1
`I
`(12) Unlted btates Patent
`Bertinato et al.
`
`USU06949572B2
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 6,949,572 B2
`Sep. 27, 2005
`
`(54) TRIAMIIJE-SUHST['[iU'[iEI)
`HETER()[;[cYc[,1C COMPOUNDS
`
`(75)
`
`Inventors: Peter Bertinato, Old Lyme, Cl‘ (US);
`Brian S_ Bmnkj Gales Ferry, Cl‘ (US);
`.
`.
`Alan E. Blue, New London, CT{US);
`H'3"3m"‘° Ch‘~‘“B~ 535‘ Llimc» C1‘
`(US); Jill Us Pawcaiucks C1‘ (U3);
`Hiep Huatan, Maidstonc (GB); Clive
`Mason, Deal (GB)
`
`(73) Assignee: Pfizer In(:., New York, NY (US)
`
`[* ) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`ii‘S'C' i54ibJ by 0 iiiiis‘
`
`(21) App1.N0‘i 1016397855
`
`(22) Filed:
`
`Aug. 13, 2003
`
`(65)
`
`Prior Publication Data
`g
`I
`I
`Us Zfloiiioflsflizb A1 May 6-‘ 2004
`Related U.S. Application Data
`
`[62) Division of application No. 10,-"17'?,858, filed on Jun. 20,
`2002_. now Pat. No. 5,720,351.
`Provisional application No. 601301,644, filed on Jun. 28,
`3001'
`Int. Cl.’
`
`[60)
`
`(51)
`
`A61K 31744; (2070 40700;
`Amp 300
`5141339; 5461'2'17.4; 54613781
`5141339; 54612714,
`54612781
`
`(52) U.S. CI.
`(58) Field of Search
`
`At3lKf31,-“I95
`.. C07)1401,-'14
`.. A6ll"7'37'06
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`C12N»'i1l_5»"i12_
`B261’),-37:10
`(.0'1')7i2U7,-'12
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`(€073:-"2111tIJ
`C07 37211700
`00737295714
`00737241700
`CU’? 11241104
`CU?’ 31211,-"44
`(‘E17 77213,.-'33
`
`C-97D1i2ii51il35
`
`312001
`512001
`272002
`
`619002
`811997
`1111997
`23.2000
`1272000
`172001
`372001
`772001
`2,-"2001
`112001
`1077.001
`
`1313091
`
`172002
`512002
`1072002
`
`iiiiiiiii 00707235792
`C07')7"4-01106
`c07072957135
`
`EP
`1.-‘P
`F.I’
`
`I-iii
`W0
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`
`“'0
`
`W0
`W0
`W0
`
`1080724
`1099701
`1181954
`
`0534445
`W0 9727929
`W092432:17
`W0 0005201
`W0 0075971
`W0 0105752
`W0 0121504
`W0 0147893
`W0 0147899
`W0 0153260
`W0 0177077
`
`W0 0192241
`
`W0 0204403
`W0 0242291
`W0 0283658
`
`OTHER PUBLICATIONS
`
`.I.R., el al., Sczlrmce, "Absence of Microsomal
`Wallerau,
`Triglyceride Translier Protein in Individuals with Abetalipo-
`proteinemia", vol. 258, (Nov. 6, 1992).
`Wallerau,
`.I.R., et al., B7'oc:irr'771ica
`er Bi0_p17y.s7'ca Acre,
`“Localization of Intracellular Triacyglycerol and Choles-
`iciyi Esici Transfer Aciiiiiiy iii Rai Tissues’: VOL 875 pp‘
`610-017 (1930)-
`Jundong Zhang, et al., Bioorganic & Medicinal Chemistry,
`“Identification of Inhibitors of Heparin—growth factor inter-
`a°“°"5 f‘°,m 9°mb{""[?“a1 L1'”a“°5 Of *°“F—9°mI3°"°“_‘
`Condensation Reaction , (2001), vol. 9 No. 4, p. 823-830.
`Prirrrary£xa77r.i77er4l‘aofiq Solola
`/1ss1'.s'rL7m‘Ex.sm1i77er—Robert Shiao
`(74) A11o7'nc_}-‘, Agent, or I-}'r77I—Gregg C. Benson; Robert
`M. Kennedy
`ABS,],RAC,l,
`(57)
`The invention relates to lriamide M'l‘I-‘1/\poI3 inhibitors of
`[[13 fgfmula ]_
`
`1
`
`?
`(“"1-7
`
`1
`
`R4
`/
`-‘i
`/
`R3
`
`0
`
`
`
`R.
`
`wherein Ri—Rii are as defined in the specification, as Well as
`pharmaceutical compositions and uses thereof, and pre-
`1‘
`'
`h
`~
`l..'l‘h~
`cl
`111
`?§3§ET1,.'Li ff:iifiéirlfi ‘1§i‘1?1‘l‘i§?c”aiI§,Zn. J;1‘i?7§i§i§§i§“a§’a°11,Zt§
`1-li5’Ul'd'-51'5-
`
`54 Claims, 6 Drawing Sheets
`
`
`
`1 0‘ 46
`
`PENN Ex. 2293
`
`CFAD V. UPENN
`IPR20l5-01836
`
`References Cited
`Uisi PATENT DOCUMENTS
`4,022,900 A
`51197? Mathison
`4_.39?_.855 A
`811933 Sircar
`5,416,009 A
`511995
`Iazzeri at al.
`5,212,279 A
`111998 Biller etal.
`5,"7'31,340 A
`311998 Bras ct al.
`5,"7‘41,804 A
`411998 Keenan et al.
`5,919,795 A
`771999 Chang el :11.
`5,968,950 A
`1011099 Ouallicltet a1.
`5,055,553 A
`572000 Gregg el :11.
`6_.l21_.283 A
`912000 Cltang ct al.
`6,197,798 B1
`312001 Fink et :11.
`6,235,230 B1
`512001 Sato ct al.
`6_.281_.228 B1
`812001 Tino
`6,288,234 B1
`912001
`(iriiifin
`5_.33"7_,344 31
`172002 Dcfossa ct a1_ H
`2002.-0032238 A1
`372002 Priepke ct at.
`FOREIGN PATENT DOCUMENTS
`19945594
`3,-"2001
`(I07"I)7'2951'04
`0043057
`311995
`C0'7'D140l104
`1006122
`672000
`C(t'1K15108
`
`4241258
`4241250
`4351693
`5|-11252
`5141415
`.. 5141394
`5147310
`5141310
`5147325
`514130?
`51-11354
`. 5141211.11
`5141319
`5461190
`5147415
`5141616
`
`
`
`.
`
`(56)
`
`DI‘.
`EP
`I.-‘P
`
`

`
`U.S. Patent
`
`Scp. 27,2005
`
`Sheet 1 of6
`
`US 6,949,572 B2
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`50
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`40
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`2030
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`10
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`2 of 46
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`PENN EX. 2293
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`FIG.1
`
`250
`
`

`
`U.S. Patent
`
`Scp. 27,2005
`
`Sheet 2 of6
`
`US 6,949,572 B2
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`FIG.2
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`200
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`180
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`160
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`140
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`100120
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`80
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`60
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`50
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`3 0*’ 46
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`PENN EX. 2293
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`CFAD V. UPENN
`IPR20l5-01836
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`

`
`U.S. Patent
`
`Scp. 27,2005
`
`Sheet 3 of6
`
`US 6,949,572 B2
`
`FIG.3
`
`C5
`CD
`5|I:
`
`1200
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`4 0*’ 46
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`PENN EX. 2293
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`CFAD V. UPENN
`IPR20l5-01836
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`

`
`U.S. Patent
`
`Scp. 27,2005
`
`Sheet 4 of6
`
`US 6,949,572 B2
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`1200
`
`C)
`I'2
`
`CH
`
`FIG.4
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`5 0*’ 46
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`PENN EX. 2293
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`CFAD V. UPENN
`IPR20l5-01836
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`

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`U.S. Patent
`
`Scp. 27,2005
`
`Sheet 5 of6
`
`US 6,949,572 B2
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`C)
`"'*-«I,_
`
`Gl
`
`1200
`
`FIG.5
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`6 0*’ 46
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`PENN EX. 2293
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`CFAD V. UPENN
`IPR20l5-01836
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`

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`U.S. Patent
`
`Scp. 27,2005
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`Sheet 6 of6
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`US 6,949,572 B2
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`7 of 46
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`PENN EX. 2293
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`CFAD V. UPENN
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`1
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`

`
`US 6,949,572 B2
`
`1
`TRIAYIIDE-SUBSTITUTED
`HETEROBICYCLIC COMPOUNDS
`
`2
`SUMMARY OI‘ 'l'III_-' INVI_-'N'l'I()N
`
`The present invention relates to compounds of the for-
`mula 1:
`
`This application is a divisional of U.S. patent application
`Ser.No.10i’177",858 filed on Jun. 20, 2002 now U.S. Pat. No.
`6,720,351 which claims the benefit of US. Provisional
`Patent Application No. 60i’301,644 filed on Jun. 28, 2001,
`both of which are incorporated herein by reference in their
`entirety.
`
`10
`
`FIELD OF THE INVENTION
`
`"I5
`
`This invention relates to triamide—substituted heterobicy—
`clic compounds. These compounds are inhibitors of
`microsomal triglyceride transfer protein (MTP) andfor apo-
`lipoprotein B (Apo B) secretion and are useful for
`the
`treatment of obesity and related diseases. These compounds
`are also useful for the prevention and treatment of athero-
`sclerosis and its clinical sequelae, for lowering serum lipids,
`and in the prevent ion and treatment of related diseases. The m
`invention further relates to pharmaceutical compositions ‘
`comprising these compounds and to methods of treating
`obesity, atherosclerosis, and related diseases andfor condi—
`tions with said compounds, either alone or in combination
`with other rnedicanients, including lipid lowering agents. mg
`Further still, the invention relates to certain processes and “
`intermediates related thereto which are useful in the prepa-
`ration of the compounds of the instant invention.
`
`B/\(TK(3ROUNIJ ()1-‘ 'I‘III_-' INVEN'l‘I()N
`Microsomal
`triglyceride transfer protein catalyzes the
`transport of triglyceride, cholesteryl ester, and phospholipids
`and has been implicated as a putative mediator in the
`assembly of Apo I3-containing lipoproteins, biomolecules
`which contribute to the formation of atherosclcrotic lesions.
`Specifically,
`the subcellular (lumen of the microsomal
`fraction) and tissue distribution (liver and intestine) of lVI'I'l-’
`have led to speculation that it plays a role in the assembly of
`plasma lipoproteins, as these are the sites of plasma lipo-
`protein assembly. The ability of MTP to catalyze the trans-
`port of triglyceride hctwccn nicmbrancs is consistent with
`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 MTP andfor oth-
`erwise inhibit Apo B secretion are useful in the treatment of
`atherosclerosis and other conditions related thereto. Such
`
`compounds are also useful in the treatment of other diseases
`or conditions in which, by inhibiting MTP andfor Apo B
`secretion, serum cholesterol and triglyceride levels may be
`reduced. Such conditions may include,
`for example,
`hypercholesteroleniia, hypertriglyceridentia, pancreatitis,
`and
`obesity;
`and
`hypercholesterolemia,
`hypertriglyceridemia, and hyperlipidernia associated with
`pancreatitis, obesity, and diabetes. For a detailed discussion,
`see for example, Wetterau et al., Science, 258, 999-1001,
`(1992), Wetterau et al., Bicchem. Biophys. Acta., 875,
`610-617 (1986), Liuropean patent application publication
`Nos. 0 584 446 A2, and 0 643 057 At, the latter of which
`refers to certain compounds which have utility as inhibitors
`of MTP. Other examples of MTP inhibitors may be found in
`e.g., US. Pat. Nos. 5,712,279, 3,741,804, 5,968,950, 6,066,
`653, and 6,121,283; PCT International Patent Application
`publications W0 96,"-40640, W0 97_.-’-43257, W0 9827979,
`WFJ 99133800 and W0 00f0520l; and European patent
`application publications I.-"P 584446 and l_iP 643,057.
`
`‘U
`
`3,5
`
`41]
`
`45
`
`S0
`
`60
`
`65
`
` NR°'R7
`
`or a pharmaceutically acceptable salt thereof, wherein:
`R1 is substituted at the 5 or 6 position of formula 1 and has
`the structure:
`
`R10
`
`|_L_
`(Ru _"
`ll 5/
`
`ITI is an irllfigtif 130111 U 10 5;
`n is an integer from 0 to 3;
`P 18 F111 integer i‘T0T|'|
`[3 10 3;
`L is —C(O)N(R9)—, i.e., L has the structure:
`
`R9
`IL
`
`0
`
`X is N or (I(R");
`R2, R“, R", R”, R13 and R1“ are each independently
`selected from halo, cyano, nitro, azido, amino, hydroxy,
`(C,—C,,)alkyl,
`(C2—C,.,)alkoxy, methoxy,
`(C,—C,,)alkoxy
`(C1—CL-)alkyl, mono-, di— or tri—halo(C3—C,,-)alkyl, perlluoro
`(C2—C,,)alkyl, trifluoromcthyl, trifluoromethyl(C,—C5)alkyl,
`mono-,
`di— or
`tri-halo(C,_—CE,)all\'oxy,
`trifluoromethyl
`(C,—C5)alkoxy, (C1-C3-)alkylthio, hydroxy(Cl—C,,-)alkyl,
`(C3—(I3)cycloalkyl{CR"R5’)q—,
`[(T3—C5)alkenyl,
`(C2-C5)
`alkynyl, ((T,—C,.,)all<ylarr|ino-, [C1—Cfi)dialkylaniino, amino
`((“.,—(“.b)a|kyI—, —((“.R”R”)q5NR"R"', —(“.(0)NR"R"',
`—NR”C(O)R15, —NR”0Rl , —CH=NORl5, —NR”C
`(O)OR15, —NR”S[O)-R15, —C(O)R15,
`C(S)R”,
`—C{O]OR15, —0C(0)R ’, —SO2NR“R14, —S(O);.R15, or
`—(CR"R£’),°,S(O)J-R15;
`each R" and R” is independently II or ((.'1—(T6]alkyl;
`R" is H or R“;
`each q is independently an integer from 0 to 6;
`eachj is independently 0, 1 or 2;
`R7’
`is II, halo,
`((I1—(T,_.,)all<yl, or mono-, di— or tri-halo
`(C,—C,.,)alkyl;
`R" is II, ((I1—(I,.,)alkyl, (C3—C,,)cycloalkyl, —(T(()]R'5,
`—C(S)R'5, —(CR”R"’),O(C,—C,, alkyl),
`(CR"R"’),S
`(C1-C6 alkyl), —(CR"R"),C(0)R15,
`(CR"R"),R'5,
`—SO3R‘5 or —(CR"R")q—phenyl, wherein the phenyl moi-
`ety is optionally substituted with from one to five indepen-
`dently selected R1“;
`each r is independently an integer from 2 to 5;
`each I is independently an integer from 1 to 6;
`R5, R“ and I{° are each independently H, ((.',—(.',,)alkyl,
`(C_«,—C3)cycloalkyl, —C(0)R15, —C[S]R15, —(CR“R£’),O
`PENN EX. 2298
`
`8of46
`
`CFAD V. UPENN
`IPR20l5—0l836
`
`

`
`US 6,949,572 B2
`
`4
`In another embodiment of the invention, X is CIR”), m is
`0, n is U, and p is U or "I , and R10 is phenyl attached at the
`3 position of R1, wherein the phenyl moiety of Rm is
`optionally substituted with one to five independently
`selected R”.
`
`10
`
`"I5
`
`ll]
`
`In another embodiment of the invention, R7 is phenyl—Z1,
`wherein the phenyl moiety is optionally substituted with one
`to five independently selected R”. In a preferred embodi-
`ment of the invention, Z1 is —((TR“'Rf’)‘—, and in a more
`preferred embodiment, Z1 is methylene, i.e., —CH.;—.
`In another embodiment of the invention, R", R5, Rf’ and
`R” are each independently selected from II, (C,—C,,)alkyl,
`—((?R"R")q()((?,—(I,, alkyl) or —(c:R"R”),R“‘.
`is
`In another embodiment of the invention, each R‘:
`independently selected from halo, hydroxy, (C,—(T,,)alkyl,
`methoxy,
`(C2—C,,)alkoxy,
`(C,—Cfi)alkoxy(C,—C_,,)alkyl,
`mono—,
`di— or
`tri—halo[C,._—C<,)alkyl,
`trifluoromcthyl,
`trifluoromethyl(C,—C5)alkyl, mono—, di— or tri—halo(C2—C,,)
`alkoxy,
`trifluoromethyI((I,—C5)alkoxy,
`((.',—Cfi)alkylthio
`and hydroxy((T,—C,,,)alkyl.
`In another embodiment of the invention, each R” is
`independently selected from halo, hydroxy, amino, cyano,
`(C,—(f,_,)alkyl,
`((I_._—(T5)alkenyl, methoxy,
`((.'3—Cb.)alkoxy,
`(C,—C5)alkoxy(C,—C6)alkyl, mono—, di— or tri—halo(C2—C,,)
`alkyl, trifluoromethyl, trifluoromethyl(C,—C5)alkyl, mono—,
`di- or tri-halo(C:—CU-)alkoxy, trifluor0methyl(C,—C5)alkoxy,
`(C,—C,-)alkylthio, hydroxy(C,—CL,-)alkyl,
`C(0)0R15 and
`—NR“C(())R15; wherein R14 is II or ((.',—(.'6)alkyl; and
`wherein R15 is II or (C._—Ct.,)alkyl.
`In another embodiment of the invention, R1“ is phenyl
`attached at the 3 position of R1, wherein the phenyl moiety
`of Rm is optionally substituted with one R13. In a preferred
`embodiment, R'” and R‘ both are phenyl, such that R‘ and
`Rm together fonn a l,l'-biphenyl group, wherein Rm com-
`prises the 1‘—{i‘ positions of the biphenyl group and R” is
`substituted at the 4" position of the biphenyl.
`In another embodiment of the invention, R4 is H, (C1-C6)
`alkyl or —((:R“R”),,t)((?,—(t, alkyl).
`the carbon
`In another embodiment of the invention,
`4:1 designated “a” in formula I is in the "[S)” configuration.
`In a preferred embodiment of the invention, R13 is trif-
`luoromethyl.
`In another preferred embodiment of the invention, R3 is
`II, halo, or ((I,—(I,.,)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)-1-ethyl-5-[(45
`trifluoromethyl—biphenyl—2—carbonyl)—amino]—IH—indole—2—
`carboxylic acid {2-[benzyl(methyl]amino]-2-oxo-"I-
`phenylethyl}amide.
`In another particularly preferred embodiment of the
`invention, the compound of formula I
`is (S)-N-{Z-[benxyl
`(methyl)amino]-2-oxo-l-phenylethyl}-1-methyl-5-[45
`{trilluoromethyl)[1,1'—biphenyl]—2—carboxamido]—1II-
`indole-2-carboxamide.
`
`35
`
`45
`
`Sf]
`
`3
`(c,—(:,., alkyl), —((.‘R"R”),S((I,—(I,, alkyl), —((?R"R"’),(f(())
`R1‘ , —{CR"R"’)rR'5 or —SO:R'5;
`R7 is phenyl, pyridyl, phenyl-Z5 or pyridyl-Z1-, wherein
`the phenyl or pyridyl moiety is optionally substituted with
`one to live independently selected R”;
`21 is —so,— or —((IR“R"),.—;
`v is independently an integer from 1 to 6;
`R10 is phenyl, pyridyl, phenyl-Z15 or pyridyl-Z2-, wherein
`the phenyl or pyridyl moiety is optionally substituted with
`one to live independently selected R”;
`2“ is —s(o).—. —o—, —(Cl{"R"),,_—, or —(o),
`((TR"R”),_,(()),((?R“R"),{—;
`w is independently an integer from I to 6;
`each k is independently U or 1;
`(C3-C3)
`((.'1—C,,}alkyl,
`each R” is
`independently H,
`cycloalkyl, —(?(r))R1‘-‘, —(?(s)R1-‘, —(c:R"R‘*),()((:,—(:,
`alkyl), —(r7R"R”),s((:,—r.‘, alkyl), —((?R”R”)_.(f(())R'5,
`—{CR"R"’),_R'5 or —SO2Rl5;
`(C3-C3)
`(C,—C,,}alkyl,
`each R1’
`is
`independently H,
`cycloalkyl,
`trifluoromethyl,
`trifluoromethyl((;1—C5)alkyl,
`wherein the alkyl, moieties of the foregoing R" groups are
`independently optionally substituted with I to 3 substituents
`independently selected from C,—Cfi alkyl,
`(f,—C,., alkoxy,
`amino, hydroxy, halo, cyano, nitro,
`trilluoromethyl and
`trifiuoromethoxy;
`and wherein any of the above “alkyl”, “alkenyl” or
`“alkynyl" moieties comprising a (TII3 (methyl), CII2
`(methylene), or (711 (methine] group which is not substituted
`with halogen, S0 or S02, or attached to a N, 0 or 5 atom,
`optionally bears on said methyl, methylene or methine group
`a substituent selected from the group consisting of halo,
`—()R“, mm“ and —NR“R".
`In an embodiment of the invention, L is attached to the 2
`position of R1 and to the 5 position of formula I, i.e., the
`compound of formula 1 has the structure of formula la:
`
`"la
`
`
`
`0
`
`R“
`
`Kh
`(R"),,‘— 6
`
`lN
`
`In another embodiment of the invention, I. is attached to
`the 2 position of R‘ and to the 5 position of formula "I, and
`R10 is attached at the 3' position.
`In another embodiment of the invention, I. is attached to
`the 3 position ofRl and to the position formula 1. In another
`embodiment of the invention, I. is attached to the 3 position
`of RI and to the 5 position of formula I and X is N. In still
`another embodiment of the invention, I. is attached to the 3
`position of R1 and to the 5 position of formula 1, X is N and
`R10 is attached at the 2 position of R1. In other embodiments
`of the invention, the attachment of L to R‘ is selected from
`the 3, 4, 6 or 6 position and the attachment of L to the
`compound of formula 1 is selected from the 5 position or 6
`position.
`In another embodiment of the invention, X is C(R"').
`In another embodiment of the invention, X is (f(R"), n1 is
`I), n is [1, and p is U or I.
`In another embodiment of the invention, X is (f(R"), n1 is
`I), n is [1, and p is U or 1, and Rm is phenyl-Z2- attached at
`the 3 position of R1, wherein the phenyl moiety of R10 is
`optionally substituted with one to five independently
`selected R13.
`
`60
`
`65
`
`In another more preferred embodiment of the invention
`R3 is chloro.
`In another particularly preferred embodiment of the
`invention, the compound of formula 1
`is selected from the
`group consisting of:
`3—chloro—5—[(4’—trifluoromethyl—biphenyl—2—carbonyl)—
`amino]—1H—ir1dole—2—carboxylic acid {2—[benzyl(mcthyl)
`amino]—2—oxo—1—phenylethyl}amide;
`3-chloro-"l -methyl-5-[[4'-trilluoromethyl-biphenyl-2-
`carbonyl)-amino]-III-indole-2-carboxylic acid {2-[benxyl
`(methyl)amino]-2-oxo-l-phenylethyl}amide;
`
`9of46
`
`PENN EX. 2298
`
`CFAD V. UPENN
`IPR20l5-01836
`
`

`
`US 6,949,572 B2
`
`5
`
`4'-trilluoromethyl-biphenyl-2-carboxylic acid [2-({
`[(benzyl-methyl-carbamoyl)-phenyl-methyl]-methyl-
`amino}-methyl)-3-chloro-I -methyl-I I I-indol-5-yl]-amide,
`which is alternately named: 3—ch|oro—I —methy|—5—[(4‘—
`trifluoromethyl—biphenyl—2—earbonyl)—amino]—1H—indole—2—
`earboxylie acid {N—[2—(benzyl(methyl)amino)—2—oxo—1—
`phenylethyl]methyl}amide;
`3—chloro—1—methyI-5—[methyl—(4‘—trifluoromethyl—
`biphenyl-2-carbonyl)-amino}III-indole-2-carboxylic acid
`{2—[benzyl[methyl)amino]—2—oxo—Lphenylethyl}amide; and
`3—ehloro—1—ethyl—5—[(4'—trifiuoromethyl—biphenyl—2—
`carbonyl)-amino]-1II-indole-2-carboxylic acid {2-[benzyl
`{methyl)amino]-2-oxo-I-phenylethyl}amide.
`In another embodiment ofthe invention, X is C(R"), m is
`I), n is U, and p is U or 1, and Rm is phenyl-Z2- attached at
`the 3’—position, wherein the phenyl moiety of R” is option-
`ally substituted with one to five independently selected R”
`and Z3 is O or S.
`
`In another embodiment of the invention, R7 is phenyl-Z‘,
`wherein the phenyl moiety is optionally substituted with one
`to five independently selected R12 and Z'
`is 0 or S.
`In another embodiment of the invention, R7 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 —((TII:._]—.
`In another embodiment of the invention, X is N and Rm
`is phenyl optionally substituted with one to five indepen-
`dently selected R”.
`In another embodiment ol‘ the invention, X is N and Rm
`is phenyl optionally substituted with one to five indepen-
`dently sclected R13, and R7 is phenyl-Z1, wherein the phenyl
`moiety is optionally substituted with from one to five
`independently selected R13.
`'I'he present invention also relates to a compound of the
`formula lb:
`
`1 l1
`
`,
`lR"ln
`Rt;//l
`K
`
`O
`
`X1
`/
`R:
`
`\
`N [RS)m;
`X
`
`|
`
`a
`
`If
`5
`
`O
`
`xR"R7
`
`or a pharmaeeutically acceptable salt thereof, wherein:
`R1 is substituted at the 5 or 6 position of formula 1b and
`has the structure:
`
`Rm
`\/-_»“~:.~_. X,
`(R111 _“E
`;L:_
`|.1
`:5
`E‘
`‘
`5/
`
`or when R7 is phenyl, pyridyl, phenyl—Z1—or pyridyI—Z‘—
`optionally substituted with one to five independently
`selected R”, R1
`is
`(C1-C3-)alkyl,_ (C3—C3)eycloalkyl,
`(C5—C1O)bicycloalkyl, —(CR”R”)_,0((.‘,—C,, alkyl),
`—(CR"R‘l’),S(Cl—(."5 alkyl), —(CR"Rb),_C(())R15,
`—((TR"R”),R 15, 402R 15, (C,,—Cm)heterocyclyl, ((f5—Cw)
`heteroaryl, aryl or —(CR“Rl’)q-aryl, wherein the cycloalkyl,
`heterocyclyl, heteroaryl or aryl moiety is optionally substi-
`tuted with from one to live independently selected Rm;
`tn is an integer from U to 5;
`n is an integer from 0 to 3;
`
`10
`
`"I5
`
`ll]
`
`35
`
`4E]
`
`6
`p is an integer from [J to 3;
`I. is —C(O)N(R"’)—, as described above;
`X' is N(R"), S or 0;
`X: is N or C(R“);
`R3, R”, R“, R”, R” and R” are each independently
`selected from halo, cyano, nitro, azido, amino, hydroxy,
`{C1—C6)alkyl,
`(C_._—C6)alkoxy, methoxy,
`(C1—C°—)alIioxy
`((f1—C5)alkyl, mono-, di- or tri-halo((T3—(Ib.)alkyl, perlluoro
`((f2—C,,)alkyl, trilluoromethyl, triIluoromethyl(C,—(T5]alkyl,
`mono-, di- or
`tri-halo[C:,_—CU.)alkoxy,
`trilluoromethyl
`(C,—C5)alkoxy,
`(C1-C3-)alky1thio, hydroxy(Cl—C°-)a1kyl,
`(C3—(IR)cycloalkyl{CR"R5’)q—,
`[(T2—C6)alkenyl,
`(C2-C6)
`alkynyl, (C,—C5)alkylamino—, [C1—CL,-)dialkylamino, amino
`((T1—(I?)alkyl-, —((IR“R”)%NR“R1“, —(I((J)NR“R”,
`—NRl'C(O)R15, —NR”OR ', —CH=N0R15, —NR”C
`(o)oR”, —NR“S[()){.R‘5, —(?(())R15,
`(I(S)R”,
`—(T(()]()R”, —o(:§o)R 5, —sr),NR"R“‘, fls(o),.R“'*, or
`—(CR"R")qS(O).R" ;
`each R“ and R5’ is independently H or (C1-C6-)alkyl;
`R" is II or R“;
`each q is independently an integer from U to 6;
`eachj is independently 0, 1 or 2;
`R7’
`is II, halo,
`((I1—(T,_,,)alkyl, or mono-, di- or tri-halo
`(C1—{'I5)alkyl;
`R4 is H, (C1-C0-)alkyl, (C3—C3)eyeloalkyl, —C(O)R‘5,
`—C(S)R1S, —{(IR"R£'),()(C1—CU. alkyl),
`((TR“R£’]_,S
`(c,—c,., alkyl), —(cR“R”),c(o)R‘-‘, —(cR"R”),R'-"’,
`—SO3R‘5 or —(CR"R")q—phenyl, wherein the phenyl moi-
`ety is optionally substituted with from one to five indepen-
`dently selected Rm;
`each r is independently an integer from 2 to 5;
`each I is independently an integer from '1
`to 6;
`R5 and R9 are each independently H,
`(C,—Cfi)alkyl,
`(C3—C3)eycloalkyl, —C[0)R15, —C[S)R15, —(CR“R£’),O
`((f,—Cfi alkyl), —(CR"Rb),S(C1—Cfi alkyl), —(CR"Rb),C((l)
`R‘-“,
`(CR”R"’),R“‘ or
`so,12‘-‘;
`RE‘
`is H, (C1—Co.)a]kyl, (C3—C3)eycloalkyl, —C(O)R'5,
`—C(S)R1S, —(CR"Rb),,!0[C1—C<,- alkyl), —(CR“R£;],,S
`(C1-C6 alkyl), —{(TR"R ’),.C[())R15, —((7R”Rh),_Rl' or
`—SO2R15;
`y is an integer from [J to 5;
`I{7 is ((I1—(Tfi)alkyl,
`(C2—(Tg)alkenyl, {C2—(T,,]alkynyl,
`—(CR"R"’),,O(C,—Cfi alkyl), _—{CR"R"’),,1S(C,—C,,, alkyl];
`(C3—CR)cycloalkyl,
`C(O)R1’, —C(Sb)R 5, —{CR“Rl’),t“,
`(0)1115, —(CR"R ’),C[S)Rl5, —{(TR"R ),.R15 or fi‘3(]2Rl”;
`or R7 is phenyl, pyridyl, phenyl—Z'—or pyridyl—Z‘— option-
`ally substituted with one to five independently selected R”;
`or R5 and R7 taken together with the nitrogen atom to
`which they are attached together comprise (C,,—Cm)
`heterocyclyl, wherein the heterocyclyl moiety is monoey—
`Sn clic;
`wherein the alkyl, cycloalkyl, and heterocyclyl moieties
`of the foregoing R“ and R7 groups are optionally substituted
`independently with I
`to 3 substituents independently
`selected from halo, cyano, nitro,
`trilluoromethyl,
`trilluoromethoxy, azido, OR”, —C(O)R15, —C(O)OR '5,
`—()(?(())R”,—NR1‘*(I(())R15,—(I(())NR“R“‘,—NR“R“‘,
`and —NRM()R15, (I1—(f,_,, alkyl, (T2—(T,., alkenyl, and (T2—(Tfi
`alkynyl; and
`R10 is phenyl, pyridyl, phenyl-Z13 or pyridyl-Z3-, wherein
`the phenyl or pyridyl moiety is optionally substituted with
`one to five independently selected R”;
`Z2 is —S(O),—, —O—, —(CR“Rl’),_.—, or —(O)k
`(CR”R”)..(0)i(CR”R'’)q
`;
`w is independently an integer from 1 to 6;
`each k is independently 0 or 1;
`or R1” is OR”, wherein R” is [C,—Cfi]alkyl, (C1-C5)
`alkoxy((I1—(I6)alkyl, mono-, di- or
`tri-halo(C2—C6)alkyl,
`PENN EX. 2298
`
`45
`
`of]
`
`65
`
`10 0f46
`
`CFAD V. UPENN
`IPR20l5—0l836
`
`

`
`US 6,949,572 B2
`
`7
`trifluoromethyl(C,—C5)alkyl,
`perfluoro(C2—C,,)alkyl,
`(C3—C3)eyeloalkyl(CR”R"’)q—,
`hydroxy(C,—CU.)alkyl,
`[C:—C,.,)alkenyl, or (C2—C,,]alkynyl;
`(C3-C3)
`(C,—C6}alkyl,
`each R” is
`independently H,
`cycloalkyl,
`C(O)RlS, —C(S)R1i‘, —(CR“R")_,O(C,—C-
`alkyl), —(CR“'R£’)_,S(C1—C,% alkyl), —(CR"R£’),_C(())R1 ,
`—(cR“R”),R‘-‘ or —so,R‘-;
`(C3-C3)
`(C1—C5}alkyl,
`each R15 is
`independently II,
`cycloalkyl,
`triiluoromethyl,
`trilluoromethyl((f,—C5)alkyl,
`wherein the alkyl, moieties of the foregoing R15 groups are
`independently optionally substituted with 1 to 3 substituents
`independently selected from C1-C3“ alkyl, C1-C6 alkoxy,
`amino, hydroxy, halo, cyano, nitro,
`trifluoromethyl and
`trifluoromethoxy;
`and wherein any of the above “alkyl”, “alkenyl” or
`“alkynyl" moieties comprising a CI[3 (methyl), CII2
`(methylene), or CII (methine) group which is not substituted
`with halogen, S0 or S02, or attached to a N, O or S atom,
`optionally bears on said methyl, methylene or methine group
`a substituent selected from the group consisting of halo,
`—()R", ask" and —NR"R"’.
`In an embodiment of the invention, X2 is C{R‘).
`In another embodiment of the invention, X2 is C(R") and
`I. is attached to the 2 position of R‘ and to the 5 position of
`formula 1b.
`
`8
`5-[(Iliphenyl-2-carbonyl)-amino]-3-chloro-1-methyl-lII-
`indole-2-earboxylic acid [2-[isopropylamino-2-oxm1-
`phenylethyl]amide.
`_
`In an embodiment of the invention, R” and R7 in formula
`lb taken together with the nitrogen atom to which they are
`attached together comprise (C,,—Cm)heterocyclyl, wherein
`the heteroeyclyl is optionally substituted independently with
`l or 2 substituents independently selected from (C1-C5)
`alkyl, (C2—C5)alkenyl, and (C,._—CL,-)alkyny1 and trifluororn—
`ethyl. In a preferred embodiment thereof, the heterocyclyl is
`selected from pyrrolidinyl, pipericlinyl, morpholino and
`thiomorpholino.
`In a particularly preferred embodiment
`thereof, the heterocyclyl is pyrrolidinyl or morpholino.
`The present invention also relates to compounds of the
`formula 2:
`
`g.)
`
`Nt<5R7
`
`o
`
`10
`
`"I5
`
`ll]
`
`or a pharmaceutieally acceptable salt thereof, wherein:
`R1 is substituted at the 5 or 6 position of formula 1 and has
`the structure:
`
`R10
`l4\’2~\-x
`(R1i)p—%
`6'—1 —
`5/
`
`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 1b, R10 is OR” and R7 is phenyl—Z1, wherein the
`phenyl moiety is optionally substituted with one to five
`independently selected R”.
`In a preferred embodiment
`thereof, 2' is —(CR"R”J,—.
`In another embodiment of the invention, X3 is C(R") and
`I. is attached to the 2 position of R1 and to the 5 position of
`formula lb, and R1“ is phenyl attached at the 3 position of
`_
`_
`_
`R1, wherein the phenyl moiety of Rm is optionally substi-
`m_15 i“'1_1“le8‘3T _iT0m 010 53
`tuted with one to five independently selected R13.
`In a 35
`D 1,5 an lnlcgcr “Om 0 1° 3}
`preferred embodiment of the invention, R" in formula 1b is
`{’
`‘Ff fl(‘£“(‘;3,";'f]§{,"‘“ _° *0 3-
`H or (c,—c,)a1ky1.
`N
`8 R(,, _)—’
`the
`In another preferred embodiment of the invention,
`_l d
`1
`,
`[1
`d
`, _h - d
`Rzlskx (H-11'(RI
`’_ d R13_
`carbon designated “a'" in formula lb is in the (S) absolute
`,
`,
`an
`,
`are can.
`111 epen en y se ee e
`wnfigurauhnl
`from halo, cyano, nitro, azido, amino, hydroxy, (C1-C5)
`In another embodiment of the invention, R13 in formula
`alkyl,
`(C3—C5)alkoxy, methoxy,
`(C1-C3-)alkoxy((T,—(T,,)
`1b is H or trifluoromethyl.
`alkyl, mono—, di— or tri—halo[C,_—C,,)alkyl, perl‘luoro(C2—C_,)
`In another preferred embodiment of the invention, R3 in
`al.kyl, trilluoromethyl, trilluoromethyl(C1—C5)al.kyl, mono—,
`formula lb is II, halo, or (C,—Cfi]alkyl
`di— or tri—halo(C2—Co-)alkoxy, trifluoromethy1(C1—C5)alkoxy,
`In another preferred embodiment of the invention, R7 in
`(C,—C,,2alkylthio, hydroxy(C1—Cfi)alkyl, (C_,—C,,]cycloalkyl
`formula 1b is (C1-C3-Jalkyl,
`(C2—C,,)alkenyl or (C2-C5)
`(CR"R ,,—,
`(C2—Cfi)alkenyl,
`[C2—Cfi)alkynyl,
`(C1-C6)
`alkynyl.
`alkylamino—,
`(C,—Cc,)dialkylamino, amino(C,—C5)alkyl—,
`—(CR"R"’) NR"R14, —C(0)NR"RH, —NRl'lC(O)R13,
`In a particularly preferred embodiment of the invention,
`—NR “OR ' 5, —(T]I=N[)R ' 5,
`NR ' "(T(0)() R ' 5,
`the compound is selected from the group consisting of:
`3-Chloro-'1-methyl-5-[(4'-trifluoromethyl-|)iphcnyl-2- Sn —NR"'S{O)—R15, —C(O)R15,
`C(S)l-I15, —C(O)RO]5,
`—()C(())R1',
`carbonyl)-amino}1II-indole-2-carboxylic acid [2-oxo-l-
`so,NR"R"',
`s(()),.R“‘, or —(iR*’R”),,s
`phenyl—2—(prop—2—ynylamino)ethyl]amide;
`(0),-R”;
`each R” and R” is independently II or (C,—C,,]alkyl;
`3-Chloro-l-methyl-5-[(4'-tri[luoromethyl-biphenyl-2-
`R‘ is H or R“;
`carbonyl)-amino]-1II-indole-2-carboxylic acid [2-
`each q is independently an integer from U to 6;
`[isopropylamino—2—oxo—1—phenylethyl)amide;
`each j is independently 0, 1 or 2;
`3-Chloro-l-methyl-5-[(4'-tri[luoromethyl-biphenyl-2-
`R7’
`is II, halo,
`(C1—Ct.,)all<yl, or mono—, di— or tri-halo
`carbonyl)-amino}1II-indole-2-carboxylic acid [2-oxo-l-
`(C1—C,-)alkyl;
`phenyl—2—(propylamino)ethyl]amide;
`each r is independently an integer from 2 to 5;
`3-Chloro-l-methyl-5-[methyl-(4'-tri[luoromethyl-
`
`each 1 is inde endentl, P
`
`
`Y
`an inte ‘er from 1E:
`to 6;
`biphenyl-2-carbonyl)-amino}III-indole-2-earboxylie acid
`R’ and R9 are each inde endently H,
`(Cl—C,,-)a1kyl,
`[2—[ethylamino)—2—oxo—'l—phenylethyl]amide;
`EE33‘E8’“t.“‘i3a%?~t‘ti»‘§i?&7 =:‘tStt*:,a:a*:;*:i;>t;;
`3—Chloro—1—methyl—5—[methyl—(4'—trifluoromethyl—
`'§_ Gas); '5
`15
`‘W '1_1é°a iy '
`'
`''
`biphenyl—2—carbonyl)—amino]—lH—indele—2—carboxylic acid
`R1 , —{(.R R
`or —b()3R ;
`[2—[isopr0pylamino—3—oxo—l—phenylethyl]amide;
`Rf’
`is Ills, ((I1—(Ifi)allfHyl, (C_,_—CH)cycloalkyl, —C(()]£{'5,
`5-[[Biphenyl-2-carbonyI]-amino]-3-chloro-"l-methyl-'lII-
`—C(S)R , —(CR“R ),0(C1—C6 alkyl), —(CR"R_),_,S
`indole-2-carboxylic acid [2-oxo-l-phenyl-2-(propylamino)
`(C§;)C7,l,-{1a;lkyl), —(CR"R‘!’),C(O)R15, —(CR“R£’),R1’ or
`ethyl]amide; and
`PENN EX. 2298
`
`C“?
`
`30
`
`4”
`
`45
`
`fit]
`
`65
`
`110f46
`
`CFAD V. UPENN
`IPR20l5-01836
`
`

`
`US 6,949,572 B2
`
`10
`In a preferred embodiment of the invention, R13 in
`formula 2 is trifluoromethyl.
`In another prefe1Ted embodiment of the invention, R3 in
`formula 2 is H, halo, or [C,—C,,)alkyl.
`The invention also relates to a process for preparing a
`compound of formula 1 which comprises forming an amide
`linkage between a compound of the formula A131:
`
`R3)it
`I
`
`A131
`
`/
`
`
`
`t
`
`\
`
`N |
`
`R9
`
`R10 0
`
`(RI|)pT¢"/:%J|\
`ks/
`
`/5%
`
`and a compound of the formula Q:
`
`
`
`wherein
`m is an integer from O to 5; n is an integer from 0 to 3;
`p is an integer from 0 to 3;
`the amide nitrogen atom of —C(0)N(R'°)— above is
`bonded to the 5 or 6 position of the indole;
`X is N or C(R°'), wherein R“ is H or R”;
`R2, R“, R", R12, R17’ and R1“ are each independently
`selected from halo, eyano, nitro, azido, amino, hydroxy,
`(C,—C,-_)alkyl,
`(C_~_—C,,-)alkoxy, methoxy,
`(C,—C,,-)alkoxy
`(C,—C,-)alkyl, mono—, di— or tri—halo(C3—C,,-)alkyl, perfluoro
`(C2—C,,)alkyl, trifluoromethyl, trifluoromethyl(C,—C5)alkyl,
`mono—,
`di— or
`tri—halo[C,._—C,,-)alkoxy,
`trifluoromethyl
`(C1—C5)alkoxy,
`(C1—Cfi)alkylthi(t, hydroxy((‘l—C°)alkyl,
`(C3—(I,,)cycloalkyl{CR”R"’),,
`,
`[(T2—C,.,)alkenyl,
`(C2-C6)
`alkynyl, (C,—C,,)alkylamino—, [C,—C,,-)dialkylamino, amino
`(C,—CS,)alkyl-, —(CR"R”)fi5NR"R“‘, —C§0)NR"R“,
`—NR1 C(O)R15, —NR“0R , —CH=NOR 5, —NR“'C
`(O)0R”, —NR1‘*S[0)-R15, —C(O)Rl5,
`C(S)R”,
`—C(())()R”, —o(:(o)R‘-‘,
`st),NR'*R“‘, fls((J),.R“'*, or
`—(CR"R"’)qS(0) .12 '5;
`each R“ and R5’ is independently H or (C,—C,,-)alkyl;
`each q is independently an integer from U to 6; eachj is
`independently 0, 1 or 2;
`R3 is H, halo, (C,—C,,)a1kyl, or mono—, di— or tri—halo
`((f,—C,,)alkyl,
`R4 is H, (C,—C,,-)alkyl, (C3—C,,)eyeloalkyl, —C(O)R’5,
`—C(S)R'5, —(CR”R"’),O(C,—C,, alkyl),
`(CR"R"’),_S
`(C,—C,._ alkyl), —(CR"R”),C[0)R15,
`(CR“R*’),.R"‘,
`—SO2R'5 or —(CR"R"),,—phenyl, wherein the phenyl moi-
`ety is optionally substituted with from one to live indepen-
`dently selected Rm;
`each r is independently an integer from 2 to 5; each t is
`independently an integer from 1 to 6;
`R5, R5 and R9 are each independently II, (C,—(T6)alkyl,
`((T3—C,,)cycloalkyl, —(f(())R15, —(T(S)R15, —(CR”Rb),(]
`(C1-C5 alkyl), —((TR"Rf’),S(C,—CU. alkyl), —(CR“Rl‘)rC((])
`R‘-“, —((:R"R”),R‘-“ or —so,R‘-‘;
`R7 is phenyl, pyridyl, phenyl—Z1— or pyridyl—Z‘-, wherein
`the phenyl or pyridyl moiety is optionally substituted with
`one to five independently selected R13;
`
`9
`y is an integer from U to 5;
`(C3—C6)alkynyl,
`R7 is (C,—C6)alkyl,
`(C,._—C°.)alkenyl,
`—{(?R"R”), t)(t?,—(.‘, alkyl), —((?R“R”),,s((:,—(:, alkyl);
`(C3—C§,)eyeloalkyl, —C(O)R15, —C(S]R'5, —(CR"R”)i.C
`(0)R1 , —(CR“'R£’),C(S)R15, —(CR"R"),R‘5 or —SO3R 5;
`or R7 is phenyl, pyridyl, phenyl-Z1-or pyridyl-Z5 option-
`ally substituted with one to five independently selected R '2;
`or R5 and R7 taken together with the nitrogen atom to
`which they are attached together comprise ((f,,—(f,,,)
`heterocyclyl, wherein the heterocyclyl moiety is monocy-
`elie;
`wherein the alkyl, cycloalkyl, and heterocyclyl moieties
`of the foregoing R5 and R7 groups are optionally substituted
`independently with 1
`to 3 substituents independently
`selected from halo, eyano, nitro,
`triiluoromethyl,
`trilluoromethoxy, azido, —(]Rl5, —C(()}R15, —C(())()R15,
`—()(l(t))R‘5,—NR"'(T(())R‘5,—(?(())NR"R“',—NR"R“‘,
`and —NR"‘OR'5, C,—C,, alkyl, C2—C,, alkenyl, and C2-C6
`alkyncyl; and
`R1
`is phenyl, pyridyl, phenyl-Z15 or pyridyl-Z2-, wherein
`the phenyl or pyridyl moiety is optionally substituted with
`one to five independently selected R”;
`2‘ is
`s(o).—, —o—, —(c:tt"R”)_,.—, or —(o),,
`{CR"R"),,.(O),,[CR"R“),,—;
`w is independently an integer from I to 6;
`each k is independently U or 1;
`or Rm is ()R”, wherein R17 is (C,—C6)alkyl, (C1-C6)
`alkoxy(C,—CU.)alkyl, mono—,
`di— or
`tri-halo(C3—C5)alkyl,
`perlluoro((T2—(T,,)alkyl,
`triiluoromethyl(C,—(f5)alkyl,
`hydroxy(C,—C,,.)alkyl.
`(C_.,—C,,)cyeloalI{yl(CR"R"’),,—,
`(C3-C0-)alkenyl, or (C3-C6-)alkynyl;
`(C3-C3)
`((f,—C,,)alkyl,
`each R“ is
`independently II,
`eyeloalkyl, —C(O)R15, —C(S)R15, —(CR“R"),O(C,—C-
`alkyl), —(CR‘“'R£’),S(C,—(."fi alkyl), —((fR“R£’),(f(())R15{:
`—(cR"R”),R‘-‘ or —so,R‘5;
`((f_.,—C,,)
`((f,—C,,)alkyl,
`each R15 is
`independently II,
`eyeloalkyl,
`trifiuoromethyl,
`trifluoromethyl(L;—C5)alky1,
`wherein the alkyl, moieties of the foregoing R" groups are
`independently optionally subs