US20150031627A1 - Therapeutically active compounds and their methods of use - Google Patents

Therapeutically active compounds and their methods of use Download PDF

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Publication number
US20150031627A1
US20150031627A1 US14/341,426 US201414341426A US2015031627A1 US 20150031627 A1 US20150031627 A1 US 20150031627A1 US 201414341426 A US201414341426 A US 201414341426A US 2015031627 A1 US2015031627 A1 US 2015031627A1
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compound
optionally substituted
alkyl
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US14/341,426
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Inventor
Rene M. Lemieux
Janeta Popovici-Muller
Jeremy Travins
Zhenwei Cai
DaWei Cui
Ding Zhou
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PHARMARESOURCES (SHANGHAI) CO Ltd
Servier Pharmaceuticals LLC
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Agios Pharmaceuticals Inc
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Publication of US20150031627A1 publication Critical patent/US20150031627A1/en
Assigned to AGIOS PHARMACEUTICALS, INC. reassignment AGIOS PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PHARMARESOURCES (SHANGHAI) CO., LTD.
Assigned to PHARMARESOURCES (SHANGHAI) CO., LTD. reassignment PHARMARESOURCES (SHANGHAI) CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CAI, Zhenwei, CUI, DAWEI, ZHOU, DING
Assigned to AGIOS PHARMACEUTICALS, INC. reassignment AGIOS PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LEMIEUX, RENE M., POPOVICI-MULLER, JANETA, TRAVINS, JEREMY
Priority to US15/347,407 priority Critical patent/US20170057994A1/en
Priority to US15/915,213 priority patent/US10689414B2/en
Priority to US16/871,777 priority patent/US11021515B2/en
Assigned to SERVIER PHARMACEUTICALS, LLC reassignment SERVIER PHARMACEUTICALS, LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: AGIOS PHARMACEUTICALS, INC.
Assigned to SERVIER PHARMACEUTICALS, LLC reassignment SERVIER PHARMACEUTICALS, LLC CORRECTIVE ASSIGNMENT TO CORRECT THE APPLICATION NO. 10,172,864 TO THE CORRECT APP NO. 61/160,253 PREVIOUSLY RECORDED ON REEL 056179 FRAME 0417. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT. Assignors: AGIOS PHARMACEUTICALS, INC.
Assigned to SERVIER PHARMACEUTICALS LLC reassignment SERVIER PHARMACEUTICALS LLC CORRECTIVE ASSIGNMENT TO CORRECT THE ASSIGNEE NAME SERVIER PHARMACEUTICALS LLC BY REMOVAL OF COMMA AND UPDATING ZIP CODE TO 02210 PREVIOUSLY RECORDED ON REEL 056224 FRAME 0921. ASSIGNOR(S) HEREBY CONFIRMS THE CORRECTIVE ASSIGNMENT. Assignors: AGIOS PHARMACEUTICALS, INC.
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Definitions

  • Isocitrate dehydrogenases catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate (i.e., ⁇ -ketoglutarate). These enzymes belong to two distinct subclasses, one of which utilizes NAD(+) as the electron acceptor and the other NADP(+).
  • NAD(+) the electron acceptor
  • NADP(+)-dependent isocitrate dehydrogenases 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.
  • IDH1 isocitrate dehydrogenase 1 (NADP+), cytosolic
  • IDP isocitrate dehydrogenase 1
  • IDCD isocitrate dehydrogenase 1
  • PICD protein encoded by this gene
  • 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-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 IDH1 gene encodes a protein of 414 amino acids.
  • the nucleotide and amino acid sequences for human IDH1 can be found as GenBank entries NM — 005896.2 and NP — 005887.2 respectively.
  • the nucleotide and amino acid sequences for IDH1 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.
  • Non-mutant e.g., wild type
  • IDH1 catalyzes the oxidative decarboxylation of isocitrate to ⁇ -ketoglutarate thereby reducing NAD + (NADP + ) to NADH (NADPH), e.g., in the forward reaction:
  • Described herein are methods of treating a cancer characterized by the presence of a mutant allele of IDH1 or IDH2.
  • the methods comprise the step of administering to a subject in need thereof a compound of formula I, or a pharmaceutically acceptable salt, tautomer, isotopologue or hydrate thereof, wherein:
  • R 1 is optionally substituted C 4 -C 6 carbocyclyl
  • each R 2 and R 3 is independently selected from optionally substituted aryl or optionally substituted heteroaryl;
  • R 4 is alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, or optionally substituted heteroaralkyl;
  • ring A is 4-6 membered non-aromatic ring having 0-1 additional heteroatoms selected from N, O or S, wherein ring A is optionally substituted with one or two R 5 groups;
  • each R 5 is independently halo; —CF 3 ; —CN; —OR 6 ; —N(R 6 ) 2 ; —C(O)C 1 -C 4 alkyl; C 1 -C 4 haloalkyl; C 1 -C 4 alkyl optionally substituted with —OR 6 or —N(R 6 ) 2 ; —O—C 1 -C 4 alkyl optionally substituted with halo, —OR 6 or —N(R 6 ) 2 ; —SO 2 N(R 6 ) 2 ; —SO 2 (C 1 -C 4 alkyl); —NR 6 SO 2 R 6 ; C 3 -C 5 carbocyclyl optionally substituted with one or two R 6 groups; —O—(C 3 -C 6 carbocyclyl optionally substituted with one or two R 6 groups); 5-6 membered heteroaryl; —C 1 -C 4 alkyl-C(O)O—C 1 -C
  • each R 6 is independently H or C 1 -C 3 alkyl.
  • the compound of formula I inhibits mutant IDH1/2, particularly mutant IDH1 having alpha hydroxyl neoactivity. Also described herein are pharmaceutical compositions comprising a compound of formula I.
  • halo or halogen refers to any radical of fluorine, chlorine, bromine or iodine.
  • 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.
  • 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).
  • arylalkyl or “aralkyl” refer to an alkyl moiety in which an alkyl hydrogen atom is replaced by an aryl group.
  • Arylalkyl or aralkyl includes groups in which more than one hydrogen atom has been replaced by an aryl group.
  • arylalkyl or aralkyl include benzyl, 2-phenylethyl, 3-phenylpropyl, 9-fluorenyl, benzhydryl, and trityl groups.
  • heteroarylalkyl or heterooaralkyl refer to an alkyl moiety in which an alkyl hydrogen atom is replaced by a heteroaryl group.
  • Heteroarylalkyl or heteroaralkyl includes groups in which more than one hydrogen atom has been replaced by a heteroaryl group.
  • alkylene refers to a divalent alkyl, e.g., —CH 2 —, —CH 2 CH 2 —, and —CH 2 CH 2 CH 2 —.
  • alkenyl refers to a straight or branched hydrocarbon chain containing 2-12 carbon atoms and having one or more double bonds.
  • 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.
  • 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.
  • alkoxy refers to an —O-alkyl radical.
  • 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).
  • 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.
  • 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.
  • cycloalkyl 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 norbornyl. Unless otherwise specified, any ring atom can be substituted by one or more substituents.
  • 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, O, 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, o
  • 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 O, 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.
  • heteroalkyl 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—O, S(O), and S(O) 2 .
  • substituted refers to the replacement of a hydrogen atom with another moiety.
  • substituents include alkyl (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12 straight or branched chain alkyl), cycloalkyl, haloalkyl (e.g., perfluoroalkyl such as CF 3 ), aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, alkenyl, alkynyl, cycloalkenyl, heterocycloalkenyl, alkoxy, haloalkoxy (e.g., perfluoroalkoxy such as OCF 3 ), halo, hydroxy, carboxy, carboxylate, cyano, nitro, amino, alkyl amino, SO 3 H, sulfate, phosphate, methylenedioxy (—O—CH 2 —O— wherein oxygens are
  • tautomer refers to each of two or more isomers of a compound (e.g., a compound described herein) that exist together in equilibrium, and are readily interchangeable by migration of a hydrogen atom or proton, accompanied by a switch of a single bond and an adjacent double bond.
  • the term “elevated levels of 2HG” means 10%, 20% 30%, 50%, 75%, 100%, 200%, 500% or more 2HG than is present in a subject that does not carry a mutant IDH1 or IDH2 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.
  • blood e.g., blood plasma
  • serum Cerebrospinal fluid
  • cerumen cerumen
  • chyme chyme
  • Cowper's fluid female ejaculate
  • interstitial fluid lymph
  • breast milk mucus (e.g., nasal drainage or phlegm)
  • mucus e.g., nasal drainage or phlegm
  • pleural fluid pus, saliva, sebum, semen, serum
  • inhibitor or “prevent” include both complete and partial inhibition and prevention.
  • An inhibitor may completely or partially inhibit.
  • 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.
  • an amount of a compound effective to treat a disorder 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.
  • 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.
  • non-human animals of the invention includes all vertebrates, e.g., non-mammals (such as chickens, amphibians, reptiles) and mammals, such as non-human primates, domesticated and/or agriculturally useful animals, e.g., sheep, dog, cat, cow, pig, etc.
  • R 1 is optionally substituted C 4 -C 6 carbocyclyl
  • each R 2 and R 3 is independently selected from optionally substituted aryl or optionally substituted heteroaryl;
  • R 4 is alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, or optionally substituted heteroaralkyl;
  • ring A is 4-6 membered non-aromatic ring having 0-1 additional heteroatoms selected from N, O or S, wherein ring A is optionally substituted with one or two R 5 groups;
  • each R 5 is independently halo; —CF 3 ; —CN; —OR 6 ; —N(R 6 ) 2 ; —C(O)C 1 -C 4 alkyl; C 1 -C 4 haloalkyl; C 1 -C 4 alkyl optionally substituted with —OR 6 or —N(R 6 ) 2 ; —O—C 1 -C 4 alkyl optionally substituted with halo, —OR 6 or —N(R 6 ) 2 ; —SO 2 N(R 6 ) 2 ; —SO 2 (C 1 -C 4 alkyl); —NR 6 SO 2 R 6 ; C 3 -C 5 carbocyclyl optionally substituted with one or two R 6 groups; —O—(C 3 -C 6 carbocyclyl optionally substituted with one or two R 6 groups); 5-6 membered heteroaryl; —C 1 -C 4 alkyl-C(O)O—C 1 -C
  • each R 6 is independently H or C 1 -C 3 alkyl.
  • R 1 is optionally substituted C 4 -C 6 carbocyclyl
  • each R 2 and R 3 is independently selected from optionally substituted aryl or optionally substituted heteroaryl;
  • R 4 is alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, or optionally substituted heteroaralkyl;
  • ring A is 4-6 membered non-aromatic ring having 0-1 additional heteroatoms selected from N, O or S, wherein ring A is optionally substituted with one or two R 5 groups;
  • each R 5 is independently halo, —CF 3 , —CN, —OR 6 , —N(R 6 ) 2 , —C(O)CH 3 ; C 1 -C 3 haloalkyl, C 1 -C 3 alkyl optionally substituted with —OR 6 or —N(R 6 ) 2 ; or
  • each R 6 is independently H or C 1 -C 3 alkyl.
  • R 1 is C 4 -C 6 carbocyclyl optionally substituted with one to three R 7 groups;
  • each R 2 and R 3 is independently selected from aryl or heteroaryl, wherein said aryl or heteroaryl is independently optionally substituted with one to three R 7 groups;
  • R 4 is alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, wherein said aryl, heteroaryl, aralkyl, and heteroaralkyl are each independently optionally substituted with one to three R 7 groups;
  • ring A is 4-6 membered non-aromatic ring having 0-1 additional heteroatoms selected from N, O or S, wherein ring A is optionally substituted with one or two R 5 groups;
  • each R 5 and R 7 is independently halo; —CF 3 ; —CN; —OR 6 ; —N(R 6 ) 2 ; —C(O)C 1 -C 4 alkyl; C 1 -C 4 haloalkyl; C 1 -C 4 alkyl optionally substituted with —OR 6 or —N(R 6 ) 2 ; —O—C 1 -C 4 alkyl optionally substituted with halo, —OR 6 or —N(R 6 ) 2 ; —SO 2 N(R 6 ) 2 ; —SO 2 (C 1 -C 4 alkyl); —S(O)—C 1-4 alkyl, —NR 6 SO 2 R 6 ; C 3 -C 5 carbocyclyl optionally substituted with one or two R 6 groups; —O—(C 3 -C 6 carbocyclyl optionally substituted with one or two R 6 groups); 5-6 membered heteroaryl; —C 1 -
  • each R 6 is independently H or C 1 -C 4 alkyl.
  • R 1 is C 4 -C 6 carbocyclyl optionally substituted with one to three R 7 groups;
  • each R 2 and R 3 is independently selected from aryl or heteroaryl, wherein said aryl or heteroaryl is independently optionally substituted with one to three R 7 groups;
  • R 4 is alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, wherein said aryl, heteroaryl, aralkyl, and heteroaralkyl are each independently optionally substituted with one to three R 7 groups;
  • ring A is 4-6 membered non-aromatic ring having 0-1 additional heteroatoms selected from N, O or S, wherein ring A is optionally substituted with one or two R 5 groups;
  • each R 5 and R 7 is independently halo, —CF 3 , —CN, —OR 6 , —N(R 6 ) 2 , —C(O)CH 3 ; C 1 -C 3 haloalkyl, C 1 -C 3 alkyl optionally substituted with OR 6 or —N(R 6 ) 2 ; or
  • each R 6 is independently H or C 1 -C 3 alkyl.
  • R 1 is optionally substituted C 4 -C 6 cycloalkyl. In one aspect of this embodiment, R 1 is C 4 -C 6 cycloalkyl optionally substituted with one to three R 7 groups. In another aspect of this embodiment, R 1 is C 4 , C 5 , or C 6 cycloalkyl optionally substituted with one to two R 7 groups and R 7 is halo. In another aspect of this embodiment, R 1 is C 4 or C 6 cycloalkyl optionally substituted with one to two R 7 groups and R 7 is halo. In yet another aspect of this embodiment, R 1 is
  • R 1 is
  • R 2 is optionally substituted aryl. In one aspect of this embodiment, R 2 is aryl optionally substituted with one to three R 7 groups. In another aspect of this embodiment, R 2 is phenyl optionally substituted with one to two R 7 groups and R 7 is —Cl.
  • R 3 is optionally substituted aryl or optionally substituted aryl heteroaryl. In one aspect of this embodiment, R 3 is optionally substituted heteroaryl. In another aspect of this embodiment, R 3 is heteroaryl optionally substituted with one to three R 7 group. In yet another aspect of this embodiment, R 3 is pyridinyl, indazolyl, benzoimidazolyl, indolyl, or N-methylindolyl, wherein each R 3 is optionally substituted with one R 7 wherein R 7 is F. In another aspect of this embodiment, R 3 is optionally substituted aryl. In another aspect of this embodiment, R 3 is aryl optionally substituted with one to three R 7 groups.
  • R 3 is phenyl optionally substituted with one R 7 wherein R 7 is —F.
  • R 3 is phenyl optionally substituted with one or two R 7 s wherein each R 7 is independently halo; —CN; —N(R 6 ) 2 ; C 1 -C 4 alkyl optionally substituted with —OR 6 ; —O—C 1 -C 4 alkyl optionally substituted with halo, or —OR 6 ; —SO 2 N(R 6 ) 2 ; —SO 2 (C 1 -C 4 alkyl); —S(O)—C 1-4 alkyl, —NR 6 SO 2 R 6 ; C 3 -C 5 carbocyclyl optionally substituted with one R 6 ; —O—(C 3 -C 6 carbocyclyl); 5-membered heteroaryl.
  • R 3 is phenyl optionally substituted with one or two R 7 s wherein each R 7 is independently —F, —SO 2 NH 2 , —SO 2 CH 3 , —S(O)CH 3 , —CN, methoxy, —OCH 2 OH, —CH 2 OH, —SO 2 N(CH 3 ) 2 , —SO 2 NHCH 3 , —NHSO 2 CH 3 , —CH 2 CH 2 OH, —N(CH 3 ) 2 , t-butyl, cyclopropyl, —C(OH)(CH 3 ) 2 , —OCF 3 , —OCHF 2 , —O-cyclopropyl, -1-methyl-cyclopropyl, or pyrazolyl.
  • R 4 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, or optionally substituted heteroaralkyl.
  • R 4 is aryl, heteroaryl, aralkyl, or heteroaralkyl, wherein said aryl, heteroaryl, aralkyl, and heteroaralkyl are each independently optionally substituted with one to three R 7 groups.
  • R 4 is aryl or heteroaryl, each aryl or heteroaryl is optionally substituted with one to three R 7 groups.
  • R 4 is 6-membered aryl or 5-6 membered heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one to three R 7 groups.
  • R 4 is:
  • each member of R 4 is optionally substituted with one or two R 7 groups and each R 7 is independently F, Cl, methyl, CF 3 , CN, OMe, or N(R 6 ) 2 .
  • R 4 is:
  • R 100 is independently H, methyl, F, Cl, CF 3 , CN, OCH 3 , or N(R 6 ) 2 .
  • R 4 is:
  • R 100 is H, methyl, F, C 1 , CF 3 , CN, OCH 3 , or N(R 6 ) 2 .
  • R 4 is:
  • R 100 is H, methyl, C 1 , CF 3 , CN, OCH 3 , or N(R 6 ) 2 and R 101 is H, F or methyl.
  • ring A is
  • ring A denotes ring A's attachment to R 4 ; and each member of ring A is optionally substituted with one or two R 5 groups.
  • ring A is
  • each R 5 is independently halo; —OR 6 ; —C(O)C 1 -C 4 alkyl; C 1 -C 4 alkyl optionally substituted with —OR 6 ; —C 3 -C 5 carbocyclyl optionally substituted with one or two R 6 groups; —C 1 -C 4 alkyl-C(O)O—C 1 -C 4 alkyl; or —C(O)O—C 1 -C 4 alkyl.
  • each R 5 is independently —OH, —F, —CH 2 CH 2 OH, —CH 2 C(O)OCH 2 CH 3 , —C(O)O-t-butyl, cyclopropyl, methyl or —C(O)CH 3 .
  • each R 5 is independently methyl or —C(O)CH 3 .
  • ring A is:
  • ring A is:
  • R 1 , R 4 , ring A and R 7 are as defined in formula I or any one of the above embodiments and R 10 is CR 11 or N wherein R 11 is —F, —SO 2 NH 2 , —SO 2 CH 3 , —CN, methoxy, —OCH 2 OH, —CH 2 OH, —SO 2 N(CH 3 ) 2 , —SO 2 NHCH 3 , —NHSO 2 CH 3 , —CH 2 CH 2 OH, —N(CH 3 ) 2 , t-butyl, cyclopropyl, —C(OH)(CH 3 ) 2 , —OCF 3 , —OCHF 2 , —O-cyclopropyl, -1-methyl-cyclopropyl, or pyrazolyl.
  • R 1 , R 4 , and ring A are as defined in formula I or any one of the above embodiments;
  • R 7′ is H or Cl; and
  • R 10 is CR 11 or N wherein R 11 is —F, —SO 2 NH 2 , —SO 2 CH 3 , —CN, methoxy, —OCH 2 OH, —CH 2 OH, —SO 2 N(CH 3 ) 2 , —SO 2 NHCH 3 , —NHSO 2 CH 3 , —CH 2 CH 2 OH, —N(CH 3 ) 2 , t-butyl, cyclopropyl, —C(OH)(CH 3 ) 2 , —OCF 3 , —OCHF 2 , —O-cyclopropyl, -1-methyl-cyclopropyl, or pyrazolyl.
  • R 1 , R 4 , and ring A are as defined in formula I or any one of the above embodiments and R 7 is H or Cl.
  • R 100 is H, methyl, C 1 , CF 3 , CN, OCH 3 , or N(R 6 ) 2 and R 101 is H, F or methyl;
  • R 4′ is H or R 4 and R 1 , R 2 , R 3 , R 4 and ring A as defined in Formula I or in any of the embodiments described herein.
  • R 4 is alkyl.
  • R 4 is aryl or heteroaryl, each independently substituted with one to three R 7 groups.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and ring A are as defined in any of the embodiments herein.
  • the compounds of this invention may contain one or more asymmetric centers and thus occur as racemates, racemic mixtures, scalemic mixtures, and diastereomeric mixtures, as well as single enantiomers or individual stereoisomers that are substantially free from another possible enantiomer or stereoisomer.
  • substantially free of other stereoisomers means a preparation enriched in a compound having a selected stereochemistry at one or more selected stereocenters by at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%.
  • enriched means that at least the designated percentage of a preparation is the compound having a selected stereochemistry at one or more selected stereocenters.
  • the compound is enriched in a specific stereoisomer by at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%.
  • the compounds of formula I, II, II-a, II-a-1, II-b or II-b-1 may also comprise one or more isotopic substitutions.
  • H may be in any isotopic form, including 1 H, 2 H (D or deuterium), and 3 H (T or tritium);
  • C may be in any isotopic form, including 11 C, 12 C, 13 C, and 14 C;
  • N may be in any isotopic form, including 13 N, 14 N and 15 N;
  • O may be in any isotopic form, including 15 O, 16 O and 18 O;
  • F may be in any isotopic form, including 18 F; and the like.
  • the compound is enriched in a specific isotopic form of H, C, N, O and/or F by at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%.
  • the compounds of this invention may also be represented in multiple tautomeric forms, in such instances, the invention expressly includes all tautomeric forms of the compounds described herein, even though only a single tautomeric form may be represented (e.g., alkylation of a ring system may result in alkylation at multiple sites, the invention expressly includes all such reaction products). All such isomeric forms of such compounds are expressly included in the present invention.
  • Synthetic chemistry transformations and protecting group methodologies useful in synthesizing the applicable compounds are known in the art and include, for example, those described in Larock R, Comprehensive Organic Transformations , VCH Publishers (1989); Greene, T W et al., Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley and Sons (1999); Fieser, L et al., Fieser and Fieser's Reagents for Organic Synthesis , John Wiley and Sons (1994); and Paquette, L, ed., Encyclopedia of Reagents for Organic Synthesis , John Wiley and Sons (1995) and subsequent editions thereof.
  • a corresponding salt of the active compound for example, a pharmaceutically acceptable salt.
  • a pharmaceutically acceptable salt examples are discussed in Berge et al., 1977, “Pharmaceutically Acceptable Salts.” J. Pharm. Sci. Vol. 66, pp. 1-19.
  • a salt may be formed with a suitable cation.
  • suitable inorganic cations include, but are not limited to, alkali metal ions such as Na + and K + , alkaline earth cations such as Ca 2+ and Mg 2+ , and other cations such as Al 3+ .
  • Suitable organic cations include, but are not limited to, ammonium ion (i.e., NH 4 + ) and substituted ammonium ions (e.g., NH 3 R + , NH 2 R 2+ , NHR 3+ , NR 4+ ).
  • suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine.
  • An example of a common quaternary ammonium ion is N(CH 3 ) 4 + .
  • a salt may be formed with a suitable anion.
  • suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.
  • Suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric.
  • a reference to a particular compound also includes salt forms thereof.
  • compositions may be formulated together with a pharmaceutically acceptable carrier or adjuvant into pharmaceutically acceptable compositions prior to be administered to a subject.
  • pharmaceutically acceptable compositions further comprise additional therapeutic agents in amounts effective for achieving a modulation of disease or disease symptoms, including those described herein.
  • pharmaceutically acceptable carrier or adjuvant refers to a carrier or adjuvant that may be administered to a subject, together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.
  • Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d- ⁇ -tocopherol polyethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-
  • Cyclodextrins such as ⁇ -, ⁇ -, and ⁇ -cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl- ⁇ -cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of the formulae described herein.
  • compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection.
  • the pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles.
  • the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • the pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • suitable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions.
  • surfactants such as Tweens or Spans and/or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions.
  • carriers which are commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried corn starch.
  • compositions of this invention may also be administered in the form of suppositories for rectal administration.
  • These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components.
  • suitable non-irritating excipient include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
  • Topical administration of the pharmaceutical compositions of this invention is useful when the desired treatment involves areas or organs readily accessible by topical application.
  • the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier with suitable emulsifying agents.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches are also included in this invention.
  • compositions of this invention may be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
  • compositions of this invention comprise a combination of a compound of the formulae described herein and one or more additional therapeutic or prophylactic agents
  • both the compound and the additional agent should be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen.
  • the additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition.
  • the compounds described herein can, for example, be administered by injection, intravenously, intraarterially, subdermally, intraperitoneally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.5 to about 100 mg/kg of body weight, alternatively dosages between 1 mg and 1000 mg/dose, every 4 to 120 hours, or according to the requirements of the particular drug.
  • the methods herein contemplate administration of an effective amount of compound or compound composition to achieve the desired or stated effect.
  • the pharmaceutical compositions of this invention will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion.
  • Such administration can be used as a chronic or acute therapy.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a typical preparation will contain from about 5% to about 95% active compound (w/w).
  • such preparations contain from about 20% to about 80% active compound.
  • a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level. Subjects may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
  • compositions described above comprising a compound of formula I, II, II-a, II-a-1, II-b, or II-b-1 or a compound described in any one of the embodiments herein, may further comprise another therapeutic agent useful for treating cancer.
  • a method for inhibiting a mutant IDH1 or IDH2 activity comprising contacting a subject in need thereof with a compound (including its tautomers and/or isotopologues) of structural formula I, II, II-a, II-a-1, II-b, or II-b-1 or a compound described in any one of the embodiments herein, or a pharmaceutically acceptable salt thereof.
  • the cancer to be treated is characterized by a mutant allele of IDH1 or IDH2 wherein the IDH1 or IDH2 mutation results in a new ability of the enzyme to catalyze the NAPH-dependent reduction of ⁇ -ketoglutarate to R( ⁇ )-2-hydroxyglutarate in a subject.
  • the mutant IDH1 has an R132X mutation.
  • the R132X mutation is selected from R132H, R132C, R132L, R132V, R132S and R132G.
  • the R132X mutation is R132H or R132C.
  • the R132X mutation is R132H.
  • Also provided are methods of treating a cancer characterized by the presence of a mutant allele of IDH1 comprising the step of administering to subject in need thereof (a) a compound of formula I, II, II-a, II-a-1, II-b, or II-b-1, or a compound described in any one of the embodiments herein, or a pharmaceutically acceptable salt thereof, or (b) a pharmaceutical composition comprising (a) and a pharmaceutically acceptable carrier.
  • the cancer to be treated is characterized by a mutant allele of IDH1 wherein the IDH1 mutation results in a new ability of the enzyme to catalyze the NAPH-dependent reduction of ⁇ -ketoglutarate to R( ⁇ )-2-hydroxyglutarate in a patient.
  • the IDH1 mutation is an R132X mutation.
  • the R132X mutation is selected from R132H, R132C, R132L, R132V, R132S and R132G.
  • the R132X mutation is R132H or R132C.
  • a cancer can be analyzed by sequencing cell samples to determine the presence and specific nature of (e.g., the changed amino acid present at) a mutation at amino acid 132 of IDH1.
  • mutant alleles of IDH1 wherein the IDH1 mutation results in a new ability of the enzyme to catalyze the NAPH-dependent reduction of ⁇ -ketoglutarate to R( ⁇ )-2-hydroxyglutarate, and in particular R132H mutations of IDH1, characterize a subset of all types of cancers, without regard to their cellular nature or location in the body.
  • the compounds and methods of this invention are useful to treat any type of cancer that is characterized by the presence of a mutant allele of IDH1 imparting such activity and in particular an IDH1 R132H or R132C mutation.
  • the efficacy of cancer treatment is monitored by measuring the levels of 2HG in the subject. Typically levels of 2HG are measured prior to treatment, wherein an elevated level is indicated for the use of the compound of formula I, II, II-a, II-a-1, II-b, or II-b-1 or a compound described in any one of the embodiments described herein to treat the cancer.
  • the level of 2HG is determined during the course of and/or following termination of treatment to establish efficacy.
  • the level of 2HG is only determined during the course of and/or following termination of treatment. A reduction of 2HG levels during the course of treatment and following treatment is indicative of efficacy.
  • a determination that 2HG levels are not elevated during the course of or following treatment is also indicative of efficacy.
  • the these 2HG measurements will be utilized together with other well-known determinations of efficacy of cancer treatment, such as reduction in number and size of tumors and/or other cancer-associated lesions, improvement in the general health of the subject, and alterations in other biomarkers that are associated with cancer treatment efficacy.
  • 2HG can be detected in a sample by LC/MS.
  • the sample is mixed 80:20 with methanol, and centrifuged at 3,000 rpm for 20 minutes at 4 degrees Celsius.
  • the resulting supernatant can be collected and stored at ⁇ 80 degrees Celsius prior to LC-MS/MS to assess 2-hydroxyglutarate levels.
  • LC liquid chromatography
  • Each method can be coupled by negative electrospray ionization (ESI, ⁇ 3.0 kV) to triple-quadrupole mass spectrometers operating in multiple reaction monitoring (MRM) mode, with MS parameters optimized on infused metabolite standard solutions.
  • ESI negative electrospray ionization
  • MRM multiple reaction monitoring
  • Metabolites can be separated by reversed phase chromatography using 10 mM tributyl-amine as an ion pairing agent in the aqueous mobile phase, according to a variant of a previously reported method (Luo et al. J Chromatogr A 1147, 153-64, 2007).
  • Another method is specific for 2-hydroxyglutarate, running a fast linear gradient from 50%-95% B (buffers as defined above) over 5 minutes.
  • a Synergi Hydro-RP, 100 mm ⁇ 2 mm, 2.1 ⁇ m particle size (Phenomonex) can be used as the column, as described above.
  • Metabolites can be quantified by comparison of peak areas with pure metabolite standards at known concentration.
  • Metabolite flux studies from 13 C-glutamine can be performed as described, e.g., in Munger et al. Nat Biotechnol 26, 1179-86, 2008.
  • 2HG is directly evaluated.
  • a derivative of 2HG formed in process of performing the analytic method is evaluated.
  • a derivative can be a derivative formed in MS analysis.
  • Derivatives can include a salt adduct, e.g., a Na adduct, a hydration variant, or a hydration variant which is also a salt adduct, e.g., a Na adduct, e.g., as formed in MS analysis.
  • a metabolic derivative of 2HG is evaluated.
  • examples include species that build up or are elevated, or reduced, as a result of the presence of 2HG, such as glutarate or glutamate that will be correlated to 2HG, e.g., R-2HG.
  • Exemplary 2HG derivatives include dehydrated derivatives such as the compounds provided below or a salt adduct thereof:
  • the cancer is a tumor wherein at least 30, 40, 50, 60, 70, 80 or 90% of the tumor cells carry an IDH1 mutation, and in particular an IDH1 R132H or R132C mutation, at the time of diagnosis or treatment.
  • IDH1 R132X mutations are known to occur in certain types of cancers as indicated in Table 2, below.
  • IDH1 R132H mutations have been identified in glioblastoma, acute myelogenous leukemia, sarcoma, melanoma, non-small cell lung cancer, cholangiocarcinomas, chondrosarcoma, myelodysplastic syndromes (MDS), myeloproliferative neoplasm (MPN), colon cancer, and angio-immunoblastic non-Hodgkin's lymphoma (NHL).
  • the methods described herein are used to treat glioma (glioblastoma), acute myelogenous leukemia, sarcoma, melanoma, non-small cell lung cancer (NSCLC) or cholangiocarcinomas, chondrosarcoma, myelodysplastic syndromes (MDS), myeloproliferative neoplasm (MPN), colon cancer, or angio-immunoblastic non-Hodgkin's lymphoma (NHL) in a patient.
  • glioma glioblastoma
  • NSCLC non-small cell lung cancer
  • MDS myelodysplastic syndromes
  • MDN myeloproliferative neoplasm
  • COL angio-immunoblastic non-Hodgkin's lymphoma
  • the cancer is a cancer selected from any one of the cancer types listed in Table 2, and the IDH R132X mutation is one or more of the IDH1 R132X mutations listed in Table 2 for that particular cancer type.
  • the methods described herein are used to treat glioma (glioblastoma), acute myelogenous leukemia, sarcoma, melanoma, non-small cell lung cancer (NSCLC), cholangiocarcinomas (e.g., intrahepatic cholangiocarcinoma (IHCC)), chondrosarcoma, myelodysplastic syndromes (MDS), myeloproliferative neoplasm (MPN), prostate cancer, chronic myelomonocytic leukemia (CMML), B-acute lymphoblastic leukemias (B-ALL), B-acute lymphoblastic leukemias (B-ALL), myeloid sarcoma, multiple myeloma, lymphoma colon cancer, or angio-immunoblastic non-Hodgkin's lymphoma (NHL) in a patient.
  • glioma glioblastoma
  • IHCC intrahepatic
  • the cancer to be treated is an advanced hematologic malignancy selected from lymphoma (e.g., Non-Hodgkin lymphoma (NHL) such B-cell lymphoma (e.g., Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and mantle cell lymphoma) and T-cell lymphoma (e.g., mycosis fungoides, anaplastic large cell lymphoma, and precursor T-lymphoblastic lymphoma).
  • NHL Non-Hodgkin lymphoma
  • B-cell lymphoma e.g., Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)
  • Also provided are methods of treating a disease selected from Maffucci syndrome and Ollier disease, characterized by the presence of a mutant allele of IDH1 comprising the step of administering to subject in need thereof (a) a compound of Formula I, II, II-a, II-a-1, II-b, or II-b-1 or a compound described in any one of the embodiments herein, or a pharmaceutically acceptable salt thereof, or (b) a pharmaceutical composition comprising (a) and a pharmaceutically acceptable carrier.
  • Treatment methods described herein can additionally comprise various evaluation steps prior to and/or following treatment with a compound of formula I, II, II-a, II-a-1, II-b, or II-b-1 or a compound described in any one of the embodiments described herein.
  • the method further comprises the step of evaluating the growth, size, weight, invasiveness, stage and/or other phenotype of the cancer.
  • the method further comprises the step of evaluating the IDH1 genotype of the cancer. This may be achieved by ordinary methods in the art, such as DNA sequencing, immuno analysis, and/or evaluation of the presence, distribution or level of 2HG.
  • the method further comprises the step of determining the 2HG level in the subject.
  • This may be achieved by spectroscopic analysis, e.g., magnetic resonance-based analysis, e.g., MRI and/or MRS measurement, sample analysis of bodily fluid, such as serum or spinal cord fluid analysis, or by analysis of surgical material, e.g., by mass-spectroscopy.
  • the methods described herein comprise the additional step of co-administering to a subject in need thereof a second therapy e.g., an additional cancer therapeutic agent or an additional cancer treatment.
  • additional cancer therapeutic agents include for example, chemotherapy, targeted therapy, antibody therapies, immunotherapy, and hormonal therapy.
  • Additional cancer treatments include, for example: surgery, and radiation therapy. Examples of each of these treatments are provided below.
  • co-administering means that the additional cancer therapeutic agent may be administered together with a compound of this invention as part of a single dosage form (such as a composition of this invention comprising a compound of the invention and an second therapeutic agent as described above) or as separate, multiple dosage forms.
  • the additional cancer therapeutic agent may be administered prior to, consecutively with, or following the administration of a compound of this invention.
  • both the compounds of this invention and the second therapeutic agent(s) are administered by conventional methods.
  • composition of this invention comprising both a compound of the invention and a second therapeutic agent
  • administration of a composition of this invention does not preclude the separate administration of that same therapeutic agent, any other second therapeutic agent or any compound of this invention to said subject at another time during a course of treatment.
  • co-administering as used herein with respect to an additional cancer treatment means that the additional cancer treatment may occur prior to, consecutively with, concurrently with or following the administration of a compound of this invention.
  • the additional cancer therapeutic agent is a chemotherapy agent.
  • chemotherapeutic agents used in cancer therapy include, for example, antimetabolites (e.g., folic acid, purine, and pyrimidine derivatives), alkylating agents (e.g., nitrogen mustards, nitrosoureas, platinum, alkyl sulfonates, hydrazines, triazenes, aziridines, spindle poison, cytotoxic agents, topoisomerase inhibitors and others) and hypomethylating agents (e.g., decitabine (5-aza-deoxycytidine), zebularine, isothiocyanates, azacitidine (5-azacytidine, 5-fluoro-2′-deoxycytidine, 5,6-dihydro-5-azacytidine and others).
  • antimetabolites e.g., folic acid, purine, and pyrimidine derivatives
  • alkylating agents e.g., nitrogen mustards, nitrosoure
  • agents include Aclarubicin, Actinomycin, Alitretinoin, Altretamine, Aminopterin, Aminolevulinic acid, Amrubicin, Amsacrine, Anagrelide, Arsenic trioxide, Asparaginase, Atrasentan, Belotecan, Bexarotene, bendamustine, Bleomycin, Bortezomib, Busulfan, Camptothecin, Capecitabine, Carboplatin, Carboquone, Carmofur, Carmustine, Celecoxib, Chlorambucil, Chlormethine, Cisplatin, Cladribine, Clofarabine, Crisantaspase, Cyclophosphamide, Cytarabine, dacarbazine, Dactinomycin, Daunorubicin, Decitabine, Demecolcine, Docetaxel, Doxorubicin, Efaproxiral, Elesclomol, Elsamitrucin, Eno
  • two or more drugs are often given at the same time.
  • two or more chemotherapy agents are used as combination chemotherapy.
  • the additional cancer therapeutic agent is a differentiation agent.
  • Such differentiation agent includes retinoids (such as all-trans-retinoic acid (ATRA), 9-cis retinoic acid, 13-cis-retinoic acid (13-cRA) and 4-hydroxy-phenretinamide (4-HPR)); arsenic trioxide; histone deacetylase inhibitors HDACs (such as azacytidine (Vidaza) and butyrates (e.g., sodium phenylbutyrate)); hybrid polar compounds (such as hexamethylene bisacetamide ((HMBA)); vitamin D; and cytokines (such as colony-stimulating factors including G-CSF and GM-CSF, and interferons).
  • retinoids such as all-trans-retinoic acid (ATRA), 9-cis retinoic acid, 13-cis-retinoic acid (13-cRA) and 4-hydroxy-phenretinamide (4-HPR)
  • the additional cancer therapeutic agent is a targeted therapy agent.
  • Targeted therapy constitutes the use of agents specific for the deregulated proteins of cancer cells.
  • Small molecule targeted therapy drugs are generally inhibitors of enzymatic domains on mutated, overexpressed, or otherwise critical proteins within the cancer cell.
  • Prominent examples are the tyrosine kinase inhibitors such as Axitinib, Bosutinib, Cediranib, dasatinib, erlotinib, imatinib, gefitinib, lapatinib, Lestaurtinib, Nilotinib, Semaxanib, Sorafenib, Sunitinib, and Vandetanib, and also cyclin-dependent kinase inhibitors such as Alvocidib and Seliciclib.
  • Monoclonal antibody therapy is another strategy in which the therapeutic agent is an antibody which specifically binds to a protein on the surface of the cancer cells.
  • Examples include the anti-HER2/neu antibody trastuzumab (HERCEPTIN®) typically used in breast cancer, and the anti-CD20 antibody rituximab and Tositumomab typically used in a variety of B-cell malignancies.
  • Other exemplary antibodies include Cetuximab, Panitumumab, Trastuzumab, Alemtuzumab, Bevacizumab, Edrecolomab, and Gemtuzumab.
  • Exemplary fusion proteins include Aflibercept and Denileukin diftitox.
  • the targeted therapy can be used in combination with a compound described herein, e.g., a biguanide such as metformin or phenformin, preferably phenformin.
  • Targeted therapy can also involve small peptides as “homing devices” which can bind to cell surface receptors or affected extracellular matrix surrounding the tumor. Radionuclides which are attached to these peptides (e.g., RGDs) eventually kill the cancer cell if the nuclide decays in the vicinity of the cell.
  • RGDs Radionuclides which are attached to these peptides
  • An example of such therapy includes BEXXAR®.
  • the additional cancer therapeutic agent is an immunotherapy agent.
  • Cancer immunotherapy refers to a diverse set of therapeutic strategies designed to induce the subject's own immune system to fight the tumor. Contemporary methods for generating an immune response against tumors include intravesicular BCG immunotherapy for superficial bladder cancer, and use of interferons and other cytokines to induce an immune response in renal cell carcinoma and melanoma subjects.
  • Allogeneic hematopoietic stem cell transplantation can be considered a form of immunotherapy, since the donor's immune cells will often attack the tumor in a graft-versus-tumor effect.
  • the immunotherapy agents can be used in combination with a compound or composition described herein.
  • the additional cancer therapeutic agent is a hormonal therapy agent.
  • the growth of some cancers can be inhibited by providing or blocking certain hormones.
  • hormone-sensitive tumors include certain types of breast and prostate cancers. Removing or blocking estrogen or testosterone is often an important additional treatment.
  • administration of hormone agonists, such as progestogens may be therapeutically beneficial.
  • the hormonal therapy agents can be used in combination with a compound or a composition described herein.
  • Other possible additional therapeutic modalities include imatinib, gene therapy, peptide and dendritic cell vaccines, synthetic chlorotoxins, and radiolabeled drugs and antibodies.
  • DCM dichloromethane
  • TEA triethylamine
  • DPPA diphenylphosphoryl azide
  • TPA trifluoroacetic acid
  • DIPEA N,N-Diisopropyiethylamine
  • TFAA trifluoroacetic anhydride
  • Step B Tert-butyl 3,3-difluorocyclobutylcarbamate
  • tert-butyl 3,3-difluoro-cyclobutylcarbamate (12.1 g, 58.42 mmol) was added in one portion dropwise at 0° C.
  • the reaction mixture was stirred at 0° C. for 20 min, and then allowed to warm up to r.t and stirred for another 1.5 h.
  • the reaction mixture was concentrated and dissolved in H 2 O (200 mL).
  • Step A Benzyl 3-oxocyclobutanecarboxylate
  • Step B Benzyl 3,3-difluorocyclobutanecarboxylate
  • Step D Tert-butyl 3,3-difluorocyclobutylcarbamate
  • the compound was synthesized as outlined in step D of method A set forth above.
  • the compound was synthesized as outlined in step E of method A set forth above.
  • the compound was synthesized via the general procedure as the step G in method A set forth above.
  • Step B Tert-butyl 4-oxocyclohexylcarbamate
  • Step C Tert-butyl 4,4-difluorocyclohexylcarbamate
  • Step A Tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate
  • Step B 4-(3-Nitrophenyl)-1H-pyrazole
  • Step B 2-(3-(dibenzylamino)phenyl)propan-2-ol
  • Methylmagnesium bromide (1 M in THF, 2.4 mL, 2.4 mmol) was dissolved in THF (5 mL) and placed in an ice-water bath.
  • Methyl 3-(dibenzylamino)-5-fluorobenzoate (280 mg, 0.8 mmol) in THF (5 mL) was then slowly added to the reaction mixture. This mixture was stirred for 3 hr while maintaining an internal temperature range between 15 to 25° C. Then the mixture was cooled to 0° C. and treated with ammonium chloride solution, then extracted with ethyl acetate (3 ⁇ 30 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 , and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the desired product. MS: 350 (M+1) + .
  • Step A (S)-3-Amino-2-(((benzyloxy)carbonyl)amino)propanoic acid
  • Step B (S)-Methyl 3-amino-2-(((benzyloxy)carbonyl)amino)propanoate hydrochloride
  • Step C (S)-Methyl 3-((2-(benzyloxy)-2-oxoethyl)amino)-2-(((benzyloxy)carbonyl)amino)pro-paneate
  • Step D (S)-Methyl 3-((2-(benzyloxy)-2-oxoethyl)(tert-butoxycarbonyl)amino)-2-(((benzyloxy) carbonyl)amino)propanoate
  • Step E (S)-2-((2-Amino-3-methoxy-3-oxopropyl)(tert-butoxycarbonyl)amino)acetic acid
  • Step E (S)-1-tent-Butyl 3-methyl 5-oxopiperazine-1,3-dicarboxylate
  • Step F (S)-4-(tent-Butoxycarbonyl)-6-oxopiperazine-2-carboxylic acid
  • Compound 2 was prepared according to the following scheme, using the following protocol.
  • Step B (S)-1-Methyl-5-oxopyrrolidine-2-carboxylic acid
  • Step A (S)—N-(1-(2-Chlorophenyl)-2-((4,4-difluorocyclohexyl)amino)-2-oxoethyl)-N-(3-fluoro-phenyl)-5-oxopyrrolidine-2-carboxamide
  • Step B (S)—N—((S)-1-(2-Chlorophenyl)-2-((4,4-difluorocyclohexyl)amino)-2-oxoethyl)-N-(3-fluorophenyl)-5-oxo-1-(pyrimidin-2-yl)pyrrolidine-2-carboxamide and (S)—N—((R)-1-(2-chlorophenyl)-2-((4,4-difluorocyclohexyl)amino)-2-oxoethyl)-N-(3-fluorophenyl)-5-oxo-1-(pyrimidin-2-yl)pyrrolidine-2-carboxamide
  • Compound 44 was prepared according to the following scheme, using the following protocol.
  • Compound 9 was prepared according to the following scheme, using the following protocol.
  • Step B (4S)—N-(1-(2-Chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethyl)-N-(3-fluoro-phenyl)-2-oxooxazolidine-4-carboxamide
  • Step C (S)—N-aR)-1-(2-Chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethyl)-N-(3-fluorophenyl)-2-oxo-3-(pyrimidin-2-yl)oxazolidine-4-carboxamide and (S)—N—((S)-1-(2-chloro-phenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethyl)-N-(3-fluorophenyl)-2-oxo-3-(pyrimidin-2-yl)oxazolidine-4-carboxamide
  • Step B (S)—N-(1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-N-(3-fluoro-phenyl)-6-oxopiperidine-2-carboxamide
  • Step C (S)—N—((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-N-(3-fluorophenyl)-6-oxo-1-(pyrimidin-2-yl)piperidine-2-carboxamide and (S)—N—((R)-1-(2-chloro-phenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-N-(3-fluorophenyl)-6-oxo-1-(pyrimidin-2-yl)piperidine-2-carboxamide
  • Compound 30 was prepared according to the following scheme, using the following protocol.
  • Step B (S)-Benzyl-4-(4-methoxybenzyl)-5-oxomorpholine-3-carboxylate
  • Step E (S)—N—((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-N-(3-fluorophenyl)-5-oxomorpholine-3-carboxamide
  • Step D 5-((2S)—N-(1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)1-(4-cyano pyridin-2-yl)-5-oxopyrrolidine-2-carboxamido)isophthalamide
  • Step E (2S)—N-(1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)1-(4-cyano pyridin-2-yl)-N-(3,5-dicyanophenyl)-5-oxopyrrolidine-2-carboxamide
  • Compound 97 was synthesized via the UGI reaction procedure set forth herein, using the appropriate aldehyde, amine, carboxylic acid, isocyanide and halo-substituted aromatic ring or heterocyclic (heteroaromatic) ring and purified via standard methods.
  • Oxazole-5-carboxamide (560 mg, 5.0 mmol) was dissolved in anhydrous THF (7.5 mL) and flushed with N 2 . The solution was cooled to ⁇ 42° C. and treated with fresh LiHMDS (15 mL, 1 M in THF). The solution became dark yellow was stirred for 20 min and followed by the addition of a solution of ZnCl 2 (30 mL, 0.5 M in THF). The reaction was warmed to 0° C. for 1 hr. After solid iodine (1.65 g, 6.5 mmol) was added, the reaction mixture was stirred at room temperature for another 1 hr and then poured into saturated Na 2 S 2 O 3 solution containing 25% aq. NH 3 solution.
  • Step C 2-((S)-2-(((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)(3,5-difluorophenyl)carbamoyl)-5-oxopyrrolidin-1-yl)oxazole-5-carboxamide
  • Step D (S)—N—((S)-1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(5-cyanooxazol-2-yl)-N-(3,5-difluorophenyl)-5-oxopyrrolidine-2-carboxamide
  • Step A (2S,4R)-1-tert-Butyl 2-methyl 4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate
  • Step B (2S,4R)-1-tert-Butyl 2-methyl 4-((tert-butyldimethylsilyl)oxy)-5-oxopyrrolidine-1,2-dicarboxylate
  • Step F (2S,4R)—N-(1-(2-Chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-N-(3-cyano-phenyl)-1-(4-cyanopyridin-2-yl)-4-hydroxy-5-oxopyrrolidine-2-carboxamide
  • Step D (2S)-4-(tert-Butyldimethylsilyloxy)-N-(1-(2-chlorophenyl)-2-(3,3-difluorocyclobut-ylamino)-2-oxoethyl)-N-(3-fluorophenyl)-4-methyl-5-oxopyrrolidine-2-carboxamide
  • Step E (2S)-4-(tert-Butyldimethylsilyloxy)-N-(1-(2-chlorophenyl)-2-(3,3-difluorocyclobutyl-amino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-N-(3-fluorophenyl)-4-methyl-5-oxopyrrolidine-2-carboxamide
  • Step F (2S)—N—((R)-1-(2-Chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-N-(3-fluorophenyl)-4-hydroxy-4-methyl-5-oxopyrrolidine-2-carboxamide

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Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150087600A1 (en) * 2012-01-19 2015-03-26 Agios Pharmaceuticals, Inc Therapeutically active compounds and their methods of use
US20150316278A1 (en) * 2013-03-22 2015-11-05 Qingdao Hisense Hitachi Air-conditioning Systems Co., Ltd. Air conditioner heat-radiating circulation system
US9512107B2 (en) 2012-01-06 2016-12-06 Agios Pharmaceuticals, Inc. Therapeutically active compositions and their methods of use
WO2017005674A1 (en) * 2015-07-07 2017-01-12 Bayer Pharma Aktiengesellschaft 2-aryl- and 2-arylalkyl-benzimidazoles as midh1 inhibitors
US9579324B2 (en) 2013-07-11 2017-02-28 Agios Pharmaceuticals, Inc Therapeutically active compounds and their methods of use
US9662327B2 (en) 2011-06-17 2017-05-30 Agios Pharmaceuticals, Inc Phenyl and pyridinyl substituted piperidines and piperazines as inhibitors of IDH1 mutants and their use in treating cancer
US9724350B2 (en) 2013-07-11 2017-08-08 Agios Pharmaceuticals, Inc. N,6-bis(aryl or heteroaryl)-1,3,5-triazine-2,4-diamine compounds as IDH2 mutants inhibitors for the treatment of cancer
US9850277B2 (en) 2012-01-19 2017-12-26 Agios Pharmaceuticals, Inc. Therapeutically active compositions and their methods of use
US9856279B2 (en) 2011-06-17 2018-01-02 Agios Pharmaceuticals, Inc. Therapeutically active compositions and their methods of use
US9968595B2 (en) 2014-03-14 2018-05-15 Agios Pharmaceuticals, Inc. Pharmaceutical compositions of therapeutically active compounds
US9982309B2 (en) 2009-10-21 2018-05-29 Agios Pharmaceuticals, Inc. Method for treating cell proliferation related disorders
US9980961B2 (en) 2011-05-03 2018-05-29 Agios Pharmaceuticals, Inc. Pyruvate kinase activators for use in therapy
US10017495B2 (en) 2013-07-11 2018-07-10 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
US10029987B2 (en) 2009-06-29 2018-07-24 Agios Pharmaceuticals, Inc. Therapeutic compounds and compositions
US10202339B2 (en) 2012-10-15 2019-02-12 Agios Pharmaceuticals, Inc. Therapeutic compounds and compositions
US10376510B2 (en) 2013-07-11 2019-08-13 Agios Pharmaceuticals, Inc. 2,4- or 4,6-diaminopyrimidine compounds as IDH2 mutants inhibitors for the treatment of cancer
EP3402571A4 (en) * 2016-01-15 2019-08-28 The J. David Gladstone Institutes METHOD FOR THE TREATMENT OF DISORDERS BY METABOLIC CONTROL OF T-CELL DIFFERENTIATION
US10610125B2 (en) 2009-03-13 2020-04-07 Agios Pharmaceuticals, Inc. Methods and compositions for cell-proliferation-related disorders
US10653710B2 (en) 2015-10-15 2020-05-19 Agios Pharmaceuticals, Inc. Combination therapy for treating malignancies
US10689414B2 (en) 2013-07-25 2020-06-23 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
US10980788B2 (en) 2018-06-08 2021-04-20 Agios Pharmaceuticals, Inc. Therapy for treating malignancies
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
US11234976B2 (en) 2015-06-11 2022-02-01 Agios Pharmaceuticals, Inc. Methods of using pyruvate kinase activators
US11419859B2 (en) 2015-10-15 2022-08-23 Servier Pharmaceuticals Llc Combination therapy for treating malignancies
US11739943B2 (en) 2021-12-01 2023-08-29 William B. McEvoy Tabletop cooking assembly

Families Citing this family (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP6272833B2 (ja) * 2013-04-04 2018-01-31 武田薬品工業株式会社 複素環化合物
TW201736341A (zh) * 2016-03-22 2017-10-16 Chia Tai Tianqing Pharmaceutical Group Co Ltd 丙啶磺醯胺類化合物及其使用方法
ES2842448T3 (es) 2016-03-22 2021-07-14 Lianyungang Runzhong Pharmaceutical Co Ltd Compuesto de sultama y método de aplicación del mismo
CN107556366B (zh) * 2016-06-30 2025-02-07 上海海和药物研究开发股份有限公司 具有突变型异柠檬酸脱氢酶抑制活性的化合物、其制备方法及用途
CA3067035A1 (en) * 2017-06-12 2018-12-20 Agios Pharmaceuticals, Inc. Methods of treating brain tumors using combination therapy
US12064436B2 (en) 2017-06-12 2024-08-20 Servier Pharmaceuticals Llc Methods of treating brain tumors using combination therapy
KR102707847B1 (ko) * 2017-09-22 2024-09-23 치아타이 티안큉 파마수티컬 그룹 주식회사 결정형 설파마이드 화합물
AU2018346597B2 (en) 2017-10-06 2023-07-13 Forma Therapeutics, Inc. Inhibiting Ubiquitin Specific Peptidase 30
WO2019099653A1 (en) * 2017-11-16 2019-05-23 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
JP7449242B2 (ja) 2018-05-17 2024-03-13 フォーマ セラピューティクス，インコーポレイテッド ユビキチン特異的ペプチダーゼ３０（ｕｓｐ３０）阻害剤として有用な縮合二環化合物
JP7530889B2 (ja) 2018-10-05 2024-08-08 フォーマ セラピューティクス，インコーポレイテッド ユビキチン特異的プロテアーゼ３０（ｕｓｐ３０）阻害剤として作用する縮合ピロリン
US12358886B2 (en) 2019-08-09 2025-07-15 Artios Pharma Limited Heterocyclic compounds for use in the treatment of cancer
TW202120486A (zh) * 2019-08-09 2021-06-01 英商阿帝歐斯製藥有限公司 新穎化合物
CN111349081B (zh) * 2020-04-28 2021-01-15 宁波大学科学技术学院 一种Ivosidenib及其中间体的手性合成方法
CN116332905B (zh) * 2021-12-23 2025-07-08 上海翊石医药科技有限公司 (s)-n-苯基-1-(吡啶-2-基)吡咯烷-2-甲酰胺衍生物
EP4455129A4 (en) * 2021-12-30 2025-05-07 Shanghai Apeiron Therapeutics Company Limited Dna polymerase theta inhibitor and use thereof
KR20240167786A (ko) 2022-01-10 2024-11-28 레클루딕스 파마, 인크. Stat 조정제 및 그의 용도
CN118221638B (zh) * 2022-12-19 2025-09-19 艾立康药业股份有限公司 作为DNA聚合酶Theta抑制剂的杂环化合物
JP2026513172A (ja) * 2023-03-31 2026-04-23 アヴェロス セラピューティクス インコーポレイテッド 置換されたスルタム化合物誘導体及びその薬学的用途

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130190249A1 (en) * 2012-01-19 2013-07-25 Agios Pharmaceuticals, Inc Therapeutically active compositions and their methods of use

Family Cites Families (158)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2390529A (en) 1942-02-03 1945-12-11 Ernst A H Friedheim Hydrazino-1,3,5-triazino derivatives of substituted phenylarsenic compounds
NL125847C (https=) 1963-02-15
BE754242A (fr) 1970-07-15 1971-02-01 Geigy Ag J R Diamino-s-triazines et dinitro-s-triazines
US3867383A (en) 1971-03-29 1975-02-18 Ciba Geigy Corp Monoanthranilatoanilino-s-triazines
BE793501A (fr) 1971-12-31 1973-06-29 Ciba Geigy Composes heterocycliques et produits phytopharmaceutiques qui en contiennent
CH606334A5 (https=) 1974-06-21 1978-10-31 Ciba Geigy Ag
DE2928485A1 (de) 1979-07-14 1981-01-29 Bayer Ag Verwendung von harnstoffderivaten als arzneimittel bei der behandlung von fettstoffwechselstoerungen
JPS58186682A (ja) 1982-04-27 1983-10-31 日本化薬株式会社 セルロ−ス又はセルロ−ス含有繊維材料の染色法
DE3512630A1 (de) 1985-04-06 1986-10-23 Hoechst Ag, 6230 Frankfurt Verfahren zum faerben oder bedrucken von cellulosefasern oder cellulosemischfasern
US5041443A (en) 1989-02-21 1991-08-20 Dainippon Pharmaceutical Co., Ltd. Medicament for treating cerebral insufficiency diseases, novel 2-(1-piperazinyl)-4-phenylcycloalkanopyrimidine derivatives, and process for the production thereof
DK0385237T3 (da) 1989-03-03 1994-07-25 Dainippon Pharmaceutical Co 2-(1-Piperazinyl)-4-phenylcycloalkanopyridinderivater, fremgangsmåde til fremstilling deraf og farmaceutisk præparat indeholdende dem
JPH0499768A (ja) 1990-08-17 1992-03-31 Dainippon Pharmaceut Co Ltd ４―（４―フェニルピリジン―２―イル）ピペラジン―１―オキシド誘導体
JPH05140126A (ja) 1991-11-26 1993-06-08 Hokko Chem Ind Co Ltd トリアゾール誘導体および除草剤
CA2131004A1 (en) 1992-02-28 1993-09-02 Hideshi Kobayashi S-triazine derivative and remedy for estrogen-dependent disease containing said derivative as effective component
IL115420A0 (en) 1994-09-26 1995-12-31 Zeneca Ltd Aminoheterocyclic derivatives
IL117580A0 (en) 1995-03-29 1996-07-23 Merck & Co Inc Inhibitors of farnesyl-protein transferase and pharmaceutical compositions containing them
FR2735127B1 (fr) 1995-06-09 1997-08-22 Pf Medicament Nouvelles piperazines heteroaromatiques utiles comme medicaments.
ES2100129B1 (es) 1995-10-11 1998-02-16 Medichem Sa Nuevos compuestos aminopiridinicos policiclicos inhibidores de acetilcolinesterasa, procedimiento para su preparacion y su utilizacion.
GB9602166D0 (en) 1996-02-02 1996-04-03 Zeneca Ltd Aminoheterocyclic derivatives
US6313127B1 (en) 1996-02-02 2001-11-06 Zeneca Limited Heterocyclic compounds useful as pharmaceutical agents
US5807876A (en) 1996-04-23 1998-09-15 Vertex Pharmaceuticals Incorporated Inhibitors of IMPDH enzyme
JPH09291034A (ja) 1996-02-27 1997-11-11 Yoshitomi Pharmaceut Ind Ltd 縮合ピリジン化合物およびその医薬としての用途
US6262113B1 (en) 1996-03-20 2001-07-17 Smithkline Beecham Corporation IL-8 receptor antagonists
AU722662B2 (en) 1996-05-20 2000-08-10 Darwin Discovery Limited Quinoline sulfonamides as TNF inhibitors and as PDE-IV inhibitors
US5984882A (en) 1996-08-19 1999-11-16 Angiosonics Inc. Methods for prevention and treatment of cancer and other proliferative diseases with ultrasonic energy
CA2271744A1 (en) 1996-11-14 1998-05-22 Isao Hashiba Cyanoethylmelamine derivatives and process for producing the same
US6399358B1 (en) 1997-03-31 2002-06-04 Thomas Jefferson University Human gene encoding human chondroitin 6-sulfotransferase
JPH11158073A (ja) 1997-09-26 1999-06-15 Takeda Chem Ind Ltd アデノシンａ３拮抗剤
US7517880B2 (en) 1997-12-22 2009-04-14 Bayer Pharmaceuticals Corporation Inhibition of p38 kinase using symmetrical and unsymmetrical diphenyl ureas
WO1999032463A1 (en) 1997-12-22 1999-07-01 Bayer Corporation INHIBITION OF p38 KINASE USING SYMMETRICAL AND UNSYMMETRICAL DIPHENYL UREAS
WO2000002864A1 (en) 1998-07-10 2000-01-20 Martens Juergen Precusors for pna-monomers
ATE498409T1 (de) 1998-08-06 2011-03-15 Mountain View Pharmaceuticals Peg-uricase konjugate und verwendung davon
US6783965B1 (en) 2000-02-10 2004-08-31 Mountain View Pharmaceuticals, Inc. Aggregate-free urate oxidase for preparation of non-immunogenic polymer conjugates
UY25842A1 (es) 1998-12-16 2001-04-30 Smithkline Beecham Corp Antagonistas de receptores de il-8
AU5379900A (en) 1999-06-07 2000-12-28 Shire Biochem Inc. Thiophene integrin inhibitors
WO2001016097A1 (en) 1999-08-27 2001-03-08 Sugen, Inc. Phosphate mimics and methods of treatment using phosphatase inhibitors
CZ2002959A3 (cs) 1999-09-17 2002-07-17 Millennium Pharmaceuticals, Inc. Inhibitory faktoru Xa
ES2316383T3 (es) 1999-09-17 2009-04-16 Millennium Pharmaceuticals, Inc. Benzamidas e inhibidores relacionados del factor xa.
EP1246823A1 (en) 1999-12-28 2002-10-09 Pharmacopeia, Inc. Pyrimidine and triazine kinase inhibitors
WO2001064642A2 (en) 2000-02-29 2001-09-07 Cor Therapeutics, Inc. Benzamides and related inhibitors of factor xa
EP1301484A2 (en) 2000-07-20 2003-04-16 Neurogen Corporation Capsaicin receptor ligands
JP4113323B2 (ja) 2000-08-07 2008-07-09 富士フイルム株式会社 アゾ色素及びそれを含むインクジェット記録用インク、並びにインクジェット記録方法
US6525091B2 (en) 2001-03-07 2003-02-25 Telik, Inc. Substituted diarylureas as stimulators for Fas-mediated apoptosis
EP1389194A2 (en) 2001-04-27 2004-02-18 Vertex Pharmaceuticals Incorporated Inhibitors of bace
CN1800185A (zh) 2001-06-11 2006-07-12 比奥维特罗姆股份公司 取代的磺酰胺化合物、其制备方法及其作为治疗cns疾病、肥胖和ii型糖尿病的药物的应用
CA2450934A1 (en) 2001-06-19 2002-12-27 Marco Dodier Pyrimidine inhibitors of phosphodiesterase (pde) 7
DE60238066D1 (de) 2001-08-17 2010-12-02 Basf Se Triazinderivate und deren verwendung als sonnenschutzmittel
JP4753336B2 (ja) 2001-09-04 2011-08-24 日本化薬株式会社 新規アリル化合物及びその製法
US6878196B2 (en) 2002-01-15 2005-04-12 Fuji Photo Film Co., Ltd. Ink, ink jet recording method and azo compound
US20040067234A1 (en) 2002-07-11 2004-04-08 Paz Einat Isocitrate dehydrogenase and uses thereof
EP2256108B1 (en) 2002-07-18 2016-03-23 Janssen Pharmaceutica NV Substituted triazine kinase inhibitors
JP2004083610A (ja) 2002-08-22 2004-03-18 Fuji Photo Film Co Ltd インクセット、インクカートリッジ、記録方法、プリンター及び記録物
JP2004107220A (ja) 2002-09-13 2004-04-08 Mitsubishi Pharma Corp ＴＮＦ−α産生抑制剤
TWI335913B (en) 2002-11-15 2011-01-11 Vertex Pharma Diaminotriazoles useful as inhibitors of protein kinases
WO2004050033A2 (en) 2002-12-02 2004-06-17 Arqule, Inc. Method of treating cancers
NZ541050A (en) 2002-12-16 2010-06-25 Genmab As Human monoclonal antibodies against interleukin 8 (IL-8)
WO2004062604A2 (en) 2003-01-10 2004-07-29 Threshold Pharmaceuticals, Inc. Treatment of cancer with 2-deoxyglucose
US7358262B2 (en) 2003-01-29 2008-04-15 Whitehead Institute For Biomedical Research Identification of genotype-selective anti-tumor agents
WO2004074438A2 (en) 2003-02-14 2004-09-02 Smithkline Beecham Corporation Ccr8 antagonists
WO2004073619A2 (en) 2003-02-14 2004-09-02 Smithkline Beecham Corporation Ccr8 antagonists
ATE482747T1 (de) 2003-04-11 2010-10-15 High Point Pharmaceuticals Llc Neue amide derivate und deren pharmazeutische verwendungen
WO2005013982A1 (en) 2003-08-06 2005-02-17 Vertex Pharmaceuticals Incorporated Aminotriazole compounds useful as inhibitors of protein kinases
WO2005035507A2 (en) 2003-10-10 2005-04-21 Bayer Pharmaceuticals Corporation 4-aminopyrimidine derivatives for treatment of hyperproliferative disorders
US20070196395A1 (en) 2003-12-12 2007-08-23 Mackerell Alexander Immunomodulatory compounds that target and inhibit the py'binding site of tyrosene kinase p56 lck sh2 domain
MXPA06008157A (es) 2003-12-24 2007-09-07 Johnson & Johnson Tratamiento de gliomas malignos con inhibidores de factor de crecimiento transformante-beta.
JP2005264016A (ja) 2004-03-19 2005-09-29 Fuji Photo Film Co Ltd インクジェット記録用インク、インクセット及びインクジェット記録方法
US7335770B2 (en) 2004-03-24 2008-02-26 Reddy U5 Therapeutics, Inc. Triazine compounds and their analogs, compositions, and methods
GB0412526D0 (en) 2004-06-05 2004-07-14 Leuven K U Res & Dev Type 2 diabetes
BRPI0515500A (pt) 2004-09-20 2008-07-29 Xenon Pharmaceuticals Inc derivados piridazina para inibição de estearoil-coa-desaturase
CA2581454A1 (en) 2004-09-23 2006-03-30 Reddy Us Therapeutics, Inc. Novel pyrimidine compounds, process for their preparation and compositions containing them
WO2006038594A1 (ja) 2004-10-04 2006-04-13 Ono Pharmaceutical Co., Ltd. Ｎ型カルシウムチャネル阻害薬
WO2006070198A1 (en) 2004-12-30 2006-07-06 Astex Therapeutics Limited Pyrazole derivatives as that modulate the activity of cdk, gsk and aurora kinases
CN101146789A (zh) 2005-01-25 2008-03-19 阿斯利康(瑞典)有限公司 化合物
MX2007012548A (es) 2005-04-11 2008-03-11 Savient Pharmaceuticals Inc Formas variantes de urato oxidasa y uso de las mismas.
ES2624863T3 (es) 2005-06-08 2017-07-17 Millennium Pharmaceuticals, Inc. Métodos para identificación, evaluación, y tratamiento de pacientes con terapia de cáncer
GB0513702D0 (en) 2005-07-04 2005-08-10 Sterix Ltd Compound
US8071597B2 (en) 2005-08-26 2011-12-06 Merck Serono Sa Pyrazine compounds and uses as PI3K inhibitors
US8133900B2 (en) 2005-11-01 2012-03-13 Targegen, Inc. Use of bi-aryl meta-pyrimidine inhibitors of kinases
TW200815426A (en) 2006-06-28 2008-04-01 Astrazeneca Ab New pyridine analogues II 333
US8343548B2 (en) 2006-08-08 2013-01-01 Shin-Etsu Chemical Co., Ltd. Solid dosage form comprising solid dispersion
US20100297673A1 (en) 2006-09-20 2010-11-25 Reddy Us Therapeutics Methods and compositions for upregulation of peroxiredoxin activity
US20080109846A1 (en) 2006-10-23 2008-05-08 Ewertz C Christian System and method for audiovisual content playback
US7906555B2 (en) 2006-10-26 2011-03-15 Arizona Board Of Regents On Behalf Of The University Of Arizona Aquaporin modulators and methods of using them for the treatment of edema and fluid imbalance
HUP0600810A3 (en) 2006-10-27 2008-09-29 Richter Gedeon Nyrt New sulfonamide derivatives as bradykinin antagonists, process and intermediates for their preparation and pharmaceutical compositions containing them
PE20081229A1 (es) 2006-12-01 2008-08-28 Merck & Co Inc Antagonistas de receptor de orexina de diazepam sustituido
JP2010511727A (ja) 2006-12-04 2010-04-15 ニューロクライン バイオサイエンシーズ，インコーポレイテッド アデノシン受容体アンタゴニストとしての置換ピリミジン
KR101472765B1 (ko) 2006-12-08 2014-12-15 밀레니엄 파머슈티컬스 인코퍼레이티드 경구용 Ｘａ 인자 억제제를 포함하는 단위 용량 제형 및 경구용 Ｘａ 인자 억제제를 사용하는 혈전증의 치료 방법
WO2008076883A2 (en) 2006-12-15 2008-06-26 Abraxis Bioscience, Inc. Triazine derivatives and their therapeutical applications
JP5450381B2 (ja) 2007-04-30 2014-03-26 プロメティック・バイオサイエンスィズ・インコーポレーテッド 化合物、そのような化合物を含有する組成物、及びそのような化合物を用いるがん及び自己免疫疾患の治療法
EP2166849A4 (en) 2007-06-11 2010-09-15 Miikana Therapeutics Inc SUBSTITUTED PYRAZOL COMPOUNDS
PT2176231T (pt) 2007-07-20 2016-12-09 Nerviano Medical Sciences Srl Derivados de indazol substituídos activos como inibidores de quinases
US8415340B2 (en) 2007-07-25 2013-04-09 Bristol-Myers Squibb Company Triazine kinase inhibitors
TW200906818A (en) 2007-07-31 2009-02-16 Astrazeneca Ab Chemical compounds
WO2009048101A1 (ja) 2007-10-10 2009-04-16 Takeda Pharmaceutical Company Limited アミド化合物
WO2009051910A1 (en) 2007-10-16 2009-04-23 The Regents Of The University Of California Compounds having activity in increasing ion transport by mutant-cftr and uses thereof
WO2009086303A2 (en) * 2007-12-21 2009-07-09 University Of Rochester Method for altering the lifespan of eukaryotic organisms
JP5277685B2 (ja) 2008-03-26 2013-08-28 富士ゼロックス株式会社 電子写真感光体、画像形成装置、プロセスカートリッジ及び画像形成方法
GB0805477D0 (en) 2008-03-26 2008-04-30 Univ Nottingham Pyrimidines triazines and their use as pharmaceutical agents
US20090281089A1 (en) 2008-04-11 2009-11-12 Genentech, Inc. Pyridyl inhibitors of hedgehog signalling
CN101575408B (zh) 2008-05-09 2013-10-30 Mca技术有限公司 用作阻燃剂和光稳定剂的聚三嗪基化合物
PL3692983T3 (pl) 2008-05-15 2021-12-27 Celgene Corporation Doustne formulacje analogów cytydyny i sposoby ich zastosowania
FR2932483A1 (fr) 2008-06-13 2009-12-18 Cytomics Systems Composes utiles pour le traitement des cancers.
WO2010007756A1 (ja) 2008-07-14 2010-01-21 塩野義製薬株式会社 Ｔｔｋ阻害作用を有するピリジン誘導体
US20100144722A1 (en) 2008-09-03 2010-06-10 Dr. Reddy's Laboratories Ltd. Novel heterocyclic compounds as gata modulators
US8685660B2 (en) 2008-09-03 2014-04-01 The Johns Hopkins University Genetic alterations in isocitrate dehydrogenase and other genes in malignant glioma
JP2010079130A (ja) 2008-09-29 2010-04-08 Fuji Xerox Co Ltd 電子写真感光体、プロセスカートリッジ、及び画像形成装置
JP2012509321A (ja) 2008-11-21 2012-04-19 ミレニアム ファーマシューティカルズ， インコーポレイテッド 癌および他の疾患または障害の処置のための、４−［６−メトキシ−７−（３−ピペリジン−１−イル−プロポキシ）キナゾリン−４−イル］ピペラジン−１−カルボン酸（４−イソプロポキシフェニル）−アミドの乳酸塩およびその薬学的組成物
JP2010181540A (ja) 2009-02-04 2010-08-19 Fuji Xerox Co Ltd 電子写真感光体、プロセスカートリッジ、及び画像形成装置
US8673891B2 (en) 2009-02-06 2014-03-18 Nippon Shinyaku Co., Ltd. Aminopyrazine derivative and medicine
US20120121515A1 (en) 2009-03-13 2012-05-17 Lenny Dang Methods and compositions for cell-proliferation-related disorders
DK2427441T3 (en) 2009-05-04 2017-03-20 Agios Pharmaceuticals Inc PKM2 Activators for use in the treatment of cancer
WO2010130638A1 (en) 2009-05-14 2010-11-18 Evotec Ag Sulfonamide compounds, pharmaceutical compositions and uses thereof
WO2010144338A1 (en) 2009-06-08 2010-12-16 Abraxis Bioscience, Llc Triazine derivatives and their therapeutical applications
JP2012529518A (ja) 2009-06-09 2012-11-22 アブラクシス バイオサイエンス リミテッド ライアビリティー カンパニー ヘッジホッグシグナル伝達のピリジル−トリアジン阻害剤
WO2010144522A1 (en) 2009-06-09 2010-12-16 Abraxis Bioscience, Llc Ureidophenyl substituted triazine derivatives and their therapeutical applications
TWI598337B (zh) 2009-06-29 2017-09-11 阿吉歐斯製藥公司 治療化合物及組成物
JP2013503846A (ja) 2009-09-01 2013-02-04 ファイザー・インク ベンズイミダゾール誘導体
WO2011032169A2 (en) 2009-09-14 2011-03-17 Phusis Therapeutics Inc. Pharmaceutical compositions and formulations including inhibitors of the pleckstrin homology domain and methods for using same
JP5473851B2 (ja) 2009-09-30 2014-04-16 富士フイルム株式会社 高分子フィルム、位相差フィルム、偏光板及び液晶表示装置
US8652534B2 (en) 2009-10-14 2014-02-18 Berry Pharmaceuticals, LLC Compositions and methods for treatment of mammalian skin
WO2011050210A1 (en) 2009-10-21 2011-04-28 Agios Pharmaceuticals, Inc. Methods and compositions for cell-proliferation-related disorders
CN102574843B (zh) 2009-10-22 2015-06-17 法博太科制药有限公司 抗纤维化剂的稠环类似物
ES2642109T3 (es) 2009-12-09 2017-11-15 Agios Pharmaceuticals, Inc. Compuestos terapéuticamente activos para su uso en el tratamiento de cáncer caracterizados por tener una mutación de IDH
NZ578968A (en) 2010-02-10 2011-03-31 Allans Sheetmetal And Engineering Services Fuel feed system for a pellet fire
US20130197106A1 (en) 2010-04-01 2013-08-01 Agios Pharmaceuticals, Inc Methods of identifying a candidate compound
WO2011143160A2 (en) 2010-05-10 2011-11-17 The Johns Hopkins University Metabolic inhibitor against tumors having an idh mutation
US10064885B2 (en) 2010-07-09 2018-09-04 Massachusetts Institute Of Technology Metabolic gene, enzyme, and flux targets for cancer therapy
CN103097340B (zh) * 2010-07-16 2018-03-16 安吉奥斯医药品有限公司 治疗活性组合物及其使用方法
KR20190120458A (ko) 2010-10-21 2019-10-23 메디베이션 테크놀로지즈 엘엘씨 결정질의 (8s,9r)-5-플루오로-8-(4-플루오로페닐)-9-(1-메틸-1h-1,2,4-트리아졸-5-일)-8,9-디하이드로-2h-피리도[4,3,2-de]프탈라진-3(7h)-온 토실레이트 염
WO2012078288A2 (en) 2010-11-08 2012-06-14 Washington University Methods of determining risk of adverse outcomes in acute myeloid leukemia
AU2011336764B2 (en) 2010-11-29 2017-02-23 Galleon Pharmaceuticals, Inc. Novel compounds as respiratory stimulants for treatment of breathing control disorders or diseases
TWI549947B (zh) 2010-12-29 2016-09-21 阿吉歐斯製藥公司 治療化合物及組成物
WO2012173682A2 (en) 2011-03-29 2012-12-20 The Broad Institute, Inc. Compounds and methods for the treatment of isocitrate dehydrognase related diseases
CN103608016A (zh) 2011-05-03 2014-02-26 安吉奥斯医药品有限公司 丙酮酸激酶激活剂在治疗中的用途
TWI555737B (zh) 2011-05-24 2016-11-01 拜耳知識產權公司 含有硫醯亞胺基團之４－芳基－ｎ－苯基－１，３，５－三氮雜苯－２－胺
JP2014522242A (ja) 2011-06-06 2014-09-04 メルク・シャープ・アンド・ドーム・コーポレーション イソクエン酸デヒドロゲナーゼ（ｉｄｈ１）遺伝子発現のｒｎａ干渉媒介抑制
CN102827073A (zh) 2011-06-17 2012-12-19 安吉奥斯医药品有限公司 治疗活性组合物和它们的使用方法
CN102827170A (zh) 2011-06-17 2012-12-19 安吉奥斯医药品有限公司 治疗活性组合物和它们的使用方法
CA2840883C (en) 2011-07-07 2019-07-16 Merck Patent Gmbh Substituted azaheterocycles
EP3111937B1 (en) 2011-07-08 2020-06-17 Helmholtz-Zentrum für Infektionsforschung GmbH Medicament for treatment of liver cancer
AU2012287103B2 (en) 2011-07-22 2017-03-30 University Of Louisville Research Foundation, Inc. Anti-biofilm compounds
BR112014007310A2 (pt) * 2011-09-27 2017-04-04 Novartis Ag 3-pirimidin-4-il-oxazolidin-2-onas como inibidores de idh mutante
CN102659765B (zh) * 2011-12-31 2014-09-10 沈阳药科大学 嘧啶及三嗪类化合物的制备方法和应用
PE20142098A1 (es) 2012-01-06 2015-01-08 Agios Pharmaceuticals Inc Compuestos terapeuticamente activos y sus metodos de uso
US20150087600A1 (en) 2012-01-19 2015-03-26 Agios Pharmaceuticals, Inc Therapeutically active compounds and their methods of use
EP2634259A1 (en) 2012-03-01 2013-09-04 Deutsches Krebsforschungszentrum Means and methods for the determination of (D)-2-hydroxyglutarate (D2HG)
KR20140131955A (ko) 2012-03-09 2014-11-14 카나 바이오사이언스 인코포레이션 신규 트리아진 유도체
WO2014015422A1 (en) 2012-07-27 2014-01-30 Ontario Institute For Cancer Research Cellulose-based nanoparticles for drug delivery
EP2906212A4 (en) 2012-10-15 2016-06-08 Agios Pharmaceuticals Inc THERAPEUTIC COMPOUNDS AND COMPOSITIONS
WO2015003360A2 (en) 2013-07-11 2015-01-15 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
WO2015010297A1 (en) 2013-07-25 2015-01-29 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
WO2015127173A1 (en) 2014-02-20 2015-08-27 Agios Pharmaceuticals, Inc Therapeutically active compounds and their methods of use
NZ723859A (en) 2014-03-14 2023-01-27 Servier Lab Pharmaceutical compositions of therapeutically active compounds and their uses
MA39725B1 (fr) 2014-03-14 2021-09-30 Les Laboratoires Servier Sas Compositions pharmaceutiques de composés thérapeutiquement actifs
FI3362065T3 (fi) 2015-10-15 2024-06-19 Servier Lab Ivosidenibiä, sytarabiinia ja daunorubisiinia tai idarubisiinia käsittävä yhdistelmähoito akuutin myelooisen leukemian hoitamiseksi
KR102699521B1 (ko) 2015-10-15 2024-08-26 르 라보레또레 쎄르비에르 악성 종양의 치료를 위한 조합물 요법
ES2905915T3 (es) 2015-12-04 2022-04-12 Servier Lab Procedimientos de tratamiento de neoplasias malignas
MA43640A (fr) 2016-02-26 2018-11-28 Agios Pharmaceuticals Inc Inhibiteurs de idh1 pour le traitement de cancers hématologiques et de tumeurs solides

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130190249A1 (en) * 2012-01-19 2013-07-25 Agios Pharmaceuticals, Inc Therapeutically active compositions and their methods of use

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
The radiation fact sheet published by the national cancer institute, http://www.cancer.gov/about-cancer/treatment/types/radiation-therapy/radiation-fact-sheet, reviewed 30 June 2010 *

Cited By (51)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10610125B2 (en) 2009-03-13 2020-04-07 Agios Pharmaceuticals, Inc. Methods and compositions for cell-proliferation-related disorders
USRE49582E1 (en) 2009-06-29 2023-07-18 Agios Pharmaceuticals, Inc. Therapeutic compounds and compositions
US11866411B2 (en) 2009-06-29 2024-01-09 Agios Pharmaceutical, Inc. Therapeutic compounds and compositions
US10988448B2 (en) 2009-06-29 2021-04-27 Agios Pharmaceuticals, Inc. Therapeutic compounds and compositions
US10029987B2 (en) 2009-06-29 2018-07-24 Agios Pharmaceuticals, Inc. Therapeutic compounds and compositions
US12428376B2 (en) 2009-06-29 2025-09-30 Agios Pharmaceuticals, Inc. Therapeutic compounds and compositions
US10711314B2 (en) 2009-10-21 2020-07-14 Agios Pharmaceuticals, Inc. Methods for diagnosing IDH-mutant cell proliferation disorders
US9982309B2 (en) 2009-10-21 2018-05-29 Agios Pharmaceuticals, Inc. Method for treating cell proliferation related disorders
US11793806B2 (en) 2011-05-03 2023-10-24 Agios Pharmaceuticals, Inc. Pyruvate kinase activators for use in therapy
US10632114B2 (en) 2011-05-03 2020-04-28 Agios Pharmaceuticals, Inc. Pyruvate kinase activators for use in therapy
US12377093B2 (en) 2011-05-03 2025-08-05 Agios Pharmaceuticals, Inc. Pyruvate kinase activators for use in therapy
US9980961B2 (en) 2011-05-03 2018-05-29 Agios Pharmaceuticals, Inc. Pyruvate kinase activators for use in therapy
US9856279B2 (en) 2011-06-17 2018-01-02 Agios Pharmaceuticals, Inc. Therapeutically active compositions and their methods of use
US9662327B2 (en) 2011-06-17 2017-05-30 Agios Pharmaceuticals, Inc Phenyl and pyridinyl substituted piperidines and piperazines as inhibitors of IDH1 mutants and their use in treating cancer
US9656999B2 (en) 2012-01-06 2017-05-23 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
US9512107B2 (en) 2012-01-06 2016-12-06 Agios Pharmaceuticals, Inc. Therapeutically active compositions and their methods of use
US10640534B2 (en) 2012-01-19 2020-05-05 Agios Pharmaceuticals, Inc. Therapeutically active compositions and their methods of use
US9850277B2 (en) 2012-01-19 2017-12-26 Agios Pharmaceuticals, Inc. Therapeutically active compositions and their methods of use
US10717764B2 (en) 2012-01-19 2020-07-21 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
US20150087600A1 (en) * 2012-01-19 2015-03-26 Agios Pharmaceuticals, Inc Therapeutically active compounds and their methods of use
US11667673B2 (en) 2012-01-19 2023-06-06 Servier Pharmaceuticals Llc Therapeutically active compounds and their methods of use
US10202339B2 (en) 2012-10-15 2019-02-12 Agios Pharmaceuticals, Inc. Therapeutic compounds and compositions
US20150316278A1 (en) * 2013-03-22 2015-11-05 Qingdao Hisense Hitachi Air-conditioning Systems Co., Ltd. Air conditioner heat-radiating circulation system
US10376510B2 (en) 2013-07-11 2019-08-13 Agios Pharmaceuticals, Inc. 2,4- or 4,6-diaminopyrimidine compounds as IDH2 mutants inhibitors for the treatment of cancer
US10028961B2 (en) 2013-07-11 2018-07-24 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
US10946023B2 (en) 2013-07-11 2021-03-16 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
US9724350B2 (en) 2013-07-11 2017-08-08 Agios Pharmaceuticals, Inc. N,6-bis(aryl or heteroaryl)-1,3,5-triazine-2,4-diamine compounds as IDH2 mutants inhibitors for the treatment of cancer
US10111878B2 (en) 2013-07-11 2018-10-30 Agios Pharmaceuticals, Inc. N,6-bis(aryl or heteroaryl)-1,3,5-triazine-2,4-diamine compounds as IDH2 mutants inhibitors for the treatment of cancer
US11844758B2 (en) 2013-07-11 2023-12-19 Servier Pharmaceuticals Llc Therapeutically active compounds and their methods of use
US10172864B2 (en) 2013-07-11 2019-01-08 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
US9579324B2 (en) 2013-07-11 2017-02-28 Agios Pharmaceuticals, Inc Therapeutically active compounds and their methods of use
US10017495B2 (en) 2013-07-11 2018-07-10 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
US12433895B2 (en) 2013-07-11 2025-10-07 Servier Pharmaceuticals Llc Therapeutically active compounds and their methods of use
US11021515B2 (en) 2013-07-25 2021-06-01 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
US10689414B2 (en) 2013-07-25 2020-06-23 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
US11504361B2 (en) 2014-03-14 2022-11-22 Servier Pharmaceuticals Llc Pharmaceutical compositions of therapeutically active compounds
US10799490B2 (en) 2014-03-14 2020-10-13 Agios Pharmaceuticals, Inc. Pharmaceutical compositions of therapeutically active compounds
US9968595B2 (en) 2014-03-14 2018-05-15 Agios Pharmaceuticals, Inc. Pharmaceutical compositions of therapeutically active compounds
US10449184B2 (en) 2014-03-14 2019-10-22 Agios Pharmaceuticals, Inc. Pharmaceutical compositions of therapeutically active compounds
US11234976B2 (en) 2015-06-11 2022-02-01 Agios Pharmaceuticals, Inc. Methods of using pyruvate kinase activators
US10179123B2 (en) 2015-07-07 2019-01-15 Bayer Pharma Aktiengesellschaft 2-aryl- and 2-arylalkyl-benzimidazoles as mIDH1 inhibitors
JP2018522886A (ja) * 2015-07-07 2018-08-16 バイエル・ファルマ・アクティエンゲゼルシャフト ｍＩＤＨ１阻害剤としての２−アリール−および２−アリールアルキル−ベンズイミダゾール
CN107949557A (zh) * 2015-07-07 2018-04-20 拜耳制药股份公司 作为mIDH1抑制剂的2‑芳基‑和2‑芳烷基‑苯并咪唑类
WO2017005674A1 (en) * 2015-07-07 2017-01-12 Bayer Pharma Aktiengesellschaft 2-aryl- and 2-arylalkyl-benzimidazoles as midh1 inhibitors
US11419859B2 (en) 2015-10-15 2022-08-23 Servier Pharmaceuticals Llc Combination therapy for treating malignancies
US10653710B2 (en) 2015-10-15 2020-05-19 Agios Pharmaceuticals, Inc. Combination therapy for treating malignancies
US11241455B2 (en) 2016-01-15 2022-02-08 The J. David Gladstone Institutes, A Testamentary Trust Established Under The Will Of J. David Gladstone Methods of treating disease by metabolic control of T-cell differentiation
EP3402571A4 (en) * 2016-01-15 2019-08-28 The J. David Gladstone Institutes METHOD FOR THE TREATMENT OF DISORDERS BY METABOLIC CONTROL OF T-CELL DIFFERENTIATION
US10980788B2 (en) 2018-06-08 2021-04-20 Agios Pharmaceuticals, Inc. Therapy for treating malignancies
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
US11739943B2 (en) 2021-12-01 2023-08-29 William B. McEvoy Tabletop cooking assembly

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