(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`19 January 2012 (19.01.2012)
`
`PCT
`
`1111111111111111 IIIIII IIIII 111111111111111 II Ill 11111111111111111111 IIIII IIII IIIIIII IIII 11111111
`
`(10) International Publication Number
`WO 2012/009678 Al
`
`(51) International Patent Classification:
`C07C 237/22 (2006.01)
`A61K 31/40 (2006.01)
`C07C 271/22 (2006.01)
`A61K 31/415 (2006.01)
`A61K 31/4164 (2006.01)
`C07C 271/44 (2006.01)
`A61P 43/00 (2006.01)
`A61K 31/4192 (2006.01)
`A61K 31/16 (2006.01)
`A61K 31/426 (2006.01)
`A61K 31/18 (2006.01)
`A61K 31/435 (2006.01)
`A61K 31/357 (2006.01)
`A61K 31/495 (2006.01)
`A61K 31/381 (2006.01)
`
`(21) International Application Number:
`PCT/US20l l/044254
`
`(22) International Filing Date:
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`15 July 201 l (15.07.2011)
`
`English
`
`English
`
`(30) Priority Data:
`61/365,072
`
`16 July20l0 (16.07.2010)
`
`us
`(71) Applicant (for all designated States except US): AGIOS
`PHARMACEUTICALS, INC. [US/US]; 38 Sidney
`Street, Cambridge, MA 02139 (US).
`
`(72) Inventors; and
`(for US only): POPOVICI(cid:173)
`(75) Inventors/Applicants
`MULLER, Janeta [US/US]; 5 Beaver Brook Road,
`Waltham, MA 02452 (US). SALITURO, Francesco, G.
`[US/US]; 25 Baker Drive, Marlbourough, MA Ol 752
`(US). SAUNDERS, Jeffrey, O. [US/US]; 117 Seymour
`Street, Concord, MA 01742 (US). TRAVINS, Jeremey
`[US/US]; 380 Township Line Road, Downington, PA
`
`-;;;;;;;;;;;;;;
`;;;;;;;;;;;;;; ---
`
`19335 (US). YAN, Shunqi [US/US]; 55 Stepping Stone,
`Irvine, CA 92603 (US).
`
`(74) Agent: McCARTY, Catherine, M.; Landon & Anastasi,
`LLP, One Main Street, Eleventh Floor, Cambridge, MA
`02142 (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, VG, 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,
`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, RS, 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))
`
`-;
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`;;;;;;;;;;;;; -
`-;;;;;;;;;;;;;;
`;;;;;;;;;;;;;; -
`,-.-1 <
`'° O'I
`0
`~
`M
`,-.-1
`0
`M
`0
`(57) Abstract: Provided are methods of treating a cancer characterized by the presence of a mutant allele of IDH I comprising ad(cid:173)
`~
`ministering to a subject in need thereof a compound described here.
`
`;;;;;;;;;;;;;;
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`;;;;;;;;;;;;;;
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`Q0
`t---
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`(54) Title: THERAPEUTICALLY ACTIVE COMPOSITIONS AND THEIR METHOD OF USE
`
`Rigel Exhibit 1010
`Page 1 of 254
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`WO 2012/009678
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`PCT/0S2011/044254
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`THERAPEUTICALLY ACTIVE COMPOSITIONS AND THEIR METHODS OF USE
`
`BACKGROUND OF INVENTION
`
`Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitrate to
`
`2-oxoglutarate (i.e., a-ketoglutarate). These enzymes belong to two distinct subclasses, one of
`
`which utilizes NAD( +) as the electron acceptor and the other NADP( + ). Five isocitrate
`
`dehydrogenases have been reported: three NAD( + )-dependent isocitrate dehydrogenases, which
`
`localize to the mitochondrial matrix, and two NADP(+)-dependent isocitrate dehydrogenases,
`
`one of which is mitochondrial and the other predominantly cytosolic. Each NADP( + )-dependent
`
`isozyme is a homodimer.
`
`IDHl (isocitrate dehydrogenase 1 (NADP+), cytosolic) is also known as IDH; IDP;
`
`IDCD; IDPC or PICD. The protein encoded by this gene is the NADP( + )-dependent isocitrate
`
`dehydrogenase found in the cytoplasm and peroxisomes. It contains the PTS-1 peroxisomal
`
`targeting signal sequence. The presence of this enzyme in peroxisomes suggests roles in the
`
`regeneration of NADPH for intraperoxisomal reductions, such as the conversion of 2, 4-dienoyl(cid:173)
`
`CoAs to 3-enoyl-CoAs, as well as in peroxisomal reactions that consume 2-oxoglutarate, namely
`
`the alpha-hydroxylation of phytanic acid. The cytoplasmic enzyme serves a significant role in
`
`cytoplasmic NADPH production.
`
`The human IDHl gene encodes a protein of 414 amino acids. The nucleotide and amino
`
`acid sequences for human IDHl can be found as GenBank entries NM_005896.2 and
`
`NP _005887.2 respectively. The nucleotide and amino acid sequences for IDHl are also
`
`described in, e.g., Nekrutenko et al., Mol. Biol. Evol. 15: 1674-1684(1998); Geisbrecht et al., J.
`
`Biol. Chem. 274:30527-30533(1999); Wiemann et al., Genome Res. 11:422-435(2001); The
`
`MGC Project Team, Genome Res. 14:2121-2127(2004); Lubec et al., Submitted (DEC-2008) to
`
`UniProtKB; Kullmann et al., Submitted (JUN-1996) to the EMBL/GenBank/DDBJ databases;
`
`and Sjoeblom et al., Science 314:268-274(2006).
`
`Non-mutant, e.g., wild type, IDHl catalyzes the oxidative decarboxylation of isocitrate to
`
`a-ketoglutarate thereby reducing NAD+ (NADP+) to NADP (NADPH), e.g., in the forward
`
`reaction:
`
`Isocitrate + NAD+ (NADP+) ~a-KG+ CO2 + NADH (NADPH) + H+.
`
`1
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`Rigel Exhibit 1010
`Page 2 of 254
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`WO 2012/009678
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`PCT/0S2011/044254
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`It has been discovered that mutations of IDHl present in certain cancer cells result in a
`
`new ability of the enzyme to catalyze the NAPH-dependent reduction of a-ketoglutarate to R(-)-
`
`2-hydroxyglutarate (2HG). The production of 2HG is believed to contribute to the formation and
`
`progression of cancer (Dang, Let al, Nature 2009, 462:739-44).
`
`The inhibition of mutant IDHl and its neoactivity is therefore a potential therapeutic
`
`treatment for cancer. Accordingly, there is an ongoing need for inhibitors of IDHl mutants
`
`having alpha hydroxyl neoactivity.
`
`SUMMARY OF INVENTION
`
`Described herein are methods of treating a cancer characterized by the presence of a
`
`mutant allele of IDHl. The methods comprise the step of administering to a subject in need
`
`thereof a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein:
`Rs R2 Rg V
`
`R,, N 0 ~ ,1,_R.
`
`R3
`V and Ware independently =0 or CF3 ;
`R1 is selected from C2-C6 alkyl, -(C 1-C3 alkylene)-O-(C 1-C3 alkyl), carbocyclyl, -(C 1-C2
`alkylene)-(carbocyclyl), aryl, -(C 1-C2 alkylene)-(aryl), -(C 1-C2 alkylene)-(heteroaryl), and -(C 1-
`C2 alkylene)-(heterocyclyl);
`R2 is selected from C4-C8 alkyl, carbocyclyl, aryl, heterocyclyl, heteroaryl, -(C 1-C4
`alkylene)-(aryl), and -(C 1-C4 alkylene)-(heteroaryl);
`R3 is selected from C2-C6 alkyl optionally substituted with =0 or -OH; C2-C6 alkenyl;
`-(C 1-C3 alkylene)-O-(C 1-C3 alkyl); carbocyclyl; aryl, heterocyclyl, heteroaryl, -(C 1-C2 alkylene)(cid:173)
`(carbocyclyl), -(C 1-C2 alkylene)-(aryl), -(C 1-C2 alkylene)-(heterocyclyl), and -(C 1-C2 alkylene)(cid:173)
`(heteroaryl);
`R4 is selected from -CF3 , -CH2-O-CH3 and-Rs-R6-R7
`Rs is selected from a bond; C 1-C3 straight or branched alkyl wherein one methylene unit
`in the alkyl of Rs is optionally replaced with -0-, -S- or -S(O); and CrC 3 alkenyl or alkynyl;
`R6 is selected from a bond, -NH-C(O)-, -C(O)-NH-, -NH-S(O) 1_2-, -S(O) 1_2-NH-, and
`tetrazolyl;
`
`W
`
`formula I
`
`, wherein:
`
`2
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`Rigel Exhibit 1010
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`R7 is a carbocyclyl, aryl, heterocyclyl, or heteroaryl;
`R8 is selected from hydrogen and C 1-C4 alkyl; or R8 and R1 are taken together with the
`nitrogen atom to form a 5-12 membered heterocyclyl; and
`R9 is selected from hydrogen and C 1-C4 alkyl; or R9 and R2 are taken together to form a
`6-12 membered carbocyclyl or a 5-12 membered heterocyclyl; or
`
`wherein any carbocyclyl, aryl, heterocyclyl or heteroaryl is optionally substituted with
`
`one or more substituents.
`
`The compound of formula I inhibits mutant IDHl, particularly mutant IDHl having alpha
`
`hydroxyl neoactivity. Also described herein are pharmaceutical compositions comprising a
`
`compound of formula I.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`This invention is not limited in its application to the details of construction and the
`
`arrangement of components set forth in the following description or illustrated in the drawings.
`
`The invention is capable of other embodiments and of being practiced or of being carried out in
`
`various ways. Also, the phraseology and terminology used herein is for the purpose of
`
`description and should not be regarded as limiting. The use of "including," "comprising," or
`
`"having," "containing", "involving", and variations thereof herein, is meant to encompass the
`
`items listed thereafter and equivalents thereof as well as additional items.
`
`Definitions:
`
`The term "halo" or "halogen" refers to any radical of fluorine, chlorine, bromine or
`
`iodine.
`
`The term "alkyl" refers to a hydrocarbon chain that may be a straight chain or branched
`
`chain, containing the indicated number of carbon atoms. For example, C 1-C 12 alkyl indicates
`
`that the group may have from 1 to 12 (inclusive) carbon atoms in it. The term "haloalkyl" refers
`
`to an alkyl in which one or more hydrogen atoms are replaced by halo, and includes alkyl
`
`moieties in which all hydrogens have been replaced by halo (e.g., perfluoroalkyl). The terms
`
`"arylalkyl" or "aralkyl" refer to an alkyl moiety in which an alkyl hydrogen atom is replaced by
`
`an aryl group. Aralkyl includes groups in which more than one hydrogen atom has been replaced
`
`3
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`by an aryl group. Examples of "arylalkyl" or "aralkyl" include benzyl, 2-phenylethyl, 3-
`
`phenylpropyl, 9-fluorenyl, benzhydryl, and trityl groups.
`
`The term "alkylene" refers to a divalent alkyl, e.g., -CHr, -CH2CHr, and -CH2CH2CHr.
`
`The term "alkenyl" refers to a straight or branched hydrocarbon chain containing 2-12
`
`carbon atoms and having one or more double bonds. Examples of alkenyl groups include, but
`
`are not limited to, allyl, propenyl, 2-butenyl, 3-hexenyl and 3-octenyl groups. One of the double
`
`bond carbons may optionally be the point of attachment of the alkenyl substituent. The term
`
`"alkynyl" refers to a straight or branched hydrocarbon chain containing 2-12 carbon atoms and
`
`characterized in having one or more triple bonds. Examples of alkynyl groups include, but are
`
`not limited to, ethynyl, propargyl, and 3-hexynyl. One of the triple bond carbons may optionally
`
`be the point of attachment of the alkynyl substituent.
`
`The term "alkoxy" refers to an -O-alkyl radical. The term "haloalkoxy" refers to an
`
`alkoxy in which one or more hydrogen atoms are replaced by halo, and includes alkoxy moieties
`
`in which all hydrogens have been replaced by halo (e.g., perfluoroalkoxy).
`
`The term "carbocyclyl" refers to a monocyclic, bicyclic or tricyclic, hydrocarbon ring
`
`system that is not fully aromatic, wherein any ring atom capable of substitution can be
`
`substituted by one or more substituents. A carbocyclyl can be fully or partially saturated. A
`
`bicyclic or tricylic carbocyclyl may contain one (in the case of a bicycle) or up to two (in the
`
`case of a tricycle) aromatic rings, as long as at least one ring in the carbocyclyl is non-aromatic.
`
`Unless otherwise specified, any ring atom capable of substitution in a carbocyclyl can be
`
`substituted by one or more substituents.
`
`The term "aryl" refers to a fully aromatic monocyclic, bicyclic, or tricyclic hydrocarbon
`
`ring system. Examples of aryl moieties are phenyl, naphthyl, and anthracenyl. Unless otherwise
`
`specified, any ring atom in an aryl can be substituted by one or more substituents.
`
`The term "cycloalkyl" as employed herein refers to a saturated cyclic, bicyclic, tricyclic,
`
`or polycyclic hydrocarbon group. Unless otherwise specified, any ring atom can be substituted
`
`by one or more substituents. The cycloalkyl groups can contain fused rings. Fused rings are
`
`rings that share a common carbon atom. Examples of cycloalkyl moieties include, but are not
`
`limited to, cyclopropyl, cyclohexyl, methylcyclohexyl, adamantyl, and norbomyl. Unless
`
`otherwise specified, any ring atom can be substituted by one or more substituents.
`
`4
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`Rigel Exhibit 1010
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`WO 2012/009678
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`PCT/0S2011/044254
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`The term "heterocyclyl" refers to a monocyclic, bicyclic or tricyclic, ring structure that is
`
`not fully aromatic and includes one to four heteroatoms independently selected from N, 0, or S
`
`in one or more of the rings. A heterocyclyl can be fully or partially saturated. A bicyclic or
`
`tricylic heterocyclyl may contain one (in the case of a bicycle) or up to two (in the case of a
`
`tricycle) aromatic rings, as long as at least one ring in the heterocyclyl is non-aromatic. Unless
`
`otherwise specified, any ring atom capable of substitution in a heterocyclyl can be substituted by
`
`one or more substituents. Heterocyclyl groups include, for example, thiophene, thianthrene,
`
`furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole,
`
`isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole,
`
`indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline,
`
`quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine,
`
`phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine,
`
`oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as
`
`azetidinones and pyrrolidinones, sultams, sultones, and the like.
`
`The term "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic ring system having 1-3
`
`heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said
`
`heteroatoms independently selected from 0, N, or S, wherein each ring in a heteroaryl is fully
`
`aromatic. Unless otherwise specified, any ring atom capable of substitution in a heteroaryl can
`
`be substituted by one or more substituents. The terms "hetaralkyl" and "heteroaralkyl", as used
`
`herein, refers to an alkyl group substituted with a heteroaryl group. The ring heteroatoms of the
`
`compounds provided herein include N-0, S(0), and S(Oh.
`
`The term "substituted" refers to the replacement of a hydrogen atom with another moiety.
`
`Typical substituents include alkyl (e.g., Cl, C2, C3, C4, C5, C6, C7, C8, C9, ClO, Cll, Cl2
`
`straight or branched chain alkyl), cycloalkyl, haloalkyl (e.g., perfluoroalkyl such as CF3), aryl,
`
`heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, alkenyl, alkynyl, cycloalkenyl,
`
`heterocycloalkenyl, alkoxy, haloalkoxy (e.g., perfluoroalkoxy such as OCF3), halo, hydroxy,
`
`carboxy, carboxylate, cyano, nitro, amino, alkyl amino, SO3H, sulfate, phosphate,
`
`methylenedioxy (-O-CHrO- wherein oxygens are attached to vicinal atoms), ethylenedioxy, oxo
`
`(not a substituent on heteroaryl), thioxo (e.g., C=S) (not a substituent on heteroaryl), imino
`
`(alkyl, aryl, aralkyl), S(O)nalkyl (where n is 0-2), S(O)n aryl (where n is 0-2), S(O)n heteroaryl
`
`5
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`Rigel Exhibit 1010
`Page 6 of 254
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`(where n is 0-2), S(O)n heterocyclyl (where n is 0-2), amine (mono-, di-, alkyl, cycloalkyl,
`
`aralkyl, heteroaralkyl, aryl, heteroaryl, and combinations thereof), ester ( alkyl, aralkyl,
`
`heteroaralkyl, aryl, heteroaryl), amide (mono-, di-, alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl,
`
`and combinations thereof), sulfonamide (mono-, di-, alkyl, aralkyl, heteroaralkyl, and
`
`combinations thereof). In one aspect, the substituents on a group are independently any one
`
`single, or any subset of the aforementioned substituents. In another aspect, a substituent may
`
`itself be substituted with any one of the above substituents.
`
`As used herein, the term "elevated levels of 2HG" means 10%, 20% 30%, 50%, 75%,
`
`100%, 200%, 500% or more 2HG then is present in a subject that does not carry a mutant IDHl
`
`allele. The term "elevated levels of 2HG" may refer to the amount of 2HG within a cell, within a
`
`tumor, within an organ comprising a tumor, or within a bodily fluid.
`
`The term "bodily fluid" includes one or more of amniotic fluid surrounding a fetus,
`
`aqueous humour, blood (e.g., blood plasma), serum, Cerebrospinal fluid, cerumen, chyme,
`
`Cowper's fluid, female ejaculate, interstitial fluid, lymph, breast milk, mucus (e.g., nasal
`
`drainage or phlegm), pleural fluid, pus, saliva, sebum, semen, serum, sweat, tears, urine, vaginal
`
`secretion, or vomit.
`
`As used herein, the terms "inhibit" or "prevent" include both complete and partial
`
`inhibition and prevention. An inhibitor may completely or partially inhibit.
`
`The term "treat" means decrease, suppress, attenuate, diminish, arrest, or stabilize the
`
`development or progression of a cancer (e.g., a cancer delineated herein), lessen the severity of
`
`the cancer or improve the symptoms associated with the cancer.
`
`As used herein, an amount of a compound effective to treat a disorder, or a
`
`"therapeutically effective amount" refers to an amount of the compound which is effective, upon
`
`single or multiple dose administration to a subject, in treating a cell, or in curing, alleviating,
`
`relieving or improving a subject with a disorder beyond that expected in the absence of such
`
`treatment.
`
`As used herein, the term "subject" is intended to include human and non-human animals.
`
`Exemplary human subjects include a human patient having a disorder, e.g., a disorder described
`
`herein or a normal subject. The term "non-human animals" of the invention includes all
`
`vertebrates, e.g., non-mammals (such as chickens, amphibians, reptiles) and mammals, such as
`
`6
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`non-human primates, domesticated and/or agriculturally useful animals, e.g., sheep, dog, cat,
`
`cow, pig, etc.
`
`Compounds
`
`Provided is a compound having formula A:
`Ra R2 Rg V
`
`W
`
`(A), or a pharmaceutically acceptable salt thereof, wherein:
`
`R"N-y(~AR.
`R3
`V and Ware independently =0 or CF3;
`R1 is selected from C2-C6 alkyl, -(C1-C3 alkylene)-0-(C1-C3 alkyl), carbocyclyl, -(C1-C2
`alkylene)-(carbocyclyl), aryl, -(C1-C2 alkylene)-(aryl), -(C1-C2 alkylene)-(heteroaryl), and -(C1-
`C2 alkylene)-(heterocyclyl);
`R2 is selected from C4-C8 alkyl, carbocyclyl, aryl, heterocyclyl, heteroaryl, -(C1-C4
`alkylene)-(aryl), and -(C1-C4 alkylene)-(heteroaryl);
`R3 is selected from C2-C6 alkyl optionally substituted with =0 or -OH; C2-C6 alkenyl;
`-(C1-C3 alkylene)-0-(C1-C3 alkyl); carbocyclyl; aryl; heterocyclyl; heteroaryl; -(C1-C2 alkylene)(cid:173)
`(carbocyclyl); -(C1-C2 alkylene)-(aryl); -(C1-C2 alkylene)-(heterocyclyl); and -(C1-C2 alkylene)(cid:173)
`(heteroaryl);
`R4 is selected from -CF3, -CH2-0-CH3, -CH2Cl, -C(R 11 )-N(R 11)-C(0)-0-(C1-C4 alkyl)
`and-Rs-R6-R7
`, wherein:
`Rs is selected from a bond; C1-C3 straight or branched alkyl wherein one methylene unit
`in the alkyl of Rs is optionally replaced with -0-, -S-, -S(O)- or -S(Oh-; and CrC 3 alkenyl or
`
`)-, -N(R11)-S(0)1_2-,
`
`alkynyl;
`R6 is selected from a bond, -N(R11)-C(O)-, -C(O)-N(R 11
`-S(0)1-rN(R11)-, -NH-, -N(C1-C3 alkyl)-, and tetrazolyl;
`R7 is a carbocyclyl, aryl, heterocyclyl, or heteroaryl;
`R8 is selected from hydrogen and C1-C4 alkyl; or R8 and R 1 are taken together with the
`nitrogen atom to form a 5-12 membered heterocyclyl;
`R9 is selected from hydrogen and C1-C4 alkyl; or R9 and R2 are taken together to form a
`6-12 membered carbocyclyl or a 5-12 membered heterocyclyl; and
`7
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`Rigel Exhibit 1010
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`each R 11 is independently hydrogen or methyl,
`
`wherein any carbocyclyl, aryl, heterocyclyl or heteroaryl is optionally substituted with one or
`
`more substituents; and wherein any hydrogen atom is replaced with deuterium.
`
`In one embodiment, the compound has formula I:
`Rs R2 Rg V
`
`R,, N 0 ~ )___ R4
`
`W
`
`(I), or a pharmaceutically acceptable salt thereof, wherein:
`
`, wherein:
`
`R3
`V and Ware independently =0 or CF3 ;
`R1 is selected from CrC6 alkyl, -(C 1-C3 alkylene)-0-(C 1-C3 alkyl), carbocyclyl, -(C 1-C2
`alkylene)-(carbocyclyl), aryl, -(C 1-C2 alkylene)-(aryl), -(C 1-C2 alkylene)-(heteroaryl), and -(C 1-
`C2 alkylene)-(heterocyclyl);
`R2 is selected from C4-C8 alkyl, carbocyclyl, aryl, heterocyclyl, heteroaryl, -(C 1-C4
`alkylene)-(aryl), and -(C 1-C4 alkylene)-(heteroaryl);
`R3 is selected from CrC6 alkyl optionally substituted with =0 or -OH; CrC6 alkenyl;
`-(C 1-C3 alkylene)-0-(C 1-C3 alkyl); carbocyclyl; aryl, heterocyclyl, heteroaryl, -(C 1-C2 alkylene)(cid:173)
`(carbocyclyl), -(C 1-C2 alkylene)-(aryl), -(C 1-C2 alkylene)-(heterocyclyl), and -(C 1-C2 alkylene)(cid:173)
`(heteroaryl);
`R4 is selected from -CF3, -CHrO-CH3 and-Rs-R6-R7
`Rs is selected from a bond; C 1-C3 straight or branched alkyl wherein one methylene unit
`in the alkyl of Rs is optionally replaced with -0-, -S- or -S(O); and C2-C3 alkenyl or alkynyl;
`R6 is selected from a bond, -NH-C(O)-, -C(O)-NH-, -NH-S(O)i-r, -S(0) 1_rNH-, and
`tetrazolyl;
`R7 is a carbocyclyl, aryl, heterocyclyl, or heteroaryl;
`R8 is selected from hydrogen and C 1-C4 alkyl; or R8 and R 1 are taken together with the
`nitrogen atom to form a 5-12 membered heterocyclyl; and
`R9 is selected from hydrogen and C 1-C4 alkyl; or R9 and R2 are taken together to form a
`6-12 membered carbocyclyl or a 5-12 membered heterocyclyl; or
`
`wherein any carbocyclyl, aryl, heterocyclyl or heteroaryl is optionally substituted with one or
`
`more substituents.
`
`8
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`In one embodiment of formula A or I, V is CF3 and W is =0. In another embodiment, W
`is CF3 and Vis =0.
`Provided also is a compound having formula I-a, or a pharmaceutically acceptable salt
`, R2
`, R3
`, R4
`thereof, wherein R 1
`, R 8 and R9 are as defined in formula I.
`
`Provided also is a compound having formula I-b, or a pharmaceutically acceptable salt
`, R2
`, R3
`, R4
`thereof, wherein R 1
`, R 8 and R9 are as defined in formula A.
`
`In another embodiment, any carbocyclyl, aryl, heterocyclyl or heteroaryl in formula A, I,
`
`I-a or I-bis optionally substituted with one or more substituents independently selected from =0,
`-C(O)-(C1-C3 alkyl), -C(O)-N(R10h, -C(O)-O-(C1-C3 alkyl), -C1-C4 alkoxy, -C1-C4 alkyl, -C1-C4
`haloalkyl, -C2-C4 alkenyl or alkynyl, -C3-C8 cycloalkyl, halo, morpholinomethyl,
`morpholinosulfonyl, morpholinyl, -N(R10h, -NH-C(O)-(C1-C3 alkyl), -O-CHrC(O)-N(R10h,
`-OH, -O-phenyl, phenyl, -S(Oh-piperidin-1-yl, and tetrazolyl; wherein each R 10 is
`
`independently selected from hydrogen, C1-C3 alkyl, and C3-C8 cycloalkyl; and
`any cycloalkyl, phenyl or piperidinyl portion of a substituent is optionally further
`
`substituted with one or more substituents independently selected from halo, C1-C3 alkyl, CF3,
`-NH2, and C1-C4 alkoxy.
`In another embodiment of Formula A, I, I-a or I-b:
`any carbocycl yl, aryl, heterocycl yl or heteroaryl portion of R 1 is optionally substituted
`with halo, or C1-C4 alkoxy;
`the carbocyclyl, aryl, heterocyclyl or heteroaryl in R2 is optionally substituted with one or
`more substitutents independently selected from =0, -OH, halo, C1-C4 alkyl, C1-C4 alkoxy,
`morpholinyl, -N(R8h and -O-CH2-C(O)-N(R8h;
`
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`any carbocyclyl, aryl, heterocyclyl or heteroaryl in R3 is optionally substituted with one
`
`or more substitutents independently selected from -OH, halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4
`alkoxy, -NH-C(O)-(C1-C3 alkyl), -C(O)-(C1-C3 alkyl), -C(O)-O-(C1-C3 alkyl), tetrazolyl, C3-C8
`
`cycloalkyl, phenyl, -0-phenyl, and -S(Oh-piperidin-1-yl;
`any cycloalkyl, phenyl or piperidinyl portion of a substituent of R3 is optionally further
`
`substituted with one or more substituents independently selected from halo, C 1-C3 alkyl, CF3 ,
`
`-NH2, and C 1-C4 alkoxy; and
`R7 is optionally substituted with one or more substituents independently selected from
`=0, -OH, halo, C1-C4 alkyl, CrC4 alkenyl or alkynyl, C1-C4 haloalkyl, -C(O)-N(R8h, -N(R8h,
`C1-C4 alkoxy, morpholinomethyl, morpholinosulfonyl, and phenyl, wherein the phenyl
`substituent of R7 is optionally further substituted with one or more substituents independently
`
`selected from halo, C1-C3 alkyl, CF3 , -NH2, and C1-C4 alkoxy.
`In another embodiment of Formula A, I, I-a or I-b, R1 is piperazinyl, morpholinyl,
`thiomorpholinyl, tetrahydrothiopyranyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, or
`tetrahydrofuranyl, wherein each member of R 1 is optionally substituted.
`In another embodiment of Formula A, I, I-a or I-b, R2 is selected from carbocyclyl, aryl,
`heterocyclyl, and heteroaryl, wherein each member of R2 is optionally substituted.
`In another embodiment of Formula A, I, I-a or I-b, R3 is carbocyclyl; aryl, heterocyclyl,
`
`heteroaryl, -(C1-C2 alkylene)-(carbocyclyl), -(C1-C2 alkylene)-(aryl), -(C1-C2 alkylene)(cid:173)
`(heterocyclyl), and -(C1-C2 alkylene)-(heteroaryl), wherein each member of R3 is optionally
`substituted.
`In another embodiment of Formula A, I, I-a or I-b, R3 is cyclopropyl, cyclopentyl,
`cyclohexyl or benzyl, wherein each member of R3 is optionally substituted.
`In another embodiment of Formula A, I, I-a or I-b, -R5-R6-R7 is not phenyl or N(cid:173)
`
`methyleneisoindoline-1,3-dione.
`In another embodiment of Formula A, I, I-a or I-b, R6 is not -NHC(O)-.
`In another embodiment of Formula A, I, I-a or I-b, R 8 and R1 are taken together with the
`nitrogen atom to form a 5-12 membered heterocyclyl. In one aspect of this embodiment, R2 is
`selected from carbocyclyl, aryl, heterocyclyl, and heteroaryl. In another aspect of this
`
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`embodiment, -R5-R6-R7 is not phenyl or N-methyleneisoindoline-1,3-dione. In another aspect of
`this embodiment, R6 is not -NHC(O).
`In another embodiment of Formula A, I, I-a or I-b, R9 is H. In another embodiment, R9 is
`
`methyl or ethyl.
`In another embodiment of Formula A, I, I-a or I-b, R9 and R2 are taken together to form a
`
`6-12 membered carbocyclyl or a 5-12 membered heterocyclyl, wherein carbocyclyl or
`
`heterocyclyl is optionally substituted.
`
`In another embodiment, provided is a compound of Formula I-c, or a pharmaceutically
`
`acceptable salt thereof.
`R2
`
`0
`
`R"~0~).l_R4
`R3
`I-c, wherein:
`0
`R 1 is selected from a C4-C7 monocyclic or bicyclic cycloalkyl optionally substituted on a
`single carbon atom with 1 to 2 fluoro; tetrahydropyranyl, pyrrolidinyl, phenyl, and t-butyl,
`
`wherein the phenyl and pyrrolidinyl are optionally substituted;
`R2 is selected from phenyl, biphenyl, thien-2-yl, and furanyl, wherein R 2 is optionally
`
`substituted;
`R3 is selected from phenyl, biphenyl, pyridinyl, thiazolylmethyl, thienylmethyl,
`
`cyclohexyl and pyrazolyl, wherein any phenyl, biphenyl, pyridinyl, thiazolyl, thienyl, cyclohexyl
`or pyrazolyl portion of R3 is optionally substituted; and
`R 4 is as defined in formula A.
`In certain embodiments of Formula I-c, R 1 is selected from cyclohexyl, cyclopentyl,
`
`cycloheptyl, cyclobutyl, 3,3-difluorocyclobutyl, 4,4,-difluorocyclohexyl, bicyclo[2.2. l]heptanyl,
`
`tertahydropyran-3-yl, tertahydropyran-4-yl, l-t-butoxycarbonylpyrrolidin-3-yl, t-butyl, 2-
`
`bromophenyl, 2-methylphenyl, and bicyclo[3. l.0]hexan-3-yl.
`In certain embodiments of Formula I-c, R2 is selected from phenyl, 2-methylphenyl, 2-
`
`fluorphenyl, 2-chlorophenyl, 2-bromophenyl, 2-bromo-5-fluorophenyl, 2,5-dichlorophenyl, 2-
`
`fluoro-5-methylphenyl, thien-2-yl, 4-fluorophenyl, 5-bromofuran-2-yl, 3-methylthien-2-yl, 2,4,5-
`
`trifluorophenyl, 3-fluoro-5-chlorophenyl, 2,5-difluoro-6-chlorophenyl, 3-chlorophenyl, 3-
`
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`fluorophenyl, 3-methylphenyl, 2,6-dimethylphenyl, 3-bromopohenyl, 2-ethylphenyl, 2-
`
`nitrophenyl, 3' -methoxybiphenyl-3-yl, 2,5-dibromo-6-fluorophenyl, 2-trifluoromethylphenyl, 4-
`
`hydoxyphenyl, 3-hydroxyphenyl, 2-hydroxyphenyl, 2-methoxyphenyl, and 2-fluoro-5-
`
`methoxyphenyl.
`In certain embodiments of Formula I-c, R3 is selected from 3-fluorophenyl, 3-
`
`methylphenyl, 3-chlorophenyl, thien-2-ylmethyl, 3-(1-methyl-lH-pyrazol-4-yl)phenyl, l-methyl(cid:173)
`
`lH-pyrazol-3-yl, 4-chlorophenyl, 3-acetylaminophenyl, 3' -trifluoromethoxy-biphenyl-3-yl,
`
`pyridin-3-yl, 4-fluorophenyl, thiazol-2-ylmethyl, cyclohexyl, 2-methylphenyl, 3-fluoro-4-
`
`methylphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, phenyl, 3-bromophenyl, 2-
`
`fluorophenyl, 3-chloro-4-methylphenyl, 3-(pyriminidin-5-yl)phenyl, biphenyl-3-yl, 3-
`
`trifluoromethylphenyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, 3-aminophenyl, 3-
`
`ethylcarbonylaminophenyl, 3-t-butoxycarbonylaminophenyl, 3-chloro-4-bromophenyl, 4-
`
`methlyphenyl, 3-methoxyphenyl, 3-(1-methyl-lH-pyrazol-5-yl)phenyl, 3-
`
`methoxycarbonylaminophenyl, 3-cetylphenyl, 3-(morpholin-4-yl)phenyl, 3,4-difluorophenyl,
`
`and 3-(4-t-butoxycarbonylpiperazin-1-yl)phenyl.
`In some embodiments, R4 is selected from 1-(methylmethoxycarbonylamino)ethyl,
`
`1,2,3,4-tetrahydroquinolin-1-yl, l-ethoxycarbonylpiperidin-2-yl,
`
`l-ethoxycarbonylpyrrolidin-2-yl, lH-benzimidazol-1-ylmethyl, lH-indazol-3-ylmethyl,
`
`indolin-1-ylmethyl, lH-indol-3-ylmethyl, lH-indol-5-ylmethyl,
`
`1H-pyrrolo[2,3-b]pyridine-3-ylmethyl, 1H-pyrrolo[3,2-b]pyridin-3-ylmethyl,
`
`l-methoxycarbonylpiperidin-2-yl, l-methoxycarbonylpyrrolidin-2-yl,
`
`2-fluoropyridin-3-ylaminomethyl, 2-imino-4-fluoropyridin-1-ylmethyl,
`
`2-methoxyphenylaminomethyl, 2-methyl-lH-benzimidazol-1-ylmethyl,
`
`2-methylimidazol-1-ylmethyl, 2-trifluoromethyl-lH-imidazol-1-yl, 3-cyanophenylaminomethyl,
`
`3-fluoropyridin-2-ylaminomethyl, 3-methoxyphenylaminomethyl,
`
`4-( 1,3,4-oxadiazole-2-yl)phenylaminomethyl, 4-( dimethylaminocarbonyloxy )phenylmethyl,
`
`4,5-dichloroimidazol-1-ylmethyl, 4-cyanophenylaminomethyl, 4-fluorophenylaminomethyl,
`
`4-fluoropyridin-2-ylaminomethyl, 4-hydroxyphenylmethyl, 4-methoxycarbonylmorpholin-3-yl,
`
`4-methoxycarbonylpiperazin-1-ylmethyl, 4-methoxyphenylaminomethyl,
`
`4-methylcarbonyloxyphenylmethyl, 5-fluoropyridin-2-aminomethyl,
`
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`5-fluoropyridin-2-oxymethyl, 6-fluoropyridin-3-ylaminomethyl, benzomorpholin-4-ylmethyl,
`
`methoxycarbonylaminomethyl, methylmethoxycarbonylaminomethyl,
`
`methylphenylaminomethyl, phenylaminomethyl, pyridin-2-oxymethyl, pyridin-2-ylaminomethyl,
`
`pyridin-2-yloxymethyl, pyridin-3-oxymethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl,
`
`thiazol-4-ylmethyl, and thien-2-ylmethyl.
`
`In another embodiment, exemplary compounds of formula I are depicted below in Table
`
`1.
`
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`
`
`o Formula I. Table 1 • Exempl ary Compounds f
`
`
`
`Structure
`
`Structure
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`14
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`Cmpd
`
`No.
`
`7
`
`Structure
`
`CH3
`
`0
`
`~I
`8 ~N CH3
`0
`
`0y'f:ND
`F'y
`~~ 12
`N 0
`CH, Q
`N~ 0 D
`
`Cmpd
`
`No.
`
`Structure
`
`11
`
`13
`
`H3C>l
`H C
`N
`3
`
`CH,YyQ
`(YN!!D
`
`-&
`
`F
`
`cr:NJrO
`(YN!!D
`
`\
`
`/;
`
`0
`
`F UN)/)
`(XN!!D
`c~J!)
`(XN!!D
`
`H3C>l
`H C
`N
`3
`
`-&
`
`CH3
`
`F
`
`CH3
`
`9
`
`10
`
`CH~S
`
`N
`
`N
`
`0
`
`'1/'
`~I
`
`y-, o",f'o
`O-N~1N''O
`
`F ~ \
`::::,..._
`
`14
`
`15
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`Structure
`
`Structure
`
`QN~
`r'YN!!D
`yo
`~~
`0--}-)-c~
`
`F
`
`F
`
`H3C
`
`16
`
`17
`
`18
`
`22
`
`16
`
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`Structure
`
`Structure
`
`F
`
`F
`
`0 y o,,O
`°'NtrN..,..S''o
`0 y o"O
`QN~NrN..,..S''o
`
`H3C ~
`lo
`
`H3C ~
`lo
`
`24
`
`25
`
`26
`
`27
`
`29
`
`30
`
`17
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`

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`Cmpd
`No.
`
`Structure
`
`Cmpd
`No.
`
`Structure
`
`31
`
`32
`
`33
`
`34
`
`~
`Q o YF r
`'('u
`
`N
`
`~
`
`35
`
`36
`
`37
`
`38
`
`18
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`Cmpd
`No.
`
`Structure
`
`Cmpd
`No.
`
`Structure
`
`39
`
`40
`
`41
`
`42
`
`43
`
`44
`
`45
`
`46
`
`19
`
`0 ~ : (
`
`QN N'('D
`I '°
`
`'.:::::
`
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`PCT/