United States Patent
`
`[L9]
`
`[11] Patent Number:
`
`6,140,343
`
`DeNinn0 et al.
`
`[45] Date of Patent:
`
`Oct. 31, 2000
`
`US[JU6l 40343A
`
`[54]
`
`4-AMINO SUBS'1‘ITUTED-2-SUBS'1‘ITUTl£D-1,
`2,3,4-TETRAHYDROQUINOLINES
`
`OTHER PUBLICATIONS
`
`[75]
`
`Invmlmsi Michael R DeNimm’ Galas Ferry;
`George T. Magnus-Aryitey, Lcdyard;
`Roger, B_ Ruggeri, wamrmrd; Ronald
`T- W95“: L¢<‘>’a“1~ all of Com
`
`Gordon D], et al., Circulation. 79[1):8—l5. Jan. 1989,
`"Hir-h—density lipoprotein cholesterol and cardiovascular
`disease. Four prospective American studies".
`Chemical Abstracts vol. 116, 1992, 116:151569g.
`
`I73" Assignee: Pfizer, New York, NY.
`
`Chemical Abstracts vol. 123, 1995, l23:55716b.
`
`[2l' App]. No; 09,891,313
`_
`‘_
`“led:
`
`Sell 79 1999
`
`lgg
`
`Related U.S. Application Data
`Provisional application No. 6U;'1UU,‘J2?, Sep. 1?, 1998.
`
`[6U_
`
`Int: Cl-7 ~~~~~~~~~~~~~~~~~~“ AGIK 3”“? CU7D_21_5’i:j8
`l51:
`
`[52: U5. (,l.
`. ....... ...... ....
`.... ...... ...... 514,813; 34(J;"'lD9
`[58
`Field Of Search .............................. 546,-"l59; 514»,-"313
`,_
`References Cited
`Us, PATENT DOCUMENTS
`
`'56
`
`5,231,101 W1993 Ilonda ct al.
`’
`SFZSUUE H1993 Baker CI 31’
`5__238__-;25
`2,1994 wflhemp el al“
`li()Rl_-'l(}N P/NF].-'.l\l'l‘ [)()(IUMlJN'l'S
`
`_
`_
`......................... .. 1114.-'29U
`
`1’rimm'y Examr'ner—lJ. Margaret Seaman
`Ah'r)rm'y, Agent‘, or Firm—l-’e1er (3. Richardson; Gregg C.
`Benson; A. Dean Olson
`
`[57]
`
`ABSTRACT
`
`Cholesteryl ester transfer protein inhibitors, pharmaceutical
`compositions containing Such inhibitors and the use of Such
`inhibitors to elevate certain plasma lipid levels‘ including
`high density lipoprolein-cholesterol and to lower certain
`other plasma lipid levels, such as LDL—cholesterol and
`triglycerides and accordingly to treat diseases which are
`exacerbated by low levels of IIDL cholesterol andfor high
`levels ot LDL—cholesterol and triglycerides. such as athero-
`sclerosis and cardiovascular diseases in some mammals,
`including humans.
`
`C-818448 M1998
`
`Luropcan Pat. Off. .
`
`44 Claims, No Drawings
`
`1 of 45
`
`PENN EX. 2221
`CFAD V. UPENN
`
`lPR2015-01836
`
`

`
`6,140,343
`
`2
`l_".I-’t)8I8448 (970624) discloses the preparation of certain
`5,ti,7,8 substituted tetrahydroquinolincs and analogs as cho-
`lesteryl ester transfer protein inhibitors.
`U.S. Pat. No. 5,231 ,](E discloses a class of 4-substituted
`I,2,3,4-letrahydroquinolines that possess an acidic group (or
`group convertible thereto in vivo) at the 2-position that are
`specific antagonists of N-methyl-D-aspartate (NMDA)
`receptors and are therefore useful in the treatment andfor
`prevention of neurodegenerative disorders.
`U.S. Pat. No. 5,288,725 discloses pyrroloquinoline brady-
`kinin antagonists.
`SUMMARY OF THE INVENTION
`
`This invention is directed to compounds of Formula I
`
`-I
`
`Formula I
`
`3
`S R~\_\_/R
`
`R
`
`prodrugs thereof, and pharmaceutically acceptable salts of
`said compounds and of said prodrugs;
`wherein R‘ is Y, W—X or W—Y;
`wh:1r]?0nnT_]
`'5 a Carbonyl’ thlocarbonyl’ Sulhnyl or
`X
`_S_Y _N(H)_-Y or _N_(Y),
`whereinitfor each occurrence is indepenldentlyzcr
`a fully Saturated, partially unsaturated or fully
`unsaturated one To
`ten mcmbcrcd Straioht or
`branched carbon chain wherein the carbonsijothcr
`than the connecting carbon, may optionally be
`replaced with one or two hctcromoms Sclcctcd
`mdcpcndcmly from oxygen, Sulfur and nitmgcn
`and Said carbon is optionally mono“ di_ or U.i_
`Substituted 1-ndcpcndcmlywhh ha1O,Saidc‘.u.b0niS
`optionally m0n0_SubSmutcd with hydroxy, Said
`carbon is optionally mono—substituted with cxo,
`said sulfur is optionally mono— or di—substituted
`with OX0, Said nitrogen 1'5 optionally mom}, or
`di—substituted with oxo, and said carbon chain is
`optionally m0n0_Sub5n'mtc(] with Z;
`whercin Z is 3 panjauy Samralcd, fuuy Saluraled or
`[‘u]]y unsaturated thmc K, cigl-,1 mcmbcrcd ring
`optionally having one to four heteroatoms selected
`independently from oxygen, sulfur and nitrogen,
`or a bicyclic ring consisting of two fused partially
`Salurawd, funy saluralcd or fun), unsalurawd lhrcc
`to six rnernbered rings,
`taken independently,
`optionally having one to four hcteroatoms selected
`independently from nitrogen, sulfur and oxygen;
`wherein said Z substituent is optionally mono—, di- or
`[]'[—_n;]_[b51iI_u1c{_1 indcpcndently with halo, ((]2—(]fi)
`alkcnyl, ((fI—(jfi) alkyd, hydmxy, ((_‘,_(_‘6)a11mxy,
`((“_1_C4)a1ky]1hio, amino, nit.-oi cyano, mm,
`carbtjxy, ((I1—(:fi)a1ky1()xy(;arb(3ny1, m(3n(3—N— or
`d[_N,N.{Cl_C6)a1ky1;.mino wherein said (Cl_C6)
`alkyl gubglitucnl 13, 0p11'(ma11y mom-’ (ii- or Hi-
`substituted independently with halo, hydroxy,
`(C,—C,.,)alkoxy,
`(C,—C,,)alkylthio, amino, nitro,
`cyano, oxo, carboxy, ((7,—(T,,)alkyloxycarbonyl,
`mono—N— or di—N,N—(C,—C,,)alkylamino, said
`
`2 of 45
`
`PENN EX. 2221
`CFAD V. UPENN
`
`lPR2015-01836
`
`1
`4-AMINO SUBSTITUTED-2-SUBSTITUTEILl,
`2,3,4-TETRAHYDROQUINOLINES
`
`This application claims priority from provisional appli-
`cation U.S. Ser. No. 6UflOU,927 filed Sep.
`[7,
`I998, the
`benefit of which is hereby claimed under 37' C.F.R. §1.'.r'8
`(a)(3).
`
`B/\(IKGR()UN]J 01-‘ INVEN'l'[()N
`
`10
`
`20
`
`'l'l'iis invention relates to cholesteryl ester transfer protein
`((Il_i'l'P) inhibitors, pharmaceutical compositions containing
`such inhibitors and the use of such inhibitors to elevate
`certain plasma lipid levels, including high density lipopro-
`tein (IIDL)-cholesterol and to lower certain other plasma
`lipid levels, such as
`low density lipoprotein (LDL)-
`cholesterol and triglycerides and accordingly to treat dis-
`eases which are atfected by low levels of HDL cholesterol
`andfor high levels of I.DI.-cholesterol and triglycerides,
`such as atherosclerosis and cardiovascular diseases in cer-
`tain mammals [i.e., those which have CETP in their plasma),
`including humans.
`Atherosclerosis and its associated coronary artery disease
`(CAD) is the leading cause of mortality in the industrialized
`world. Despite attempts to modify secondary risk factors
`(smoking, obesity, lack of exercise) and treatment of dys-
`lipidemia with dietary modification and drug therapy, coro-
`nary heart disease (CIID) remains the most common cause
`of death in the U.S., where cardiovascular disease accounts
`for 44% of all deaths, with 53% of these associated with
`atherosclerotic coronary heart disease.
`Risk for development of this condition has been shown to
`be strongly correlated with certain plasma lipid levels. While 30
`elevated l.[)l.-C may be the most
`recognized form of
`dysfiriidcmia’ his by "0 mam’ the only Significanl lipid
`associated contributor to CHI). Iiow HDI.-C is also a known
`risk factor lor (.111) (Gordon, 1).
`.I., et al.,: “I[1gh-density 35
`Llipoproicin Cholesterol and Cardiovascular Discascm’
`Cflcillamn‘ U989)’_79: 845)‘ ,
`,
`_,
`lligh l.[)l.-cholesterol and triglyceride levels are pos1-
`lively correlated, while high levels of IIDI.-cholesterol are
`negatively correlated with the risk for developing cardio- 40
`vascular diseases. Thus, dyslipidemia is not a unitary risk
`profile -for (XIII) but may be comprised ofone or more lipid
`ab°m'“0n5'
`Ammlg the man)’ h'i¢‘10TS ‘3“h”“1hh8 P13-‘W3 15”]-‘i Ur
`these disease dependent principles, cholesteryl ester transfer 45
`Pmleih (CETP) 3‘3hVhY 353915 ah ‘h1’e3- The ‘Ole hf ‘his
`7{l,{l0(] dalton plasma glycoprotein found in a number of
`animal species, including humans, is to transfer cholesteryl
`ester and triglyceride between lipoprotcin particles, includ—
`ihg high dchshy h130P1'0l°ih5 (HDL): 10W (l°h5hY hI30P1'0‘ 50
`wins (LDL): Vcry low d°h5ily 1iI30P1'0["~5ih5 (\/LDL)» and
`Chylgmicmhsv The‘ hi-it 1":-'3‘-‘ll of CETP acthiity is a 1D“"°"ih8
`of HDL cholesterol and an increase in LDL cholesterol. This
`cfibcl Uh lipopmlcih Profilc £5 b°lh'~5"'°d to [35 Pro‘
`alhcfhgchics 55135’-'h<"11Y ih -‘3”hJ"3C‘5 “"h05‘3 hlhd I3"0h1° 00h‘ 55
`Slit‘-“$5 ah ihcrcascd risk for CHD-
`tl‘1Cf5lPi0S CXlS1-
`N0 Wh0lly 5a1iSfaCl0l‘Y HDL-elevating,
`Niacin can significantly increase HDL, but has serious
`toleration issues which reduce compliance. Fibrates and the
`HMG CoA rcductase inhibitors raise HDI.—C only modestly an
`AS fl I'CSUlI, li]CI'C IS a Sig[]ii'lCEl1'1[ IIIIIDCI I'['lC(iiCEll
`a well—tolerated agent which can significantly
`need for
`elevate plasma HDL levels, thereby reversing or slowing the
`IJi'0}_3,I"-'«S‘51'0f1 Of a1l'1€'«l'0SCl0I'0SlS-
`Thus, although there are a variety of anti-atherosclerosis 65
`therapies, there is a continuing need and a continuing search
`in this field of art for alternative therapies.
`
`

`
`6,140,343
`
`35
`
`10
`
`3
`[C,—C,.,)alkyl substituent is also optionally substi-
`tuted with from one to nine fluorines;
`R2 is a partially saturated, fully saturated or fully unsat-
`urated one to six membered straight or branched carbon
`chain wherein the carbons, other than the connecting
`carbon, may optionally be replaced with one or two
`heteroatoms selected independently from oxygen, sul-
`fur and nitrogen wherein said carbon atoms are option-
`ally mono—, di- or tri—substituted independently with
`halo, said carbon is optionally mono-substituted with
`oxo, said carbon is optionally mono—substituted with
`hydroxy, said sulfur
`is optionally mono- or
`di-substituted with oxo, said nitrogen is optionally
`mono- or di-substituted with oxo; or said R2 is a
`partially saturated, fully saturated or fully unsaturated 15
`three to seven membered ring optionally having one to
`two heteroatoms selected independently from oxygen,
`sulfur and nitrogen, wherein said R2 ring is optionally
`attaehed through (C,-C4)alkyl;
`wherein said R2 ring is optionally mono-, di- or tri- 20
`substituted independently with halo,
`(C2-C5)
`alkenyl,
`(C1-C5) alkyl, hydroxy, (C,-C,,)alkoxy,
`[(T,—C4)all\'ylthio, amino, nitro, cyano, oxo, carboxy,
`[C1-CL,-)alkyloxycarbonyl, mono—N— or di—N,N—
`[(T,—C6)all\'ylamino wherein said (C,—C5)alkyl sub-
`stituent is optionally mono-, di- or tri—substituted
`independently with halo, hydroxy, (C,-C6)alkoxy,
`[(T,—C,,)all\'ylthio, oxo or ((T1—(T,,)alkyloxycarbonyl;
`R3 is hydrogen or Q;
`wherein Q is a fully saturated, partially unsaturated or 30
`fully unsaturated one [0
`membered straight or
`branched carbon chain whcfgin [hc cat-13333, othcr
`than the ;;.;mm;¢-ting carbon, may optionally be
`replaced with one hctcfoatom sclcctcd from oxygen,
`sulfur and nitrogen and said carbon is optionally 35
`mono-, di- or tri—substituted independently with halo,
`said carbon is optionally mono—substituted with
`hydroxy, said carbon is optionally mono-substituted
`OX0, said Sulfur
`is Qptionally mono- gr
`di-substituted with oxo, said nitrogen is optionally 40
`mono-, or di-substituted with oxo, and said carbon
`chain is optionally mono-substituted with V;
`wherein V is a partially saturated, fully saturated or
`fully unsaturated three to eight membered ring
`optionally having one to four heteroatoms selected 45
`independently from oxygen, sulfur and nitrogen,
`or a bicyclic ring consisting of two fused partially
`saturated, fully saturated or fully unsaturated three
`to six membered rings,
`taken independently,
`optionally having one to four heteroatomsseleeted so
`independently from nitrogen, sulfur and oxygen;
`wherein said V substituent is optionally mono-, di-,
`tri-, or tetra-substituted independently with halo,
`(C,-C,.,)alkyl, (C2-C,,)alkenyl, hydroxy, (C,-C6)
`alkoxy,
`[C1-C,,)alkylthio, amino, nitro, cyano, 55
`oxo, carboxamoyl, mono—N— or di—N,N—(C,-C6)
`alkylcarboxarnoyl, carboxy,
`(C,-C5)
`alkyloxycarbonyl, mono-N- or di-N,N-((f,—(f,.,)
`alkylamino wherein said (C,-C,,)alkyl or (C2-C6)
`alkenyl substituent
`is optionally mono-, di- or G0
`tri—substituted independently with hydroxy,
`(C,-C,,)alkoxy,
`(C,-C_,)alkylthio, amino, nitro,
`cyano, oxo, carboxy, (C,-C,,)alkyloxycarbonyl,
`mono—N— or di—N,N—(C,-C6)alkylamino, said
`(C,-C,.,)alkyl or (C2-C,,)alkenyl substituents are 65
`also optionally substituted with from one to nine
`fluorines;
`
`4
`
`R" is cyano, formyl, W'O', W1\/1, ((T,—C,,)alkylene\/1 or
`V3;
`wherein W1 is carbonyl, thiocarbonyl, S0 or S02,
`wherein Q' a fully saturated, partially unsaturated or
`fully unsaturated one to six membered straight or
`branched carbon chain wherein the carbons, may
`optionally be replaced with one heteroatom selected
`from oxygen, sulfur and nitrogen and said carbon is
`optionally mono-, di- or tri—substituted indepen-
`dently with halo, said carbon is optionally mono-
`substituted with hydroxy, said carbon is optionally
`mono—substituted with oxo, said sulfur is optionally
`mono- or di-substituted with oxo, said nitrogen is
`optionally mono-, or di-substituted with oxo, and
`said carbon chain is optionally mono-substituted
`with V‘;
`wherein V1 is a partially saturated, fully saturated or
`fully unsaturated three to six membered ring option-
`ally having one to two heteroatoms selected inde-
`pendently from oxygen, sulfur and nitrogen, or a
`bicyclie ring consisting of two fused partially
`saturated, fully saturated or fully unsaturated three to
`six membered rings, taken independently, optionally
`having one to four heteroatoms selected indepen-
`dently from nitrogen, sulfur and oxygen;
`wherein said V‘ substituent is optionally mono-, di-,
`tri-, or
`tetra—substituted independently with halo,
`((f,—(I,.,)alkyl, ((I,—(T,_,,)all<oxy, hydroxy, oxo, amino,
`nitro, cyano, (C,-C,,)alkyloxycarbonyl, mono—N— or
`(ii-N,N-((31-C5)iiik)t'iiimiH0 Wilfirtlifl Said (C1-C5)
`iilkyl substituent is optionally l'l'l01'10-.‘5l.1b.‘SliIUl¢‘:d Wilh
`oxo, said ((Tl—C5)all<yl substituent is also optionally
`substituted with from one to nine Iluorines;
`wherein V2 is 3. partially saturated, fully S£lIllt'£lICCl or
`fully unsaturated five to seven membered ring con-
`laining one 10 four heteroatoms sclcctctl
`indepen-
`dtmlil’ fmm OXYSCT1» Sulfur and Tlilmgcflé
`Whtiffiifl Said V: Slli')S1i1LlC1'11 i5 0Pli01'12iii)’ IT10l'l0-, di- Or
`lfi-SI.ll')SlilLllC(.l
`iI']dCpCI'][lCI]T.ly
`halo,
`(C1-C2)
`alkyl,((31—(32)a1k0xy,hydroxymr 0x0 wherein said
`(C1—C;)alkyl optionally has from one to Five fluo-
`Til“!-‘ii
`include oxycarbonyl
`wherein R" does not
`diffifiliy l0 the Cl Tliimgfifli
`Whtiffiifl Cilhfif R3 1711181 C0l'l12ii1'1 V 0T R4 E11151 C0l'l1ail'|
`V1; and
`R5, R5, R7 and R8 are independently hydrogen, a bond,
`nitro or halo wherein said bond is substituted with '1‘ or
`a partially saturated, fully saturated or fully unsaturated
`(C,-C12) straight or branched carbon chain wherein
`carbon may optionally be replaced with one or two
`heteroatoms selected independently from oxygen, sul-
`fur and nitrogen,wherein said carbon atoms are option-
`ally mono-, di- or tri—substituted independently with
`halo, said carbon is optionally mono—substituted with
`hydroxy, said carbon is optionally mono—substituted
`with oxo, said sulfur
`is optionally mono- or
`di-substituted with oxo, said nitrogen is optionally
`mono- or di-substituted with oxo, and said carbon chain
`is optionally mono—substituted with T;
`wherein T is a partially saturated, fully saturated or
`fully unsaturated three to twelve membered ring
`optionally having one to four heteroatoms selected
`independently from oxygen, sulfur and nitrogen, or a
`bicyclie ring consisting of two fused partially
`saturated, fully saturated or fully unsaturated three to
`six membered rings, taken independently, optionally
`
`linked
`
`3 of 45
`
`PENN EX. 2221
`CFAD V. UPENN
`
`lPR2015-01836
`
`

`
`6,140,343
`
`5
`having one to four heteroatoms selected indepen-
`dently from nitrogen, sulfur and oxygen;
`wherein said '1‘ substituent is optionally mono-, di— or
`tri—substituted independently with halo,
`(C,—C,.,)
`alkyl,
`(C2—C,.,)alkenyl, hydroxy,
`(C,—Cfi)alkoxy,
`[C,—C,,)alkylthio, amino, nitro, eyano, oxo, carboxy,
`[C,—C,,)alkyloxycarbonyl, mono—N— or di—N,N—
`[C,—C,.,)alkylamino wherein said (C,—C,,)a1kyl sub-
`stituent
`is optionally mono—, di— or tri—substituted
`independently with hydroxy,
`(C,—Cfi)alkoxy,
`[C,—C4)alkylthio, amino, nitro, eyano, oxo, carboxy,
`[C,—C,,)alkyloxycarbonyl, mono—N— or di—N,N—
`[C,—C,,)a1kylamino, said (C,—Cd)alkyl substituent
`also optionally has from one to nine fluorines;
`wherein R5 and R“, or R“ and R7, and,-"or R7 and R“ may
`also be taken together and can form at least one ring
`that is a partially saturated or fully unsaturated four
`to eight membered ring optionally having one to
`three heteroatoms independently selected from
`nitrogen, sulfur and oxygen;
`wherein said rings formed by R5 and R“, or R” and R7,
`andfor R7 and R3 are optionally mono-, di— or tri-
`substituted independently with halo, (C,—C,.,)alkyl,
`[C1—C4)alkylsulfonyl,
`(C2—C6)alkenyl, hydroxy,
`[(I,—C,.,)alkoxy,
`(C,—(.',,)alkylthio, amino, nitro,
`cyano, oxo, carboxy,
`(C1—C,,]alkyloxycarbonyl,
`rnono-N- or di-N,N-((7,—(T,,]alkylamino wherein
`said (C,—Cfi)alkyl substituent is optionally mono-,
`di— or tri—substituted independently with hydroxy,
`[(I,—C,.,)alkoxy,
`(C,—(.',,)alkylthio, amino, nitro,
`cyano, oxo, carboxy,
`(C,—C,,)alkyloxyearbonyl,
`rnono-N- or di-N,N-(C,—(T,,)alkylamino, said
`[(T,—C,.,)alkyl substituent also optionally has from
`one to nine fluorines.
`
`A preferred group of compounds, designated the /\Group,
`contains those compounds having the Formula I as shown
`above wherein
`
`the (I2 substituent is beta;
`the C4 nitrogen is beta;
`R1 is W-X;
`W is carbonyl, thiocarbonyl or sulfonyl;
`X is —()-Y-, S-Y-, N(II]-Y- or —N-(Y),-;
`Y for each occurrence independently is (C,—C,,)alkyl,
`said [C1—(T4)alkyl optionally having hydroxy or from
`one to nine fluorines or said (C,—C,,)alkyl optionally
`mono-substituted with Z;
`wherein Z is a partially saturated, fully saturated or
`fully unsaturated three to six membered ring
`optionally having one to two heteroatoms selected
`independently from oxygen, sulfur and nitrogen;
`wherein said Z substituent is optionally mono—, di— or
`tri—substituted independently with halo, (C1-C4)
`alkyl,
`(C,—C,,)alkoxy,
`(C,—C,]alkylthio, nitro,
`cyano, 0x0, or
`(C1-C6-)alkyloXyearbonyl, said
`[C,—C,,)alkyl optionally substituted with from one
`to nine fluorines;
`
`10
`
`20
`
`30
`
`40
`
`50
`
`R3 is a partially saturated, fully saturated or fully unsat-
`urated [(T,—C,,) straight or branched carbon chain
`wherein the carbons, other than the connecting carbon,
`may optionally be replaced with one heteroatom 60
`selected independently from oxygen, sulfur and nitro-
`gen wherein said carbon atoms are optionally mono—,
`di— or tri—substituted independently with halo, said
`carbon is optionally mono-substituted with oxo or
`hydroxy, said sulfur
`is optionally mono- or 65
`di—substituted with 0x0, said nitrogen is optionally
`mono— or di—substituted with oxo; or said R2 is a
`
`6
`partially saturated, fully saturated or fully unsaturated
`three to five membered ring optionally having one
`heteroatom selected independently from oxygen, sulfur
`and nitrogen;
`wherein said R2 ring is optionally mono-, di— or tri-
`substituted independently with halo, hydroxy,
`(C1—C6}alkoxy, amino, nitro,
`(C1—C_,)
`alkyloxycarbonyl or carboxy;
`R3 is Q-V wherein Q is ((I1—C4)alkyl and V is a live or six
`membered partially saturated, fully saturated or fully
`unsaturated ring optionally having one to three heteroa-
`toms selected independently from oxygen, sulfur and
`nitrogen;
`tri- or
`wherein said V n.ng is optionally mono-. di—,
`tetra-substituted independently with halo, (C,—Cfi)
`alkyl, hydroxy,
`[C,—C,.,)alkoxy,
`(C,—Cfi]
`alkoxycarbonyl, nitro, cyano or oxo, wherein said
`((f,—(I,.,)alkyl substituent optionally has from one to
`nine fluorines;
`R4 is carbonyl or carbamoyl wherein said carbonyl moiety
`is optionally mono-substituted with V1 or ((.',—(.'2]alkyl
`and said earbamoyl moiety is optionally mono— or
`di—substituted independently with V1 or (C 1—C:)alkyl,
`in either instance said [(I,—C:)alkyl optionally mono-
`substituted with V1 or said [C,—C3)alkyl optionally
`having one to live lluorines;
`wherein V‘ is a partially saturated, fully saturated or
`fully unsaturated three to six membered ring option-
`ally having one to two heteroatoms selected inde-
`pendently from oxygen, sulfur and nitrogen;
`wherein said V‘ substituent is optionally mono-, di— or
`tri—substituted independently with halo, nitro or
`(C‘,—C‘2)alkyl, said [C,—C2)alkyl optionally having
`from one to five fluorines;
`
`R“ and R7 are each independently hydrogen, halo, T,
`((f,—(I,.,)alkoxy or ((I,—(I,.,)alkyl, said (C,—Cfi)alkoxy or
`(C,—C,.,)alkyl substituent optionally having from one to
`nine fluorines or said [C,—C,.,)alkoxy or (C.‘,—C,,)alkyl
`substituent optionally mono-substituted with T;
`wherein T is a partially saturated, fully saturated or
`fully unsaturated five to six membered ring option-
`ally having one to two heteroatoms selected inde-
`pendently from oxygen, sulfur and nitrogen;
`wherein said T substituent is optionally mono—, di— or
`tri—substituted independently with halo,
`(C ,—C,,)
`alkyl, hydroxy,
`(C,—C,.,)alkoxy,
`(C,—C,,)alkylthio,
`amino, oxo, carboxy,
`(C1—C,,)alkyloxycarbonyl,
`mono—N— or di—N,N—(C,—C,,)alkylamino wherein
`said ((I,—(I,.,)alkyl substituent optionally has from
`one to nine fluorines; or
`wherein R6 and R7 are taken together and form one ring
`that is a partially saturated or fully unsaturated five
`or six membered ring optionally having one to two
`heteroatoms independently selected from nitrogen,
`sulfur and oxygen;
`R5 and R3 are II; and
`phannaceutically acceptable salts thereof.
`A group of compounds which is preferred among the A
`Group of compounds, designated the B Group, contains
`those compounds wherein
`W is carbonyl;
`X is O—Y wherein Y is (C,—C,,)alkyl, wherein said
`(C,—C_,)alkyl substituent optionally has hydroxy or
`from one to nine Iluorines;
`is (C,—C_,)alkyl,
`[C1—C.__)alkyloxymethylene or
`R‘
`(C_.,—C5)eycloalkyl;
`
`4 of 45
`
`PENN EX. 2221
`CFAD V. UPENN
`
`lPR2015-01836
`
`

`
`7
`Q is ((Ii—C,,)alkyl and V is phenyl, pyridinyl, or pyrim-
`idinyl;
`wherein said V ring is optionally mono-, di- or tri-
`substituted independently with halo, (C ,—C5)alkyl,
`hydroxy, [Ci—Cs)alkoxy, nitro, cyano or oxo wherein
`said (Ci—Ci.i)alkyl substituent optionally has from
`one to nine fluorines;
`R‘ is carbonyl or carbamoyl wherein said carbonyl or
`carbamoyl is optionally mono—substituted with hydro-
`gen or (Ci—C,)alky1;
`R“ and R7 are each independently hydrogen, (C1-C3)
`alkoxy or (C,—Cs)a1kyl, said (C,—C3)alkoXy optionally
`having from one to seven fluorines, said (Ci—C‘i,)alkyl
`optionally having from one to nine fluorines; and
`pharmaceutically acceptable salts thereof.
`A group of compounds which is preferred among the B 15
`Group oi‘ compounds, designated the (T Group, contains
`those compounds wherein
`O is meihyi and V is iihsnyi or pyridiiiyii
`wherein said V ring is optionally mono—, di- or tri—
`substituted independently with halo, nitro or (C1-C2) 20
`alkyl, wherein said (Ci—C2]alkyl optionally has from
`one to five fluorines; and pharmaceutically acceptable
`salts thereof.
`Especially preferred compounds of Formula I are the
`compounds:
`[2S;4S]4-[(3;5-bis-triiluoromethyl-benzyl)-forrnyl—a1nino]—
`2—cyclopropyl—6—trifluoromethyl—3,4—dihydro—2H—
`quinoline-l-calrboirylic acid isopropyl ester;
`I
`[2S,4S]4—[(3,5—bis—trifiuoromethyl—benzyl)—formyl—am1no]—
`2-cyclopropyl-6-tr1[luoromethyl-3,4-dthydro-21L 30
`quinoline-l-carboxylic acid propyl ester;
`[2S,4S]4—[acetyl—[3,5—bis—trifluoromethyl—benzyl)—amino]—
`2-cyclopropyl-6-tri[luoromethyl-3,4-dihydro-2II-
`quinoline—1—carboxylic acid tert—butyl ester;
`[ZR,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-
`2—cthyl—6—triiluoromethyl—3,4—dihydro—2H—quinolinc—1—
`carboxylic acid isopropyl ester;
`[ZR,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-
`2-methyl—6—trit‘luoromethyl—3,4—dihydro—2H—quinoline—1—
`carhoxylic acid ethyl ester;
`and pharmaceutically acceptable salts of said compounds.
`Other especially preferred compounds of liormula I are
`the corn aounds:
`[2S,4S]£t—[1—(3,5—bis—trifluoromethyl—benzyl)—ureido]—2—
`cyclopropyl-6-trilluoromethyl-3,4-dihydro-ZIL 45
`quino1ine—1—carboxy1ic acid isopropyl ester;
`[ZR,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-
`2-ethyl-6-trilluoromethyl-3,4-dihydro-21[-quinoline-]-
`carboxylic acid ethyl ester;
`[2S,4S]4—[acetyl—[3,5—bis—trii'luoromethyl—benzyl)—amino]— 50
`2-methoxyrnethyl-6-trilluoromethyl-3,4-dihydro-2|I-
`quinoline—1—carboxylic acid isopropyl ester;
`[?.S,4S) 4-[acetyl-(3,5-his-tri[luoromethyl-benzyl)-an1ino]-
`2—cyclopropyl—6—trifluoromethyl—3,4—dihydro—2H—
`quinoline—'1—carboxylie acid propyl ester;
`[2S,4S]4—[acetyl—[3,5—bis—trifluoromethyl—benzyl)—amino]—
`2—cyclopropyl—6—trifluoromethyl—3,4—dihydro—2H—
`quinoline-l-carboxylic acid ethyl ester;
`[ZR,4S]4—[(3,5—bis—trit‘luoromethyl—benzyl)—formyl—amino]—
`2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinolinc-1- G0
`carboxylic acid isopropyl ester;
`and pharmaceutically acceptable salts of said compounds.
`Other especially preferred compounds of Formula I are
`the compounds:
`[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]- 65
`2-methyl—6—trit‘luoromethyl—3,4—dihydro—2H—quinoline—1—
`carboxylic acid ethyl ester;
`
`35
`
`35
`
`40
`
`55
`
`6,140,343
`
`10
`
`8
`[28,45]4-[acetyl-(3,5-bis-trilluoromethyl-benzyl)-amino]-
`2—cyclopropyl—(i—trirluoromcthyl—3,4—dihydro—2H—
`quinoline-1-carboxylic acid isopropyl ester;
`[2R,4S]4-[(3,5-I’)is-trilluoromethyl-benzyl)-l"ormyl-amino}
`2-ethyl-6-triIluoromethyl-3,4-dihydro-2II-quinoline-1-
`carboxylic acid ethyl ester;
`[2S,4S]4—[(3,5—|)is-trifluoromethyl—l)enzyl)—formyl—amino]—
`2-cyclopropyl-6-trilluoromethyl-3,4-dihydro-21I-
`quinoline—1—carboxylic acid ethyl ester;
`[2R,4S]4-[(3,5-I’)is-trilluoromethyl-benzyl)-l"ormyl-amino}
`2-n1ethyl-6-trilluoromethyl-3,4-dihydro-21I-quinoline-l-
`carboxylic acid isopropyl ester;
`[2R,4S]4-[acetyl-(3,5-bis-trilluoromethyl-benzyl]-amino}
`2—methyl—6—trifluoromethyl—3,4—dihydro—2H—quinoline—l—
`Carbuxyhc acid lmpmpyl cslcri
`,
`and phalimaocutlcally acceptable SallS_Of,S‘11d compounds‘,
`Especially preferred compounds within the C.‘ Group ot
`compounds are compounds wherein
`3'
`_
`A
`Ya“? ”"""l""’PY]3
`R; '9 ‘-'}’ClUPTUI3}'1§
`R3 i5 3:5'bi5"1'ifl“01'0m°‘hYlPh°nY1m°ih}’1§
`R‘? is formyl;
`R“ is trifluoromethyl; and
`R7 is H;
`
`i,_
`
`Y is ii_pi.0pyi;
`R: is cyciopropyii
`R3 is 3,5_bis_ii.ifluommcihyiphcnyimcihyii
`R-4 is i-Ormyii
`R6 is iriiiuommcih i. and
`R7 is H;
`y ‘
`
`C
`
`' Y is ici_i_buiyi_
`i_
`R3 .8 C do F0’
`R3 is sy.i_bi¥:_iiEiHi;iimmcihvi hm imcih i,
`RA is 'a;ciyii_
`‘ P
`y
`y ’
`R5 is ii_iflu0'i_0mcihyi_ and
`R7 is H_
`’
`'
`d‘ Y is iwpmpyi_
`._.‘_
`‘
`’
`R_ '5 ethyl;
`R: 5*‘ 3i5'bif"‘“"“‘”""‘""‘3’l1"“‘“3"‘“"”‘5’l5
`E6 is fiéfityl’
`ih i_
`d
`Ri.{Sii':' uommc 3'
`‘ an
`15'
`’
`_
`Y}? °‘h3'1§
`_
`R; {5 m‘-"lh3_’l3
`Rii {*5 3=5‘b15‘mfluommclhylphcnylmclhyb
`R6 {5 3‘3_"3W1J
`R? {*5 mfl"01'0m°rhY1§ and
`R '5 H?
`_
`V
`YQIS ISOIJFOIJYI;
`R" 19 CYCIOPFOPYI;
`R3 i5 3.5—bis—trifluoromcthylphcnylmcthyl;
`R? i5 carbamoyl;
`RU i5 1l'ifl|10I'0fi'i0ih)’1; and
`R7 i5 H;
`
`'73-
`
`f.
`
`g.
`
`Y is ethyl;
`R2 is ethyl;
`Rgis 3,5-his-trifluoromethylphenylmethyl;
`R“ is aoetyl;
`R“ is trifluorornethyl; and
`
`5 of 45
`
`PENN EX. 2221
`CFAD V. UPENN
`
`IPR2015-01836
`
`

`
`Rjis II;
`
`9
`
`Y 18 lmpmpyk
`R: is rnethoxynielhyl;
`R3 is 3,5—bis—trit‘luoromethylphenylmethyl;
`R4 is acetyl;
`R5 is lFifl“0Y0m°‘hY13 and
`R7is H;
`
`Y is n—propyl;
`R3 is cyclopropyl;
`R7’is 3,5-bis-trilluoroniethylphenylniethyl;
`R" is acetyl;
`Rf‘
`t
`"[1
`R7
`
`Lmmmc
`
`‘
`
`’
`
`th 1;
`y
`
`d
`
`an
`
`h_
`
`1'-
`
`.
`
`-
`
`Y is ethyl;
`R3 is cyclopropyl;
`R3iS 3,5_bis_tI-ifluOromcthylphcnylmcthvl;
`Relis acetyl;
`'
`Re is mfluommalhyl, and
`7 ,
`_
`’
`R ‘S H’
`_
`_
`_
`Y is isopropyl;
`R3’
`thl;
`R3isS3[:5-his-trilluoroniethylphenylniethyl;
`R“ is formyl;
`R3 is T_1'ifl]_[()r0rn3[hyl; and
`R715 11;
`
`' Y is cthyl_
`R: is mct1,’1yl_
`Rsis 3,5_bis_;rifluOromcthylphcnylmcthvl;
`R4 1-Sformyl.
`'
`R5 is mvfluorlomcthyl, and
`R71-‘H.
`'
`i
`’
`
`'
`,
`_
`E is lsoliropyli 1
`15 Cyc Opropy ;
`R3 is 3 5—bis—trifluoromethylphenylmethyl
`.
`’
`’
`R4.
`‘
`t
`l;
`Rfil?SaI:?fl)1;]0rOmcthyl‘ and
`R7 is H_
`'
`’
`
`'
`
`-
`
`.
`
`Y is ethyl;
`R3'thl;
`R3
`3 5¥bis-trilluoronieth)‘1Phei1)'lniethyl'
`R4 is myl_
`9
`R5 1}; mflumvomclhyr and
`7
`_
`'
`R 1:’ H’
`
`Y_i5 Clhyll
`R* is cyclopropyl;
`géirtlifiiiitrifluoromethylphenylmethyl;
`R5 is mfluosromcth 1‘ md
`R? _ H
`Y -
`‘
`15
`3
`
`Y is isopropyl;
`R: is methyl;
`R3is 3,5 —bis—trifluoromethylphenylmethyl;
`R“is formyl;
`RE‘ is trifluoromethyl; and
`R7 is H; and
`
`6,140,343
`
`q.
`
`10
`
`Y is isopropyl;
`R2 is methyl;
`R3 is 3,5—bis—trifluoromethylphenylmethyl;
`R4 iq ace‘ 1,
`Re L; trifllkmmcihyl. and
`R7‘ is H; and
`pharmaceutically acceptable salts of said compounds.
`Apreferred group of compounds, designated the D Group,
`contains those compounds having the Formula I as shown
`above wherein
`
`the C2 substituent is beta;
`the C‘ nitrogen is beta;
`R1 is W—Y;
`W is carbonyl, thiocarbonyl or sulfonyl;
`.
`.
`.
`.
`Y is (C1—C5)alkyl,_said [C1—_C,,)alkyl optionally having
`from one to nine lluorines or said ((.',—(.'6)alkyl
`optionally mono—substituted with Z wherein Z is a
`partially saturated, fully saturated or fully unsatur-
`ated three to six niernbercd ring optionally having
`one to two heteroatoms selected independently from
`oivlilygeri, sulcllué anlgl riitroge-n;
`'
`11
`I‘
`W erein sai
`su stituent is optiona y mono-, ( i— or
`tri—substituted independently with halo, (C1-C4)
`alkyl,
`(C,—C,,)alkoxy,
`(C,—C,,)a1kylthio, nitro,
`c ano, 0x0, or C —C- alk lox carbon 1, said
`3'
`1
`o
`Y
`Y
`Y
`(C1—C_,)alkyl substituent optionally substituted
`'thf
`t "ll
`'
`;
`R2 is a‘Eartiaifiinisafliifatgdriliiillyusiiilitildiisied or fully unsat-
`urated (C1-C4) straight or branched carbon chain
`wherein the carbons, other than the connecting carbon,
`may optionally be replaced with one heteroatom
`selected independently from oxygen, sulfur and nitro-
`gen wherein said carbon atoms are optionally mono-,
`di- or
`tri-substituted independently with halo, said
`carbon is optionally rnor-io-substituted with oxo or
`hydroxy, said sulfur
`is optionally mono- or
`di-substituted with oxo, said nitrogen is optionally
`mono- or di-substituted with oxo; or said R2 is a
`partially saturated, fully saturated or fully unsaturated
`three to five membered ring optionally having one
`heteroatom selected independently from oxygen, sulfur
`and nitrogen‘
`3 .
`’
`.
`.
`,
`,
`.
`.
`R‘ is ()-V wherein Q is ((. —(. )alkyl and V is a live or six
`.
`1
`"
`membered partially saturated, fully saturated or fully
`unsaturated ring optionally having one to three heteroa-
`toms selected independently from oxygen. sulfur and
`nitrogen;
`lI‘l- or
`wherein said V ring is optionally mono- di-
`‘v
`mtrafiubsmmcd mdcpbndcmly wvlth halo’ (crcfi)
`alkyl, hyrlroxy, (C,—Cg)alkoxy, ‘t'11iI'O, cyano or oxo
`fwherein said (C1—§Tfi)all{yl substituent optionally has
`rom one 0 nine uorines;
`R4 is carbonyl or carbamoyl wherein said carbonyl nioiety
`is optionally mono—substituted with V‘ or (C,—C2)alkyl
`and said carbarnoyl moiety is optionally mono— or
`di—substitu ted independently with V‘ or (C,—C2)alkvl,
`yntfythcr iélstapficst-iljd (g1T(]C3)§11k}£y0Ph£oTa11y‘m{y,fi,_
`su stitute Wll.‘
`or'sai
`[ .1— .2)a y optiona y
`having onel to live fluorines;
`wherein V is a partially saturated, fully saturated or
`fully unsaturated three to six membered ring option-
`ally having one to two heteroatoms selected inde-
`pendently from oxygen, sulfur and nitrogen;
`wherein said V‘ substituent is optionally mono-, di- or
`tri-substituted independently with halo, nitro or
`(C1—C3)alkyl, said [C1—C:)alkyl substituent option-
`ally having from one to five fluorines;
`
`_
`'"
`
`in
`
`i.‘
`i
`
`2"
`
`25
`
`30
`
`35
`
`40
`
`45
`
`so
`
`55
`
`60
`
`65
`
`6 of 45
`
`PENN EX. 2221
`CFAD V. UPENN
`
`IPR2015-01836
`
`

`
`6,140,343
`
`11
`
`'I',
`Rf’ and R7 are each independently hydrogen, halo,
`(C,—C‘,._.,)alkoxy or (C,—C¢)al.kyl, said (C‘,—C5)alkoxy or
`{(T,—(I,.,)alkyl substituent optionally having from one to
`nine fiuorines or said (C,—C,,)alkoxy or (C,—C‘,,)alkyl
`substituent optionally mono-substituted with T;
`wherein T is a partially saturated, fully saturated or
`fully unsaturated five to six membered ring option-
`ally having one to two heteroatoms selected inde-
`pendently from oxygen, sulfur and nitrogen;
`wherein said '1‘ substiluenl is optionally mono-, di- or
`tri-substituted independently with halo,
`(C1-C6)
`alkyl, hydroxy,
`(C,—Cb.)alkoxy,
`((f,—C4)alkylthio,
`amino, oxo, earboxy,
`(C1-C1,-)alkyloxycatbonyl,
`mono-N- or di-N,N-((7,—(T8]alkylamino wherein
`said (C,—C5)alltyl substituenl optionally has from
`gm; 10 mm; fiurtrincg; or
`whercin R“ and R7 are taken together and {mm [Jug ring
`that is a partially saturated or fully unsaturated live
`0]’ six membered ring (3p[i011a_l[y having [mc 10 [w()
`heteroatoms independently selected from nitrogen, 70
`sulfur and oxygen;
`R5 and R“ are II; and
`pharmaceutically acceptable salts thereof.
`Apreferred group of eompou nds, designated the B Group,
`contains those compounds having the lionnula I as shown
`above wherein
`
`10
`
`15
`
`33
`
`30
`
`the (I2 substituent is beta;
`the (I4 nitrogen is beta;
`R‘ is W-Z;
`W is carbonyl, thiocarbonyl or sulfonyl;
`Z is a partially saturated, fully saturated or fully unsat-
`urated three to six membered ring optionally having
`one to two heteroatoms selected independently from
`oxygen, sulfur and nitrogen;
`wherein said Z substituent is optionally mono-, di- or
`tri-substituted independently with halo, (C1-C4)
`alkyl,
`(C,—C,,)alkoxy,
`((T,—(f,,]alkylthio, nitro,
`cyano, oxo, or
`(C1—(T,,]alkyloxycarbonyl, said
`[C,—