tJ9
`
`(19)
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`(12)
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`Europaisches Patentamt
`
`European Patent Office
`
`Office europeen des brevets
`
`1~11~I~1~1111111 ~Ill Ill~~~ 11111~111~1 ~~Ill~ ~~ll~mll
`EP 1 181 954 A2
`
`c11)
`
`EUROPEAN PATENT APPLICATION
`
`(43) Date of publication:
`27.02.2002 Bulletin 2002/09
`
`(21) Application number: 01119323.2
`
`(22) Date of filing: 07.06.1995
`
`(51) Int c:1.1: -A61 P 3/06, A61 K 31/47
`
`(84) Designated Contracting States:
`AT BE CH DE DK ES FR GB GR IE IT LI LU NL PT
`.
`SE
`
`(62) Document number(s) of the ear1ier application(s) in
`accordance with Art. 76 EPC:
`95918722.0 I O 832 069
`
`(71) Applicant: PFIZER INC.
`New York, N.Y. 10017 (US).
`
`(72) Inventors:
`• Chang, George
`lvoryton, Connecticut 06442 (US)
`
`• Dorff, Peter H.
`Norwich, Connecticut 06360. (US) ,
`• Quallich, George J.
`North Stonington, Connecticut 06359 (US)
`
`(7 4) Representative:
`Atkinson, Jonathan David Mark et al
`Urquhart-Dykes & Lord Tower House Memon ·
`Way
`Leeds LS2 SPA (GB) .
`
`Remarks:
`This application was flied on 10 - 08- 2001 as a
`divisional application to the applicatipn mentioned
`·
`under INID code 62.
`
`(54)
`
`Biphenyl-2-carboxylic acid-tetrahydro-isoquinolin-6-yl amide derivatives, their preparation
`and use as inhibitors of microsomal triglyceride transfer protein and/or apolipoprotein B
`(ApoB) secretion
`·
`
`(57) Compositions comprising a lipid lowering ·agent selected from cholesterol biosynthesis inhibitors, bile acid
`sequestrants, fibrates, cholesterol absorption inhibitors, and niacin; and an inhibitor of microsomal triglyceride transfer
`protein for treating atherosclerosis, obesity and related diseases.
`
`N
`<(
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`O'>
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`Printed by Jouw, 75001 PARIS {FR)
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`Description
`
`Field Of The Invention
`
`(0001] This invention relates to compounds 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 atheroselerosis
`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 arid/or conditions
`with the compounds.
`
`Background Of The Invention
`
`(0002] 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 8-containing lipoproteins, biomole-
`cules which contribute to the formation of atherosclerotic lesions. See European Patent application publication no. 0
`643 057 A1, European Patent application publication no. 0 584 446 A2, and Wetterau et al., Science, 258, 999-1001, ·
`( 1992). Compounds which inhibit MTP and/or otherwise inhibit Apo B secretion are accordingly useful iri the treatment
`of atherosclerosis. Such compounds are also useful in the treatment of other diseases or conditions in which, by in(cid:173)
`hibiting 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, obesity, and diabetes.
`
`Summary Of The Invention
`
`[0003] The present invention provides a composition comprising a lipid lowering agent selected from cholesterol
`biosynthesis inhibitors, bite.acid sequestrants, fibrates, cholesterol absorption inhibitors, and niacin; and an inhibitor
`of MTP. The MTP inhibitor is preferably a compound of formula I.
`
`wherein
`
`X is CH2, CO, CS, or S02;
`Y is selected from:
`
`a direct 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, (CrC10)acyl, (C1-C10)acyloxy, or (C6-C10)aryl,
`NH, and 0,
`
`provided that if X is CH2, Y is a direct link;
`Z is selected from the following groups:
`
`(1) H, halo, cyano,
`(2) hydroxy, (C1-C10)alkoxy, (C1-C10)alkylthio; (C1-C10)acyl, thiophenylcarbonyl, (C1-C10)alkoxycarbonyl,
`(3) (C1-C10)alkylamino, di(C 1-C 10)alkylamino, (Cs-C 1o)aryl(C 1-C 10)alkylamino, provided that Y is not 0 or NH,
`(4) unsubstituted vinyl, (C6-C10)aryl, (C3-C8)cycloalkyl and fused benz derivatives thereof, (CrC10)polycy-
`
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`cloalkyl, (C4-C8)cycloalkenyl, (<;-C 10)polycycloalkenyl,
`(5) (C 6-C10)aryloxy, (C6-C 10)arylthio, (C6-C10)aryl(C1-C10)alkoxy, (C6-C 10)aryl(C1-C 10)alkylthio, (C3-C5)cy(cid:173)
`cloalkyloxy, (C4-C8)cycloalkenyloxy,
`(6) heterocyclyl selected from the group consisting of monocyclic radicals and fused polycyclic radicals, where(cid:173)
`in said radicals contain a total of from 5 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 independently saturated, partially unsaturated, or aromatic,
`
`provided that if Xis CH2, Z is Hor is selected from groups (4) and (6),
`
`wherein, when Z contains or}e or more rings, said rings may each independently bear 0 to 4 substituents inde(cid:173)
`pendently selected from halo, hydroxy, cyano, nitro, oxo (O=), thioxo(S=), aminosulfonyl, phenyl, phen6xy,,phenylthio,
`halophenylthio, benzyl, benzyloxy, (C1-C10)alkyl, (C 1-C10)alkoxy, (C 1-C10)alkoxycarbonyl, (C1-C10)alkylthio, (C1-C10)
`alkylamino, (C1-C10)alkylaminocarbonyl, di(C1-C10)alkylamino, di(C1-C 10)alkylaminocarbonyl, di(C 1-C 10)alkylamino
`(C1-C 10)alkoxy, (C 1-C3)perfluoroalkyl, (C 1-C 3)perfluoroalkoxy, (C1-C 10)acyl, (C 1-C 10)acyloxy, (C1-C 10)acyloxy(C1-C:10)
`alkyl, and pyrrolidinyl;
`and pharmaceutically acceptable salts thereof.
`[0004] Reference to Z as •heterocyclyt• means any single ring or fused ring system containing at least one ring
`heteroatom independently selected from 0, N, and 5. 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 het(cid:173)
`erocyclyl so long as the system also contains at least one fused ring which contains at least one of the aforementioned
`heteroatoms. As .a substituent, such heterocyclyls may be attached to the remainder of the molecule from either a
`carbocyclic (e.g., benz) ring or from a heterocyclic ring.
`[0005) 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 carbocyclic or heterocyclic, saturated or partially unsaturated, and aromatic
`or non-aromatic.
`(0006) Reference to a fused polycyclic ring system or radical means that all rings in the system are fused.
`(0007) Reference to 'halo' in this specification is inclusive of fluoro, chloro, bromo, and iodo unless noted otherwise.
`(0008) Reference to an 'aryl' substitutent (e.g. (C6-C 10)aryl) means the ring or substitutent is carbocyclic. Aromatic
`moieties which contain 1 or more heteroatoms are included as a subset of the term •heterocyclyl', as discussed above ..
`(0009) Reference to an •acyl" substituent refers to an aliphatic or cyclic hydrocarbon moiety attached to a carbonyl
`group through which the substituent bonds.
`(001 OJ Reference to "alkyl" and "alkoxy• include both straight and branched chain radicals, but it is to be understood
`that references to individual 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.
`(0011] The central benz-heterocyclic ring system of formula I, i.e .• the fused bicyclic ring system attached through
`its single ring nitrogen to -XYZ, is referred to herein as a "1,2,3,4-tetrahydroisoquinoline• for convenience, and this is
`the convention used most frequently when naming compounds according to the invention as 2-substituted 1,2,3,4-tet(cid:173)
`rahydroisoquinolin-6-yl amides. It is noted that less frequently, when named as a substituent in a compound, this· central
`ring system is also denoted as a 6-subslituted "3,4,-<iihydro-1 H-isoquinolin-2-yl~ moiety.
`(0012) A subgroup of compounds of formula I as defined above includes those
`wherein:
`
`xis CH2, CO, or 502;
`Y is selected from:
`
`a direct link, NH,
`(C1-C10)alkylene and (C2-C10)alkenylene, either of which may be substituted with phenyl,
`
`provided that if X is CH2 , Y is a direct link,
`Z is selected from the following groups:
`
`(1) H,
`(2) (C1-C 10)alkoxy, (C1-C10)alkylthio,
`(3) (C1-C10)alkylamino, di(C1-C10)alkylamino, (C6-C10)aryl(C1-C 10)alkylamino, provided that Y is not NH,
`(4) unsubstituted vinyl, (C6-C10)aryl, (C3-C8)cycloalkyl, (C4-C8)cycloalkenyl,
`(5) (C6-C10)aryloxy.
`(6) heterocyclyl selected from the group consisting of five- and six-membered heterocyclic radieals; which may
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`be saturated, partially unsaturated, or 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 sulfur,
`
`provided that if X is CH2, Z is selected from groups (4) and (6)
`
`wherein, when Z contains one or more rings, said rings may each independently bear 0 to 3 substituents inde(cid:173)
`pendently selected from halo, hydroxy, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, di(C1-C6)alkylaminocarbonyl, (C1-C3)per(cid:173)
`nuoroalkoxy, (C1-C10)acyl, and (C1-C10)acyloxy,
`and phannaceutically acceptable salts thereof.
`(0013) A more particular subgroup includes those compounds within the above subgroup wherein Xis methylene,
`Y is a direct link, and Z is selected from (C6-C10)aryl, (C3-C8)cycloalkyl, and (C4-C8)cycloalkenyl each of which may
`bear 0 to 3 of the independent substituents noted for Zin the above subgroup, unsubstituted vinyl, and pharmaceutically
`acceptable salts thereof. Specific values for each include the illustrative values for each given hereinafter.
`(0014) Another more particular subgroup includes those compounds within the above subgroup wherein X is meth-
`ylene or CO, Y is a direct link, and Z is heterocyclyl selected from thiophenyl, pyrrolidinyl, pyrrolyl, furanyl, thiazolyl, ·
`isoxazolyl, imidazolyl, 1,2,4-triazolyl, pyridyl, pyrimidinyl, and the fused bicyclic (ortho) benz derivatives thereof, includ(cid:173)
`ing benzimidazolyl, benzthiazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzthiazolyl, quinolinyl;isoqui(cid:173)
`nolinyl, and quinazolinyl, each of which may bear 0 to 3 of the independent substituents noted for Z in the above
`subgroup, and pharmaceutically acceptable salts thereof.
`.
`·
`·
`(0015) Specific values for Z as heterocyclyl which may bear 0-3 independent substituents noted for Zin the above
`subgroup include 2-, and 3-thiophenyl; 2- and 3-benzo[b)thiophenyl; 1-, 2-and 4-imidazolyl; 2-benzimidazolyl; 2-, 4-,
`and 5-thiazolyl; 2-benzothiazolyl; 3-, 4-, and 5-isoxazolyl; 2-quinoxalinyl; 1-, 2-, and 3-pyrrolidinyl; 2-, 3-, and 4-pyridyl;
`2- and 4-pyrimidinyl; 2-. 3-, and 4-quinolinyl; 1-, 3-, and 4-isoquinoline; 1-, 2-, and 3-indolyl; 1-, 2-, and.3-isoindolyl; 2-
`and 3-tetrahydrofuranyl; 1-, 2-, and 3-pyrrolyl; 2- and 3-furanyt; 2- and 3-benzo[b)furanyl; 1-, 3-, and 4-pyrazolyl; and
`1,2,4-triazol-3-yl.
`[0016) ·A preferred group of compounds includes those compounds wherein
`
`Xis C~orCO;
`Y is a direct link;
`z is
`
`H, unsubstituted vinyl, phenyl,
`imidazolyl, thiazolyl, thiophenyl, 1,2.4-triazolyl, pyridinyl. and pyrimidinyl each of which may bear 0 to 3 of the
`independent substituents 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.
`
`(0017) Within the above preferred group, a subgroup includes those compounds wherein X is;CO.
`[0018} Within the above preferred group, a second subgroup includes those compounds wherein Xis Ct-Ii ..
`[0019) The invention further provides a pharmaceutical composition suitable for the treatment of conditions including
`atherosclerosis, pancreatitis, obesity, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, and diabetes, com(cid:173)
`prising a compound of formula I as hereinbefore defined, and a pharmaceutically acceptable carrier.
`[0020) The compounds of this invention inhibit or decrease apo B secretion, likely by the inhibition of MTP, although
`it may be possible that other mechanisms are involved 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, pancreatitis, obesity, hypercholesteremia,
`hypertriglyceridemia, hyperlipidemia, and diabetes, comprising administering to a mammal, especially a human, in
`need of 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 conditions includes atherosclerosis, obesity, pancreatitis, and diabe(cid:173)
`tes. A more particular subgroup includes atherosclerosis.
`· [0021} The term •treating• as used herein includes preventative as well as disease remitative treatment.
`[0022} 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.·
`[0023) Certain intermediates are additionally provided as a further feature of the invention:
`
`4'-trifluoromethyl-biphenyl-2-<:arboxylic acid (1,2,3,4-tetrahydro-isoquinolin-6-yl)-amide,
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`4'-triHuoromethyl-biphenyl-2-carboxylic acid-[3-(2-hydroxy-ethyl)-4-hydroxylmethylphenyl]-amide,
`2-(2-hydroxymethyl-5-nitro-phenyl)-ethanol,
`6-nitro-3,4-dihydro-1 H-isoquinoline-2-carboxylic acid tart-butyl ester,
`6-amino-3,4-dihydro-1 H-isoquinoline-2-carboxylic acid tert-butyl ester, and
`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
`(0024)
`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 encoll'ipasses any racerriic,
`optically-active. polymorphic or stereoisomeric form, or mixtures thereof, which form possesses properties useful in
`the treatment of atherosclerosis, obesity, and the other conditions noted herein, it being well known in the art how to
`prepare optically-active forms (for example, by resolution of the racemic form by recrystallization techniques, by syn(cid:173)
`thesis 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.
`(0025) The chemist of ordinary skill will recognize that certain combinations of substituents or moieties listed in this
`invention define compounds which will be less stable under physiological conditions (e.g., those containing arilinal or
`acetal linkages). Accordingly, such compounds are less preferred.
`·
`·
`. (0026) An •aliphatic hydrocarbylene radical" for purposes of this invention means a divalent open-chain organic rad-
`ical containing carbon and hydrogen only. The radical serves as a linking group, denoted above as Y. The radical may
`be straight chain or branched and/or saturated or unsaturated, containing up to three unsaturated bonds, 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 "alkylidene• is subsumed under this definition. The radical will typically be classified as a
`(C1-C20)alkylene radical, a (C2-C20)alkenylene radical, or a (CrC20)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 Examples.
`(0027) Alkylene radicals include those saturated hydrocarbon groups having 1-20, preferably 1-10 ,carbon atoms,
`derived by removing two hydrogen atoms from a corresponding saturated acyclic hydrocarbon. Illustrative values hav(cid:173)
`ing 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, hexamethylene, heptamethylene, octamethylene, non(cid:173)
`amethylene and so forth. Also included are alkylidene radicals such as ethylidene, propylidene, butylidene, and sec(cid:173)
`butylidene. Also included are branched isomers such as 1,1-dimethyldimethylene, 1,1-dimethyltetramethylene,
`2,2-dimethyltrimethylene and 3,3-dimethylpentamethylene,
`(0028) Alkenylene radicals include those straig.ht or branched chain radicals having 2-20 carbon atoms, preferably
`2-10 carbon atoms, derived by removal of two hydrogen atoms from a corresponding acyclic hydrocarbon group con(cid:173)
`taining at least one double bond. Illustrative values for alkenylene radicals having one double bond include .ethenylene
`(vinylene), propenylene, 1-butenylene, 2-butenylene, and isobutenylene. 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. An illustrative value for
`an alkylene radical containing three double bonds (an alkatrienylene radical) is 9, 11, 13-heptadecatrienylene.
`(0029] Alkynylene radicals include those straight or branched chain radicals having 2-20 carbon atoms; preferably
`2-10 carbon atoms, derived by removal of two hydrogen atoms from a corresponding acyclic hydrocarbon group con(cid:173)
`taining at least one triple bond. Illustrative values include ethynylene, propynylene. 1-butynylene, 1-pentynylene, 1-hex(cid:173)
`ynylene, 2-butynylene. 2-pentynylene, 3,3-dimethyl-1-butynylene, and so forth.
`(0030) Following are illustrative values for other moieties and substituents named above, which are not to be taken
`as limiting. It is noted that throughout the 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; reference to 'pyridyl" means 2-, 3-, or 4-pyridyl; reference to 'indolyl" means attachment or bonding
`through any of the 1-. 2-, 3-, 4-, 5-, 6-, or 7- positions.
`Illustrative values for (C1-C10)alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy,
`(0031]
`hexoxy, heptoxy, and so forth.
`Illustrative values for (C1-C10)alkylthio include the corresponding sulfur-containing compounds of (C1-C10)
`(0032]
`alkoxy listed above, including methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, pentylthio, hexylth-
`io, heptylthio, and so forth.
`Illustrative values for (C1-C10)acyl include values for (C1-C 10)alkanoyl such as formyl, acetyl, propionyl, bu(cid:173)
`(0033]
`tyryl, and isobutyryl Also included are other common cycle-containing radicals such as benzoyl.
`Illustrative values for (C1-C10)acyloxy include values for (C1-C10)alkanoyloxy such as formyloxy, acetyloxy,
`[0034]
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`propionyloxy, butyryloxy, and isobutyryloxy. Also included are other common cycle-containing radicals such as ben(cid:173)
`zoyloxy.
`Illustrative values for (C1-C 10)alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
`(0035]
`isopropoxycarbonyl, butoxycarbonyl, and isobutoxycarbonyl.
`·
`Illustrative values for (C1-C 10)alkylamino include methylamino, ethylamino, propylamino, isopropylamino,
`(0036]
`butylamino, and isobutylamino.
`.
`Illustrative values for di-(C1-C10)alkylamino include dimethylamino, diethylamino, dipropylamino, dibUtylami(cid:173)
`(0037)
`no, and diisobutylamino.
`(0038)
`Illustrative values for (C6-C10)aryl(C1-C10)alkylamino are benzylamino, (1-phenylethyl)amino, and (2-phe-
`nylethyl)amino.
`.
`(0039)
`Illustrative values for (Cs-C10)aryl include phenyl and naphthyl.
`Illustrative values of (C3-C8)cycloalkyl include cycfopropyl, cyclobutyl, cyclopentyl, cycfohexyl; and cyciohep- ·
`[0040)
`tyl.
`Illustrative values for fused benz derivatives of (Ca-C8)cycloalkyl include 1,2,3,4-tetrahydronaphthalenyl, in-
`(0041)
`danyl, and fluorenyl.
`Illustrative values of polycycloalkyl include adamantyl and 2-bicyclo (2.2.1]heptyl.
`(0042]
`[0043]
`Illustrative values for (C4-C8)cycloalkenyl include cyclobutenyl, cyclopentyenyl, cyclohexenyl, and cyclohep(cid:173)
`tenyl.
`Illustrative values for polycycloalkenyl include bicyclo(3.1.1 ]hept-2-enyl.
`(0044)
`Illustrative values for (Cs-C10)aryloxy include phenoxy and naphthyloxy.
`(0045]
`Illustrative values for (Cs-C10)arylthio include phenythio and naphthylthio.
`[0046]
`Illustrative values for (Cs-C10)aryl(C 1-C 10)alkoxy include benzyloxy and phenylethoxy.
`(0047)
`Illustrative values for (Cs-C10)aryl(C1-C10)alkylthio include benzylthio and phenylethylthio.
`(0048)
`Illustrative values for (C3-C8)cycloalkyloxy include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexy-
`(0049)
`loxy, and cycloheptyloxy.
`(0050)
`Illustrative values for (C4-C8)cycloalkenyloxy include cyclobutenyloxy, cyclopentenyloxy, cyclohexenyloxy,
`and cycloheptenyloxy.
`(0051)
`Illustrative values for heterocyclyl substituents which are five-member monocyclic radicals include furanyl,
`thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl,
`1,2,4-triazolyl, and 1,3,4-thiadiazolyl, and the like.
`(0052)
`Illustrative values for heterocyclyl substituents which are six-membered monocyclic radicals include 2H- and
`4H-pyranyl, pyridyl, piperidinyl, piperazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, morpholinyl, thiomorpholinyl, 1,3,5-tri(cid:173)
`azinyl, and the like.
`(0053)
`Illustrative values for heterocyclyl substituents which are fused benz derivatives of five-membered heterocyclic
`radicals include indolyl, isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzthiazolyl, and carba-
`·
`zolyl.
`Illustrative values for heterocyclyl substituents which are fused benz derivatives of six-membered heterocyclic
`(0054)
`radicals include quinolinyl, isoquinolinyl, quinazolinyl, phthalazinyl, phenothiazinyl, acridinyl, and phenoxazinyl.
`(0055)
`Illustrative examples for heterocyclyl groups which are fused polycyclic radicals other than the fused benz
`systems exemplified above include purinyl and pteridinyl.
`[0056)
`Illustrative values of (C1-C10)alkyl include methyl, ethyl, propyl, isopropyl, isobutyl, butyl, tert-butyl, pentyl,
`hexyl, and the like.
`Illustrative values for (C1-C3)perfluoroalkyl include trifluoromethyl, pentafluoroethyl, and heptafluoropropyl.
`(0057)
`(0058)
`Illustrative values for (C1-C3)perfluoroalkoxy include trifluoromethoxy and pentafluoroethoxy.
`[0059) Compounds according to the invention can frequenUy be categorized into groups based on the linking group
`. formed by the ring nitrogen of the 1 ,2,3,4-tetrahydroisoquinoline ring (shown in formula I) taken together with the group
`in -XYZ which links the XYZ moiety to the said ring nitrogen. Such categories include
`
`5
`
`10
`
`f 5
`
`20
`
`25
`
`30
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`35
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`40
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`45
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`50
`
`55
`
`R11ides
`
`Ureas
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`5
`
`10
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`15
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`20
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`25
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`30
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`35
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`40
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`45
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`50
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`55
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`EP 1181 954 A2
`
`tn:YHi
`
`N-allcyls
`
`Thioamides
`
`s
`
`~~ Carbamale
`
`Thioureas
`
`Sulfona111ides
`
`. [0060] Referring to the above linking groups as illustrated, for amides and thioamides (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 carbonyl 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. Bonding can also preferably be through the carbonyl
`or thiocarbonyl group to a cyclic carbon atom. By •cyclic carbon atom" is meant a saturated or unsaturated carbon
`atom contained in a (saturated, partially unsaturated, or aromatic) carbocyclic or heterocyclic ring. For compounds
`wherein Y is hydrocarbylene, bonding is through the carbonyl or thiocarbonyl group to an aliphatic carbon atom in Y.
`(0061] For ureas and thioureas wherein X=CO or CS, respectively and Y=NH, 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 (easternmost) amino nitrogen is part of Z. In this case bonding is preferably through the easternmost amino
`group to an aliphatic carbon atom in the remaining portion of Z.
`(0062] 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 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 dir~ctly to an amino nitrogen in Z.
`(0063] N-alkyls (X=CH2, Y=direct link) preferably bond through the methylene group to a cyclic carbon atom in Z.
`(0064] . For carbamates wherein X=CO and Y=O bonding is preferably through the oxy (0) portion of the linkage to
`a cyclic carbon atom in the·remaining portion of Z. For carbamates wherein X=CO and Y=direct link the oxy linkage is
`part of Z, and 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.
`(0065] 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.
`(0066] When grouping compounds below and in the Examples. it is the above structural categories to which reference
`is made.
`[0067] 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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`EP 1181 954A2
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`AMIDES
`
`[0068)
`
`5
`
`4'-Trifluoromethyl-biphenyl-2-carboxylic acid (2-phenyl-acetyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide
`
`4' -Trifluoromethyl-biphenyl-2-carboxylic acid (2-phenoxy-acetyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide
`
`4 '-Trifluoromethyl-biphenyl-2-carboxylic acid (2-pentanoyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide
`
`10
`
`4'-Trifluoromethyl-biphenyl-2-carboxylic acid (2-cyclobutane-carbonyl-1,2,3,4-tetrahydroisoquinolin-6..,yl)-amide .
`
`4 '-T rifluoromethyl-biphenyl-2-carboxylic acid f2-(thiophen-2-yl-acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide
`
`15
`
`4'-Trifluoromethyl-biphenyl-2-carboxylic acid (2-butyryl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide ·
`
`20
`
`25
`
`30
`
`35
`
`40
`
`4' -Trifluoromethyl-biphenyl-2-carboxylic acid (2-ethoxy-acetyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide
`
`4'-Trifluoromethyl-biphenyl-2-carboxylic acid
`amide
`
`{2-[(4-fluoro-phenyl)-acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl}-
`
`4' -Trifluoromethyl-biphenyl-2-carboxylic acid [2-{3-methyl-butyryl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide
`
`4'-T rifluoromethyl-biphenyl-2-carboxylic acid (2-but-3-enoyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide
`
`4'-Trifluoromethyl-biphenyl-2-carboxylic acid {2-methoxy-acetyl-1 ,2,3,4-tetrahydroisoquinolin-6-yl)-amide
`
`4'-Trifluoromethyl-biphenyl-2-carboxylic acid (2-ethylthio-acetyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide
`
`4 '-Trifluoromethyl-biphenyl-2-carboxylic acid (2-(6-diethyl-carbamoyl-cyclohex-3-enecarbonyl)-1,2,3;4-tetrahydr(cid:173)
`oisoquinolin-6-yl]-amide
`
`4 '-T rifluoromethyl-biphenyl-2-carboxylic
`amide
`
`acid
`
`[2-(cyclopent-1-enyl-acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl](cid:173)
`
`4'-Trifluoromethyl-biphenyl-2-carboxylic acid (2-hex-3-enoyl-1,2,3,4-tetrahydroisoquinolin.;.s.,yl)-amide
`
`4 '-Trifluoromethyl-biphenyl-2-carboxylic acid (2-(tetrahydrofuran-3-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)(cid:173)
`amide
`
`4' -Trifluoromethyl-biphenyl-2-carboxylic acid (2-(thiophen-3-yl-acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide
`
`4 '-Trifluoromethyl-biphenyl-2-carboxylic acid (2-(pyridine-2-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide
`
`45
`
`UREAS
`
`[0069)
`
`50
`
`ss
`
`6-[(4'-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinoline-2-carboxylic·acid phenylamide
`
`6-[( 4 '-Trifluoromethyl-biphenyl-2-carbonyl)-amino)-3,4-dihydro-1 H-isoquinoline-2-carboxylic.acid hexylamide
`
`6-[( 4'-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4-di-hydro-1 H-isoquinoline-2-carboxylic acid benzylamide
`
`6-[(4'-Trifluoromethyl-biphenyl-2-carbonyl)-amino)-3,4-dihydro-1 H-isoquinoline-2-carboxylic acid [(R)-1-phenyl(cid:173)
`ethyl)-amide
`
`6-[( 4 '-Trifluoromethyl-biphenyl-2-carbonyl)-amino)-3,4-dihydro-1 H-isoquinoline-2-carboxylic acid. pyridin-2-yla-
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`EP 1181 954 A2
`
`mide
`
`SULFONAMIDES
`
`5
`
`[0070)
`
`10
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`15
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`20
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`25
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`30
`
`4 '-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(propane-2-sulfonyl)-1,2,3,4-tetrahydroisoquinofin:.a-yi]-amide
`
`4'-Trifluoromethyl-biphenyl-2-carboxylic acid (2-dimethylsulfamoyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide
`
`4 '-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(2-trifluoromethoxy-benzenesulfonyl)-1,2,3,4-tetrahydroisoquino-.
`lin-6-yl]-amide
`
`THIOUREAS
`
`[0071)
`
`4'-Trifluoromethyl-biphenyl-2-carboxylic acid
`amide
`
`(2-cyclopropyllhiocarbamoyl-1,2,3,4-tetrahydroisoquinolin-6-yl)(cid:173)
`
`N-ALKYLS
`
`[0072)
`
`4'-T rifluoromethyl-biphenyl-2-carboxylic acid [2-(2,6,6-trimethyl-cyclohex-2-enylmethyl)-1,2,3,4-tetrahydroisoqui(cid:173)
`nolin-6-yl]-amide
`
`4' -Trifl uoromethyl-biphenyl-2-carboxylic acid (2-(2,4-dichloro-benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide
`
`4 '-Trifluoromethyl-biphenyl-2-carboxylic acid
`2,3,4-tetrahydroisoquinolin-6-yl]-amide
`
`[2-( 1,5a,6,9,9a,9b-hexahydro-4H-dibenzofuran-4a-ylmethyl)-1 ,
`
`4 '-T rifluoromethyl-biphenyl-2-carboxylic acid (2-thiophen-2-ylmethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide
`
`35
`
`4'-Trifluoromethyl-biphenyl-2-carboxylic acid (2-(1 H-pyrrol-2-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide
`
`40
`
`45
`
`50
`
`4 '-Trifluoromethyl-biphenyl-2-carboxylic acid (2-furan-2-ylmethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide
`
`Acetic acid 5-{6-(( 4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4-dihydro-1 H-isoquinolin-2-ylmethyl}-furan-
`2-ylmethyl ester
`
`4 '-T rifluoromethyl-biphenyl-2-carboxylic acid (2-thiophen-3-ylmethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide
`
`4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(2,5-dimethoxy-tetrahydrofuran-3-ylmethyl)-1 ,2,3,4-tetrahydro-
`isoquinolin-6-yl]-amide
`
`4'-Trifluoromethyl-biphenyl-2-carboxylic acid (2-benzyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide
`
`4 '-Trifluoromethyl-biphenyl-2-carboxylic acid (2-pyridin-2-ylmethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide
`
`4' -T rifl uoromethyl-biphenyl-2-carboxylic acid (2-quinolin-2-ylmethyl-1,2 ,3,4-tetrahydroisoquinolin-6-yl)-amide
`
`4'-Trifluoromethyl-biphenyl-2-carboxylic acid [2-(3-chloro-benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide
`
`55
`
`4' -Trifluoromethyl-biphenyl-2-carboxylic acid (2-pyrimidin-2-ylmethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide
`
`4' -T rifluoromethyl-biphenyl-2-carboxylic acid [2