(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization _
`International Bureau
`
`'HMWMMWMWMMMWWWWMWMWWW
`
`(43) International Publication Date
`
`28 September 2006 (28.09.2006)
`
`(10) International Publication Number
`
`WO 2006/100310 A1
`
`
`
`(51) International Patent Classification:
`C07D 471/04 (2006.01)
`A6IP 31/00 (2006.01)
`A61K 31/495 (2006.01)
`
`(21) International Application Number:
`PCT/EP2006/061070
`
`(22) International Filing Date:
`
`27 March 2006 (27.03.2006)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`60/665 , 1 51
`60/680,405
`
`25 March 2005 (25.03.2005)
`12 May 2005 (12.05.2005)
`
`US
`US
`
`(71) Applicant (for all designated States except US): TI-
`BOTEC PHARMACEUTICALS LTD [IE/IE]; Little
`Island, Co Cork (IE).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): SIMMEN, Kenneth
`Alan [GB/BE]; Boterbloemenlaan 35, B—3080 Tervuren
`(BE). CHAKRAVARTY, Sarvajit [US/US]; 1888 Mi—
`ramonte Avenue, California, CA 94040 (US). HART,
`Barry [US/US]; 920 Palo Alto Avenue, CA 94301 (US).
`SURLERAUX, Dominique Louis Nestor Ghislain; —.
`LIN, Tse-I; —. LENZ, Oliver; —. RABOISSON, Pierre,
`Jean-Marie, Bernard; —.
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
`CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI,
`GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE,
`KG, KM, KN, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV,
`LY, MA, MD, MG, MK, MN, MW, MX, MZ, NA, NG, NI,
`NO, NZ, OM, PG, PH, PL, PT, RO, RU, SC, SD, SE, SG,
`SK, SL, SM, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US,
`UZ, VC, VN, YU, ZA, ZM, ZW.
`
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI,
`FR, GB, GR, HU, IE, IS, IT, LT, LU, LV, MC, NL, PL, PT,
`RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA,
`GN, GQ, GW, ML, MR, NE, SN, TD, TG).
`
`Declarations under Rule 4.17:
`
`as to applicant’s entitlement to apply for and be granted a
`patent (Rule 4.1 7(ii))
`as to the applicant’s entitlement to claim the priority of the
`earlier application (Rule 4.1 7(iii))
`of inventorship (Rule 4.17(iv))
`
`Published:
`
`— with international search report
`
`(74) Agent: WANTE, Dirk; Tibotec—Virco Comm. VA, Gen—
`eral De Wittelaan L 11b 3, B—2800 Mechelen (BE).
`
`For two—letter codes and other abbreviations, refer to the ”Guid—
`ance Notes on Codes and Abbreviations ” appearing at the begin—
`ning of each regular issue of the PCT Gazette.
`
`(54) Title: HETEROBICYLIC INHIBITORS OF HCV
`
`(57) Abstract: Fused bicyclic pyrimidine compounds having an amide—substi—
`tuted pyridylamine group at C—4 of the pyrimidine of formula (I) ring are useftul
`in the treatment of conditions associated with HCV.
`
`m
`
`O
`
`1
`R \/N
`R2
`
`a
`
`/ N
`l
`\Nu
`
`\N
`féw l \N
`y A\Z
`
`N
`
`Ar
`
`
`
`W02006/100310A1|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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`WO 2006/100310
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`PCT/EP2006/061070
`
`HETEROBICYLIC INHIBITORS OF HVC
`
`Field of the Invention
`
`The invention relates to methods of treating disorders associated with hepatitis C
`
`infection. More specifically, it concerns certain fused bicyclic pyrimidine compounds
`
`5
`
`that have an amide-substituted 4-pyridylamine group on the pyrimidine ring that are
`
`useful in these methods.
`
`Background Art
`
`Transforming grth factor-beta (TGFB) denotes a superfamily of proteins that
`
`includes, for example, TGFBl, TGFBZ, and TGFBB, which are pleiotropic modulators
`
`10
`
`of cell grth and differentiation, embryonic and bone development, extracellular
`
`matrix formation, hematopoiesis, and immune and inflammatory responses (Roberts
`
`and Spom Handbook of Experimental Pharmacology (1990) 95:419-58; Massague, et
`
`al., Ann. Rev. Cell. Biol. (1990) 6:597-646). Other members of this superfamily
`
`include activin, inhibin, bone morphogenic protein, and Mullerian inhibiting substance.
`
`15
`
`The members of the TGFB family initiate intracellular signaling pathways leading
`
`ultimately to the expression of genes that regulate the cell cycle, control proliferative
`
`responses, or relate to extracellular matrix proteins that mediate outside-in cell
`
`signaling, cell adhesion, migration and intercellular communication.
`
`Therefore, inhibitors of the TGFB intracellular signaling pathway are useful treatments
`
`20
`
`for fibroproliferative diseases. Specifically, fibroproliferative diseases include kidney
`
`disorders associated with unregulated TGFB activity and excessive fibrosis including
`
`glomerulonephritis (GN), such as mesangial proliferative GN, immune GN, and
`
`crescentic GN. Other renal conditions include diabetic nephropathy, renal interstitial
`
`fibrosis, renal fibrosis in transplant patients receiving cyclosporin, and HIV-associated
`
`25
`
`nephropathy. Collagen vascular disorders include progressive systemic sclerosis,
`
`polymyositis, scleroderma, dermatomyositis, eosinophilic fascitis, morphea, or those
`
`associated with the occurrence of Raynaud’s syndrome. Lung fibroses resulting from
`
`excessive TGFB activity include adult respiratory distress syndrome, chronic
`
`obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, and interstitial
`
`30
`
`pulmonary fibrosis often associated with autoimmune disorders, such as systemic lupus
`
`erythematosus and scleroderma, chemical contact, or allergies. Another autoimmune
`
`disorder associated with fibroproliferative characteristics is rheumatoid arthritis.
`
`Fibroproliferative conditions can be associated with surgical eye procedures. Such
`
`procedures include retinal reattachment surgery accompanying proliferative
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`-2-
`
`vitreoretinopathy, cataract extraction with intraocular lens implantation, and post
`
`glaucoma drainage surgery.
`
`In addition, members of the TGFB family are associated with the progression of various
`
`cancers. M.P. de Caestecker, E. Piek, and AB. Roberts, J. National Cancer Inst.,
`
`5
`
`92(17), 1388-1402 (2000). For example, it has been found that TGFBl inhibits the
`
`formation of tumors, probably by inhibition of the proliferation of nontransformed
`
`cells. However, once a tumor forms, TGFBl promotes the grth of the tumor. N.
`
`Dumont and CL. Arteaga, Breast Cancer Res., Vol. 2, 125-132 (2000). Thus
`
`inhibitors of the TGFB pathway are also useful for the treatment of many forms of
`
`10
`
`cancer, such as lung cancer, skin cancer, and colorectal cancer. In particular, they are
`
`useful to treat cancers of the breast, pancreas, and brain, including glioma.
`
`The compounds of the invention herein are derivatives of pyrimidine having an
`
`additional ring fused onto the pyrimidine. PCT publication W001/47921 describes
`
`pyrimidine and triazine compounds that are inhibitors of kinase activities associated
`
`15
`
`with various inflammatory conditions, as opposed to the treatment of fibroproliferative
`
`disorders described herein. The above mentioned PCT publication describes the use of
`
`the disclosed compounds only for treatment of the inflammatory aspects of certain
`
`autoimmune diseases. Further, the compounds described differ from those described
`
`herein by virtue of the substitutions required on the pyrimidine nucleus; among other
`
`20
`
`distinctions, the compounds disclosed in the PCT publication do not include phenyl
`
`bound directly to the pyrimidine ring.
`
`Related compounds, some of which have the 4-pyridylamine group at C-4 on the
`
`pyrimidine, are disclosed in two published U.S. Patent Applications, publications no.
`
`US 2004-0132159-A1 and US 2005/0004143-A1. Those applications, however,
`
`25
`
`disclose a preference for certain electron-donating substituents on the pyridine ring of
`
`the 4-pyridylamine group, including alkyl, amine and alkoxy groups, and do not
`
`disclose a preferred position for substituents. The present invention provides
`
`compounds specifically including a 4-pyridylamine containing an essential
`
`carboxamide group attached at position 3 on the pyridine ring.
`
`30
`
`U.S. Patent No. 6,476,031 also discloses compounds containing a quinazoline ring,
`
`which cam be a fused bicyclic derivative of a pyrimidine; it includes compounds where
`
`the quinazoline ring is linked to an aryl group at C-4 of the quinazoline. The
`
`compounds are reported to act at the TGFB site, and the compounds can include a 4-
`
`pyridylamine group as the aryl group linked to the quinazoline at C-4. However, that
`
`35
`
`patent only discloses that a quinazoline compound linked to a pyridyl that is
`
`unsubstituted:
`
`it does not disclose any compounds with a 4-pyridyl that includes an
`
`amide substituent such as the ones at the 3-position of the 4-pyridyl group in the
`
`compounds of the present invention.
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`WO 2006/100310
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`PCT/EP2006/061070
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`Disclosure of the Invention
`
`The invention is directed to methods, compositions, and novel compounds useful in
`
`treating conditions that are characterized by excessive TGFB activity. These conditions
`
`are, most prominently, fibroproliferative diseases, such as conditions associated with
`
`hepatitis C virus infection, and certain cancers. However, the conditions for which the
`
`compounds and methods are useful include any medical condition characterized by an
`
`undesirably high level of TGFB activity. The compounds of the invention have been
`
`found to inhibit TGFB and are thus useful in treating diseases mediated by the activity
`
`of this family of factors. The compounds of the invention are of the formula (I):
`
`/
`
`R2
`
`/ N
`
`10
`
`15
`
`20
`
`or a pharmaceutically acceptable salt or prodrug thereof, wherein:
`R1 represents H or OH, or an optionally substituted alkyl, alkoxy, heteroalkyl, amino,
`
`acyl, heteroacyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl group;
`R2 represents H or optionally substituted alkyl, heteroalkyl, acyl, heteroacyl, aryl,
`
`heteroaryl, arylalkyl, or heteroarylalkyl;
`
`B represents H or a C1-C8 acyl group that may be substituted or unsubstituted;
`
`each of W, X, Y and Z is independently C-H, C-J or N, provided that not more than
`
`two of W, X, Y and Z represent N;
`
`Ar represents an optionally substituted phenyl ring;
`
`each J independently represents halo, OH, SH, or optionally substituted alkyl, alkenyl,
`
`alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, acyl, heteroacyl, or
`heteroaryl, or NR1R2,N02, CN, CF3, COOR, CONRz, or 802R, wherein each R
`
`is independently H or an optionally substituted alkyl, alkenyl, alkynyl, acyl, aryl,
`
`heteroalkyl, heteroalkenyl, heteroalkynyl, heteroacyl or heteroaryl group,
`R1 and R2 of any NRIR2 can cyclize to form a 3-8 membered ring that can be saturated,
`
`25
`
`unsaturated, or aromatic, and that contains 1-3 heteroatoms selected from N, O
`
`and S as ring members, and is optionally substituted; and
`
`n is 0-3;
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`
`-4-
`
`0
`
`HM
`2
`
`\
`
`N
`
`/ N
`H\N \ I
`(N I
`\N F
`
`/
`
`N
`
`provided the compound is not 4-[2-(5-chloro-2-fluorophenyl)-pteridin-4-ylamino]-
`
`nicotinamide:
`
`Cl
`
`The invention is also directed to pharmaceutical compositions containing one or more
`
`compounds of formula (I) or their pharmaceutically acceptable salts, or prodrug forms
`
`thereof, as active ingredients and to methods of treating conditions characterized by an
`
`excessive level of TGFB activity, particularly fibroproliferative conditions, using
`
`compounds of formula (I) or compositions containing such compounds.
`
`Modes of Cming Out the Invention
`
`10
`
`15
`
`20
`
`The compounds of formula (I) are useful in treating conditions which are characterized
`
`by an excessive level of TGFB activity. As used herein, “TGFB” refers to the
`
`superfamily which includes TGFBl, TGFBZ, and TGFB3 as well as other members of
`
`the family known or which become known in the art such as inhibin, bone morphogenic
`
`protein, and the like. One or more of these family members may be more active than
`
`desired in the conditions which the compounds of the invention are designed to
`
`ameliorate or prevent.
`
`Conditions “characterized by an excessive level of TGFB activity” include those
`
`wherein TGFB synthesis is stimulated so that TGFB is present in enhanced amount, and
`
`those wherein TGFB latent protein is undesirably activated or converted to active TGFB
`
`protein, and those wherein TGFB receptors are upregulated, and those wherein the
`
`TGFB protein shows enhanced binding to cells or extracellular matrix in the location of
`
`the disease. Thus, in each case, “excessive level of TGFB activity” refers to any
`
`condition wherein the activity of TGFB is undesirably high, regardless of the cause and
`
`regardless of whether the actual amount or activity of TGFB present is within a
`
`25
`
`‘normal’ range.
`
`Compounds of the present invention moreover show antiviral activity against the
`
`hepatitis C virus.
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`The Invention Compounds
`
`The compounds useful in the invention are fused bicyclic derivatives of pyrimidine
`
`containing mandatory substituents at positions corresponding to the 2- and 4-positions
`
`of the pyrimidine ring. The bicyclic pyrimidines further have another aromatic ring
`
`5
`
`fused onto the pyrimidine at positions 5 and 6 of the pyrimidine ring. They further
`
`include a 4-pyridylamine group at position 4 of the pyrimidine ring and a phenyl group
`
`at position 2 of the pyrimidine ring. Optionally, the 4-pyridyl group may be a pyridine-
`
`N—oxide. The compounds further include an amide group that is attached at position 3
`
`of the pyridyl ring through its carbonyl carbon. Other substituents may also be
`
`10
`
`included on the pyrimidine, pyridine and phenyl rings and on the aromatic ring fursed
`
`onto the pyrimidine.
`
`As used herein, the terms “alkyl,” “alkenyl” and “alkynyl” include straight-chain,
`
`branched-chain and cyclic monovalent hydrocarbyl radicals, and combinations of these,
`
`which contain only C and H when they are unsubstituted. Examples include methyl,
`
`15
`
`ethyl, isobutyl, cyclohexyl, cyclopentylethyl, 2-propenyl, 3-butynyl, and the like. The
`
`total number of carbon atoms in each such group is sometimes described herein, e.g.,
`
`either as 1-10C or as C1-C10 when the group can contain up to ten carbon atoms.
`
`When heteroatoms (N, O and S typically) are allowed to replace carbon atoms as in
`
`heteroalkyl groups, for example, the numbers describing the group represent the sum of
`
`20
`
`the number of carbon atoms in the group plus the number of such heteroatoms that are
`
`included as replacements for carbon atoms.
`
`Typically, the alkyl, alkenyl and alkynyl substituents of the invention contain 1-10C
`
`(alkyl) or 2-10C (alkenyl or alkynyl). Preferably they contain 1-8C (alkyl) or 2-8C
`
`(alkenyl or alkynyl). Sometimes they contain 1-4C (alkyl) or 2-4C (alkenyl or
`
`25
`
`alkynyl). A single group can include more than one type of multiple bond, or more
`
`than one multiple bond; such groups are included within the definition of the term
`
`“alkenyl” when they contain at least one carbon-carbon double bond, and are included
`
`within the term “alkynyl” when they contain at least one carbon-carbon triple bond.
`
`Alkyl, alkenyl and alkynyl groups are often substituted to the extent that such
`
`30
`
`substitution makes sense chemically. Typical substituents include, but are not limited
`
`to, halo, =0, =N-CN, =N-OR, =NR, OR, NR2, SR, 802R, SOzNRz, NRSOzR,
`
`NRCONR2, NRCOOR, NRCOR, CN, COOR, CONR2, OOCR, COR, and N02,
`
`wherein each R is independently H, C1-C8 alkyl, C2-C8 heteroalkyl, C1-C8 acyl,
`
`C2-C8 heteroacyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8
`
`35
`
`heteroalkynyl, C6-C10 aryl, or C5-C10 heteroaryl, and each R is optionally substituted
`
`with halo, =O, =N-CN, =N-OR’, =NR’, OR’, NR’2, SR’, SOzR’, SOzNR’z, NR’SOzR’,
`
`NR’CONR’2, NR’COOR’, NR’COR’, CN, COOR’, CONR’2, OOCR’, COR’, and
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`-6-
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`N02, wherein each R’ is independently H, C1-C8 alkyl, C2-C8 heteroalkyl, C1-C8
`
`acyl, C2-C8 heteroacyl, C6-C10 aryl or C5-C10 heteroaryl.
`
`“Heteroalkyl”, “heteroalkenyl”, and “heteroalkynyl” are defined similarly to the
`
`corresponding hydrocarbyl (alkyl, alkenyl and alkynyl) groups, but the ‘hetero’ terms
`
`5
`
`refer to groups that contain 1-3 0, S or N heteroatoms or combinations thereof within
`
`the backbone residue; thus at least one carbon atom of a corresponding alkyl, alkenyl,
`
`or alkynyl group is replaced by one of the specified heteroatoms to form a heteroalkyl,
`
`heteroalkenyl, or heteroalkynyl group. The typical and preferred sizes for heteroforms
`
`of alkyl, alkenyl and alkynyl groups are the same as for the corresponding hydrocarbyl
`
`10
`
`groups, and the substituents that may be present on the heteroforms are the same as
`
`those described above for the hydrocarbyl groups. For reasons of chemical stability, it
`
`is also understood that, unless otherwise specified, such groups do not include more
`
`than two contiguous heteroatoms except where an oxo group is present on N or S as in
`
`a nitro or sulfonyl group.
`
`15 While “alkyl” as used herein includes cycloalkyl and cycloalkylalkyl groups, the term
`
`“cycloalky ” may be used herein to describe a carbocyclic non-aromatic group that is
`
`typically connected via a ring carbon atom, and “cycloalkylalkyl” may be used to
`
`describe a carbocyclic non-aromatic group that is connected to the molecule through an
`
`alkyl linker. Similarly, “heterocyclyl” may be used to describe a non-aromatic cyclic
`
`20
`
`group that contains at least one heteroatom as a ring member and that is typically
`
`connected to the molecule via a ring atom, which may be C or N; and
`
`“heterocyclylalkyl” may be used to describe such a group that is connected to another
`
`molecule through a linker. The sizes and substituents that are suitable for the
`
`cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl groups are the same as
`
`25
`
`those described above for alkyl groups As used herein, these terms also include rings
`
`that contain a double bond or two, as long as the ring is not aromatic.
`
`As used herein, “acyl” encompasses groups comprising an alkyl, alkenyl, alkynyl, aryl
`
`or arylalkyl radical attached at one of the two available valence positions of a carbonyl
`
`carbon atom, and heteroacyl refers to the corresponding groups wherein at least one
`
`30
`
`carbon other than the carbonyl carbon has been replaced by a heteroatom chosen from
`
`N, O and S. Thus heteroacyl includes, for example, -C(=O)OR and -C(=O)NR2 as well
`
`as —C(=O)-heteroaryl.
`
`Acyl and heteroacyl groups are bonded to any group or molecule to which they are
`
`attached through the open valence of the carbonyl carbon atom. Typically, they are
`
`35
`
`C1-C8 acyl groups, which include formyl, acetyl, pivaloyl, and benzoyl, and C2-C8
`
`heteroacyl groups, which include methoxyacetyl, ethoxycarbonyl, and 4-pyridinoyl.
`
`The hydrocarbyl groups, aryl groups, and heteroforms of such groups that comprise an
`
`acyl or heteroacyl group can be substituted with the substituents described herein as
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`generally suitable substituents for each of the corresponding components of the acyl or
`
`heteroacyl group.
`
`“Aromatic” moiety or “aryl” moiety refers to a monocyclic or fused bicyclic moiety
`
`having the well-known characteristics of aromaticity; examples include phenyl and
`
`5
`
`naphthyl. Similarly, “heteroaromatic” and “heteroaryl” refer to such monocyclic or
`
`fused bicyclic ring systems which contain as ring members one or more heteroatoms
`
`selected from O, S and N. The inclusion of a heteroatom permits aromaticity in
`
`5-membered rings as well as 6-membered rings. Typical heteroaromatic systems
`
`include monocyclic C5-C6 aromatic groups such as pyridyl, pyrimidyl, pyrazinyl,
`
`10
`
`thienyl, furanyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, and imidazolyl and the fused
`
`bicyclic moieties formed by fusing one of these monocyclic groups with a phenyl ring
`
`or with any of the heteroaromatic monocyclic groups to form a C8-C10 bicyclic group
`
`such as indolyl, benzirnidazolyl, indazolyl, benzotriazolyl, isoquinolyl, quinolyl,
`
`benzothiazolyl, benzofuranyl, pyrazolopyridyl, quinazolinyl, quinoxalinyl, cinnolinyl,
`
`15
`
`and the like. Any monocyclic or fused ring bicyclic system which has the
`
`characteristics of aromaticity in terms of electron distribution throughout the ring
`
`system is included in this definition. It also includes bicyclic groups where at least the
`
`ring which is directly attached to the remainder of the molecule has the characteristics
`
`of aromaticity. Typically, the ring systems contain 5-12 ring member atoms.
`
`20
`
`Preferably the monocyclic heteroaryls contain 5-6 ring members, and the bicyclic
`
`heteroaryls contain 8-10 ring members.
`
`Aryl and heteroaryl moieties may be substituted with a variety of substituents including
`
`halo, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, OR, NR2, SR, 802R, SOzNRz,
`
`NRSOzR, NRCONRz, NRCOOR, NRCOR, CN, COOR, CONR2, OOCR, COR, and
`
`25
`
`N02, wherein each R is independently H, C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8
`
`alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C6-C10 aryl,
`
`C5-C10 heteroaryl, C7-C12 arylalkyl, or C6-C12 heteroarylalkyl, and each R is
`
`optionally substituted as described above for alkyl groups.
`
`Similarly, “arylalkyl” and “heteroarylalkyl” refer to aromatic and heteroaromatic ring
`
`30
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`systems which are bonded to their attachment point through a linking group such as an
`
`alkylene, including substituted or unsubstituted, saturated or unsaturated, cyclic or
`
`acyclic linkers. Typically the linker is C1-C8 alkyl or a hetero form thereof. These
`
`linkers may also include a carbonyl group, thus making them able to provide
`
`substituents as an acyl or heteroacyl moiety. An aryl or heteroaryl ring in an arylalkyl
`
`35
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`or heteroarylalkyl group may be substituted with the same substituents described above
`
`for aryl groups. Preferably, an arylalkyl group includes a phenyl ring optionally
`
`substituted with the groups defined above for aryl groups and a C1-C4 alkylene that is
`
`unsubstituted or is substituted with one or two C1-C4 alkyl groups or heteroalkyl
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`groups, where the alkyl or heteroalkyl groups can optionally cyclize to form a ring such
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`as cyclopropane, dioxolane, or oxacyclopentane. Similarly, a heteroarylalkyl group
`
`preferably includes a C5-C6 monocyclic heteroaryl group that is optionally substituted
`
`with the groups described above as substituents typical on aryl groups and a C1-C4
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`5
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`alkylene that is unsubstituted or is substituted with one or two C1-C4 alkyl groups or
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`heteroalkyl groups, or it includes an optionally substituted phenyl ring or C5-C6
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`monocyclic heteroaryl and a C1-C4 heteroalkylene that is unsubstituted or is
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`substituted with one or two C1-C4 alkyl or heteroalkyl groups, where the alkyl or
`
`heteroalkyl groups can optionally cyclize to form a ring such as cyclopropane,
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`10
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`dioxolane, or oxacyclopentane.
`
`Where an arylalkyl or heteroarylalkyl group is described as optionally substituted, the
`
`substituents may be on either the alkyl or heteroalkyl portion or on the aryl or
`
`heteroaryl portion of the group. The substituents optionally present on the alkyl or
`
`heteroalkyl portion are the same as those described above for alkyl groups generally;
`
`15
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`the substituents optionally present on the aryl or heteroaryl portion are the same as
`
`those described above for aryl groups generally.
`
`“Arylalkyl” groups as used herein are hydrocarbyl groups if they are unsubstituted, and
`
`are described by the total number of carbon atoms in the ring and alkylene or similar
`
`linker. Thus a benzyl group is a C7-arylalkyl group, and phenylethyl is a C8-arylalkyl.
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`20
`
`“Heteroarylalkyl” as described above refers to a moiety comprising an aryl group that
`
`is attached through a linking group, and differs from “arylalkyl” in that at least one ring
`
`atom of the aryl moiety or one atom in the linking group is a heteroatom selected from
`
`N, O and S. The heteroarylalkyl groups are described herein according to the total
`
`number of atoms in the ring and linker combined, and they include aryl groups linked
`
`25
`
`through a heteroalkyl linker; heteroaryl groups linked through a hydrocarbyl linker
`
`such as an alkylene; and heteroaryl groups linked through a heteroalkyl linker. Thus,
`
`for example, C7-heteroarylalkyl would include pyridylmethyl, phenoxy, and
`
`N—pyrrolylmethoxy.
`
`“Alkylene” as used herein refers to a divalent hydrocarbyl group; because it is divalent,
`
`30
`
`it can link two other groups together. Typically it refers to —(CH2)n- where n is 1-8 and
`
`preferably 11 is 1-4, though where specified, an alkylene can also be substituted by other
`
`groups, and can be of other lengths, and the open valences need not be at opposite ends
`
`of a chain. Thus —CH(Me)- and —C(Me)2- may also be referred to as alkylenes, as can a
`
`cyclic group such as cyclopropan-1,1-diyl. Where an alkylene group is substituted, the
`
`35
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`substituents include those typically present on alkyl groups as described herein.
`
`In general, any alkyl, alkenyl, alkynyl, acyl, or aryl or arylalkyl group or any
`
`heteroform of one of these groups that is contained in a substituent may itself
`
`optionally be substituted by additional substituents. The nature of these substituents is
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`similar to those recited with regard to the primary substituents themselves if the
`
`substituents are not otherwise described. Thus, where an embodiment of, for example,
`
`R7 is alkyl, this alkyl may optionally be substituted by the remaining substituents listed
`
`as embodiments for R7 where this makes chemical sense, and where this does not
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`5
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`undermine the size limit provided for the alkyl per se; e.g., alkyl substituted by alkyl or
`
`by alkenyl would simply extend the upper limit of carbon atoms for these
`
`embodiments, and is not included. However, alkyl substituted by aryl, amino, alkoxy,
`
`=0, and the like would be included within the scope of the invention, and the atoms of
`
`these substituent groups are not counted in the number used to describe the alkyl,
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`10
`
`alkenyl, etc. group that is being described. Where no number of substituents is
`
`specified, each such alkyl, alkenyl, alkynyl, acyl, or aryl group may be substituted with
`
`a number of substituents according to its available valences; in particular, any of these
`
`groups may be substituted with fluorine atoms at any or all of its available valences, for
`
`example.
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`15
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`“Heteroform” as used herein refers to a derivative of a group such as an alkyl, aryl, or
`
`acyl, wherein at least one carbon atom of the designated carbocyclic group has been
`
`replaced by a heteroatom selected from N, O and S. Thus the heteroforms of alkyl,
`
`alkenyl, alkynyl, acyl, aryl, and arylalkyl are heteroalkyl, heteroalkenyl, heteroalkynyl,
`
`heteroacyl, heteroaryl, and heteroarylalkyl, respectively. It is understood that no more
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`20
`
`than two N, O or S atoms are ordinarily connected sequentially, except where an oxo
`
`group is attached to N or S to form a nitro or sulfonyl group.
`
`“Optionally substituted” as used herein indicates that the particular group or groups
`
`being described may have no non-hydrogen substituents, or the group or groups may
`
`have one or more non-hydrogen substituents. If not otherwise specified, the total
`
`25
`
`number of such substituents that may be present is equal to the number of H atoms
`
`present on the unsubstituted form of the group being described. Where an optional
`
`substituent is attached via a double bond, such as a carbonyl oxygen (=0), the group
`
`takes up two available valences, so the total number of substituents that may be
`
`included is reduced accordingly.
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`
`“Halo” as used herein includes fluoro, chloro, bromo and iodo. Fluoro and chloro are
`
`ofien preferred.
`
`“Amino” as used herein refers to NH2, but where an amino is described as “substituted”
`
`or “optionally substituted”, the term includes NR’R” wherein each R’ and R” is
`
`independently H, or is an alkyl, alkenyl, alkynyl, acyl, aryl, or arylalkyl group or a
`
`35
`
`heteroform of one of these groups, and each of the alkyl, alkenyl, alkynyl, acyl, aryl, or
`
`arylalkyl groups or heteroforms of one of these groups is optionally substituted with the
`
`substituents described herein as suitable for the corresponding group. The term also
`
`includes forms wherein R’ and R” are linked together to form a 3-8 membered ring
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`which may be saturated, unsaturated or aromatic and which contains 1-3 heteroatoms
`
`independently selected from N, O and S as ring members, and which is optionally
`
`substituted with the substituents described as suitable for alkyl groups or, if NR’R” is
`
`an aromatic group, it is optionally substituted with the substituents described as typical
`
`5
`
`for heteroaryl groups.
`
`The compounds of the invention include a pyrimidine ring, and another six-membered
`
`aromatic ring is fused onto the C5 and C6 positions of the pyrimidine. The C2 position
`
`of the pyrimidine is occupied by an optionally substituted phenyl group referred to in
`
`formula (I) as Ar. The C4 position of the pyrimidine is linked by a nitrogen linker to
`
`10
`
`the C-4 carbon of a pyridine ring. The pyridine is substituted by an amide group at
`
`position 3 of the pyridyl ring, and may also be oxidized to its N-oxide. It is optionally
`
`substituted by up to three substituents J. In preferred embodiments, the pyridine is not
`
`oxidized (m=0).
`
`Substituents J may be present on the pyridine ring in formula (I) at any or all of the
`
`15
`
`positions not otherwise expressly occupied. Thus 11 in formula (I) can be 0-3. In many
`
`preferred embodiments, n is 0; in some embodiments n is 1 or 2.
`
`Typical embodiments of J in formula (I) include the substituents described herein as
`
`substituents for an aryl group generally. Preferred embodiments for J include CF3 and
`
`CN, as well as halo, C1-C4 alkyl, OR, SR, and NR2, wherein each R is independently
`
`20
`
`H or C1-C4 alkyl or C1-C4 heteroalkyl, where each alkyl or heteroalkyl is optionally
`
`substituted with the substituents described above for alkyl groups, and where two R
`
`groups on N can optionally cyclize to form a 3-8 membered ring containing one or two
`
`heteroatoms selected from N, O and S as ring members. Halo, methyl, methoxy and
`
`CF3 are often preferred for each J present.
`
`25
`
`Ar represents phenyl which may be unsubstituted, but is typically substituted with at
`
`least one and preferably two or more substituents selected from the group consisting of
`
`halo, C1-C4 alkyl, CN, CF3, OR, N02, COOR, CONR2, 802R, NR2, and C1-C8 acyl,
`
`where each R is independently H, C1-C4 alkyl, C1-C8 acyl, or C2-C8 heteroacyl. In
`
`certain embodiments, Ar is substituted with one or two substituents.
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`30
`
`The substituents on Ar may be at any available position on the phenyl ring, but
`
`frequently one substituent occupies a ring position adjacent to the atom through which
`
`Ar is linked to the pyrimidine ring. For convenience, the position of the phenyl ring
`
`that is attached to the pyrimidine ring in formula (I) is referred to as position 1, and
`
`other positions on the phenyl ring are numbered relative to that position. Preferred
`
`35
`
`embodiments often have Ar as a phenyl ring that is substituted by at least one halo
`
`substituent, which may be at position 2 of that phenyl. A preferred embodiment
`
`includes a phenyl ring substituted with two groups, which may both be halo. 2,5-dihalo
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`phenyl is sometimes specifically preferred, particularly where each halo is F or Cl; and
`
`2-fluoro-5-chlorophenyl is especially preferred.
`The carboxamide on the pyridine ring in formula (1) attaches substituents R1 and R2 to
`
`the pyridyl ring specifically at the 3-position. The selection of R1 and R2 is important
`
`5
`
`f