(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`18 November 2010 (18.11.2010)
`
`PCT
`
`11111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111
`
`(10) International Publication Number
`WO 2010/132601 A1
`
`(51) International Patent Classification:
`C07D 401114 (2006.01)
`C07D 417104 (2006.01)
`C07D 403104 (2006.01)
`C07D 417114 (2006.01)
`C07D 403114 (2006.01)
`C07D 495/04 (2006.01)
`C07D 405114 (2006.01)
`A61K 31/4188 (2006.01)
`C07D 409/14 (2006.01)
`A61K 31/4178 (2006.01)
`C07D 413104 (2006.01)
`A61P 31/12 (2006.01)
`
`(21) International Application Number:
`PCT /US20 I 0/034600
`
`(22) International Filing Date:
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`12 May 2010 (12.05.2010)
`
`English
`
`English
`
`(30)
`
`(71)
`
`(72)
`(75)
`
`;;;;;;;;;;;;;;;
`
`;;;;;;;;;;;;;;; -----;;;;;;;;;;;;;;;
`-;;;;;;;;;;;;;;; ----------
`;;;;;;;;;;;;;;; ---;;;;;;;;;;;;;;; ---;;;;;;;;;;;;;;;
`;;;;;;;;;;;;;;; ------;;;;;;;;;;;;;;; -
`
`Priority Data:
`61/177,972
`61/224,745
`61/238,760
`
`13 May2009 (13.05.2009)
`10 July 2009 (I 0.07 .2009)
`I September 2009 (01.09.2009)
`
`us
`us
`us
`Applicants
`(for all designated States except US):
`GILEAD SCIENCES, INC. [US/US]; 333 Lakeside
`(US). KIM,
`Drive, Foster City, California 94404
`Choung, U. [US/US]; 333 Lakeside Drive, Foster City,
`California 94404 (US).
`
`Inventors; and
`Inventors/Applicants (for US only): GUO, Hongyan
`[CN/US]; 333 Lakeside Drive, Foster City, California
`94404 (US). KATO, Darryl [US/US]; 333 Lakeside
`Drive,
`Foster City,
`California
`94404
`(US).
`KIRSCHBERG, Thorsten, A. [DE/US]; 333 Lakeside
`Drive, Foster City, California 94404 (US). LIU, Hongtao
`[CN/US]; 333 Lakeside Drive, Foster City, California
`94404 (US). LINK, John, 0. [US/US]; 333 Lakeside
`Drive, Foster City, California 94404 (US). MITCHELL,
`Michael, L. [US/US]; 333 Lakeside Drive, Foster City,
`California 94404 (US). PARRISH, Jay, P. [US/US]; 333
`Lakeside Drive, Foster City, California 94404 (US).
`SQUIRES, Neil [CA/US]; 333 Lakeside Drive, Foster
`City, California 94404 (US). SUN, Jianyu [CA/US]; 333
`Lakeside Drive, Foster City, California 94404 (US).
`TAYLOR, James [US/US]; 333 Lakeside Drive, Foster
`City, California 94404 (US). BACON, Elizabeth, M.
`[US/US]; 333 Lakeside Drive, Foster City, California
`94404 (US). CANALES, Eda [US/US]; 333 Lakeside
`Drive, Foster City, California 94404 (US). CHO, Aesop
`[US/US]; 333 Lakeside Drive, Foster City, California
`94404 (US). COTTELL, Jeromy, J. [US/US]; 333
`Lakeside Drive, Foster City, California 94404 (US). DE(cid:173)
`SAI, Manoj, C. [US/US]; 333 Lakeside Drive, Foster
`City, California 94404 (US). HALCOMB, Randall, L.
`[US/US]; 333 Lakeside Drive, Foster City, California
`94404 (US). KRYGOWSKI, Evan, S. [US/US]; 333
`Lakeside Drive, Foster City, California 94404 (US).
`
`LAZERWITH, Scott, E. [US/US]; 333 Lakeside Drive,
`Foster City, California 94404 (US). LIU, Qi [CNIUS];
`333 Lakeside Drive, Foster City, California 94404 (US).
`MACKMAN, Richard [GB/US]; 333 Lakeside Drive,
`Foster City, California 94404 (US). PYUN, Hyung-Jung
`[KRIUS]; 333 Lakeside Drive, Foster City, California
`94404 (US). SAUGIER, Joseph, H. [US/US]; 333 Lake(cid:173)
`side Drive, Foster City, California 94404 (US). TREN(cid:173)
`KLE, James, D. [US/US]; 333 Lakeside Drive, Foster
`City, California 94404 (US). TSE, Winston, C. [US/US];
`333 Lakeside Drive, Foster City, California 94404 (US).
`VIVIAN, Randall, W. [US/US]; 333 Lakeside Drive,
`Foster City, California 94404 (US). SCHROEDER,
`Scott, D. [US/US]; 333 Lakeside Drive, Foster City, Cali(cid:173)
`fornia 94404 (US). WATKINS, William, J. [GB/US];
`333 Lakeside Drive, Foster City, California 94404 (US).
`XU, Lianhong [US/US]; 333 Lakeside Drive, Foster
`City, California 94404
`(US). YANG, Zheng-Yu
`[CNIUS]; 333 Lakeside Drive, Foster City, California
`94404 (US). KELLAR, Terry [US/US]; 333 Lakeside
`Drive, Foster City, CA 94404 (US). SHENG, Xiaoning
`[US/US]; 333 Lakeside Drive, Foster City, CA 94404
`(US). CLARKE, Michael, O'Neil, Hanrahan [US/US];
`333 Lakeside Drive, Foster City, CA 94404 (US).
`CHOU, Chien-hung [US/US]; 333 Lakeside Drive, Fos(cid:173)
`ter City, CA 94404 (US). GRAUPE, Michael [AT/US];
`333 Lakeside Drive, Foster City, CA 94404 (US). JIN,
`Haolun [CA/US]; 333 Lakeside Drive, Foster City, CA
`94404 (US). MCFADDEN, Ryan [US/US]; 333 Lake(cid:173)
`side Drive, Foster City, CA 94404 (US). MISH, Michael,
`R. [US/US]; 333 Lakeside Drive, Foster City, CA 94404
`(US). METOBO, Samuel, E. [-IUS]; 333 Lakeside
`Drive, Foster City, CA 94404 (US). PHILLIPS, Barton,
`W. [US/US]; 333 Lakeside Drive, Foster City, CA 94404
`(US). VENKATARAMANI, Chandrasekar [IN/US];
`333 Lakeside Drive, Foster City, CA 94404 (US).
`
`(74) Agents: HARRIS, Robert, H. et al.; Viksnins Harris &
`Padys PLLP, P.O. Box 111098, St. Paul, Minnesota
`55111-1098 (US).
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,
`CA,CH,CL,CN,CO,CR,CU,CZ,DE,DK,DM,DO,
`DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT,
`HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP,
`KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD,
`ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI,
`NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD,
`SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR,
`TT, TZ, VA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG,
`
`[Continued on next page]
`
`(54) Title: ANTIVIRAL COMPOUNDS
`
`(57) Abstract: The invention is related to anti-viral compounds, compositions containing such compounds, and therapeutic meth(cid:173)
`ods that include the administration of such compounds, as well as to processes and intermediates useful for preparing such com(cid:173)
`pounds.
`
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`W 0 2010/13 2 601 A 1 11111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111
`
`ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ,
`TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK,
`EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU,
`LV, MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK,
`SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
`GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`
`with international search report (Art. 21 (3))
`
`before the expiration of the time limit for amending the
`claims and to be republished in the event of receipt of
`amendments (Rule 48.2(h))
`
`Declarations under Rule 4.17:
`-
`ofinventorship (Rule 4.17(iv))
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`
`ANTIVIRAL COMPOUNDS
`
`PRIORITY OF INVENTION
`
`This application claims priority to United States Provisional Application Numbers
`
`61/177,972, filed 13 May 2009; 61/224,745, filed 10 July 2009; and 61/238,760, filed 01
`
`September 2009. The entire content of each of these applications is hereby incorporated herein
`
`by reference.
`
`BACKGROUND OF THE INVENTION
`
`Hepatitis Cis recognized as a chronic viral disease of the liver which is characterized by
`
`liver disease. Although drugs targeting the liver are in wide use and have shown effectiveness,
`
`toxicity and other side effects have limited their usefulness. Inhibitors of hepatitis C virus
`
`(HCV) are useful to limit the establishment and progression of infection by HCV as well as in
`
`diagnostic assays for HCV.
`
`There is a need for new HCV therapeutic agents.
`
`SUMMARY OF THE INVENTION
`
`In one embodiment the invention provides a compound of the invention which is a
`
`compound of formula (I):
`
`J-)(-J
`
`(I)
`
`as described herein, or a pharmaceutically acceptable salt, or prodrug thereof.
`
`The invention also provides isotopically enriched compounds that are compounds of
`
`formula I that comprise an enriched isotope at one or more positions in the compound.
`
`The present invention also provides a pharmaceutical composition comprising a
`
`compound of the invention and at least one pharmaceutically acceptable carrier.
`
`The present invention also provides a pharmaceutical composition for use in treating
`
`disorders associated with HCV.
`
`The present invention also provides a pharmaceutical composition further comprising an
`
`interferon or pegylated interferon.
`
`The present invention also provides a pharmaceutical composition further comprising a
`
`nucleoside analog.
`
`The present invention also provides for a pharmaceutical composition wherein said
`
`nucleoside analogue is selected from ribavirin, viramidine, levovirin, an L-nucleoside, and
`
`isatoribine and said interferon is a-interferon or pegylated a-interferon.
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`The present invention also provides for a method of treating disorders associated with
`
`hepatitis C, said method comprising administering to an individual a pharmaceutical
`
`composition which comprises a therapeutically effective amount of a compound ofthe
`
`invention.
`
`The present invention also provides a method of inhibiting HCV, comprising
`
`administering to a mammal afflicted with a condition associated with HCV activity, an amount
`
`of a compound of the invention, effective to inhibit HCV.
`
`The present invention also provides a compound of the invention for use in medical
`
`therapy (preferably for use in inhibiting HCV activity or treating a condition associated with
`
`HCV activity), as well as the use of a compound of the invention for the manufacture of a
`
`medicament useful for inhibiting HCV or the treatment of a condition associated with HCV
`
`activity in a mammal.
`
`The present invention also provides synthetic processes and novel intermediates
`
`disclosed herein which are useful for preparing compounds of the invention. Some of the
`
`compounds of the invention are useful to prepare other compounds of the invention.
`
`In another aspect the invention provides a compound of formula I, or a pharmaceutically
`
`acceptable salt or prodrug thereof, for use in the prophylactic or therapeutic treatment of
`
`hepatitis C or a hepatitis C associated disorder.
`
`In another aspect the invention provides a method of inhibiting HCV activity in a sample
`
`comprising treating the sample with a compound of the invention.
`
`In one embodiment the invention provides a compound having improved inhibitory or
`
`pharmacokinetic properties, including enhanced activity against development of viral resistance,
`
`improved oral bioavailability, greater potency (for example, in inhibiting HCV activity) or
`
`extended effective half-life in vivo. Certain compounds of the invention may have fewer side
`
`effects, less complicated dosing schedules, or be orally active.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`Reference will now be made in detail to certain embodiments of the invention, examples
`
`of which are illustrated in the accompanying structures and formulas. While the invention will
`
`be described in conjunction with the enumerated embodiments, it will be understood that they
`
`are not intended to limit the invention to those embodiments. On the contrary, the invention is
`
`intended to cover all alternatives, modifications, and equivalents, which may be included within
`
`the scope of the present invention as defined by the embodiments.
`
`2
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`Compounds of the Invention
`
`The compounds of the invention exclude compounds heretofore known. However, it is
`
`within the invention to use compounds that previously were not known to have antiviral
`
`properties for antiviral purposes (e.g. to produce an anti-viral effect in an animal). With respect
`
`to the United States, the compounds or compositions herein exclude compounds that are
`
`anticipated under 35 USC §102 or that are obvious under 35 USC §103.
`
`Whenever a compound described herein is substituted with more than one of the same
`designated group, e.g., "RI" or "A3
`
`", then it will be understood that the groups may be the same
`
`or different, i.e., each group is independently selected.
`
`"Absent"- Some groups are defined such that they can be absent. When a group is
`
`absent it becomes a bond connector. The two groups that would otherwise be connected to that
`
`absent group are connected to each other through a bond. For example, when W is absent, M is
`
`bonded toM.
`
`"Alkyl" is C t-C 18 hydrocarbon containing normal, secondary, tertiary or cyclic carbon
`
`atoms. Examples are methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl,
`
`-CH2CH2CH3), 2-propyl (i-Pr, !-propyl, -CH(CH3)2), 1-butyl (!1-Bu, n-butyl, -
`
`CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, !-butyl, -CH2CH(CH3)2), 2-butyl ~-Bu, ~-butyl, -
`
`CH(CH3)CH2CH3), 2-methyl-2-propyl (1-Bu, !-butyl, -C(CH3)3), 1-pentyl (!1-pentyl,(cid:173)
`
`CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-
`
`methyl-2-butyl ( -C(CH3)2CH2CH3), 3-methyl-2-butyl ( -CH(CH3)CH(CH3)2), 3-methyl-1-
`
`butyl ( -CH2CH2CH(CH3)2), 2-methyl-1-butyl ( -CH2CH(CH3)CH2CH3), 1-hexyl ((cid:173)
`
`CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl ((cid:173)
`
`CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl ( -C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl
`
`( -CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl ( -CH(CH3)CH2CH(CH3)2), 3-methyl-3-
`
`pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl ( -CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-
`
`butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3, and cyclopropylmethyl
`
`"Alkenyl" is C2-C18 hydrocarbon containing normal, secondary, tertiary or cyclic carbon
`atoms with at least one site ofunsaturation, i.e. a carbon-carbon, sp2 double bond. Examples
`
`include, but are not limited to, ethylene or vinyl ( -CH=CH2), allyl ( -CH2CH=CH2),
`cyclopentenyl (-CsH7), and 5-hexenyl (-CH2 CH2CH2CH2CH=CH2).
`
`3
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`"Alkynyl" is C2-C18 hydrocarbon containing normal, secondary, tertiary or cyclic
`
`carbon atoms with at least one site ofunsaturation, i.e. a carbon-carbon, sp triple bond.
`
`Examples include, but are not limited to, acetylenic (-C=CH) and propargyl (-CHzC=CH).
`
`"Alkylene" refers to a saturated, branched or straight chain or cyclic hydrocarbon radical of
`
`1-18 carbon atoms, and having two monovalent radical centers derived by the removal of two
`
`hydrogen atoms from the same or two different carbon atoms of a parent alkane. Typical alkylene
`
`radicals include, but are not limited to, methylene (-CH2-) I ,2-ethyl ( -CHzCHz-), 1 ,3-propyl
`
`(-CH2CHzCHz-), 1,4-butyl (-CHzCHzCHzCHz-), and the like.
`
`"Alkenylene" refers to an unsaturated, branched or straight chain or cyclic hydrocarbon
`
`radical of 2-18 carbon atoms, and having two monovalent radical centers derived by the removal of
`
`two hydrogen atoms from the same or two different carbon atoms of a parent alkene. Typical
`
`alkenylene radicals include, but are not limited to, I ,2-ethylene ( -CH=CH-).
`
`"Alkynylene" refers to an unsaturated, branched or straight chain or cyclic hydrocarbon
`
`radical of 2-18 carbon atoms, and having two monovalent radical centers derived by the removal of
`
`two hydrogen atoms from the same or two different carbon atoms of a parent alkyne. Typical
`
`alkynylene radicals include, but are not limited to, acetylene (-C=C-), propargyl ( -CH2C=C-), and
`
`4-pentynyl ( -CHzCH2CHzC=CH).
`
`"Aryl" means a monovalent aromatic hydrocarbon radical of 6-20 carbon atoms derived by
`
`the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
`
`Typical aryl groups include, but are not limited to, radicals derived from benzene, substituted
`
`benzene, naphthalene, anthracene, biphenyl, and the like.
`
`"Arylalkyl" refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded
`
`to a carbon atom, typically a terminal or s/ carbon atom, is replaced with an aryl radical.
`
`Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl,
`
`naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and the like.
`
`The arylalkyl group comprises 6 to 20 carbon atoms, e.g., the alkyl moiety, including alkanyl,
`alkenyl or alkynyl groups, of the arylalkyl group is 1 to 6 carbon atoms and the aiyl moiety is 5
`
`to 14 carbon atoms.
`
`The term "polycarbocycle" refers to a saturated or unsaturated polycyclic ring system
`
`having from about 6 to about 25 carbon atoms and having two or more rings (e.g. 2, 3, 4, or 5
`
`rings). The rings can be fused and/or bridged to form the polycyclic ring system. For example,
`
`the term includes bicyclo [4,5], [5,5], [5,6] or [6,6] ring systems, as well as the following
`
`bridged ring systems:
`
`4
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`and
`
`( i.e., [2.1.1 ], [2.2.1 ], [3.3.3], [ 4.3.1 ], [2.2.2], [ 4.2.2], [ 4.2.1 ], [ 4.3.2], [3.1.1 ], [3.2.1 ], [ 4.3.3],
`
`[3.3.2], [3.2.2] and [3.3.1] polycyclic rings, respectively) that can be linked to the remainder of
`
`the compound of formula (I) through any synthetically feasible position. Like the other
`
`polycarbocycles, these representative bicyclo and fused ring systems can optionally comprise
`
`one or more double bonds in the ring system.
`
`The term "polyheterocycle" refers to a polycarbocycle as defined herein, wherein one or
`
`more carbon atoms is replaced with a heteroatom (e.g., 0, S, S(O), S(0)2, N+(O)Rx, or NR11);
`wherein each Rx is independently H, (Cl-lO)alkyl, (C2-10)alkenyl, (C2-10)alkynyl, (C1-
`
`10)alkanoyl, S(0)2NR.nRp, S(0)2Rx, or (Cl-lO)alkoxy, wherein each (Cl-lO)alkyl, (C2-
`
`1 O)alkenyl, (C2-1 O)alkynyl, (C 1-1 O)alkanoyl, and (C 1-1 O)alkoxy is optionally substituted with
`
`one or more halo).
`
`"Substituted alkyl", "substituted aryl", and "substituted arylalkyl" mean alkyl, aryl, and
`
`arylalkyl respectively, in which one or more hydrogen atoms are each independently replaced
`
`with a non-hydrogen substituent. Typical substituents include, but are not limited to: halo (e.g.
`
`F, Cl, Br, 1), -R, -OR, -SR, -NR2, -CF3, -CCh, -OCF3, -CN, -N02, -N(R)C(=O)R, -C(=O)R,(cid:173)
`OC(=O)R, -C(O)OR, -C(=O)NRR, -S(=O)R, -S(=0)20R, -S(=0)2R, -OS(=0)20R, -S(=0)2NRR,
`
`and each R is independently -H, alkyl, aryl, arylalkyl, or heterocycle. Alkylene, alkenylene, and
`
`alkynylene groups may also be similarly substituted.
`
`The term "optionally substituted" in reference to a particular moiety of the compound of
`
`formula I, (e.g., an optionally substituted aryl group) refers to a moiety having 0, 1, 2, or more
`
`substituents.
`
`5
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`The symbol"-----" in a ring structure means that a bond is a single or double bond. In a
`
`non-limiting example, (i,X) can be \-Cl or (DX)_.
`
`E
`
`L
`
`E
`
`L
`
`EI(L~
`
`"Haloalkyl" as used herein includes an alkyl group substituted with one or more
`
`halogens (e.g. F, Cl, Br, or 1). Representative examples ofhaloalkyl include trifluoromethyl,
`
`2,2,2-trifluoroethyl, and 2,2,2-trifluoro-1-(trifluoromethyl)ethyl.
`
`"Heterocycle" as used herein includes by way of example and not limitation these
`
`heterocycles described in Paquette, Leo A.; Principles of Modem Heterocyclic Chemistry (W.A.
`
`Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; The Chemistry of
`
`Heterocyclic Compounds, A Series of Monographs" (John Wiley & Sons, New York, 1950 to
`
`present), in particular Volumes 13, 14, 16, 19, and 28; andJ Am. Chern. Soc. (1960) 82:5566.
`
`In one specific embodiment of the invention "heterocycle" includes a "carbocycle" as defined
`
`herein, wherein one or more (e.g. 1, 2, 3, or 4) carbon atoms have been replaced with a
`
`heteroatom (e.g. 0, N, or S).
`
`Examples of heterocycles include by way of example and not limitation pyridyl,
`
`dihydropyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur oxidized
`
`tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl,
`
`benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl,
`
`piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl,
`
`tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl,
`
`azocinyl, triazinyl, 6H-1 ,2,5-thiadiazinyl, 2H,6H-1 ,5,2-dithiazinyl, thienyl, thianthrenyl,
`
`pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl, isothiazolyl,
`
`isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, I H-indazolyl, purinyl,
`
`4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl,
`
`4H-carbazolyl, carbazolyl, 13-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl,
`
`phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl,
`
`imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl,
`
`quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl,
`
`benzoxazolinyl, isatinoyl, and bis-tetrahydrofuranyl:
`
`oCJ.
`~_).
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`By way of example and not limitation, carbon bonded heterocycles are bonded at
`
`position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6
`
`of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan,
`
`tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an
`
`oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole,
`
`position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of
`
`a quinoline or position I, 3, 4, 5, 6, 7, or 8 of an isoquinoline. Still more typically, carbon
`
`bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl,
`
`4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-
`
`pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-
`
`thiazolyl.
`
`By way of example and not limitation, nitrogen bonded heterocycles are bonded at
`
`position I of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole,
`
`imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline,
`
`piperidine, piperazine, indole, indo line, 1 H-indazole, position 2 of a isoindole, or isoindoline,
`
`position 4 of a morpho line, and position 9 of a carbazole, or ~-carboline. Still more typically,
`
`nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-
`
`pyrazolyl, and 1-piperidinyl.
`
`"Carbocycle" refers to a saturated, unsaturated or aromatic ring having up to about 25
`
`carbon atoms. Typically, a carbocycle has about 3 to 7 carbon atoms as a monocycle, about 7 to
`
`12 carbon atoms as a bicycle, and up to about 25 carbon atoms as a polycycle. Monocyclic
`
`carbocycles typically have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms. Bicyclic
`
`carbocycles typically have 7 to 12 ring atoms, e.g., arranged as a bicyclo [4,5], [5,5], [5,6] or
`
`[6,6] system, or 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system. The term
`
`carbocycle includes "cycloalkyl" which is a saturated or unsaturated carbocycle. Examples of
`
`monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-
`
`cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-
`
`cyclohex-3-enyl, phenyl, spiry) and naphthyl.
`
`The term "chiral" refers to molecules which have the property of non-superimposability
`
`of the mirror image partner, while the term "achiral" refers to molecules which are
`
`superimposable on their mirror image partner.
`
`The term "stereoisomers" refers to compounds which have identical chemical
`
`constitution, but differ with regard to the arrangement of the atoms or groups in space.
`
`"Diastereomer" refers to a stereoisomer with two or more centers of chirality and whose
`
`molecules are not mirror images of one another. Diastereomers have different physical
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`properties, e.g., melting points, boiling points, spectral properties, and reactivities. Mixtures of
`
`diastereomers may separate under high resolution analytical procedures such as electrophoresis
`
`and chromatography.
`
`"Enantiomers" refer to two stereoisomers of a compound which are non-superimposable
`
`mirror images of one another.
`
`The term "treatment" or "treating," to the extent it relates to a disease or condition
`
`includes preventing the disease or condition from occurring, inhibiting the disease or condition,
`
`eliminating the disease or condition, and/or relieving one or more symptoms of the disease or
`
`condition.
`
`Stereochemical definitions and conventions used herein generally followS. P. Parker,
`
`Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New
`
`York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994) John Wiley
`
`& Sons, Inc., New York. Many organic compounds exist in optically active forms, i.e., they
`
`have the ability to rotate the plane of plane-polarized light. In describing an optically active
`
`compound, the prefixes (D and L) or (RandS) are used to denote the absolute configuration of
`
`the molecule about its chiral center(s). The prefixes d and I or(+) and(-) are employed to
`
`designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning
`
`that the compound is levorotatory. A compound prefixed with(+) or dis dextrorotatory. For a
`
`given chemical structure, these stereoisomers are identical except that they are mirror images of
`
`one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of
`
`such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is
`
`referred to as a racemic mixture or a racemate, which may occur where there has been no
`
`stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic
`
`mixture" and "racem.ate" refer to an equimolar mixture of two enantiomeric species, devoid of
`
`optical activity. The invention includes all stereoisomers of the compounds described herein.
`
`, f. ro. V0
`, WO. L0
`Specific Definitions for Groups A0
`, E0
`, Z0
`, P0
`, M0
`, ro, V0
`, WO, L 0
`, Z0
`, E0
`, P0
`For the groups A 0
`, M0
`, J0
`, and R9° the following definitions
`apply. These definitions also apply for all other A, M, W, L, P, J, T, B, V, Z, E, and R9
`
`, and R9°
`
`groups unless those groups are otherwise defined herein.
`
`Unless stated otherwise, all aryl, cycloalkyl, and heterocyclyl groups of the present
`
`disclosure may be substituted as described in each of their respective definitions. For
`
`example, the aryl part of an arylalkyl group may be substituted as described in the definition
`
`of the term 'aryl'.
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`The term "alkenyl," as used herein, refers to a straight or branched chain
`
`group of two to six carbon atoms containing at least one carbon-carbon double bond.
`
`The term "alkenyloxy," as used herein, refers to an alkenyl group attached to the parent
`
`molecular moiety through an oxygen atom.
`
`The term "alkenyloxycarbonyl," as used herein, refers to an alkenyloxy group attached
`
`to the parent molecular moiety through a carbonyl group.
`
`The term "alkoxy," as used herein, refers to an alkyl group attached to the parent
`
`molecular moiety through an oxygen atom.
`
`The term "alkoxyalkyl," as used herein, refers to an alkyl group substituted with one,
`
`two, or three alkoxy groups.
`
`The term "alkoxyalkylcarbonyl," as used herein, refers to an alkoxyalkyl group
`
`attached to the parent molecular moiety through a carbonyl group.
`
`The term "alkoxycarbonyl," as used herein, refers to an alkoxy group attached to the
`
`parent molecular moiety through a carbonyl group.
`
`The term "alkoxycarbonylalkyl," as used herein, refers to an alkyl group
`
`substituted with one, two, or three alkoxycarbonyl groups.
`
`The term "alkyl," as used herein, refers to a group derived from a straight or branched
`
`chain saturated hydrocarbon containing from one to six carbon atoms.
`
`The term "alkylcarbonyl," as used herein, refers to an alkyl group attached to the parent
`
`molecular moiety through a carbonyl group.
`
`The term "alkylcarbonylalkyl," as used herein, refers to an alkyl group
`
`substituted with one, two, or three alkyl carbonyl groups.
`
`The term "alkylcarbonyloxy," as used herein, refers to an alkylcarbonyl group attached to
`
`the parent molecular moiety through an oxygen atom.
`
`The term "alkylsulfanyl," as used herein, refers to an alkyl group attached to the parent
`
`molecular moiety through a sulfur atom.
`
`The term "alkylsulfonyl," as used herein, refers to an alkyl group attached to the parent
`
`molecular moiety through a sulfonyl group.
`
`The term "aryl," as used herein, refers to a phenyl group, or a bicyclic fused ring system
`
`wherein one or both ofthe rings is a phenyl group. Bicyclic fused ring systems consist of a
`
`phenyl group fused to a four- to six-membered aromatic or non-aromatic carbocyclic ring. The
`
`aryl groups of the present disclosure can be attached to the parent molecular moiety through any
`
`substitutable carbon atom in the group. Representative examples of aryl groups include, but are
`
`not limited to, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl. The aryl groups of
`
`the present disclosure are optionally substituted with one, two, three, four, or five substituents
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`independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a
`
`second aryl group, arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl,
`
`heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, -NRxR v,
`
`-(NRxR v)alkyl, oxo, and -P(O)OR2, wherein each R is independently selected from hydrogen
`and alkyl; and wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted
`
`and wherein the second aryl group, the aryl part of the arylalkyl, the aryl part of the
`
`arylcarbonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and the
`
`heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents
`
`independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro.
`
`The term "arylalkenyl, 11 as used herein, refers to an alkenyl group substituted with one,
`
`two, or three aryl groups.
`
`The term "arylalkoxy," as used herein, refers to an aryl group attached to the parent
`
`molecular moiety through an alkoxy group.
`
`The term "arylalkoxyalkyl, 11 as used herein, refers to an alkyl group substituted
`
`with one, two, or three arylalkoxy groups.
`
`The term 11arylalkoxyalkylcarbonyl, 11 as used herein, refers to an
`
`arylalkoxyalkyl group attached to the parent molecular moiety through a carbonyl
`
`group.
`
`The term 11arylalkoxycarbonyl, 11 as used herein, refers to an arylalkoxy group attached to
`
`the parent molecular moiety through a carbonyl group.
`
`The term 11arylalkyl, 11 as used herein, refers to an alkyl group substituted with one, two,
`
`or three aryl groups. The alkyl part of the arylalkyl is further optionally substituted with one or
`
`two additional groups independently selected from alkoxy, alkylcarbonyloxy, halo, haloalkoxy,
`
`haloalkyl, heterocyclyl, hydroxy, and -NRcRd, wherein the heterocyclyl is further optionally
`
`substituted with one or two substituents independently selected from alkoxy, alkyl, unsubstituted
`
`aryl, unsubstituted arylalkoxy, unsubstituted arylalkoxycarbonyl, halo, haloalkoxy, haloalkyl,
`
`hydroxy, and -NRxRv;
`
`The term 11arylalkylcarbonyl, 11 as used herein, refers to an arylalkyl group attached to
`
`the parent molecular moiety through a carbonyl group.
`
`The term 11arylcarbonyl, 11 as used herein, refers to an aryl group attached to the
`
`parent molecular moiety through a carbonyl group.
`
`The term 11aryloxy, 11 as used herein, refers to an aryl group attached to the parent
`
`molecular moiety through an oxyge