (m, 1 H), 1.87 (s, 3 H), 0.52 - 0.41 (m, 2 H), 0.28 - 0.17 (m, 1 H), 0.04 - 0.05 (m, 1 H) ; MS (ES) m/z 327 [M+1]", :57 Example 3'-(3-Amino-1-methyl-1H-isoindol- 1-yl)-5-methoxybiphenyl-2-carbonitrile acetate

NH, and ll N \ (scheme number VA as described in Example 14a) The compound mentioned in the title was prepared with yield (8) (Example 1-(3-bromophenyl)-1-methyl -1H-isoindol-3-amine (NE 4-methoxy-2-(4,4,5,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)benzonitrile '" H NMR (DMSO) -dg) 8 7.86 (d, J = 8.78 Hz, 1 H), 7.77 - 7.71 (m, 2 H), 7.66 - 7.62 (m, 1

H), 7.54 - 7.50 (m, 1 H), 7.41 - 7.35 (m, 4 H), 7.12 (dd, J = 8.66, 2.64 Hz, 1 H), 7.06 (d, Vo

J=2.51 Hz, 1 H), 3.89 (5, 3 H), 1.89 (s, 3 H), 1.73 (5, 3 H); MS (ES) m/z 354 [M+1]".

_ \ VY m — (48 e.g. 1-(3',5-Dichlorobiphenyl-3-yl)-1-methyl- 1H-isoindol-3-amine hydrochloride

NH, Cl

CL

LL cl starting from NV E (Chart No. YA) The compound mentioned in the title was prepared as described for Example (YY (Example 30) (4.except mg 1-(3-bromophenyl)-1- methyl-1H-isoindol-3-amine © except that Lag (mmol) 1749 ana £V.£ (3,5-dichlorophenylboronic acid ml) and 1) dichloromethane were added by dissolving the product In hydrochloride the solution was stirred for an hour. (Molar diethyl ether) in 1 ml; 'H NMR (DMSO-de) & 8.23 (d, J =7.78 Hz, 1 H), 7.91 - 7.87 (m, 1 H), 7.84 - 7.74 (m, Ve 4H), 7.71 (d,] =7.78 Hz , 1 H), 7.67 - 7.62 (m, 2 H), 7.47 (, J=7.78 Hz, 1 H), 7.43 - 7.38 (m, 1 H), 2.06 (s, 3 H); /z 367, 369, 371 [M+] I. 190 Example 1-Methyl-1-(3-pyrimidin-5-ylphenyl)-1H-isoindol-3-amine acetate

NH, \_N

Ch

Oo

Yo

Ya¥Yy

- vi - (Chart No. VA) The compound mentioned in the title was prepared with a yield of 84 / as described in an example: starting from () 04 pyrimidin-S-ylboronic 5 (0 JU) 1-(3-bromophenyl)- 1-methyl-1H-isoindol-3-amine except that the product was purified by column chromatography using a stepwise solution of Leg acid by © : 40 M methanol in ¥.© ammonia : dichloromethane to © dichloromethane Preparative HPLC purification by 71.1 (DMSO-dg) 89.19 (s, 1 H), 9.11 (s, 2 H), 7.94 (t, J = 1 76 Hz, 1 H), 7.82 - 7.77 (m , 1 H), 7.70 (dd, J = 6.40, 0.88 Hz, 1 H), 7.65 - 7.61 (m, 1 H), 7.54 - 7.50 (m, 1 H), 747 -7.37 (m, 3 H), 1.90 (5, 3H), 1.80 (s, 3H); MS (ES) m/z 301 M+17".4 Ex 0 1-[3-(2-Fluoropyridin-3-yl)phenyl}-1 -methyl-1H-isoindol-3-amine acetate

N

NH, F—

Jr (scheme number VA as described in Example LVR) The compound mentioned in the title was prepared with yield: starting from (N AR and ) 00 (Example 1-(3-bromophenyl)-1 -methyl-1H-isoindol-3-amine 0.(2-fluoropyridine-3-yl)boronic acid

- except - 'H NMR (F01150-4) 5 8.27 - 8.20 (m, 1 H), 8.10 - 8.02 (m, 1 H), 7.80 - 7.73 (m, | H), = 771d, 1 1.25Hz, 1H), 7.66 - 7.61 (m, 1H), 7.59 - 7.53 (m, 1H), 7.50 - 7.35 (m, 5

H), 1.87 (s, 3H), 1.74 (s, 3H); MS (ES) m/z 318 [M+1]" av Example 1-Isopropyl-1-(3-pyrimidin-5-ylphenyl)-1 H-isoindol-3-amine acetate 5

N

NH, / L Br W at the beginning (N) (scheme No. P VA), then prepare the compound mentioned in the title as then described it in the example of Ad chart (Example 1 - (3-bromophenyl) -1-isopropyl-1H-isoindol-3-amine hydrochloride (mM); eon (8 mg; 1°) (PA No. 1.0) (Q «VV] (Chart No. 1-(3-bromophenyl)-1-isopropyl-1H-isoindol-3-amine acetate Ve mmol) +: YA mg; 0.4) pyrimidine-5-ylboronic acid mmol) and CoV MGI .7 AY mg (toll 18.7 µH NMR (DMSO-dg) 3 9.19 (d, J = 2.14 Hz, 1 H), 9.10 (d, J = 2.14 Hz, 2 H) ), 8.06 (d,

J=1.23 Hz, 1 H), 7.85 (d, 12 8.58 Hz, 1 H), 7.73 (1, ] = 9.19 Hz, 2 H), 7.62 (d, J = 7.66

Hz, 1 H), 7.48 - 7.31 (m, 3 H), 3.02 - 2.91 (m, 1 H), 1.89 (5, 3H), 0.86 (d, J = 6.74 Hz,3 1°

H), 0.43 (d, J = 6.43 Hz, 3H); MS (ES) m/z 329 [M+1]". 7e

1/8 - - Diagram No. YA F 8 NH, Or NH, N Oe. —— Br > Hexamethy!ditin - F 0Rom© R (AA Jl 1-[3-(5-Fluoropyridin-3-yl)phenyl]-1-methyl-1H-isoindol -3-amine acetate (Chart No. YA 5 0 : NH, > J dissolved Y+ 0) 3-Bromo-5-fluoropyridine mg 01117 mmol) 3 hexamethylditin YE). + mL; 010 mmol) 5 tetrakis(triphenylphosphine)palladium (zero) Tt) mg; 0.54 mmol) in dry tetrahydrofuran (?mL) and heated to 0 dC for 00 min in a microwave. Added: AY. 5( (A+ JL) 1-(3-Bromophenyl)-1-methyl-1H-isoindol-3-amine mg 1774 mmol) and tetrakis(triphenylphosphine)palladium (0) 0 1.1197 ae 00 mmol) and heat the deli mixture to 1730°C for 10 hours in a microwave. No product was found by LC-MS analysis. YA silver oxide was added. ((Az:0) mg $ for 0 Y mmol) 39

Ava - - tetrakis(triphenylphosphine)palladium (0) V/Y.0) mg; 10117 mmol) and heat the reaction mixture (Vr) m for SHEET ©196 m for 2 hours in a microwave. During cooling to ambient temperature, the mixture was filtered and purified by column chromatography using a stepwise solution of ammonia: dichloromethane dichloromethane 0.¥ M in methanol © 40: © and 1101.0 Preparation 7007 (Yield 70 7) of the compound mentioned in Title.'H NMR 0150-40 5 8.74 ben J = 1.76 Hz, 1 H), 8.57 (d, J = 2.76 Hz, 1 H), 8.07 - 7.99 (m, 1 H), 7.90 (t, J = 1.63 Hz, 1 H), 7.78 - 7.72 (m, 1 H), 7.69 (dd, J = 6.15, 1.88 Hz, 1

H), 7.62 - 7.55 (m, 1 H), 7.54 - 7.47 (m, 1 H), 7.43 - 7.34 (m, 3 H), 1.87 (5, 3 H), 1.76 (5, 3 H); MS (ES) m/z 318 [M+1]" 0 Experiments Compounds were tested in at least one of the following trials: Secretase B The enzyme used in the IGEN Cleavage-, Fluorescent-, TR- trial is described. FRET and Experiment 065 as follows: 5" soluble fraction of human secretase f460 (AA 1 - AA) was cloned into the mammalian expression vector 502-7010-1-1855-011-0601AD. The gene is in a Fo domain of 1:01 (affinity card) and stably transcribed into HEK-293 cells and purified 538015-56 is stored in Tris buffer at pH 9.7 and labeled Purity 40 Oh, oh, bitter

- 18.

IGEN fission experiment 1 enzyme was diluted at a ratio of 1:50 in 56 mM MES pH©. The raw base material was diluted at 11 µM in 56 mM MES at pH ©#. Solution 8 was added to the base material solution (1:001 dilution). Crude solutions of DMSO of compounds or 0 alone were diluted to the desired concentration in 460 mM MES at pH©. The compounds were diluted to the desired concentration in dimethylsulphoxide (the final concentration was dimethylsulphoxide in experiment © 7). The experiment was performed in a 37-sample PCR plate from (#650201) Greiner and the compound in DMSO (? µl) was added to the plate and then enzyme YY (µl) was added and incubation was performed 0 Pre-use of the compound for 10 minutes. After that, the reaction was started with the base material (0,00 μl). The final dilution of the enzyme was eT:1 and the final concentration of the raw material was 1 µL. and after 10 minutes of reaction at room temperature; The reaction was stopped by removing 0 µL of the reaction mixture and diluted at a YO:1 ratio in 0.70 M Trizma-HCI at A pH. Diluted and added to the plate by Biomek FX or by hand.

Biomek 2000 and then all remaining fluid circulation was performed on instrument 0 containing PBS and all antibodies and streptavidin-coated beads were diluted to: 1 μL of 50 and product was quantified by addition of Tween 207 + 20 M BSA and Yo dilution: 1 μL of © 0 ratio dilution of fresh adhesive antibody to 5 of M858 and 7 0.8 μL PBS (0.01) Then, Dynabeads M-IGEN 0.7 mL fone beads containing (Tween 20 of / 0 0 vary) was added.

-YAY-

(280 and dilution ratio) 3 90060 from a goat anti-rabbit antibody treated with ruthenyl(80-08). The final dilution ratio of the new epitope antibody was:1

0 and the final dilution of (Ru-Gar) was in the ratio of 00001:1 and the final concentration of the beads was

is 000 mg/mL. The mixture was read on the (BioVeris) IGEN instrument using an experimental software

Abbiochemical© and after a 2-hour incubation period with shaking at room temperature. Experience the shimmering brilliance

Enzyme 1:78 was diluted in 40 mM MES pH 0. The crude substrate (Dabeyl) was diluted to 01 μM in 46 mM MES pH 0. pH ©. The enzyme and crude solutions of the base material were kept on ice until lysed

0 Put it in the raw material dishes. The Biomek FX tool was used to perform all liquid trades. Enzyme (9 µL) was added to the plate and then 1 µL of compound was added

in dimethylsulphoxide to the plate and a pre-incubation was performed for 10 minutes. When performing a dose-response curve test for the compound; The dilution was carried out on 10*10M 01016101501 just. Base material (01 μL) was added and the reaction was continued in the dark for 1 min at

0 room temperature. The experiment was carried out in a Corning surface that has YAS eyes and has a “round layer” and a low volume; and non-adhesive.”) #3676 (Corning). The final dilution of the enzyme is 1:50; the final concentration of the substrate is 15 μM (Km of YO μM).

The fluorescence of the product was measured on a Victor 1 dish reader [1] with excitation to a wavelength of 30.

nanomolar and an emission wavelength of 485 nm using protocol digitized peptide

ve 5. The comparative sample of dimethylsulphoxide identifies activity level 70010 and it is determined that YoVYY

YAY - - activity zero #7 by excluding the enzyme (using £0 mM of MES at pH© from buffer solution instead). TR-FRET Experiment Dilute enzyme (photo cut off top) to 1 μg/mL (raw material VY mg/©mL) and substrate (Europium)CEVNLDAEFK(Qsy7) to 001n molar (0 μM raw material) in reaction buffer (NaAcetate, chaps, triton x-100, EDTA) pH 8.0) and Biomek FX was used for all liquid handling procedures and the enzyme and substance solutions were kept The bases were placed on ice until placed in Biomek FX and enzyme (9 μL) was added to the plate after which 1 μL of the compound in dimethylsulphoxide Ve was added to the plate and pre-incubation was performed for 10 minutes. Then the base material (01 μL) was added, mixed, and the reaction was continued in the dark for 0 min at room temperature, and the reaction was stopped using the addition of a stop solution (1 μL NaAcetate pH pH 3) The fluorescence of the product was measured on a Victor If plate reader with an excitation wavelength of aly 7460 nm and an emission wavelength of 119 nm. The experiment was performed in a Coming Surface with Lie YAS layer round»; at a reduced volume; non-adhesive; .)#3676 (Corning) The final concentration of the enzyme is 17 nm; the final concentration of the base substance is 100 nm (168 nm of YO). The comparator sample from 010607150101010 identifies the activity level. 70010 is determined to have zero activity #7 only by the addition of a baseline peptide.The comparator inhibitor is also used in 0 dose-response experiments and has a 1650 nanomolar OVO value.

VAY - - Beta-Secretase Whole Cell Experiment Composition:HEK293-APP695 A peDNA plasmid with human full-length cDNA ex 5 was stably transfected into HEK- cells. 293 using Jail infection reagent Lai, Lipofectamine © to manufacturer's protocol (Invitrogen) and clones were selected using =o)0.9 mg/mL of clones by expression levels of APP and 0M secreted into the media. conditioned using an ELISA experiment prepared in a greenhouse. [LMA]:Vs culture and HEK293 cells expressing wild-type human APP (HEK293-APP69S) at YY m were stably cultured in DMEM containing +£04 g/ L GlutaMAX” GlutaMAX supplemented with FBS 701, 1 72 Non-Essential Amino Acids and 000 mg/mL of a thermogenic inhibitor; and 500 mg/mL of the antibiotic Zeocin for selection. Vo 040 release experiment: Cells were collected when the flow ratio was between 880 to 90 7 and nucleated at XY concentration 001 sede [LBA 1 0 mL of cell suspension/eye] on a black +9 clear plate. the mom"

186 - - an eye covered with poly-D case material. and after incubation of the dish at TV C overnight; The cell medium was replaced with 01 cell culture medium (penicillin and streptomycin μ/mL; 001 μm faba mL; respectively) containing the test compounds at a final dimethylsulphoxide concentration of .71 and the cells were exposed to the test compounds for 74 hours at 9pm » © 7 002. To determine © the amount of SHAR fired; 100 μl of cell medium was transferred to a round plate with 1 well of polypropylene (experimental dish). Cell culture dishes for the ATP experiment were preserved as described for the ATP experiment below. to match the experience; 50 µL of detection primary solution containing +10 µg/mL of rabbit anti-ABAD antibody and 020 µg/mL of biotinylated 6810 antibody (prepared 0 in 1) was added. DPBS with 0.9 7 858 and 0.8 7 7280-20 per eye and incubated overnight at 4' C. Thereafter; μl Or secondary detection solution containing 20+ μg/mL of ruthenylated goat anti-rabbit antibody and 1.7 mg/mL streptavidin-coated Dyn beads per eye.The plate was shaken vigorously at room temperature for 1-?h.Then the measurements were plate to perform chemiluminescence electroluminescence counting in IGEN M8 Analyzer Yo and standard curves of AB were obtained using standards at concentrations of Sete 0 and AB pba sili LY 1/ml in cell culture medium using penicillin and 001 (streptomycin 0 μg/L streptomycin 0 μg/eda, respectively). Cells to detect <AB40 0 The plate was used for cytotoxicity analysis using the experimental kit (ViaLight™ Plus) for the reproduction of Leah Lalla Maraba

YAo - - cytotoxicity/cytotoxicity of Cambrex 8105016066 which measures total cellular ATP. The experiment was performed according to the manufacturer's protocol. In short; to each eye of the dishes; 500 µL of reagent was added for cell analysis. The plates were incubated at room temperature for 10 minutes. Two minutes after the addition of 100 µL of reconstituted ViaLight™ Plus© reagent for ATP measurement, the scintillation fluorescence was measured for each eye in a Wallac Victor® 1420 multi-label plate reader. BIAcore BACE protocol Sensor chip preparation: BACE was experimented on a 3 200-performance scale by immobilizing either a stereoisomer transition state “peptide” (TSI) or a scrambled copy of a TSI peptide to the surface of a Biacore sensor chip 5. The surface of the CMS sensor chip contained four distinct ls that could be used to conjugate peptides KFES-statine-ETIAEVENV conjugated the scraped peptide in channel 1 and KTEBISEVN- conjugated statine-VAEF of TSI inhibitor in channel No. 1 of the same slide.The peptides were dissolved at 17 mg/mL in mM Yo of Na acetate with a pH of 0.£ ( VO ) and the The solutions were then centrifuged at VE at krpm to remove any particulate matter.The carboxyl groups were activated on the dextran layer by injection of a one-to-one mixture of: N-ethyl-N' (3-dimethylaminopropyl )-carbodiimide (EDC) and .+2 M of hydroxy =N succinamide (NHS) at a concentration of µl/min for “min. Then, the crude solution of the control sample peptide was injected into channel no. 1 for 1 minutes at a concentration of © µl/min; And it was after, oh, oh, oh, oh, father

-VAY-

This is to block the remaining activated carboxyl groups by injecting 1 M of ethanolamine for a period of V.

Gl at a concentration of μl/min.

Experiment protocol:

The BACE Biacore experiment was performed by diluting BACE to 0.0 μM in solution

© buffer Na acetate at pH 4.5 (running buffer solution minus DMSO)

Mixing diluted BACE with dimethylsulphoxide or compound diluted in dimethylsulphoxide

With a final concentration of 75 dimethylsulphoxide. The BACE/cleat mixture was incubated for 1 hour at

8 m and then injected over channels 1 and 7 of the CMS Biacore chip at a rate of 01 μl/l

a minute. While BACE was bound in the chip, the signal was measured in response units (RU) 0. The binding of BACE in the TSI inhibitor on channel number ? a specific signal. It reduced the presence of a BACE inhibitor

of signaling by binding to BACE and inhibiting interaction with peptidic TST on the slide. No link was

In channel No. 1, it was unspecified and then extrapolated from the responses of channel No. B, and the comparison sample was determined from

dimethylsulphoxide as 0 # and the effect of the compound was reported as a percentage inhibition

From the comparison sample of dimethylsulphoxide.

1 hERG cell culture experiment

YAY - - Chinese hamster ovary (CHO) KI-expressing 101580 cells described by (Persson, Carlsson, Duker, & Jacobson, 2005) were cultured to semi-flush at TV m in medium ( CO2 7©) Lee in porcine medium 1-12 containing 0 Loglutamine, 7 01 fetal calf serum (FCS) and do [ae 01 hygromycin] (all from Sigma). -Aldrich prior to 0 | to use; the monolayer was washed with ?mL of equal parts pre-warmed Versene (Invitrogen) 938 1 After aspiration of this solution the YY sie flask was incubated in an incubator with ¥ additional mL of Versene at a ratio of 1:000 for a period of 1 min.Then the cells were separated from the bottom of the flask by tapping and 01 mL of EVERY Molar calcium containing Dulbecco's Buffered Saline and Magnesium Phosphate (1.9 0 mM) (PBS; Invitrogen) was added to the flask and aspirated into a 10 mL centrifuge tube prior to centrifugation (0 g for 1 lb min). The resulting supernatant was discarded, the pellets were resuspended delicately in ¥ mL of PBS, 0.8 mL of equal parts of the cell suspension was removed, and the number of live cells was determined (based on trypan blue exclusion) on an auto-reader. (Cedex; Innovatis) so that the volume of resuspending cells can be adjusted using PBS to give us the final Vo required for the cells. The concentration of cells at this point in the experiment was used when referring to this variable. 0110-6:1.5 cells were maintained; which was used to adjust the displacement of the floats on HT Tia and 1 ; It is prepared for use in the same way. Electrophysiology The basics and operation of this device are described by Schroeder, Neagle, Trezise, & Worley, 2003. In short, this is an AE based on a 384-layout (PatchPlate™) lie that has been There is an attempt by Arab

M1 - recording in each eye using sucking to the designated position and fixing the cell in a small hole separating the two isolated fluid chambers. Once segregation occurs; The solution on the underside of the PatchPlate™ was changed to a plate containing amphotericin B. This makes the patch membrane permeable and coats the vacuoles in each eye; In terms of reality; Allows full-cell perforated clip-on patch recording to be made. A P-test TonWorks™ HT from Instrument 2596©0 was used. There were no 3538 to warm the solutions in this medium and therefore it was run at room temperature (~71 °C); As follows. The tank was loaded in the “buffer solution” mode using; ml and that in Cells mode using LDA annotation 0110-8586 described above. A plate of 96 (V-bottom, Greiner Bio-one) Lue containing the compounds to be tested (at a concentration ? times greater than the final test concentration) was placed in “Dish 1” mode and the PatchPlate™ was connected to a station. PatchPlate™. Each composite plate is laid out in 11 columns to enable focus effect curves to be created from A points; The remaining two columns were adsorbed onto the plate with salatransferase (final concentration) (DMSO Lexy) to determine the initial value of the experiment; 0 was inhibited with an ultra-maximum concentration of cisapride (final concentration 100 µM) to determine 1001 inhibition level. A 5 μL Y.0 TonWorks™ HT fluid head (F-head) is then added to each well of the PatchPlate™ and percolated bottom side with an “inside” solution of the following composition (in mM): 3.2, 261483 K-Gluconate 100, KCI 40, MgCl, and HEPES 5) all from Sigma-Aldrich; pH VY - 1.70 pH using 01 molar YT of 16011). After initial bubble arousal and Lei reinstatement the electronic head (E-) was moved around the PatchPlate™ to perform the sf test. Apply a voltage pulse to determine if the YoVYY

- Qom -

The slit in each eye is open. 3.5 µL of tip© from the cell suspension described above was then pipetted into each well of the PatchPlate™ and 001 WAN xis sec was made to reach and isolate the hole in each well. After this procedure; The head of BE was rotated around p to determine the insulation resistance obtained in each eye. and then; Changes done

© The solution on the underside of the PatchPlate™ into a “Wool” solution that had the following composition (in mM): 20 KCI 140, EGTA I, MgCl 1 and HEPES (pH 7.75 2.70 using 01 molar of KOH plus 100 μg/

ml of 8 (Sigma-Aldrich) amphotericin and after allowing 9 minutes for patch perforation to occur; And it was moved

E tip around 48 PatchPlate™ eyes at a given time to get current 0280 measurements before

0 compound. Then the head of F added 3.8 µl of solution from each well of the compound dish to ; Eyes on (Sled DMSO concentration was 7 077 in each eye). This was achieved by moving from the eye containing the most diluted substance to the most concentrated substance of the compound dish to minimize the effect of accumulation of any compound. After approximately TO minutes of incubation; E's head then moved around all 48 eyes; from the PatchPlate™ to obtain measurements

0 0586 the current post-boat. In this way; It was possible to produce non-cumulative concentration-effect curves where; Adequate percentage of eyes were met to meet acceptance criteria. (see below); OSs

The effect of each concentration of the test compound is based on a score between 1 and ; eyes.

The current 18586 is excited before and after the compound by a single voltage pulse containing 01

sec fixation period at Lage Vem volts; and a step of 061 msec to -60 m aly (

0 to obtain an estimate of leakage)”; a step of 100 milliseconds back to -V megavolts; f 1 second step to +£0 MV; and step? seconds to -Yo megavolts and eventually a step of 500

No, no, no

- 1 and.

Milliseconds to Vie megavolts. Between the pre- and post-compound voltage pulses, there was no membrane force clamping. The currents extrapolated from the leakage were based on an estimate of the current evoked during the +01 mV step at the onset of the voltage pulse protocol. Any voltage offsets in the TonWorks™ HT are adjusted in one of two ways. when determining the strength of the compound; The dls© depolarization curve was applied to CHO-KVLS cells and the voltages at which aie was the bending point in the current trace (ie the point at which channel activation was seen using the curve protocol) were observed. The voltage at which it occurred was previously determined using the same electrophysiology voltage command and was found to be - VO mV (data not shown); In this way the possible displacement can be entered into the TonWorks™ HT software - using this value as a reference point. When characterizing 0 basic electrophysiology of the ERG any offset was modified by quantifying the back current from the hERG in the TonWorks™ HT; and compare it to the value found in conventional electrophysiology (AY -) mV; See Figure 1c) After that, the necessary offset adjustment was done in a program

JonWorks™ HT and then set the sample current at 7.0 kHz. The current intensity for 115180 pre- and post-scanning was measured automatically from the leakage traces extracted by TonWorks™ HT Ye software by taking an average of 50 µm of the current during the initial retention period at -V mV (initial value current) and extracting these from The peak of the last current response. The acceptance criteria for evoked currents in each eye were as follows: pre-scanning insulation resistance > 160 MO, 6's final current capacitance before scanning > ¢pA VO, and post-scanning insulation resistance > 01 MQ. The degree of 0 current inhibition was evaluated by dividing the current hERG post-scan by pre-scanning hERG stream for each

Te eye.

Na not m father

- 191 -

Results

Typical values for the compounds of the present invention are in the range from about 1 to about 000001 nanomolar. Biological data on examples are presented in the following table.

Table 0 in the TR-FRET experiment in 0 nano mola no Ji example no. ov

Claims (1)

= yay - protective_element J Compound of formula - 1 1 (R3)m A = =N R2 HN Cas HRD ¢ Picked from: hydrogen, nitro, cyano, -Q-C alkyl, -Q-Cs. salkenyl, -Q-Cy alkynyl, -Q-Cs. o cycloalkyl, -Q-Cs.,cycloalkenyl, -Q-C.salkylCs cycloalkyl, -Q-aryl, -Q-heteroaryl, 1 - 0-0 b. . For salkylheterocyclyl, A 4 where there is an optional substitution in: -Q-Cy.¢alkyl, RANLPSOLADER 0-0- EGGCL-9-0-, -Q-Cs.ecycloalkyl, -Q-Cs. 01 cycloalkenyl, -Q-Cy.alkylCs.¢cycloalkyl, -Q-aryl, -Q-heteroaryl, -Q-C;salkylaryl, - 11 Q-C, salkylheteroaryl, -Q-heterocyclyl, or -Q-Cy.salkylheterocyclyl VY R7 mentioned with one, two or three yy : these are SRY 4 (CRHR)R®, C,.alkenylR®, Cs. salkynylR®, Cs.;cycloalkenylR®, nitro or cyano 1° are independent of the other groups; CRHORY) then all 1 > « and if yy : independently of RP _17 is selected Ba Amrab - Vay - hydrogen, halogen, Ci.alkyl, Cs.salkenyl, Cs.salkynyl, Cs.cycloalkyl, Cs. YA cycloalkenyl, aryl, heteroaryl, heterocyclyl, Ci.salkylCs.scycloalkyl, C salkylaryl, 1 C-alkylheteroaryl and C; salkylheterocyclyl, Ye : where there is an optional substitution in 1 Banole. , C,. ¢alkylheteroaryl or C. YY salkylheterocyclyl ve (A mentioned by one, two, or three Yo groups: be direct bonding; or -©- 1 -CONH-, -CO-, -CON(C; salkyl)-, -CON(Cs) .¢cycloalkyl)-, -50- -S0;-, -SO;NH-, - vy SO,N(C;salkyl)-, -SO,N(Cs.cycloalkyl)-, -NHSO,-, -N (C1.6alkyl)SO,-, -NHCO-, - YA N(C,6alkyl)CO-, -N(Cs.cycloalky)CO- or -N(Cs.geycloalkyl)SOz-; v4 are selected as Independent of: 87 GRY 0 0x0, Ci. or that together form ¢ hydrogen, Ci.alkyl, cyano, halo or nitro; From R ® select a non-methyl, Cs.¢cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted for Ye; whereby any of the said RT congeners may be combined with between one and four of the groups © or ©; or 6 or 7 ef atoms of the OH or 1 optionally heterocyclic groups of 7 _ to form a heterocyclyl dicyclic ring system or a cycloalkenyl group or ¢ cycloalkyl ~~ YV and where there is Optional replacement in two-loop loop system Optional YA (A) One to four groups 4 ¥ per lamp - Vat - 6 RT is independently selected from : halogen, nitro, CHO, Co.calkylCN, null: 00 10, CocalkylOR?, OC, 6alkylOR®, 3 hydroxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, For difluoromethoxy, trifluoromethoxy, Co.calkyINR*R', 0C,.alkyINR'R', Ev 0C,.salkylOCy.alkyINR*R’, NR*OR’, Co.calkylCO,R?, OC 6alkylCO,R®, td Co.salkyINR®R', OC, alkyl CONR'R', 0C,.¢alkyINR{CO)R', Co.calkyINR® to (CO)R', O(CONR'R', NR}(CO)OR ', NR*(CO)NR'R', O(CO)OR?, O(CO)R®, 3 Co.calkylCOR®, 06 NTM Bulav 118(60()60) NR}CO)CO)NR®R', tv CosalkylSR?, Co.salkyl(SO2)NR'R', OC 1salkyINR¥(SO2) R', eA OCoalkyl(SO)NR'R', Cosalkyl(SONR®R', OC; ¢alkyl(SONRR?, 050:5 £4 SO:R?, CosalkyINR}(SO)NRR', Co.calkyINR¥ (SO)R', OC,.salkyINR*(SO)R', or OC ,.salkylSO;R®, C;.6alkylSO:R', Co.calkylSOR®, Cy salkyl, Ca.calkenyl, 2 Ca.ealkynyl, Co.alkylCs.cycloalkyl, Co-alkylaryl, Co.salkylheteroaryl, ov Co.salkylheterocyclyl, and 0OC,.¢alkylheterocyclyl, ov : where is an optional substitution in of © , ov. Casalkenyl, Cy.galkynyl, Co.salkylCs.scycloalkyl, Co-galkylaryl, 00 Cosalkylheteroaryl, Co.salkylheterocyclyl or 0C, .¢alkylheterocyclyl 2 or aryl and where any of the said RY groups may be combined with one or more OV group or cycloalkyl atoms optionally odd 0 heterocycles with 4 or *; or 1 or aryl © A _ to form a bicyclic ring system in which there is a heterocyclyl or a cycloalkenyl group 4 A optional substitution in the bicyclic ring system by between one and four of the 0 groups: provided that the bicyclic ring system 61 eride indane, benzo[1,3]dioxole or 2,3-dihydrobenzo[1,4]-dioxine ring system 21 halogen, nitro, CHO, Co.calkylCN, 06 is not available independently from ,1071 And the reciter RM Selection ay YF Co.alkylOR?, OC;.salkylOR?, fluoromethyl, difluoromethyl, trifluoromethyl, 1 fluoromethoxy, difluoromethoxy, trifluoromethoxy, Co.calkyINR*R’, 12 0C,.calkyINR*R?, OCp.5alkylOC; salkyINR*R®, NR*OR’, Co salkylCO:R’, 1 OC, alkylCO:R?, Co.calkyl CONR’R®, OC,.calkylCONR’R’, wv 0C,.salkyINR¥(CO)R®, Co.calkyINR® (CO)R', O(COINR'R', NR*(CO)OR', A NR} (CO)NR®R', O(CO) )OR®, O(CO)R®, Co.salkylCOR®, OC 1salkylCOR®, 14 NR}(CO)(CO)R?, NR¥(CO)(CO)NR'R', Co.calkylISR®, Co. calkyl(SO)NR'R', Ve 0C,.6alkyINR}(SO,)R', OCy.salkyl(SO)NR'R', Co.calkyl(SO)NR*R', O.C., Olmy 60715 OSOR®, Ramamoh Co.salkyINR (50)15 67 LBP Co. alkyINRASO)R®, OC. calkyINR*(SO)R®, 00: for PCO-WAD 150 machines Co.calkylSOR®, Cs.salkenyl bitumen, Cy.¢alkynyl, Co.salkylCs.cycloalkyl, vi Co.calkylaryl, Co.salkylheteroaryl, Coalkylheterocyclyl and 0OC,.salkylheteroaryl ve: where an optional substitution in VA, aniolysine 0, an alkyl anhydride, anoleer is CosalkylCs.qcycloalkyl, Cosalkylaryl, vy Cocalkylheteroaryl, Co.salkylheterocyclyl or OCy elalkylheterocyclyl VA tA listed with between one and four va hydrogen, C-salkyl, Ca-salkenyl, Ca-salkynyl groups, independently selecting 1 and 13 of oy 0 fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, AY trifluoromethoxy, Co -salkylCs-cycloalkyl, Co-salkylaryl, Co-salkylheteroaryl, AY Co-salkylheterocyclyl and C; -salkyINR''R!, AY 19716 - - Ad where there is an optional substitution in: C-salkyl, Ca-salkenyl, Co-salkynyl, Co-salkylCs-¢cycloalkyl, Co-galkylaryl, Co- Ao alkylheteroaryl or Co.salkylheteroaryl AT AV of group tA 8 and can form and put together a heterocyclic system having a number of © to 6 AS atoms containing one or more heteroatoms picked from 87 or 0; or 5 0 _which is optionally substituted for group 8; And when two *8 groups occur in the 1 structural formula then they together optionally form a heterocyclic system having a number of © or 1 AY atoms containing one or more unexamined atoms that are picked from JON AT © or 8; which has an optional substitution of group (A yy 4 pick 8 "and independently of : hydrogen, Ci-salkyl, Cs-alkenyl, Cs-salkynyl, Co-galkylCs-ecycloalkyl, Co- ie salkylaryl , Cosalkylheterocyclyl and Cg-salkylheteroaryl, wherein said Ci-salkyl, Cs- 1 alkenyl, Cs-galkynyl, Co-salkylCs-scycloalkyl, Co-galkylaryl, Co-salkylheteroaryl or av Co.salkylheterocyclyl A 4 with group JA 0 and together the “!C RY” can form together a heterocyclic system with 4 to 6 011 atoms _ containing one or more heteroatoms being Picked from 8 or ©0; or S 01" _which optionally substituted for the group (A 0" " be null or 1 or 7 or ?; 04 " be row or 1 or of JY 0 and m is selected from: YAYY - 1O-oxo, halogen, nitro, CN, OR", C,.salkyl, Ca.alkenyl, Coealkynyl, Co.salkylaryl, Co. 01 salkylheteroaryl, CoalkylCs.cicycloalkyl, Cosalkylheterocyclyl, fluoromethyl, Voy diflucromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, 01 rifluoromethoxy, OC.calkyINR?R'%, obituary of CONRR", NR'%CO)RY, 01 6012, 0.23 Olafi 60(06) Balulaki ©(0)00 NSO,R%, SOR, SOR, 00 (CO)CrealkyNRR™, (SO;)C.calkylNR''R'>, OSO,R and 1 50:85 : where there is an optional substitution in 1 Cealkyl, anon lark Ca .salkynyl, Co.calkylaryl, Co-salkylheteroaryl, Co. Ny salkylheterocyclyl or Co.¢alkylCs.cycloalkyl 18 : 0 halo, 0SO,R'2, SO3R'?, nitro, cyano, OR", C,.¢alkyl, fluoromethyl, difluoromethyl, 11 trifluoromethyl, fluoromethoxy, difluoromethoxy or trifluoromethoxy; or three (opal with one or Cpgalkyl, Csecycloalkyl, aryl, heteroaryl or heterocyclyl 071; or alkyloxy or m “halo” or “cyano” or “hydroxy” of groups 7 together a cyclic system heterocyclic having from − to 6 RY atoms and can form YY, ©0, or N _containing one or more heteroatoms picked from 4 « cyano si 1 alkyloxy ; or of hydroxy in which the groups of Ss Ye ¢ halo or 7 are optionally substituted, provided that the following compounds are excluded: 111 - 118 pounds 3-amino-1- cyano-N-phenyl-1H-isoindole-1- carboxamide, YYA 3-amino-1-(1H-benzimidazol-2-yl)- 1H-isoindole-1-carbonitrile; 1 4,4'-(3-amino-1H-isoindole-1,1 -diyl)diphenol; 00 1-phenyl-1H-isoindol-3-amine; 11 1-methyl-1H-isoindol-3-amine; WY 1,1-dimethyl-1H-isoindol-3-amine; yy 2-[3-amino-1-(4-hydroxyphenyl)-1 H-isoindol-1-yl]phenol; WW 4-[3-amino-1-(4-hydroxyphenyl)-isoindol-1-yl]phenol; 1 2-[3-amino-1-(4-hydroxypheny!) -isoindol-1-yl]phenol; vl 4-[3-amino-1-(4-hydroxy — 3,5- dimethyl-phenyl) - isoindol-1-y1]-2,6- dimethyl - WY phenol;y in the form of a free base, its salt, or a pharmaceutically acceptable soluble or soluble of its salt. 4 :; where 1 is a compound according to the claim - “1 18 and 87 are selected independently from: hydrogen, ,,,O-t© Co-salkenyl, C,-alkynyl, fluoromethyl, difluoromethyl, ¥ trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, Co-salkylCs- ¢ cycloalkyl, Co-salkylaryl, Co-salkylheteroaryl, Cosalkylheteroyl and C- © salkyINR'R", 1 : where there is an optional substitution in 11 4 Batulki C,-salkenyl, Bangtolq- Co-salkylCs-¢cycloalkyl, Co-salkylaryl, Co-salkylheteroaryl 1 or Cg.salkylheterocyclyl 01 YAYY - 11989 - '(A) in group 11 together a heterocyclic system having from ; to 6 ROS RY atoms and can form NY S or ©0; or ON containing one or more atoms The heterocyclic ones that are picked from 1" and when there are two groups of 8 in tA optionally replaced by the group Les of which 04 is the structural formula then together they optionally form a heterocyclic ring system with a number ranging from * or 0 SON Atoms containing one or more unpaired atoms that are picked from 1 7 . or 5; and for which an optional substitution of the group m©1" 1*-compound of claim no. 0; where RY Y is picked from a -0-aryl; or a -9-aryl heterocyclic; and where Optionally substitute YF in the -0- entropy; or aryl -Q- heterologous mentioned by one, two, or three R?; © 880 is a CRORMDR® or if “ > 1 So all 6089087 are derived from the other groups; , aryl, heteroaryl, heterocyclyl, Ci.salkylCs.cycloalkyl, C 1.salkylaryl, 1 C1.salkylheteroaryl or Cj.salkylheteroaryl, 01 : where there is an optional substitution in 11 C1.salkyl, Cssalkenyl, Cs.salkynyl, Cs cycloalkyl, Cs..cycloalkenyl, aryl, heteroaryl, VY heterocyclyl, C.salkylCs.scycloalkyl, C.calkylaryl, Cy.salkylheteroaryl or Ci. 0 salkylheterocyclyl Vi (A) listed with one, two, or three groups VO 7e .a -0- is Al) direct; GRY VY 8 is selected independently from: cyano, halo or nitro YA, anoleqir 0 hydrogen, or ROG RY together form: oxo, Csecycloalkyl or heterocyclyl 4 RE is selected from aryl or aryl heterocyclic; 0 where there is an optional substitution of aryl ; or heterozygous aryl mentioned between 71 and one in four of the 87 groups; Whereas any of the aryl aryl groups other than the YY odd homodimers may optionally combine with a number of ef, ©, 1, or V atoms of cycloalkenyl 4 « cycloalkyl YY or a heterocyclyl group _ to form a dicyclic ring system; Yi R7 is independently selected from ¢ halogen 02 Th 1 hydroxy sf alkyl » or sf < OSO,R® 0 ben alkyl » R alkyl aryl Cog and alkyl aryl Cos is inhomogeneous; where 7 . There is an optional substitution in the alkyl Cis or the alkenyl min ; or alkyl aryl Cos and YV mm6 alkyl mentioned with one or more of the group (R' YA R™ is selected independently from the halogen « 5 050:1 r mm » alkyl OR® YA R® is selected independently from hydrogen m alkyl and 0 trifluoromethyl 1 > -compound according to claim (in) X to be a -9- aryl; where -9- aryl optional has the ¥ substituted by one; or two; or three of R7 4 82 be (CRHRPR® © - © - be direct link; 1 85 be that where said aryl has an optional substitution between one and 1" four of RT and where a single aryl group can be optionally fused to a heterocyclyl A group having 4, ©, OR, or 1 atoms to form a dicyclic ring system; YAYY Cv 9 187 are independently selected from hydroxy sl “alkyl OR®OCo.s sl “halogen” or sl < OSOR® 0 from alkyl ¢ or alkyl aryl Co and alkyl aryl Cos heterocyclic ; where 11 there is an optional substitution in said alkyl aryl Cos sl « alkenyl Cos sf ¢ alkyl Cris and alkyl Cos VY with one or more of the group (R' VY RM is selected independently of halogen ¢ 5 050:8 t calkyl OR® Cos Independent selection of 8 hydrogen and trifluoromethyl s alkyl 0 « be a row; Ja be « 7 1 © - Compound according to Claim No. 0 where -0- and aryl -0- are heterogeneous; and where aryl -0- and aryl -0- are from Rell the said heterogeneous Y RT is optional substituted by one; or two; or three of ¥ 4 182 is {CRHRNR® © can be a halogen ; 1 - 0 - be direct link; 1 RS is selected from heterocyclic aryls aryl wherein the aryl A said heteroaryl A has an optional substitution of between one and four RTs 4 17 are independently selected from i ¢ halogen 9 e calkyl CN R 020 “alkyl OR® 01 or trifluoromethyl” or 011111010161077 or non-alkyl aryl and non-alkyl aryl Cog 11 homogeneous; where there is an optional substitution in said alkyl aryl Cos and non-VY alkyl aryl Cog congeners with one or more of group R' OCo. or calkyl CN 00 sl “CHO” or “halogen” independently from RM VY ¢ alkyl rmn (CO)R® or calkyl 00118387 Cog sf 083 04 is first selected — 7.7 - Ye 1 and 87 are independently selected from hydrogen and 0 alkyl bitter; I « is Jia or 1; and VY « is an row. 1 1 - The compound according to claim No. 1 or Cun oY Y for a part is Z,90-0- alkyl ; "tees is (CRORNDR ; -0 - is a direct link; ©" c is an aryl where said aryl has an optional substitution between one or -two of 17; 01 is Selection of R independently from alkyl OR® 00 calkyl CN OC sf “ halogen A or heterocyclic alkyl aryl Cogs alkyl aryl Cog; and where there is an optional substitution 4 in alkyl aryl Cogs alkyl aryl Cos heterogeneous mentioned with one or more of the R™ 00 RM is independently selected from the halogen « 5 mm06 talkkyl OR® 06 sf alkyl CN 11 to be a f-© alkyl NY “is a zero, and OY” is a Ble about a zero. -isoindol-1-ylamine; Y 3-(3'-Methoxy-biphenyl-3-yl)-3-(4-methoxy-phenyl)-3H-isoindol- 1 -ylamine ¥ trifluoroacetate; ¢ Trifluoro-methanesulfonic acid 5-[3-amino-1 -(4-methoxy-phenyl)-1H-isoindol-1- ° ?l]-3'-methoxy-biphenyl-2-yl ester trifluoroacetate; 1 5-[3-Amino-1-(4-methoxy-phenyl)-1H-isoindol-1-yl]-3'-methoxy-biphenyl-2-ol v trifluoroacetate; A 4,4'-(3-amino-isoindole-1, I -diyl)-bis-phenol; 1 4-[3-Amino-1-(4-methoxy-phenyl)-1H-isoindol-1-yl]-2-pyridin-3-yl-phenol 01 trifluoroacetate; 1 4-[3-Amino-1-(4-methoxy-phenyl)-1H-isoindol-1-yl}-2-pyrimidin-5-yl-phenol "° trifluoroacetate; L-3-(4-Methoxy -phenyl)-3-(3-pyridin-3-yl-phenyl)-3H-isoindol-1-ylamine Ve trifluoroacetate; Yo 3-[3-(2-Fluoro-pyridin-3-yl)-phenyl]-3 -(4-methoxy-phenyl)-3H-isoindol-1-ylamine 1 trifluoroacetate;Vv 3-(3-Bromo-phenyl)-3-(4-methoxy-phenyl)-3H-isoindol-1-ylamine;YA 3 -(4-Methoxy-phenyl)-3-[3-(5-methoxy-pyridin-3-yl)-phenyl]-3H-isoindol-1- 1 ylamine trifluoroacetate;ve 3-(4-Methoxy-phenyl)- 3-(3-pyrimidin-5-yl-phenyl)-3H-isoindol-1-ylamine 7 trifluoroacetate;by Methanesulfonic acid 3'-[3-amino-1-(4-methoxy-phenyl)-1H-isoindol-1 -yl]-5- vy methoxy-biphenyl-3-yl ester trifluoroacetate; vi 3-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-3-(3-(2-fluoropyridin) -3-yl)phenyl)-3H- Yo isoindol-1-amine trifluoroacetate;vi 3-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-3-(3-(5- methoxypyridin-3-yl)phenyl)-3H-vv isoindol-1-amine trifluoroacetate; YA Yovy 07.60 3+(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-3-(3-(pyridin-3-yl)phenyl)-3H-isoindol-1- v4 amine trifluoroacetate ; ve 3-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-3-(3-(pyrimidin-5-yl)phenyl)-3H-isoindol- 9 1-amine trifluoroacetate; vy 3-(3-Bromo-phenyl)-3-(4-methoxy-3-methyl-phenyl)-3H-isoindol-1-ylamine 7" trifluoroacetate; ve 3-(3'-Methoxy-biphenyl-3-yl) )-3-(4-methoxy-3-methyl-phenyl)-3H-isoindol-1- vo ylamine trifluoroacetate;71 3-(4-Methoxy-3-methyl-phenyl)-3-[3-(5-methoxy) -pyridin-3-yl)-phenyl]-3H- vy isoindol-1-ylamine trifluoroacetate;YA 3-(4-Methoxy-3-methyl-phenyl)-3-(3-pyridin-3-yl-phenyl)- 3H-isoindol-1-ylamine va trifluoroacetate;2 3-(4-Methoxy-3-methyl-phenyl)-3-(3-pyrimidin-5-yl-phenyl)-3H-isoindol-1- 23 ylamine trifluoroacetate; L-3-[3-(2-Fluoro-pyridin-3-yl)-phenyl]-3-(4-methoxy-3-methyl-phenyl)-3H-isoindol- L 1-ylamine trifluoroacetate; te Methanesulfonic acid 3'-[3-amino-1-(4-methoxy-3-methyl-phenyl)-1H-isoindol-1- to yl]-5-methoxy-biphenyl-3-yl ester trifluoroacetate; 3 5" -(3-Amino-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-isoindol-1-yl)-5- 2 methoxybiphenyl-3-yl methanesulfonate trifluoroacetate; EA 3-(2,3-Dihydrobenzo[b][1,4]dioxin-6-y1)-3-(3'-methoxybiphenyl-3-yl)-3H-isoindol-£9 1-amine trifluoroacetate; os 3-Benzo[1,3]dioxol-5-yl-3-(3-pyridin-3-yl)-3H-isoindol-1-ylamine trifluoroacetate; 2 Yovy - Y.o- 3-Benzo[1,3]dioxol-5-yl-3-(3-bromophenyl)-3H-isoindol-1-ylamine; A 3-Benzo[1,3]dioxol-5-yl-3-(3-pyrimidin-5-ylphenyl)-3H-isoindol-1-ylamine oy trifluoroacetate; ot 3-Benzo[ 1,3]dioxol-5-yl-3-[3-(2-fluoropyridin-3-yl)-phenyl]-3H-isoindol-1-ylamine ~~ °° trifluoroacetate; 81 3-Benzo[1,3]dioxol-5-yl-3-[3-(5-methoxypyridin-3-yl)-phenyl]3H isoindol-1- ov ylamine trifluoroacetate; SA 04 In the form of a free base, a salt, a soluble, or a soluble of a salt thereof, pharmaceutically acceptable. A - Compound according to Claim 1 or oF where it is selected from the following compounds: 3-Benzo[1,3]dioxol-5-yl-3-(3'-methoxy-biphenyl-3- yl)-3H-isoindol-1-ylamine Y trifluoroacetate; 1 Methanesulfonic acid 3'-(3-amino-1-benzo[ 1,3]dioxol-5-yl-1H-isoindol-1-yl)-5- ¢ methoxy-biphenyl-3-yl ester trifluoroacetate ; © Methanesulfonic acid 4-[3-amino-1-(3-pyridin-3-yl-phenyl)-1H-isoindol-1-yl]- 1 phenyl ester trifluoroacetate; v Methanesulfonic acid 4-[3-amino-1-(3-bromo-phenyl)-1H-isoindol-1-yl]-phenyl A ester trifluoroacetate; 1 Methanesulfonic acid 4-{3-amino-1-[3-(2-fluoro-pyridin-3-yl)-phenyl]-1H- Ve isoindol-1-yl}-phenyl ester trifluoroacetate; 1 Methanesulfonic acid 4-[3-amino-1-(3-pyrimidin-5-yl-phenyl)-1H-isoindol-1-yl]- lA phenyl ester trifluoroacetate; 0 Methanesulfonic acid 4-{3-amino-1-[3-(5-methoxy-pyridin-3-yl)-phenyl]-1H- V4 Yovy - 07.1 isoindol-1-yl}-phenyl ester trifluoroacetate; Vo Methanesulfonic acid 4-[3-amino-1 -(3'-methoxy-biphenyl-3-yl)-1H-isoindol-1-yl]- 1 phenyl ester trifluoroacetate; Vv Methanesulfonic acid 4-[3-amino-1 -(5'-methanesulfonyloxy-3'-methoxy-biphenyl- YA 3-yl)-1H-isoindol-1-yl]-phenyl ester trifluoroacetate; 14 3-[3~(2-Fluoro-pyridin-3-yl)-phenyl]-3-pyridin-4-yl-3H-isoindol- 1 -ylamine v trifluoroacetate; 7 3-(3-Bromo-phenyl)-3-pyridin-4-yl-3H-isoindol-1-ylamine trifluoroacetate; YY 3-Pyridin-4-y1-3-(3-pyridin-3-yl-phenyl)-3H-isoindol-1-ylamine trifluoroacetate; vy 3-Pyridin-4-yl-3-(3-pyrimidin-5-yl-phenyl)-3H-isoindol-1 -ylamine trifluoroacetate; ve 3-[3-(5-Methoxy-pyridin-3-yl)-phenyl]-3-pyridin-4-yl-3H-isoindol-1 -ylamine for trifluoroacetate ; 571 3-(3"-Methoxy-biphenyl-3-yI)-3-pyridin-4-yl-3H-isoindol-1 -ylamine vv trifluoroacetate;YA 3-{3-[3-Amino-1-(4- methoxyphenyl)-1H-isoindol-1 -yl]phenyl} thiophene-2- va carbaldehyde 1.5 acetate; ve 4-[3-Amino-1-(3-bromophenyl)-1H-isoindol-1 -yl]benzonitrile; 791 1 -(3-Bromophenyl)-1-[4-(trifluoromethyl)phenyl]-1H-isoindol-3 -amine;vy 1-(3-Bromophenyl)-1-[6-(trifluoromethyl)pyridin-3 -yl]- 1H-isoindol-3-amine vy acetate; ve 1-[3-(1-Isobutyl-1H-pyrazol-4-yl)phenyl]-1 -(4-methoxyphenyl)-1H-isoindol-3- Yeo amine 0.5 acetate 71 1-(4-Methoxyphenyl)-1-[3 -(5-methyl-2-furyl)phenyl]-1H-isoindol-3-amine 0.5 ry YoYY except acetate; TA 3'-[3-Amino-1-(4-methoxyphenyl)- 1H-isoindol-1-yl]biphenyl-2-carboxamide 0.5 4 acetate; 3 1-[3-(5-Fluoropyridin-3-yl)phenyl]-1-[4-(trifluoromethoxy)phenyl]-1H-isoindol-3-£)amine 0.75 acetate; ty 1-(3-Pyrimidin-5-ylphenyl)-1-[4-(trifluoromethoxy)phenyl]-1H-isoindol-3-amine L 0.25 acetate; ¢ 4-[3-Amino-1-(3-pyrimidin-5-ylphenyl)-1H-isoindol-1-yl]benzonitrile 0.25 acetate; to 1-[3-(5-Fluoropyridin-3-yl)phenyl]-1-[4-(trifluoromethyl)phenyl]-1H-isoindol-3- 3 amine 0.25 acetate; BD 1-(3-Pyrimidin-5-ylphenyl)-1-[4-(trifluoromethyl)phenyl}-1H-isoindol-3-amine A 0.25 acetate; £4 3-[3-(3-Amino-1-pyridin-4-yl-1H-isoindol-1-yl)phenyl]thiophene-2-carbaldehyde; or 1-[3-(1-Isobutyl-1H-pyrazol-4-yl)phenyl]-1-pyridin-4-yl-1H-isoindol-3-amine 0.25 51 acetate; oY 1-[3-(5-Methyl-2-furyl)phenyl]-1-pyridin-4-yl-1H-isoindol-3-amine acetate; al 3'-(3-Amino-1-pyridin-4-yl-1H-isoindol-1-yl)biphenyl-2-carboxamide 0.25 acetate; ot 4-{3-Amino-1-[3-(2-fluoropyridin-3-yl)phenyl]-1H-isoindol-1-yl} benzonitrile; 98 1-[3-(2-Fluoropyridin-3-yl)phenyl]-1-[4-(trifluoromethyl)phenyl}-1H-isoindol-3- 2% amine; ov 1-[3-(5-Fluoropyridin-3-yl)phenyl]-1-pyridin-4-yl-1H-isoindol-3-amine 0.75 2A acetate; 51 - 7.8 1-(4-Fluoro-3-pyrimidin-5-ylphenyl)-1-pyridin-4-yl-1H-isoindol-3-amine 5 Te acetate; 1 1-[4-Fluoro-3-(5-fluoropyridin-3-yl)phenyl]-1-pyridin-4-yl-1H-isoindol-3-amine 1 0.75 acetate; 1 1-(3-Fluoropyridin-4-yl)-1-[3-(5-fluoropyridin-3-yl)phenyl]-1H-isoindol-3-amine it 0.5 acetate; 15 1-(3-Fluoropyridin-4-yl)-1-(3-pyrimidin-5-ylphenyl)-1H-isoindol-3-amine 1.25 1 acetate; P 1-(3-Fluoropyridin-4-yl)-1-[3-(2-fluoropyridin-3-yl)phenyl]- 1H-isoindol-3-amine 1A 1.25 acetate; 1A 1-(3-Fluoropyridin-4-yl)-1-(4-fluoro-3-pyrimidin-5-ylphenyl)-1H-isoindol-3-amine 1.25 acetate; except 1-[4-Fluoro-3-(5-fluoropyridin-3-yl)phenyl]-1-(3-fluoropyridin-4-yl)-1H-isoindol-L 3-amine 1,5 acetate ; vy -[4-Fluoro-3-(2-fluoropyridin-3-yl)phenyl]-1-(3-fluoropyridin-4-yl)-1H-isoindol- ~~ Y? 3-amine 1,5 acetate; vo 5-[3-(3-Amino-1-pyridin-4-yl-1H-isoindol-1-yl)phenyl]nicotinotrile acetate; vi 6-Fluoro-1-(4-methoxyphenyl)-1-(3-pyrimidin-5-ylphenyl)-1H-isoindol-3-amine; vy 6-Fluoro-1-(4-methoxyphenyl)-1-(3-pyridin-3-ylphenyl)-1H-isoindol-3-amine; VA 6-Fluoro-1-(3'-methoxybiphenyl-3-yl)-1-(4-methoxyphenyl)-1H-isoindol-3-amine; va 6-Fluoro-1-(4-methoxyphenyl)-1-[3-(5-methoxypyridin-3-yl)phenyl}- 1H-isoindol- As 3-amine; A) 6-Fluoro-1-pyridin-4-yl-1-(3-pyridin-3-ylphenyl)-1H-isoindol-3-amine; Ay Yovy - 07.8 6-Fluoro-1-pyridin-4-yl-1-(3-pyrimidin-5-ylphenyl)-1H-isoindol-3-amine; AY 6-Fluoro-1-[3-(5-methoxypyridin-3-yl)phenyl]-1-pyridin-4-yl-1H-isoindol-3-amine; At 6-Fluoro-1-[3-(2-fluoropyridin-3-yl)phenyl]-1-pyridin-4-yl-1H-isoindol-3-amine; Ao 1-(3',5'-Dichlorobiphenyl-3-yl)-1-(4-methoxyphenyl)-1H-isoindol-3-amine acetate; AT 1-(3-Bromophenyl)-1-isopropyl-1H-isoindol-3-amine hydrochloride; AY 3'-(3-Amino-1-cyclopropyl-1H-isoindol-1-yl)-5-methoxybiphenyl-2-carbonitrile AA acetate; 1m 1-Cyclopropy!-1-(3-pyrimidin-5-ylphenyl)-1H-isoindol-3-amine acetate; i 3'-(3-Amino-1-methyl-1H-isoindol-1-yl)-5-methoxybiphenyl-2-carbonitrile acetate; 1 1-(3',5'-Dichlorobiphenyl-3-yl)-1-methyl-1H-isoindol-3-amine hydrochloride; ay 1-Methyl-1-(3-pyrimidin-5-ylphenyl)-1H-isoindol-3-amine acetate; av 1-[3-(2-Fluoropyridin-3-yl)phenyl]-1-methyl- 1H-isoindol-3-amine acetate; it 1-Isopropyl-1-(3-pyrimidin-5-ylphenyl)-1H-isoindol-3-amine acetate; and 1s 1-[3-(5-Fluoropyridin-3-yl)phenyl]-1-methyl-1H-isoindol-3-amine acetate; 41 AY in the form of a free base, salt, soluble or soluble of a salt thereof is pharmaceutically acceptable. 1 1 - Compound according to any of the Claims No. 1 to A for use in treatment. -01-1 Pharmaceutical formulation comprising a therapeutically effective quantity of a Ly compound of any of the "protection No. 1 to / as active ingredients in association with excipients, carriers 1 5 or diluents Pharmaceutical Acceptable.-11-1 Compounded according to any of Claims 1 through (A) for use as a drug. YoYY - “11. 1?1- Use of a compound in accordance with any of claims Nos. 1 to 8; 7 In the manufacture of a drug to treat or prevent an AP-related disease -1"1 Use compounded according to any of claims Nos. 1 through 8; In the manufacture of a drug to treat 7 or prevent a disease related to Cus AR, the aforementioned disease related to AP is Downs’ syndrome and p-amyloid angiopathy, to name a few; cerebral amyloid angiopathy and cerebral hemorrhage (hs) hereditary cerebral hemorrhage 0 and disorders associated with Shay! Sha 1 mild cognitive impairment (“Alzheimer’s” disease “memory loss” and attention deficit symptoms associated with Alzheimer 1; Neurodegeneration 0 associated with diseases fie Alzheimer's disease or dementia including Lae 11 dementia of mixed vascular and atrophic origin “degenerative degenerative origin” dementia VY senile pre-senile dementia » dementia associated with Parkinson's 0 or 4 progressive supranuclear palsy or 4 cortical basal degeneration. AB where the said disease related to the use of pursuant to Claim No. 14-1 . Alzheimer's is Alzheimer's disease