UNITED STATES PATENT AND TRADEMARK 0mc1=.
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`IINITEIJSTATES DEPA.R'l'Mfll"l'OFCDIlIllllCE
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`AA|a|||:mMMISS|ONEIlFORPATD¢'1'!
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`223i!-I450
`IIInv.qio.|av
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`09:-mzooz '
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`DomlIl3.P.PinIn
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`PH-1398
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`mo
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`-«mm .
`we
`BRISTOL-_MYERS SQUIBB PHARMA COMPANY
`nuns. anucle
`PATENIT DEPARTMENT
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`1=.o.sox mo
`PRINCETON, NJ 08543-4000
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`'
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`8,
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`mu
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`DATE MAILED: l0f23I2lI)3
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`Please find below and/or attached an Office communication concerning this application or proceeding.
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`PTO-90C (Rev. INO3)
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`CFAD EX 1002
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`PG 001
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`CFAD EX 1002
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`Appllcati n n .
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`Exarnln r
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`Appllcanttsl
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`Artunlt
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`Ofiice'Action Summary
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`- The MAHJN6 DATE fthis communication appears n the cover sheet with the c rrespondenc address»-
`Period for Reply
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`A SHORTENED STATUTORY PERIOD FOR REPLY rs SET TO EXPIRE ,2 MONTH(S) FROM
`..‘.Fri.§.MAlLlt.!.£3..9ATE-.9E THIS Q9..MMiJN|.GAI'0N- .
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`3 Eite'rrdons"o1"time1ruy be’eveileble'undertheprevlsions'ef97 crn-1.13am in no event. ti:wever.1-nay-a npiyl5e‘itrneiylll'ed -W '
`otter six (8) MONTHS from the melting date otthis conrrnunlcetion.
`lfti-uperiodicrrepiynpecifiedahove ItiesattIanthirty'(3D)deye.ereplywili1ihestemoryntininrumotthirtytailldaylwlbeoonslderediirneiy.
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`ifNO period lorruply is specified above. the mardmum statutory period will apply and will expire six (G) MONTHS from the mailing-date oflhls communication.
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`- Fauetoreptywithin theeetorexiended period iorreplyvrillmyshtute. csusethe epp|lcetioniobeoomeABANDONED (35 u.s.c_§1sa}.
`- Anyreplylecehedbyllteoflhaeiatertirantireenuniitseiharlra nualtlrrgrhtaoflhisonrrnnmrinetim. even ifttmeiyfled. mayredueeeny
`eamerl petenttennedjuatment. see 31 cr=a1.ro4ret
`Statue
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` 1) Responsive to communication{s) flied on 16 $2003.
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`'Tfii§‘aTt-:tioniiis’iFiN‘At.
`"'"'2b)E'"l'his'ectiorris'norr-final:
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`3)I:] Since this application is in condition for allowance except for formal matters. prosecution as to the merits is
`closed in accordance with the practice under Ex parte Quayle, 1935 C.D. 11.453 0.6. 213.
`Disposition of claims
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`4) ciaim(s) fie islare pending in the pplicaiion.
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`4a) Of the above claims)E isiare withdrawn fron1 consideration.
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`4) El Interview Surnmary (PTO-413) Paper No(s).
`1) D Notice er nerereneee Oiled (PTO-B92)
`5) [:1 Notice of infomrai Patent Application (PTO-152)
`21 [3 Notice or Dlaitspereorfs Patent Drawing Renew (PTO—9Il8)
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`3) 8 Information Disdosure sraremenus) (PTO-1449) Paper No(s)g_.3,1,z.
`6) El Othec
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`us. were and Trederrerlr Olliu
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`BJEI clalrn(s) __ are subject to restriction andlor election requirement.
`Application Papers
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`9)I:! The specification is objected to by the Examiner.
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`10)D The drawlng(s) filed on_ islarez a)i'_'l accepted or b)I:I objected to by the Examiner.
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`Applicant may not request that ny objection to the drawing(s) be held in abeyanoe. See 37 CFR 1.B5(a).
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`11)I:I The proposed drawing correction filed on __ is: a)I:I approved tall] disapproved bythe Examiner.
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`if approved. corrected drawings are required In reply to this Office action.
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`12)Ei The oath or declaration is objected to by the Examiner.
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`Priority under 35 u.s.c. §§ 119 and 120
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`13)I:I Acknowledgment is made of a claim for foreign priority under 35 U.S.C. § 119(a)-(d) or (f).
`e)|:i All ell] some * c)|j None of:
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`I 1.[:I Certified copies of the priority documents have been received.
`2.I:I Certified copies of the priority documents have been received in Application No. __ .
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`3.[:] Copies of the certified copies of the priority documents have been received in this National Stage
`application from the international Bureau (PCT Rule 17.2(a)).
`* See the attached detailed Office action for a list of the certified copies not received.
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`14) Acknowledgment is made ofa claim for domestic priority under 35 U.S.C. § 119(e) (to a provisional application}.
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`a} I] The translation of the foreign language provisional application has been received.
`15)l___I‘Acknowiedgrnent is made of a claim for domestic priority under 35 U.S.C. §§ 120'andIor 121.
`Attacltmentls)
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`PTOL-326 (Rev. 04-01)
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`Ofiice Action summery
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`Pan or Paper No. 3
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`PG 002
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`5)C] CIaim(s): islare allowed.
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`5) Claims) E israre rejected.
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`7)]: Claims) __ islare objected to.
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`PG 002
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`Application/Control Number: ]0l245,122
`Art Unit: 1624
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`Page 2
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`Election/Restritaions
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`Applicant's election with traverse ofthe species ofExample 2 in Paper No. 6 is
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`acknowledged. The traversal is on the ground that no reasons have been provided to show that
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`there would be a serious burden if restriction were not required. This is not found persuasive
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`because the search and examination, in fact, places the office under undue burden. The rings
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`embraced at “P-M" are patentably distinct and are so diverse in scope that a serious
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`exists
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`to search the application as a whole. Therefore restriction to a specific core is required Each ring
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`"P-M” supports a different patent. For example, considering a tiny subset‘ ofrings embraced by
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`“P-M”, isoquinolinone is classified in 546/139; benzothiaiines in 544/11; quinazolines in
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`544/233; pyridobenzothiazepinones in 540/488;" 1,4-benaodiazepinonesiin 546604; etc. These
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`exemplary classifications indicate the serious burden office.
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`The search required is too burdensome for the ofliee: The‘compounds offonnula I
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`embrace varying sizes ofrings with multiple heteroatoms and further ring fusions that a
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`reasonable search ofthe entire genus could not be conducted without undue burden.
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`The compoturds embraced by claim 1 are drawn to structurally dissimilar compounds.
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`They are made and used independently. They are independent and patentably distinct.
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`If, say a naphthale as “P-M” were anticipated,.applieants would not acquiesce in the
`rejection of, say, aprnine thereover or vice-versa. They
`patentably distinct.
`The search required for any one ofthe rings at P-‘M’-’.is not for another.
`The elected species was not found and the search expanded according to MPEP
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`803.02 to embrace compounds of formula I wherein "P-M" together form the elected 1,4,5,6-
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`tetrahydro-7H-pyrazolo[3,4-cjpyridin-7-one ring; M4 represents —Z-A-B, wherein Z is a bond, A
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`PG 003
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`PG 003
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`Application/Conhol Number: 10/245,122
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`Art Unit: 1624
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`Page 3
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`is C3-Cm carbocycle and B represents N-piperidin-2-one (containing 0-2 double bonds) along
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`with the full scope ofP4. Claims 22-30 and subject matter not braced by the group indicated
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`as being examined from the remaining claims are withdrawn fromiconsideration as being drawn
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`to non-elected subject matter.
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`Note that compounds, corresponding compositions, a method ofuse and a process of
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`melting-t_l1_at
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`the painter smpe"ar_e considered to’forrn"i"s'in'gl_e'invtive’ "22?
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`30 are drawn to methods of treatment comprising additional therapeutic agents and articles of
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`manufacture. These claims are not so linked as to form a single inventive concept.
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`The requirement is still deemed proper and is
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`Improper Marlmsh
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`Claims 1-21 are rejected under a-judicially
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`lasbeing
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`to an
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`improper Markush group, that is, the claims lack unity of invention. The variables P and M are
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`defined in such a way that they keep changing the core o‘fthecon1po.und.that determines the
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`classification. By changing these values, several patentably distinct and independent compounds
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`are claimed. In orderto have unity ofinvention the compounds must have "a community of
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`chemical or physical characteristics" whichjustify their inclusion in a common group, and that
`such inclusion is not repugnant to principles ofscitific classification” Inre JONES (CCPA) 74
`USPQ 149 (see footnote 2). The structural formula (1) does
`have a significant structural
`feature that is shared by all ofits alternatives which is inventive. Compounds emhraced by
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`formula (I) are so diverse in nature that a prior art anticipating ‘a claim with respect to one
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`member under 35 USC 102 would not render obvious the same claim under 35 USC 103. This is
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`evidentiary ofpatentably distinct and independent inventions.
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`Application/Control Number: 10/245,122
`Art Unit: 1624
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`Page4
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`Limiting the claims to the subject matter indicated above as being searched and examined
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`would overcome this rejection.
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`Applicant is advised that -should claim 17 be found allowable, claims 20 and 21 will be
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`objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an
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`application are duplicates or else are so close in content that they both cover the same thing,
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`despite a slight difierence in wording, it is proper afier allowing one claim to object to the other
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`as being a substantial duplicate of the allowed claim. See MPEP § 706.03(k).
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`Any inquiry concerning this communication or earlier communications from the
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`examiner should be directed to Bruck Kifle, Ph.D. whose telephone number is 703-3 05-4484.
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`The examiner can normally be reached on 9:30-6:00.
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`If attempts to reach the examiner by telephone are unsuccessful, the exarru’ner’s
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`supervisor, Mulcund J. Shah can be reached on 703-308-4716. The fax phone number for the
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`organization where this application or proceeding is assigned is (703) 872-9306.
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`Any inquiry ofa general nature orrelating to the status of this application or proceeding
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`should be directed to the receptionist whose telephone number. is 703-308-1235.
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`M “
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`Brock Kifle, Ph.D.
`Primary Examiner
`Art Unit 1624
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`BK
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`October 21, 2003
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`my N0.: PH-7398
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`FILING av "expness MAIL"
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`UNDER 37 CFR 1.10
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`EV323S0020l US
`November 19, 2003
`Exptess Mail ixbei Number
`Dine ofneposit
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`PATENT
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`IN THE UNITED STA% PATENT AND TRADEMARK OFFICE
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`In re application of: D. Pinto et al.
`Examiner:
`Kifle, B.
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`Serial No.:
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`l0I245,l22
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`Gmup Art Unit:
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`1624
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`Filed:
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`September 17, 2002
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`Confirmation No. 6870
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`D
`LACTAM-CONTAINING COMPOUNDS AND DERIVATIVES THEREOF AS
`For:
`FACTOR XA INHIBITORS
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`_ RECENE
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`
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`Commissioner for Patents
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`Po. Box 1450
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`Alexandria, VA 22313-1450
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`EC“[;ENlE\"\15001290“
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`Dearsir:
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`AMENDMENT AND REQUEST FOR RECONSIDERATION
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`Responsive to the Offiee Action mailed October 23, 2003, Applicant respectfully
`requests reconsideration in view of the following amendments and remarks.
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`Amendments to the Claims are represented by the listing of claims which begins on page‘
`2 of this paper.
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`Remarks begin on page 93 of this paper.
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`DOCKET NO.: PH-7398
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`USSN: 10I245,l22
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`Amendment
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`‘
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`AMENDLIENT
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`Suhject matter to be added is in bold and underlined.
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`Subjectmatter to be deleted
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`bold and strikethrough.
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`In the Claims:
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`Please (a) cancel Claims 9-15 and 20-30; (h) enlaer rewritten Claims 1-8; and, (c) add new
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`Claims 31-121 as follows.
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`This listing of claims will replace all prior versions and listings of claims in the
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`application.
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`of Claims:
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`Claim 1. (Currently Amended) A compoundofFormula I:
`C NOV 2 s 23113
`I)-a’P2‘M{ ‘M4
`TECHCENTER1
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`P
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`l
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`M
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`IVED
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`60012900
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`P4
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`P4-P-M-M4
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`I
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`or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;
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`ring l\_rI_, including Pl, Pl, M and M is substituted with 0-2 R1“ and is O
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`.....—.—
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`DOCKET NO.: PH-7398
`USSN: 10/245,122
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`Amendment
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`PG 009
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`DOCKET N0.: Pl-I-7398
`USSN: 10I245,122
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`Amendment
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`ring -D, including the two atoms of Ring E to which it is attached, is a 5-6 mernbcred ring
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`consisting of: carbon atoms and 0-2 heteroatoms selected from the group consisting of
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`N, o, and s(o),,;.
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`ring D is substituted with 0-2 R and there are 0-3 ring double bonds;
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`"Bis se1EcTédi','pyridyl'.' 'pyrin1idyI;pyrazinyl:and py=ridazi1rryl-,—and-—is--substituted wi-th —
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`1-2 R;
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`alternatively, ring D is absent end ring B is selected from phenyl, pyridyl, pyrimidyl. pyrazinyl,
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`pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl. oxazolyl. triazolyl, thienyl, and
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`thiazolyl, and ring E is substituted with 1-2 R:‘
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`alternatively, ring D is absentand ring E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl,
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`pyridazinyl, pyrrolyl, pyrazolyl, imidazoly1,isoxaz.olyl, oxazolyl, triazolyl, thienyl, and
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`thiazolyl, and ring E is substituted with 1 R and with a 5-6 rnembered heterocycle
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`eonsisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of
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`N, 0, and S(0)p, wherein the 5-6 membered hcterocycle is substituted with 0-1 carbonyl
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`and 1-2 Rand there are 0-3 ring double bonds;
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`R is selected from H, C14 alkyl, F, Cl, Br,_ I, OH, OCH3. 0CH2CI-I3, OCH(CH3)2,
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`OCH2CH2CH3, CN, C(=NR3)NR7R9, NHc(=NR8)NR7R9, oNHc(=NR8)NR7R9,
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`NR8CH(=NR7), NH2. NH(C1—3 alkyl). N(Cl-3 a1kyl)2. C(=NH)NH2. CH2NH2..
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`CH2NH(C1-3 alkyl). .CH2N(C1-3 alk¥l)2. CH2CH2NH2. CH2CH2NH(C1.3 alkyl).
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`CH2CI-I2N(C1.3 alkyl)1, (cR3R9).c(o)H, (cR8R9).C(o)R2<=, (cR8R9).NR7R8,
`(CR8R9).c(o)NR7R8, (cR5R9),NR7c(o)R7, (CR3R9)pR3, (cR8R9).s(o),,_NR7R8,
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`(CR8R9).NR7s(o),,R7, (cR8R9).sR3, (CR8R9),s(o)R3, (cR8R9).s(o)2R3, and OCF3;
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`PG 010
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`DOCKET NO.: PH-7398
`USSN: 10/245,122
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`Amendment
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`~ alternatively, when 2 R groups are attached to adjaceht atoms, they combine to form
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`methylenedioxy or ethylenedioxy;
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`A is selected from:
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`(23.10 carbocycle substituted with 0-2 R4,-and
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`_x\(:5
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`; provided that Z and B are attached to diffelent atoms oil A and that the
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`B is
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`A-X-N moiety forms other than a N-N-N group;
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`Q1 is selected-from C—-O and-S93;
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`.~- - .-ring Q is a g 4-8 membered nionocyclic opbieyelie ring -.: u
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`—..
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`and-S69-)3, wherein:
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`0-2 double bonds are present within
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`ring and the ring is substituted with 0-2
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`PG 011
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`PG 011
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`DOCKET NO.: PH-7398
`USSN: 10I245,122 '
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`Amendment
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`G1 is absent or is selected from (CR3R3“)1_5,_ (CR3R3“)0_2CR3—-CR3(CR3R33)Q_2, (CR3R3a)_o_
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`2C-='C(CR3R3“)(>2- (CR3R3“}uCC0)(CR3R3“)w. (CR3R3“)uC(0)0(CR3R3”)w.
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`(CR3R3n).,oc_(o)(cR3R?§a).;,, (CR3R3a).,o(cR3R3a)..., (CR3R3a).,N3b(cR3R3a).,,,
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`(CR3R3“)uC(0)N3"(CR3R3“)w..(CR3R3a).,N3bc(o)(CR3R3a)...,
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`(CR3R33),,0C(O)N3b(CR3R3=)w, (cR3R3a).,N3bc(o)o(cR3R3a)..,
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`(CR3R3*')uN3"C(0)N3"(CR3R3")w. (CR3R3")uN3"C(S)N3"(CR3R3“)w,
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`(CR3Rf=*a).,s(cR3R3a)..., (cR3R3a).,s(0)(cR3R3a)..., (cR3R3a).,s(0)2(CR3R3a)w,
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`(cR3R3a)..s(o)N3b(cR3R3a).., (cR3R3a).,N3bs(o)2(cR3R3a)w,
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`PG 012
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`PG 012
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`DOCKET NO.: PH-7398
`USSN: 10/245,122
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`Amendment
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`'
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`(CR3R3*')_.,S(0)2N3b(CR3R31')..,., (CR3R3fl),,N3bS(0)2N3'J(CR3R33)w,
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`(CR3R3=)uNR3°(CR3R33)w, (c1z31_23a)..c(o)(cR3R3a)uC(o)(cR3R3a).,,,
`(CR3R3a)uNR3b(CR3R3=)uC(O)NR3b(CR3R3fl)w,
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`(CR3R3**)..NR3*’C(0)(CR3R3“)uC(0)(CR3R3*)w.
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`(CR3R3“)uC(0)(CR3R3“)uC(O)NR3"(CR3R3’)m
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`(CR3R3*)"NR3bC(0)(CR3R3a).,C(0)NR3"(CR3R33)w,
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`(CR3R33)..S(0)NR3bC(O)(CR3R35)w, (cR3R3a)..c(o)NR3bs(o)2(cR3R3a)w. and
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`(CR3R31)uS(0)2NR3bC(0)NR3bCR3R3")w, wherein u + w total 0, 1, 2. 3, or 4, [provided
`that G; does not form an
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`N—S, NCH3N, NCH20, or NCH2S bond with either group to which it is attached;
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`PG 013
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`PG 013
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`DOCKET NO.: PI-I-7398
`USSN: 10I245,122
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`Amendment
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`R12, at each occurrence, is selected from H, -(cR3R3a),-Rib, -(CR3R3‘),»-CR3R1'3R“’,
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`—(CR3R3‘),-0-(CR3R3F);-R15, -C24; alkenylene-R15, -C26 alkynylene-R15,
`_(cR3R3a)r_C(=NR1b)NR3R1h, N]£3CR3R3aR1c’ 0CR3R3aRlc_ sCR3R3aR1c'
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`NR3(CR3R3°)2(CR3R3“);R3b, C(0)NR2(CR3R3")2(CR3R3a)tR11’,
`CQ2(cR3R3a)2(C1.{3R3a)tR1b, 0(CR3R3a)2(cR3R3a)tR1b’ s(CR3R3a)2(cR3R3a)tR1b,
`s(o)p(cR3R3a)l_R1d, 0(CR3R3a)l_Rld’ NR3(CR3R3a)l_R1d' 0C(Q)NR3(CR3R3a)l_R1d’
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`NR3C(O)NR3(CR3R3°)rR1", NR3C(0)O(CR3R33),R1'd, and NR3C(0)(CR3R3a),R1d,.
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`provided that R1‘ fomis other than an N-halo, N-S, 0-0, or N-CN bond;
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`alternatively, when two R13 groups are attached to adjacent atoms, together with the atoms to
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`which they are attached they form a 5-7 membered ring consisting of: carbon atoms and
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`0—2 heteroatoms selected from the group consisting of N, 0, and S(O)p, this ring being
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`substituted with 0-2 R4” and 0-3 ring double bonds;
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`PG 014
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`PG 014
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`DOCKET NO.: PH-7398
`USSN: 10I245,122
`
`Amendment
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`- Rlb is selected from H, c1_3 alkyl, F, Cl, Br, 1, -09, -N02, -CHO, (CF-2),CF3, (cR3R3a),oR2.
`NR3R2fi, c(o)R2b, coznzb, oc(o)ia2, (cF2),co2n2a._s{o),,R2b, NR2{CI-Ig),0R3,
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`C(=NR2=)NR2R2a, NR2c(o)R2b, NR2C(o)NHR2, NR2c(o)2R2a, oc(o)NR2R2a,
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`c(o)NR2R2a, C(0)NR2(CH2),0R2, so2NR2R2a, NR2so2R2, C(O)NR2S02R2, (23.5
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`carbocycle substituted with 0-2 R4”, and 5-10 membered heterocycle consisting of carbon
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`atoms and from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p,
`and substituted with 0-2 R4”, provided that R15 forms other than an 0-0, N-halo, N-S, or
`N-CN bond;
`
`Ric is selected from H, CH(CH20R3)2, c(o)R2<=, c(o)Nn2R2a, s('o)R2. s(o);n2, and
`
`S02NR2R2a;
`
`R” is selected from 03.5 carbocycle substituted with 0~2 R45 and 5-10 membered heterocycle
`consisting of carbon atoms and from 1-4 heteroatoms selected from the group consisting
`of N, O, and S(O)p, and substituted with 0-2 R4”, provided that R15 forms other than an
`
`N-S bond;
`
`R2, at each occurrence, is selected from H, CF3, C145 alkyl, benzyl, -(CH2),~C3_1o carbocyclc
`
`substituted with 0-2 R4”, and ~(CHg),—5-10 rnembered heterocycle consisting of: carbon
`
`atoms and 1—4 heteroatoms selected from the group consisting of N, O, and S(O)p, and
`
`substituted with 0-2 R41’;
`
`R23, at each occurrence. is selected from H, CF3,
`
`C145 alkyl, benzyl, -(CH2).-C340 carbocycle substituted with 0-2 R4”, and -(CH2),—5-10
`
`membeted heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from
`
`the group consisting of N, O. and S(0)P, and substituted with 0-2 R4”;
`
`,3...
`
`PG 015
`
`PG 015
`
`

`
`DOCKET NO.: PH-7398
`
`USSN: 10I24S,122
`
`Amendment
`
`' alternatively, R2 and R33, together with the atom to which they are attached, combine to form a 5
`
`or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R4” \
`
`andggconsistinig
`and 8(0):’:
`
`__(_)—l_additi_onal_ lieteroatoms selected from the group consisting _of_ N, 0.
`.
`e
`r
`t
`be
`.
`.. .
`
`R2”, at each occurrence, is selected from CF3. C14 alkoxy substituted with 0-2 R4”, C14; alkyl
`
`substituted with 0-2 R4”, -'(CH1).«-C340 carbocycle substituted with 0-2 R4“, and -(CH2),-
`W [5110 membered hetemcsrcle consisting of: carbon atoms and 1-Qiihetenroahtortls sellectednH
`I
`
`from the group consisting oi’ N, 0, ‘and S(_0)p, and substituted with 0-2 R4”;
`
`R2“, at each occurrence, is selected from CF3, OH, C14 alkoxy, C145 alkyl, -(CH2),-C340
`
`carbocycle substituted with 0-2 R45, and -(CH2),-5—10 membered heterocycle containing
`from 1-4 heteroatoms selected from the group consisting of N, 0, and S(O)P, and
`L
`
`substituted with 0-2 R45;
`
`R3, at each occurrence, is selected from H, CH3, CH;;_CH3, CH2CH2CH3, CH(CH3)2,
`
`CHQCHZCHECH3, CH§CH(CH3)2, CH(CH3)CH2CH3, C(CI’13)3. benzyl, and phenyl;
`
`R3“. at each occurrence, is selected from _H, CH3, CHQCH3, CH2CH2CH3, CH(CH3)2,
`
`VCHQCHZCHQCH3,
`
`CH(CH3)CH2CH3, C(CH3)3, benzyl, and phenyl;
`
`alternatively, R3 "and R33, together with the nitrogen atom to which they are attached, combine to
`
`form a 5 or 6 rnembcrcd saturated, partially unsaturated, or unsaturated ring consisting of:
`
`carbon atoms, the nitrogen atom to which R3 and R33 are attached. and 0-1 additional
`
`heteroatoms selected from the group consisting of N, 0, and S(O)p;
`
`R3”, at each occurrence, is selected from H, C145 alkyl substituted with 0-2 R1“, C2.5- alkenyl
`
`substituted with 0-2 R“, C2.5 alkynyl substituted with 0-2 R1“,
`
`10
`
`PG 016
`
`PG 016
`
`

`
`DOCKET NO.: PH-7398
`U_SSN: 10/245,122
`
`Amendment
`
`-(C94 alkyl}-5-10 rnembered carbocycle substituted with 0-3 R1“. and -(C04 alkyl)- 5-10
`
`membered heterocycle substituted with 0-3 R1“ and consisting of: carbon atoms and 1-4
`
`heteroatoms selected from the group consisting of N, 0, and S(O)p;
`
`R3°, at each occurrence, is selected from CH3, CHQCH3, CH2CH2CH3, CH(CH3)2,
`
`CI-I2CH2CH2CH3, CH2CH(CH3)2, CH(CI-I3)CH2CH3, C(CH3)3, benzyl, and phenyl;
`
`R3“, at each occurrence, is selected from H, CH3, CH2CH3, CH2CH2CI-I3, CH(CH;,-)2,
`
`CH2CH2CHg_CH3, CH2CH(CH3)2, CH(CH3)-CH2CH3, C14 alkyl-phenyl, and C(=O)R3°;
`
`R3°, at each occurrence, is selected from I-I, SO2N"HR3, SO2NR3R3, C(0)R3, C(0)NHR3,
`
`c(o)oR3f, s(o)R3f, S(0)2R31_°, c1.5 alkyl substituted with 0-2 R1“, C;--5 alkenyl
`
`substituted with 0-2 R1“, C245 alkynyl substituted with Q-ZR“, -(Co..4 alkyl)-5-I0
`
`membered carbocycle substituted with 0-3 R1’. and -(C94 alkyl)-5-10 mernbered
`
`heterocycle substituted with 0-3 R13 and consisting of: carbon atoms and 1-4
`
`heteroatoms selected from the group consisting of N, 0, and S(O)p;
`
`R3f, at each occurrence. is selected from: C14; alkyl substituted with 0-2 R1“, C2.5 alkenyl
`
`substituted with 0-2111“, C2.5 alkynyl substituted with 0-2 R“,
`
`—(Co_.; alkyl)-5-10 membered carbocycle substituted with 0-3 R1“, and -(C04 alkyl)-5-10
`
`membered heterocycle substituted with 0-3 R1“ and consisting _of: carbon atoms and 1-4
`
`heteroatoms selected from the group consisting of N, O, and S(0)p;
`
`R4, at each occurrence, is" selected from H, =0, (CR3R53),0R2, F, Cl, Br, I, C14 alkyl,
`((£R3R3a)l,CN’(CR3R3a)1_NQ2, (CR3R3a}lNR2R2a_ (CR3R3a)rc(_Q)R2c_
`
`(CR3R33),-NR2C(O)R2b, (CR3R33),-C(O)NR2R23, (CR3R33).-NR2C(O)NR2R23,
`
`(CR3R3“),C(=NR2)NR3R23, (CR3R33),-C(=NS(O}2R5)NR2R2‘,
`
`11
`
`PG 017
`
`PG 017
`
`

`
`DOCKET NO.: ‘PH-7398
`USSN: 10f245,122
`
`Amendment
`
`(CR3R33),NHC(=NR2)NR2R23, (CR3R33),C(0)NHC(=NR2)NR3R2°.
`
`(CR3R3“).S02NR2R3", (cR3R3a),NR1'_so2NR2R?a, (cR3R3a),NR2so2-CM alkyl.
`
`-(CR3R3“)rNR2SQ2R5. (CR3R3“)r5(0)pR5‘l» .(QR3R3‘_');(CEg_):;CF3; 1‘lH§H2R‘°,
`
`0CH2R‘°. SCH2R‘°. NH(CH2)2(CH2)tR“’. 0(CH2)2(.CH2):R"’. S(CH2)2(CH2):R"’.
`
`(CR3R3fl).-5-6 membered cerbocycle substituted with 0-1 R5, and a (CR3R33).-5-6
`mcmbered heteroeyc-le consisting of: carbon atoms and 1-4 heteroatoms selected from
`
`the grgup 9_qz!si_stf-pa 9f H191 a_n§_§(9)p: aAdcs1!b§titutt:¢!oF1VitJ!_F_*_1_R_53
`
`R4“, at each occum-.nce,' is selected from H, =0, (cR3R3a),oR2, (cR3R3a),1=, (CR3R3*),-Br,
`
`(cR3R3a),C1, C1_4 alkyl, (CR3R33),-CN, (CR3R3“),-N02, (CR3R3a),NR2R2a,
`(CR3.R3a),c(o)R2c, (CR3R3a),NR2c(o)R2b, (CR3R3a),c(o)NR2R2a,
`
`(ct-13R3a),N=c:HoI-13, (cR3R3a),C(o)NH(cH2)2NR?-R?-a. (c:R3R3a),NR2c(o)NR2R2a,
`
`(cR3R3a),c(=NR2)NR2R2a., (cR3R3a),NHc(=NR2)NR2R2a, (CR3R35),S0gNR3R33,
`
`(CR3R39),NR2S02NR2R2-*1, (CR3R33),NR2SO2-C1.4 alkyl, (cR3R3a),c(o)NHso2—c1._4
`
`alkyl, (CR3R3')NR2SOjR5, (cR31_z3a),s(o),,R5a, (CR3R3“);(CF2)rCF3. (CR3R’-*8),-5-6
`membered carbocycle substituted with 0-1 R5, and a (CR3R3“),-5-6 membercd
`
`heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group
`
`consisting of N, O, and S(O)p—, and substituted with 0-1 R5;
`
`R4”. at each occurrence, is selected from H, =0, (CH2).0R3, (CH2),F', (CH2).-C1, (CI-Ig),Br,
`
`(CH2)1-I. C14 alkyl. (CH2)rCN. (CH2)rN02. (CH2)rNR3R3‘. (CH2)rC(0)R3.
`
`(cH2),c(o)oR3<=, (CI-I_2),NR3C(0)R33, (CH2),-C(0)NR3R3°, (cH;._),NR3C(o)NR3R3a,
`
`(CH2),-C(=NR3)NR3R33, (CH2)..NR3C(=NR3)NR3R3a, (CH2),-S0zNR3R3a,
`
`(CH2),NR3SO2NR3R3a. (CH2),-NR3S02—C1-.4 alkyl, (CI.-I2),NR3SO2CF3,
`
`(CH2):NR3S02-Phenyl. (CH2_):S(0)pCF3. (CH2)rS(0)p-Ci.4 a1ky1.(CH2)rS(0)p-phenyl.
`
`- and (CH2)r(CF2)rCF3;
`
`PG 018
`
`PG 018
`
`

`
`DOCKET NO.: PH-7398
`USSN: 10l245,122
`
`Amendment
`
`' R46, at each occurrence, is selected from H, C14 alkyl (cR3R3a),;oR2, (CR3R38),1F,
`
`(CR3R39),1Br, (CR3R33),1CI, (CR3R3"),;CN, (CR3R3a),1No2, (CR3R3a),1NR3R?a,
`(cR3R3a),c(o)R2<=, tcR3R3a),,NRic(o)R2b, (cR3R3a),c(o)NR2R2a,
`.
`
`(CR3R3a),1N=CH0R3, (cR3R3a),c(0)NH(cH2)2NR2R2a, (cR3R3a),1NR2c(o)NR2R2a,
`
`(CR3R3a)r]C(=NR2)NR2R2a_ (CR3R3a)rlNHc(='NR2)NR2R2a_ (CR3R3a)rso2NR2R2a_
`
`(cR3R3a),1NR2so2NR2R2a, (CR3R3fl),1NR2SO2-C1_4 alkyl,
`
`(CR3R3fl),C(O)NHS02-C1.4 aikyl, (CR3R3a),1NR2so2R5, (cR3R3a),s(0),,R5a,
`
`(cR3R3a),(cF2),c1=3, (cR3R3a),-5-6 membered carbocycle substituted with 0-1 R5, and 3
`
`(CR3R33),-5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms
`
`selected from the‘ group consisting of N, 0, and S(O)p, and substituted with 0-1 R5;
`
`R5, at each occurrence,'is selected from H, C145 alkyl, =0, (CH;:_),0R3, F, Cl, B131,‘ LCN, N02,
`
`(CH2)rNR3R3“- (CH2)rC(0)R3. (CH2):-C(0)0R3". (CH2)rNR3C(0)R3“.
`
`(CH2),-C(O)NR3R3", (CH2),-NR3C(0)NR3R33, (CH2)rCH(=N0R3d).
`
`(CH2),-C(=NR3)NR3R33, (CH2),-NR3C(=NR3)NR3R3“, (CH1)rSO2NR3R3“,
`
`(CH2)rNR3302NR3R3“» (CH2)rNR3S02‘C1-4 811<YL (CH2)rNR3S02CF3.
`
`(CH2),-NR3S02—pl1enyl, (CH2),-S(0)PCF3. (CH2),-S(0)p-C14 alkyl,
`
`(CH2),S(O)P—phcnyl, (CF2),CF3, phenyl substituted with 0-2 R5, naphthyl substituted
`
`with 0-2 R5, and benzyl substituted with 0-2 R5;
`
`R5“, at each occurrence, is selected from C[-5 alkyl, (CI-I2),OR3, (CH2),-NR3R33. (CH2),C(0)R3,
`
`(CH2),-C(O)OR3°, (CH2),-NR3C(0)R3“, (CH2),-C(0)N'R3R3‘, (CF2),-CF3, phenyl
`
`substituted with 0-2 R5, naphthyl substituted with 0-2' R5, and benzyl substituted with 0-2
`R6, provided that R53 does not form a S-N or s(o),,—c(o) bond;
`
`PG 019
`
`PG 019
`
`

`
`DOCKET NO.: PH-7398
`
`USSN: 10I24S_,l22
`
`Amendment
`
`_
`
`' R5, at each occurrence, is selected from H, OH, (CH2),0R3, halo. C1.4 alkyl, CN, N02,
`
`(CH2)rNR2R2"‘- (CH2}rC(0)R2". NR2C(0)1’$2b. NR2C(0)NR3R2“. C(=NH)NH2.'
`NI-IC(=NH)NHg, so2NR2R2a, NR2so2NR2R_2a, and NR’-‘!so2c1.4 alkyl;
`
`R7, at each occunence, is selected from H, OH, C1.5 alkyl, (31-5 alkyl-C(0)-, C145 alkyl-0-,
`
`(CH2)n-Phenyl. C14 alkvl-0C(0)-. C5-1o aryl-0-. C6-10 aryl-0C(0)-. Cs-10 a1'Jr1-CH2-
`
`C(0)-. C1-4 alkyl-C(0)0-C1.-4 alkyl-0C(0)-. C6-10 SW1-C(0)0-C14 3]1<Y1'0C(0)-.
`
`” "”’”"<:H, a1ky1;NH2-c('ojZ,‘'phei§'i4NH,-C(Q)i; aid '1511¢a3r1‘:C1‘;;‘ 9]l'<§r1'—‘C'(0)'-";
`
`'-
`
`R3. at each occurrence, is selected from H, .C1_5 alkyl, and (CH2),,-phenyl;
`
`alternatively, R7 an_.d R3, when attached to the same nitrogen, combine to form a 5-10 memtgered
`heterocyclic ring consisting of carbon atoms and 0-2 addiiional heteroatoms selected
`
`from the group consisting of N, 0, and S(0)P;
`
`R9, at each occurrence, is selected from H, C15 alkyl, and (CHg).,-phenyl;
`
`n, at each occurrence, is selected from 0, 1, 2, and 3;
`
`p, at each occurrence, is selected from 0, 1, and 2;
`
`r, at each occurrence, is selected from 0, 1, 2, 3, 4, 5, and 6;
`
`r1, at each occurrence, is selected from 1, 2, 3, 4, 5, and 6;
`
`t, at each occunence, is selected from 0, 1, 2, and 31-and;
`
`provided-that-whens
`
`14
`
`PG 020
`
`PG 020
`
`

`
`DOCKET NO.: PH-7398
`USSN: 10/245,122
`
`Amendment
`
`
`
`Formula-II:
`
`PG 021
`
`PG 021
`
`

`
`DOCKET NO.: PHJI398
`
`USSN: 10i'245,122
`
`Amendment
`
`m#4mm a
`
`G is a group of Formula Ila or ]Ib:
`
`’ -
`
`Ha
`
`£6)
`
`Hb
`
`ring D, including the two atoms of Ring E to which it is attached-, is a 5-6 membered ring
`
`consisting of: carbon atoms and 0-2 heteroatoms selected from the group consisting of
`
`N, 0, and s(o),,;
`
`ring D is substituted with 0-2 R and there are 0—3 ring double bonds;
`
`E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, and is substituted with
`
`1-2 R;
`
`alternatively, ring D is absent, and ring E is selected from phenyl, pyridyl, pyrimidyl, and
`
`thienyl. and ring E is substituted with 1-2 R;
`
`alternatively. ring D is absent, ring E is selected from phenyl, pyridyl, and thienyl, and ring E is
`substituted with 1 R and substituted with a 5 membened heterocjicle consisting of: carbon
`
`atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(0)p,
`wherein the 5 membered heterocycle is substituted with 0-1 carbonyl and 1-2 R and there
`
`are 0-3 ring double bonds;
`
`PG 022
`
`PG 022
`
`

`
`DOCKET NO.: PH-7398
`USSN: 10I'245,122
`
`Amendment
`
`- R is selected from H, C, 4 alkyl, F, C], OH, OCI-I3, OCI-12C!-I3, OCH(CI-13);, CN, C(=NH)NH2,
`
`C(=NI-DNHOH, C(=NI-I)NH0CI-I3, NH2. NH(C;.3 alkyl), N(C1.3 alkyl)g, C(=NI~I)NH2,
`
`CHQNI-I2, CH2NH(C1_3 alkyl), CH2N(C1.3 a1kyl)2, (CR3R9)tNR7R3, c(o)NR7R8,
`
`CH2C(O)NR7R3, S(O)pNR7R3, CH2S(O)pNR7R3, so2R3. and OCF3;
`
`alternatively, when 2 R groups are attached to adjacent atoms. they combine to form
`
`methylenedioxy or cthylenedioxy;
`
`A is selected from:
`
`C540 carbocycle substituted with 0-2 R4;-and
`
`PG 023
`
`PG 023
`
`

`
`DOCKET NO.: PH-7398
`
`USSN: 10l245,122
`
`Amendment
`
`R1‘ is selected from H, -(CH2),-Rn’, -(CI-I(CH3)),-R15, -(C(CH3-)2),-Rn’, NI-ICH2R1°, OCH2R1°.
`
`SCI-I_-;_R1°, NH(CHg)2(CI-Ig)¢R“’,land O(CH2)g(CH2)¢R“’, provided that R13 forms other
`
`‘than an N—hal_o. N—S, or N—CN bond;
`
`alternatively, when two R13 groups are attached to adjacent atoms. together with the atoms to
`
`which they are attached they form a 5-7 membered ring consisting of: carbon atoms and
`
`PG 024
`
`PG 024
`
`

`
`DOCKET NO.: PH-7398
`USSN: 10I245,122
`
`Amendment
`
`‘ 0-2 heteroatoms selected from the group consisting of N, O, and S(0)p, this ring being
`
`substituted with 0-2 R41’ and 0-3 ting double bonds;
`
`Rib is selected from H, CH3, CI-IZCI-I3, CH2CI-IZCH3, CH(CI-13);, F, (:1, Br, 1, -CN, 4:Ho', CF3,
`
`0R2, NR2R2a, c(o)R2b, C02R3'3, oc(o)R2, co2R2=, s(o),,R2, NR3(CH2),-0R2,
`
`NR2c(o)R2b, NR2c(o)NHR2, NR2c(o)2R2a, oC(o)NR2R2a, c(o)NR2R_2a,.
`
`c(o)NR2(c'H2),oR2, S02NR2R33, NR2so2R2,
`
`C545 carbocycle substituted with 0-2 R4”, and
`
`5-6 membered heterocycle consisting of carbon atoms and from 1-4 heteroatoms selected
`
`from the group consisting of N, O, and S(O)p, and substituted with 0-2 R4”, provided that
`
`R15 forms other than an 0-0,
`
`N-halo, N-S, or N-CN bond;
`
`R1° is selected from H, CH(CH20R3)2, c(o)R2<=, c(o)NR2R2a. s(o)s2, S(0)2R2, and
`
`S02NR2R23;
`
`'
`
`R2, at each occurrence, is selected from H, CF3, CH3, CHZCH3. CHZCHZCH3, CI-I(CH3)2,
`
`CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2_CH3, C(CI-I3)3, benzyl, C545 carbocycle
`
`substituted vyith 0-2 R4”, a C54 carbocyclic-CH2—group substituted with 0-2 R45, and 5-6
`
`. membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from
`
`the group consisting of N, O, and S(0)p, and substituted with 0-2 R4”;
`
`R2“, at each occurrence, is selected from H, CF3, CH3, CHZCH3, CH2CH2CH3, CH(CH3)3,
`
`CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, C(CI‘I3)3, benzyl, C5..6 carbocycle
`
`substituted with 0-2 R41’, and 5-6 membered heterocycle consisting of: carbon atoms and
`
`1-4 heteroatoms selected from the group consisting of N, 0, and S‘(0)p, and substituted
`with 0-2 R4”;
`
`PG 025
`
`PG 025
`
`

`
`DOCKET NO.: PH-7398
`USSN: 10I245,122
`
`Amendment
`
`alternatively, R2 and R33, together with the atom to which they are attached, combine to form a 5
`or 6
`samrated, partially saturated or unsatilratcd ring substituted with 0-2 R4”
`and consisting of: 0-1 additional heteroatoms selected from the group consisting of N. 0,
`
`and S(0)p;-
`
`R3”, at each occurrence, is selected from CF3, C14 alkoxy, CH3, CH2CH3, CH2CH2CH-3,
`
`CI-I(CH3)2, CH2CH2CH2CI-I3, CH2CH(CH3)2, CH(CH3}CH2CH3, C(CH3)3, benzyl,
`
`C545 carbocycle substituted with 0-2 R4”, and 5-6 membered heterocycle consisting of:
`
`carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 0, and S(0)p,
`
`and substituted with 0-2 R45;
`
`R3“, at each occurrence, is selected from CF3, OH, C1.4 alkoxy, CH3, CHZCH3, CH2CH2CI-I3,
`
`CH(CH3)2, CH2CH2CH2CH3, CI-I2CH(CH3)2, CH(CI-I3)CH2C‘.H3, C(CH3)3, benzyl,
`
`.‘C5.5 carbocycle substituted with 0-2 R4”, and 5-6 membered heterocyclc containing from
`
`1-4 heteroatoms selected from the group consisting of N, O, and S(0)p, and substituted
`
`with 0-2 R45;
`
`R3, at each occurrence, is selected from H, CH3, CI-I2CH3, CH2CH2CH3, CH(CH3)2, benzyl,
`
`and phenyl;
`
`R3“, at each occurrence, is selected from H, CH3, CHZCH3. CH2CH2CH3, CH(CI-13);, benzyl,
`
`and phenyl;
`
`alternatively, R3 and R33, together with the nitrogen atom to which they are attached, combine to
`form a 5 or 6 membered saturated,Vpartially unsaturated, or unsaturated ring consisting of:
`carbon atoms and the nitrogen atom to which R3 and R33 are attached;
`
`20
`
`PG 026
`
`PG 026
`
`

`
`Ii(.lCKET N0.: PH-7398
`USSN: 10!245,l22
`
`Amendment
`
`' R3°, at each occurrence, is selected from CH3, Cl-I2CH3, CHQCI-I2CH3,_ Cl-I(CH3)2, benzyl, and
`
`phcnyl;
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`R3“, at each occurrence, is selected from H, CH3. CI-I2CH3, CH2CH2CH3, CI-I(CH3)2, CH2-
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`phenyl, CHQCH2-phenyl, and C(=O)R3°;
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`R4, at each occurrence, is selected from H, =0, OR2, CI-I2OR2, (CH2)2OR2, F, Cl, Br, I, C14
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`alkyl, -CN, N02, NRZR7-*1, CH2NR2R2", (CH2)2NR2R2“, C(O)R2°, NR2C(O)R3b,
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`,
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`C(0)NR?R3*, SOzNR7-‘R23, S(0)pR5“, CF3, CF2CF3,
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`5-6 membered carbocycle substituted with 0-1 R5, and a 5-6 Inernbered heterocycle
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`consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of
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`N, O, and 8(0),, and substituted with 0-1 R5;
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`R43, at each occurrence, is selected from H, =0, CH2OR2, OR2, CHQF, F, CHzBr, Br, CH2Cl,
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`Cl, C1.4 allcyl, CH2-CN, -CN, CH2NO2, N02, CH2NR3R2“, NRZR23, CH2—C(0)R3°,
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`C(O)R3°, NR2C(0)R3b, (CH2),C(0)NR2R2“, NR2C(O)NR3R3‘*. (CH2),SOgNR2R3°,
`NR3S02NR2R3a, NRZSO2-C1.4 alkyl, N_R2S02R5, .(CH2l,-S(0)plt5a, CI-IgCF3, CF3, CH2-
`5-6 membered carbocycle substituted with 0-1 R5, 5-6 membered carbocycle substituted
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`with 0-1 R5, and
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`a CH2-5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms
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`selected from the group consisting o