(12) United States Patent
`Atwal et al.
`
`(10) Patent N0.:
`
`(45) Date of Patent:
`
`US 6,916,813 B2
`Jul. 12, 2005
`
`USU069l 6813132
`
`(54)
`
`(75)
`
`(1-PHENYI.-2-HETE()ARY[.) F.'['HY[i-
`GUANIDINE COMPOUNDS AS INHIBITORS
`or MITOCHONDRLAL F1F0 ATP
`HYDROLASF
`L
`‘
`
`Inventors: Karnail S. Atwal, Pennington, NJ
`(US); Gary J. Grover, Stockton, NJ
`(US); Charles Z. Ding, Dallas, TX
`(US); Philip D_ Stein! Pennington! NJ
`(US); John Lloyd, Yardley, PA (US);
`Saleem Ahmad, Wall, NJ (US);
`Law,-nu. G_ Hamann, Chcfly Hill’ NJ
`(US); [)1];-id Green’ [1awr[-.11], MA
`(US); Francis N. Ferrara, Bedminster,
`NJ (US)
`
`(73) AWSHCCI B1'i5t01'M}'91"5 Silllihh C0-4 Prim-"€10".
`NJ (US)
`Subiect to any disclaimer the term ofthis
`pawm i5’_“xl““d“d m adjusted under 35
`
`[ * ) Notice:
`
`(21) APPL N“? 1013155818
`(22)
`l-‘iled:
`l)ec. 10,2002
`
`(65)
`
`Prior Publication Data
`
`FOREIGN PATENT DOCUMENTS
`.
`
`W0
`W0
`
`'
`W0 00135449
`W0 UU1‘-43415
`
`-
`612000
`—.-"1‘2UUU
`
`0'l‘Hl:LR l’UBLICAl”IONS
`_
`7
`‘
`_
`_
`_
`‘
`,
`llawley s (:(0l'l(.lt:1'lS6&L; (.h::m1:al [)1ct1onar31, 12th ed., Rich-
`ard
`liewis, Sr.
`,
`1913
`)1 Van Nostrand Reinhold, p.
`5‘94'
`_
`_
`_
`‘
`‘
`_
`_
`(_onc1se Lincyclopedia Chemistry, edited by Drs.
`lIans—l)1-
`cter Jakubkc and Ilans Jeschkeit, © 1993 by Walter de
`GWYICT 3‘ C0 P 490*
`McGraw—Hill Dictionary of Chemical Terms, 3rd ed. edited
`by Sybil P. Parker, (0 1984 McGraw—Hill, Ine., p. 200.*
`Al—Dabbagh and Smith, "Species differences in oxidative
`drug metabolism: some basic considerations.“ Archives of
`2-” Toxlkologlci Supple-
`Ilans Iiundgaard, Design ol‘l-’rod1‘ugs, p. l.© 1985 Elsevier
`Scicnce
`Richard B. Silverman, The Organic Chemistry of Drug
`Design and Drug Action, pp. 352-400. © 1992 Academic
`P‘°"*“- 1"”
`Shimada et 1111., Chem. Pharm. Bull. vol. 32, No. 12, pp.
`4893_490(j (]984)_
`
`US 200410030033 Al 1-‘ch. 26, 2004
`
`1.1 cited by examiner
`
`(60)
`
`Related U-S- Applicatifln Dam
`Provisional application No. 60,-"339,t(IS_. filed on Dec. 10,
`mm‘
`A01N 43150; A61K 311415
`lnt. CL?
`(51)
`51412353; 5l41’254.[ll;
`(52) U.S. CI.
`5141314: 5141357; 514.-""351; 5141374; 5145383;
`5'l4;"394; 51411397; 5141390; 5441113‘); 5445370;
`5461164; 546,-"'275.1; 5481127; 5485204;
`54812628; 54813()9.'1'; 54s_.-314.7; 5481315.];
`54813154; 5481’336.5
`(58) Field of Search
`5141235.s, 254.01,
`5141314, 357, 361, 374, 383, 394, 397,
`399; 5441139, 370; 5461164, 275.1; 5481127,
`204, 262.8, 309.7, 314.7, 315.1, 315.4,
`336.5
`
`(56)
`
`References Cited
`
`U,S, PATENT DOCUMENTS
`.
`anscn e a.
`_.
`_.
`5 43:8 845 A
`lzflqgs H
`I
`I
`5,482,948 A
`M1995 S0)“ el al_
`5_.521_.lT" A
`511996 Rics Ct at.
`6,162,790 A
`1212000 Bemis e1 al.
`
`
`
`.
`.
`.
`__‘14”2¥
`SHBI8
`51-11'37(l
`514118
`
`James 0. Wilson
`Priiimry Exaiiiiner
`A551‘;-1am: Exgm;m3_y_Zachary C, Tuckcr
`(74) Attorney, /igem‘, or FrTmi—Laurelee A. Duncan
`
`ABSTRACT
`(57)
`Compounds having the formula (1), and pharmaceutically
`acceptable salts, Ihcrcofj
`
`(1)
`
`7
`
`|
`
`\
`\/
`I
`
`(R411,
`
`R2-R /R3
`N
`)\
`E \ .x-
`Eli
`
`1"
`
`are useful for modulating mitochondrial I-‘,1-‘U [K11-’ase activ-
`-
`-
`,
`,
`v
`-
`,
`v
`,
`-
`ity and treating ischernic conditions including myocardial
`infarction, congestive heart failure, and Lc't1'(l1aL arrhythmias.
`
`25 Claims, N0 Drawings
`
`I of 65
`
`PENN EX. 2233
`
`CFAD V. UPENN
`IPR20l5-01836
`
`

`
`US 6,916,813 B2
`
`RELATED APPLICATIONS
`
`1
`['1-PHENYI.-2-HETEOARYL)ETHYI.-
`GUANIDINE COMPOUNDS AS INHIBITORS
`OF MITOCHONDRIAI. FIFO ATP
`HYDROLASE
`
`2
`thesis needs to be closely matched to its rate of consumption.
`Arguably, the most important ATPase is the mitochondrial
`litI"ii-A'I'Pase. Unlike other A'I'Pases which function typi-
`cally to hydrolyze ATP and release energy, the F ,Ft,—ATPase
`5 has both hydrolytic and synthetic states. As "ATP synthase",
`the mitochondrial liil-‘O-/\'l‘Pase catalyzes the production of
`AFP via oxidative phosphorylation of ADP and P,-. Thus,
`[51II‘0—/\'I'Pa_\;{; is responsible for producing [[13 ccllis main
`EippllC2ill0l'] claims ll']6 llflfltlill. Of U.S. Provisional
`energy source, /\'l'P. In normoxic conditions, mitochondrial
`/\PpliCii1i0l'l N0. 6Uti339,1U8 fiitli-i DCC iii, Ziiiiii
`in FiF0—ATPase modulates this ATP production via its two
`‘
`t
`t
`_
`,_
`units, the F1 and F0 complexes. F0 is the inner membrane
`i"ii5-LD Oi" ii’ii3 ii‘iVi3'NiiON
`domalii’ and F} '5 a Caiaiimii dC_)ma,m Consisting Fit
`i-We
`This invention relates to compounds that inhibit nitochon-
`Subunits (,(0i'i57i-bE—ihc caiiilyilc Sm: 15,011 the ii’ limo’ “lat
`drial
`l-‘il-ii, NIP hydrolase and are useful
`for
`treating
`proirudc tr°_m ihc 1:0 domain ‘m0 the miiochondnai mainx‘
`isehemia—related diseases. The invention further pertains to
`methods of treating conditions associated with depleted ‘I5 when Suflicicm icvcis of °’SY=‘%°ii are prcscmi electrons “Om
`levels ol‘ adenosine triphosphate (/(l'P) due to hydrolysis by
`Arpasc Subsiraics iirc iransftcrmd icf Oxygen} and protons ‘mi
`mitochondrial t;~1t;~DATt3aSc_
`transported out 01 the mitheondrial matrix. This proton.-'
`electron transport creates an electrochemical proton gradient
`across the mitochondrial membrane and through the ['0
`lgA(jlqil{[)Ul\]l) ()l.‘ 'l‘lll_.' ll\]Vl_:N'l‘l()N
`1“ domain which drives the Ft domain to synthesize ATP.
`_
`_
`l
`_
`In tschcmtc conditions however
`thts ctcctrochcmtcat
`Ischemic heart disease is a common and serious health
`gradient collapses, and l-itI-it,-/(l‘Pase,switches to its hydro-
`i_)r0b1cn,]' Every ,Y°‘“v large ,numbcrS,Of Paiicnis dic from
`lytic state. This hydrolvsis of ATP seems to serve no useful
`'SCh°r_mC heart disease and, “5_C‘,’mi)l',cai'°"S' Maiiy others
`purposfl Also’ as t;ll_7O_Arltt:aSc operates in its hwtrotytic
`experience acute myocardial intarcation, congestive heart
`35 state there is a down-regulation of liil-‘O-/UP synthase.
`rifliurc’ Cariiiaii iflrl-iyli-imlatst or ("her d1Smdc”i‘_'
`_
`l:ll.‘0_/\'l‘l1 Syi-ttl-last; activities in vesicles from iscltemic
`Myocardial ischemia exists when the heart tissue experi-
`muscle typically are substantially [up to —-50-80%] less than
`“"935 ii diiniaiid ii” iliiligiiii and -‘iiiii-‘iiiiiiti-‘i ii'”ii iixt-'i'i‘5i-i
`ii'ii'3
`those olicontrol muscle./\native peptide called Ilii inhibitor
`-‘iiiPlii)"-
`imbaianws iwiwiicn ilxygflii
`-‘iiiPPi)’ and dcmand
`protein (or IF.) may be bound to the Ft unit under ischemic
`SP3-D 3 ii’-i!§‘= ranges and iii‘-‘Se iiieie iii“ V3i'i0ii5 SYi'i(ii'9iTi¢5
`and bioehemieal pathways involved in the pathogenesis of 30 Conditions to inhibit
`the ATP hydrolase activity of the
`iiiciiciiiiau 98-: from i9W‘8i"'iCiC ii‘ 59V'9i'C i5CiiCii1iC C0Ii(ii-
`enzyme; however, IFi is highly pH dependent and in severe
`ii0ii5v F01’ °XaiiiPi°= ‘3i'ii'0iii‘3 5i"ibi° iiiigiiia P°°i0ii5 i5 3
`conditions can provide only a modicum of control. The
`low—grade condition, in which the resting coronary blood
`cgnvcfglgn Qf F11:0_ATp synthasc to 1:‘1F0-ATp hy(]rQla3c is
`ii00d may bi‘ ii0i'mt'ii iliii iii‘? i‘i00Ci ii0W F"~‘S°t'V° i5 iI13"fl5-
`reversible, as addition of substrate and oxygen to the mito-
`eient to meet an increased energy demand. In more extreme 3,, chondria of ischcmic muscle can reactivate the F tFt,—ATPase
`situations, the ischemic muscle can develop an impaired
`and Alp levels to control levels-
`contractile iunction and potential to generate aiThythmias.
`AS may bi, aiipieciatgdt iii ischgmic conditions the activity
`Mali” C0i'iii‘3ili-Wiice-‘i Oi m)’0‘-Viidiiii
`i-‘ii-'i""""ia
`i"i5i“d"
`of I"ilic,-/\'l'Pa.se produces a futile cycling and waste of /\'[‘l’.
`mechanicai and ciiiciiicai ‘-i)‘-‘3iiili"‘-'ii'1iiia iiiii-5‘-'i¢ CC“ damage:
`It is believed that this depletion of All’ andfor ATP synthase
`and development of necrosis. Acute ischeiiiic events may 4“ may Stiiiiircss the Na_t_K_t_
`iiiimii
`to increase Cardiac
`d’3"'i3i9l7 “’i'i’3i'° ii'i’3i'° is Coronary 5iiiii3i05Ci9i'9i‘ii5‘ Uiiimaiciys
`contractility, vasoconstriction, sensitivity to vasoactive
`ii iii“ i5‘3ii°-iiiiii i5 Siiiiiciciiiiy 5i3""«'i'° iii°i¢ Wiii b9 an iiiiiii°'
`agents, and arterial blood pressure. Several inhibitors of
`diate reduction (or cessation] of contractile function in the
`l::1l:0_ATpaSc have been described’ including cfmpcptint
`ii°ai'i'
`oligomycin, autovertin B, and azide. Oligomycin targets Ft,
`The impairment of contractile function in ischemic 45 and reportedly postpones cell injury by preserving ATP
`muscle is associated with mitochondrial levels of adenosine
`during ischemia. However,
`the only known inhibitors of
`triphosphate (ATP) and adenosine tripliosphatases
`liiI",_,-A'I‘Pase are large proteins or peptides which are not
`[ATPases). ATPases are enzymes that typically catalyre the
`orally bioavailable.
`ii3'iii'0iY5i5 Of ATP:
`iii‘? miiiii 5i15i8Y ‘3Ui'i'°ii‘3Y iii C°ii5a i0
`The instant
`invention provides N—substituted—N'—(l—
`3d°ii05iii° ii'i0ii0I7ii05Pii5ii'-3 (AMP) OT ad‘-'5ii95iiiC diPh0-"‘»]3ii3i° Sn phenyl-2-heteraryl)ethyl-guanidine compounds including
`lADP)- Pi‘-is Piiospiiiiic i°ii5 and °ii°i'gY- Tiic C0iiii'3Ciii°
`cyanoguanidine and benzoylguanidine compounds that are
`function of the heart is regulated by the transport of calcium,
`pot;-,m and sclcctivc lnhlbltgl-5 Qf ]:‘11:‘D_A”_[‘p hydt-01;t5¢_ Tl-19
`Sodiuiiis i'i'i(i Poiassii-‘iii i0ii5s which iii iiiiii i5 iii0(iUi3i'3(i i3Y
`compounds of the present invention are useful in treating or
`ATP and Aiiii']ii5'-"39 M9”: l7iiiii‘5iliiiii3's iiiiTi1C'5ii'-iii” ATP i-5
`preventing conditions associated with iscliemia, particularly
`-‘5l3iii by N“-K+AiiPa"5°= “ii enzyme iiiiii i5 W5-PUi'i5ibi‘3 [OT 55 myocardial
`ischemia and associated conditions, such as
`iiiiiiniainiiig 3 giiiiiiciii iii 50diii'T' and Piliasiiiiim iii"-‘i FETUS‘-‘5
`muscle cell damage, necrosis, and cardiac arrhythmias. Also,
`iii‘: “iii i'i'iei'i'ii"iaiic- iiiiw -‘iliiiiiiiig iii ATP by N3+aK+/\'i‘P3-‘*3
`in view of their inhibitory activity, the inventive compounds
`Teiiiii-“*3-*5 iii‘? CWTB)’ iifiiiiifiii
`ii‘
`iiiiii-‘ipiiii Ki‘ and N34 iii"-5
`may be used to treat cancer and tumor growth. Cyano-
`against CUl'lCCl'll.l'2il.lUl'l gl'?:lLllCI'll.S.
`Clliihlflfi lhfl CXISICTICC
`gllanldlng
`C()]'np[_)ll]'ld_\; [hr lfgallrlg \,ral'l0l_lS (llhgf indl-
`Oi 3 i35iiii8 Piiitiiiiiiii iii iii‘? i'i'i°ii'ibi3-iii’ (i-‘ii: Ni” Uiii» K+ iii)
`tin cations (e.g., diseases relating to the CNS-system, gastric
`which initiates the contractile response. Contraction is trig—
`gccfcllong inflammation, HIV, t-,tc_) gm; (ligclgsgd in shim-ada
`801159 by Naica °X‘3i1"iii85 iiiiii C519 ii'iiii5P0i'i» iii‘? "~'ii"~‘i'8Y ifiii‘
`et al,
`“.S_i;rit‘l'ie.s'.i.s and Gastric Aririseererorjy AeIit>t'ry of
`which i5 8'-3i1°i'iii°(i
`'33’
`iii‘?
`i1Ydi'9iY5i5 Oi ATP bit’ C3"+
`N—Cyrm0—N'(pi.=tm_vl—p_vrid.iriyt'mer:'tyl)guariidine
`ATP«'|5C-
`Derivativtzs, " Chem. Plttmii. Bull, Vol. 32(12), (1984), at
`To maintain homeostasis, the cells’ supply oi‘ ATP must be 65 pp. 4893-4906; W0 0055449, "N-UreidrmIkyl-Piperidines
`replenished as
`it
`is consumed (e.g., with muscle
`as Moa'm'nIor.s'(,}'C:'i.9i.iir)tlrine ReceptorAcrii=i3r_y,” to Du Pont
`contraction). During the steady state, the rate of ATP syn-
`Pharmaceuticals (Io.; US. Pat. No. 5,478,845, "‘I’ipcridi'nc
`PENN EX. 2233
`
`2 of 65
`
`CFAD V. UPENN
`IPR20l5-01836
`
`

`
`US 6,916,813 B2
`
`3
`l')eJ‘r'1rntr'1-'95,” issued Dec. 26, 1995 and assigned to Novo
`Nordisk AIS; W0 93f05U26, "'Pepn'.de [voters Containing a
`Hetetvcycie as H.I.'.( Irn'n'bit()r.s',” to Smith- Kline lleecham
`Corp; and W0 00;‘-43415, “Compotmds wiricir t'nhr'bit Leu-
`kocyte Adhesion Mediated by VLA—4,”
`to Elan
`Pharmaceuticals, Inc. Cyano—guanidine compounds useful
`for lowering blood pressure or treating thrombotic or platelet
`aggregating conditions are disclosed in U.S. Pat. No. 5,521,
`177, U.S. Pat. No. 5,482,948, and W() 96,t'237'7l.
`Each of the patents, patent applications and publications
`referred to in this application are incorporated herein by
`reference.
`
`SUMMARY OF THE INVENTION
`
`The invention is directed to compounds having the for-
`111ula (I):
`
`10
`
`"I5
`
`(U
`
`10
`
`I
`
`2
`
`R
`
`_\
`
`R
`
`‘-..N/
`
`l
`
`\\
`
`x\/
`(R-‘Ur;
`
`N/KN
`H
`I
`R'
`
`or a pharmaceutically—aeceptable salt, hydrate, or prodrug
`thereof, wherein:
`R, is cyano, —S()2R,,, —(T(=()]R9, or heteroaryl,
`R3 is
`independently hydrogen, alkyl, or substituted alkyl,
`or (ii) taken together with R3 forms a heterocyclo;
`R3 is
`independently alkyl, substituted alkyl, alkylthio,
`aminoalkyl, carbamyl, A-aryl, A-heterocyclo,
`A—hcteroaryl, or A—cycloalkyl, or (ii) taken together with
`R2 forms a heterocyclo;
`Z is heteroaryl provided that when R, is cyano, Z is not
`2—pyridinyl;
`A is
`a bond, C,_,,alkylene, C2_,,alkenylene, substituted
`C,__,alkylene, substituted C,__,,alkenylene, —C(=0)
`NR1_,,—, —(T1_4alkylene—(T(—())NR19—, or substituted
`(T,_,,alkylene-(T[=U)NR,,,—;
`R4 at each occurrence is selected independently of each
`other R,,
`from the group consisting of halogen, alkyl,
`haloalkyl, nitro, cyano, haloalkoxy, OR25, SR25,
`NR2.-sR2a» NR2sS02R27s 50:R:7a SOZNRZSRZG’ C02R26!
`<‘.(=0>R
`C-(=)NR25R2r'n 0(“-(=0)R2_~—,. -0!“-(=0)
`NR35R:,_6, NR:5C(=0)R:°., NR25(‘_03R25, aryl,
`heteroaryl, heterocyclo and cycloalkyl;
`R8 is alkyl, substituted alkyl, aryl, or heteroaryl,
`R9 is —NRmRH, alkyl, substituted alkyl, alkoxy, alkylthio,
`cycloalkyl, aryl, heteroaryl, heterocycle, or —(f()2R,2;
`Rm and R1,, are
`independently selected from hydrogen,
`alkyl, substituted alkyl, alkoxy, heteroeyelo, cycloalkyl,
`aryl, and heteroaryl; or (ii) taken together form a hetero-
`cyclo or heteroaryl;
`R13 and R1,, are hydrogen or alkyl;
`R25 and R36 are independently selected from hydrogen,
`alkyl, or substituted alkyl, or
`taken together form a
`heterocyclo or heteroaryl ring;
`R2, is alkyl or substituted alkyl, and
`q is 0,1, 2, or 3.
`Also included within the scope of the invention are
`pharmaceutical compositions comprising one or compounds
`of formula (I), and methods of treating ischemic conditions
`and;"or conditions associated with depleted levels of adcnos—
`ine triphosphate (KFP) andfor the activity of mitochondrial
`
`35
`
`40
`
`45
`
`S0
`
`60
`
`65
`
`4
`'I'hese methods comprise administering an
`/\'I'l-‘ase.
`15 ,I",,
`effective amount of at least one compound of fom1ula (I) to
`a patient
`in need thereof. Additionally, applicants have
`discovered that
`l-‘,1-‘U-/(l'P hydrolase can be selectively
`inhibited via use of a small organic molecule, ie, a non-
`peptidic organic compound having less than 1000 molecular
`weight, and this invention is also claimed herein.
`I)l_-'.'l'AIl.l_i[) D].-lS(TRIPTI[)N OF TIIE
`INVENTION
`
`The following are delinitions of terms used in this speci-
`fication. The initial definition provided for a group or term
`herein applies to that group or term throughout the present
`specification, individually or as part of another group, unless
`otherwise indicated.
`
`The term “alkyl" refers to straight or branched chain
`hydrocarbon groups having 1 to 12 carbon atoms, preferably
`1 to 8 carbon atoms. Lower alkyl groups, that is, alkyl
`groups of 1 to 4 carbon atoms, are most preferred.
`The term “substituted alkyl” refers to an alkyl group as
`defined above having one, two, three, or four substituents
`selected from the group consisting of halogen,
`trifluoromethyl, alkenyl, alkynyl, nitro, cyano, keto (=0),
`OR”, SR”, NRaR,,, NR,,S()2, NR,,S()2RC, S()2Rn,
`SO:NR,,R,,, COZRJ’ C(=O)R,,, C[=O)NR,,R ,, OC(=O)
`Rn, —()(T(=())NR,,R,,, NR,,(I(=[))R,,, NR,,(T()2R,,,
`=N—()II, =N—()-alkyl, aryl, heteroaryl, heterocyclo and
`cycloa lkyl, wherein R, and R,, are selected from hydrogen,
`alkyl, alkenyl, cycloalkyl, heterocyclo, aryl, and heteroaryl,
`and RC is selected from hydrogen, alkyl, cycloalkyl, hetero-
`cyclo aryl and heteroaryl, When a substituted alkyl includes
`an aryl, heterocyclo, heteroaryl, or cycloalkyl substituent,
`said rirtged systems are as defined below and thus may in
`turn have zero to four substituents (preferably 0-2
`substituents), also as defined below. When either Ra, Rb or
`RC is an alkyl, said alkyl may optionally be substituted with
`1-2 of halogen,
`trifluoromethyl, alkenyl, alkynyl, nitro,
`cyano, keto (=0), Oil, O(alkyl), phenyloxy, benzyloxy,
`SII, S(alkyl), N112, NIl(alkyl), N(alkyl)2, NIISO2, NlIS(]2
`(al.kyl), SO2(a1kyl), SOENH2, SO2NH(al.kyl], COZH, C02
`(alkyl), C(=O)H, C(=O)alkyl, C(=0)NH;._, C(=O)NH
`(alkyl), (I(=())N(alkyl)3, ()(T[
`())alkyl, —()(T(=())N[I2,
`—OC(=O)N'H(alkyl), NHC(=O)alkyl, andfor NHCO3
`(alkyl). “Alkyl” when used in conjunction with another
`group such as in arylalkyl refers to a substituted alkyl in
`which at least one of the substituents is the specifically-
`named group. For example,
`the term arylalliyl
`includes
`benzyl, or any other straight or branched chain alkyl having
`at least one aryl group attached at any point of the alkyl
`chain. As a further example, the term carbamylalkyl includes
`the group —((TIl2)N—NIl C[=())alkyl, wherein n is l
`to
`12.
`
`The term “alkenyl” refers to straight or branched chain
`hydrocarbon groups having 2 to 12 carbon atoms and at least
`one double bond. Alkenyl groups of 2 to 6 carbon atoms and
`having one double bond are most preferred.
`The term “alkynyl" refers to straight or branched chain
`hydrocarbon groups having 2 to 12 carbon atoms and at least
`one triple bond. Alkynyl groups of 2 to 6 carbon atoms and
`having one triple bond are most preferred.
`The term “alkylene” refers to bivalent straight or
`branched chain hydrocarbon groups having 1 to 12 carbon
`atoms, preferably 1 to 8 carbon atoms, e.g., {—CH,_—},,,
`wherein n is "l to '12, preferably 1-8. l_ower alkylene groups,
`that is, alkylene groups of 1 to 4 carbon atoms, are most
`prefened. The terms “alkenylene” and "alkynylene" refer to
`PENN EX. 2233
`
`3of65
`
`CFAD V. UPENN
`IPR20l5-01836
`
`

`
`US 6,916,813 B2
`
`5
`bivalent radicals of alkenyl and alknyl groups, respectively,
`as defined above.
`
`When reference is made to a substituted alkylene,
`alkenylene, or alkynylene group, these groups are substi-
`tuted with one to four substitutents as defined above for alkyl
`groups. A substituted alkylene, alkenylene, or alkynylene
`may have a ringed substituent attached in a spiro fashion as
`In
`
` El
`
`\‘C
`H3
`
`(2% i\ -'
`H
`
`E2
`
`c.‘/ '\ =
`H3
`
`\‘‘(T
`H
`
`3
`
`and so forth.
`The term "alkoxy" refers to an alkyl or substituted alkyl
`group as defined above having one, two or three oxygen
`atoms [—O—) in the alkyl chain. For example, the term
`“alkoxy” includes the groups —()—(f1_13alkyl, —(f1_5
`alkylene-()—(T,_,.,alkyl, —CMalkylene-(J-phenyl, and so
`forth.
`
`10
`
`"I5
`
`ll]
`
`The term "thioalkyl” or "alkylthio” refers to an alkyl or
`substituted alkyl group as defined above having one or more
`sulfur (—S—) atoms in the alkyl chain. For example, the
`term “thioalkyl”
`or "alkylthio” includes the groups _,d
`—{CI 12)" %}—CI Igaryl, —(CII2]”a‘§—aryl, etc. etc.
`The term “aminoalkyl" refers to an alkyl or substituted
`alkyl group as defined above having one or more nitrogen
`{ NR'—) atoms in the alkyl chain. For example, the term
`“aminoalkyl” includes the groups —NR'—C,_,3alkyl and
`—(flI3—NR'-aryl, etc. (where R‘
`is hydrogen, alkyl or
`substituted alkyl as defined above.) "Arnino” refers to the
`group —l\lII3.
`When a subscript is used as in C,_3alkyl, the subscript
`refers to the number of carbon atoms the group may contin.
`Zero when used in a subscript denotes a bond, e.g., L.‘0__,aLkyl
`refers to a bond or an alkyl of l to 4 carbon atoms. When
`used with alkoxy, thiealkyl or aminoalkyl, a subscript refers
`to the number of carbon atoms that the group may contain
`in addition to heteroatoms. Thus, for example, monovalent.
`(ilgaminoalkyl includes the groups —(f[I3—NlI3,—NII—
`(:H_,,
`(c:H.,)., N11,,
`NH (TH,
`(:H._,,
`(TH,
`NH2—CH3, and —N—(CH_,)2. A lower aminoalkyl com-
`prises an aminoalkyl having one to four carbon atoms.
`The alkoxy,
`thioalkyl, or aminoalkyl groups may be
`monovalent or bivalent. By "monovalent” it is meant that the
`group has a valency (i.e., power to combine with another
`group). of one, and by "bivalent” it is meant that the group
`has a valency of two. For example, a monovalent alkoxy
`includes groups such as —O—C,_,2alkyl, —C,_fialkylene—
`O—C,_,,-alkyl, ete., whereas a bivalent alkoxy includes
`groups such as —()—C1_2alkylene-, —C,_fialkylene-()—
`C,_6alkylene—, etc.
`The term “acyl” refers to a carbonyl
`
`35
`
`4E]
`
`45
`
`Sf]
`
`6
`The term “alkoxycarbonyl" refers to a group having a
`carboxy or ester group
`
`O
`
`(—c7—o—)
`
`linked to an organic radical, i.e.,
`
`D
`
`TC-’0—Ra.
`
`wherein Rd is as defined above for acyl.
`The term “carbamyl” refers to a functional group in which
`a nitrogen atom is directly bonded to a carbonyl, i.e., as in
`—N'R,_,C(=O)RJ,\or —C(—O)N'R,,RJ,, wherein R‘, and R, can
`be hydrogen, alkyl, substituted alkyl, alkenyl, substituted
`alkenyl, alkoxy, cycloalkyl, aryl, heterocyclo, or heteroaryl,
`or they may join to form a ring.
`The term “sulfonyl” refers to a sulphoxide group (i.e.,
`—S(()], _2) linked to an organic radical RC, as defined above.
`The term “sulfonamide” or “sulfonamido” refers to the
`
`group 4(O)2NR!?Rf) wherein R, and Rf are as defined
`above. Preferably when one of R‘, and RI is optionally
`substituted heteroaryl or heterocycle (as defined below), the
`other of R‘. and R, is hydrogen or alkyl.
`The term “cycloalkyl” refers to fully saturated and par-
`tially unsaturated hydrocarbon rings of 3 to 9, preferably 3
`to 7 carbon atoms. The term “cycloalkyl" includes such
`rings having zero to four substituents (preferably 0-2
`substituents), selected from the group consisting of halogen,
`alkyl, substituted alkyl (e.g., trifluoromethyl), alkenyl, sub-
`stituted alkenyl, alkynyl, nitro, cyano, keto,
`()R,,, SR“,
`Nl{dl{€, NRCS03, NRc.$D3l{£., C(=())H, acyl, —CO2H,
`alkoxyearbonyl, carbamyl, sulfonyl, sulfonamide, —0C
`(=O)R,,, =N OH, =N—0—alkyl, aryl, heteroaryl,
`heterocyclo, a 4 to 7 membered carbocyclic ring, and a five
`or six membered ketal, e,g., 1,3—dioxolane or 1,3—dioxane,
`wherein R6, Rd and R‘, are defined as above. The term
`“cycloalkyl” also includes such rings having a phenyl ring
`fused thereto or having a carbon-carbon bridge of 3 to 4
`carbon atoms. Additionally, when a cyeloalkyl is substituted
`with a
`further
`ring,
`i.e., aryl, arylalkyl, heteroaryl,
`heteroarylalkyl, heterocyelo, heteroeycloalkyl,
`cycloalkylalkyl, or a further eycloalkyl ring, such ring in
`turn may be substituted with one to two of (T0_,,alkyl
`optionally substituted with halogen,
`trilluoromethyl,
`alkenyl, alkynyl, nitro, cyano, keto (=0), OII, (](alkyl),
`phenyloxy, hcnzyloxy, SH, S(alkyl), NH2, NH(alkyl),
`N(alkyl):, NHS02,
`l\lllSO:(alkyl), S():(alkyl), S()2N[I:,
`SO:NH(alkyl), COEH, CO2(alkyl), C(=O)H, C(=0)al.kyl,
`(T(=())NIl:,
`(T(=())NII(alkyl),
`(I(=())N(alkyl),,
`()(T(=())alkyl, —()(I[=())NII3, —[)(I(=())NII(alkyl),
`NlIC(=O)alkyl, and l\lllCO;._(al.kyl).
`The term “halo” or “halogen” refers to chloro, bromo,
`lluoro and iodo.
`
`0
`
`(:C:}
`
`linked to an organic group i.e.,
`
`()
`
`||
`j C: Rd.-
`
`wherein Rf, may be selected from alkyl, alkenyl, substituted
`alkyl, substituted alkenyl, aryl, heterocyclo, cycloalkyl, or
`heteroaryl, as defined herein.
`
`60
`
`65
`
`The term “haloalkyl” means a substituted alkyl having
`one or more halo substituents. For example, "haloalkyl”
`includes mono, hi, and trifiuoromethyl.
`The term “haloalkoxy” means an alkoxy group having
`one or more halo substituents. For example, "haloalkoxy”
`includes ()(Tl53.
`The term “aryl” refers to phenyl, biphenyl, 1—naphthyl,
`2-naphthyl, and anthracenyl, with phenyl being preferred.
`The term “aryl” includes such rings having zero to four
`substituents (preferably 0-2 substituents), selected from the
`PENN EX. 2233
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`US 6,916,813 B2
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`7
`group consisting of halo, alkyl, substituted alkyl (e.g.,
`trifiuoromethyl), alkenyl, substituted alkenyl, alkynyl, nitro,
`cyano, URJ, SR,“ NR,,.R_,, NR,,S()2, NR,,.S()2Rc, (f(=[))II,
`acyl, —CO._,II, alkoxycarbonyl, carbamyl, sulfonyl,
`sulfonamide, —OC(=0)R,,, heteroaryl, heterocyclo,
`cycloalkyl, phenyl, benzyl, napthyl, including phenylethyl,
`phenyloxy, and phenylthio, wherein IL, Rd and R, are
`defined as above. Additionally, two substituents attached to
`an aryl, particularly a phenyl group, may join to form a
`further ring such as a fused or spiro—ring, e.g., cyclopentyl or
`cyclohexyl or fused heterocycle or heteroaryl. When an aryl
`is substituted with a further ring, such ring in turn may be
`substituted with one to two of C0 ,,alkyl optionally substi-
`tuted with halogen, trifluoromethyl, alkenyl, alkynyl, nitro,
`cyano, keto (=()), ()II, ()(alkyl), phenyloxy, benzyloxy,
`SH, S(al.kyl), NH2, NH(alkyl], N(al.kyl]2, NHSOQ’ NHSO:
`(alkyl), SO3(alkyl), SOSNH3, SO2NH(alkyl), COSH’ C02
`(alkyl), C(=0)H, C(=O)alkyl, C(=O)NH3, C(=O)NH
`(alkyl), C(=[))N[alkyl)2, ()C(
`()]alkyl, —()(f(=())NII2,
`—()(T(=())NII[alkyl], N11(?(=o)a1ky1, and Ntltio,
`(alkyl).
`The term “heterocyclo" refers to substituted and unsub-
`stituted non-aromatic 3 to 7 membered monocyclic groups,
`7 to 11 membered bicyclic groups, and 10 to 15 membered
`tricyclic groups, in which at least one of the rings has at least
`one heteroatom selected from O, S and N. Each ring of the
`heterocyclo group containing a heteroatom can contain one
`or two oxygen or sulfur atoms andfor from one to four
`nitrogen atoms provided that the total number of heteroat-
`oms in each ring is four or less, and further provided that the
`ring contains at
`least one carbon atom. The fused rings
`completing bicyclic and tricyclic groups may contain only
`carbon atoms and may be saturated, partially saturated, or
`unsaturated. The nitrogen and sulfur atoms may optionally
`be oxidized and the nitrogen atoms may optionally be
`quaternized. The heterocyclo group may be attached at any
`available nitrogen or carbon atom. The heterocyclo ring may
`contain zero to four substituents (preferably 0-2
`substituents), selected from the group consisting of halo,
`alkyl, substituted alkyl (e.g., trifluoromethyl}, alkenyl, sub-
`stituted alkenyl, alkynyl, nitro, cyano, keto, ()R,,, SR4,
`NR,,R__,, NRJS02, NRJSOQRC‘ SO2R,,, C(=O)H, acyl,
`—C02H, alkoxycarbonyl, carbamyl, sulfonyl, sulfonamide,
`()(l(—())R,,., —N ()II, —N ()-alkyl, aryl, heteroaryl,
`cycloalkyl, a five or six membered ketal, e.g., 1,3—dioxolane
`or l,3—dioxanc, or a monocyclic 4 to 7 membered non-
`aromatic ring having one to four heteroatorns, wherein R“,
`R, and R_, are defined as above. The term “heterocyclo" also
`includes such rings having a phenyl ring fused thereto or
`having a carbon-carbon bridge of 3 to 4 carbon atoms.
`Additionally, when a heterocyclo is substituted with a fur-
`ther ring, i.e., aryl, arylalkyl, heteroaryl, heteroarylalkyl,
`cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or a further
`heterocyclo ring, such ring in turn may be substituted with
`one to two of C0__,alkyl optionally substituted with halogen,
`trifluoromethyl, alkenyl, alkynyl, nitro, cyano, keto (=0),
`()lI, [)[alkyl), phenyloxy, benzyloxy, SII, S(alkyl), NII2,
`NH(alkyl), N(alkyl)2, NHSO2, NHSO2(alkyl), S02(alkyl),
`S():l\lIl2, S[)2NII(alkyl),
`(T0211, C()2(alkyl), (f(=())Il,
`C(=0)alkyl, C(=O]NII2, C(=0)NlI(alkyl), C(=O)N
`[alkyl)2, 0C(=O)alkyl, —OC(=O)NH2, —OC(=O)NH
`(alkyl), NHC[=O)alkyl, and NHCO:(al.kyl).
`Exemplary monocyclic groups include azetidinyl,
`pyrrolidinyl, oxetanyl,
`imidazolinyl, oxazolidinyl,
`isoxazolinyl,
`thiazolidinyl,
`isothiazolidinyl,
`tetrahydrofuranyl, piperidinyl, piperazinyl,
`2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl,
`
`10
`
`"I5
`
`ll]
`
`.1.
`
`35
`
`4E]
`
`45
`
`Sf]
`
`an
`
`65
`
`8
`2-oxoanepinyl, azepinyl, 4-piperidonyl, tetrahydropyranyl,
`morpholinyl,
`thiamorpholinyl,
`thiamorpholinyl sulfoxide,
`thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-l,l-
`dioxothienyl and the like. Exemplary bicyclic heterocyclo
`groups include quinuclidinyl.
`The term “heteroaryl" refers to substituted and unsubsti-
`tuted aromatic 5 to 7 membered monocyclic groups, 9 or 10
`membered bicyclic groups, and 11 to 14 membered tricyclic
`groups which have at least one heteroatom selected from O,
`S and N in at
`least one of the rings. Each ring of the
`heteroaryl group containing a heteroatom can contain one or
`two oxygen or sulfur atoms andfor from one to four nitrogen
`atoms provided that the total number of heteroatoms in each
`rin
`is four or less and each rin
`has at least one carbon
`3
`3
`atom. The [used rings completing the bieyclic and tricyclic
`groups may contain only carbon atoms and may be
`saturated, partially saturated, or unsaturated. The nitrogen
`and sulfur atoms may optionally be oxidized and the nitro-
`gen atoms may optionally be quaternized. Heteroaryl groups
`which are bicyclic or tricyclic must include at least one fully
`aromatic ring but
`the other fused ring or rings may be
`aromatic or non-aromatic. The heteroaryl group may be
`attached at any available nitrogen or carbon atom of any
`ring. The heteroaryl ring system may contain zero to four
`substituents (preferably 0-2 substituents), selected from the
`group consisting of halo, alkyl, substituted alkyl (e.g.,
`trifluoromethyl), alkcnyl, substituted alkenyl, alkynyl, nitro,
`cyano, OR,” SR,,, NR,,R,,, NR,,SO;._, NR,,SO;._R(., SO2R,,,
`(f(=())II, acyl, —(I()2lI, alkoxycarbonyl, carbamyl,
`sulfonyl, sulfonamide, —()(f[=())R,,, heterocyclo,
`cycloalkyl, aryl, or a monocyclic 4 to 7 membered aromatic
`ring having one to four heteroatoms, including phenylethyl,
`phenyloxy, and phenylthio, wherein RC, R0. and R‘, are
`defined as above. Additionally, when a heteroaryl is substi-
`tuted wilh a further ring, i.e., aryl, arylalkyl, heterocyclo,
`heterocycloalkyl, cycloalkyl, cycloalkylalkyl,
`heteroarylalkyl, or a further heteroaryl ring. such ring in turn
`may be substituted with one to two of CD_4alkyl optionally
`substituted with halogen, lrifluoromethyl, allienyl, alkynyl,
`nitro, cyano, keto (=0), OH, O(alkyl), phenyloxy,
`benzyloxy, SI}, S(alkyl), NII3, Nllfalkyl], N(alkyl]3,
`NHso,, NHS()2(alkyl),n so,(a1ky1), so,NH,, so,NH
`(alkyl), C021}, (I{):[alkyl), (I(=O)I I, C(=()]all\'yl, (f(=(])
`NI-I2, C(=O)NH(alkyl), C(=0)N[alkyl):, OC(=O)alkyl,
`—o(:(=o)NI1,, —()c:(=o)N11(a1ky1), NII(I(=O)alkyl,
`and NHCO2(alkyl).
`Exemplary monocyclic heteroaryl groups include
`pyrrolyl, pyrazolyl, pyrazolinyl,
`imidazolyl, oxazolyl,
`isoxazolyl, thiamlyl
`
`R5 l
`(i.e., <\\_
`
`J,
`
`thienyl, oxadiazolyl,
`furanyl,
`isothiazolyl,
`thiadiazolyl,
`pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and
`the like.
`
`Exemplary bicyclic heteroaryl groups include indolyl,
`benmthiamlyl, benzodioxolyl, benzoxaxolyl, benmthienyl,
`quinolinyl,
`tetrahydroisoquinolinyl,
`isoquinolinyl,
`benzimidazolyl, benzopyranyl,
`indolizinyl, benzofuranyl,
`chromonyl, coumarinyl, benzopyranyl, cinnolinyl,
`quinoxalinyl,
`indazolyl, pyrrolopyridyl,
`furopyridinyl,
`dihydroisoindolyl, tetrahydroquinolinyl and the like.
`Exemplary lricyclic heteroaryl groups include carbamlyl,
`benzidolyl, phenanthrollinyl, acridinyl, phenanthridinyl,
`xanthenyl and the like.
`
`5of65
`
`PENN EX. 2233
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`CFAD V. UPENN
`IPR20l5-01836
`
`

`
`US 6,916,813 B2
`
`P1'°f°1'1"-3d C0ml30u"d5
`Prcfcrrcd Compounds U1-the present invcmion are those
`45 having the following formula, or salts, hydrates, and pro-
`drugs thereof’
`
`10
`9
`All stereoisomers of the present compounds, such as
`the specification, groups and substituents
`'I'hroughout
`thereof maybe chosen by one skilled in the field to provide
`those, for example, which may exist due to asymmetric
`stable moieties and compounds.
`carbons, including enantiomeric forms (which may exist
`The compounds of formula I form salts which are also
`even in the absence of asynmmetric carbons) and diastereo-
`within the scope ofthis invention. Reference to a compound
`5 meric forms, are contemplated and within the scope of this
`,
`,
`_
`_
`invention. Individual stereoisomers of the compounds of this
`"1 ‘he fmmula I h"“"“ 15 ‘”,ld“r_-""“_“d I“ ”_“fl“d" '“f"'“"‘-"’ '“
`invention may’ for example, be Substantially frcc of other
`salts thereof, unless otherwise indicated. [he _teiin “salt(s)”,
`isomers or may bc admixed for example as mccmatcs or
`as employed herein, denotes acidic andfor basic salts formed
`with all’ other or other selecled stereoisohiers. The chiral
`with inorganic “dim Organic acids and bases‘ In addiliun’
`In comers of the prcgcm invcntign can have the S or R
`when acompound of formulalcontainsbothabasic moiety,
`configuration as defined bv the IUP/\(' 1974 Recommenda-
`asi bin noidlimiicffll-to all ammch or I: pyridlmc. 0;
`.
`‘
`-
`'
`imi azo erin ,an an aci
`ic moiety, suc as, ut not
`imite
`“ms”
`..
`.
`to a carboxylic acid, zwitterions (“inner salts”) may be
`"“*3f hi?“
`the formulas I
`In addmon’ Compounds’ 01
`formed and are included within the term “salt(s)” as used
`prodrug: f°rmS'A_ny °f:'mp0und that will be’ convcrlcd 1“ “V0
`herein. Pharmaceutically acceptable (i.e., non—toxic, physi—
`to provide the bioactive agent [i.e., a compound of formula
`Olugically acccplable) Sans are preferred, ahhmlgh mhcr ‘I5
`I) I5 3 Pmdrug within the 590130 and Spirit Oflh‘-3 lm'°ml°n-
`salts are also useful, e.g., in isolation or purification steps
`F01’ °XamP1°- I3i'0'd1'“3 C0mP0‘m‘l5 °flh° f01'mU1"l5 I may
`which may be employed during preparation. Salts of the
`DC carboxylate CSICF t’I10i0il0S. A carboxylate ester may be
`compounds ofthc formula I may be formal, for cxamplc, by
`conveniently formed b