UNITED STATES DEPARTMENT OF COMMl~ RCE
`
`United Stntcs Pnh.•nt nnd Trndcmnrk Oflicl'
`
`August 11, 2016
`
`THIS IS TO CERTIFY THAT ANNEXED HERETO IS A TRUE COPY FROM
`THE RECORDS OF THE UNITED STATES PATENT AND TRADEMARK
`OFFICE OF THOSE PAPERS OF THE BELOW IDENTIFIED PATENT
`APPLICATION THAT MET THE REQUIREMENTS TO BE GRANTED A
`FILING DATE UNDER 35 USC 111.
`
`APPLICATION NUMBER: 601654,060
`FILING DATE: February 16, 2005
`
`THE COUNTRY CODE AND NUMBER OF YOUR PRIORITY
`APPLICATION, TO BE USED FOR FILING ABROAD UNDER THE PARIS
`CONVENTION, IS US60/654,060
`
`Certified by
`
`<---ltc, "vt:\Le_e.__ ;c~ :z;_A._ - -
`
`Under Secretary of Commerce
`for Intcllcctual Property
`and Director of the United States
`Patent and Trademark Office
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1064 - Page 1 of 43
`
`

`
`Atty. Dkt. No. 045471-0750
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Applicant: Yong-Kang ZHANG, et al.
`
`Title:
`
`BORON-CONTAINING SMALL
`MOLECULES FOR USE IN THE
`TOPICAL TREATMENT OF
`ONYCHOMYCOSIS AND
`CUTANEOUS FUNGAL
`INFECTIONS
`
`CERTIFICATE OF EXPRESS MAILING
`I hereby certify that this <orrespondence is being deposited with the
`United States Postal Service's "Express Mail Post Office To
`Addressee" service under 37 C.F.R. § 1.10 on the date indicated
`below and is addressed to: Commissioner for Patents, P.O. Box
`1450, Alexandria, VA 22313-1450.
`
`ED435510583US
`(Express Moil Label Number)
`
`Fcb!UBfY 16, 2005
`
`Lisa Kaiser
`
`AppL No.: Unknown
`
`Filing Date: Herewith
`
`Examiner: Unknown
`
`Art Unit:
`
`Unknown
`
`PROVISIONAL PATENT APPLICATION
`TRANSMITTAL
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Sir:·
`
`Transmitted herewith for filing· under 37 C.F.R. § l.53(c) is the provisional patent
`application of:
`
`Yong-Kang Zhang
`5151 Westmont A venue
`San Jose, CA 95130
`
`Stephen J. Baker
`1568 Begen A venue
`Mountain View, California 94040
`
`[ X] Applicant claims small entity status under 37 CFR l .27(c)(l).
`
`016.352550.1
`
`-1-
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1064 - Page 2 of 43
`
`

`
`Atty. Dkt. No. 045471-0750
`
`Enclosed are:
`
`[ X] Description (35 pages).
`
`[ ]
`
`[ ]
`
`[ ]
`
`[ ]
`
`Informal drawings (0 sheets, Figures 0).
`
`Assignment of the invention.
`
`Assignment Recordati~n Cover Sheet.
`
`Small Entity statement(s).
`
`[ X] Application Data Sheet (37 CFR 1.76).
`
`The filing fee is calculated below:
`
`Basic Fee
`=
`- 100
`35 -
`Size Fee
`Surcharge under 3 7 CFR 1.16( e) for late
`payment of filing fee
`
`0
`
`x
`+
`
`Rate
`$200.00
`$250.00
`
`$50.00
`
`=
`
`[ x]
`
`SUBTOTAL: =
`Small Entity Fees Apply (subtract Y2 of above):
`TOTAL FILING FEE:
`+
`$40.00
`=
`TOTALFEE =
`
`Assignment Recordation Fee:
`
`Fee
`Totals
`$200.00
`$0.00
`
`. $0.00
`
`$200.00
`$100.00
`$100.00
`$0.00
`$100.00
`
`[ x]
`
`A check in the amount of $100. 00 to cover the filing fee is enclosed.
`.
`.
`
`[ ]
`
`[ ]
`
`The required filing fees are not enclosed but will be submitted in response to the Notice
`to File Missing Parts of Application.
`
`Further, Applicant, by and through his attorney ofrecord, hereby expressly abandons the
`application as of the filing date of this letter. This is an abandonment of the application
`only, and is not to be construed as an abandonment of the invention disclosed in the
`application. It is respectfully requested that the Office acknowledge abandonment of the
`application as of the filing date of this letter in a communication mailed to the
`undersigned.
`
`016.352550.1
`
`-2-
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1064 - Page 3 of 43
`
`

`
`Atty. Okt. No. 045471-0750
`
`[ X ] The Commissioner is hereby authorized to charge any additional fees which may be
`required regarding this application under 37 C.F.R. §§ 1.16-1.17, or credit any
`overpayment, to Deposit Account No. 50-0872. Should no proper payment be enclosed
`herewith, as by a check being in the wrong amount, unsigned, post-dated, otherwise
`improper or informal or even entirely missing, the Commissioner is authorized to charge ·
`the unpaid amount to Deposit Account No. 50-0872.
`
`Please direct all correspondence to the undersigned attorney or agent at the address
`indicated below.
`
`Respectfully submitted,
`
`Date ~ ~~410:
`
`FOLEY & LARDNER LLP
`1530 Page Mill Road
`Palo Alto, San Francisco, California 94304
`Telephone:
`( 415) 438-6454
`Facsimile:
`(650) 856-3710
`
`David P. Lentini
`Attorney for Applicant
`Registration No. 33,944
`
`•
`
`016.352550.1
`
`-3-
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1064 - Page 4 of 43
`
`

`
`Attorney Docket No: 045471-0750
`
`U.S. PATENT APPLICATION
`
`FOR
`
`BORON-CONTAINING SMALL MOLECULES FOR USE IN THE TOPICAL
`TREATMENT OF ONYCHOMYCOSIS AND CUTANEOUS FUNGAL
`INFECTIONS
`
`Inventors:
`
`YONG-KANG ZHANG
`
`STEPHEN J. BAKER
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1064 - Page 5 of 43
`
`

`
`Attorney Docket No: 045471-0750
`
`BORON-CONTAINING SMALL MOLECULES FOR USE IN THE TOPICAL
`TREATMENT OF ONYCHOMYCOSIS AND CUTANEOUS FUNGAL INFECTIONS
`
`Field of the Invention
`
`[0001)
`
`This invention relates to compounds useful for treating fungal
`
`infections, more specifically topical treatment of onychomycosis and/or cutaneous fungal·
`
`infections. This invention is directed to compounds that are active against fungi and have
`
`properties that allow the compound, when placed in contact with a patient, to reach the .
`
`particular part of nail or skin infected by the fungus. In particular the present compounds
`
`have physiochemical properties that facilitate penetration of the nail plate.
`
`State of the Art
`
`[0002)
`
`Onychomycosis is a fungal infection of the toe and finger nails. The
`
`causative pathogens in this infection include the dermatophytes, Trichophyton, Microsporum
`
`and Epidermophyton species and yeast-like fungi including Candida species.
`
`[0003)
`
`In the USA, onychomycosis is currently managed by only one FDA
`
`approved topical treatment, PENLAC®, which contains the active ingredient ciclopirox:
`
`0
`
`[0004)
`
`PENLAC® is known to have very poor efficacy rates: it is only
`
`effective in 8% of all onychomycosis cases treated using this topical treatment. Thus, there
`
`remains a need for new antifungal agents that can applied safely to toe- and finger nails. The
`
`present invention meets these and other needs.
`
`025.11326.1
`
`- 1 -
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1064 - Page 6 of 43
`
`

`
`SUMMARY OF THE INVENTION
`
`[0005)
`
`The compounds useful for treating fungal infections, more specifically
`
`topical treatment of cutaneous fungal infections and/or onychomycosis, have the structure
`
`given by Formula I below:
`
`I
`
`wherein
`Z is selected from a bond, -CH2, and -CHR4;
`R3 is selected from hydrogen and methyl; alternatively, R3 and R4 and the
`atoms bonded thereto join together to form a substituted or unsubstituted aryl;
`R 1 is selected from OH, substituted or unsubstituted C 1•4alkyl, substituted or
`unsubstituted C3•7cycloalkyl, substituted or unsubstituted C24alkenyl, substituted or
`unsubstituted C2.4alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted
`heteroaryl; and
`
`pis 0, 1 or 2;
`R2 is selected from halo, OH, CN, substituted or unsubstituted C 1•4alkyl,
`substituted or unsubstituted C3.7cycloalkyl, substituted or unsubstituted C24alkenyl,
`substituted or unsubstituted C2.4alkynyl, acyl, aminoacyl, acylamino, carboxyl, carboxyl
`ester, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or
`
`unsubstituted alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted
`heteroaryloxy, and NRaRb, wherein R8 and Rb arc independently selected from hydrogen,
`
`substituted or unsubstituted C 1.4alkyl, substituted or unsubstituted C3•7cycloalkyl, substituted
`or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
`
`025.11326.1
`
`2
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1064 - Page 7 of 43
`
`

`
`alternatively, when pis 2 and the two R2 groups are bonded to adjacent
`carbon atoms, then these two R2 groups and the atoms bonded thereto may join together to
`form a substituted or unsubstituted aryl.
`
`In a preferred embodiment, the physicochemical properties of the molecuie of
`
`Formula I; described by quantities predictive for migration of the compound through the nail
`
`plate, including, but not limited to, molecular weight, logP, solubility in water and activity in
`
`the presence of keratin, and the like, are effective to provide substantial penetration of the
`
`nail plate.
`
`[0006]
`
`Compounds with a molecular weight of less than 200 Da penetrate the
`
`nail plate in a manner superior to the commercially available treatment for onychomycosis
`
`(See Examples). In one embodiment of the present invention the antifungal compounds have
`
`·a molecular weight of less than 170 Da. In another embodiment of this invention, the
`
`compounds have a molecular weight of from about 145 to about 170 Da. In yet another
`
`embodiment the molecular weight is either 151.93 or 168.39 Da.
`
`[0007]
`
`In one embodiment of the present invention the antifungal compounds
`
`have a LogP value of less than about 2.5. In another embodiment, the antifungal compounds
`
`have a LogP value of from about 1.0 to about 2.0. In yet another embodiment, the antifungal
`
`compounds have a LogP value of 1.9 or 2.3.
`
`[0008]
`
`Also contemplated by the present invention are compounds with a
`
`LogP value greater then 2.5, with a molecular weight less than 200 Da, that are still able to
`
`penetrate the nail plate.
`
`[0009]
`
`In one embodiment of the present invention the antifungal compounds
`
`have a water solubility greater than about 0.1 mg/mL in octanol saturated water.
`
`[0010]
`
`In one embodiment of the present invention, the minimum inhibitory
`
`concentration, MIC, against Trichophyton rub rum of the antifungal compo\lnds of the present
`
`invention did not change in the presence of about 5% keratin. In one embodiment, the MIC
`
`of the compound exhibits less than about an 8 fold decrease in activity in the presence of of
`
`about 5% keratin.
`
`[0011]
`
`In one embodiment, Z is a bond.
`
`3 ·
`
`025.11326.1
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1064 - Page 8 of 43
`
`

`
`-CHR4
`
`In another embodiment Z is CH2. In yet another embodiment Z is
`[0012)
`, and R3 and R4 and the atoms bonded thereto join together to form a phenyl group.
`In one embodiment R 1 is OH.
`In one embodimentp is 1 and R2 is selected from fluor6, chloro,
`
`[0013)
`
`[0014)
`
`methyl, cyano, methoxy, hydroxymethyl, and p-cyanophenyloxy.
`In one embodiment pis 2 and each R2 is independently selected from
`
`[0015)
`
`fluoro, chloro, methyl, cyano, methoxy, hydroxymethyl, and p-cyanophenyl.
`In one embodimentp is 2 and the two R2 groups, which are on adjacent
`
`[0016)
`
`carbon atoms, join to form a phenyl group.
`
`[0017)
`
`Some examples of molecules with optimal physicochemical properties
`
`are given in the table below.
`
`Structure:
`Formula:
`Molecular weight (Da):
`Plasma protein binding
`(%):
`LogP:
`Water solubility (ug/mL):
`
`OH
`
`OH
`
`F ~b Cl f;Co
`
`(compound 1)
`(compound 2)
`·c1H6BF02 C1H6BCl02
`151.93
`168.39
`
`66
`1.9
`>100
`
`83
`2.3
`>100
`
`(0018)
`
`Compound 3 below is an example of a compound similar in molecular
`
`weight to ciclopirox, and like ciclopirox, does not penetrate the nail plate.
`
`9
`VJ 0
`
`F .
`(compound 3)
`C13HwBFO
`212.03
`100
`not determined
`not determined
`
`Structure:
`Formula:
`Molecular weight (Da):
`Plasma protein binding(%):
`LogP:
`Water solubility (µg/mL):
`
`4
`
`025.11326.1
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1064 - Page 9 of 43
`
`

`
`[0019)
`
`This invention is also directed to pharmaceutical compositions
`
`comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a
`
`compound described herein or mixtures of one or more of such compounds.
`
`[0020)
`
`In another embodiment, the present invention is directed to topical
`
`formulations comprising a pharmaceutically acceptable topical carrier and at least one
`
`compound of Formula I as described above.
`
`[0021)
`
`In a preferred embodiment the topical formulations the compound of
`
`Formula I described structurally above has a total molecular weight of less than 200 Da, has
`
`a logP of less than 2.5, and a minimum inhibitory concentration against Trichophyton rubrum
`
`that is substantialJy unchanged in the presence of 5% keratin.
`
`[0022)
`
`This invention is still further directed to methods for treating a viral
`
`infection mediated at least in part by dermatophytes, Trichophyton, Microsporum or
`
`Epidermophyton species, or a yeast-like fungi including Candida species, in mammals,
`
`which methods comprise administering to a mammal, that has been diagnosed with saiq viral
`
`infection or is at risk of developing said viral infection, a pharmaceutical composition
`
`comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a
`
`compound described herein or mixtures of one or more of such compounds. In one
`
`embodiment the infection is onychomycosis. Penetration of the nail by the active ingredient
`
`may be effected by the polarity of the formulation. However, the polarity of the formulation
`
`is not expected have as much influence on nail penetration as some of the other factors, such
`
`as the molecular weight or the LogP of the active ingredient. The presence of penetration
`
`enhancing agents in the formulation are likely to increase penetration of the active agent
`
`when compared to similar formulations containing no penetration enhancing agent.
`
`[0023)
`
`Compounds contemplated by the present invention may have broad
`
`spectrum antifungal activity and as such may be candidates for use against other cutaneous
`
`fungal infections.
`
`Utility
`
`[0024)
`
`It is believed that poor penetration of the active agent through the nail
`
`plate and/or excessive binding to keratin, (the major protein in nails and hair) are the reasons
`
`5
`
`025.11326.1
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1064 - Page 10 of 43
`
`

`
`for the poor efficacy of PENLAC® and other topical treatments (that have failed in clinical
`
`trials).
`
`In mild cases of onychomycosis, the pathogenic fungi reside in the nail plate only.
`
`In moderate to severe cases the pathogenic fungi establish a presence in the nail plate and in
`
`the nail bed. If the infection is cleared from the nail plate but not from the nail bed, the fungal
`
`pathogen can re-infect the nail plate. Therefore, to effectively treat onychomycosis, the
`
`infection must be eliminated from the nail plate and the nail bed. To do this, the active agent
`
`must penetrate and disseminate substantially throughout the nail plate and nail bed.
`It is believed that in order for an active agent to be effective once
`
`[0025)
`
`disseminated throughout the infected area, it must be bioavailable to the fungal pathogen and
`
`cannot be so tightly and/or preferentially bound to keratin that the drug is rendered inactive.
`
`[0026]
`
`An understanding of the morphology of the nail plate suggests certain
`
`physicochemical properties of an active agent that would facilitate penetration of the nail
`
`plate. The desired physicochemical properties are described throughout. The tested
`
`compounds of the present invention are able to penetrate the nail plate and were also active
`
`against Trichophyton rubrum and mentagrophytes and other species. In addition, the tested
`
`compounds are also. active against Trichophyton rubrum in the presence of 5% keratin
`
`powder. Finally, penetration of the nail plate by the compounds of this invention is weakly,
`
`if at all, influenced by the polarity of the formulation within which the active compound is
`
`dispersed.
`
`Administration and Pharmaceutical Composition
`
`[0027)
`
`In general, the compounds prepared by the methods, and from the
`
`intermediates, described herein will be administered in a therapeutically effective amount by
`
`any of the accepted modes of administration for agents that serve similar utilities. The actual
`
`amount of the compound of this invention, i.e., the active ingredient, will depend upon
`
`numerous factors such as the severity of the disease to be treated, the age and relat.ive health
`
`of the subject, the potency of the compound used, the route and form of administration, and
`
`other factors . The drug can be administered more than once a day, for example, about4 times
`
`a day, and preferably once or twice a day.
`
`025.11326.1
`
`6
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1064 - Page 11 of 43
`
`

`
`[0028)
`
`The pharmaceutical compositions of the present invention are
`
`comprised of in general, a compound of the present invention in combination with at least
`
`one pharmaceutically acceptable diluent or excipient. Acceptable excipients are non·toxic,
`
`aid administration, and do not adversely affect the therapeutic benefit of the active
`
`compound. Such excipient may be any solid, liquid, semi·solid or, in the case of an aerosol
`
`composition, gaseous excipient that is generally available to one of skill in the art.
`
`·
`
`[0029)
`
`Solid pharmaceutical excipients include starch, cellulose, talc, glucose,
`
`lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium
`
`stearate, glycerol monostearate, sodium chloride, dried skim milk ar.d the like. Liquid and
`
`semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and
`
`various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut
`
`oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for
`
`injectable solutions, include water, saline, aqueous dextrose, and glycols.
`
`[0030)
`
`The amount of the compound in a topical formulation can vary within
`
`the full range employed by those skilled in the art. Typically, the topical formulation will
`
`contain, on a weight percent (wt%) basis, from about 0.01·99.99 wt% of a compound of the
`
`present invention based on the total formulation, with the balance being one or more suitable
`
`pharmaceutical excipients. Preferably, the compound is present at a level of about 1-50 wt%,
`
`more preferably about 1 to about 25%, even more preferably about 1 to about 10%, still more
`
`preferably about 5 to about 10%.
`
`[0031)
`
`The topical formulations may be administered 1 to 4 times per day.
`
`More preferably the formulation is applied to th.e patient 1 to 2 times per day.
`
`EXAMPLES
`
`(0032)
`
`Proton NMR are recorded on Varian AS 300 spectrometer and
`
`chemical shifts are reported as 8 (ppm) down field from tetramethylsilane. Mass spectra are ·
`
`determined on Micromass Quattro II.
`
`025.11326.1
`
`7
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1064 - Page 12 of 43
`
`

`
`Example 1
`
`5-Chloro-1,3-Dihydro-1-Hydroxy-2, 1-Benzoxaborole
`
`BH3fTHF
`
`Overnight
`0-25°C
`
`~1b~~CI
`I
`1. t-BuLifTHF ~r
`OH
`I
`-78°C
`i(YB,o _2_. B_(O_M_e_)3__
`Cl~ 3. HCllH20
`MeOH
`reflux
`
`DCM
`
`Cl
`
`0
`
`I
`
`O......._
`
`[0033]
`
`(a) 2-bromo-5-chlorobenzyl alcohol. To a solution of 2-bromo-5-
`
`chlorobenzoic acid (5.49 g, 23.3 mmol) in anhydrous THF (70 ml) under nitrogen was added
`dropwise a BH3 THF solution (1.0 M, 55 mL, 55 mmol) at 0°C and the reaction mixture was
`stirred overnight at room temperature. Then the mixture was cooled again with ice bath and
`
`MeOH (20 mL) was added dropwise to decompose excess BH3• The resulting mixture was
`stirred until no bubble was released and then 10%NaOH (10 mL) was added. The mixture
`
`was concentrated and the residue was mixed with water (200 mL) and extracted with EtOAc.
`
`The residue from rotary evaporation was purified by flash column chromatography over
`
`silica gel eluted with a mixed solvents of hexane and EtOAc (5: 1, v/v) to give 4.58gof2-
`bromo-5-chlorobenzyl alcohol as a white solid (yield 88.8%). 1H NMR (300 MHz, DMSO(cid:173)
`d6): & 7.57 (d, J = 8.7 Hz, lH), 7.50-7.49 (m, lH), 7.28-7.24 (m, lH), 5.59 (t, J = 6.0 Hz, lH)
`and 4.46 (d, J = 6.0 Hz, 2H) ppm.
`(b) 2-bromo-5-chloro-1-(methoxymethoxymethyl)benzene. The obtained
`[0034]
`
`2-bromo-5-chlorobenzyl alcohol was dissolved in CH2Ch (150 mL) and cooled to 0°C with
`ice bath. To this solution under nitrogen were added in sequence di-isopropyl ethyl amine
`
`(5.4 mL, 31.02 mmol, 1.5 eq) and chloromethyl methyl ether (2 mL, 25.85 mmol, 1.25 eq).
`
`The reaction mixture was stirred overnight at room temperature and washed with N;:tHC03-
`saturated water and then NaCl-saturated water. The residue after rotary evaporation was
`
`8
`
`025. 11326. 1
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1064 - Page 13 of 43
`
`

`
`purified by flash column chromatography over silica gel eluted with a mixed solvents of
`
`hexane and EtOAc (5:1, v/v) to give 4.67gof2-bromo-5-chloro-1-
`(methoxymethoxymethyl)benzene as a colorless liquid (yield 85 .0%). 1H NMR (300 MHz,
`DMSO-dt;): 8 7.63 (d, J = 8.7 Hz, lH), 7.50 (dd, J = 2.4 & 0.6 Hz, lH), 7.32 (dd, J = 8.4 &
`2.4 Hz, lH), 4.71 (s, 2H), 4.53 (s, 2H) and 3.30 (s, 3H) ppm.
`
`[0035)
`
`(c) S -Chloro-J,3-dihydro-J-hydroxy-2,1-benzoxaborole. To a solution
`
`of 2-bromo-5-chloro-l-(methoxymethoxymethyl)benzene ( 4.6 g, 17 .3 mmol) in anhydrous
`
`THF (80 mL) at -78°C under nitrogen was added dropwise tert-BuLi (1.7 Min n-pentane,
`
`11.7 mL, 1.15 eq) and the solution became brown colored. Then, B(OMe)3 (1.93 mL, 17.3
`
`mmol) was injected in one portion and the cooling bath was removed. The mixture was
`
`warmed gradually with stirring for 30 min and then stirred with a water bath for 2 h. After
`
`addition of 6N HCl (6 mL), the mixture was stirred overnight at room temperature and about
`
`50% hydrolysis has happened as shown by TLC analysis. The solution was rotary evaporated
`
`and the residue was dissolved in MeOH (50 mL) and 6N HCl (4 mL). The solution was
`
`refluxed for 1 h and the hydrolysis was completed as indicated by TLC analysis. Rotary
`
`evaporation gave a residue which was dissolved in EtOAc, washed with water, dried and then
`
`evaporated. The crude product was purified by flash column chromatography over silica gel
`
`eluted with mixed solvents of hexane and EtOAc (2:1, v/v) to provide a solid with 80%
`
`purity. The solid was further purified by washing with hexane to afford 1.22 g of the desired
`title compound as a white solid (yield 41.9%). M.p. 142-150°C. MS (ESI): m/z = 169 (M+l,
`positive) and 167 (M-1, negative). HPLC (220 run): 99% purity. 1H NMR (300 MHz,
`DMSO-dt;): 8 9.30 (s, lH), 7.71 (d, J = 7.8 Hz, lH), 7.49 (s, IH), 7.38 (d, J = 7.8 Hz, lH) and
`4.96 (s, 2H) ppm.
`
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`

`
`Example 2
`
`l ,3-Dihydro-1-Hydroxy-2, 1-Benzoxaborole
`?H
`
`lXo
`
`[0036)
`
`The title compound was prepared by using 2-bromobenzyl alcohol as a
`
`starting material and following the procedures as described in Example 1 band le. The
`
`product of the title compound was obtained as a white solid. M.p. 83-86°C. MS (ESI): m/z =
`135 (M+l, positive) and 133 (M-1, negative). HPLC (220 nm): 95.4% purity. 1H NMR (300
`
`MHz, DMSO-d6): c5 9.14 (s, lH), 7.71(d,J=7.2 Hz, lH), 7.45 (t, J = 7.5 Hz, lH), 7.38 (d, J
`= 7.5 Hz, lH), 7.32 (t, J = 7.1 Hz, lH) and 4.97 (s, 2H) ppm.
`
`Example3
`
`6-Hydroxy-6H-Dibenz[c,e] [ l ,2]oxaborin
`
`[0037)
`
`To a three-necked flask with hexane (250 mL) under nitrogen were
`
`added in sequence BCh (1.0 M, 45 mL, 45 mmol) and 2-phenylphenol solid (5 g, 29.3 mmol)
`
`at room temperature. After the solid was dissolved, AlCh (0.2 g, 5 mol%) was added in one
`
`portion. The mixture was refluxed for 5 hand then cooled to 0°C. Ethanol (30 mL, 0.51 mol)
`
`were slowly added and the mixture was stirred for a while. Water was added and the mixture
`
`was extracted with EtOAc. Evaporation gave the residue that was purified by flash column
`
`chromatography over silica gel eluted with mixed solvents of hexane and EtOAc ( 4: 1, v/v) to
`
`provide 3.13 g of the desired title compound as a cream solid (yield 54.5%). M.p. 203-206°C.
`
`MS (ESI): m/z = 197 (M+l, positive) and 195 (M-1, negative). HPLC (220 nm): 98.9%
`. purity. 1H NMR (300 MHz, DMSO-d6+D20): 8 9.42 (s, trace), 8.27-8.21 (m, 2H), 8.05 (dd, J
`= 7.2 & 0.9 Hz, lH), 7.71 (td, J1 = 7.8 Hz, Jd = 1.8 Hz, lH), 7.46 (td, J1 = 7.4 Hz, Jd = 0.9 Hz,
`lH), 7.41-7.35 (m, lH) and 7.25-7.17 (m, 2H) ppm.
`
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`

`
`Example 4
`
`5-Fluoro-1-hydroxy-3-methyl-2, 1-benzoxaborolane
`
`OH
`
`F~b
`
`Me
`
`[0038)
`
`To a solution of2-bromo-5-fluoro-[1-(methoxymethoxy)ethyl]benzene
`
`(1.32 g, 5.00 mmol) in dry tetrahydrofuran (10 mL) were added sec-butyl lithium (1.4 mol/L
`
`in cyclohexane; 5.0 mL) and trimethyl borate (1.1 mL, 10 mmol) at -78°C und.er nitrogen
`
`atmosphere, and the mixture was stirred for lh while allowing to warm to room temperature.
`
`The reaction was quenched with 2 mol/L hydrochloric acid, and the mixture was extracted
`
`with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium
`
`sulfate. The solvent was removed under reduced pressure. To a solution of the residue in
`
`tetrahydrofuran (15 mL) was added 6 mol/L hydrochloric acid (3 mL), and the mixture was
`
`stirred at room temperature for overnight. Water was added and the mixture was extracted
`
`with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium
`
`sulfate. The solvent was removed under reduced pressure. Recrystallization from pentane
`
`gave the target compound (473 mg, 58%) as a white powder.
`1H-NMR (300.058 MHz, DMSO-d6) o ppm 1.37 ( d, J = 6.4 Hz, 3H),
`5.17 (q, J= 6.4 Hz, lH), 7.14 (m, lH), 7.25 (dd, J= 9.7, 2.3 Hz, lH), 7.70 (dd, J= 8.2, 5.9
`
`[0039]
`
`Hz, lH), 9.14 (s, lH).
`
`. Example 5
`
`2-Bromo-5-fluoro-[ 1-(methoxymethoxy)ethyl]benzene
`
`[0040]
`
`To a solution of 2-bromo-5-fluorobenzaldehyde (4.23 g, 20.0 mmol) in
`
`tetrahydrofuran (30 mL) was added methylmagnesium bromide (1.4 mol/L in
`
`tetrahydrofuran; 18 mL, 25 mmol) at - 78 °C under nitrogen atmosphere, and the mixture
`
`was stirred for 2 h while allowing to warm to room temperature. The reaction was quenched
`
`with 2 mol/L hydrochloric acid, and the mixture was extracted with ethyl acetate. The
`
`organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent
`
`was removed under reduced pressure. To a solution of the residue (4.62 g) in
`
`11
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`
`dichloromethane (100 mL) were added diisopropylethylamine (5.2 mL, 30 mmol) and
`
`chloromethyl methyl ether (2.0 mL, 26 mmol) at 0 °C, and the reaction mixture was stirred at
`
`room temperature fro overnight. Water was added, and the mixture was extracted with
`
`chloroform. The organic layer was washed with brine and dried on anhydrous sodium
`
`sulfate. The solvent was removed under reduced pressure. The residue was purified by silica
`
`gel column chromatography (15:1 hexane/ethyl acetate) to give 2-bromo-5-fluoro-[1-
`
`(methoxymethoxy)ethyl]benzene (4.97 g, 2 steps 94%).
`1H-NMR (300.058 MHz, CDC13) 8 ppm 1.43 (d, J = 6.5 Hz, 3H), 3.38
`(s, 3H), 4.55 (d,J= 6.5 Hz, lH), 4.63 (d,J= 6.5 Hz, lH), 5.07 (q, J= 6.5 Hz, lH), 6.85 (m,
`
`[0041]
`
`lH), 7.25 (dd, J= 9.7, 2.6 Hz, lH), 7.46 (dd, J= 8.8, 5.3 Hz, lH).
`
`Example 6
`
`5-Fluoro-1-hydroxy-1,2,3,4-tetrahydro-2,l-benzoxaborine
`
`OH Fro
`
`[0042]
`
`A mixture of -bromo-5-fluorobenzaldehyde (4.23 g, 20.0 mmol),
`
`(methoxymethyl)triphenylphosphonium chloride (8.49 g, 24. 0 mmol), and potassium tert(cid:173)
`
`butoxide (2.83 g, 24.0 mol) in N,N-dimethylformamide (50 mL) was stirred at room
`
`temperature for overnight. The reaction was quenched with 6 mol/L hydrochloric acid, and
`
`the mixture was extracted with ethyl acetate. The organic layer was washed with water (x 2)
`
`and brine, and dried on anhydrous sodium sulfate. The solvent was removed under reduced.
`
`To the residue were added tetrahydrofuran (60 mL) and 6 mol/L hydrochloric acid, and the
`
`mixture was heated at reflux for 8 h. Water was added, and the mixture was extracted with
`
`ether. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The
`
`solvent was removed under reduced pressure to afford 2-bromo-5-fluorophenylacetaldehyde
`
`(3 .60 g, 83%).
`
`[0043]
`
`To a solution of2-bromo-5-fluorophenylacetaldehyde (3.60 g, 16.6
`
`mmol) in methanol (40 mL) was added sodium borohydride (640 mg, 16.6 mmol) at 0 °C,
`
`and the mixture was stirred at room temperature for 1 h. Water was added, and the mixture
`
`12
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`was extracted with ethyl acetate. The organic layer was washed with brine and dried on
`
`anhydrous sodium sulfate. The solvent was removed under reduced pressure. To the residue
`
`were added dichloromethane (50 mL), diisopropylethylamine (3 .5 mL, 20 mmol) and
`
`chloromethyl methyl ether (1.5 mL, 20 mmol) at 0 °C, and the reaction mixture was stirred at
`
`room temperature fro overnight. Water was added, and the mixture was extracted with
`
`chloroform. The organic layer was washed with brine and dried on anhydrous sodium
`
`sulfate. The solvent was removed under reduced pressure. The residue was purified by silica
`
`gel column chromatography (15: !hexane/ethyl acetate) to give 2-bromo-5-fluorophenyl-O(cid:173)
`
`methoxymethylethanol (2.99 g, 2 steps 68%).
`1H-NMR (300.058 MHz, CDC'3) 8 ppm 3.04 (t, J= 6.7 Hz, 2H), 3.31
`
`[0044)
`
`(s, 3H), 3.77 (t, J= 6.7 Hz, 2H), 4.62 (s, 2H), 6.82 (td, J= 8.2, 3.2 Hz, lH), 7.04 (dd, J= 9.4,
`
`2.9 Hz, lH), 7.48 (dd, J= 8.8, 5.3 Hz, lH).
`
`[0045)
`
`The above compound was converted into the cyclic boronic ester by
`
`following the general procedure (A). Silica gel column chromatography (2: 1 hexane/ethyl
`
`acetate) followed by trituration with pentane gave the target compound as a white powder.
`1H-NMR (300.058 MHz, DMSO-d6) 8 ppm 2.86 (t, J = 5.9 Hz, 2H),
`4.04 (t, J= 5.9 Hz, 2H), 7.0-7.1(m,2H), 7.69 (dd, J= 8.2, 7.2 Hz, lH), 8.47 (s, lH).
`
`[0046)
`
`Example 7
`
`5,6-Difluoro-l-hydroxy-2, 1-benzoxaborolane
`
`Fms·
`
`OH
`IQ o
`
`F
`
`[0047)
`
`To a solution of 2-bromo-4,5-difluoro-O-methoxymethylbenzylalcohol
`
`(2.97 g; 11.1 mmol) and triisopropoxyborane (2.8 mL, 12 mmol) in tetrahydrofuran (30 mL)
`
`was added n-butyllithium (1 .6 mol/L in hexane; 7.5 mL, 12 mmol) over 30 min at- 78°C
`
`under nitrogen atmosphere, and the mixture was stirred for lh while allowing to warm to
`
`room temperature. The reaction was quenched with 2 mol/L hydrochloric acid, and the
`
`mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried
`
`13
`
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`

`
`on anhydrous sodium sulfate. The solvent was removed under reduced pressure. To a
`
`solution of the residue in tetrahydrofuran (25 mL) was added 6 mol/L hydrochloric acid (5
`
`mL), and the mixture was stirred at room temperature for overnight. Water was added and
`
`the mixture was extracted with ethyl acetate. The organic layer was washed with brine and
`
`dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure.
`
`Recrystallization from ethyl acetate/diisopropyl ether gave the target compound (1 .14 g,
`
`60%) as a white powder.
`1H-NMR (300.058 MHz, DMSO-d6) 8 ppm 4.94 (s, 2H), 7.50 (dd, J=
`10.7, 6.8 Hz, lH), 7.62 (dd, J= 9.7, 8.2 Hz, lH), 9.34 (s, lH).
`
`[0048)
`
`Example 8
`
`2-Bromo-4,5-difluoro-0-(methoxymethyl)benzylalcohol
`
`[0049)
`
`To a solution of 2-bromo-4,5-difuluorobenzoic acid (6.11 g, 25.0
`
`mmol) in tetrahydrofuran (40 mL) was added borane-tetrahydrofuran (1 mol/L solution in
`
`tetrahydrofuran; 50 mL, 50 mmol) at 0 °C, and the mixture was stirred at room temperature
`for overnight. The mixture was cooled to 0 °C, then water was added dropwise, and the
`
`mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried
`
`on anhydrous sodium sulfate. The solvent was removed under reduced pressure. To the
`
`residue were added dichloromethane ( 100 mL ), diisopropylethylamine ( 6.1 mL, 3 5 mmol)
`
`and chloromethyl methyl ether (2.3 mL, 30 mmol) at 0 °C, and the reaction mixture was
`
`stirred at room temperature for overnight. Water was added, and the mixture was extracted
`
`with chloroform. The organic layer was washed with brine and dried on anhydrous sodium
`
`sulfate. The solvent was removed under reduced pressure. The residue was purified by silica
`
`gel column chromatography (9: 1 hexane/ethyl acetate) to give 2-bromo-4,5-difluoro-O(cid:173)
`
`methoxymethylbenzylalcohol (5.69 g, 2 steps 85%).
`1H-NMR (300.058 MHz, CDC13) 8 ppm 3.42 (s, 3H), 4.57 (d, J= 1.2
`Hz, 2H), 4.76 (s, 2H), 7.3-7.5 (m, 2H).
`
`[0050)
`
`025.11326.1
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`14
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`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1064 - Page 19 of 43
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`

`
`Example 9
`
`5-Cyano-1-hydroxy-2, 1-benzoxaborola