(13) United States Patent
`Bisacehi et al.
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 6,344,450 B1
`Feb. 5, 2002
`
`US0063444-S0131
`
`(54)
`
`LACTAM C()Ml’()UNI)S AND THEIR USE AS
`INHIBITORS OF SERINE PROTEASES AND
`
`OTHER PUBLICATIONS
`
`METHOD
`
`(75)
`
`(73)
`
`(*)
`
`Inventors: Gregory S. Bisacchi, Ringoes; Steven
`M_ gene“ penningmn, bolh of NJ (US);
`11- Micllacl Lawrence, Yardley; PA
`(US); James L. button, .Ir., Princeton
`_]um1im, N] (U3); wi[[i-am A_
`Slusarehyk, Skillman, NJ (US);
`Guohua Zhao’ Princeton’ NJ (US)
`Assignee: Bristol-Myers Squibb Company,
`11.-jnccmnj NJ (US)
`
`N 1'“;
`0 mu
`
`Sulfe ‘L to an ' d's;claimer, the term of th's
`pateJ11tL[s extc):11d1ed or adjusted under 315
`U.s.c. 15411:) 13310 (lays.
`
`(31)
`
`Appl. No.: 09f633,75l
`
`Filed:
`
`Aug. 7, 2000
`
`Lowe et a1., Biootg. & Med. Chem. Iettets, vol. 4, p.
`2877-2882 (1994).
`_
`‘
`Sernple el 31., J. Med. (.hem., vol. 39, p 4531-4536 (1996).
`l-'re1'ding_er et al., J. Org. Chem, vol. 47,1». 104-109 (1992).
`_
`_
`‘
`breentvasan e1 £11.,
`.1. Med. Chem. vol. 36, p. 256-263
`(1993)-
`Skiles el al., Bittttrg. 8:. Med. Chem. Letters, vol. 3, p.
`773-778 1993.
`(
`)
`Adang et al., Bioorg. & Med.
`3603-3608 {1998).
`.
`.
`. -
`5:I(]J%EluCci 01 al" J‘ Med’ Chem“ Vol‘ 36‘ p‘ 15114319
`(
`-*1‘
`
`[_etters, vol. 8, p.
`
`(Them.
`
`* cited by examiner
`
`Prirrtttry Exm:1ine1'—Brue1t"Ki11e
`(74) A1'1’orne_t-‘. Agent, or 1‘1rm—Burton Rodney
`
`Related U.S. Application Data
`
`(57)
`
`ABgTRACT
`
`(63)
`
`(00)
`
`(51)
`
`Conlintlution in part oftlppliculion No. 0.‘J1’47'8,632, filed on
`Jan. 6, 2.(1U'(J.
`Provisional application No. 60.-’1l9,374_. [lied on Feb. 9,
`1999.
`_
`Int. Cl.“
`
`(52)
`
`U.S. CI.
`
`(53)
`
`Field of Search
`
`Laclarn inhibitors are provided which have the structure
`
`ll
`x/‘
`
`"
`
`N
`
`/R‘
`.
`hep‘,
`
`O
`
`X is
`
`A61K 31155; C071) 223710;
`C071) 403712
`5l4,!2l2.03;5l4;‘2'l2.08;
`54(l,'524; 5411525; 5401527
`5401524, 525,
`540,-“S27; :'>l4,(2l2.U3, 212.08
`
`References Cited
`US. P/\'I'1_-'N'l‘ |)()(TUM1_-'N'[‘S
`
`R‘—fi— or
`Y
`
`R3—%
`
`(56)
`
`El‘
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`Wt)
`W0
`WI)
`W0
`Wt)
`W0
`
`wherein
`4_
`,
`V15 O “F 3 “"5 R '5
`
`R3
`\
`INT’
`I’:
`
`R
`
`10.51992 Giannessi el :11.
`1,='1‘J9(1
`Inwi".
`45199? Lowe
`951997 I): et al.
`12,1199? Sample et al.
`8./1999 Semple e1 :11.
`
`
`
`514.1212
`_ 54-(l1"57.3
`.5l41’218
`5147212
`530.-(331
`546.5188
`
`5,155,102 A
`5,484,917 A
`5,r;1s_311 A
`5_.m2,s<.:s A
`5_.703,208 A
`5,932,733 A
`
`FOREIGN 1’A1'l:'.N'1'DOCUMl:iN'l‘S
`
`761680
`‘:93,-‘[4115
`95135311
`95135313
`%,“q40
`961,293 13
`97114417
`97116425
`WO 97117363
`97330073
`
`VVC)
`
`98312211
`98116523
`Vt-'0 98.-"5t‘J365
`HI],-'(I52f]8
`WO 00153254
`
`3,-‘1‘.J‘J7
`7.-"1993
`1211095
`1211005
`4_,mg6
`9:1 L996
`4,.-‘L997
`5.-‘I997
`5,-"1997
`3/1997
`
`3.-“L998
`4,51‘.-J98
`12.31998
`2,-"2(l0(l
`9.1200111
`
`*
`
`Q
`
`Rv0_ or Rs
`.
`.
`‘
`,.
`_
`2
`_
`and R1. R ,1{3,R5.R', l{7.ant1 R”, are as deltned heretn.
`These compounds are inhibitors of Factor X51 and thus
`are useful as a1111coagu1a11t.s, and are 111111b1lors of
`tryptase and thus are useful in treating asthma. Methods
`for treating cardiovascular diseases associated with
`lh
`b 3
`111'
`1
`1'
`'.'th ‘
`' d
`1'tc_l1_l'.'
`.-
`flr::I.):iIS[:);)Cr‘(s):l]:1dc(El' 1'63 ]l'Jg d‘:
`IT1d dl'1
`TC d 0
`lSCd‘sC‘\
`
`1 of 101
`
`29 Claims, No Drawings
`
`PENN Ex. 2225
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`US 6,344,450 B1
`
`YisOorSand R“is
`
`115
`
`\I
`
`R6
`
`R7o— or R“
`
`R3 is selected from alkyl, alkcnyl. alkynyl, aryl,
`hctcroaryl, arylalkyl, hctcroarylalkyl, cyeloalkyl,
`cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl,
`cycloalkenyl, cycloheteroalkyl, cycloalkenylalkyl,
`polycycloalkcnyl, or polycycloalkcnylalkyl; all option-
`ally substitutcd through available carbon atoms with I,
`2, 3 or 4 groups selected from liydrogen, halo, alkyl,
`haloalkyl, alkoxy, haloalkoxy, alkcnyl, alkynyl,
`cycloalkyl, cycloalkylalkyl, cyclohctcroalkyl,
`cyclolieteroalkylalkyl, aryl, heteroaryl, arylalkyl,
`arylcycloalkyl, arylalkenyl, arylalkynyl, aryloxy,
`aryloxyalkyl, arylalkoxy, arylazo_ hetcroaryloxo,
`hctcroarylalkyl, heteroarylalkcnyl. heteroaryloxy,
`hydroxy, nitro, cyano, amino, substituted amino,
`alkylamino, dialkylarnino,
`thiol. alkylthio, aryllhio,
`heteroarylthio, arylthioalkyl, alkylcarbonyl,
`arylcarbonyl, arylaminocarbonyl, alkoxycarbonyl,
`aminocarbonyl, alkynylaminocarbonyl,
`alkylarniriocarbonyl, alkenylaminocarbonyl,
`alkylcarbonyloxy,
`arylearbonyloxy,
`alkylcarbonylamino, arylcarbonylamino, arylsulfinyl,
`arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl,
`arylsulfonylamino, heteroarylcarbonylamino,
`heteroarylsulfinyl, hctcroarylthio, hctcroarylsulfonyl,
`or alkylsulfinyl;
`R5 and R5 are the same or dillerent and are independently
`selected from alkyl, alkcnyl, alkynyl, aryl, hctcroaryl,
`arylalkyl, heleroarylalkyl, cycloalkyl, cycloalkylalkyl,
`polycycloalkyl, polycycloalkylalkyl, cycloalkenyl,
`cyclohctcroalkyl, cycloalkcnylalkyl, polycycloalkcnyl,
`polycycloalkenylalkyl, arylearbonyl. alkylcarbonyl,
`alkoxycarbonyl, aryloxycarbonyl, arylsulfonyl, or
`alkylsullbnyl, or R5 and R” can be taken with the
`nitrogen to which they are attached to form a cyclo-
`lieleroalhyl
`ring; all optionally substituted through
`available carbon atoms with 1. 2. 3 or 4 groups selected
`lirom hydrogen, halo, alkyl, haloalkyl, alkoxy,
`haloalkoxy, alkcnyl, alkynyl. eycloalkyl,
`cycloalkylalkyl,
`cycloheteroalkyl,
`cyclohctcroalkylalkyl, aryl, hctcroaryl, arylalkyl,
`aryleycloalkyl, arylalkenyl, arylalkynyl, aryloxy,
`aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo,
`heteroarylalkyl, heteroarylalkenyl, heteroaryloxy,
`hydroxy, nitro, cyano, amino, substituted amino,
`alkylamino, dialkylarnino,
`thiol, alkylthio, arylthio,
`heteroarylthio, arylthioalkyl, alkylcarbonyl,
`arylcarbonyl, arylaminocarbonyl, alkoxyearbonyl,
`aminocarbonyl, alkynylaminocarbonyl,
`alkylaminocarbonyl, alkenylaminocarbonyl,
`alkylcarbonyloxy,
`arylearbonyloxy,
`alkylcarbonylamino, arylcarbonylamino, arylsulfinyl,
`arylsulilnylalkyl, arylsulfonyl, Ellli}'lSUlf0l'l)«'l,
`
`1U
`
`I5
`
`30
`
`35
`
`4U
`
`45
`
`SU
`
`55
`
`6E]
`
`65
`
`1
`LACTAM COMPOUNI)S ANI) THEIR USE AS
`INHIBITORS OF SERINE PROTEASES AND
`METHOD
`
`This application is a continuation-in-part of U5. appli-
`cation Ser. No. U9;‘478,632 filed Jan. 6, 2000, which claims
`priority from provisional application No. (J'Ot'119,374 [iled
`Feb. 9, 1999.
`
`FIELD OF THE. [N V[:'N'l‘I()N
`
`The present invention relates to Iaetam inhibitorsofserine
`proteases such as Factor X21 and tryptase, which are useful
`as anticoagulants in the treatment of cardiovascular diseases
`associated with thromboscs, and as anti—inflammatory agents
`particularly in the treatment of chronic asthma and related
`diseases.
`
`BRIEF DESCRIPTION OF THE INVENTION
`
`invention, novel substi-
`In accordance with the present
`tuted lactarn derivatives are provided which are in hibitors of
`serine proteases and have the structure I
`
`including pharmaceutically acceptable salts thereof and all
`stereoisoniers thereof, and prodrug esters thereof, wherein
`
`Ill and R2 are the same or different and are independently
`selected from hydrogen, alkyl, alkenyl, alkynyl, aryl,
`aminoalkylaryl, aminocycloalkylalkyl, aminoalkyl,
`aminoalkylcycloalkyl, hctcroaryl, arylalkyl,
`heteroarylalkyl, cycloalkyl, cycloalkylalkyl,
`polycycloalkyl, polycycloalkylalkyl, cycloalkenyl,
`cycloheteroalkyl, cycloallienylalkyl, polycycloalkenyl,
`polycycloalkenylalkyl, or R1 and R2 can be taken with
`the nitrogen to which they are attached to form a
`cycloheteroalkyl
`ring; all optionally substituted
`through available carbon atoms with "I, 2, 3 or4 groups
`selected from hydrogen. halo, alkyl, haloalkyl, alkoxy.
`haloalkoxy, alkenyl, allcynyl, cycloalkyl,
`cycloalkylalkyl,
`eyeloheteroalkyl,
`cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl,
`aryleyeloalkyl, arylalkenyl, arylalkynyl, aryloxy,
`aryloxyalkyl. arylalkoxy, arylazo, heteroaryloxo,
`heteroarylalkyl, heteroarylalkenyl, heteroaryloxy,
`hydroxy, nitro, cyano, amino, subslitiltecl amino,
`alkylamino, dialkylamino,
`thiol, alkylthio, arylthio,
`hctcroarylthio, arylthioalkyl, aminoalkyl,
`alkyloxycarhnnylaminnalkyl,
`arylall-iyloxycarbonylan'1ino—alkyl, alkylcarbonyl,
`arylcarbonyl, arylarninocarbonyl, aminocarbonyl,
`alkynylaminocarbonyl, alkylaminocarbonyl,
`alkcnylaminoearbonyl, alkylcarbonyloxy,
`arylcarbonyloxy,
`alkylcarbonylamino,
`arylcarbonylamino, arylsulfinyl, arylsulllnylalkyl,
`arylsulfonyl, alkylsulfonyl, arylsullonylamino,
`heteroarylcarbonylamino, heteroarylsullinyl,
`heteroarylthio, heteroarylsulfonyl, or alkylsulfinyl;
`
`2ufll]l
`
`PENN EX. 2225
`
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`US 6,344,450 B1
`
`3
`arylsulfonylamino, heteroarylearbonylamino,
`heteroarylsulfinyl, heteroarylthio, heteroarylsulfonyl,
`or alkylsullinylg
`R7 and R8 can be the same or different and are indepen-
`dently selected from alkyl, alkenyl, alkynyl, aryl,
`heteroaryl, arylalkyl, heteroarylalkyl, eyeloalkyl,
`eyeloalkylalkyl, polyeyeloalkyl, polyeyeloalkylalkyl,
`eyeloalkenyl, eyeloheteroalkyl, eyeloalkenylalkyl,
`polycycloalkenyl, polyeycloal_kenyl—alkyl, all option-
`ally substituted through available carbon atoms with 1,
`2, 3 or 4 groups selected from hydrogen, halo, alkyl,
`haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl,
`eyeloalkyl, eyeloalkylalkyl, eyeloheteroalkyl,
`eyeloheteroalkylall-zyl, aryl, heteroaryl, arylalkyl,
`aryleyeloalkyl, arylalkenyl, arylalkynyl, aryloxy,
`aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo,
`heteroarylalkyl, heteroarylalkenyl, heteroaryloxy,
`hydroxy, nitro, eyano, amino, substituted amino,
`alkylamino, dialkylamino,
`thiol, alkylthio, arylthio,
`lieleroaryltliio, arylthioztlkyl, alkylcarbotlyl,
`arylearhonyl, arylaminoearlionyl, alkoxyearhonyl,
`arninoearbortyl, alkynylaminocarbonyl,
`alkylaminoearbonyl, alkenylaminoearbonyl,
`alkylcarhrinyloxy,
`arylearhonyloxy,
`alkylearhonylamino, arylearhonylamino, arylsnlfinyl,
`arylsullinylalkyl, arylsulfonyl, alkylsulfonyl,
`arylsulfonylarnino, heteroarylearbonylamino,
`heteroarylsullinyl, heteroarylthio, heteroarylsulfonyl,
`or alkylsullinyl; with the proviso that
`where in the formula 1 compounds
`
`R:N—c— Ur
`Y
`,:
`n
`
`1<“—C—
`Y
`n
`
`and (1) R‘ and R2 are independently alkyl, eyeloalkyl,
`alkenyl, phenyl, benzyl, eyanoalkyl, alkoxycarbnnylalkyl,
`or phenyl mono- or disubstituted with lower alkyl, eyano,
`hydroxy, dialkylamino, al.k.oxy, benzyloxy, alkylarrtino,
`allioxyearbonyl, pyrrolidino, niorpholino, halogen, alkyl
`substituted with one or more fluorines, then Y is S;
`
`(2) where R] and R2 are alkyl, then Y is S; and
`(3) where one of R1 and R2 is alkyl and Y is 0, then the
`other
`is alkynyl, heteroaryl, heteroarylalkyl,
`cycloalkenyl, eycloheteroalkyl, heteroaryloxy,
`eyeloalkenylalkyl, polyeyeloalkenyl, polyeyeloalkeny-
`lalkyl or R1 and R: can be taken with the nitrogen to
`which they are attached to form a eycloheleroalkyl
`ring, all optionally substituted through available carbon
`atoms with 1, 2, 3 or 4 siihstittients as defined for R1
`and R2.
`Thus, the compounds of formula [ of the invention can
`have the following structural formulae:
`
`5
`
`1U
`
`I5
`
`30
`
`35
`
`4U
`
`45
`
`SU
`
`55
`
`—continued
`
`R5
`
`O
`
`a
`
`\
`R5/i \H/
`Y
`
`R‘
`
`J
`' “Wt?
`
`l\
`
`O
`
`R70
`
`T
`Y
`
`0
`
`R1
`
`31/
`N“
`
`‘
`
`0
`
`H
`N
`
`()
`
`‘fil
`
`R
`
`Y
`
`/R1
`N.‘
`R“
`
`0
`
`IB
`
`[(7
`
`ID
`
`Preferred eompounds are compounds of formula IB
`wherein l{1 and R2 together with the nitrogen to which they
`are attached form a cycloheteroalkyl
`ring, preferably a
`pyrrolidinyl ring, Y is S, one of R5 and R” is hydrogen and
`the other of R5 and R” is aryl, alkylaryl or alkoxyaryl such
`as phenyl, 3-rnethylphenyl or 3-methoxyphenyl,
`4-eyanophenyl, 3-lluorophenyl, 3-ehlorophenyl,
`4-ehlorophenyl, 4-rnethoxyphenyl. 3-ehloro-4-
`nlethylplienyl, 3,5-dieliloroplienyl, 3-iodophenyl, 3,5-
`dimethylphenyl or naphthyl.
`Also preferred are compounds of formula ID wherein one
`of R] and R3 is hydrogen and Y is O.
`In addition, preferred are compounds of formula ID
`wherein one of R' and R2 is aminoalkylaryl such as
`
`N1 1-:
`
`and
`
`C[I_\
`
`E
`
`E
`
`.NH3_.
`
`,NH-3
`
`S
`
`(TI
`
`and aminoeyeloalliylalkyl, such as
`
`g
`
`R‘
`\%f
`
`0
`
`JR‘
`“R2
`
`0
`
`[A 6!!
`
`[-|
`
`3|-1
`
`as
`
`and y is O.
`
`3 of 101
`
`PENN EX. 2225
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`5
`Preferred compounds of the invention havc the structures
`
`US 6,344,450 B1
`
`(gr gr Cr“/O
`
`6
`
`Chiral
`
`N
`
`F
`
`(Thiml
`
`0
`
`ET/K/l\_
`0
`
`Chiral
`
`11
`
`S
`
`51%
`
`N
`
`C1
`
`s
`
`K
`
`°
`
`(Thiml
`
`:
`
`N
`
`_\I
`
`
`
`Xfl/\N
`0
`
`Chiral
`
`0
`
`ct]
`
`(Tl
`
`Wu
`5
`
`11 >~—N
`
`N
`
`N
`
`0
`
`('71
`
`O
`
`C)
`
`/(?H_.
`
`H!’
`
`0
`
`/K
`0
`
`N
`
`N
`
`N
`YuS
`
`0
`
`Chiral
`
`
`
`l
`
`Chiral
`
`Q
`
`x
`
`4 of 101
`
`PENN EX. 2225
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`US 6,344,450 B1
`
`—c0ntinucd
`
`Claim]
`
`CH3
`
`C‘t‘.i1'a]
`
`5 of 101
`
`PENN EX. 2225
`CFAD V. UPENN
`lPR2015-01836
`
`

`
`US 6,344,450 B1
`
`—c0ntinucd
`
`10
`
`6uflI]l
`
`PENN EX. 2225
`
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`US 6,344,450 B1
`
`—c0ntinucd
`
`12
`
`N113
`
`7uflI]l
`
`PENN EX. 2225
`
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`13
`
`US 6,344,450 B1
`
`—c0ntinucd
`
`NH;
`
`14
`
`NII-3
`
`3 of 101
`
`PENN EX. 2225
`CFAD V. UPENN
`lPR2015-01836
`
`

`
`US 6,344,450 B1
`
`—c0ntinucd
`
`16
`
`1 5
`
`O
`
`31%CH;
`
`N
`
`N
`
`N
`
`\—<0
`
`0
`
`NH;
`
`C1
`
`C1
`
`NH;
`
`NH;
`
`.\'
`
`0
`
`-.._____
`
`O N
`
`/yo_\'
`
`O 8
`
`LNN
`E
`
`0 N
`
`0
`
`NH;
`
`0 N NII2
`
`O 2
`
`\NN
`T)
`
`\
`
`U
`
`U
`
`H_1{I
`
`9uflI]l
`
`PENN EX. 2225
`
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`17
`
`US 6,344,450 B1
`
`—c0ntinucd
`
`18
`
`H3N
`
`H_.(7
`
`CI:
`mxflgwf
`
`I0ufll]1
`
`PENN EX. 2225
`
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`19
`
`US 6,344,450 B1
`
`—continued
`
`20
`
`I133‘
`
`N
`
`N
`
`0
`
`It will be appreciated that in compounds illustrated above
`and throughout, where a nitrogen is included with an appar-
`ent open valence, the nitrogen includes a hydrogen atom.
`In addition,
`in accordance with the present invention, a
`method for treating andfor preventing medical conditions
`related to tryptase (such as asthma, chronic asthma or
`allergic rhinitis) or Factor Xa (such as thromboses, coronary
`artery disease or cerebrovascular disease)
`is provided,
`wherein a compound of formula I
`is administered in a
`therapeutically effective amount which inhibits Factor Xa or
`tryptasc.
`
`DI.-'.'l'AlLljD D].-'.SCRIP'l'ION OI" TIILE
`INVENTION
`
`The following definitions apply to the terms as used
`throughout
`this specification, unless otherwise limited in
`specific instances.
`the term "lower alkyl”,
`Unless otherwise indicated,
`“alkyl" or “alk” as employed herein alone or as pan of
`another group includes both straight and branched chain
`hydrocarbons, containing 1 to 40 carbons (in the ease of
`alkyl or alk), preferably 1 to 20 carbons, more preferably 1
`to l2 carbons (in the case of lower alkyl),
`in the normal
`ehain,sueh as methyl,ethyl, propyl, isopropyl, butyl, t—butyl,
`isobutyl, peutyl, hexyl, isohexyl, heptyl, 4,4—dituethylpeutyl,
`oetyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodeeyl,
`the various additional branched chain isomers thereof, and
`the like as well as such groups including 1 to 4 substituents
`which may be any of the R1 or the R1 substituents set out
`herein.
`
`the term “cycloalkyl" as
`Unless otherwise indicated,
`employed herein alone or as part of another group includes
`saturated or partially unsaturated (containing 1 or 2 double
`bonds) cyclic hydrocarbon groups containing 1 to 3 rings,
`including monocyclicalkyl, bicyclicalkyl and tricyclicalkyl,
`containing a total of 3 to 20 carbons forming the rings,
`preferably 4 to '12 carbons, forming the ring and which may
`be fused to one aromatic ring as described for aryl, which
`include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
`eycloheptyl, eyelooetyl, cyclodeeyl and cyclododecyl,
`cyclohexenyl,
`
`any of which groups may be optionally substituted with "l to
`4 substituents which may be any of the R1 groups, or the R1
`substituents set out herein.
`
`I5
`
`30
`
`35
`
`4U
`
`45
`
`5U
`
`6U
`
`65
`
`The term “cycloalkeny1" as employed herein alone or as
`part of another group refers to cyclic hydrocarbons contain-
`ing 5 to 20 carbons, preferably 6 to '12 carbons and I or 2
`double bonds. Exemplary eycloalkenyl groups include
`cyclopentenyl, cyclohexenyl, eyeloheptenyl, cyelooetenyl,
`cyclohexadienyl, and cycloheptadienyl, which may be
`optionally substituted as defined for cycloalkyl.
`The term “aryl” as employed herein alone or as part of
`another group refers to monocyclie and hicyclic aromatic
`groups containing 6 to 10 carbons in the ring portion (such
`as phenyl or naphthyl including 'l—naphthyl and 2—naphthyl)
`and may optionally include one to three additional rings
`fused to a carbocyclic ring or a heterocyclic ring (such as
`aryl, cycloalkyl, heteroaryl or cycloheteroalkyl rings) and
`may be optionally substituted through available carbon
`atoms with l, 2, or 3 groups selected from hydrogen, halo,
`haloalkyl, alkyl, haloalkyl, alkoxy,
`ltaloalkoxy, alkenyl,
`trilluoromethyl, trifluoromethoxy, alkynyl, cycloalkylalkyl,
`cycloalkyl, eyeloheteroalkyl, eyeloheteroalkylalkyl, aryl,
`aminoalkyl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl,
`arylalkoxy, arylthio, arylazo, heleroarylalkyl,
`heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy,
`hydroxy, nitro, cyano, amino, substituted amino wherein the
`amino includes 1 or 2 substituents (which are alkyl, aryl or
`any of the other aryl compounds mentioned in the
`definitions),
`thiol, alkylthio, arylthio, heteroarylthio,
`arylthioalkyl, alkoxyarylthio, alkylcarbonyl, arylcarbonyl,
`alkyl-aminocarhonyl, arylaminocarbonyl, alkoxycarbonyl,
`aminocarbonyl, alkylcarbonyloxy, arylearbonyloxy,
`alkylcarbonylamino, arylcarbonylamino, arylsulfinyl,
`arylsulfinylalkyl, arylsulfonylamino or arylsulfon-
`aminocarbonyl or any ofthe R1 groups or the R1 substituents
`set out herein.
`The term “aralkyl”, “aryl—all<yl" or "aryllower alkyl" as
`used herein alone or as part of another group refers to alkyl
`groups as discussed above having an aryl substituent. such
`as benzyl or phenethyl, or naphthylpropyl, or an aryl as
`delined above.
`
`The term “lower alkoxy", “alkoxy”, "aryloxy” or
`“aralkoxy” as employed herein alone or as part of another
`group includes any of the above alkyl, aralkyl or aryl groups
`linked to an oxygen atom.
`The ten'n “amiuo" as employed herein alone or as part of
`another group may optionally be independently substituted
`with one or two substituents, which may be the same or
`different, such as alkyl, aryl, arylalkyl, hetcroaryl,
`heteroarylalkyl, eycloheteroalkyl, cycloheteroalkylalhyl,
`cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl,
`alkoxyalkyl or thioalkyl. These substitucnts may he ftrrther
`substituted with a carboxylic acid or any of the R1 groups or
`R1 substituents thereof as set out above. In addition, the
`amino substituents maybe taken together with the nitrogen
`atom to which they are attached to fonn 1—pyrrolidinyl,
`l-piperidinyl,
`1-azepinyl, 4-morpholinyl,
`4-thiamorpholinyl,
`'1-piperazinyl, 4-alkyl-1-piperazinyl,
`
`11 ufllll
`
`PENN EX. 2225
`
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`US 6,344,450 B1
`
`21
`4—arylalkyl—1—piperazinyl, 4—di:trylalkyl—1—piperazinyl,
`l—pyrrolidinyl, '1 —piperidinyl, or l—a7cpinyl, optionally sub-
`stituted with alkyl, alkoxy, alkylthio, halo, trifluorometliyl or
`hydroxy.
`The term "lower alkylthio”, alkylthio”, "arylthio” or
`“aralkylthio” as employed herein alone or as part of another
`group includes any ofthe above alkyl, aralkyl or aryl groups
`linked to a sulfur atom.
`The term "lower alkylamino”, “alkylamino”,
`“aryla1:nino", or "arylal.kylamino” as employed herein alone
`or as part of another group includes any of the above alkyl,
`aryl or arylalkyl groups linked to a nitrogen atom.
`The term “acyl" as employed herein by itself or part of
`another group, as defined herein, refers to an organic radical
`linked to a carbonyl
`
`(ti)
`
`group; examples of acyl groups include any of the R' groups
`attached to a carbonyl, such as alkanoyl, alkcnoyl, aroy],
`aralkanoyl, heteroaroyl, cycloalkanoyl, cycloheteroalkanoyl
`and the like.
`
`The term "alkanoyl“ as used herein alone or as part of
`another group refers to alkyl linked to a carbonyl group.
`Unless otherwise indicated, the term "lower alkenyl” or
`“alkenyl"' as used herein by itself or as part of another group
`refers to straight or branched chain radicals of 2 to 20
`carbons, preferably 3 to 12 carbons, and more preferably 1
`to 8 carbons in the normal chain, which include one to six
`double bonds in the normal chain, such as vinyl, 2-propenyl,
`3—butenyl, 2—butenyl, 4—pentenyl, 3—pentcnyl, 2—hexenyl,
`3—hcxcnyl, 2—hcptcnyl, 3—heptenyl, 4—heptenyl, 3—octcnyl,
`3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, 4,8,12-
`tetradeeatrienyl, and the like, and which may be optionally
`substituted with 1
`to 4 substituents, namely, halogen,
`haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl,
`eyeloalkyl, amino, hyrlroxy, heteroaryl, cyclohcteroalkyl,
`alkanoylamino, alkylamido, arylcarbonyl—amino, nitro,
`cyano, thiol, alkylthio or any of the R‘ groups, or the R1
`substituents set out herein.
`
`Unless otherwise indicated, the term “lower alkynyl” or
`"alkynyl" as used herein by itself or as part ol‘ another group
`refers to straight or branched chain radicals of 2 to 20
`carbons, preferably 2 to 12 carbons and more preferably 2 to
`8 carbons in the normal chain, which include one triple bond
`in the normal chain, such as 2-propynyl, 3-butynyl,
`2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl,
`2—l1cptynyl, 3—l1cptynyl, 4—hcptynyl, 3—uctynyl, 3—nonynyl,
`4-decynyl,3-undecynyl, 4-dodecynyl and the like, and which
`may be optionally substituted with l
`to 4 substituents,
`natnely, halogen, haloalkyl, alkyl, alkoxy, alkcnyl, alkynyl,
`aryl, arylalkyl, cycloalkyl, amino, heteroaryl,
`eycloheteroalkyl, hydroxy, alkanoylamino, alkylamido,
`arylearbonylamino, nitro, cyano, thiol, andfor alkylthio, or
`any of the R1 groups, or the R1 substituents set out herein.
`Where alkyl groups as defined above have single bonds
`for attachment to other groups at two different carbon atoms,
`they are termed "alkylene” groups and may optionally be
`substituted as defined above for “alkyl”.
`Where alkcnyl groups as defined above and alkynyl
`groups as defined above, respectively, have single bonds for
`attachment at two different carbon atoms, they are termed
`“alkenylene groups” and "alkynylene groups”, respectively,
`and may optionally be substituted as defined above for
`“alkenyl"' and "alkynyl”.
`
`IU
`
`I5
`
`30
`
`35
`
`4U
`
`45
`
`SU
`
`55
`
`oil
`
`65
`
`22
`Suitable alkylene, alkenylene or alkynylene groups
`(Cl-I2), (where, p is "l
`to 8, preferably 1 to 5) (which may
`include alkylene, alkenylene or alkynylene groups) as
`delined herein, may optionally include I, 2, or 3 substituents
`which include any of the R1 groups, or the R1 substituents
`set out herein.
`Examples of alkylene, alkenylene and alkynylene include
`
`j(_ii]'7ClljCll_-5*, TC} I;C[:CII: _,
`
`j(“%(":(_"ll3j_, —(‘II3— fr _,
`O
`
`jCH3—Cl-ll’ CH3’(|i.‘j_.
`U
`CH3
`
`‘(ill-i3C%C'C['l-3* ,
`
`t‘=('n
`
`fill:
`
`(Fl {.3}:
`Cl I3
`
`[(—‘llz_\);-,
`
`((TH_1')_‘
`
`,
`
`(CH3):
`
`T
`Cl I3
`
`(iH_3CTl'lg
`
`,
`
`TCHEWTHT _, TCHETHCHE
`CH3
`C3115
`T(‘Ht't"Hg("Hg
`, T(‘H(‘H("Hg
`
`_, TCHCH1
`CH3
`,
`
`,
`
`Cgllf,
`
`CH;
`CH,
`
`$11};
`j(iH2—{li*(iH-3? _, j(CH-95* _,
`CH3
`
`T
`fl:
`F
`
`CH3
`
`((TH_1)_1‘
`
`W]
`CH
`CH3
`
`CH3
`CH3
`
`CH~
`
`j(CH3)_1‘*CHj _. ‘(_‘.H3*C'.I-l?f_'.j ,
`
`C113
`jClI2’CilljCII*ClI;,j _.
`
`I'_‘.[I_1
`
`(ill; C";
`
`CH3
`
`jClI3“Cill—‘CII3“ClI*‘ _. jcl l:'ClI3CH_\,—" ,
`
`CH3
`
`CH3
`
`UCU5
`
`jCH—*CH3(_iH3—* 01'
`
`(CH-_a]_\‘—CF_q—*.
`
`The term “halogen" or "halo” as used herein alone or as
`part of another group refers to chlorine, bromine, fluorine,
`and iodine as well as C173, with chlorine or fluorine being
`preferred.
`The term “metal ion” refers to alkali metal ions such as
`sodium, potassium or lithium and alkaline earth metal ions
`such as magnesium and calcium, as well as zinc and
`aluminum.
`The term “cycloheteroalkyl", as used herein alone or as
`part oi‘ another group refers to a 5-, 6- or 7-membered
`saturated or partially unsaturated ring which includes 1 to 2
`hetero atoms such as nitrogen, oxygen andfor sulfur, linked
`through a carbon atom or a heteroatom, where possible,
`optionally via the linker (CH3)? (which is defined above),
`such as
`
`12 of 101
`
`PENN EX. 2225
`
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`23
`
`US 6,344,450 B1
`
`24
`—cor1tinued
`
`530
`
`”
`”\>
`.s(\j[JA
`
`cu,
`
`[IH30
`
`N
`
`and the like.
`The ten'n “cycloheteroalkylal.kyl” as used herein alone or
`as part of another group refers to cyclolleteroalkyl groups as
`defined above linked through a C atom or heteroatom to a
`(Cl-I2)” chain.
`The term “hctcroarylalkyl” or "heteroarylalkenyl” as used
`herein alone or as part of another group refers to a heteroaryl
`group as defined above linked through a L‘ atom or hereroa—
`tom to a —((fll3),,— chain, alkylene or alkenylene as
`defined above.
`
`The term “polyhaloa1kyl" as used herein refers to an
`“alkyl” group as delined above which includes from 2 to 9,
`preferably from 2 to 5, halo substituents, such as l5 or (71,
`preferably [7, such as Cl’3CII3, Cl-'3 or Cl-‘3Cl-‘:ClI:.
`The term “polylialoalkyloxy” as used l1ereir1 refers to an
`“alkoxy” or “alkyloxy" group as defined above which
`includes from 2 to 9, preferably from 2 to 5, halo
`substituents, such as F or Cl, preferably F, such as
`Cl~‘3CH3O, CF30 or Cl~‘3Cl~‘3CH3O.
`The compounds of formula I can be present as salts, in
`particular pharrriaccutically acceptable salts. [f the com-
`pounds of formula 1 have, for example, at least one basic
`center, they can form acid addition salts. These are formed,
`for example, with strong inorganic acids, such as mineral
`acids,
`for example sulfuric acid, phosphoric acid or
`a
`hydrohalie acid, with strong organic carhoxylie acids, such
`as alkaneearboxylic acids of '1
`to 4 carbon atoms which are
`unsubstituted or substituted, for example, by halogen, for
`example acetic acid, such as saturated or unsaturated dicar-
`boxylic acids, for example oxalic, malonic, succinic, maleic,
`fumarie, phthalic or terephthalie acid, such as hydroxycar-
`boxylic acids, for example ascorbic, glycolic, lactic, malic,
`tartaric or citric acid, such as amino acids, (for example
`asparlic or glutamic acid or lysine or arginine), or benzoic
`acid, or with organic sulforiic acids, such as (C,—C,,)—a1ky1—
`or aryl-sulfonic acids which are unsubstituted or substituted,
`
`IU
`
`I5
`
`30
`
`35
`
`4U
`
`45
`
`55
`
`oil
`
`65
`
`Cr“, C/7,
`C} 0+ E},
`C7 C3’ “"”“ “”
`,
`,KA_k),
`
`and the like. The above groups may include 1 to 4 substitu-
`ents such as alkyl, halo, oxo and,-“or any of of the R‘ groups,
`or the R‘ substituents set out herein. in addition, any of the
`above rings can be fused to a cycloalkyl, aryl, heteroaryl or
`eycloheteroalliyl ring.
`
`The term “heteroaryl” as used herein alone or as part of
`another group refers to a 5- or (i—membered aromatic ring
`which includes 1, 2, 3 or 4 hetero atoms such as nitrogen,
`oxygen or suli‘ur,and such rings fused to an aryl, cycloalkyl,
`hctcroaryl or eycloheteroalkyl ring (e.g. bemiolhiophenyl,
`indolyl), and includes possible N-oxides. The heteroaryl
`group may optionally include 1 to 4 substituents such as any
`of the R1 groups or the R1 substituents set out above.
`Examples of heterearyl groups include the following:
`
`/ \
`
`/m as,
`
`13 of 101
`
`PENN EX. 2225
`
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`US 6,344,450 B1
`
`25
`for example by halogen, for example methane— or p—toluene—
`sulfonic acid. Corresponding acid addition salts can also be
`formed having,
`if desired, an additionally present basic
`center. The compounds of formula I having at least one acid
`group (for example (_'()()ll) can also form salts with bases.
`Suitable salts with bases are, for example, metal salts, such
`as alkali metal or alkaline earth metal salts, for example
`sodium, potassium or magnesium salts, or salts with ammo-
`nia or an organic amine, such as morpholine,
`thiomorpholine, piperidine, pyrrolidine, a mono—,
`(|i— or
`tri—lower alkylamine,
`for example ethyl—,
`tert—butyl—,
`diethyl—,
`r|iisopropyl—,
`triethyl—,
`tributyl— or
`(limethyl—
`propylamine, or
`a mnno—,
`di— or
`trihydroxy lower
`alkylaniinc,
`for example mono-, di- or
`trictlianolaluinc.
`Corresponding internal salts may furthermore be formed.
`Salts which are unsuitable for pharmaceutical uses but
`which can be employed, for example, for the isolation or
`purification of free compounds I or their pharmaceutically
`acceptable salts, are also included.
`include
`Preferred salts of the compounds of formula I
`monohydroehloride, hydrogensulfate, methanesulfonate,
`phosphate or nitrate.
`All stercoisomers of the compounds of the instant inven-
`tion are contemplated, either in admixture or in pure or
`substantially pure form. The compounds of the present
`invention can have asymmetric centers at any ofthe carbon
`atoms including any one of the R substituents.
`Consequently, compounds of formula I can exist in enan—
`tiomerie or diastereomerie forms or in mixtures thereof. The
`
`processes for preparation can utilize racemates, enantiomers
`or diaslereomers as starting, materials. When enantiomerie or
`diastereomerie products are prepared, they can be separated
`by conventional methods for example, chromatographic or
`fractional crystallization.
`It should be understood that the present invention includes
`prodrug forms of the compounds of formula I such as
`alkylesters of acids or any known prodrugs for
`laetam
`derivatives.
`
`The compounds of the instant invention may, for example,
`be in the free or hydrate form, and may be obtained by
`methods exemplified by the following descriptions.
`The compounds of formula I may be prepared by the
`exemplary processes described in the following reaction
`schemes. Exemplary reagents and procedures for these reac-
`tions appear hereinafter and in the working Examples.
`Compounds of formula I of the invention can be prepared
`from the corresponding amine I by using the sequence of
`steps outlined in Scheme I set out below.
`
`Re-acLio:1 Scheme I
`
`0
`
`l
`
`R
`
`II_-,N
`
`N!
`_\J/\“/ \R3
`o
`
`+
`
`?.o1'3or4or5
`
`0
`AKCl
`2
`
`1+ 33
`
`T...
`
`IU
`
`I5
`
`30
`
`35
`
`4U
`
`45
`
`SU
`
`55
`
`6E
`
`65
`
`R I
`/’
`N
`\.R3;
`
`0
`
`0
`
`26
`—continued
`
`R
`
`II
`N
`
`0
`Y N
`
`0
`
`[D
`
`OI’
`
`St: I fonylati on
`
`(Kg//o
`19/‘ \‘‘(:t
`3
`
`R"\ ‘/ix!
`//"\\
`0
`0
`
`In
`
`or
`
`;
`
`0
`
`Cl
`
`Co ndensaiion
`
`01‘
`
`or
`
`C0 ndensaiion
`
`It‘
`
`[B
`
`in an inert organic solvent such as
`Reaction of amine l
`dichloromethane, chloroform or tetrahyclrofuran with reac-
`tant acid chloride 2, sulfonyl chloride 3, ehloroformate 4 or
`carbamoylehloride 5, employing a molar ratio of reactan-
`t:amine 1 within the range from about 5:'l
`to about 1:5,
`optionally in the presence of an acid scavenger such as
`triethylamine, diisopropylethylamine. pyridine, or
`polyvinylpyridine, forms compounds ID, IA, IC or IE ofthe
`invention.
`
`Starting compound 1 can be prepared by methods known
`in the art as outlined in Reaction Scheme IA below.
`
`14 of 101
`
`PENN EX. 2225
`
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`US 6,344,450 B1
`
`28
`
`Rezn;'.iuJ1 Scltt-:n'J: l[
`
`27
`
`Re action Scheme IA
`
`Bociifi
`
`0
`
`NH.
`
`Oil
`
`NW
`U
`
`D
`
`R‘
`\
`R6/.
`
`at
`
`0
`
`ProcedurL'.A
`Amidation
`
`1; nNR‘R” (21)
`D[G"[IOAU'CH;Cl3;'D.\:IF
`
`2) SCX l".trigication
`Procedure B
`Ainitlation
`
`1) nNR‘R3 (9.1)
`EDACJDMAI’.-"ClI—_:Cig
`2] SCX P‘.lt‘iglCflIi0t1
`O
`
`R‘
`
`J
`NW. ex“?
`
`0
`
`11;
`
`Procedu re A
`
`For amines where R‘ andfor R” contain additional basic
`nitrugens.
`
`Procedure B
`
`For amines where R1 andfor R3 contain no additional
`basic nitrogcns.
`
`In Procedure A {for amines where R1 andfor R7‘ contain
`additional basic nitrogens), a mixture of a solution of amine
`21 in an inert organic solvent such as THE, rI1ctl1ylct1ccl1lo—
`ride or chlorofonrt. a carbodiimide such as diisopropylcar-
`bodiimide (DIC) and 7—aza—1—hydroxy—benzotriazole
`(HOAt] is reacted with acid 20, employing a molar ratio of
`amine Zltacid '20 within the range from about 5:] to about
`1:5, preferably at about l:l.1, to form a reaction mixture
`which is purified via an SCX column to separate out
`compound IB of the invention.
`
`The DIC will be employed in a molar ratio to acid 20
`within the range from about 5:1 to about 1:5, preferably at
`about 1_t'i:'l , and the HOAI will be employed in a molar ratio
`acid 20 within the range from about 5:1 to about 1:5,
`preferably at about 1.6:l.
`
`In Procedure R (foramines where R1 anrlfor R: contain no
`additional basic nitrogens) a mixture of a solution of amine
`2|
`in an inert organic solvent such as THE methylenechlo-
`ride or chloroform, ethyldimethylaminopropylcarbodiimidc
`(EDAC) and dimethylaminopyridine (DMAP) with acid 20,
`employing a molar ratio of amine 2l:acid 20 within the
`range from about 5:1 to about 1:5, preferably at about 15:1,
`to form a reaction mixture which is purified via a SCX
`column to separate out compound 1B of the invention.
`
`The EDAC will be employed in a molar ratio to acid 20
`within the range from about 5:1 to about 1.5, preferably at
`about 15:1, and the DMAP will be employed in a molar
`ratio to acid 20 within the range from about 5:1 to about l:5,
`preferably at about 1.5:1.
`
`Starling compound 20 can be prepared by methods known
`in the art as outlined in Reaction Scheme IIA.
`
`IU
`
`I5
`
`30
`
`35
`
`4U
`
`45
`
`SU
`
`55
`
`oil
`
`65
`
`O
`
`15
`
`14
`
`Acylalion
`I'It3N, (.‘Hg(T|3_. ll" (T.-r.t., 36 h. .
`
`BI’
`
`()
`
`I R
`
`\N
`18/ 16
`
`13 t
`
`o
`.
`ljnlkvlation
`.._\
`_
`-
`‘J5 on -
`L'.llMDS,'I'lIl"
`”‘
`N
`r.t._. ‘l-4h
`2)Deprotection
`'I‘l*'J’\;'(THg(Tl-3
`
`/R‘
`N
`‘EH3
`
`()
`
`Compound '1 is a novel compound provided that R‘ and R:
`are as defined herein, but excludes alkyl, alkcnyl, aryl,
`arylalkyl, cycloalkyl or polycycloalkyl.
`
`Compounds of formula I of the invention wherein
`
`that is
`
`it“
`
`t~'—c?,
`
`I25
`
`0
`
`can be prepared from the cor