1
`I
`(12) United btates Patent
`Bertinato et al.
`
`USUU6979692B2
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 6,979,692 B2
`Dec. 27, 2005
`
`(54) TRIAMIDIE-SUHSTITUTEI)
`]-1ETER()[;[(jY(3[,1C COMPOUNDS
`
`(75)
`
`Inventors: Peter Bertinato, Old Lyme, Cl‘ (US);
`Alan E. Blize, New London, (.‘1‘(US);
`Bria"
`Bmnk’ Galcs Fwy’ CT ius);
`H'3"3m"‘° Ch‘~‘“B~ 1305‘ 1-3000» U
`(US); Jill Us P0“’001001i~ C1‘ (U3);
`Hiep Huatnn, 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
`1549
`
`EP
`I.-‘P
`F.I’
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`W0
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`1099101
`1181954
`0584440
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`9327939
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`W0 0075971
`W0 0105752
`W0 0121504
`W0 0147898
`W0 0147899
`“K311153261!
`W0 0lT’0"7'7
`W0 01922.41
`
`W0 0195337
`W0 019781”
`731712121
`W0 0283658
`
`572001
`272002
`672002
`
`371997
`157,33;
`1272000
`172001
`372001
`772001
`772001
`'7,-"2001
`1072001
`1272.011]
`
`1373001
`1272001
`_
`1072002
`
`
`
`.. C0'7374-(11714
`A61P73,-'06
`Cl2N7l5712
`
`B26l_D"[37"'16
`-A ggggggg,2,
`:1: 0073,-'211700
`C073,-211700
`C07 37295714
`00737241700
`00737241704
`.. C07 37211744
`C0'7')7213,-"38
`(‘.07I)7)95,-"I35
`
`50777401712
`"‘,5'Kf'3”4l_4-3
`.
`7
`1053171:
`C07D72957"l35
`
`(21) Appl. No.: l[|7639,854
`
`(22) Filed:
`
`Aug. 13, 2003
`
`(65)
`
`P110" P“"h"'3"°n Dam
`US 200570030103 A1 Apr. 14, 2005
`
`Related U_S_ Application Data
`
`(62) Division of application No. 10,-"17’?,858, filed on Jun. 20,
`_
`3003; [TOW P9-L N0: 15.-720.-35L
`(00)
`Pmvlslonal “PPhC‘m°" No‘ 6U’i3m’444’ filed 0" hm‘ 28’
`2001.
`
`(51)
`
`Int. CL?
`
`A6 1K 31744; C071) 213728;
`AGIP 3700
`5147339; 54572774
`.
`540; 77 4’ 514” 9
`
`(521 U.s. Cl.
`1
`..
`(58) “dd of Smmh
`(56)
`References Cited
`U.S. PATENT DOCUMENTS
`
`4247258
`4247250
`435769.3
`51-17252
`5147415
`5147394
`5147310
`5|-17310
`.. 5147325
`514730?
`5147354
`5]472]l.]l
`5147319
`5467190
`5147415
`5147515
`
`
`
`..
`
`571977 Mathison
`4_.022_..900 A
`871983 Sircar
`4_.3.97_.s55 A
`571995 Lazzeriet al.
`5_.416_.009 A
`171998 Biller etal.
`5,712,229 A
`371998 Bras ct al.
`5_."7'31_.340 A
`471998 Keenan ct al.
`5_."7‘41_.804 A
`271999 Chang ctal.
`5,919,795 A
`1071999 Quallich et al
`5,968,950 A
`572000 Gregg ct al.
`6_.066_.653 A
`972000 Chang ct al.
`6_.l21_.283 A
`372001
`I"ink ct al.
`6_.l9'7_."7‘.98 B1
`572001 Sato et al.
`6,235,730 B1
`872001 Tino
`6.281.228 B1
`972001 Griffilt
`6,288,234 B1
`172002 Dcfossa ctal.
`5,337,344 131
`372002 Priepke ct al.
`2002.-0032238 A1
`l-‘OREIGN P/(I'l.'lN'l‘ D(JCUMI_-‘NTS
`199145594
`V2001
`CU?Df2q5f04
`0543057
`371995
`.. 170707401704
`1006122
`672000
`C‘07K75708
`
`.. 7\61K731719:'i
`1080724
`372001
`
`()'l'IIl_".R I-’UBl.I(7NI"I()NS
`
`Watterau, J .R., et al., Sc7Te71ce, “Absence of Microsomal
`Triglyceride Transfer Protein in Individuals with Abetalipo—
`PT0‘0i“0““0"~ V01’ 353» (N0"- 0; 1,9931
`,
`_
`Watterau, JR., et al., B1oc7117711ca er B1op71ys1c17 Acre,
`“I1ocali7.ation of Intracellular Triacylglycerol and Choles-
`teryl Ester Transfer Activity in Rat Tissues“, vol. 875 pp.
`610-617 (1986).
`Jundong Zhang, et al., Bioorganic & Medicinal Chemistry,
`“Identification of Inhibitors of lIe7arin— rowth factor inter-
`.
`.
`.
`I
`.
`I
`.
`3.
`actions trom Combinatorial Libraries of F0ur—C0mp0r1cnt
`Condensation Reaction", (2001), vol. 9 No. 4, pp. 825-836.
`_
`‘
`_
`H
`1
`1’”’”0’.V 0100000’
`1001130 5013010
`A..s'.s'i.s'7a'r1i' Exa771im'r—Rri ert S iao
`(74) A7707'r1e‘, Agent, or F1'r711—(}regg (I. Benson; Robert
`M‘ Kcnncdy
`(57)
`
`ABSTRACT
`
`The invention relates to triamidc MTPMPOB inhibitors of
`the formula 1
`
`-1
`
`
`
`,,
`,,
`-
`_
`-
`.
`__
`4,
`1
`.
`wh‘°""" R _.R ‘in’ “” d“.I'.“°d "1 the ”p°"h“‘“"“.’ “” we" ‘”’
`pharmaceutical compositions and uses thereof, and pro-
`cesses for preparing the compounds, The compounds of the
`invention are useful for the treatment of obesity and lipid
`"‘S°rd°r5'
`
`12 Claims, 6 Drawing Sheets
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`DE
`EP
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`PENN EX. 2158
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`CFAD V. UPENN
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`Dec. 27,2005
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`Sheet 1 of6
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`US 6,979,692 B2
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`50
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`FIG.1
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`U.S. Patent
`
`Dec. 27,2005
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`Sheet 2 of6
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`US 6,979,692 B2
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`FIG.2
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`100120
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`Dec. 27,2005
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`Sheet 3 of6
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`US 6,979,692 B2
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`CD
`"*4
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`0(
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`1200
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`FIG.3
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`Dec. 27,2005
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`Sheet 4 of6
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`US 6,979,692 B2
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`FIG.4
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`C3
`C}
`("VI1
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`Dec. 27,2005
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`Sheet 5 of6
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`US 6,979,692 B2
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`FIG.5
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`CD
`CD
`(‘II-
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`Sheet 6 of6
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`US 6,979,692 B2
`
`1
`TRIAMIDE-SUBSTITUTED
`HETEROBICYCLIC COMPOUNDS
`
`2
`SUMMARY ()1? 'l'IIl_-' INVl_-'N'l'I()N
`
`The present invention relates to compounds of the for-
`mula 1:
`
`This application is :1 divisional of pending U.S. patent
`application Ser. No. '10i’177",858 filed on Jun. 20, 2002, now
`U.S. Pat. No. 6,720.35'l which claims the benefit of US.
`Provisional Patent Application No. 6[l;’301,644 filed on Jun.
`28, 2001, both of which are incorporated herein by reference
`in their entirety.
`
`FIELD OF THE INVENTION
`
`This invention relates to triamide—substituted heterobicy—
`clic compounds. These compounds are inhibitors of
`microsomal triglyceride transfer protein (MTP) andfor apo-
`lipoprotein B (Ape 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 prevention and treatment of related diseases. The
`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 medicaments, including lipid lowering agents.
`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.
`BACTKCEROUNIJ ()1-‘ TIIl_-' INVEN'l‘I()N
`
`triglyceride transfer protein catalyzes the
`Microsomal
`transport of triglyceride, cholesteryl ester, and phospholipids
`and has been implicated as a putative mediator in the
`assembly of Apo B-containing lipoproteins, biomolecules
`which contribute to the formation of atherosclcrotic lesions.
`
`the subcellular (lumen of the microsomal
`Specifically,
`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 between membranes 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,
`hypercholesterolemia, hypertriglyceridemia, 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 Al, 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 99393800 and W0 00f0520l; and European patent
`application publications El’ 584446 and l_iP 643,057.
`
`10
`
`"I5
`
`20
`
`35
`
`40
`
`45
`
`Sf]
`
`60
`
`65
`
`.\'R"'R7
`
`or a pharmaceutically acceptable salt thereof, wherein:
`R‘ is substituted at the 5 or 6 position of formula 1 and has
`the structure:
`
`R10
`m\’;~‘<~.-_,,
`(Rtlhfi
`ET
`-‘Z
`
`1.—'-
`
`m is an integer from 0 to 5;
`n is an integer from 0 to 3;
`p is an integer from 0 to 3;
`I.is —C(())N(R9)—, i_e_, I. has the structure:
`
`R9
`
`N
`
`D
`
`X is N or (I(R");
`R: , R“, R", R12, R” and R” are each independently
`selected from halo, cyano, nitro, azido, amino, hydroxy,
`Eg,—((§,,3allll‘<yll,
`(C2—Cfi?alkoxy,hr1'l1eEl(1:ox3C,r, )(CuT\,—1C,,)al1koxy
`.1»
`.-a 'y ,mono— ,(1-0Ill'1- a o
`3- ..a 'y ,per uoro
`(C2—C:)a(l]k_yl, trifluoriprrlieélgyl, (tril)lu1c1J\rometl1ylE1C,—C5)al1Byli
`tr1-
`a 0
`‘3— ‘
`a city,
`tr1 uoromet y
`mono-,
`1- or
`(C,—C5)alkoxy,
`(C1-C3-)a£t)lkylthE]io, hydroxy(Cl—C<,-)alkyl,
`(E1334I£f)&yel:al;<y1l{{]TR"l1 Lrd, l_‘(7g-fit,-)l«'i1‘11~'i=r1y‘1.
`((72-95)
`a 'yny ,
`.
`.
`a 'y amino-,
`.
`.,.,
`1a 'y amino, amino
`(C,_(“.,,)aIi.vyIi, —((“.R”R”),Nl2"R"', —(“.(0)NR"R“',
`—NR”C(O)R15, —NR”0R1g, —CH=N0Rl5, —NR”C
`(O)OR”, —NR”S[O)-R15, —C[O)R15,
`C(S)R”,
`—C{O]0R15, —0C(0)R 5, —SO3NR"R1“, —S(0)-R15, or
`—(cR“R*'),,s(o),R”;
`I
`each R" and 55’ 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,
`((I,—(T,_.,)all<yl, or mono-, di- or tri-halo
`(C,—C,-)alkyl;
`R" is II, ((I,—(I,.,)alkyl, (C3—CH)cycloalkyl, —(T(()]R'5,
`mt ‘it :tCR:2:a:£§“t:.%;aaa .c.:a:;::t§
`. — .6
`a
`y ,
`F .
`',
`r
`',
`—§()2l-{I5 or —((TR"Rl’)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 t_is independently an integer from 1 to 6;
`R5, R" and I{° are each independently H, ((.',—(.',,)atkyl,
`(C_.,—C3)cycloalkyl, —C(0)R15, —C[S)R15, —(CR“R£’),O
`PENN EX. 2158
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`US 6,979,692 B2
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`3
`(c,—(:,., alkyl),—((7R"R1’),S(C,—Cfi alkyl),—((TR‘°R1’),(T(())
`R1‘ , —{CR"R"’)rR15 or —SO:R15;
`R1 is phenyl, pyridyl, phenyl-Z1- or pyridyl-Z1-, wherein
`the phenyl or pyridyl moiety is optionally substituted with
`one to five independently selected R11;
`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 R17’;
`2“ is —s(o).—. —o—, —(Cl{"R1’),,_—, 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, —(?([))R15, —(?(s)R1-‘, —(c:R"R‘*),()((:,—(:,
`alkyl), —((7R"R”),s((:,—(?, alkyl), —((?R”R”)_.(f(())R'5,
`—{CR"R"’),_R15 or —SO2R15;
`(C3-C3)
`(C,—C,,}alkyl,
`each R1’
`is
`independently H,
`cycloalkyl,
`trifluoromethyl,
`trilluoromethyl((;1—C5)alkyl,
`wherein the alkyl, moieties of the foregoing R1‘ 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 1, ie, the
`compound of formula 1 has the structure of formula la:
`
`10
`
`"I5
`
`ll]
`
`35
`
`la
`
` o
`
`/I 1“ N!
`2
`|
`\ \
`/
`1:9
`R1
`
`0
`
`R10
`/at
`(RIIJVT;
`kl
`
`In another embodiment of the invention, I. is attached to
`the 2 position of R1 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 of R1 and to the 5 position formula 1. In
`another embodiment of the invention, I. is attached to the 3
`position of R1 and to the 5 position of formula I and X is N.
`In still another embodiment ofthe invention, [.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 R1 is
`selected from the 3, 4, 6 or 6 position and the attachment of
`L to the compound of formula I 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"), m is
`I), n is [1, and p is U or I.
`In another embodiment of the invention, X is (f(R"), m 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.
`
`4E]
`
`45
`
`Sf]
`
`60
`
`65
`
`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 R10 is
`optionally substituted with one to five independently
`selected R13.
`
`In another embodiment of the invention, R7 is phenyl—Z1,
`wherein the phenyl moiety is optionally substituted with one
`to five independently selected R13. In a preferred embodi-
`ment of the invention, Z1 is —((TR“'R1’)‘—, 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”),,()((?,—(:,a1ky1) or —((?R"R1’),R15.
`In another embodiment of the invention, each R12 is
`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,
`trilluoromethyI((I,—C5)alkoxy,
`((.',—Cfi)alkylthio
`and hydroxy((T,—C,,,)alkyl.
`In another embodiment of the invention, each R13 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
`—NR11C(())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 R1” is optionally substituted with one R13. In a preferred
`embodiment, R'” and R1 both are phenyl, such that R1 and
`R1” together fonn a l,l'-biphenyl group, wherein Rm com-
`prises the 1—'6‘ positions of the biphenyl group and R13 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,
`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, R1‘ 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.
`
`In another more preferred embodiment of the invention
`R1 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—indole—2—earboxylic acid {2—[benzyl(methyl)
`amino]—2~oxo—1—phenylethyl} amide;
`3-chloro-"l-methyl-5-[[4'-trilluoromethyl-biphenyl-2-
`carbonyl)-amino]-lII-indole-2-carboxylic acid {2-
`[benzyl(methyl)amino]-2-oxo-I -phenylethyl }amide;
`PENN EX. 2158
`
`9of44
`
`CFAD V. UPENN
`IPR20l5-01836
`
`

`
`US 6,979,692 B2
`
`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°—)allioxy
`((i1—C5)alkyl, mono-, di- or tri-halo((T3—(Ib.)alkyl, perlluoro
`((i2—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"Ri’)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=NOR15, —NR”C
`(o)oR”, —NR“s(o).R15, —(?(())R15,
`(I(S)R”,
`—(?(o)()R‘-“, —()(:§t))R‘-‘, —so,NR"R“‘, fls(o),.R“'*, or
`—(CR"R")qS(O).R" ;
`each R“ and R5’ is independently H or (C1-C6-)alkyl;
`RC. 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
`((i1—Ce.)alkyl;
`R4 is H, (C1-C0-)alkyl, (C3—C3)eycloalkyl, —C(O)R’5,
`—C(S)R15, —(CR"R£’),O(C1—CL,- alkyl),
`(CR“R£’)_,_S
`{C1-C6 alkyl), —(CR"Ri’),C[O)R15, —(CR"Ri’),R”,
`—SO3R‘5 or —(CR"Ri’)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 t is independently an integer from '1
`to 6;
`R5 and R9 are each independently II,
`(C1—Cfi)alkyl,
`(C3—C,,)eycloalkyl, —C(0)R15, —C[S]R15, —(CR‘°R"’),O
`((i,—Cfi alkyl), —(CR"Rb),S(C1—Cfi alkyl), —(CR"Rb),C((l)
`R‘-‘, —(CR”R"’),R“‘ or —so,R‘-‘;
`RE‘
`is H, (C1—Co.)a]kyl, (C3—C3)eyeloalkyl, —C(O)R'5,
`C(S)R15, —(CR"R£’),,EJ)(C1—C<,lalkyl). —(gR"I;’.:’),_,S
`(C1-C6 alkyl), —((iR"R ),.C(())R ', —(CR"R ),,R ' or
`—SO2R15;
`y is an integer from [J to 5;
`I{7 is ((I1—(Tfi)alkyl,
`(C2—(Tg)alkenyl, {C2—(Tg]alkynyl,
`—(CR"R"’),,O(C,—C,., alkyl), _—(CR"R”),t,1S(C,—C,, alkyl),
`(C_.,—C,,)cycloalkyl,
`C[O)R1’, —C(S)R 5, —{CR“Ri'),E“,
`(o)R‘-‘, —((7R"R”),(?(s)R‘5, —((?R"R"’),.R‘5 or fls(J,R‘-‘;
`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)
`heterocyelyl, wherein the heterocyclyl moiety is monoey—
`clie;
`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“Ri’],_.—, or —(O)k
`(CR”R”)..(0)t(CR”R'’lq
`;
`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. 2158
`
`10
`
`"I5
`
`ll]
`
`35
`
`4E]
`
`45
`
`Sf]
`
`an
`
`65
`
`5
`
`4‘-trilluoromethyl-biphenyl-2-carboxylic acid [2-({[(hen7.yl-
`methyl-carbamoyI]-phenyl-methyl]-methyl-aminn}-
`methyl)-3-chloro-I-methyl-III-indol-5-yl]-amide, which
`is alternately named:
`3—eh|nro—I—methyl—5—[(4‘—
`trifluoromethy1—biphenyl—2—earbonyl)—amino]—1H—in(|ole—
`2—earboxylic acid {N—[2—(benzyl(methyl)amino)—2—oxo—1—
`phenylethyl]methyl} amide;
`3—ehloro-1—methyl—5—[methyl—(4'-trifluoromethyl—biphenyl—
`2-carbonyl)-amino}III-indole-2-carboxylic acid {2-
`[|3enzyl(methyl)amino]—2—oxo—l—phenylethyl}amide; and
`3—chloro—1—ethyl—5—[(4'—trifluoromethyl—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
`U, 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 selected R13, and R7 is phenyl-Z1, wherein the phenyl
`moiety is optionally substituted with from one to five
`independently selected R”.
`The present invention also relates to a compound of the
`formula lb:
`
`‘lb
`
`
`
`NR”R?
`
`x
`
`1
`
`O
`
`/
`R3
`
`“{2}”
`,,t_/7 t
`
`5 \
`
`or a pharmaeeutically acceptable salt thereof, wherein:
`R1 is substituted at the 5 or 6 position of formula 1b and
`has the structure:
`
`RIU
`_
`r~\/‘§““?.<”
`?—I_.— ,
`|-|
`5/
`
`It
`(R 1:‘
`
`or when R7 is phenyl. pyridyl, phenyl—Z1— or pyridyl—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‘i’),S(C1—(."5 alkyl), —(CR"Ri’),_C(())R15,
`—((TR"R”),R 15, 402R 15, (C,,—Cm)heterocyclyl, ((i5—Cw)
`heteroaryl, aryl or —(CR“Ri’)q-aryl, wherein the cycloalkyl,
`heterocyclyl, heteroaryl or aryl moiety is optionally substi-
`tuted with from one to live independently selected R”;
`m is an integer from U to 5;
`n is an integer from 0 to 3;
`
`10 0f44
`
`CFAD V. UPENN
`IPR20l5-01836
`
`

`
`US 6,979,692 B2
`
`7
`trilluoromethyl(C,—C5)alkyl,
`perlluoro(C2—C,,)alkyl,
`(C3—C3)cycloalkyl(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(0)RlS, —C(S)R1i‘, —(CR“R"),O(C1—C5
`alkyl), :(c?R"R*’),s((.‘,—c:,,. alkyl], —(CR“R")r(I(())R‘5 or
`—S0qR ';
`(C3-C3)
`(C1—C5}alkyl,
`independently II,
`each R15 is
`cycloalkyl,
`triiluoromethyl,
`trifluoromethyl((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
`trilluoromethoxy;
`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 1 b.
`
`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, Z‘ is —(CR"R”),—.
`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-
`tuted with one to five independently selected R13.
`In a
`preferred embodiment of the invention, R" in formula 1b is
`H or [C,—C4)alkyl.
`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, R13 in formula
`1b is H or trifluoromethyl.
`In another preferred embodiment of the invention, R3 in
`formula lb is II, halo, or (C,—Cfi]alkyl
`In another preferred embodiment of the invention, R7 in
`formula 1b is (C1-C3-Jalkyl,
`(C2—C,,)alkenyl or (C2-C5)
`alkynyl.
`In a particularly preferred embodiment of the invention,
`the compound is selected from the group consisting of:
`3-Chloro-1-methyl-5-[(4'-trifluoromethyl-|)iphcnyl-2-
`carbonyl)-amino]-1II-indole-2-carboxylic acid [2-oxo-l -
`phenyl—2—(prop—2—ynylamino)ethyl]amide;
`3-Chloro-1-methyl-5-[(4'-trilluoromethyl-biphenyl-2-
`carbonyl)-amino]-1II-indole-2-carboxylic acid [2-
`[isopropylamino—2—oxo—1—phenyletl'1yl]amide;
`3-Chloro-1-methyl-5-[(4'-trilluoromethyl-biphenyl-2-
`carbonyl)-amino]-1II-indole-2-carboxylic acid [2-oxo-l -
`phenyl—2—(propylamino)ethyl]amide;
`3-Chloro-1-methyl-5-[methyl-(4'-trilluoromethyl-biphenyl-
`2-carbonyl)-amino]-'1II-indole-2-carboxylic acid [2-
`[ethylamino)—2—oxo—'l—phenylethyl]amide;
`3—Chloro—1—methyl—5—[methyl—(4‘—tril‘luoromethyl—biphenyl—
`2—carbonyl)—amino]—'lH—indole—2—earboXylie acid [2-
`[isopropylamino—2—oxo—l—phenylethyl]amide;
`5-[[Biphenyl-2-carhonyl)-amino]-3-chloro-"l-methyl-'lII-
`indole-2-carboxylic acid [2-oxo-l-phenyl-2-
`[propylamino)ethyl]amide; and
`
`5
`
`10
`
`"I5
`
`ll]
`
`C“?
`
`35
`
`4E]
`
`45
`
`Sf]
`
`60
`
`65
`
`8
`5-[(Iliphenyl-2-carbonyl)-amino]-3-chloro-1-methyl-l II-
`indole-2-carboxylie acid [2-[isopropylamino-2-oxo-1-
`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 heterocyclyl 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, piperidinyl, 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.)
`
`
`
`or a pharmaoeutically acceptable salt thereof, wherein:
`R1 is substituted at the 5 or 6 position of formula 1 and has
`the structure:
`
`RIO
`r\’9*>.<
`I -1
`'3
`5/
`
`(R11),
`
`1.— '-
`
`m is an integer from U to 5;
`n is an integer from U to 3;
`p is an integer from 0 to 3;
`I. is —C(())N(R9)—;
`X is N or C(R° ;
`R2, R”, R”, R' and R17’ are each independently selected
`from halo, cyano, nitro, azido, amino, hydroxy, (C1-C5)
`alkyl,
`(C3—C5)alkoxy, methoxy,
`(C1-C3-)alkoxy((T,—(T,,)
`alkyl, mono—, di— or tri—halo[C,_—C<,)alkyl, perl‘luoro(C2—C_,)
`alkyl, trifluoromethyl, trifluoromethyl(C1—C5)al.kyl, mono—,
`di— or tri—halo(C2—Co-)alkoxy, trifluoromethyl(C1—C5)alkoxy,
`(C,—C,,2alkylthio, hydroxy(C1—Cfi)alkyl, (C_,—C,,]cycloalkyl
`(CR"R ,,—,
`(C2—Cfi)alkenyl,
`[C2—Cfi)alkynyl,
`(C1-C6)
`alkylamino—,
`(C,—Cc,)dialkylamino, amino(C1—C5)alkyl—,
`—(CR“R"’) NR“R”, —C(0)NR"R”, —NR”C(0)R13,
`—NR"'ofi'-“, —ct1=NoR‘5,
`NR"'(?(o)oR‘-‘,
`—NR"'S{O)rR15, —C(0)R15, —C(S)l-I15, —C(O)UR]5,
`—()(:1(p)R‘-“', —S()2NR"R"‘, fis(()),.R‘-2 or —((TR"R”),,S
`(0)-R -;
`eiach R” and RI’ is independently II or (C,—C,,]all\'yl;
`R" is H or R“;
`each q is independently an integer from U to 6;
`each j is independently 0, 1 or 2;
`R7’
`is II, halo,
`(C1—Ct.,)all<yl, or mono—, di— or tri-halo
`(C1—C,-)alkyl;
`each r is independently an integer from 2 to 5;
`each 1 is independently an integer from 1
`to 6;
`R’ and R9 are each inde endently H,
`(C1-C3-)alkyl,
`(C3—C3)cycloalkyl, —(;[[))R1 , —C[S]R15, —(C%“R£’),(}
`{C%—Ce alkyl), —(CR”R’),S(Cl—(:[, alkyl). —(CR"R ),C(())
`R‘ ,—{(:R"R*’),R15 or —so,R1>;
`Rf’
`is II, (C1—Cfi)alkyl, (C_,_—CH)cycloalkyl, —C(()]R'5,
`—C(S)R‘5, —(CR"R"’),(£)(C1—C6 alkyl), —((£“.R"Rf’)qS
`(C§;)C7,l,-{1a;lkyl), —(CR"R ’),C(O)R15, —(CR,,R ’),R” or
`PENN EX. 2158
`
`110f44
`
`CFAD V. UPENN
`IPR20l5-01836
`
`

`
`US 6,979,692 B2
`
`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,—Cg)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,—(."£, alkyl), —((fR“R£’),(f(())R1 ,
`—(cR"R”),R‘-‘or —so,R‘-;
`((f_.,—C,,)
`((f,—C,,)alkyl,
`each R15 is
`independently II,
`eyeloalkyl,
`trifiuoromethyl,
`trifluoromethyl(L;—C5)alky1,
`wherein the alkyl, moieties of the foregoing! " groups are
`independently optionally substituted with I to 3 substituents
`independently selected from C1-C6 alkyl, C1-C6 alkoxy,
`amino, hydroxy, halo, eyano, nitro,
`trifluoromethyl and
`trilluoromethoxy;
`''alkenyl’’ or
`and wherein any of the above “alkyl”,
`“alkynyl” moieties comprising a CH3 (methyl), CH:
`(methylene), or CH (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“, ask" and —NR“R".
`In an embodiment of the invention, X in formula 2 is
`C(R‘).
`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 of the invention, wherein y is 1 or
`
`7
`
`In another embodiment of the invention, Rm in formula 2
`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”.
`In another embodiment of the invention, R7 in formula 2
`is phenyl-Z1, wherein the phenyl moiety is optionally sub-
`stituted with one to five independently selected R”. In a
`preferred embodiment thereof, Z1 is —(CR"R*’ ,—.
`In another embodiment of the invention, R“ in formula 2
`is H or [C,—C_,)alkyl.
`the carbon
`In another embodiment of the invention,
`designated “a” in formula 2 is in the (S) absolute contigu-
`ration.
`
`5
`
`10
`
`"I5
`
`ll]
`
`35
`
`4E]
`
`45
`
`Sf]
`
`60
`
`65
`
`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:
`
`AB1
`
`Rm 0
`
`(R)P_K*2
`
`T
`
`
`
`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”;
`R3, R8, R11, R13, R13 and R16 are each independently
`selected from halo, cyano, nitro, azido, amino, hydroxy,
`(C,—C,,)alkyl,
`(C2—C,.,)alkoxy, methoxy,
`(C,—C,,)alkoxy
`(C,—C,-)alkyl, mono—, di— or tri—halo(C3—C,,-)alkyl, perfluoro
`(C2—C,,)alkyl, trifluoromethyl, trifluoromethyl(C,—C,,)alkyl,
`mono—,
`di— or
`tri—halo[C,._—C,,-)alkoxy,
`trifluoromethyl
`{C,—C5)alkoxy,
`(C,—C,,)alkylt