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`US[)[l672()351B2
`
`(13) United States Patent
`Bertinato et al.
`
`(111) Patent No.:
`(45) Date of Patent:
`
`US 6,720,351 B2
`Apr. 13, 20114
`
`(54)
`
`(75)
`
`'l'RlAM[lllE-5UIl.S'I'I'l'U'[‘l£[)
`HETEROBICYCIJIC C()M[’()UNl)b
`
`Inventors: Peter Bertinato, Old Lyme, CT (US);
`Alan E. Blizc, New Irmdon, (_”l'(US);
`Brian S. Fltronk, (iale:-5 Perry, (_'I' (US);
`Hengmiao Cltcng, East Lyme, CT
`(US); Jin Li. Pztwealuck, CT (US);
`Hiep Hltatan, Sandwich (GB); Clive
`Mason, Sandwich (GB)
`
`(73)
`
`Assignee: Pfizer lnc., New York, NY (US)
`
`(‘J
`
`Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U,S.C‘. 154(b) by 114 days.
`
`(21)
`
`Appl. No.: 1(l;’l'77,858
`
`(22)
`
`Filed:
`
`(55)
`
`Jun. 20, 2002
`Prior Publication Data
`
`US 200310187053 Al Oct. 2, 2003
`
`Related U.S. Appllcatinn Data
`Egg;-iisional application No. 5cI,»'301,o'44,
`tiled on Jun. 28,
`‘
`7
`1m- (-1-
`US. Cl.
`(58) Field of Search
`
`-
`
`
`
`A51K_31(‘w’5
`3481492
`548E492; 5141415
`
`(60)
`
`(51)
`
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`31"1lJ.‘J5
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`121’2UU1
`512002
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`064305?
`1080724
`1131954
`11584446
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`(}'l‘Hl:'R PUBI .I(‘A'['l0NS
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`Wattle-rau, J.R., el al., Science, "Absence mt‘ Mierusumal
`Triglycaride '1t'ansfcr Protein in lrtdividtials with Abetallpo—
`proleinelnia”, vol. 258, (Nov. 6, l992].
`Watlerau, .l.R. et al., liiocltfrrtfca of[1iopIt_)=.sicrz /lam, “I oc:tl—
`iz.alioI1 taflntraeellular Triaeylglyuerol and Cliolesteryl Ester
`'l'rans|'er Activity In Rat
`'l'i.~;s;ues", vol. 875 pp. 1110-01?
`(1986).
`
`Joscph K’ M‘-_Kam_r
`1,n.mmy Emmimfr
`A5;$I'.s't'(1nt E.t(:It1iner—Robert Shiao
`(74) /1£t0rr1e_yj.Agrertt_. or I".irm—l’eter C. Richardson; Gregg
`(L Bcn5on;Ar1cnc K_ \-‘lugscr
`(57)
`ABSTRACT
`
`(56)
`
`References Cited
`us. PAT].-'N'l‘ 1)ocUM1;N'1‘s
`
`The invention relates to triamide MTPI/\poB inhibitors of
`“W fomwla 1
`
`4_.E}22}J(I) A
`4_.39'r'_.85S A
`5,4l(),(]()9 A
`5_.7"l2_.2?‘.J A
`5,731,340 A
`S_.T"4l,8()4 A
`S.‘Jl‘)_,7‘.J5 A
`5_,‘)fi8,‘)5l') A
`I‘;v,[)l‘)f)_.t':xia3 A
`13,121,283 A
`lf:1.19?.798 131
`13,235,730 B1
`11,281,228 111
`(,:2gg’Q_34 g1
`15_33'?.344 B1
`2(J()2t’UU32238 A1
`
`.5,-"1‘J'F|'7 Mathison
`811083 Sircar
`5{1‘JF)5 Lznzzeri et al
`l_~"19‘.)8 Biller el dl
`3,."1‘JU8 Bras et .11
`4{1‘)‘.JS Keenan ct al.
`".’{1‘J‘.)9 Cltang et al.
`II'l,"I‘)‘)‘) Qtlallirrh et‘
`i>1"'z‘.UUt'.J Uregg et al.
`9;"2OUU Chang et ul.
`312001 Fink et al.
`5t2r1t11 Sato (rial.
`51121111
`"[1110
`(_,V2j_‘[]‘1
`(;,-[1-‘fin
`1{20[J2 Defossa e1a[,
`312002 l’ri.epke el al.
`
`.
`
`.
`:1].
`..
`
`
`
`4243258
`424.1250
`43369.3
`514.1252
`514.1415
`514K394
`514.1310
`51413111
`514.1325
`514.-'30?
`514.1354
`514121111
`514,319
`A 5.1(,,19[].
`5143415
`5141616
`
`1
`
`
`
`.
`..
`.
`.
`.
`\"“113-“-
`“'h°“”“ Rlfks 315 35 ‘3°'_l1P°d‘“ “"3 -‘*P¢C1“¢i“1°"s
`pharmaoeiitacal onmpnstttrms and ‘USES thereof, and pro-
`ceases lor preparing the compounds. The compounds oi the
`invention are I1se|'1J| for the treatment of rthesity and lipid
`
`I~()Rl_-l(:N PAIL-NI [)()(.UMh-NIB
`
`‘W °"‘
`
`Dli
`
`199-15594
`
`3,r2()()l
`
`CIJTIJ-’295;(14
`
`45 Claims, 6 Drawing Sheets
`
`1 of 44
`
`PENN EX. 2156
`CFAD V. UPENN
`IPR2015-01836
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`

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`U.S. Patent
`
`Apr. 13, 2004
`
`Sheet 1 of 6
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`US 6,720,351 B2
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`50
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`40
`
`2030
`
`‘E0
`
`2 0f44
`
`PENN EX. 2156
`CFAD V. UPENN
`IPR2015-01836
`
`FIG.1
`
`250
`
`

`
`U.S. Patent
`
`Apr. 13, 2004
`
`Sheet 2 of 6
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`US 6,720,351 B2
`
`FIG.2
`
`200
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`180
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`160
`
`140
`
`100120
`
`80
`
`60
`
`50
`
`3 0f44
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`PENN EX. 2156
`CFAD V. UPENN
`IPR2015-01836
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`

`
`U.S. Patent
`
`Apr. 13, 2004
`
`Sheet 3 of 6
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`US 6,720,351 B2
`
`FIG.3
`
`C.)
`C)
`<"'~l1:
`
`1200
`
`4 0f44
`
`PENN EX. 2156
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`U.S. Patent
`
`Apr. 13, 2004
`
`Sheet 4 of 6
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`US 6,720,351 B2
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`5 0f44
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`PENN EX. 2156
`CFAD V. UPENN
`IPR2015-01836
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`5C
`
`3
`(‘NI
`,._
`
`FIG.4
`
`1200
`
`

`
`U.S. Patent
`
`Apr. 13, 2004
`
`Sheet 5 of 6
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`US 6,720,351 B2
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`6 0f44
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`PENN EX. 2156
`CFAD V. UPENN
`IPR2015-01836
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`33C
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`“I-
`
`1200
`
`FIG.5
`
`

`
`U.S. Patent
`
`Apr. 13, 2004
`
`Sheet 5 of 6
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`US 6,720,351 B2
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`7 0f44
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`PENN EX. 2156
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`IPR2015-01836
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`3L
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`n-2--
`
`

`
`1
`TRIAMII)l*I-SUBS'[‘[TU'I‘EI)
`HETEROBICYCLIC COMPOUNDS
`
`US 6,72(),35 1 B2
`
`2
`SUMMARY OF THE INVENTION
`
`The present invention relates to compounds of the for-
`mula I:
`
`This application claims benefit of the provisional appli-
`cation No. otl,t3(Jl,ti44, filed on Jun. 28, 2U()l.
`l~'Il:‘.l_[) 01*" THE lNV"l:‘.N'l‘[(}N
`
`S
`
`This invention relates to trianiide-substituted heterobicy-
`clic compounds. These compounds are inhibitors of 10
`microsorrial triglyceride transfer protein (MTP) andfor apo-
`lipoprotein B [Apo B) secretion and are usel‘u|
`for the
`Ire atmcnt of obesity and related diseases. These compounds
`
`are also useful for the prevention and treatment of athcro- H
`3516.08“ and its ulimcal wquclafl’ for lijwfllng Siimln hpdds’
`and in the prevention and treatment of related rliseases. l'hc
`.
`.
`_
`,
`‘
`_
`._‘
`‘.
`.
`_
`invention further relates to pharma(.eutir..al compositions
`comprising these compounds and to methods of treating
`obesity, atherosclerosis, and related diseases andior condi— 30
`trons with said compounds, either alone or ll'I cniiihinaltoii
`with other medicamc-nts, including lipid lowering agents.
`Further still, the invention relates to certain processes and
`intermediates related thereto which are tiseftil in the prepa-
`ration of the compounds of the instant invention.
`
`'15
`
`Bi\(TK(}R()UNl) OF 'I‘I[L". [N\«’l_-‘N'|‘]t)N
`Microsoiiial
`triglyceride transfer protein catalyzes the
`transport oftriglyoeridc, cholestcryl ester, and phospholipids 30
`and has been implicated as a putative mediator in the
`assembly of A130 ll-containing lipoproteins, liiomolecules
`which contribute to the formation of atherosclerotic lesions.
`Specifically,
`the suhcellular
`(lumen oi‘
`the microsrimal “
`fraction) and tissue distribution (liver and intestine) of MTP "
`have led to speculation that it plays a role in the assembly of
`plasma lipoproteiiis, as these are the sites of plasma lipo-
`protein assembly. The ability of Mil’ to catalyze the trans—
`port of triglyceride between membranes is consistent with 40
`this speculation, and suggests that MTP may catalyze the
`transport of triglyceride from its site of synthesis in the
`endoplasmic reticulum membrane to nascent
`lipoprotein
`particles within the lumen of the endoplasmic reticulum.
`_
`_
`_
`_
`_
`_
`‘
`Accordingly, compounds which inhibit M II-’ andior oth—
`crwisc inhihit Apo B secretion are useful in the treatment of
`atherosclerosis and other conditions related‘ thereto. Such
`compounds are also useful in the treatment ol other diseases
`or coiiditions in which, by inhibiting MTP andfor Apo B 50
`secretion, serum cholesterol and triglyceride levels may be
`reduced. Such conditions may include, for example,
`hypercholestcrolemia, hypertriglyceridcmia, panereatitis,
`and
`obesity;
`and
`hypercholesterolemia,
`hypertriglyceridemia, and hyperlipidemia associated with 55
`pancreatitis, obesity, and diabetes. For at detailed discussion,
`see for example, Wctteraii er al_, Science, 258, 999—l(}t]l,
`(1992), Wctterau ct al.,
`l-liocheni.
`l-liophys.
`/\r.'t:t., 875,
`fil0—fil?' (1986),
`I-Luropean patent application publication
`Nos. 0 584 446 A2, and 0 (143057 At, the latter of which an
`refers to certain compounds which have utility as inhibitors
`ofMT'P. Other examples of MTP inhibitors may be found in
`c_g_, 1.1..‘-‘s. Pat. Nos. 5,?l2,27‘},5,'.’4t,8tl4, 5,9na,95ri, {),[l(){l,
`[$53, and 6,121,283; PCT International Patent Application
`publications W0 ‘JGI4-(tt’i4(l, Wt] 9'?i'432S7, Wt) ‘)8_t27'<}'.r'9,
`VVO 99/33800 and W0 00,’0520'l; and European patent
`application puhlirrations I-Ll’ 584446 and El’ t’i43,tJ5?_
`
`45
`
`Elf‘!
`
`1
`
`
`
`NR"???
`
`or a pharmaoeutically acceptable salt thereol‘, wherein:
`,
`_
`,
`_
`_
`,
`R is siil'is.Iit.iite(i at the J or 6 position of formula 1 and has
`the m_uCmm_
`‘
`'
`
`‘U,
`
`,,
`(R J’
`
`_
`-‘F
`"
`Ifi
`|‘ ¢:L: ‘
`I
`
`m is an integer from 0 to 5;
`n is an I-megcr from U 10 3;
`p is an mtcgcr fiom 0,m 3;
`L 15 —C(0)N{R' )—i 1'0" L has lhc Slmclumi
`0
`
`5;
`
`0
`
`X 35 N 0" CIR“);
`R2, R“, R”, R”, R” and R1“ are each independently
`selected from halo,cyano, nitro, azido, amino, hydroxy,
`(C ,—Cc,)2ill<yl,(C_._—C‘,,)alkoxy, methoxy,(C 1—Cc,]2tl.l.\'0)(}«'
`(Ci—Ct;la1k)’1- 31000‘:
`(ll-' 01'
`l1'l'hal0(C2—Cai|31kYL
`Pflfllmro ( C2‘C.-. ) 3119']:
`[Ti 1111010 me Ill Y1:
`triJ1uoron1ethyl(C,—C5)a1lr.yl.
`rnono—,
`di— or
`tri—halo
`(C2_Cfi)a1k,_,xy, Um"0mmmhy1(C1_C§)auwxy’
`((_‘1_c6]a]ky]1]qio, hyrlroxy(C1—C5)alkyl,_ (C3-C8)
`CyC10a[ky1{CR"R”)q_’
`(C__:_C6)a1ken},1’ (cfco)
`alkynyl,
`((j,—(“_,,)a]ky1amjn0.,
`(Cl—Cfi)d[a_[ky[3_n'][n{),
`amino{C,—C,,)alkyl-, —(C‘R“R"),,NRf’R”, —(_‘(tJ)
`NR"R 1" , —I\'R 1 “ C(0)R 1 5 , —NR‘ "OR ' 5,
`—(TH=N()Rl5, —NR1'l(‘([))()t{”, —Nl{l’lS(()),.lt15,
`Cl 0 }R 1 5 s
`C(0}0R15 .
`0 Cl 0 l R 1 5,
`—S02NR"R14» —-9(0);-Risa 01' —(CR"R£')qS(0L-R15;
`each R” and R" is intiepenrlcntly H or ((T,—C,,)alkyl;
`Rs [5 H gr R“;
`Each (1 is indcpcndently an integer from O In 6,
`.
`.
`.
`7
`I or 2;
`Bach-I '5 'mlCpmdcm1y 0’
`R“ is H, hi-Iv. ((‘i-‘Baikal. Dr mono-. di- or Iri-halo
`(C1 Cnlalkyli
`R" is 11, (C,—C,,)a]ky1, (C3—C3)cycloall;y], —(.‘(())R‘5,
`—C(S)R”, —(CR"R“),0(C,—C,,. alkyl), —((‘.R"R”),S
`(CJ—C,_;alliy]), —(CR"Rl’),C(O)R15, —((.'R"R"’),R'5,
`—S02R“ or —(CR”R”),,,-phenyl, wherein the phenyl
`moiety is optionally substituted with from one to live
`independently selected Rm;
`
`3 of 44
`
`PENN EX. 2156
`CFAD V. UPENN
`IPRZOIS-01836
`
`

`
`US 6,72(),35 1 B2
`
`4
`In another embodiment of the invention, X is CIR").
`In another einboditnent of the invention, X is C(R"), m is
`I), n is 0, and p is [I or I.
`In another embodiment of the invention, X is (T{R"], m is
`(I, n is (1, and p is U or I, and Rm is pheny1—Z2— attached at
`the 3 position of R1, wherein the phenyl moiety of R10 is
`optionally substituted with one to five independently
`selected R”.
`In another embodiment of the invention, X is (T{R"], m is
`I}, n is 0, and p is [J or I, and R30 is phenyl attached at the
`3 position of R1, wherein the phenyl moiety of Rm is
`optionally substituted with one to live independently
`selected R”.
`In another embodiment of the invention, R7 is phenyl-Z1,
`wherein the phony] moiety is optionally substituted with one
`to live independently selected R”. In a preferred embodi-
`ment of the invention, Z1 is —((.‘R“R"’),.—, and in a more
`preferred embodiment, Z1 is methylene, i.c., —{III,_.—_.
`In another embodiment of the invention, R‘, R5, R" and
`R9 are each independently selected from II, (C,—C,,)a1kyl,
`—(CI{“I{"),,U(CT,—C,,al.kyl) or —(CR”l{”),_l{l5.
`In another embodiment of the invention, each R” is
`independently selected from halo, hydroxy, (C ,—C,,)atkyl,
`metltoxy,
`(C:—C,.,)alkoxy,
`[C1—CU)alltoxy(Cl—C6)alkyl,
`mono—,
`di— or
`tri—halo((I2—(I,,)alkyl,
`trifluoromethyl,
`trifIuoromethyl(C,—C5)alkyl, mono—, di— or tri-halo{C1—C,,)
`alkoxy,
`trifluoromethyl(C‘,—(‘,,)alkoxy,
`((‘.,—C,,)alkylthio
`a nd hydroxy( C 1 —LT,, )alkyl.
`In another embodiment of the invention, each R13 is
`independently selected from halo, hydroxy, amino, cyano,
`(C.—C,-,)al.kyl,
`(C¢,_—C,-,)alkenyl, melhoxy,
`(C_-,_—C,,)allaoxy,
`(C,—C,,)alkoxy(C,—('7,,)alltyl, Inono-, di— or tri-ltalo(C2—C,,)
`alkyl, trilluoromethyl, triIluorornethyl[C,—C,)aII-zyl, mono—,
`di— or tri-halo[(f:—(I5)alkoxy, trifluoromcthyl((Il—(f5)alIcoxy,
`((“.,—CO?alkylthio, hydroxy[C —Cc,)all<yl, —(".(0)0R” anti
`—NR1'C(0_}R15; wherein R 'l is II or [C1—C,,)alkyl; and
`wherein R” is II or (C,—C6)alkyl.
`In another embodiment of the invention, Rm is phenyl
`attached at the 3 position ofR1, wherein the phenyl moiety
`of R10 is optionally substituted with one R13. In El preferred
`embodiment, R1” and R1 both are phenyl, such that R1 and
`R1” together form a 1,l'—biphenyl group, wherein R” com-
`prises the 1'—6" positions of the biphenyl group and R‘: is
`substituted at the 4’ position of the biphenyl.
`In another embodiment ofthe invention, R4 is II, (C,—CO)
`al.kyl or —(CR”R"’)g,O(C,—C,,aIkyI).
`the carbon
`In another embodiment of
`the invention,
`designated "a" in formula I is in the “(S)" configuration.
`In a preferred embodiment of the invention, R13 is trif-
`Iuoromethyl.
`In another preferred embodiment of the invention, R“ is
`H, halo, or ((I,—(I6)alkyl.
`In a more preferred embodiment of the invention, R" is
`methyl.
`In a particularly preferred embodiment of the invention,
`the compound of formula 1
`is
`(S)—l—cthyl—5—[(4'—
`trifluoromethyl-biphenyl-2-carbonyl)-amine]-tII-indole-2-
`carboxylic acid {2—|benzyI(methyI)amino]—2—oxo—1—
`phenylethyl]-amide.
`In another particularly preferred embodiment of the
`invention, the compound of formula 1 is (S)—N—{2—[ben7yl
`(methyl)amino]-2-oxo-'1-phenylethyl}-'1-methyl-5-[45
`(trifinoromethyI)[l,l '—hiphenyl]—2—carboxamirio]—l H-
`indole—2—carboxamide.
`In another more preferred embodiment of the invention
`R3 is ehloro.
`In another particularly preferred embodiment of the
`invention, the compound of formula 1
`is selected from the
`group consisting of:
`
`10
`
`I5
`
`‘
`
`30
`
`40
`
`4-5
`
`50
`
`55
`
`ft?!
`
`3
`each r is independently an integer from 2 to 5;
`each t is independently an integer from 1 to 6;
`R5, RI’ and R” are each independently II, (Cl—C,,)al.k.yl,
`[C_-,—C,,)cyeloalI\'yl, —C(O)R”,
`C(S)R”,
`—(CTl{"l{"),()((T,—(T,,alkyI), —((fl{"R”),S{(T,—(T,,alkyI),
`—{CR"R”),.R‘5 or fi9O;._R'5;
`R7 is phenyl, pyridyl, phenyl-Z‘— or pyridyl-Z‘—,
`wherein the phenyl or pyridyl moiety is optionally
`substituted with one to live independently selected R”;
`Z1 is fiS[J2— or —{(il{"Ri’).,—;
`v is independently an integer from I to 6;
`R” is phenyl, pyridyl, pheny1—Z3— or pyridyl—Z:—,
`wherein the phenyl or pyridyl moiety is optionally
`substituted with one to five independently selected 1113;
`Z3 is —S((J),.—, —0—, —(CR"R"’),,.—, or —(U),,
`(t.‘R"R"),,,((J),,(t.‘R"R”),,
`;
`w is independently an integer from 1 to 6;
`each It is independently D or 1;
`(C3-C3)
`(C,—C,.)alkyl,
`each R” is
`independently H,
`eycloalkyl, —C(0)R”, —C(S)Ri'5), —((“.R"Rb),0
`[C,—C,,.alkyl),
`(CR"R”),S(C,—C,,alkyI), —{(“_R"R”),
`(“[0)Rl5, —((“.R"R"’),R” or fl§O2R”;
`(C3-C3)
`each R35 is
`independently II,
`(C,—C,,)alkyl,
`cycloalkyl,
`trilluoromethyl,
`trilluoromethy|(C1—C5)
`alkyl, wherein the alkyl, moieties of the foregoing R15
`groups are independently optionally substituted with l
`to 3 substituents independently selected from
`Cl—CDaIkyl, Cl—CoaIl~'.oxy, amino, hydroxy, halo,
`cyano, nitro, trifluoromethyl and trifluoromethoxy;
`and wherein any of the above “al.kyl”, “alkenyl” or
`"alkynyl" moieties oomprising at (TII3 (methyl), CI]:
`(methylene), or CH (methine) group which is not
`su bst.it.t1 ted with halogen, S0 or 302, or attached to a N,
`U or 8 atom, optionally bears on said methyl, methyl-
`ene or methine group a snbstituent selected from the
`group consisting of halo, —UR“, %fRfl and —NR“R".
`In an entltodiment of the invention, I. is attached to the 2
`position of R‘ and to the 5 position of formula 1, i.e., the
`compound of formula I has the structure of formula Ia;
`
`;
`
` (Rub:
`
`K\
`
`\e_> X
`
`In another embodiment of the invention, I. is attached to
`the 2 position of R; and to the 5 position of formula 1, and
`Rm is attached at the 3' position.
`In another embodiment of the invention, L is attached to
`the 3 position of R1 and to the 5 position formula I.
`In
`another embodiment of the invention, L is attached to the 3
`position ofRl and to the 5 position of formula 1 and X is N.
`In still another embodiment of the invention, L is attached to
`the 3 position of R‘ and to the 5 position of formula I, X is
`N and R10 is attached at
`the 2 position of R1.
`In other
`embodiments of the invention, the attachment of L to R1 is
`selected from the 3, 4, (1 or 6 position and the attachment of
`L to the compound of formula 1
`is selected from the 5
`position or 6 position.
`
`9of44
`
`PENN EX. 2156
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`US 6,72(),35 1 B2
`
`5
`3—chloro—S—[(4'—tritlttoromethyl—biphenyl—2—ear|)onyl)—
`amino]—tH—indoIt:—2—catrhoxylie acid {2—[|:-en’/.y]
`[methyl)amino]—2—oxo—l—phenylethyl}amide;
`3—chloro—1—methyl—5—[(4'—trifluoromethyt—biphenyl-2-
`earbonyl)-amino]-1II-indole-2-carboxylic acid {2-
`[benzyl(methyl)amino]—2—oxo—I—phenylethyl]-amide;
`4'—trifluoromethyl—bipheny1—2—carhoxylic acid [2—({
`[(benzyl-methyl-carbamoyl)-phenyl-methyl]-methyh
`amino}-methyl)-3-ch1oro-J.-methyl- 1II-indol-5-yl]-
`amide, which is alternately named: 3-ehloro-l-methyl-
`5-[(4'-trilluoromeIhyl-biphenyl-2-carbonyl)-amino}
`1Il-inclole-2-earboxylie acid {N-[2-(benzyl(rnethyl)
`amino)-2-oxo-1-phenylethyl]methyl}amide;
`3—ehloro—t —methyl—5—[methyI—(4'—1ri|'|1toromethyI—
`biphenyl-2-carbonyl]-amino}II-[-indole-2-carboxylic
`acid {2—[ben'.r.yl(met.hyl)amino]—2—oxo—t—
`phenylethyl}amide; and
`3-chloro-1-ethyl-5-[(4'-trilluoromethyl-biphenyl-L
`earbonyl)—anJino]—1H—it1dole—2—carboxylic acid {2-
`[benzyl(methyl)amino]—2—oxo—I—phenylethyl}amide.
`In another embodiment of the invention, X is C(R“), n1 is
`U, n is [1, and p is U or '1, and 1?.” is phenyl—Z2—attached at
`the 3'-position, wherein the phenyl moiety of R1” is option-
`ally substituted with one to five independently selected R13
`and Z2 is 0 or S.
`In another embodiment of the invention, R7 is phenyl-Z1,
`wherein the phenyl moiety is optionally substituted with one
`to live independently selected R‘: and Z1 is O or S.
`ln another embodiment of the invention, RH’ is pyridyl-Z' ,
`wherein the pyridyl moiety is optionally substituted with
`from one to five independently selected R”. In a preferred
`embodiment thereof, Z1 is —{(T[-I.1)—.
`In another embodiment of the invention, X is N and l{m
`is phenyl optionally substituted with one to live indepen-
`dently selected II”.
`In another embodiment of the invention, X is N and Rm
`is phenyl optionally substituted with one to live indepen-
`dently selecled R”, and R7 is phenyl-Z1, wherein the phenyl
`moiety is optionally substituted with from one to live
`independently selected R”.
`The present invention also relates to a compound of the
`formula lb:
`
`10
`
`15
`
`30
`
`40
`
`lb
`
`4-5
`
`
`
`N1t*’1t7
`
`--
`
`R3
`
`or a pharmaceutically aeeeptalile salt thereof, wherein.
`R1 is substituted at the S or 6 position of Formula "II: and
`has the structure:
`
`U
`(R )9
`
`R19‘/_\
`5%;
`5'
`5/
`
`|-I
`
`LT:
`
`or when R7 is phenyl, pyridyl, phenyl-Zl— or pyridy|-
`ZJ— optionally substituted with one to live indepen-
`dently selecled R1‘, R1 is (C'J—C‘o)alkyl,
`(C3-C3)
`
`50
`
`55
`
`ft?!
`
`6
`((".R“R"),O
`(C5 C,,,)bieycloall<yl,
`cyeloalkyl,
`(C1—Cc,alkyI), —(CR”Ri‘),S(C1—C0a|kyl), —(CR"R'i’),.
`(:(0)tz”, —(t:tz“tz"),R15,
`s(J,tzl5{(:,,—(:m)
`heterocyclyl, ((“5—C1o)heteroaryl, aryl or —((‘.R"Ri')q—
`aryl, wherein the cycloalkyl, heterocyclyl, heteroaryl or
`aryl moiety is optionally snhstitutetl with From one to
`live independently selected R”’;
`m is an integer from 0 to 5;
`n is an integer lrorn (J to 3;
`p is an integer from (I to 3;
`L is —C(())N(R9')—, as described above;
`X1 is N(l~’.‘l), S or (J;
`is N or C(R");
`R3, R“, R“, R”, R” and R” are each independently
`selected from halo, cy ano, nitro, azido, amino, hydroxy,
`((.‘,—(_‘,,)a|l<yl, [(I2—(.‘,__._)alkoxy, rr1ethoxy,{(I,—(I(,)a|ko)ry
`(Cl—C6)alkyl, mono-, di- or
`lrt—halo(C;._—(.‘6)alkyl,
`perlluoro(L'3—C,,)alky],
`trilluoromethyl,
`trifluoromethy|(C,—C5)a]kyl. mono-, di- or
`tri-halo
`(C2—C(,)alkoxy,
`tril'luoromethyl(C',—C5)alkoxy,
`(C1—C5)alkyltl:tio,
`lrydroxy(C,—C6)alkyl,
`(C_.,,—(.}_,)
`cyeloalkyl{CR“R°)q—, {(".._.—Cn)alkenyl,
`(C2—Cfl)
`alkynyl,
`(C1—C,.;)alkylat11ino—,
`(C1—C6)dlall{}’l£Ll1'llt'10,
`aminn{(Jl—('.‘O)all<yl-, —(CR"R")qNR"RL“, —C(O)
`NR(rR14! T_N'RJ4C(O]R15’ TNRl40R15’
`—Cl[=NOR1”, —NR1"C(O)OR’5, —NRl‘lS(0) R15,
`—C(O)R‘5, —(".(S)R”, —C(O)OR15, —0C(OjR15,
`/St‘t.:NR"‘R“', —s(o),_R‘5 or —(CR”R”]qS{O)jR‘5;
`each R" and Rb is independently II or (C,—C,_.,)al.kyl;
`R‘ is H or R”;
`each (1 is independently an integer from 0 to 6;
`each j is independently U, 1 or 2;
`R3 is II. halo, (CJ—CC,)all<yl, or mono-, di- or tri-halo
`(C1—{f6}alkyl;
`R4 is II. (C1—C6)a1kyl, (C3—CB)cycloalkyl, —C(O)R15,
`—c(s)tt‘-‘-, —{CR”Rl’),U[C1—C°alkyl), —(CR"R"’),S
`(Cl—C,5alléyl);{—{(Tl{':l;"),Cl€]0)R1'5, h—(CR;R”),t{ '5,
`fi‘SU:R ' or
`CR“R’ ,—p eny ,w ereint ephenyt
`moiety is optionally substituted with from one to five
`independently selected R”;
`each r is independently an integer from 2 to 5;
`each I is independently an integer from 1 to 6;
`R5 and R5’ are each independently H,
`((.‘1—(_‘fi)a1kyl,
`(C.‘3—CR)cycloalkyl, —C[O)R”, —C(S)R”,
`:((CR“R:§,O$C1)—CiTi‘,all2I(l). —(E)TR"i{:'),S(CJ—C(,a|].léyl),
`CR"R ,(T 0 R ',
`[TR"R ,.R ' or fi‘~3():R ';
`11°
`is H, (C1—C6_)alkyl, (C3—CB)eyeloalk_v], —C(O)R”,
`/C(S)Rl5, —(CR"l{”), O(C1—[.‘6§ll<yl),
`(CbR"R':)
`((?1—(f6_all§yl], —((?R"R£'),(T([))R , —((IR"R ),R“ or
`—St).R '
`;
`y is an integer from (1 to 5;
`(C:—C6)alkynyl,
`R7 is ((fl—C6]alkyl,
`[C:._—(T6)alkenyl,
`,[CR“R"’)qO(CJ—CL,alkyl), —(Cl1:\:_‘"Rh)qS
`(C1—C5till()'l:I; (C3—Cg]cyeloalkyl,
`C(O)R ',
`R15’ _{CRaR.u)rC(O)R1s’
`(CRnRz;)rC(S)R15’
`—(CR"'R”),R'5 or —S02R'5;
`or R7 is phenyl, pyridyl, phenyl—Z]— or pyridyl—Z'—
`optionally substituted with one to five independently
`selected R”;
`or 11° and R7 taken together with the nitrogen atom to
`which they are attached together comprise ((?_,—(‘.m)
`heterocyclyl, wherein the heterocyclyl moiety is mono-
`cyclic;
`
`10 of 44
`
`PENN EX. 2156
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`US 6,72(),35 1 B2
`
`7
`wherein the alkyl, cyeloalkyl, and heterocyclyl moieties
`of the foregoing R“ and R7 groups are optionally
`substituted independently with I to 3 snbstirucnts inde-
`pendently selected from halo, cyano, nitro,
`tritluoromethyl,
`triiluoromethoxy, azido, —()l{‘5,
`—C.‘[O)R”, —C(O)OR15, —OC(O)R15, NR”C[O)
`R1’, —C(O)NR“R”, —NR“R“, and —NR”OR”,
`("1—(".0all<yl, C2-C6 alkenyl, and C2-C3 alkynyl; and
`R1” is phenyl. pyridyl, phenyl-Zz— or pyridyl-Z2—,
`wherein the phenyl or pyridyl moiety is oplionall
`substituted with one to five independently selected R1 ;
`Z2 is —S(0);.—, —O—, —((“R"R"’),,.—, or —(O),&
`[(?R“RE")“)((J),,((?R"R‘i‘)q
`;
`w is independently an integer from "I to 6;
`each k is independently 0 or "I;
`or Rm is OR”, wherein R17 is (Cl—C,,}al.kyl, (C1-C0)
`allt'oxy((T,—Cl,,]alkyl, mono—, or lri-halo ((l_.—[T5)alkyl,
`perfluoro(C:._—C,,)alkyl.
`Irifluoromethy](C,—C‘5)al.ltyl,
`hydroxy[C1—C,,-)alkyl,
`((T3—(Tgjucycloalkyl(CR"R")q—,
`((‘3—(T6)alkenyl, or ((T:—(‘6]al1-rynyl;
`(C3-C8)
`each R“ is
`independently Ii,
`(C,—CR)alkyl,
`eyeloalkyl, —c(o)tt”, —c(s)1t”, —(t_.‘l-’."l{")f,U
`[Cl—C6alkyl). —(CR"R”),S(C,—C6all-iyl), —{CR"R ’),.
`t.‘(o)1z15, —((:R"1t"),i{15 or fie-:i,tt”;
`(C3-C3)
`each R” is
`independently Ii,
`(C,—C,,)alkyl,
`eycloalkyl,
`trifluoromethyl,
`triilt1oromethyl{C‘,—C_.,)
`alkyl, wherein the alkyl, moieties of the foregoing R15
`groups are independently optionally substituted with "l
`to 3 substituents independently selected from
`(T, Cfialkyl,
`(I1 Cfiallcoxy, amino, hydroxy, halo,
`cyano, nitro, trilluoromethyl and trilluonomethoxy;
`and wherein any of the above “al_l.-;yl”, “alkenyl” or
`"alltynyl” moieties comprising a CH3 (methyl), CII2
`(methylene). or
`(Til
`(methine) group which is not
`substit.uled with halogen, S0 or 80.2, or attached to a N,
`O or 8 atom, optionally bears on said methyl, methyl-
`ene or methine group a substituent selected from the
`group consisting of halo, —OR", €513‘
`and
`NR"Rb.
`In an embodiment of the invention, X2 is C(R").
`In another embodiment of the invention, X3 is C(R“) and
`L is attached to the 2 position of R1 and to the 5 position of
`formula lb.
`
`In another embodiment of the invention, X2 is (.‘(R"] and
`L is attached to the 2 position of R‘ and to the 5 position of
`formula lb, R“ is OR” and R7 is phenyl-Z‘, wherein the
`phenyl moiety is optionally substituted with one to live
`independently selected R”.
`In a preferred embodiment
`thereof, Z1 is —((‘.R"Rf’),—.
`In another embodiment of the invention, X3 is C(l{"] and
`I. is attached to the 2 position of [U and to the 5 position of
`formula lb, and Rm is phenyl attached at the 3 position of
`R1, wherein the phenyl moiety of R10 is optionally substi-
`tuted with one to live independently selected R”. In a
`preferred embodiment of the invention, R6 in formula lb is
`11 or ((‘,—f_‘_,)a1ky1.
`the
`In another preferred embodiment of the invention,
`carbon designated "a"‘ in formula lb is in the (S) absolute
`configuration.
`In another embodiment of the invention, I
`ll) is H or tritluoromethyl.
`In another preferred embodiment of the invention, R” in
`formula 1b is H, halo, or {Cl C,-,]alkyl
`In another preferrerl embodiment of the invention, R7 in
`formula lb is (C,
`(7,,)all<yl, (C2 C,.,)all<enyl or {C2 Ch]
`alkynyl.
`In a particularly preferred embodiment of the invention,
`the compound is selected from the group consisting of:
`
`E” in formula
`
`10
`
`15
`
`_
`
`30
`
`40
`
`4-5
`
`50
`
`S5
`
`of‘!
`
`8
`3—Chloro—l—methyl—5—[(4'—1rifluoromethyl—biphenyl—2—
`earhonyl)—aminn]-1H—iudole—2—earhoxyliL: acid [2—oxo—
`l—phenyl-2-(prop—3—ynylamino)ethyl]amide;
`3-—(,‘hloro—].—methyl—5—[(4'—1rif1uoromeIhyl—biph-:nyl—2—
`carbonyl)-amino]-lII-indole-2-carboxylic acid [2-
`(isopropylamino—2—oxo—'l —phenylethyl]amide;
`3—(fhloro—t—metbyl—5—[(4'—1rifluorometbyl—bipheny1—2—
`carbonyl)-amino]-lII-indole-2-earboxylic acid [2-oxo-
`1-phenyl-2-(propylamino)ethyl]amide;
`3—C‘hloro—'l —methyl—S—[methyl—(4'—trifluoromethy[—
`biphenyl—3—carbonyl}—amino]—1II—indole—2—carboxylic
`acid [2—{ethylamino)—2—o)ro—1—phenylethyl]amidc;
`3-Chloro-"I -methyl-5-[methyl-(4'-trilluorometliy[-
`biphenyl-2-earhonyl)-amino]-1H-indole-2-carboxylic
`acid [2 -( isopropy lamino-3-oxo-"l -phenylethyl ]amide;
`5-[(l3iphenyl-2-carbonyl]-amino]-3-chloro-1-methyl-ll[-
`intlole-2-carboxylic acid [2-oxo-l-phenyl-L
`(propylarnino)ethyl]amide; and
`5—[(Bipheny1—2—earbony])—amino]—3—ehloro—1—methyl—1l[—
`indole-2-carboxylic acid [2-(isopropylamino-2-oxo-"l-
`phenylethyflamide.
`In an embodiment of the invention, R5 and R7 in formula
`lb taken together with the nitrogen atom to which they are
`attached together comprise (C,,—Cm)heterocyclyl, wherein
`the heterocyclyl is optionally substituted independently with
`l or 2 silbstituents independently selected from (C1-C3)
`alkyl, (C:—Cfi)alkenyl, and (C._.—C,,)alkynyl and trifluorom-
`elhyl. In a preferred embodiment thereof, the heterocyclyl is
`selected from pyrrolidinyl, piperidinyl, morpholino and
`thiomorpholino.
`In a particularly preferred embodiment
`thereof, the heteroeyelyl is pyrrolidinyl or morpholino.
`The present invention also relates to compounds of the
`formula 2:
`
`Id
`
`0
`
`_\IR‘R"
`
`or a pharmaoeutically acceptable salt thereof, wherein:
`R1 is substituted at the 5 or 6 position of formula 1 and has
`the stnlcture:
`
`m is an integer from 0 to 5;
`n is an integer from 0 to 3;
`p is an integer from D to 3;
`I. is —(“_(0]N(R”)—;
`X is N or (?(R"');
`R3, R“, R“, R” and R13 are each independently selected
`from halo, cyano, nitro, azido, amino, hydroxy,
`(C‘,—C6)alkyl, (C2—C'fi)alkoxy, methoxy, (C,—C6]alkoxy
`(C1—CU-)alkyl, mono—,
`di— or
`lri—halo(C2—(.‘6)alkyl,
`perfiuoro((T2—(T,,)all-tyl,
`trifluoromethyl,
`trifluoromethylntC,—C.;)alkyl, mono—,
`di— or
`tri—halo
`(C':—Cc,)alkoxy,
`trilluoromethyl(C,—C3)alkoxy,
`
`11 M44
`
`PENN EX. 2156
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`US 6,72(l,35 1 B2
`
`9
`(C3 C8]
`(C, Cfi)all(ylthio, hydrox}/(C, C,..,)alkyl,
`(C3-C5)
`eyeloalkyl(CR"Rl‘),,—,
`((".._,—C.'5)a|kenyI,
`alkynyl,
`((?,—C,,)alkylamino—,
`((f,—(f,.,)dialkylamino,
`aminn((‘.,—(“.G)alkyl-, —((“.R"R"),fNR“R1", —C(O)
`Nl{"R"', —NR"‘(I(()]l{”, —NR"'()l{‘5,
`—(".I-I=l\l0Rl5, —NR"‘(“.(O)0Rl5, —NRl‘lS{O)R'5,
`—(I(())R”,
`(T(S)l{"5, —(I((]){)l{”,
`t)(T[(})l{”,
`—SO2NR"Rl", —S(0],-R15, or —(CR"Rl’),,S(0),-R15;
`each R" and Rf’ is independently II or (C',—C6)a|l<yl;
`R” is H or R”;
`each {,1 is independently an integer from 0 to 6;
`eachj is independently 0,
`l or 2.;
`R" is H, halo, (CL—C6]alkyl, or mono—, di— or tri—halo
`[(T,—(I,.,)all<yl;
`each I is independently an integer from 2 to 5;
`each I is independently an integer from 1 to (1;
`R5 and R9 are each independently ll,
`(C,—(.‘,__)alkyl,
`(C_-,—C,,)eyeloalkyl, —C(O)l{'5, —C(S)l{'5,
`—{Cl{"’l{"),()[(I ,—(I,,alkyl), —((fl{"Rb),S((I,—[T,,aIkyl),
`—{CR”R"’),C(f])R‘5, —(CR"R”),R'5 or fi°.0:R‘5;
`R” is II, (Cl—C6)alkyl, (C3—C3)cycloalkyl, —C{0)R'5,
`—(.'(S)R”, —((.‘R"R"] ()(_t_‘,—(:,,arkyI), —{(Il{”R""),;§
`(C,—C,,.all\'yl), —{'_C‘R"’R%)rC(O)R]5, —((“_R"‘R”),R'5 or
`—s(),1:15;
`y is an integer from O to 5;
`R7 is (t.',—(?,,)alkyl, {(I._.—(f,,)alkenyl, {(T2—(T,,)alkynyl,
`(CR"‘R"'),,U(C,—C,,:tll~:yl}, —(Cl{5“Rf’),,S
`[(Tl‘—(3nalkyl); {C3—(T,,)cyc:loalkyl, —(l(())R ,
`(l(S]
`R1‘, —(CR"R"),.C(O)R15._ —(CR"R“),.(.‘(S)R”,
`—{(IR"R"’),.R'5 or _.sr).,1~t'-‘;
`or R7 is phenyl, pyridyl, phenyl-Z'— or pyridyl-Z'—
`optionally substituted with one to live independently
`selected R”;
`or RI‘ and R7 taken together with the nitrogen atom to
`which they are attached together comprise [C,,—Cm)
`heteroeyclyl, wherein the heterocyclyl moiety is mono-
`cyclic;
`wherein the alkyl. cycloalkyl. and hetcrocyclyl moieties
`of the foregoing R6 and R7 groups are optionally
`substituted independently with l to 3 snbstituents inde-
`pendently selected from halo, eyano, nitro,
`trifluoromethyl,
`trifluoromethoxy, azido,
`OR”,
`—c.‘(o)R‘-5, —c:(o)oR‘-‘, —()c:(())R‘-5, —Nl{”(_‘[())
`R”, —C(0)NR“R“, —NR“R“, and
`NR”OR”,
`(T]—(T,,alkyl, (.'2—(.‘5 alkenyl, and (_‘2—(f,, alkynyl; and
`R” is phenyl, pyridyl, phenyl—Z2— or pyridyl—Z:—,
`wherein the phenyl or pyridyl moiety is optionally
`stibstituted with one to live independently selected Rm;
`23 is —s(o),.—, —o—, —(CR"R”)_,.—, or —(o),,
`icR"R”),.(0)r.(cR"R”),
`;
`w is independently an integer from 1 to 6;
`each k is independently 0 or 1;
`or Rm is OR”, wherein R” is (C1—C'b}al.kyl, (C1-C0)
`alko:-;y[C1—C5)alkyl, mono—,
`di— or
`tri—haIo(C2—C,,-)
`alkyl, perlluoro(C.':—C4)alkyl,
`tri[luorornethyl(C'1—C_.,)
`allcyl, hydroxy|’,C,—C,,)alkyl,
`(C3—Cfi)eycloalkyl
`[CR"RF’),,—, (C;—C,,)al.kenyl, or (C'2—C,,)aLkynyl;
`each R“ is
`independently H,
`((r,—{:,)a1kyt,
`(i:_‘3—(.‘,.,)
`eyeloalkyl, —C(O)R”,
`C(S)R‘5, —(CR"R")f0
`[[7,—Cn-alkyl), —((7R"l{2’),S((.‘.]—(Tfialkyl), —{(fR"l{ ’),.
`C(O)R‘5 or —SO2R‘5;
`(C3 C”)
`each R” is
`independently H, (C, Cfi)alkyl,
`eyeloalkyl,
`trifluoromethyl,
`triflt1oromethyl((T,—t.‘5)
`
`l0
`
`15
`
`_
`
`30
`
`40
`
`4-5
`
`50
`
`55
`
`E1?!
`
`10
`alkyl, wherein the alkyl, moieties of the foregoing R”
`groups are independently optionally sulustituted with t
`to 3 substituents independently selected from
`('T1—C,._a|kyl,
`('T1—(".,,alkoxy, amino,
`liydroxy, halo,
`eyano, nitro, trifluoromethyl and trifluoromethoxy;
`and wherein any of the above "alkyl", "alkenyl” or
`“alkynyl” moieties. oomprising a C[I_., (methyl), (III:
`(methylene), or CH [rnethine) group which is not
`substituted with halogen, S0 or S0, or attached to a N,
`0 or S atom, optionally bears on said methyl, methyl-
`ene or methine group a substituent selected from the
`group consisting of halo, —UR“, —SR" and —NR"R”.
`In an embodiment of the invention, X in Formula 2 is
`(‘(I{”)_
`In another embodiment ofthe invention, I. in formula 2 is
`attached to the 2 position of R1 and to the 5 position of
`formula 2.
`In another embodiment ofthe invention, wherein y is l. or
`
`9
`
`In another embodiment ofthe invention, R10 in formula 2
`is phenyl attached at the 3 position of R1, wherein the phenyl
`moiety of R10 is optionally substittitecl with one to five
`independently selected R”.
`In another embodiment of the invention, R7 in formula 2
`is phenyl-Z‘, wherein the phenyl moiety is optionally sub-
`stituted with one to live independently selected R”. In a
`preferred embodiment thereof, Z1 is —{_(3lt"Rl’),—.
`In another embodiment of the invention, R“ in formula 2
`is II or (C,—C,,)al.kyl.
`the carbon
`In another embodiment of the invention,
`designated “a" in formula 2 is in the (S) absolute configu-
`ration.
`
`In at preferred embodiment of the invention, R” in
`formula 2 is triiluornmethyl.
`In another preferred embodiment of the invention, R3 in
`formula 2 is H, halo, or ((‘.1—(I6)alkyl.
`The invention also relates to :4. process for preparing a
`eompound of formula 1 which comprises forming an amide
`linkage between :1 compound of the formula AB1:
`
`R1
`
`/
`N/
`
`R3
`
`Li‘-
`
`AB]
`
`c
`
`R13
`
`0
`
`(R”J,j
`.,-
`R52
`
`U’-zln
`l
`
`_\t \\
`
`'9R
`
`and a eompound of the formula C:
`
`
`
`wherein
`
`m is an integer from [J to 5; n is an integer from (J to 3;
`p is an integer from 0 to 3;
`the arnido nitrogen atom of —C((J)N(R'°)— above is
`bonded to the 5 or 6 position of the indole;
`X is N or CTR"), wherein R" is II or R”;
`
`12 of 44
`
`PENN EX. 2156
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`US 6,72(l,35 1 B2
`
`11
`R3, R”, R“, R17‘, R” and R” are each independently
`selected from halo, eyano, nitro, azido, amino, hytlroxy,
`[(3, —(3,.,)all<yl, ((f1—(3fi)alkoxy, methoxy, {C1