PCT
`WORLD INTa.i.EcruAL PROPERTY ORGANIZATION
`International Bureau
`INTERNATIONAL APPUCATION PUBLlSHED UNDER THE PATENT COOPERATION TREAlY (PCT)
`WO' 96/40640
`
`(11) lDternational Publication Number:
`
`(SI) International Patent Clas.mication 6:
`C07D 217/04, 217/06, 405/06, 413/06,
`409106, 401/06, 417/06, 217/08, 401/10,
`C07C 23YTS, C07D 217/02, C07C
`205n9, 215168, A61K 3V47, 3V49S
`
`Al
`
`(43) International Publication Date:
`
`19 December 1996 (19.12.96)
`
`(21) International Application Number:
`
`PCT/IB95/00448
`
`(22} International Filing Date:
`
`7 Jillie 1995 (07.06.95)
`
`(81) Designated States: CA, Fl, JP, MX, US, European.patent (AT,
`BE, CH. DE, DK, ES, FR, GB, GR, IE; IT, LU, MC, NL,
`PT, SE).
`
`(71) Applicant (for all designared Stares except US): PFIZER INC. Published
`[US/US]; 235 East 42nd Street, New York, NY 10017 (US).
`With inlemarional search report.
`·
`With amended clabns.
`
`(72) Inventors; and
`(75) InventorsfApplicants (for US only):
`CHANG, George
`[US/US]; l Winthrop Hill Road, IvozytOn. er 06442 (US).
`DORFF, Peter, H. [US/US]; 63 Janice Lane. Norwich,
`er 06360 (US). QUALLICH, George, J. [US/US]; 349
`Norwich Westerly Road, North Stonington, CT06359 (US).
`
`(74) Agents: SPIEGEL, Allen, J. et al.; Pfizer Inc., 235 East 42nd
`Street, New York, NY 10017 (US).
`
`(54) Title: BIPHENYL-2-CARBOXYUC ACID-TElRAHYDRO-ISOQUINOLIN-6-YL AMIDE DERIVATIVES, THEIR PREPARA(cid:173)
`TION AND THEIR USE AS INHIBITORS OF MICROSOMAL TRIGLYCERIDE 1RANSFER PROTEIN AND/OR
`APOLIPOPROTEIN B (Apo B) SECRETION
`
`(57) Abstract
`
`(I)
`
`o ~rv---z
`N~
`
`formula
`of
`Compounds
`(I),
`wherein X is CH2, CO, CS or SQi;
`Y
`is selected from:
`a direct link,
`aliphatic
`hydrocarbylene
`radicals
`having up to 20 carbon atoms, which
`radical may be mono-substituted by
`hydroxy, (C1-C1o)alkoxy, (C1-C1o)acyl,
`(C1-C1o)acyloxy, or (C6-C1o)al)'l, NH,
`and 0, provided that if X is CH2, Y
`is a direct link; Z is selected from the
`following groups: (I) H, halo, cyano,
`(2) hydroxy, (C1-C1o)alkoxy, (C1-C1o)alkylthio, (C1-C1o)acyl, thiophenylcarbonyl, (C1-C1o)alkoxycarbonyl, (3) (C1-C1o)alkylamino,
`di(C1-C1o)alkylamino, (C6-C1o)cuyl(C1-C1o)alkylamino, provided that Y is not 0 or NH, (4) llllsubstituted vinyl, (C6-C1o)cuyl,
`(C3-Cs)cycloalkyl and fused benz derivatives thereof, (C.,.Cto)polycycloalkyl, (C4-Cs)cycloalkenyl, (C.,.C1o)polycycloalkenyl, (5) (C6-
`C1o)aJYloxy, (C6-C1o)cuylthio, (C6-C1o)al)'l(C1-C1o)alkoxy, (C6-C1o)aJYl(C1-C1o)alkylthio, (C3-Ca)cycloallcyloxy, (C4-Cg)cycloalkenyloxy,
`(6) heterocyclyl selected from the group consisting of monocyclic radicals and fused polycyclic: radicals, wherein said radicals contain a
`total of from S to 14 ring atoms, wherein said radicals contain a total of from 1 to 4 ring heteroatoms independently selected from oxygen,
`nitrogen, and sulfur, and wherein the individual rings of said radicals may be independendy saturated, partially unsaturated, or aromatic,
`provided that if X is CH2, Z is H or is selected from groups ( 4) and (6), wherein, when Z contains one or more ring's, said rings may
`each independently bear 0 to 4 substituents independently selected from halo, hydroxy, cyano, nitro, oxo, thioxo, aminosulfonyl, phenyl,
`phenoxy, phenylthio, halophenylthio, benzyl, benzyloxy, (C1-C1o)alkyl, (C1-C1o)alkoxy, (C1-C1o)alkoxycarbonyl, (C1-C10)alkylthio, (C1-
`C 1o}allcylamino, (C 1-C1o)alkylaminocarbonyl, di(C1-C 1o)alkylamino, di(C1-C 1o)alky1aminocarbonyl, di(C 1-C1o)alkylamino(C1·C1o)alkoxy,
`(C1·C3)perftuoroalkyl, (C1-C3)perftuoroalkoxy, (C1-C1o)acyl, (C1-C1o)acyloxy, (C1-C1o)acyloxy(C1-C1o)alkyl, and pyriolidinyl; and
`pharmaceutically acceptable salts thereof. This invention relates to compollllds which are inhibitors of microsomal triglyceride .transfer
`protein and/or apolipoprotein B (Apo B) secretion, and which are accordingly useful for the prevention and treatment of ather!>sclcrosis
`and its clinical sequelae, for lowering serum lipids, and related diseases. The invention funher relates to compositi0ns eomprising the
`compounds and to methods of treating atherosclerosis, obesity, and related.diseases and/or conditions with the compounds.
`
`.....
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`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international
`applications under the PCT.
`
`AM
`AT
`AU
`BB
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`Cl
`CM
`CN
`cs
`CZ
`DE
`DK
`E:E
`ES
`f1
`FR
`GA
`
`Armenia
`Auslria
`AUSll'lllia
`Bmbldos
`Belgium
`BurtiDa Faso
`Bulgaria
`Benin
`Brazil
`Belarua
`Canada
`Central Afrlcan Republic
`Congo
`Swllzerland
`~d'lvoft
`Camesoon
`China
`Czechoslovatia
`Czech Republic
`Germuy
`Denman:
`Esionia
`Spain
`Finland
`Fnmce
`Gabon
`
`GB
`GE
`GN
`GR
`HU
`IE
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LI
`LK
`LR
`LT
`LU
`LY
`MC
`MD
`MG
`ML
`MN
`MR
`
`Uailecl Kmgdom
`Georgia
`Guillea
`Gteece
`Hqary
`!Jeland
`Italy
`Japan
`Kenya
`K)'Tl)'llllll
`Oemocnllc People's Republic
`of Kolea
`Republic of Korea
`ICazU:bswl
`Lieclunstcin
`Sri Lanka
`Liberia
`Lithuania
`Luxembourg
`LaMa
`Monaco
`Republic of Moldova
`Madagascar
`Mali
`Mongolia
`Mauritania
`
`MW Malawi
`MX
`Ml:llco
`NE
`Niger
`NL
`Naberllllds
`NO
`Noiway
`New ZealaDd
`NZ
`PL
`Poland
`Ponugal
`PT
`RO
`Romania
`RU
`Rmsian Fcdcniion
`Sudan
`SD
`SE
`Sweden
`SG
`Sinppcm:
`Slovenia
`SI
`SK
`Slovakia
`SN
`Senegal
`sz
`SWUllaDd
`TD
`Owl
`Togo
`TG
`TJ
`Taji"klstan
`1T
`Trinidad and Tobago
`Ulcndne
`UA
`UG
`Uganda
`us
`United Stales of America
`uz
`Uzbelcistan
`VN
`Vici Nam
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`W096/40640
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`PCT/IB9S/00448
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`-1-
`
`BIPHENYL-2-CARBOXYLIC ACID-TETRAHYDRO-ISOQUINOLIN-6-Yl AMIDE ·DERIVATIVES,
`THEIR PREPARATION AND THEIR USE tu INHIBITORS OF MICROSOMAL TRJGLYCERIDE
`TRANSFER PROTEIN AND/OR APOLIPOPROTEIN B (ApoB)SECRETION
`.
`.
`
`...
`
`Field Of The Invention
`
`This inventio.n relates to compounds which are inhibitors of mlcro~omal
`
`5
`
`triglyceride transfer protein and/or apolipoprotein B (Apo B} secretion, and which are
`
`accordingly useful for the prevention and treatment of atherosclerosis and its clinical
`
`sequelae, for lowering serum lipids, and related diseases. The invention further relates
`
`to compositions comprising the compounds and to methods of treating atherosclerosis,
`
`obesity, and related diseases and/or conditions with the compounds.
`
`10
`
`Background Of The Invention
`
`Microsomal triglyceride transfer protein (MTP} catalyzes the transport of
`triglyceride, cholesteryl ester, and phospholipids. It has been implicated as a probable
`agent in the assembly of Apo B-containing lipoproteins, biomolecules which contribute
`
`.
`
`15 to the formation of atherosclerotlc lesions. See European Patent application publication
`.
`.
`no. O 643 057 A 1, European Patent application publication no. O 584 446 :A2., an9
`Wetterau et al., Science, 258, 999-1001, (1992). Compounds which inhibit MTP and/or
`otherwise Inhibit Apo B secretion are accordingfy useful in the treatment of
`atherosclerosis. Such compounds are also useful in the treatment of other ~iseases .
`20 or conditions in which, by inhibiting MTP and/or Apo B secretion, serum cholesterol and
`triglyceride levels can be reduced. Such conditions include hypercholesterolemia,
`
`hypertriglyceridemia,
`
`pancreatitis,
`
`and
`
`obesity;
`
`and
`
`hypercholesterolemia,
`
`hypertriglyceridemia, and hyperlipidemia associated with pancreatitis, obe~ity. and
`diabetes.
`
`Summary Of The Invention
`
`This invention provides compounds of formula I
`
`25
`
`30
`
`...
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`-2-
`
`wherein.
`X is CH2, CO, CS, or S02;
`Y is selected from:
`a direet link (I.e., a covalent bond),
`aliphatic hydrocarbylene radicals having up to 20 carbon atoms, which radical
`may be mono-substituted by hydroxy, (C1-C10)alkoxy, (C1-C10}acyl, (C1-C10}acyloxy, or
`(Ca-C1o}aryl,
`NH, and 0,
`provided that if X Is CH2, Y ls a direct link;
`Z Is selected from the following groups:
`
`(2) hydroxy,
`
`(1) H, halo, cyano,
`(C1-C 10}alkoxy,
`thiophenylcarbonyl, (C1-C10)alkoxycarbonyl,
`(3)
`(C1-C10)alkylamino, di(C1-C10)alkylamino, (C6-C10)aryl(C1-C10)alkylamino,
`provided that Y is not 0 or NH,
`
`(C1-C10}alkylthlo,
`
`(C1-C10)acyl,
`
`unsubstituted vinyl, · (C6-C;0}aryl, (C3-C8)cycloalkyl and fused benz
`(4}
`derjvatlves thereof, (c;-C10)polycycloalkyl, (C4-C8)cycloalkenyl, (c;-C1a)polycycloalkenyl,
`(5)
`(Ca-C10)aryloxy, (C6-C10)arylthio, (C8-C10)aryl(C~-C10)alkoxy,
`(C8-C10}aryl(C1-C10}alkylthio, (C3-C8)cycloalkyloxy, (C4-C8)cycloalkenyloxy,
`heterocyclyl selected from the group consisting of monocyclic radicals
`(6)
`
`5
`
`10
`
`15
`
`20
`
`25
`
`and fused polycyclic radicals, wherein said radicals contain a total of from 5 to 14 ring
`atoms, Whf3rein ·said radicals contain a total of from 1 to 4 ring · heteroatoms
`
`'
`
`'
`
`:
`
`:
`
`'
`
`30
`
`independently selected from oxygen, nitrogen, and sulfur, and wherein the individual
`
`rings of said radicals may be independently saturated, partially unsaturated, or
`
`aromatic,
`provided that if Xis CH2 , Z is Hor is selected from groups (4} and (6},
`
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`wherein, when Z contains one or more rings, said rings may each independently
`
`bear 0 to 4 substituents independently selected from halo, hydroxy, cyano, nltro, oxo
`(0=), thloxo(S=), aminosuHonyl, phenyl, phenoxy, phenYtthio, halophenytthio~ benzYI,
`benzyloxy, (C1-C10)alkyl, (C1-C10)alkoxy, (C1-C10)alkoxycarbonyl, (C1-C10)alkylthio, (C1-
`(C1-C10)alkylaminocarbonyl, di(C1-C10)alkylamino, di(C1-
`5 C10)alkylamlno,
`C10)alkylaminocarbonyl, di(C1-C10)alkylamino(C1-C10)alko>ty, (C1-CJperfluoroalkyl, (C1-
`C;,)perfluoroalkoxy, (C1-C10)acyl, (C1-C10)acyloxy, (C1-C11Jacyloxy(C1-C,0)alkyl, and
`pyrrolldinyl;
`
`and pharmaceutically acceptable salts thereof.
`
`10
`
`Reference to Z as "heterocyclyl" means any single ring or fused ring system
`
`containing at least one ring heteroatom independently selected from 0, N, and S. Thus
`a polycyclic fused ring system containing one or more carbocyclic fused saturated,
`
`partially unsaturated, or aromatic rings (usually benz rings) is within the definition of
`heterocyclyl so long as the system also contains at least one fused ring which contains
`15 at'least one of the aforementioned heteroatoms. As a substituent, such heterocyclyls
`may be attached to the remainder of the molecule from either a carbocycllc (e.g., benz)
`
`ring or from a heterocyclic ring.
`Reference to Z containing "one or more rings• is intended to mean any .(single
`
`or fused) cyclic moiety or moieties contained in Z. The rings may be carb~cyclic or
`
`20 heterocyclic, saturated or partially unsaturated, and aromatic or non-aromatic.
`Reference to a fused polycyclic ring system or radical means that all rings in the
`
`system are fused.
`
`Reference to "halo" in this specification is inclusive of fluoro, chloro, bromo, and
`
`25
`
`lodo unless noted otherwise.
`Reference to an "aryl" substitutent (e.g. (C6-C10)aryl) means the_ ring or
`substitutent is carbocyclic. Aromatic moieties which contain 1 or more heteroatoms are
`included as a subset of the tenn "heterocyclyl", as discussed above.
`Reference to an °acyl" substituent refers to an aliphatic or cyclic hydrocarcon
`
`moiety attached to a carbonyl group through which the substituent bonds:
`
`30
`
`Reference to "alkyl" and "alkoxy" Include both stnUght and branch_ed . chain
`
`radicals, but it is to be understood that references to indMdual radicals such as •propyl"
`
`or •propoxy• embrace only the straight chain ("normal") radical, branched chain isomers
`
`such as "isopropyl" or "isopropoxy• being referred to specifically.
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`The central benz-heterocyclic ring system of formula· I, i.e., the fused bicyclic .
`ring system attached through its single ring nitrogen to -x:rz. Is· referred to herein .as '
`a •1 ,2,3,4-tetrahydroisoquinoline• for convenience, and this is the convention used mo~t
`frequently when naming compounds according to the invention as 2-substttuted 1.,2,3~4- .
`tetrahydroisoquinolin-6-yl amides. It is noted that less frequently, when named ~ a •
`substituent in a compound, this central ring system is also denoted as a &-substituted ·
`
`s·
`
`"3,4,-dihydro-1 H-isoqulnolin-2-yl" moiety.
`
`A subgroup of compounds of formula I as defined above includes those :
`
`...
`
`1 O
`
`·wherein:
`X is CH2, CO, or 502;
`Y is selected from:
`
`a direct link, NH,
`(C1-C10)alkylene and (C2-C,0)alkenylene, either of which may be substituted with
`
`phenyl,
`15 provided that if X is CH2, Y is a direct link,
`Z is selected from the following groups:
`(1) H,
`(2)
`(C1-C10)alkoxy, (C1-C10)alkylthio,
`(3)
`(C1-C10)alkylamino, di(C1-C10)alkylamino, (C6-C1o)aryl(C1-C10)alkylamino,
`20 provided that Y is not NH,
`(4)
`unsubstituted vinyl, (C6-C10)aryl, (C3-CJcycloalkyl, (C4-C8)cyclo,alkenyl,
`(5)
`(C6-C10)aryloxy,
`heterocyclyl selected from the group consisting of five- and six-
`(6)
`membered heterocyclic radicals, which may be saturated,. partially unsatu~ated, . or
`25 aromatic, and the fused benz derivatives thereof, wherein said radicals may contain a
`
`total of from 1 to 3 ring heteroatoms independently selected from oxygen, nitrogen, and
`
`suHur,
`
`provided that if Xis CH2, Z Is selected from groups (4) and (6)
`wherein, when Z contains one or more rings, said rings may each independently
`30 bear 0 to 3 substituents independently selected from halo, hydroxy, nitro, (C1-C6)alkyl,
`(C1-C6)alkoxy, di(C1-C8)alkylaminocarbonyl, (C,-CJperfluoroalkoxy, (C1-C10)acyl, and
`(C1-C10)acyloxy,
`and pharmaceutically acceptable salts thereof.
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`A more particular subgroup includes those compounds within th~ .above
`subgroup wherein Xis methylene, Y is a direct link, and Z is selected from {C6~C1Jaryl,
`(C3-C8)cycloalkyl, and {C4-CJcycloalkenyl each of which may bear 0 to 3 Of the
`independent substituents noted for Z in the above subgroup, unsubstituted vinyl, and
`5 pharmaceutically acceptable salts thereof. . Specific valu~ for each include the
`illustrative values for each given hereinafter.
`
`Another more particular subgroup includes those compounds within the .above
`
`subgroup wherein X is methylene or CO, Y is a direct link, and Z Is h.eterocyclyl
`selected from thiophenyl, pyrrolidlnyl, pyrrolyl, furanyl, thiazolyl, isoxazolyl, irnidazolyl,
`10 1,2,4-triazolyl, pyridyl, pyrimidinyl, and the fused bicyclic (ortho) benz derivatives
`
`thereof, Including benzimldazolyl! benzthiazolyl, indolyl, · isoindolyl, benzofuranyl,
`
`benzothiophenyl, benzthiazolyl, quinolinyl, isoquinolinyl, and quinazolinyl, each of which ·
`
`may bear 0 to 3 of the independent substituents noted for Zin the above subgroup,
`and pharmaceutically acceptable salts thereof.
`Specific values for Z as heterocyclyl which may bear 0-3 indepE:ndent
`substituents noted for Zin the above subgroup include 2-, and 3-thiophenyl_; 2- and
`3-benzo[b]thiophenyl; 1-, 2- and 4-lmidazolyl; 2-benzimidazolyl; 2-, 4-, and 5-thlazolyl;
`2-benzothiazolyl; 3-, 4-, and 5-isoxazolyl; 2-quinoxalinyl; 1-, 2-, and 3-pyrrolidlnyl;
`5 2-, 3-, and 4-pyridyl; 2- and 4-pyrimidinyl; 2-, 3-, and 4-quinolinyl; 1-, ~. and 4-
`isoquinoline; 1-, 2-, and 3-indolyl; 1-, 2-, and 3-isoindolyl; 2- and 3-tetrahyd~ofuranyl;
`1-, 2-, and 3-pyrrolyl; 2- and 3-furanyl; 2- and 3-benzo[b]furanyl; 1-, 3-, and 4-
`
`pyrazolyl; and 1,2,4-triazol-3-yl.
`
`10
`
`A preferred group of compounds includes those compounds wherein
`Xis CH2 or CO;
`Y is a direct link;
`
`Zis
`
`H, unsubstituted vinyl, phenyl,
`
`imidazolyl, thiazolyl, thlophenyl, 1,2,4-triazolyl, pyridinyl, and pyrimidinyl
`. :
`:
`:
`15 each of which may bear O to 3 of the independent substltuents previously noted for the
`
`above subgroup;
`
`and pharmaceutically acceptable salts thereof. Specific values. of Z
`
`(as
`
`heterocycyl) for this preferred group include the corresponding specific values noted
`
`above.
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`Within the above preferred group, a subgroup includes those compounds ·
`wherein X is CO.
`
`Within the above preferred group, a second subgroup includes those
`compounds wherein X is CH2•
`The invention further provides a pharmaceutical composition suitab(e.for tlie
`treatment of conditions
`including atherosclerosis, pancreatitis, . obesity, .
`. hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, and diabetes, comprising .
`a compound of formula I as hereinbefore defined, and a pharmaceutically acicept~le ..
`carrier.
`The compounds of this invention Inhibit or decrease apo B secretion, llkely by
`the inhibition of MTP, although it may be possible that other mechanisms are involved
`
`5
`
`10
`
`..
`
`as well. The compounds are useful in any of the diseases or conditions in which apo
`B, serum cholesterol, and/or triglyceride levels are elevated. Accordingly, the invention
`further provides a method of treating a condition selected from atherosclerosis,
`15 pancreatitis, obesity, hypercholesteremia, hypertriglyceridemia, hyperlipldemia, and
`diabetes, comprising administering to a mammal, especially a human, ir:i need ()f such
`treatment an amount of a compound of formula I as defined above sufficient to
`decrease the secretion of apolipoprotein B. A subgroup of the preceding ~nditio~s
`includes atherosclerosis, obesity, paricreatitis, and diabetes. A more particular
`20 subgroup includes atherosclerosis.
`The term ii-eating• as used herein includes preventative as well as disease
`remitative treatment.
`The invention further provides a method of decreasing apo B secretion in a
`.
`.
`mammal, especially a human, comprising administering to said mammal an apo B-
`(secretion) decreasing amount of a compound of formula I as defined above ..
`Certain intermediates are additionally provided . as a further feature of the
`invention:
`41-trifluoromethyl-biphenyl-2-carboxylicacid (1,2,3,4-tetrahydro-isoquinolin-6-yl)-
`: :
`.
`amide,
`4'-trifluoromethyl-blphenyl-2:-earboxylic acid-[3-(2-hydroxy-ethyl)-4-hydroxylmethyl-·
`
`25
`
`30
`
`'
`
`.
`
`phenyl]-amide,
`2-(2-hydroxymethyl-5-nitro-phenyl)-ethanol,
`6-nitro-3,4-dihydro-1 H-isoquinoline-2-carboxylic acid tert".butyl ester,
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`6-amino-3,4-dihydro-1 H-isoquinoline-2-carboxylic acid tert-butyl ester, and
`
`5
`
`2-(5-amino-2-hydroxymethyl-phenyl)-ethanol.
`It will be appreciated by those skilled in the art that certain compounds of
`.
`formula I contain an asymmetrically substituted carbon atom and accordingly may .exist
`In, and be Isolated in, optically-active and racemic forms. Some compounds may
`exhibit polymorphism. It is to be understood that the present invention encon:ipasses
`any racemic, optically-active, polymorphic or stereoisomerlc form, or mixtures .th~re0f,
`which form possesses properties useful In the treatment of atherosclerosis, obe~ity, and
`the other conditions noted herein, it being well known in the art how to prepare
`10 optically-active forms (for example, by resolution of the racemicform by recrystallization
`
`.
`
`techniques, by synthesis from optically-active starting materials, by chiral synthesis, or
`by chromatographic separation using a chiral stationary phase) and how to determine
`efficacy for the treatment of the conditions noted herein by the standard tests described
`hereinafter.
`The chemist of ordinary skill will recognize that certain combinations of
`
`15
`
`.
`
`substituents or moieties listed in this invention define compounds which wiH be less
`stable under physiological conditions (e.g., those containing aminal or acetal linkages).
`Accordingly, such compounds are less preferred.
`An "aliphatic hydrocarbylene radical• for purposes of this invention means a
`:
`20 divalent open-chain organic radical containing carbon and hydrogen only. The ~adical
`serves as a linking group, denoted above as Y. The radical may be strcltght chain ?r
`branched and/or saturated or unsaturated, containing up to three unsaturated ~onds,
`either double, triple or a mixture of double and triple. The two valences ·may be on
`different carbon atoms or on the same carbon atom •. and thus the term "alkylide~e· is
`
`'
`
`'
`
`25 subsumed under this definition. The radical will typically be classified as a (C1-
`C20)alkylene radical, a (C2-C20)alkenylene radical, or a (C2-C20)alkynylene_ radical.
`Typically the radical will contain 1-10 carbon atoms, although longer chains are certainly
`
`feasible and within the scope of this invention, as demonstrated in the Exampl~s.
`Alkylene radicals include those saturated hydrocarbon groups having 1-20,
`
`30 preferably 1-10 carbon atoms, derived by removing two hydrogen atoms. from a
`.
`.
`corresponding saturated acyclic hydrocarbon. Illustrative values having 1-10 carbon
`atoms include straight chain radicals having the formula (CH2)n wherein n Is 1 to 10,
`such as methylene, dimethylene, trimethylene, tetramethylene, pentamethylene,
`
`:
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`hexamethylene, heptamethylene, octamethylene, nonamethylene and so forth: Also
`
`included are alkylidene radicals such as ethylidene, propylidene, butytidene, and sec>
`butylidene. Also included are branched isomers such as 1, 1-dimethyldimethylerie, 1,1-
`
`dimethyltetramethylene, 2,2-dimethyltrimethylene and 3,3-dimethylpentamethylene. :
`Alkenylene radicals include those straight or branched chain radicals having 2-
`
`5
`
`20 carbon atoms, preferably 2-10 carbon atoms, derived by removal of two hydrogen
`atoms from a corresponding acyclic hydrocarbon group containing at least one double
`bond.
`Illustrative values for alkenylene radicals having one double bond include
`ethenylene (vinylene), propenylene, 1-butenylene; 2-butenylene, and isobutenylene.
`10 Alkenylene radicals containing two double bonds (sometimes referred to in the art as
`alkadienylene
`radicals)
`include 3-methyl-2,6-heptadienylene, 2-methyl-2,4-
`heptadienylene, 2,8-nonadienylene, 3-methyl-2,6-octadienylene,and2,6-decadienylene.
`
`15
`
`20
`
`25
`
`30
`
`An illustrative value for an alkylene · radical containing three double bonds (an
`alkatrienylene radical) is 9, 11, 13-heptadecatrienylene.
`Alkynylene radicals include those straight or branched chain radicals having 2-20
`carbon atoms, preferably 2-1 O carbon atoms, derived by removal of two l')ydrogen
`atoms from a corresponding acyclic hydrocarbon group containing at least qne triple
`bond. Illustrative values Include ethynylene, propynylene, 1-butynylene, 1.-pen~ylene,
`1-hexynylene, 2-butynylene, 2-pentynylene, 3,3-dimethyl-1-butynylene, and so forth.
`Following are illustrative values for other moieties and substituents named
`
`above, which are not to be taken as limiting.
`It is noted that throughout t,he
`specification, if a cyclic or polycyclic radical which can be bonded through different ring
`.
`.
`:
`atoms is referred to without noting a·specific point of attachment, all possible points are
`intended, whether through a carbon atom or a trivalent nitrogen. As examples,
`reference to (unsubstituted) •naphthyl" means naphth-1-yl and naphth-2-yl; ref~ren.ce
`to "pyridyl" means 2-, 3-, or 4-pyridyl;
`reference to "lndolyl" means attachment or
`
`.
`
`.
`
`bonding through any of the 1-, 2-, 3-, 4-, 5-, 6-, or 7- positions.
`include methoxy, ethoxy, propo)cy,
`Illustrative values for (C1-C10)alkoxy
`isopropoxy, butoxy, isobutoxy, pentoxy, hexoxy, heptoxy, and so forth.
`Illustrative values for (C1-C10)alkylthio include the corresponding sulfur-containing
`compounds of (C1-C10)alkoxy listed above, including methylthio, ethylthio, propylthio,
`isopropylthio, butylthio, isobutylthio, pentylthio, hexylthio, heptylthio, and so forth.
`
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`1 O
`
`Illustrative values for (C1-C10}acyl include values for (C1-C1o}alkanoyl such as
`formyl, acetyl, propionyl, butyryl, and isobutyryl. Also Included are other cai:nmon
`cycle-containing radicals such as benzoyl.
`Illustrative values for (C1-C10}acyloxy include values for (C1-C1o)alkanoyloxy ~uch
`5 as formyloxy, acetyloxy, proplonyloxy, butyryloxy, and isobutyryloxy. Also·included are
`other common cycle-containing radicals such as benzoyloxy.
`Illustrative values
`for
`include methoxycarbonyl,
`(C1-C1o}alkoxycarbonyl
`ethoxycarbonyl,
`propoxycarbonyl,
`isopropo>cycarbonyl,
`butoxycarbonyl,
`: and
`isobutoxycarbonyl.
`Illustrative values . for . (C1-C10)alkylamino include methylamino, ethylamino,
`propylamino, lsopropylamino, butylamino, and lsobutylamino.
`Illustrative values for di-(C1-C10}alkylamino include dimethylamino, diethylamino,
`dipropylamino, dibutylamlno, and diisobutylamlno.
`Illustrative values
`for (C6-C10}aryl(C1-C10)alkylamino are benzylamino, (1-
`15 phenylethyl)amino, and (2-phenylethyl)amino.
`Illustrative values for (C6-C10)aryl include phenyl and naphthyl.
`Illustrative values of
`include cyclopropyl, cyclobutyl,
`(c;-C8)cycloalkyl
`cyclopentyl, cyclohexyl, and cycloheptyl.
`Illustrative values for fused benz derivatives of (C3-C8)cycloalkyl include .1.~,3,4-
`tetrahydronaphthalenyl, indanyl, and fluorenyl.
`Illustrative values of polycycloalkyl include adamantyl and 2-bicyclo[2.2.1 ]heptyl.
`Illustrative values for (C4-C8}cycloalkenyl include cyclobutenyl, cyclopentyenyl,
`cyclohexenyl, and cycloheptenyl.
`Illustrative values. for polycycloalkenyl Include bicyclo[3.1.1 Jhept-2-enyl.
`Illustrative values for (C6-C10)aryloxy include phenoxy and naphthyloxy.
`Illustrative values for {C6-C10)arylthio include phenythio and naphthylthio.
`Illustrative values
`for
`include benzyloxy and
`(C6-C10)aryl(C,-C,0}alkoxy
`phenylethoxy.
`Illustrative values
`30 phenytethylthio.
`Illustrative values for (C3-C8)cycloalkyloxy include cyclopropyloxy, cyclobutyloxy,
`cyclopentyloxy, cyclohexytoxy, and cycloheptyloxy.
`
`20
`
`25
`
`for (C6-C1o}aryl(C1-C10)alkylthio
`
`include benzylth.io and
`
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`Illustrative values
`
`for
`
`(C4-C8)cycloalkenyloxy
`cyclopentenyloxy, cyclohexenyloxy, and cycloheptenyloxy.
`Illustrative values for heterocyclyl substituents which are five-member monocyclic
`radicals Include furanyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, thlazolyl, imidazolyl,
`5 pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, and 1,3,4-thiadlazolyl,
`and the like.
`
`include cyclobutenyloxy,
`
`Illustrative values for heterocyclyl substituents which are six-membered
`monocyclic radicals include 2H- and 4H-pyranyl, pyridyl, piperidinyl, piper8zfnyi,
`pyridazinyl, pyrimidinyl, pyrazinyl, morpholinyl, thiomorpholinyl, 1,3,5-triazinyl, and the
`like.
`
`10
`
`Illustrative values for heterocyclyl substituents which are fused benz derivatives
`five-membered heterocyclic
`radicals
`Include
`lndolyl,
`isoindolyl,
`indolinyl,
`of
`benzofuranyl, benzothiophenyl, benzimidazolyl, benzth_iazolyl, and carbazolyl. .
`Illustrative values for heterocyclyl substituents which are fused benz derivatives
`15 of six-membered heterocyclic radicals include quinolinyl, isoquinolinyl, quinazolinyl,
`phthalazinyl, phenothiazinyl, acridinyl, and phenoxazinyl.
`Illustrative examples for heterocyclyl groups which are fused polycyclic radicals
`other than the fused benz systems exemplified above include purinyl and pt7ridinyl.
`lllustrativ~ values of (C1-C10)alkyl Include methyl, ethyl, propyl, lsopropyl,
`isobutyl, butyl, tert-butyl, pentyl, hexyl, and the like.
`Illustrative values
`for
`(C1-C3)perfluoroalkyl
`pentafluoroethyl, and heptafluoropropyl.
`Illustrative values for (C1-C3)perfluoroalkoxy Include trifluoromethoxy: and ·
`pentafluoroethoxy.
`Compounds according to the invention can frequently be categorized into
`groups based on the linking group formed by the ring nitrogen of the 1,2,3,~tetra­
`hydroisoquinoline ring (shown in formula I) taken together with the group in -x:{Z which
`links the XYZ moiety to the said ring nitrogen. Such categories include
`
`20
`
`25
`
`·include
`
`trifluoromethyl,
`
`30
`
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`0
`
`Ureas
`
`N-alkyls
`
`0
`
`rn
`
`Rm ides
`
`s
`I
`
`tcr-~
`~Hi
`Ki1
`~~ Carbarnate
`tcf0i
`
`0
`
`Thioamides
`
`s
`
`Thioureas
`
`Sulfonamides
`
`5
`
`10
`
`15
`
`20
`
`25
`
`Referring to the above linking groups as illustrated, for amides and thioamldes
`
`30 (X=CO or CS, respectively) Y Is preferably a direct link or hydrocarbylene. In these
`
`compounds wherein Y is a direct link, bonding is preferably through the carbony~ __ or ·
`
`thiocarbonyl group to an aliphatic (i.e., open chain) carbon atom in Z. The said
`
`aliphatic carbon atom can be part of a chain which contains one or more heteroatoms.
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`Bonding can also preferably be through the carbonyl or thiocarbonyl group to a cyclic
`
`carbon atom. By 0cycfic carbon atom• is meant a saturated or unsaturated carbon
`
`atom contained In a (saturated, partially unsaturated, or aromatic) carbocycllc or .
`
`heterocyclic ring. For compoundswherein Y Is hydrocarbylene, bonding is through the
`
`5 carbonyl or thiocarbonyl group to an aliphatic carbon atom in Y.
`
`For ureas and thioureas wherein X=CO or CS, respectively and Y::0NH,:bonding
`
`is preferably through the (easternmost as shown) amino group to a cyclic carbon atom
`
`in Z. For some ureas and thioureas (X=CO, Y=direct bond) the (eastemmost).arnino
`
`nitrogen is part of Z. In this case bonding is preferably through the easternmost amino
`
`10 group to an aliphatic carbon atom in the remaining portion of Z.
`For sulfonamides according to the invention X=S02 and Y is preferably
`hydrocarbylene, or a direct link. For sulfonamides wherein Y ·is hydrocarbylene,
`
`bonding Is through the sulfonyl group to an aliphatic carbon atom In Y. For
`
`sulfonamides wherein Y is a direct link, bonding is preferably through the sulfonyl group ·
`
`15
`
`to a cyclic carbon atom in Z. For sulfonamides wherein Y is a direct link, bonding can
`
`also be to NH which Is part of Z, in which case bonding Is through X direC'.llY ,to an
`
`amino nitrogen in Z.
`N-alkyls (X=CH2, Y=direct link) preferably bond through the methyle~e group .
`to a cyclic carbon atom in Z.
`.
`.
`. =.
`For carbamates wherein X=CO and Y ::Oo bonding is preferably through the o~
`(0) portion of the linkage to a cyclic carbon atom in the remaining portion of Z. ~or
`
`20
`
`carbamates wherein X=CO and Y=direct link the o~ linkage is part of Z, an~ in these
`bonding is preferably to a cyclic or- aliphatic carbon atom In the remaining portion of
`Z, most preferably to an aliphatic carbon atom in the remaining portion of Z ..
`
`25
`
`For those compounds of formula I wherein Y is hydrocarbylene, bonding to Z
`
`is through an aliphatic carbon atom In Y preferably to H or to a cyclic carbon atom or
`a heteroatom in Z.
`When grouping compounds below and in the. Examples, it is the. above
`structural categories to which reference is made.
`
`30
`
`Preferred compounds include the following which, where possible, have been
`
`categorized according to the types of linking groups shown in partial structure above.
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`AMIDES
`
`4'-Trifluoromethyl-blphenyl-2-carboxylic acid
`
`(2-phenyl-acetyl-1,2,3,4-tetrahydro(cid:173)
`
`isoquinolln-6-yl)-amlde
`
`5 4'-Trifluoromethyl-biphenyl-2-carboxylic acid
`
`(2-phenoxy-acetyl-1,2,3,4-tetiahydro(cid:173)
`
`isoquinolln-6-yl)-amide
`
`4'-Trifluoromethyl-biphenyl-2-carboxylic acid (2-pentanoyl-1,2,3,4-tetrahydroisoql.!inolln-6-
`
`yl)-amlde
`
`10
`
`4'-Trifluoromethyl-biphenyl-2-carboxylic acid (2-cyclobutane-Carbonyl-1,2,3,4-tetra(cid:173)
`
`hydroisoquinolln-6-yl)-amide
`
`4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(thiophen-2-yl-acetyl)-1,2,3,4-tetra-
`15 hydroisoquinolin-6-y~-amide
`
`4'-Trifluoromethyl-biphenyl-2-carboxylic acid (2-butyryl-1,2,3,4-tetrahydroisoqu~nolin-6-yl_)­
`amide
`
`20 4'-Trifluoromethyl-biphenyl-2-carboxylic acid
`
`(2-ethoxy-acetyl-1,2,3,4-tetrahydro(cid:173)
`
`isoquinolin-6-yl)-amide
`
`4'-Trifluoromethyl-biphenyl-2-carboxylic
`tetrahydroisoquinolin-6-yl}-amide
`
`acid
`
`{2-[(4-fluoro-phenyl)-a~etyl]~ 1,2,3,4-
`
`25
`
`4'-Trifluoromethyl-biphenyl-2-carboxylic acid
`isoquinolin-6-yl]-amide
`
`